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Advances in Renal Diseases and Dialysis

September 2023

Authors:

Harkesh Arora

Lovelace Health System

Rajarajeshwari Ramachandran

United States Department of Veterans Affairs

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Advances in Renal

Diseases and Dialysis

Advances in Renal

Diseases and Dialysis

India . United Kingdom

Author(s)

Maheshwari Kata a*, Harkesh Arora b, Rajeshwari Ramachandran c,

Varun Victor d, Nihar Jena e, Abid Rizvi f, Prashanth Reddy Yella g,

Atul Bali h, Deepak Chandramohan i and Roopa Naik j

a Department of Internal Medicine, MNR Medical College and Hospital,

Telangana, India.

b Department of Internal Medicine, Lovelace Medical Center, Albuquerque, New

Mexico, USA.

c Department of Gastroenterology, Brooklyn Hospital Center, Brooklyn, New

York, USA.

d Department of Cardiology, Canton Medical Education Foundation/Aultman

Hospital, Canton, Ohio, USA.

e Department of Cardiology, Trinity Health Oakland/Wayne State University,

Pontiac, Michigan, USA.

f Department of Behavioural Health and Psychiatry, West Virginia University,

Morgantown, West Virginia, USA.

g Department of Internal Medicine, Yuma Regional Medical Center, Yuma,

Arizona, USA.

h Department of Internal Medicine/Nephrology, Geisinger Wyoming Valley

Medical Center, Wilkes-Barre, Pennsylvania, USA.

i Department of Internal Medicine/Nephrology, University of Alabama at

Birmingham, Birmingham, Alabama, USA.

j Department of Internal Medicine, Geisinger Wyoming Valley Medical Center,

Wilkes-Barre, Pennsylvania, USA.

*Corresponding author: E-mail: drmaheshwarikata@gmail.com;

FIRST EDITION 2023

ISBN 978-81-19491-84-1 (Print)

ISBN 978-81-19491-85-8 (eBook)

DOI: 10.9734/bpi/mono/978-81-19491-84-1

__________________________________________________________

Contents

Preface

Abstract

Chapter 1

Acute Kidney Injury

Deepak Chandramohan, Juan J. Cintrón García,

Maheshwari Kata, Roopa Naik, Atul Bali,

Bushra Firdous Shaik, Harkesh Arora and Sreekant Avula

2-18

Chapter 2

Hepatorenal Syndrome

Roopa Naik, Atul Bali, Bushra Firdous Shaik,

Maheshwari Kata, Harkesh Arora, Deepak Chandramohan

and Rajeshwari Ramachandran

19-34

Chapter 3

Diabetic Kidney Disease

Roopa Naik, Rajeshwari Ramachandran,

Bushra Firdous Shaik and Atul Bali

35-53

Chapter 4

Continuous Renal Replacement Therapy

Atul Bali, Harkesh Arora, Roopa Naik,

Maheshwari Kata and Rajeshwari Ramachandran

54-67

Advances in Renal Diseases and Dialysis

Preface

PREFACE

As a physician who is interested in research related to kidney diseases, I always

felt the need to improve current knowledge and available research in this field. I

was fortunate to have met a group of physicians from different parts of the world

with a passion for research in medicine and especially in nephrology related

aspects. The feeling is amazing to have finally completed the project after

several dedicated preparation.

In this book we tried to cover as many key aspects related to the kidney diseases

as possible and provide updates regarding the latest research along with pointing

deficiencies in certain aspects for future. We aim to continue to contribute to the

field of medicine and nephrology in future with interesting topics. We hope this

book help to enhance knowledge among learners related to medicine and

research.

___________________________________________________________________________________

________________________________________________________________________

a Department of Internal Medicine, MNR Medical College and Hospital, Telangana, India.

b Department of Internal Medicine, Lovelace Medical Center, Albuquerque, New Mexico, USA.

c Department of Gastroenterology, Brooklyn Hospital Center, Brooklyn, New York, USA.

d Department of Cardiology, Canton Medical Education Foundation/Aultman Hospital, Canton, Ohio,

USA.

e Department of Cardiology, Trinity Health Oakland/Wayne State University, Pontiac, Michigan, USA.

f Department of Behavioural Health and Psychiatry, West Virginia University, Morgantown, West Virginia,

USA.

g Department of Internal Medicine, Yuma Regional Medical Center, Yuma, Arizona, USA.

h Department of Internal Medicine/Nephrology, Geisinger Wyoming Valley Medical Center, Wilkes-Barre,

Pennsylvania, USA.

i Department of Internal Medicine/Nephrology, University of Alabama at Birmingham, Birmingham,

Alabama, USA.

j Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre,

Pennsylvania, USA.

*Corresponding author: E-mail: drmaheshwarikata@gmail.com;

Print ISBN: 978-81-19491-84-1, eBook ISBN: 978-81-19491-85-8

Advances in Renal Diseases and Dialysis

Maheshwari Kata a*, Harkesh Arora b,

Rajeshwari Ramachandran c, Varun Victor d, Nihar Jena e,

Abid Rizvi f, Prashanth Reddy Yella g, Atul Bali h,

Deepak Chandramohan i and Roopa Naik j

DOI: 10.9734/bpi/mono/978-81-19491-84-1/CH0

ABSTRACT

This book primarily covers key areas of kidney diseases and recent

developments in dialysis. The contributions by the authors include acute kidney

injury, chronic kidney disease, newer biomarkers of AKI, epidemiology,

hepatorenal syndrome, cirrhosis, liver transplantation, acute tubular necrosis,

vasopressors, newer biomarkers of HRS, diabetic kidney disease, microvascular

damage, microalbuminuria, progression of CKD, RAS mechanism of action,

continuous renal replacement therapy, intermittent hemodialysis, hemofiltration,

hemodiafiltration, solute removal, electrolyte disorders, uremia,

hyperammonemia, diffusion. This book contains various materials suitable for

students, researchers and academicians in the field of medicine and medical

research.

Keywords: Acute kidney injury; chronic kidney disease; hepatorenal syndrome;

liver transplantation; acute tubular necrosis; vasopressors; newer

biomarkers of HRS; diabetic kidney disease; microvascular damage;

microalbuminuria; RAS mechanism of action; continuous renal

replacement therapy; intermittent hemodialysis; hemofiltration;

hemodiafiltration; solute removal; electrolyte disorders; uremia;

hyperammonemia; diffusion.

___________________________________________________________________________________

________________________________________________________________________

a Department of Internal Medicine/Nephrology, University of Alabama at Birmingham, Birmingham,

Alabama, USA.

b Department of Internal Medicine/Nephrology, Loyola University Medical Center, Maywood, Illinois,

USA.

c Department of Internal Medicine, MNR Medical College and Hospital, Telangana, India.

d Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA,

USA.

e Department of Internal Medicine/Nephrology, Geisinger Wyoming Valley Medical Center, Wilkes-Barre,

Pennsylvania, USA.

f Department of Internal Medicine, University Hospital and Clinics, Lafayette, Louisiana, USA.

g Department of Internal Medicine, Lovelace Medical Center, Albuquerque, New Mexico, USA.

h Department of Internal Medicine/Endocrinology, University of Minnesota, Minneapolis, Minnesota,

USA.

*Corresponding author: E-mail: drmaheshwarikata@gmail.com;

Chapter 1

Print ISBN: 978-81-19491-84-1, eBook ISBN: 978-81-19491-85-8

Acute Kidney Injury

Deepak Chandramohan a, Juan J. Cintrón García b,

Maheshwari Kata c*, Roopa Naik d, Atul Bali e,

Bushra Firdous Shaik f, Harkesh Arora g

and Sreekant Avula h

DOI: 10.9734/bpi/mono/978-81-19491-84-1/CH1

ABSTRACT

Acute kidney injury (AKI) is defined as the sudden loss of kidney function. AKI is

part of a group of diseases collectively called acute kidney disease and disorder

(AKD), in which a slow decline in kidney function or persistent kidney dysfunction

is associated with irreversible loss of nephrons (functional units of kidney), which

can eventually lead to chronic kidney disease (CKD). New biomarkers to detect

injury before loss of function await clinical application. AKI and AKD is a major

concern worldwide. Infections and hypovolemic shock are the main causes of

AKI in low- and middle-income countries. In high-income countries, AKI occurs

most often in hospitalized elderly patients and is associated with sepsis,

medications, or invasive procedures. Infections and trauma-induced AKI are

common in all regions. The broad spectrum of AKI involves different

pathophysiological mechanisms. Management of AKI in the intensive care setting

is complex, including appropriate volume management, careful monitoring of

nephrotoxic drugs, and choice of renal replacement therapies. Fluid and

electrolyte management is essential. Because AKI can be fatal, renal

replacement therapy is often necessary. AKI generally has a poorer prognosis in

critically ill patients due to various reasons. Long-term consequences of AKI and

AKD include chronic kidney disease and morbidity due to cardiovascular disease.

Therefore, early detection and prevention of AKI are quintessential.

Keywords: Acute kidney injury; chronic kidney disease; dialysis; nephrotoxins;

renal replacement therapy.

Advances in Renal Diseases and Dialysis

Acute Kidney Injury

1. INTRODUCTION

Acute kidney injury (AKI) remains a major problem in clinical medicine today [1].

It occurs in about 1-5% of all hospitalized patients. The incidence increases

significantly as the severity of the underlying cause progresses: up to 50% of

patients treated in the intensive care unit develop AKI, in many cases secondary

to disseminated infection or sepsis [2,3]. The term acute kidney injury replaced

acute renal failure, emphasizing that the progression of kidney damage begins

long before it is possible to measure adequate excretion of renal function by

standard laboratory tests. The term also refers to a continuum of predictions

where an increase in mortality is associated with even a small increase in serum

creatinine and a further increase in mortality as creatinine levels rise. The

prognosis has not significantly improved in the last 20-30 years, although

significant progress has been made in the field of intensive care and dialysis

treatment [4,5]. In the mid-1970s, 70% of all patients with AKI died. Mortality

decreased moderately in the early 1990s (30-50%) and has remained stable for

the last 20 years. The poor prognosis is due in part to the disease itself that

causes AKI, but also to the complications associated with AKI. Thus, the

invention of more effective therapeutic interventions remains an important goal of

the field of nephrology research.

2. DEFINITION OF AKI

AKI is defined as an acute impairment of renal function manifested by an

increase in serum creatinine [6]. In most patients (70%), urine production also

decreases. The definition of the syndrome is refined from time to time, and

according to the latest KDIGO guidelines, AKI can be diagnosed if the following

criteria are met: (I) an increase in serum creatinine of more than 0.3 mg/dL within

48 hours, or (II) a 1.5-fold increase in serum creatinine within a seven day period

(compared to a known or suspected baseline) and/or (III) a decrease in urine

output below 0.5 ml/kg per day for at least 6 hours [7,8]. It should not be

forgotten that serum creatinine is a poor parameter of renal function, because its

concentration begins to increase late in AKI, when at least 60% of renal function

is lost. The severity of AKI varies, and several scores can be used to distinguish

certain degrees of acute kidney failure. The RIFLE criteria distinguish risk (R),

injury (I), failure (F), loss (L), and end-stage kidney disease (E) depending on the

relative increase in serum creatinine and/or relative decrease in urine production

[9,10]. It should be noted that stage E can only be diagnosed if the renal

dysfunction lasts more than 3 months. Such criteria may not be important from a

therapeutic point of view, but from a prognostic point of view, since the prognosis

significantly worsens with the severity of kidney damage.

3. EPIDEMIOLOGY

The global mortality burden of AKI far exceeds mortality from breast cancer,

heart failure, or diabetes, and mortality has remained high for the past 50 years

[11,12]. Generally, the incidence of AKI is reported as either community-acquired

or hospital-acquired AKI. In high-income countries (HICs), AKI is mostly hospital-

Advances in Renal Diseases and Dialysis

Acute Kidney Injury

acquired, while community-acquired AKI is more common in low-income

countries. In HIC, AKI patients are generally elderly, have multiple co-

morbidities, and have access to dialysis and intensive care when needed. The

main causes of AKI in HIC are postoperative or diagnostic interventions or

iatrogenic factors. However, there are many community-acquired causes in poor

environments, including sepsis, body volume depletion, poisons (bites, drugs)

and pregnancy [13,14]. Patients tend to be younger than those with HIC, access

to treatment is more difficult, and women are underrepresented in the patient

population.

4. RISK FACTORS OF AKI

Risk factors for AKI include environmental, socioeconomic and/or cultural factors,

as well as factors related to the treatment process, acute exposure and patients

themselves [15,16]. Environmental factors include inadequate drinking water and

sewage systems, inadequate infectious disease control, and inadequate health

care delivery systems. Patient-related factors may be modifiable, such as volume

depletion, hypotension, anemia, hypoxia, and use of nephrotoxic medications, or

nonmodifiable, such as chronic kidney, heart, liver, or gastrointestinal disease,

diabetes, and serious infections and sepsis [17-19]. Less common causes are

genetic predisposition to myoglobinuria, hemoglobinuria and urolithiasis. Other

important risk factors for AKI are serious illness, acute infections, sepsis, malaria,

severe trauma, hypovolemia, old age, pre-existing chronic kidney disease, acute

organ failure, major surgery (including heart surgery), intensive care unit stay

with exposure to nephrotoxic medications and acquiring opportunistic infections,

cancer chemotherapy, delayed kidney transplant graft function, autoimmune

diseases with rapidly progressive kidney damage, cholesterol crystal embolism,

and urinary tract obstruction [20-23]. Although severe AKI occurs more often in

association with hospital-associated risk factors such as major surgery,

hemorrhage, septic shock, or drug intoxication in elderly patients with multiple

diseases, milder forms of AKI can also occur in the community. In contrast, in

low- and middle-income countries (LMICs), community-acquired AKI affects

younger, previously healthy individuals, and the incidence of sepsis and obstetric

complications is relatively high. COVID-19 remains a major risk factor for AKI

worldwide [24,25].

5. KIDNEY PHYSIOLOGY AND MECHANISMS OF AKI

Renal physiology and renal lifespan: The kidneys maintain the homeostasis of

body fluids, electrolytes, osmolality and pH, excrete metabolic waste products

and secrete hormones and bioactive molecules. Because AKI disrupts

homeostasis, severe AKI is potentially fatal if renal replacement therapy (RRT)

does not maintain homeostasis until renal function is restored. AKI in multiorgan

failure is often fatal despite RRT.

The kidneys consist of nephrons, small independent functional units whose

glomerular part filters fluids and small molecules from the blood, and a single

tubule that reabsorbs most of the filtered molecules and excretes metabolic

Advances in Renal Diseases and Dialysis

Acute Kidney Injury

waste products, producing 1-2 liters of urine each day. The number of nephrons

is determined at birth and decreases gradually with age after about 25 years [26].

Because metabolic activity also declines with age, healthy 70-year-olds can do

well with only half the original number of nephrons without adaptation. However,

low nephron count at birth

or loss of nephrons after normal aging shortens renal lifespan. Therefore, the

incidence of chronic kidney disease and kidney failure requiring RRT increases in

the elderly. AKI and CKD are linked because AKI can cause irreversible nephron

loss at any stage of life, thereby shortening kidney life [27,28]. Thus, AKI is an

important risk factor for chronic diseases, especially in the aging population.

The pathogenesis of inflammatory diseases of the renal parenchyma, such as

glomerulonephritis and vasculitis, is complex and involves almost all aspects of

the innate inflammatory system and mechanisms mediated by antibodies and

immune cells [29-31]. In this review, we focus on acute kidney injury due to

prerenal factors, because this form is the most common in developed countries,

in hospitals, and especially in critically ill patients. Much of our understanding of

the pathophysiology of prerenal acute kidney injury comes from animal studies

[32]. Studies in models of acute ischemia induced by acute renal artery occlusion

reveal the many pathways and mechanisms of organ injury likely involved. The

coagulation system is locally activated, leukocytes infiltrate the kidney, the

endothelium is damaged and adhesion molecules are expressed, cytokines are

released, toll-like receptors are induced, intrarenal vasoconstrictor pathways are

activated, and apoptosis is induced. It appears that kidney injury can trigger

organ injury elsewhere (so-called organ crosstalk) through obscure pathways,

further emphasizing the complexity of the biological response to acute kidney

injury.

Unfortunately, this ischemic model has little clinical relevance in diseases such

as sepsis. Sepsis is the most common cause of acute kidney injury in hospitalized

and intensive care patients [33]. The model also has little relevance for periods of

reduced perfusion that may occur during major surgery, as 80% renal artery

occlusion for 2 h does not cause permanent renal dysfunction. Thus, many of the

principles that physicians use to understand acute kidney injury are questionable

for patients in modern hospitals or intensive care units. The most common

causes of acute kidney injury in such patients are sepsis, major surgery

(especially open heart surgery), and acute decompensated heart failure [34,35].

The renal artery is not blocked in any of these situations. More appropriate

models are needed.

Neurohormonal mechanisms: Activation of the sympathetic system and

neurohormonal responses specific to the kidney are activated in acute kidney

injury [36]. The renin-angiotensin-aldosterone system, the renal sympathetic

system and the tubulo-glomerular feedback system are activated. Knowing these

changes led to further understanding of how people can develop acute kidney

injury. This framework suggests that in sepsis-like situations, infection leads to

nitric oxide synthase induction and nitric oxide-mediated vasodilation, which in

Advances in Renal Diseases and Dialysis

Acute Kidney Injury

turn leads to arterial hypoperfusion and baroreceptor activation [37]. These

circulatory changes trigger activation of the sympathetic system, which increases

renin- angiotensin-aldosterone system (RAAS) activity and renal

vasoconstriction. At the same time, arginine vasopressin is released and

promotes water retention.

Hepatorenal syndrome (HRS) is perhaps the most widely studied form of

acute kidney injury in terms of neurohormonal changes and provides useful

mechanistic insights [38]. In this syndrome, as in experimental sepsis, acute

kidney injury occurs without histopathological renal changes and is thus

functional in nature. Severe renal vasoconstriction associated with significant

RAAS activation is a characteristic finding in patients with hepatorenal syndrome,

suggesting that neurohormonal events drive the development of the disease.

Although the mechanisms leading to such activation are debated, the central

event is thought to be a decrease in systemic blood pressure due to splanchnic

vasodilation [39]. The neurohormonal response to such vasodilation supports

systemic blood flow, but renal blood flow may be adversely affected. It is not

known whether a similar condition occurs in other diseases associated with

hypotension and systemic vasodilation (eg, inflammation and sepsis). Thus,

elevations in noradrenaline, renin, and angiotensin II may contribute to other

forms of acute kidney injury, suggesting that, at least in some settings,

neurohormonal renal vasoconstriction may underlie the loss of excretory function.

6. CLINICAL MANIFESTATIONS

AKI patients do not suffer from clinical symptoms more or less specific to the

disease. On the other hand, they may indicate symptoms of some underlying

disease (eg heart failure, sepsis, systemic vasculitis, thrombotic

microangiopathy). Urine production is reduced in 70% of AKI and can result in

fluid retention with worsening blood pressure and heart failure with pulmonary

edema [40]. Due to the reduction in the secretion of electrolytes and

endogenous/exogenous residues, the whole body is affected. The term uremia

describes such poisoning and is associated with a variety of heterogeneous

symptoms, including pruritus, neurological manifestations, nausea and vomiting,

diarrhea, anorexia and loss of appetite, cardiac arrhythmias, and insomnia

[41,42]. In addition, patients have an increased risk of infections and abnormal

bleeding complications (due to platelet dysfunction). The presence of uremia is

important because in most cases dialysis therapy becomes mandatory. Polyuria

after initial oliguria usually indicates the onset of kidney function, but can cause

significant loss of water, sodium and potassium. The latter can cause heart

rhythm abnormalities [43]. If the kidney recovery takes more than 3 months, it

means AKI is transformed to CKD.

7. LONG-TERM CONSEQUENCES OF AKI

Irreversible nephron loss, fibrosis and CKD: Depending on the severity of

AKI, few, many, or most nephrons remain irreversibly destroyed and lost,

resulting in post-AKI CKD and shortened renal lifespan [44]. Albuminuria after

AKI is a clinical indicator of CKD, even when GFR appears to have fully

Advances in Renal Diseases and Dialysis

Acute Kidney Injury

recovered. The impact of AKI on renal life expectancy is most evident in older

adults, where AKI-related nephron loss increases age-related nephron loss and

often chronic kidney disease from previous injuries or chronic nephropathies,

known as AKI in CKD. Therefore, since ATN means nephron loss, the severity of

ATN determines the effect on kidney lifespan. In extreme cases, severe ATN can

lead to kidney failure and continuous need for RRT.

Hypertension and risk of cardiovascular disease: AKI survivors may have

hypertension, which may be a sign of subclinical CKD. A retrospective cohort

study showed a 22% increased risk of blood pressure >140/90 mmHg in patients

with AKI compared to those without AKI [45]. CKD after AKI is associated with

increased cardiovascular and cerebrovascular morbidity and mortality [46-48]. It

is not clear whether this increase is related to effects on the cardiovascular

system during an episode of AKI or to an increased risk of CKD after AKI.

Mortality: AKI survivors face increased post-hospital mortality. Long-term

mortality in AKI patients may also be increased. In a study of heart surgery

patients, the increase in mortality risk was independent of improvement in

kidney function at hospital discharge and did not begin until 4 to 5 years after

surgery [49]. The most common causes of death are cardiovascular disease

(28%) and cancer (28%), and the corresponding standardized mortality rates are

nearly six and eight times higher than those in the general population. Cancers

were mostly hematological or urogenital. An episode of AKI predicts the risk of

later development of kidney cancer, and an episode of AKI after partial

nephrectomy for kidney cancer increases the risk of cancer recurrence, probably

because kidney damage causes DNA damage and clonal expansion of mutated

cells during the healing phase [50,51]. Indeed, renal progenitors that leads to

tubular regeneration can become tumor cells after ischemic ATN and trigger

monoclonal lesions in the papillary renal cell adenoma-carcinoma sequence.

8. DIAGNOSIS, SCREENING AND PREVENTION

Unlike myocardial infarction and other acute organ failure, AKI does not cause

immediately alarming symptoms such as chest pain, shortness of breath,

paralysis or blindness; therefore, diagnosis requires special technical

assessments. The best overall index of kidney function is GFR, but direct

measurement of GFR is difficult. Generally, GFR is estimated using serum levels

of endogenous filtration markers such as creatinine. Several studies have shown

that small increases in serum creatinine are associated with worse outcomes in

AKI [52]. In addition, urine output is a sensitive parameter of renal function and a

biomarker of tubular damage. However, the relationship between urine output,

GFR and tubular injury is very complex.

Diagnostic and classification criteria: There is evidence to suggest that acute

and mild declines in renal function, as manifested by changes in blood chemistry

and urine output, are associated with worse outcome in AKI. In contrast to the old

term acute kidney failure, the Risk, Injury, Failure, Loss of kidney function and

End-Stage Renal Disease (RIFLE) and Acute Kidney Injury Network (AKIN)

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Acute Kidney Injury

classifications have provided updated definitions of AKI that cover the entire

spectrum of syndrome from slight increase in serum creatinine to the need for

active treatment [53]. The RIFLE and AKIN classifications have three degrees of

severity based on changes in serum creatinine or urine output, with the worse of

the two criteria being used to determine the grade. RIFLE and AKIN thus

provided a conceptual framework for the diagnosis and staging of AKI, but

further modifications were necessary to respond to the clinical complexity of AKI,

especially outside the intensive care unit (ICU) or hospital settings.

The latest KDIGO guidelines defined the diagnostic criteria for AKI. Contrary to

previous recommendations, the KDIGO criteria no longer require adequate fluid

resuscitation and exclusion of urinary tract obstruction before using the criteria.

Patients with CKD are particularly prone to AKI, as CKD is an independent risk

factor for AKI. However, the diagnosis of AKI in patients with CKD is difficult

because these patients have impaired renal function and changes in serum

creatinine levels after AKI are partially confounded with baseline renal function

levels. The KDIGO criteria use decreased urine output, but decreased urine

output is also a physiological mechanism in response to decreased fluid intake

or fluid loss that readily responds to fluid intake and usually does not indicate

tubular damage. Damaged tubules no longer respond to diuretics due to the loss

of necessary sodium transporters; thus, a single bolus of a loop diuretic that is

not followed by a significant increase in urine output, called the furosemide stress

test, indicates tubular injury [54]. In fact, the incidence of AKI is significantly

higher when both urine output and serum creatinine are abnormal, compared

with abnormal serum creatinine alone (62.1% vs. 17.7%).

9. SCREENING AND RISK ASSESSMENT WITH BIOMARKERS

About half of patients with stage 1 acute kidney injury have elevated serum

biomarkers and histological abnormalities on renal biopsy, whereas most of

those with stage 3 AKI have both [55]. Serum creatinine level and urine output

are two functional biomarkers with several limitations. The specificity of urine

production is low because several factors can affect this parameter, including

hypovolemia and the use of diuretics [56]. In contrast, serum creatinine sensitivity

in previously healthy kidneys is low because serum creatinine levels rise only

when at least 50% of functional nephrons are lost. In patients with a low baseline

GFR, small changes in kidney function can lead to a increase in serum creatinine

of 0.3 mg/dL, which defines AKI. Although novel biomarkers such as IL-18 or

kidney injury molecule 1 (KIM-1) are available and most of them have a very

good predictive value, there are limitations, including poor predictive power when

the timing of kidney injury is unknown; therefore, they are only inconsistently

applied in clinical practice.

10. PREVENTIVE MEASURES

In LMIC, prevention of volume depletion alone is thought to have a large impact

on the incidence of AKI. In addition to preventing volume depletion and

nephrotoxin exposure or overdose, new biomarkers may identify patients at high

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Acute Kidney Injury

risk of AKI. This approach can be used to stratify patient populations and

implement different interventions to prevent the development of AKI.

Implementation of the "KDIGO bundle" consisting of volume and hemodynamic

optimization, avoidance of nephrotoxic drugs and prevention of hyperglycemia in

patients with high risk of AKI identified by biomarkers can prevent AKI after

cardiac surgery [57-59]. In a Quality Initiative program, implementation of

supportive measures in biomarker-positive patients reduced the incidence of

moderate and severe AKI after cardiac surgery and the incidence of AKI in

abdominal surgery patients [60]. Despite these data, only about 5% of high-risk

patients receive these supportive measures.

11. MANAGEMENT

Management of AKI is often suboptimal. The first step in managing AKI is to

identify its causes, such as prerenal causes (hypovolemia), intrinsic renal

causes, or postrenal causes (outflow obstruction). Further treatment is influenced

by the clinical situation, location and history of the patient.

Volume status: Volume depletion may cause impairment of kidney function, but

does not damage the kidney by itself unless it is severe and persistent. However,

volume depletion can contribute to several causes of AKI, and fluid resuscitation

is the cornerstone of treatment. Patients with AKI in the community may become

dehydrated, as may hospitalized patients receiving diuretics or dehydrating from

injuries or drainage. A hospitalized patient should never become severely

dehydrated; however, correcting dehydration by giving inappropriate fluids

without properly assessing patients with AKI can lead to fluid overload, which can

have significant detrimental effects [61]. Patients requiring intravenous fluid

resuscitation should be under direct physician supervision and treatment will

benefit from guidelines for hemodynamic monitoring. In addition, the sudden

need for fluid resuscitation requires measures to determine its cause (for

example, occult bleeding or sepsis). It should be noted that patients can develop

oliguria from AKI and then become fluid overloaded with injudicious

administration of intravenous fluids in addition to fluids from medications and

nutritional support. Importantly, fluid overload has been identified as a major

cause of AKI, as venous congestion can compromise circulation and cause direct

damage to the renal parenchyma.

Hemodynamic control: Management of blood pressure and cardiac function in

the setting of AKI (eg, septic shock or cardiac surgery) is complex and involves

context-specific considerations, depending on the type of circulatory shock the

patient is experiencing. Under normal conditions, most organs, including the

kidneys, are adequately perfused with a mean arterial pressure (MAP) of 65

mmHg or above [62]. Studies examining whether MAP targets should be used in

ICU patients have produced mixed results. Patients with severe (and perhaps

poorly controlled) hypertension may benefit from a higher MAP in shock, but a

fixed target cannot be recommended. Some findings suggest individualized blood

pressure control by adjusting MAP targets based on the patient's typical blood

pressure. Also, patients with elevated venous pressure (for example due to right-

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Acute Kidney Injury

sided heart failure) may not achieve adequate renal perfusion pressure at a MAP

of 65 mmHg. Studies using functional hemodynamic monitoring to guide

hemodynamic management have shown promise in both cardiac surgery and

sepsis. Noradrenaline is the first choice as a vasopressor in vasodilatory shock

[63,64]. The other agents are generally reserved for shock requiring therapy or

emergency situations, and none are generally more "kidney friendly."

Nephrotoxic drugs and substances: The risk of AKI increases with the number

of nephrotoxic drugs used, and all potentially nephrotoxic agents that can be

discontinued should be stopped [65,66]. If possible, careful monitoring of drug

concentration is also mandatory (for example, in the case of vancomycin). The

use of arteriolar contrast agents should be limited to situations where the

therapeutic benefit outweighs the risk, and they should be used in the smallest

amounts possible.

Stepwise management of AKI: The KDIGO AKI Guidelines emphasize the

importance of AKI staging as a management guide. Prognosis is strongly

correlated with the peak phase of AKI and the duration of AKI (transient versus

persistent), so the urgency and invasiveness of diagnostic and therapeutic

measures increase with the phase of AKI [67]. However, the stages of AKI must

be interpreted in the context of baseline kidney function. For patients with

preexisting normal renal function and stage 1 AKI, treatment primarily involves

prompt identification of the likely cause of AKI and avoidance of secondary

insults. Depending on baseline GFR, drug dosage adjustments usually become

clinically relevant in stage 2 AKI. In stage 3 AKI, symptoms can be caused by a

disturbance in the acid-base balance and electrolyte levels, as well as the

accumulation of uremic toxins [68]. For example, patients may develop

tachypnea not only due to fluid overload, but also due to metabolic acidosis.

Acidosis removes potassium from cells, further exacerbating hyperkalemia. Even

relatively moderate uremia can impair platelet function and increase the risk of

bleeding. If treatment is ineffective or if the disorders are life-threatening, RRT is

necessary.

In all stages of AKI, it is recommended to stop all potentially nephrotoxic drugs as

soon as possible, because all drugs cause or contribute to AKI in most cases and

are probably the most modifiable risk factors for AKI [69,70]. Volume control and

hemodynamic monitoring are also required in all stages of AKI. Avoidance of

hyperglycemia is important because filtered glucose increases tubular

reabsorption workload and oxidative stress, a process that sensitizes renal

tubules to damage. An important yet unresolved question so far is whether the

various forms of acute kidney injury can be treated with approaches targeting the

underlying causes. This strategy is possible in conditions such as obstructive

uropathy or atypical hemolytic uremic syndrome, but other forms of AKI often

have an unknown etiology. Current knowledge indicates that risk factors and risk

modifiers such as medications, contrast agents, low cardiac output and overload

should be reduced or eliminated. Even if the cause of an AKI episode is

identifiable, this awareness may come too late to prevent the eventual common

pathway of tubular toxicity, ischemia, and inflammation.

Advances in Renal Diseases and Dialysis

Acute Kidney Injury

Management of the trajectory of AKI: Most patients with AKI who receive

medical care and whose injury resolves on its own (such as surgery) or whose

cause is resolved (such as stopping a nephrotoxic drug or treating an infection)

begin to improve kidney function usually within 24-48 hours [71]. However, in 25–

35% of patients, AKI persists for ≥72 hours. These patients have significantly

worse outcomes. Thus, persistent AKI should prompt the clinician to reconsider

their working diagnosis regarding the cause of AKI. For example, in a patient

who develops AKI after cardiac surgery, the volume status, hemodynamics, and

medication list should be carefully reviewed and any problems corrected [72].

Recurrence of AKI is common, especially in ICU patients [73]. Whether

recurrence is due to multiple insults to kidney or recurrent renal failure due to

damage from a single injury varies. It is best to assume that the recurrence may

be due to a new cause that needs to be identified. Recovery after AKI is best

assessed after hospital discharge, but follow-up of these patients has historically

been poor. Patients may be discharged with unstable renal function and are

therefore at greater risk of drug-related adverse events, since most receive drugs

that are excreted by the kidneys [74,75]. Common reasons for hospital

readmission are both treatment failure due to under dosing in patients with

improving renal function and toxic effects due to overdose in patients with

declining renal function. Therefore, patients should be referred to a nephrologist

for evaluation of kidney function immediately after discharge from the hospital.

Finally, even patients who appear to have fully recovered from AKI may be at

increased risk of developing kidney damage over an unknown period of time.

Renal replacement therapy: The various aspects of RRT have advanced

significantly over the years, making extracorporeal therapy safer and easier to

implement. The time and choice of initiation of therapy remain controversial,

often due to the heterogeneity of the populations studied. In a patient-centered

evaluation based on the principles of precision medicine, life- threatening

conditions are not the only indicators of the need to RRT but the prevention of

clinical complications should also be considered.

Peritoneal dialysis has been used for many years and is still used in areas where

access to more advanced techniques is limited or unavailable [76,77]. In the

absence of evidence to support specific techniques, the choice of method should

be based on pathophysiological considerations. In unstable and critically ill

patients, continuous RRT is often preferred [78]. After the patient is discharged

from the intensive care unit, intermittent methods such as continuous low-dose

dialysis or daily intermittent hemodialysis can be safely used. Continuous veno-

venous hemofiltration, continuous veno-venous hemodialysis, or continuous

veno-venous hemodiafiltration are used according to center experience and staff

training rather than evidence-based technique differences. A conceptual model of

sequential extracorporeal therapy with early removal of endotoxins by polymyxin-

B hemoperfusion followed by removal of cytokines and proinflammatory and anti-

inflammatory mediators by absorbent devices has been proposed for patients

with sepsis-related AKI [79,80]. The best time to initiate RRT in critically ill

patients remains controversial, in part because of conflicting renal outcomes in

Advances in Renal Diseases and Dialysis

Acute Kidney Injury

relevant studies. In fact, best practices for RRT can vary in many ways,

especially for certain populations.

12. QUALITY OF LIFE

There is no information on the quality of life of AKI patients in the intensive care

unit, where many patients receive medication while on respiratory support. AKI-

specific aspects would also be difficult to assess because the diseases are often

complex. Existing research focuses on the long-term effects of AKI on

health-related quality of life

(HRQL) and functional status in critically ill survivors [81-83]. Most studies

consistently show that survivors of AKI have significantly reduced HRQL

compared to survivors of critical illness without AKI or the general population.

HRQL was lower in patients who required intensive care for severe AKI than in

those who did not. Among AKI survivors, 20–40% developed a new disability in

at least one activity of daily living, and only 28–69% of AKI survivors with

preexisting severe disease were able to return to work [84]. After one year of AKI

requiring dialysis, 81.8% of survivors would agree to readmission to the ICU if

necessary, but after four years that number dropped to 71.4.

13. CURRENT AND FUTURE PERSPECTIVE

To date improvements in the field of diagnosis and treatment of acute kidney

injury remain unsatisfactory. From a diagnostic point of view, the introduction of a

marker of kidney damage in clinical practice remains a priority compared to the

current approach based on kidney function. Measurement of serum creatinine

does not allow early diagnosis of AKI, which is essential to improve patient

outcomes. Creatinine assessment also does not elucidate the extent to which

subclinical episodes of AKI contribute to shortened renal lifespan and CKD.

Recommendations from the 23rd ADQI Consensus Conference suggest that

combining definitions of AKI based on serum creatinine and urinary excretion

with biomarkers of kidney injury would improve the accuracy of predicting the

course of AKI.

Marlies et al. [85] Future studies have yet to show the extent to which new

biomarkers can help improve short- and long-term outcomes.

14. CONCLUSION

Due to a variety of factors, AKI often has a worse prognosis in critically ill

patients. Chronic renal disease and morbidity from cardiovascular disease are

long-term effects of AKI and AKD. Early AKI detection and prevention are so

crucial.

COMPETING INTERESTS

Authors have declared that no competing interests exist.

 
 
 
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Acute Kidney Injury 
 
 
 
 
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REFERENCES 
 
1.  Renske Wiersema, Ruben  J Eck, Mikko  Haapio, Jacqueline Koeze, Meri 
Poukkanen, Frederik Keus, Iwan C C van der Horst, et al. Burden of acute 
kidney  injury and  90-day mortality  in critically ill  patients. BMC  Nephrol. 
2019;21(1):1. 
2.  James Case, Supriya Khan, Raeesa Khalid, Akram Khan. Epidemiology of 
acute  kidney  injury  in  the  intensive  care  unit.  Crit  Care  Res  Pract. 
2013;2013:479730. 
3.  Abshiro H Mayow, Fatima Ahmad, Muhammad Sohaib Afzal, Muhammad 
Usama  Khokhar,  Daneyal  Rafique,  Sai  Krishna  Vallamchetla,  et al.  A 
Systematic  Review  and  Meta-Analysis  of  Independent  Predictors  for 
Acute Respiratory Distress Syndrome in Patients Presenting With Sepsis. 
Cureus. 2023;15(4):e37055. 
4.  Z Ricci, D Cruz, C Ronco. The RIFLE criteria and mortality in acute kidney 
injury: a systematic review. Kidney Int. 2008;73(5):538-46. 
5.  Sreekant  Avula,  Sandesh  Dewan,  Bushra  Firdous  Shaik,  Atul  Bali. 
Diabetic Kidney Disease. Int Clinc Med Case Rep Jour. 2023;2(11):1-4. 
6.  Mark  E  Thomas,  Caroline  Blaine,  Anne  Dawnay,  Mark  A  J  Devonald, 
Saoussen Ftouh, Chris  Laing, et  al. The  definition of  acute kidney  injury 
and its use in practice. Kidney Int. 2015;87(1):62-73. 
7.  Khwaja  Arif.  KDIGO  clinical practice  guidelines for  acute  kidney  injury. 
Nephron Clin Pract. 2012;120(4): c179-c184. 
8.  Palleti, Sujith  Kumar, Sreekanth Avula,  and Sandesh  Dewan. Kidney:  A 
Review on  End Stage Renal  Disease, Dialysis and  Transplant.  Int Clinc 
Med Case Rep Jour. 2023;2 (10): 1-8. 
9.  Venkataraman Ramesh, John A. Kellum. Defining acute renal failure: the 
RIFLE criteria. J Intensive Care Med. 2007;22(4):187-93. 
10.  Hanif, Muhammad O, Atul Bali, Kamleshun Ramphul. Acute renal tubular 
necrosis. StatPearls [Internet]. StatPearls Publishing. 2022. 
11.  Sawhney  Simon,  Simon  D.  Fraser. Epidemiology  of  AKI: utilizing  large 
databases  to  determine  the  burden  of  AKI.  Adv  Chronic  Kidney  Dis. 
2017;24(4):194-204. 
12.  Palleti,  Sujith  Kumar,  Sreekant  Avula,  Roopa  Naik.  Chronic  Kidney 
Disease. Int Clinc Med Case Rep Jour. 2023;2(11):1-15. 
13.  Eric A J Hoste, Sean M Bagshaw, Rinaldo Bellomo, Cynthia M Cely, Roos 
Colman,  Dinna  N  Cruz,  et  al.  Epidemiology  of  acute  kidney  injury  in 
critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 
2015;41(8):1411-23. 
14.  Barkhane  Zineb,  et  al.  Independent Predictors  of Mortality  in  Systemic 
Sclerosis-Associated  Pulmonary  Arterial  Hypertension:  A  Systematic 
Review and Meta-Analysis. Cureus. 2023;15(5). 
15.  Sandra L Kane-Gill, Florentina E Sileanu, Raghavan Murugan, Gregory S 
Trietley, Steven  M Handler, John A Kellum. Risk factors for acute kidney 
injury in older adults with critical illness: a retrospective cohort study. Am J 
Kidney Dis. 2015;65(6):860-869. 
16.  Abdulmaleek  Idanesimhe  Sado,  Muhammad  S  Afzal,  Lavanya 
Kannekanti,  Hrushikesh  Reddy  Pamreddy,  Jorge  Pimentel  Campillo, 

 
 
 
Advances in Renal Diseases and Dialysis 
Acute Kidney Injury 
 
 
 
 
14 
 
Vaishnavi  Kandukuri,  et  al.  A  Meta-Analysis  on  Predictors  of  Mortality 
Among Patients Hospitalized for  Acute Exacerbation  of Asthma.  Cureus. 
2023;15(2):e35225. 
17.  Sasa  Nie,  Li  Tang,  Weiguang  Zhang,  Zhe  Feng,  Xiangmei  Chen.  Are 
there  modifiable  risk  factors  to  improve  AKI?.  Biomed  Res  Int. 
2017;2017:5605634. 
18.  Rakesh  Pilla, Sujith  Kumar Palleti,  Renuka Rayana,  Satish Reddy Skss, 
Aminah  Abdul  Razzack,  Sruti  Kalla.  Glycated  haemoglobin  (HbA1c) 
variations  in  nondiabetics  with  nutritional  anemia.  Cureus. 
2020;12(11):e11479. 
19.  Sai  Kiran  Kondabolu, Yasitha  Kakarlapudi,  Haider  Malik, Hamza  Malik, 
Saima  Khan,  Praveen  Kumar  Komminni,  et  al.  Beneficial  Impacts  of 
Fenoldopam  on  Patients  with  or  at  Risk  for  Acute  Renal  Failure  and 
Undergoing  Surgery:  A  Meta-Analysis  of  Randomized  Clinical  Trials. 
Cureus. 2023;15(2):e34584. 
20.  Rodrigo  Cartin-Ceba,  Markos  Kashiouris,  Maria  Plataki,  Daryl  J  Kor, 
Ognjen  Gajic,  Edward  T  Casey.  Risk factors  for  development  of  acute 
kidney  injury  in  critically  ill  patients:  a  systematic  review  and  meta- 
analysis of observational studies. Crit Care Res Pract. 2012;2012:691013. 
21.  Robin Rauniyar, Rahul Rauniyar, Ankita Agrawal, Shikha Yadav, Sreekant 
Avula. Severe late‐onset neutropenia induced by ocrelizumab in a multiple 
sclerosis patient: A case report. Clin Case Rep. 2022;10(1):e05299. 
22.  Fareeha  Naseer  Syed,  Nadia  Kashif,  Mubashir  Razzaq  Khan,  Fayaz 
Ahmed Memon, Muhammad Zubair Jabbar, Sujith Kumar Palleti. Hepatitis 
C  Virus  Infection  in  Patients  with  Beta  Thalassemia  after  Multiple 
Transfusions at  a Tertiary  Care Hospital.  Pakistan Journal of  Medical & 
Health Sciences. 2023;17(1):363- 363. 
23.  Vaillant  Angel  A.  Justiz,  Roopa  Naik.  HIV-1  associated  opportunistic 
infections. StatPearls [Internet]. StatPearls Publishing. 2021. 
24.  Matthieu  Legrand,  Samira  Bell,  Lui  Forni,  Michael  Joannidis,  Jay  L 
Koyner,  Kathleen  Liu,  et al.  Pathophysiology  of  COVID-19-associated 
acute kidney injury. Nat Rev Nephrol. 2021;17(11):751-764. 
25.  Benaicha  Karima,  et  al.  Efficacy  of  Molnupiravir  for  the  Treatment  of                
Mild  or  Moderate  COVID-19  in  Adults:  A  Meta-Analysis.  Cureus. 
2023;15(5). 
26.  Lindeman  Robert D. Overview: renal  physiology and  pathophysiology of 
aging. Am J Kidney Dis. 1990;16(4):275-282. 
27.  Belayev Linda Y, Paul M. Palevsky. The link between AKI and CKD. Curr 
Opin Nephrol Hypertens. 2014;23(2):149. 
28. Bali,  Atul,  et al.  “: Atul  Bali,  Sandesh  Dewan, Roopa  Naik,  Maheshwari 
Kata,  Sreekant  Avula.  Continuous  Renal  Replacement  Therapy.” 
International  Clinical  and  Medical  Case  Reports  Journal  Review  Article. 
2023;2(12):1-13. 
29.  Jennette  J.  Charles.  Rapidly progressive  crescentic  glomerulonephritis. 
Kidney Int. 2023;63(3):1164-1177. 
30. Palleti, Sujith K,  et  al.  Sjögren’s  Syndrome  Overlap  with  Lupus  Nephritis: 
A  Case  Report  and  Literature  Review  of  a  Rare  Entity.  Cureus. 
2023;15(5). 

 
 
 
Advances in Renal Diseases and Dialysis 
Acute Kidney Injury 
 
 
 
 
15 
 
31.  Palleti  Sujith  K.  et  al.  Subarachnoid  Hemorrhage  in  Autoimmune 
Vasculitis:  A  Rare  Presentation  of  Systemic  Lupus  Erythematosus-
Antineutrophil  Cytoplasmic  Autoantibody-Associated  Vasculitis  Overlap 
Syndrome. Cureus. 2023;15(5). 
32.  P Meneton, I Ichikawa, T Inagami, J Schnermann. Renal physiology of the 
mouse. Am J Physiol Renal Physiol . 2000;278(3):F339-51. 
33.  Zarjou Abolfazl, Anupam  Agarwal. Sepsis and  acute kidney injury. J Am 
Soc Nephrol. 2011;22(6):999- 1006. 
34.  Singbartl, Kai, John  A. Kellum. AKI in  the ICU: definition,  epidemiology, 
risk stratification,  and outcomes. Kidney Int. 2012;81(9):819-25. 
35.  Muhammad  Ali  Sameer,  Bilal  Aziz  Malik,  Muhammad  Obaid  Ullah 
Choudry,  Muhammad  Shoaib  Anwar,  Muhammad  A  Nadeem,  Fizza 
Mahmood,  et  al.  Comparison  of  Coronary  Artery  Bypass  Grafting 
Combined  With  Mitral  Valve  Repair  Versus  Coronary  Artery  Bypass 
Grafting Alone in Patients With Moderate Ischemic Mitral Regurgitation: A 
Meta-Analysis. Cureus. 2023;15(4):e37238. 
36.  A Sigurdsson,  P Held, K  Swedberg. Short-and  long-term neurohormonal 
activation  following  acute  myocardial  infarction.  Am  Heart  J. 
1993;126(5):1068-76. 
37.  Vallon  Volker.  Tubuloglomerular  feedback  and the  control of  glomerular 
filtration rate. News Physiol Sci. 2003;18:169-74. 
38.  Pere Ginès , Elsa  Solà, Paolo Angeli , Florence Wong 8, Mitra K Nadim, 
Patrick  S  Kamath.  Hepatorenal  syndrome.  Nature  Rev  Dis  Primers. 
2018;4(1):23. 
39.  Hani  M  Wadei,  Martin  L  Mai,  Nasimul  Ahsan,  Thomas  A  Gonwa. 
Hepatorenal syndrome: pathophysiology and management. Clin J Am Soc 
Nephrol. 2006;1(5):1066-79. 
40.  John R Prowle, Yan-Lun Liu, Elisa Licari, Sean M Bagshaw, Moritoki Egi, 
Michael  Haase,  et  al.  Oliguria as  predictive  biomarker  of  acute kidney 
injury in critically ill patients. Critical Care. 2011;15(4):1-10. 
41.  Timothy  W  Meyer  1,  Thomas  H  Hostetter.  Uremia.  N  Engl  J  Med. 
2007;357(13):1316-25. 
42.  Atul Bali, John Kevin Hix, Peter Kouides. Safe and effective use of chronic 
transdermal estradiol for life- threatening uremic bleeding in a patient with 
coronary artery disease. Nephron Extra. 2014;4(2):134-137. 
43.  Yuki Sato, Masahiro  Takahashi, Motoko Yanagita.  Study on Recognition 
of  Heart  Arrhythmias  by  Deep  Learning  Approach  of  the  ECG Signals 
using Edge Devices. 
44.  Sato, Yuki,  Masahiro Takahashi, and Motoko Yanagita.  Pathophysiology 
of AKI to CKD progression. Semin Nephrol. 2020;40(2):206-215. 
45.  Ayodele  Odutayo,  Christopher  X  Wong,  Michael  Farkou,  Douglas  G 
Altman, Sally Hopewell, Connor A Emdin, et al. AKI and long-term risk for 
cardiovascular events  and mortality. J  Am Soc  Nephrol. 2017;28(1):377-
387. 
46.  Matthew  T  James,  William  A  Ghali,  Merril  L  Knudtson,  Pietro  Ravani, 
Marcello  Tonelli, Peter  Faris,  et al.  Associations between  acute  kidney 
injury and cardiovascular and renal outcomes after coronary angiography. 
Circulation. 2011;123(4):409-416. 

 
 
 
Advances in Renal Diseases and Dialysis 
Acute Kidney Injury 
 
 
 
 
16 
 
47.  Karthik  Gonuguntla,  Komal  Ejaz,  Chaitanya  Rojulpote,  Ayesha  Shaik, 
Abhijit  Bhattaru,  Tapan  Buch,  et  al.  A  nationwide  cohort  analysis  to 
determine  the  prevalence  of  sinus  node  dysfunction  and  rates  of 
pacemaker  implantation  in  systemic  lupus  erythematosus.  Am J 
Cardiovasc Dis. 2021;11(4):478-483. 
48.  Karedath  Jithin, et  al. Comparison  of Effectiveness  and  Safety  of Low-
Dose  Versus  Standard-Dose  Intravenous  Recombinant  Tissue 
Plasminogen  Activator  in  Patients  with Acute  Ischemic Stroke:  A Meta- 
Analysis. Cureus. 2023;15(2): e35571. 
49.  Sophie Perinel, François Vincent, Alexandre Lautrette, Jean Dellamonica, 
Christophe  Mariat,  Fabrice  Zeni,  et  al.  Transient  and  persistent  acute 
kidney  injury  and  the  risk  of  hospital  mortality  in  critically  ill  patients: 
results of a multicenter cohort study. Crit Care Med. 2015;43(8):e269-75. 
50.  Marianne  Schmid,  Nandita  Krishna,  Praful  Ravi,  Christian  P  Meyer, 
Andreas  Becker,  Deepansh Dalela,  et  al. Trends  of  acute  kidney  injury 
after  radical  or  partial  nephrectomy  for  renal  cell  carcinoma.  Urologic 
Oncology:  Seminars  and  Original  Investigations.  Urol  Oncol. 
2016;34(7):293.e1-293.e10. 
51.  Kar,  Saikat,  et  al.  A  two-center,  retrospective  cohort  trial  of  a  tumor 
necrosis  factor  inhibitor  coupled  with  intravenous  immunoglobulin  and 
heparin for the treatment of recurrent spontaneous abortion. 
52.  Rajit  K  Basu,  Anne  Andrews,  Catherine  Krawczeski,  Peter  Manning, 
Derek S Wheeler, Stuart L Goldstein, et al. Acute kidney injury based on 
corrected  serum  creatinine  is  associated  with  increased  morbidity  in 
children  following  the  arterial  switch  operation.  Pediatr  Crit  Care  Med. 
2013;14(5):e218-24. 
53.  José António Lopes, Sofia Jorge. The RIFLE and AKIN classifications for 
acute kidney  injury: a  critical  and  comprehensive review.  Clin Kidney J. 
2013;6(1):8-14. 
54.  Jay  L  Koyner,  Danielle  L  Davison,  Ermira  Brasha-Mitchell,  Divya  M 
Chalikonda, John M Arthur, Andrew D Shaw, et al. Furosemide stress test 
and  biomarkers  for  the  prediction  of  AKI  severity.  J  Am  Soc  Nephrol. 
2015;26(8):2023-31. 
55.  Edelstein,  Charles  L. Biomarkers  in acute  kidney  injury.  Biomarkers  of 
Kidney Disease. 2017;241-315. 
56.  John A Kellum,  Florentina E Sileanu, Raghavan Murugan, Nicole Lucko, 
Andrew D Shaw, Gilles Clermont. Classifying AKI by urine output versus 
serum creatinine level. J Am Soc Nephrol. 2015;26(9):2231-8. 
57.  Mira  Küllmar,  Alexander  Zarbock,  Daniel  T  Engelman,  Subhasis 
Chatterjee, Nana-Maria Wagner. Prevention of acute kidney injury. Critical 
Care Clinics. 2020;36(4):691-704. 
58.  Raza A Khan, Nidhi Patel, Atunde Folajimi, Bansari Raveena Bai, Vrushak 
Patel,  Praveen Kumar  Komminni, et  al. Comparison  of the Efficacy  and 
Safety of Metformin-Based Combination Therapy Versus Metformin Alone 
in  Children  and  Adolescents  with  Type  2  Diabetes  Mellitus:  A  Meta-
Analysis. Cureus. 2023;15(2):e35014. 
59.  Eyth Emily, Roopa Naik. Hemoglobin A1c. StatPearls [Internet]. StatPearls 
Publishing. 2022. 

 
 
 
Advances in Renal Diseases and Dialysis 
Acute Kidney Injury 
 
 
 
 
17 
 
60.  Mitra K Nadim, Lui G Forni, Azra Bihorac, Charles Hobson, Jay L Koyner, 
Andrew  Shaw,  et  al.  Cardiac  and  vascular  surgery–associated  acute 
kidney  injury: the  20th international  consensus conference  of the  ADQI 
(acute  disease  quality  initiative)  group.  J  Am  Heart  Assoc. 
2018;7(11):e008834. 
61.  Rolando  Claure-Del  Granado,  Ravindra  L  Mehta.  Fluid  overload                      
in  the  ICU:  evaluation  and  management.  BMC  Nephrol.  2016;17(1)             
:109. 
62.  Julie  Badin, Thierry  Boulain, Stephan  Ehrmann, Marie  Skarzynski, Anne 
Bretagnol, Jennifer Buret, et al. Relation between mean arterial pressure 
and renal function in the early phase of shock: a prospective, explorative 
cohort study. Crit Care. 2011;15(3):R135. 
63.  Gunnar  Gamper, Christof  Havel, Jasmin  Arrich, Heidrun  Losert,  Nathan 
Leon  Pace, Marcus  Müllner, et  al.  Vasopressors for hypotensive shock. 
Cochrane Database Syst Rev. 2016;2(2):CD003709. 
64.  Zaid Munir, Muhammad Akash, Fnu Jaiprada, Bilal Abu Tarboush, Osama 
Ijaz,  Anan  Bseiso,  et  al.  Evaluation  of  the  Effects  of  Extracorporeal 
Shockwave Therapy in Patients with Peripheral Arterial Disease: A Meta-
Analysis of Randomized Control Trials. Cureus. 2023;15(2):e34729.. 
65.  Naughton,  Cynthia  A.  Drug-induced  nephrotoxicity.  American  family 
physician. 20085;78(6):743-750. 
66.  Sujith K Palleti, Anuradha Wadhwa, Abdul H Rasheed. The First Case of 
Ceftazidime-Induced Antibiomania: A Case Report and Literature Review. 
Cureus. 2022;14(12):e32904. 
67.  Patrick  T  Murray,  Prasad  Devarajan,  Andrew  S  Levey,  Kai  U  Eckardt, 
Joseph V Bonventre, Raul Lombardi, et al. A framework and key research 
questions in AKI  diagnosis and  staging in different environments.  Clin J 
Am Soc Nephrol. 2008;3(3):864-8. 
68.  Alexandre  Braga Libório,  Tacyano Tavares  Leite, Fernanda  Macedo de 
Oliveira  Neves,  Flávio  Teles,  Candice  Torres  de  Melo  Bezerra.  AKI 
complications in  critically ill  patients: association with  mortality  rates and 
RRT. Clin J Am Soc Nephrol. 2015;10(1):21-8. 
69.  E  J Filippone,  W K  Kraft, J  L Farber.  The nephrotoxicity  of vancomycin. 
Clin Pharmacol Ther. 2017;102(3):459-469. 
70.  Palleti,  Sujith  K.,  Anuradha  Wadhwa,  Abdul  H.  Rasheed.  Ceftazidime-
induced  Antibiomania:  A  Rare  Case  Study  and  Review  of  Literature. 
Research  Highlights  in  Disease  and  Health  Research  Vol.  2023;6:                 
56-61. 
71.  Harkesh  Arora,  Sathishkumar  Ramalingam, Rajvee  Sanghavi,  Adedayo 
Balogun,  Maheshwari  Muruganandam,  et  al.  Disseminated  Nocardia 
infection-A rare presentation. Clin Case Rep. 2021;9(8):e04673. 
72.  Robert H Thiele, James M Isbell, Mitchell H Rosner. AKI associated with 
cardiac surgery. Clin J Am Soc Nephrol. 2015;10(3):500-14. 
73.  Edward D Siew, Sharidan K Parr, Khaled Abdel-Kader, Svetlana K Eden, 
Josh F  Peterson, Nisha  Bansal, et al. Predictors of recurrent  AKI. J Am 
Soc Nephrol. 2016;27(4):1190-200. 
74.  Fatemeh  Ghane  Shahrbaf,  Farahnak  Assadi.  Drug-induced  renal 
disorders. J Renal Inj Prev. 2015;4(3):57- 60. 

 
 
 
Advances in Renal Diseases and Dialysis 
Acute Kidney Injury 
 
 
 
 
18 
 
75.  Matthew A Gorris, Harkesh Arora, David C Lieb, Joseph A Aloi. A word of 
caution  when  prescribing  high-dose  vitamin  D. Am  J  Med. 
2017;130(4):e129-e130. 
76.  Daniela  Ponce,  Marina  Berbel  Buffarah,  Cassiana  Goes,  André  Balbi. 
Peritoneal  dialysis  in  acute  kidney  injury: trends  in the  outcome across 
time periods. PLoS One. 2015;10(5):e0126436. 
77.  Sujith  K  Palleti,  Santhoshi  R  Bavi,  Margaret  Fitzpatrick,  Anuradha 
Wadhwa.  First  case  report  of  Sphingobium  lactosutens  as  a  human 
pathogen  causing  peritoneal  dialysis-related  peritonitis.  Cureus. 
2022;14(7): e27293. 
78.  Antoine  G  Schneider,  Rinaldo  Bellomo,  Sean  M  Bagshaw,  Neil  J 
Glassford, Serigne Lo, Min Jun, et al. Choice of renal replacement therapy 
modality and dialysis dependence  after acute kidney injury: a systematic 
review and meta-analysis. Intensive Care Med. 2013;39(6):987-97. 
79.  Romagnoli, Stefano, Zaccaria Ricci, and Claudio Ronco. CRRT for sepsis-
induced acute kidney injury. Curr Opin Crit Care. 2018;24(6):483-492. 
80.  Sathishkumar  Ramalingam,  Harkesh  Arora,  Susan  Lewis,  Kulothungan 
Gunasekaran,  Maheswari  Muruganandam,  Sivakumar  Nagaraju,  et  al. 
COVID-19  vaccine-induced  cellulitis  and  myositis.  Cleve  Clin  J  Med. 
2021;88(12):648-650. 
81.  Pierre-Marc Villeneuve, Edward G Clark, Lindsey Sikora, Manish M Sood, 
Sean M Bagshaw. Health- related quality-of-life among survivors of acute 
kidney  injury  in  the  intensive  care  unit: a  systematic  review.  Intensive 
care medicine. Intensive Care Med. 2016;42(2):137-46. 
82.  Palleti SK.  Fellowship in the  United States as  an exceptionally qualified 
applicant. Postgraduate Medical Journal. 2023. 
83.  Sean  M  Bagshaw,  Michael  Darmon,  Marlies  Ostermann,  Fredric  O 
Finkelstein, Ron Wald, Ashita J Tolwani, et al. Current state of the art for 
renal replacement therapy in critically ill patients with acute kidney injury. 
Intensive Care Med. 2017;43:841-854. 
84.  Zhang Ting. Hospital readmissions after acute kidney injury: A systematic 
review and meta-analysis. Int J Clin Exp Med. 2016;9(7):13456-13465. 
85.  Marlies  Ostermann,  Alexander  Zarbock,  Stuart  Goldstein,  Kianoush 
Kashani, Etienne Macedo,  Raghavan Murugan,  et al. Recommendations 
on acute kidney injury biomarkers from the acute disease quality initiative 
consensus  conference:  a  consensus  statement.  JAMA  Netw  Open. 
2020;3(10):e2019209. 
___________________________________________________________________________________ 
© Copyright (2023): Author(s). The licensee is the publisher (B P International). 
 
DISCLAIMER 
This chapter is an extended version of the article published by the same author(s) in the following journal.  
Annal of Clin Med & Med Res, 1(1): 1-17, 2023. DOI: https://doi.org/10.5281/zenodo.8076523 
 

________________________________________________________________________

a Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA,

USA.

b Department of Internal Medicine/Nephrology, Geisinger Wyoming Valley Medical Center, Wilkes-Barre,

Pennsylvania, USA.

c Department of Internal Medicine, University Hospital and Clinics, Lafayette, USA.

d Department of Internal Medicine, MNR Medical College and Hospital, Telangana, India.

e Department of Internal Medicine, Lovelace Medical Center, Albuquerque, New Mexico, USA.

f Department of Internal Medicine/Nephrology, University of Alabama at Birmingham, Birmingham,

Alabama, USA.

g Department of Internal Medicine/Gastroenterology, Brooklyn Hospital Center, Brooklyn, New York,

USA.

*Corresponding author: E-mail: drmaheshwarikata@gmail.com;

Chapter 2

Print ISBN: 978-81-19491-84-1, eBook ISBN: 978-81-19491-85-8

Hepatorenal Syndrome

Roopa Naik a, Atul Bali b, Bushra Firdous Shaik c,

Maheshwari Kata d*, Harkesh Arora e,

Deepak Chandramohan f and Rajeshwari Ramachandran g

DOI: 10.9734/bpi/mono/978-81-19491-84-1/CH2

ABSTRACT

Hepatorenal syndrome is a serious complication of end-stage cirrhosis

characterized by increased splanchnic blood flow, a hyperdynamic state, reduced

central volume, activation of vasoconstrictor systems, and extreme renal

vasoconstriction leading to a decrease in GFR. In recent years, the role of

systemic inflammation, a key feature of cirrhosis, in the development of

hepatorenal syndrome has been emphasized. The mechanisms by which

systemic inflammation induces changes in renal blood flow during hepatorenal

syndrome remain to be elucidated. Early diagnosis is central to treatment, and

recent changes in the definition of hepatorenal syndrome help to identify patients

at an earlier stage. Vasoconstrictor agents such as terlipressin and albumin are

the first-line treatment options. Several controlled studies have shown that

terlipressin is effective in reversing hepatorenal syndrome and may improve

short-term survival. Not all patients respond, and even those who do have a very

high early mortality rate without liver transplantation. Liver transplantation is the

only definitive treatment for hepatorenal syndrome. In the long term, transplant

patients with hepatorenal syndrome usually have a lower GFR than patients

without hepatorenal syndrome. Differentiating hepatorenal syndrome from acute

tubular necrosis (ATN) is often a difficult but important step, as vasoconstrictor

drugs are not warranted in the treatment of ATN. Hepatorenal syndrome and

ATN can be considered a continuum rather than separate entities. Emerging

biomarkers may help distinguish between these two conditions and provide

prognostic information about renal recovery after liver transplantation and

potentially influence the decision for simultaneous liver and kidney

transplantation.

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Hepatorenal Syndrome

Keywords: Hepatorenal syndrome; liver transplantation; biomarkers of HRS;

acute kidney injury; vasopressors.

1. INTRODUCTION

Advanced liver cirrhosis is a condition characterized by impaired liver function,

portal hypertension, increased splanchnic circulation, a hyperdynamic state with

increased cardiac output, systemic vasodilatation, reduced central blood volume,

and a systemic inflammatory response. Acute kidney injury (AKI) is one of the

most important complications of cirrhosis, occurring in up to 50% of hospitalized

patients and associated with higher mortality that increases with the severity of

AKI [1]. Hepatorenal syndrome (HRS) is a type of AKI that occurs in advanced

cirrhotic patients and is mainly characterized by impaired renal perfusion

unresponsive to volume expansion. Hepatorenal syndrome is associated with

significant use of health care resources, with estimated direct medical costs of

approximately $4 billion annually in the United States [2]. Advancements in

definitions helped diagnose hepatorenal syndrome in earlier stages of liver

cirrhosis. Recent advances in the understanding of the pathophysiology of

hepatorenal syndrome indicate that, in addition to systemic and splanchnic

circulatory changes, systemic inflammation and renal circulatory changes are

also involved [3]. Although treatment of hepatorenal syndrome in combination

with vasoconstrictors and albumin has improved outcomes, the prognosis is poor

without liver transplantation. This recent literature review focuses on providing an

updated version of the HRS, with particular attention to some important changes.

2. DEFINITION OF HRS AND ACUTE KIDNEY INJURY IN CIRRHOSIS

The definition of cirrhotic AKI has changed significantly in recent years [4]. A

common theme among definitions is the use of relative changes in serum

creatinine rather than absolute cutoffs (eg, >1.5 mg/dL) and the identification of

patients at greatest risk of short-term and long-term mortality based on these

stages within each criterion. In 2012, the Acute Dialysis Quality Initiative (ADQI)

recommended adapting the AKI Network serum creatinine criteria for defining

AKI [5]. These criteria were independent of the cause of AKI, and as such,

hepatorenal syndrome type 1 was classified as a specific type of AKI and

hepatorenal syndrome type 2 was classified as a form of CKD. The International

Ascites Club (ICA) further modified the definition of AKI based on serum

creatinine criteria developed by Kidney Disease Improving Global Outcomes

(KDIGO) using baseline serum creatinine in the last 3 months [6]. Although

oliguria is not included in the current definition of AKI in cirrhotic patients, urine

output has been found to be a sensitive and early marker of AKI in critically ill

cirrhotic patients and is associated with adverse events. Therefore, despite an

increase in serum creatinine in cirrhotic patients, a decrease in urine output or

development of anuria should be considered as AKI in cirrhosis until proven

otherwise.

Changes in the definition of AKI in cirrhotic patients led to changes in the

definition of hepatorenal syndrome, so that the serum creatinine cut-off was

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Hepatorenal Syndrome

removed and replaced by the ICA AKI criteria, which allows earlier diagnosis and

treatment of patients with hepatorenal syndrome. An important limitation of the

criteria for hepatorenal syndrome is that it does not allow patients with liver

disease to have other forms of acute or chronic kidney disease at the same

time, such as diabetic nephropathy or glomerular disease [7-9]. However,

patients with concomitant renal disease may develop "hepatorenal physiology".

Thus, ADQI proposed the term "hepatorenal diseases" to describe all patients

with advanced cirrhosis and concomitant renal failure, taking into account the

appropriate classification and management of these patients, retaining the term

hepatorenal syndrome.

3. PATHOPHYSIOLOGY OF HEPATORENAL SYNDROME

Cirrhosis is characterized by a decrease in systemic vascular resistance due to

splanchnic artery vasodilation [10]. In the early stages of the disease, splanchnic

vasodilatation is moderate and decreased systemic vascular resistance is

balanced by increased cardiac output. In advanced stages, vasodilatation is

more pronounced because the synthesis of vasodilatory factors increases and

cannot be balanced by an increase in cardiac output. The result is effective

arterial hypovolemia due to the difference in intravascular blood volume and the

greatly expanded arterial circulation [11,12]. Cirrhotic cardiomyopathy is a

disease entity that combines diastolic dysfunction, a dull increase in cardiac

output after stimulation and various electromechanical abnormalities [13,14]. The

inflammatory response during cirrhosis, where circulating TNF-α is elevated,

may contribute to impaired cardiac response. In advanced cirrhosis with ascites,

reduced cardiac output appears to precede hepatorenal syndrome. Decreased

cardiac output can reduce blood flow to the kidneys. Finally, changes in renal

hemodynamics and autoregulation of renal blood flow contribute to a decrease in

GFR.

To maintain arterial pressure, systemic vasoconstrictor systems (renin-

angiotensin-aldosterone system, sympathetic nervous system and arginine

vasopressin) are activated, which, together with the increased cardiac output

associated with the hyperdynamic state, help to maintain renal blood flow.

Although activation of these systems has a positive effect by increasing arterial

pressure, they cause renal vasoconstriction, sodium retention leading to edema

and ascites, and secretion of insoluble water leading to hyponatremia and

decreased GFR [15]. In the most advanced stages of cirrhosis, severe renal

vasoconstriction occurs, and renal perfusion is no longer compensated by

increased cardiac output and GFR decreases, eventually leading to hepatorenal

syndrome. Recently, the concept of systemic inflammatory disease has emerged

in patients with cirrhosis, and there is increasing evidence that inflammation

plays a role in hepatorenal syndrome [16,17]. Cirrhosis is associated with

systemic inflammation that correlates with the severity of liver disease and portal

hypertension. The main mechanism is the translocation of bacterial and/or

pathogen-associated molecular patterns from the gut due to altered intestinal

permeability [18,19]. Inflammatory components can reach the systemic

circulation and peripheral organs, causing extrahepatic organ dysfunction,

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including the kidneys. Inflammation can affect systemic circulation disorders and

impair renal perfusion. Patients with bacterial translocation have increased levels

of pro-inflammatory cytokines (TNF-α and IL-6) and vasodilators (such as nitric

oxide) [20,21]. Bacterial infections are a typical trigger for HRS; however,

approximately 30% of these patients develops systemic inflammatory response

syndrome (SIRS) without documented evidence of bacterial infection [22,23].

4. INCIDENCE OF HRS

HRS is thought to be a common complication in patients with advanced cirrhosis.

However, most classic studies on the prevalence of HRS in cirrhotic patients

were conducted many years ago and used atypical diagnostic criteria. Therefore,

the current incidence of HRS or its incidence relative to other causes of renal

failure in cirrhosis is unknown.

5. CLINICAL FINDINGS AND INVESTIGATIONS

In the setting of cirrhosis, HRS usually occurs in the late stages of the disease,

when patients have already had several episodes of some of the more serious

complications of cirrhosis, especially ascites. Patients with renal sodium retention

and dilutional hyponatremia with ascites are at high risk for HRS. The

predominant finding of HRS is renal failure, although many patients have other

manifestations, such as electrolyte imbalances, cardiovascular and infectious

complications, and complications related to liver disease [24-26]. Currently, when

frequent biochemical monitoring is widely used, the most common diagnosis of

HRS is an increase in serum creatinine or blood urea nitrogen concentration. In

some patients, serum creatinine and urea nitrogen concentrations rapidly rise to

very high values. Most of these patients have progressive oligo-anuria. In other

patients, the elevations in serum creatinine and blood urea nitrogen are

moderate and have no (or very little) tendency to progress over time, at least in

the short term. These two different patterns of renal failure progression define

two different clinical types of HRS [27,28]. The rate of progression used to define

type 1 HRS is arbitrarily set as a 100% increase in serum creatinine to a value

greater than 221 μmol/L (2.5 mg/dL) in less than 2 weeks. Patients with type 1

HRS have a very low GFR, usually less than 20 mL/min, and a very high serum

creatinine concentration (average approximately 356 μmol/L). In contrast, most

patients with type 2 HRS have milder GFR and creatinine (average 178 μmol/L).

An important clinical difference between the two types of HRS is that type 1

patients have a very poor short-term outcome compared to type 2 patients

[29,30].

In addition to renal failure, patients with HRS have sodium retention with salt and

water overload. In most cases, sodium retention is present and evident before

the development of HRS, but renal sodium excretion may further deteriorate as

renal failure occurs due to decreased GFR and activation of anti-natriuretic

systems [31,32]. As a result, increased positive sodium balance leads to weight

gain due to increased ascites volume and peripheral edema. Hyponatremia is

almost universal in HRS, so if serum sodium is normal in a patient with cirrhosis

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and renal failure, the diagnosis of HRS is highly unlikely and the patient should

be investigated for another cause of renal failure. Hyponatremia is caused by a

decreased ability of the kidneys to excrete insoluble water, resulting in

disproportionate water retention relative to sodium (dilutional hyponatremia).

Severe metabolic acidosis is rare in HRS, except in patients who develop severe

infection [33,34].

Cardiovascular function is severely impaired in patients with HRS. Systemic total

vascular resistance is greatly reduced and arterial pressure is low in most

cases, despite strong activation of important vasoconstrictor mechanisms such

as renin-angiotensin and the sympathetic nervous system [35,36]. Cardiac output

is increased in most patients, while arterial pressure is usually low but stable

(mean arterial pressure approximately 70 mm Hg). In case of hemodynamic

instability, there is reason to suspect an infectious complication. Apart from

arterial pressure, the other cardiovascular abnormalities are not detected in the

clinical situations, unless invasive vascular monitoring is performed. However,

these procedures are not usually necessary in the clinical management of HRS

patients. Pulmonary edema, a common and serious complication of acute renal

failure, is very rare in patients with HRS unless treated aggressively with plasma

expanders [37]. Serious bacterial infections, particularly septicemia (either

spontaneous or indwelling catheter-related), spontaneous bacterial peritonitis,

and pneumonia are common complications in patients with HRS and are major

causes of death [38-40]. Both kidney failure and advanced liver disease are

believed to increase susceptibility to infection.

Finally, most patients with HRS have signs and symptoms of advanced liver

failure and portal hypertension, particularly jaundice, coagulopathy, malnutrition,

and hepatic encephalopathy, although HRS develops in some patients with only

moderate liver failure [41-43]. Ascites is common in patients with HRS, so the

absence of ascites in patients with cirrhosis and renal failure argues against HRS

as a cause of renal failure and points to other causes, particularly prerenal failure

due to volume depletion from excessive diuresis.

6. PRECIPITATING FACTORS

In some patients, HRS develops spontaneously without an obvious precipitating

event, while in others it occurs in close chronological association with a number

of precipitating factors that can cause circulatory disturbances and subsequent

renal hypo-perfusion. Known precipitating factors include bacterial infections,

large paracentesis without plasma expansion, and gastrointestinal bleeding

[44,45]. Among the different types of bacterial infections with cirrhosis, a clear

chronological and pathogenic relationship between infection and HRS was found

only in spontaneous bacterial peritonitis. This disorder is characterized by

spontaneous ascites infection, most often with gram-negative intestinal bacteria,

without intra-abdominal infection or intestinal perforation. Approximately 20% of

patients with spontaneous bacterial peritonitis develop HRS during or shortly

after infection - mostly type 1.

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Whether HRS can also occur as a result of other serious bacterial infections has

not been studied. Another known cause of HRS is large-volume paracentesis

without plasma expansion [46]. Up to 15% of patients with ascites develop HRS

when large volumes of ascitic fluid (more than 5 L) are removed without

administration of a plasma expander. This association is one of the reasons why

large amounts of intravenous albumin should be administered during

paracentesis. Finally, renal failure occurs in approximately 10% of patients with

cirrhosis and gastrointestinal bleeding. However, a significant proportion of

episodes of renal failure after gastrointestinal bleeding are due to acute tubular

necrosis associated with hypovolemic shock rather than HRS. Intravascular

volume depletion (ie, diuretic-induced extrarenal fluid loss) has traditionally been

considered the trigger for HRS. However, conclusive evidence to support this

pathogenic association has not yet been reported.

7. PROGNOSIS

Of all the complications of cirrhosis, HRS has the worst prognosis [47]. Survival

is very low and spontaneous recovery is extremely rare. The main determinant of

survival is the type of HRS. Type 1 has an in-hospital survival rate of less than

10% and an expected median survival time of only 2 weeks. In contrast, type 2

patients have a much longer median survival time (about 6 months). Another

determinant of survival is the severity of liver disease. Patients with severe

hepatic impairment (Child-Pugh class C) have a much worse outcome than

patients with moderate hepatic impairment (class B). For many years, the

development of kidney failure was not considered to contribute to the dismal

results of HRS, and the cause of death was largely thought to be liver disease.

However, recent research suggests that kidney failure is an important factor in

outcomes, with patients whose kidney function improves after treatment living

longer than those who do not.

8. APPROACH TO DIAGNOSIS

The first step in diagnosing HRS is to demonstrate renal failure (low GFR).

Serum creatinine is generally considered a better marker of GFR [48]. However,

serum creatinine is not an ideal marker of GFR in cirrhosis, as it is usually lower

than any GFR expected due to low endogenous creatinine production associated

with reduced muscle mass present in most patients with advanced cirrhosis.

However, because the use of more sensitive elimination methods to measure

GFR is expensive and not available in all situations, serum creatinine is currently

the most popular method to estimate GFR in cirrhosis. In patients receiving

diuretics with elevated serum creatinine, serum creatinine should be remeasured

after the diuretic is discontinued, as diuretic use may be associated with a mild

and reversible increase in serum creatinine.

Because there are no specific diagnostic tests, the diagnosis of HRS should

always be made after other conditions that can cause kidney failure in cirrhosis

have been ruled out. Acute renal failure of prerenal origin due to gastrointestinal

losses (vomiting, diarrhea, bleeding, nasogastric tube) or renal related losses

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Hepatorenal Syndrome

(excessive diuresis) should be investigated in all patients with renal failure based

on history and physical examination [49]. When renal failure is secondary to

volume deficit, renal function improves rapidly after volume expansion, whereas

no improvement occurs in patients with HRS. The presence of shock before the

onset of renal failure excludes the diagnosis of HRS and suggests the diagnosis

of acute tubular necrosis. Hypovolemic shock due to gastrointestinal bleeding is

common and easily recognized in cirrhosis. However, septic shock can be more

difficult to diagnose because some patients with cirrhosis have no symptoms of

bacterial infection, and arterial hypotension caused by sepsis can be confused

with advanced liver disease, at least in the early stages [50,51]. Therefore,

bacterial infection (leukocyte count, ascitic fluid examination, cultures, C-reactive

protein) must always be ruled out before diagnosis of HRS. In contrast, some

patients with cirrhosis and bacterial infection develop transient renal failure,

which in most cases improves after the infection resolves. Therefore, HRS

should only be diagnosed if renal failure persists after complete resolution of the

infection. Cirrhotic patients are at high risk of developing kidney failure when

using nephrotoxic agents such as NSAIDs, aminoglycosides or other drugs

[52,53]. Therefore, treatment with these nephrotoxic drugs in the days or weeks

before the onset of renal failure must always be excluded. Renal failure can also

occur after the administration of radiocontrast agents. However, whether cirrhotic

patients are at high risk for this complication has never been assessed. Finally,

patients with cirrhosis may also develop renal failure due to parenchymal kidney

disease, particularly glomerulonephritis [54-56]. It can occur with any cause of

cirrhosis, but is particularly common with chronic hepatitis B or C infection or

chronic alcoholism. These cases can be recognized by proteinuria, hematuria or

both. In some cases, the diagnosis can be confirmed with a kidney biopsy.

9. PREVENTION OF HEPATORENAL SYNDROME

Strategies to prevent the development of hepatorenal syndrome include

preventing progression of liver disease in the well-compensated patient, reversing

decompensation in patients with advanced cirrhosis, avoiding agents that

aggravate AKI, and avoiding factors that further impair blood flow and reduce

renal perfusion [57,58]. Prophylactic antibiotics to prevent spontaneous bacterial

peritonitis and intravenous albumin after variceal bleeding in patients with

spontaneous bacterial peritonitis and patients undergoing large paracentesis (> 5

L) have been shown to reduce the incidence of hepatorenal syndrome. There is

no evidence that albumin in addition to antibiotics reduces the incidence of AKI in

patients with bacterial infection other than spontaneous bacterial peritonitis. In a

controlled trial, long-term administration of albumin to patients with

decompensated cirrhosis was associated with improvements in spontaneous

bacterial peritonitis, hepatorenal syndrome, and survival [59].

β-blockers are very effective in preventing variceal bleeding and are widely used

in patients with cirrhosis and significant portal hypertension. A recent meta-

analysis indicates that the use of beta-blockers is not associated with a significant

increase in mortality in patients with ascites or refractory ascites [60]. However,

some series have shown increased mortality in patients with refractory ascites

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receiving β-blockers compared with patients not receiving beta-blockers. It has

been suggested that the reduction in cardiac output caused by β-blockers may

lead to AKI. Clinicians must individually weigh the risks and benefits of

continuous nonselective beta-blockers in patients with refractory ascites.

10. MANAGEMENT OF HEPATORENAL SYNDROME

The etiology of AKI should be urgently investigated to prevent further worsening

of AKI, as progression to advanced AKI is associated with higher mortality. This

is especially important for those with hepatorenal syndrome, because early

treatment can increase the likelihood of improvement in hepatorenal syndrome,

which can improve short-term survival. Albumin administration is a crucial step in

the treatment and diagnosis of hepatorenal syndrome; However, it is important

to be cautious when administering fluids to patients with AKI to avoid significant

fluid retention and pulmonary edema, as renal excretion of sodium and water is

reduced in cirrhotic patients.

11. PHARMACOLOGICAL TREATMENT

Vasoconstrictive agents along with albumin are the main choice in the treatment

of hepatorenal syndrome. Terlipressin is the most commonly used vasopressin

analog; however, it is not accepted in all countries [61]. The effectiveness of

terlipressin and albumin in the treatment of hepatorenal syndrome has been

demonstrated in several studies with a response rate of 25-75%. The most

important side effects of terlipressin are related to vasoconstriction, with a risk of

myocardial infarction and intestinal ischemia [62,63]. Baseline serum creatinine

and degree of acute chronic liver failure are associated with response to

terlipressin. However, there have been no studies on the use of vasoconstrictors

with lower serum creatinine in the early stages of hepatorenal syndrome.

Other vasoconstrictors have been recommended in combination with albumin.

Norepinephrine (administered intravenously at a dose of 0.5-3 mg/h) is an

alternative agent that has been shown to be effective in increasing arterial

pressure and reversing renal insufficiency in patients with hepatorenal syndrome

in small studies; however, a recent controlled trial indicates that norepinephrine is

inferior to terlipressin in terms of hepatorenal syndrome, need for renal

replacement therapy (RRT), and overall survival [64]. A combination of midodrine

and octreotide, used in countries where terlipressin is not yet available, was

shown to be less effective than terlipressin in a study [65].

12. TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

Theoretically, a transjugular intrahepatic portosystemic shunt may improve renal

function in hepatorenal syndrome by reducing portal hypertension and by

reducing and reversing the circulatory changes (and possibly systemic

inflammation) that cause hepatorenal syndrome [66]. Small studies have shown

that transjugular intrahepatic portosystemic shunt is associated with a reduction

in serum creatinine that may improve survival in patients with hepatorenal

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syndrome, but patients with advanced liver disease have a high incidence and

further exacerbation of hepatic encephalopathy.

13. RENAL REPLACEMENT THERAPY

Initiation of RRT in patients with hepatorenal syndrome is controversial and has

generally been considered a bridge in patients scheduled for transplantation [67].

Recent studies have shown that disease severity and degree of organ failure are

better predictors of 28-day mortality than the cause of AKI in patients with acute

and chronic liver failure. Therefore, it seems reasonable to consider a RRT trial in

selected patients, regardless of the transplant candidate. The ideal time of RRT

initiation in cirrhotic patients has not been studied, so it should be individualized

and based on clinical reasons, such as renal impairment with electrolyte

imbalance unresponsive to medical therapy or diuretic intolerance/resistance.

RRT should also be considered to prevent fluid retention if daily fluid balance

cannot be maintained or is negative regardless of their urine output.

14. LIVER SUPPORT SYSTEM

Although initial results suggested that albumin dialysis with a molecular

adsorptive circulation system may improve outcomes in patients with hepatorenal

syndrome, this has not been confirmed in larger randomized trials [68]. A

randomized trial of patients with acute or chronic liver failure found no significant

difference in 28-day mortality between patients with hepatorenal syndrome who

underwent molecular adsorptive recirculation compared with conventional

medical therapy. There is currently no evidence that albumin dialysis is better

than conventional filtration in patients requiring CRT.

15. LIVER TRANSPLANT ALONE VERSUS SIMULTANEOUS LIVER-

KIDNEY TRANSPLANT

Predicting the recovery of renal function and its extent of improvement after liver

transplantation is difficult because it is difficult to delineate the relative impact of

preexisting comorbidities, undetected intrinsic renal disease, perioperative

events, and post transplant immunosuppression on renal failure after liver

transplantation. Onset of AKI before liver transplantation has been shown to be

associated with a higher risk of CKD and ESKD after liver transplantation and

has also been associated with an increased risk of mortality [69]. Liver

transplantation is the primary form of treatment for patients with hepatorenal

syndrome, and in theory, kidney function is fully reversible after transplantation.

Renal recovery and patient survival after liver transplantation were significantly

higher in patients with hepatorenal syndrome than in patients with acute tubular

necrosis and comparable to patients without AKI or stage 1 AKI, regardless of

their dialysis status before transplantation.

The introduction of organ allocation based on the end-stage liver disease model

in 2002 led to a sharp increase in the number of simultaneous liver-kidney

transplants, as liver transplant candidates with kidney failure were preferred. At

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present simultaneous liver and kidney transplants account for 10% of all liver

transplants in the United States, and approximately 5% of transplanted

deceased donor kidneys are removed from kidney-only transplant candidates,

causing concern in the kidney transplant community, especially because of the

uncertain benefits in case of simultaneous liver and kidney transplantation

[70,71]. The decision to perform simultaneous liver-kidney transplantation and

liver transplantation is not only a concern for post-transplant mortality, but also a

concern for lack of renal recovery, which is thought to increase mortality. Studies

have shown that liver transplant patients on the waiting list have a higher

mortality compared to patients waiting only for a kidney transplant. The Organ

Procurement and Transplantation Network recently developed criteria for

simultaneous liver and kidney transplantation based on previous consensus

recommendations that include factors such as AKI and duration of dialysis and

evidence of chronic kidney disease. Age, comorbidities or cause of AKI, which

may influence renal recovery, are not currently in the criteria [72].

16. NEWER BIOMARKERS

Early diagnosis and recognition of the AKI phenotype is crucial, as treatment

varies depending on the different causes. Conventional measures such as

urinary excretion or sodium or urea fraction have been shown to be significantly

limited in patients with advanced cirrhosis and to correlate poorly with biopsy

findings. Several novel biomarkers have recently been investigated, the most

studied of which are neutrophil-gelatinase-associated lipocalin, kidney molecule-

1, liver fatty acid-binding protein, and IL-18 [73-75]. These specific biomarkers

usually reflect early signs of ischemia-related events and may play a role in the

diagnosis of AKI before liver transplantation. These biomarkers are not specific

for kidney damage, can be influenced by inflammation or infection, and have not

been validated using kidney biopsy as the gold standard. Furthermore,

considerable overlap between the different phenotypes was observed, and no

clear cut-off value distinguishes hepatorenal syndrome from acute tubular

necrosis. Biomarkers that predict recovery from AKI after liver transplantation

may improve decision algorithms regarding the need for liver-kidney

transplantation or kidney-sparing therapies.

17. IMAGE STUDIES

Renal ultrasonography is a useful noninvasive test to rule out structural causes of

AKI, such as obstructive uropathy and intrinsic parenchymal renal disease, which

preclude the diagnosis of hepatorenal syndrome [76]. Assessment of renal artery

resistive indices by Doppler ultrasound, contrast-enhanced ultrasound, and

magnetic resonance elastography has been shown in very small studies to be

associated with the development of hepatorenal syndrome. Whether these

methods help in the early diagnosis of hepatorenal syndrome, distinguish

hepatorenal syndrome from other AKI phenotypes, or predict vasoconstrictor

response, need to be further investigated in larger studies.

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18. CONCLUSIONS AND PERSPECTIVES

In recent years, significant advances have been made in the diagnosis and

treatment of hepatorenal syndrome. Even with vasoconstrictors and albumin,

three-month mortality is particularly high without liver transplantation. In addition

to splanchnic and systemic circulatory changes, inflammation may also play

significant role in the development of hepatorenal syndrome. Therapeutic

interventions designed to control inflammation may help prevent or reverse

hepatorenal syndrome. A new biomarker combined with imaging studies may

improve the diagnostic performance of AKI in cirrhotic patients. Irreversible renal

changes are probably underestimated; In the future, new biomarkers and

imaging studies may provide additional information on the healing potential of the

kidney after liver transplantation and may influence the decision for simultaneous

liver and kidney transplantation.

COMPETING INTERESTS

Authors have declared that no competing interests exist.

REFERENCES

1. Raseen Tariq, Yousaf Hadi, Khusdeep Chahal, Sivani Reddy, Habeeb

Salameh, Ashwani K Singal. Incidence, mortality and predictors of acute

kidney injury in patients with cirrhosis: A systematic review and meta-

analysis. J Clin Transl Hepatol. 2020;8(2):135-142.

2. Ashwani K Singal, Yong-Fang Kuo, K Rajender Reddy, Ramon Bataller,

Paul Kwo. Healthcare burden and outcomes of hepatorenal syndrome

among cirrhosis‐related hospitalisations in the US. Aliment Pharmacol

Ther. 2022;56(10):1486-1496.

3. Ahmed Adel Amin, Eman Ibrahim Alabsawy, Rajiv Jalan, Andrew

Davenport. Epidemiology, pathophysiology, and management of

hepatorenal syndrome. Semin Nephrol. 2019;39(1):17-30.

4. Wong Florence. Acute kidney injury in liver cirrhosis: new definition and

application. Clin Mol Hepatol. 2016;22(4):415-422.

5. Mitra K Nadim, Lui G Forni, Ravindra L Mehta, Michael J Connor Jr,

Kathleen D Liu, Marlies Ostermann, et al. COVID-19-associated

acute kidney injury: consensus report of the 25th Acute Disease

Quality Initiative (ADQI) Workgroup. Nat Rev Nephrol. 2020;16(12):747-

764.

6. Paolo Angeli, Pere Gines, Florence Wong, Mauro Bernardi, Thomas D

Boyer, Alexander Gerbes, et al. Diagnosis and management of acute

kidney injury in patients with cirrhosis: revised consensus

recommendations of the International Club of Ascites. Gut.

2015;64(4):531-7.

7. J P Mulkay, H Louis, V Donckier, N Bourgeois, M Adler, J Deviere, O Le

Moine. Long-term terlipressin administration improves renal function in

cirrhotic patients with type 1 hepatorenal syndrome: a pilot study. Acta

Gastroenterol Belg. 2001;64(1):15-9.

Advances in Renal Diseases and Dialysis

Hepatorenal Syndrome

8. Palleti, Sujith Kumar, Sreekanth Avula, and Sandesh Dewan. Kidney: A

Review on End Stage Renal Disease, Dialysis and Transplant. Int Clinc

Med Case Rep Jour. 2023;2(10):1-8.

9. Avula Sreekant, et al. Diabetic Kidney Disease. Int Clinc Med Case Rep

Jour. 2023;2(11):1-4.

10. Yasuko Iwakiri, Roberto J Groszmann. Groszmann. Vascular endothelial

dysfunction in cirrhosis. J Hepatol. 2007;46(5):927-34.

11. J Clària, W Jiménez, J Ros, M Asbert, A Castro, V Arroyo, F Rivera, J

Rodés. Pathogenesis of arterial hypotension in cirrhotic rats with ascites:

role of endogenous nitric oxide. Hepatology. 1992;15(2):343-9.

12. Abshiro H Mayow, Fatima Ahmad, Muhammad Sohaib Afzal, Muhammad

Usama Khokhar, Daneyal Rafique, Sai Krishna Vallamchetla, et al. A

Systematic Review and Meta-Analysis of Independent Predictors for

Acute Respiratory Distress Syndrome in Patients Presenting with Sepsis.

Cureus. 2023;15(4):e37055.

13. Møller, Søren, Jens H. Henriksen. Cirrhotic cardiomyopathy. Journal of

Hepatology. 2021;53(1):179-190.

14. Andrés Cárdenas, Vicente Arroyo. Study on Recognition of Heart

Arrhythmias by Deep Learning Approach of the ECG Signals using Edge

Devices.

15. Cárdenas, Andrés, and Vicente Arroyo. Mechanisms of water and sodium

retention in cirrhosis and the pathogenesis of ascites. Best Pract Res Clin

Endocrinol Metab. 2003;17(4):607-22.

16. Vicente Arroyo, Paolo Angeli, Richard Moreau, Rajiv Jalan, Joan Clària,

Jonel Trebicka, et al. The systemic inflammation hypothesis: towards a

new paradigm of acute decompensation and multiorgan failure in

cirrhosis. J Hepatol. 2021;74(3):670-685.

17. Ramalingam, Sathishkumar, et al. Acute pancreatitis and hepatitis: A rare

presentation of Epstein–Barr virus.

18. Reiner Wiest, Guadalupe Garcia-Tsao. Bacterial translocation (BT) in

cirrhosis. Hepatology. 2005;41(3):422-33.

19. Vaillant, Angel A. Justiz, and Roopa Naik. HIV-1 associated opportunistic

infections. StatPearls [Internet]. StatPearls Publishing, 2021.

20. Reiner Wiest, Melissa Lawson, Markus Geuking. Pathological bacterial

translocation in liver cirrhosis. J Hepatol. 2014;60(1):197-209.

21. Sujith K Palleti, Santhoshi R Bavi, Margaret Fitzpatrick, Anuradha

Wadhwa. First case report of Sphingobium lactosutens as a human

pathogen causing peritoneal dialysis-related peritonitis. Cureus.

2002;14(7).

22. Puneeta Tandon, Guadalupe Garcia-Tsao. Bacterial infections, sepsis,

and multiorgan failure in cirrhosis." Seminars in liver disease. Semin Liver

Dis. 2008;28(1):26-42.

23. Fareeha Naseer Syed, Nadia Kashif, Mubashir Razzaq Khan, Fayaz

Ahmed Memon, et al. Hepatitis C Virus Infection in Patients with Beta

Thalassemia after Multiple Transfusions at a Tertiary Care Hospital.

Pakistan Journal of Medical & Health Sciences. 2023;17(01):363-363.

24. Pere Ginès, Mónica Guevara, Vicente Arroyo, Juan Rodés. Hepatorenal

syndrome. Lancet. 2003;362(9398):1819-1827.

Advances in Renal Diseases and Dialysis

Hepatorenal Syndrome

25. Sai Kiran Kondabolu, Yasitha Kakarlapudi, Haider Malik, Hamza Malik,

Saima Khan, Praveen Kumar Komminni, et al. Beneficial Impacts of

Fenoldopam on Patients with or at Risk for Acute Renal Failure and

Undergoing Surgery: A Meta-Analysis of Randomized Clinical Trials.

Cureus . 2023;15(2):e34584.

26. Palleti Sujith K, et al. Study about Sphingobium Lactosutens: A Human

Pathogen Causing Peritoneal Dialysis Related Peritonitis. Perspective of

Recent Advances in Medical Research. BP International 9. 2023:31-35.

27. Vicente Arroyo, Carlos Terra, Pere Ginès. Advances in the pathogenesis

and treatment of type-1 and type-2 hepatorenal syndrome. J Hepatol.

2007;46(5):935-46.

28. Palleti, Sujith Kumar, Sreekant Avula, and Roopa Naik. Chronic Kidney

Disease. Int Clinc Med Case Rep Jour. 2023;2(11):1-15.

29. Florence Wong, Wesley Leung, Mohammed Al Beshir, Max Marquez,

Eberhard L Renner, et al. Outcomes of patients with cirrhosis and

hepatorenal syndrome type 1 treated with liver transplantation. Liver

Transpl. 2015;21(3):300-7.

30. Sreekant Avula. Continuous Renal Replacement Therapy. Int Clinc Med

Case Rep Jour. 2023;2(12):1-13.

31. Pere Ginès, Mónica Guevara. Hyponatremia in cirrhosis: pathogenesis,

clinical significance, and management. Hepatology. 2008;48(3):1002-

10.

32. Hanif Muhammad O, Atul Bali, Kamleshun Ramphul. Acute renal tubular

necrosis. StatPearls. StatPearls Publishing, 2022.

33. Martin-Walter Welker, Stefan Luhne, Christian M Lange, Johannes

Vermehren, Harald Farnik, Eva Herrmann, et al. Lactic acidosis in patients

with hepatitis C virus cirrhosis and combined ribavirin/sofosbuvir

treatment. J Hepatol. 2016;64(4):790-9.

34. Bali Atul, Roopa Naik. Pseudo Metabolic Acidosis in the Setting of

Hypertriglyceridemia: A Case Report. 2020.

35. S Møller, J H Henriksen. Cardiovascular complications of cirrhosis. Gut.

2008;57(2):268-78.

36. Sameer, Muhammad Ali, et al. Comparison of Coronary Artery Bypass

Grafting Combined With Mitral Valve Repair Versus Coronary Artery

Bypass Grafting Alone in Patients With Moderate Ischemic Mitral

Regurgitation: A Meta-Analysis. Cureus. 2023;15(4).

37. Barkhane, Zineb, et al. Independent Predictors of Mortality in Systemic

Sclerosis-Associated Pulmonary Arterial Hypertension: A Systematic

Review and Meta-Analysis. Cureus. 2023;15(5).

38. Douglas A Simonetto, Laura Piccolo Serafim, Alice Gallo de Moraes,

Ognjen Gajic, Patrick S Kamath. Management of sepsis in patients with

cirrhosis: current evidence and practical approach. Hepatology.

2019;70(1):418-428.

39. Abdulmaleek Idanesimhe Sado, Muhammad S Afzal, Lavanya

Kannekanti, Hrushikesh Reddy Pamreddy, Jorge Pimentel Campillo,

Vaishnavi Kandukuri, et al. A Meta-Analysis on Predictors of Mortality

Among Patients Hospitalized for Acute Exacerbation of Asthma. Cureus.

2023;15(2).

Advances in Renal Diseases and Dialysis

Hepatorenal Syndrome

40. Sathishkumar Ramalingam, Kulothungan Gunasekaran, Harkesh Arora,

Maheswari Muruganandam, Priyesh Padmanabhan. Clostridium difficile

and noncirrhotic hyperammonnemia in a patient with COVID- 19 infection.

Cureus. 2021;13(4):e14533.

41. Scott W Biggins, Paulo Angeli, Guadalupe Garcia-Tsao, Pere Ginès,

Simon C Ling, Mitra K Nadim, et al. Diagnosis, evaluation, and

management of ascites, spontaneous bacterial peritonitis and hepatorenal

syndrome: 2021 practice guidance by the American Association for the

Study of Liver Diseases. Hepatology. 2021;74(2):1014-1048.

42. Rakesh Pilla, Sujith Kumar Palleti, Renuka Rayana, Satish Reddy Skss,

Aminah Abdul Razzack, Sruti Kalla. Glycated haemoglobin (HbA1c)

variations in nondiabetics with nutritional anemia. Cureus. 2020;12(11).

43. Atul Bali, Roopa Naik. The Impact of a Vegan Diet on Many Aspects of

Health: The Overlooked Side of Veganism. Cureus. 2023;15(2).

44. Bataller, Ramón, et al. Hepatorenal syndrome. Seminars in liver disease.

1997;17(03).

45. Jithin Karedath, Fnu Avanteeka, Muhammad Nouman Aslam, Ahmad

Nadeem, Rao Ahmed Yousaf, Sandesh Shah, et al. Comparison of

Effectiveness and Safety of Low-Dose Versus Standard-Dose Intravenous

Recombinant Tissue Plasminogen Activator in Patients with Acute

Ischemic Stroke: A Meta- Analysis. Cureus. 2023;15(2).

46. Diaconescu, Diana, et al. Hepatorenal syndrome: a review. Arch Balk Med

Union. 2018;53(2):239-245.

47. Thomas D Boyer, Arun J Sanyal, Guadalupe Garcia-Tsao, Frederick

Regenstein, Lorenzo Rossaro, Beate Appenrodt, et al. Impact of liver

transplantation on the survival of patients treated for hepatorenal

syndrome type 1. Liver Transpl. 2011;17(11):1328-32.

48. Stefan Herget-Rosenthal, Arend Bökenkamp, Walter Hofmann. How to

estimate GFR-serum creatinine, serum cystatin C or equations?. Clin

Biochem. 2007;40(3-4):153-61.

49. Kar, Saikat, et al. A two-center, retrospective cohort trial of a tumor

necrosis factor inhibitor coupled with intravenous immunoglobulin and

heparin for the treatment of recurrent spontaneous abortion.

50. Djillali Annane, Eric Bellissant, Jean-Marc Cavaillon. Septic shock. Lancet.

2005;365(9453):63-78.

51. Palleti Sujith K., et al. The First Case of Ceftazidime-Induced

Antibiomania: A Case Report and Literature Review. Cureus. 2022;14(12).

52. Naughton, Cynthia A. Drug-induced nephrotoxicity. Am Fam Physician.

2008;78(6):743-750.

53. Palleti Sujith K, Anuradha Wadhwa, Abdul H. Rasheed. Ceftazidime-

induced Antibiomania: A Rare Case Study and Review of Literature.

Research Highlights in Disease and Health Research. 2023;6:56-61.

54. V M Campese, N Mitra, D Sandee. Hypertension in renal parenchymal

disease: why is it so resistant to treatment?. Kidney Int. 2006;69(6):967-

73.

55. Palleti Sujith K, Maria M. Picken, Anuradha Wadhwa. Sjögren's Syndrome

Overlap with Lupus Nephritis: A Case Report and Literature Review of a

Rare Entity. Cureus. 2023;15(5).

Advances in Renal Diseases and Dialysis

Hepatorenal Syndrome

56. Sujith K Palleti, Hanna Larson, Sreekant Avula, Maria M Picken, Anuradha

Wadhwa. Subarachnoid hemorrhage in autoimmune vasculitis: a rare

presentation of systemic lupus erythematosus-antineutrophil cytoplasmic

autoantibody-associated vasculitis overlap syndrome. Cureus. 2023;15(5).

57. El-Sayed Ibrahim, Ayman Alsebaey, Hassan Zaghla, Sabry Moawad

Abdelmageed, Khalid Gameel, Eman Abdelsameea. Long-term rifaximin

therapy as a primary prevention of hepatorenal syndrome. Eur J

Gastroenterol Hepatol. 2017;29(11):1247-1250.

58. Atul Bali, John Kevin Hix, Peter Kouides. Safe and effective use of chronic

transdermal estradiol for life- threatening uremic bleeding in a patient with

coronary artery disease. Nephron Extra. 2014;4(2):134-7.

59. Mauro Bernardi, Paolo Angeli, Joan Claria, Richard Moreau, Pere Gines,

Rajiv Jalan, et al. Albumin in decompensated cirrhosis: new concepts and

perspectives. Gut. 2020;69(6):1127-1138.

60. Mattias Mandorfer, Thomas Reiberger. Beta blockers and cirrhosis, 2016.

Dig Liver Dis. 2017;49(1):3-10.

61. Wong, Florence, et al. Terlipressin plus albumin for the treatment of type 1

hepatorenal syndrome. New England Journal of Medicine.

2021;384(9):818-828.

62. Sashidhar V Sagi, Sahil Mittal, Krishna S Kasturi, Gagan K Sood.

Terlipressin therapy for reversal of type 1 hepatorenal syndrome: a

meta‐analysis of randomized controlled trials. J Gastroenterol Hepatol.

2010;25(5):880-5.

63. Zaid Munir, Muhammad Akash, Fnu Jaiprada, Bilal Abu Tarboush, Osama

Ijaz, Anan Bseiso, et al. Evaluation of the Effects of Extracorporeal

Shockwave Therapy in Patients with Peripheral Arterial Disease: A Meta-

Analysis of Randomized Control Trials. Cureus. 2023;15(2):e34729.

64. Antonio Paulo Nassar Junior, Alberto Queiroz Farias, Luiz Augusto

Carneiro D' Albuquerque, Flair José Carrilho, Luiz Marcelo Sá

Malbouisson. Terlipressin versus norepinephrine in the treatment of

hepatorenal syndrome: a systematic review and meta-analysis. PLoS One.

2014;9(9):e107466.

65. Marta Cavallin, Patrick S Kamath, Manuela Merli, Silvano Fasolato,

Pierluigi Toniutto, Francesco Salerno, et al. Terlipressin plus albumin

versus midodrine and octreotide plus albumin in the treatment of

hepatorenal syndrome: a randomized trial. Hepatology. 2015;62(2):567-

74.

66. Tingxue Song, Martin Rössle, Fuliang He, Fuquan Liu, Xiaozhong Guo,

Xingshun Qi. Transjugular intrahepatic portosystemic shunt for

hepatorenal syndrome: A systematic review and meta-analysis. Dig Liver

Dis. 2018;50(4):323-330.

67. Achuthan Sourianarayanane, Rupesh Raina, Gaurav Garg, Arthur J

McCullough, Robert S O'Shea. Management and outcome in hepatorenal

syndrome: need for renal replacement therapy in non- transplanted

patients. Int Urol Nephrol. 2014;46(4):793-800.

68. Evangelos Tsipotis, Asim Shuja, Bertrand L Jaber. Jaber. Albumin dialysis

for liver failure: a systematic review. Adv Chronic Kidney Dis.

2015;22(5):382-90.

Advances in Renal Diseases and Dialysis

Hepatorenal Syndrome

69. Ashwani K Singal, Song Ong, Sanjaya K Satapathy, Patrick S Kamath,

Russel H Wiesner. Simultaneous liver kidney transplantation. Transpl Int.

2019;32(4):343-352.

70. M K Nadim, R S Sung, C L Davis, K A Andreoni, S W Biggins, G M

Danovitch, S Feng, et al. Simultaneous liver-kidney transplantation

summit: current state and future directions. Am J Transplant.

2012;12(11):2901-8.

71. Karima Benaicha, Raja Ram Khenhrani, Maha Veer, Sapna Devi, Usman

Shahbaz, Qais M Salah, et al. Efficacy of Molnupiravir for the Treatment of

Mild or Moderate COVID-19 in Adults: A Meta-Analysis. Cureus.

2023;15(5).

72. Erik L Lum, Andrés Cárdenas, Paul Martin, Suphamai Bunnapradist.

Current status of simultaneous liver‐ kidney transplantation in the United

States. Liver Transpl. 2019;25(5):797-806.

73. Kapil Gupta, Abhishek Bhurwal, Cindy Law, Scott Ventre, Carlos D

Minacapelli, Savan Kabaria, et al. Acute kidney injury and hepatorenal

syndrome in cirrhosis. World J Gastroenterol 2021;27(26):3984.

74. Raza A Khan, Nidhi Patel, Atunde Folajimi, Bansari Raveena Bai, Vrushak

Patel, Praveen Kumar Komminni, et al. Comparison of the Efficacy and

Safety of Metformin-Based Combination Therapy Versus Metformin Alone

in Children and Adolescents with Type 2 Diabetes Mellitus: A Meta-

Analysis. Cureus. 2023;15(2):e35014.

75. Rohan Vijay Yewale, Balakrishnan Siddartha Ramakrishna. Novel

biomarkers of acute kidney injury in chronic liver disease: Where do we

stand after a decade of research?. Hepatol Res. 2023;53(1):3-17.

76. Brian Erly, William D Carey, Baljendra Kapoor, J Mark McKinney, Mathew

Tam, Weiping Wang. Hepatorenal syndrome: a review of pathophysiology

and current treatment options. Semin Intervent Radiol. 2015;32(4):445-54.

___________________________________________________________________________________

DISCLAIMER

This chapter is an extended version of the article published by the same author(s) in the following journal.

Annal of Clin Med & Med Res, 1(1): 1-15, 2023. DOI: https://doi.org/10.5281/zenodo.8118544

________________________________________________________________________

a Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre,

Pennsylvania, USA.

b Department of Gastroenterology, Brooklyn Hospital Center, Brooklyn, New York, USA.

c Department of Internal Medicine, University Hospital and Clinics, Lafayette, Louisiana, USA.

d Department of Internal Medicine/Nephrology, Geisinger Wyoming Valley Medical Center, Wilkes-Barre,

Pennsylvania, USA.

*Corresponding author;

Chapter 3

Print ISBN: 978-81-19491-84-1, eBook ISBN: 978-81-19491-85-8

Diabetic Kidney Disease

Roopa Naik a*, Rajeshwari Ramachandran b,

Bushra Firdous Shaik c and Atul Bali d

DOI: 10.9734/bpi/mono/978-81-19491-84-1/CH3

ABSTRACT

The kidney is probably the most important target of microvascular damage in

diabetes. A significant proportion of people with diabetes develop kidney disease

because of their disease and/or other comorbidities, including hypertension and

age-related kidney loss. The presence and severity of chronic kidney disease

(CKD) identifies individuals at increased risk for adverse health outcomes and

premature mortality. Therefore, the prevention and treatment of CKD in diabetics

is now a central goal of their general care. Intensive care of diabetic patients

includes blood sugar and blood pressure control and blockade of the renin-

angiotensin-aldosterone system; these approaches reduce the incidence of

diabetic kidney disease and slow its progression. In fact, the significant reduction

in the incidence of diabetic kidney disease (DKD) over the past 30 years and the

improvement in patient prognosis is largely due to improvements in diabetes

management. However, there is a need for innovative treatment strategies to

prevent and control the progression of DKD. In this review, we summarize what

is currently known about the pathogenesis of CKD in patients with diabetes and

the key pathways and targets involved in its progression. In addition, we discuss

the current evidence that supports the prevention and treatment of DKD and

some of the controversies. Finally, we will explore ways to develop new

interventions by making urgently needed investments in targeted and focused

research.

Keywords: Diabetes; hypertension; chronic kidney disease; albuminuria; SGLT

inhibitors.

1. INTRODUCTION

Diabetic kidney disease (DKD) remains by far the most common cause of end-

stage renal disease (ESRD) in the United States and most parts of the world [1,2].

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Diabetic Kidney Disease

The involvement of the kidneys directly and indirectly increases the effects on

other organs and increases the morbidity and mortality of diabetics. With the

increasing industrialization, increased inactivity and changes in diet and lifestyle,

as well as the increasing prevalence of obesity, insulin resistance and type 2

diabetes increases. Since many of the classic diabetic symptoms of type 2

diabetes are absent, unlike type 1 diabetes, the importance of screening

methods to identify these patients for kidney involvement is very important [3,4].

Our understanding of the pathogenesis of DKD has also advanced significantly.

In addition, several new drugs have undergone clinical trials with some success.

2. EPIDEMIOLOGY

Diabetes affects 30.3 million people of all ages, which is 9.4 percent of the US

population and approximately 149 million people and 10.9 percent of the Chinese

population and 415 million worldwide [5]. DKD is the most common cause of end

stage renal disease (ESRD) worldwide and is associated with increased

morbidity and mortality especially in diabetic patients. Both types of diabetes can

lead to CKD and eventually ESRD. However, because the prevalence of type 2

diabetes is much higher than type 1 diabetes, people with ESRD often have type

2 diabetes [6,7]. The overall incidence is approximately 4-17% 20 years after

diagnosis and approximately 16% after 30 years. Although the incidence of

chronic kidney disease (CKD) in diabetics has decreased in the United States in

recent years, the prevalence remains high. In 2018, United States Renal Data

System (USRDS) annual data reported that diabetes accounted for 36 percent of

chronic diseases in the National Health and Nutrition Examination Survey

(NHANES) population from 2013 to 2016, up from 44 percent from 2001 to 2004.

However, the total number of DKD patients continued to increase due to the

increase in the number of diabetic patients. The number of adults with diabetes

over 18 years of age who started treatment for ESRD also increased

significantly, from more than 40,000 in 2000 to more than 50,000 in 2014 [8,9]. If

type 1 diabetics have diabetic nephropathy, they are likely to reach end-stage

diabetes. Although the risk of type 2 diabetes after the onset of clinical

nephropathy is approximately 20%. Perhaps one of the reasons is that many

people with type 2 diabetes die of cardiovascular events before they reach ESRD

[10,11]. About 30% of patients with type 2 diabetes who have kidney disease

actually have some other kidney disease, but not diabetic nephropathy, as

evidenced by the absence of retinopathy and albuminuria.

3. DEFINITION OF DIABETIC KIDNEY DISEASE

Diabetic kidney disease (also called "chronic kidney disease" due to diabetes

(CKD) or diabetic nephropathy) is defined as persistently elevated albuminuria

>300 mg/24 h (or >200 µg) in both type 1 and type 2 diabetes or albumin-to-

creatinine ratio (ACR) > 300 mg/g, confirmed in at least two of three samples,

without evidence of concomitant diabetic retinopathy or other forms of kidney

disease [12]. The normal range for albuminuria is 30 mg/g, but values in either

range may be associated with an increased risk of kidney and cardiovascular

disease. Moderately increased urinary albumin excretion (microalbuminuria) (30-

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Diabetic Kidney Disease

300 mg/g) is widely considered to be a precursor to diabetic nephropathy,

indicating both early risk and a target for intervention [13].

4. MECHANISMS/PATHOPHYSIOLOGY

DKD has traditionally been considered a microvascular disease grouped together

with retinopathy and neuropathy, distinct from macrovascular disease that

contributes to coronary artery disease, peripheral vascular disease, and

cerebrovascular disease [14,15]. However, each disease can be considered a

tissue-specific manifestation of the same pathogenic process, and DKD is a renal

manifestation of the same glucose-driven process that occurs elsewhere in the

body at sensitive sites. Although all cells in diabetes are exposed to chronically

high plasma glucose levels, only some show progressive dysfunction, the best

example being the endothelial cells that line blood vessels [16]. In particular,

the inability of endothelial cells to regulate their glucose transport in response

to high glucose levels leads to an overwhelming intracellular glucose flux, which

triggers the generation of pathogenic mediators that contribute to diabetic

complications, including DKD.

5. REACTIVE OXYGEN SPECIES

Excessive glucose flux leads to the generation of toxic intermediates, the most

important of which are probably reactive oxygen species (ROS) [17,18]. Excess

glucose production can generate reactive oxygen species in various ways.

Increased mitochondrial substrate oxidation and the resulting increased

mitochondrial membrane potential lead to overproduction of superoxide. The

centrality of ROS in triggering these processes is illustrated by the fact that they

can be prevented if hyperglycemia-mediated ROS production is limited.

6. PATHWAYS OF NUTRIENT RECOGNITION

Each cell has pathways that recognize nutrient abundance and respond

specifically to it to ensure efficient use of the substrate [19]. The best known of

these nutrient sensors are rapamycin (mTOR), 5'AMP-activated protein kinase

(AMPK) and sirtuins. From a kidney perspective, diabetes directly causes

changes in the expression and activity of AMPK, sirtuins, and mTOR37, as well

as downstream signaling in cellular homeostasis, including reductions in

autophagy, regeneration, mitochondrial biogenesis, and other cytoprotective

responses that promote DKD.

7. MULTIFACTORIAL PATHOGENESIS OF DKD

Only a third of people with type 1 diabetes develop overt nephropathy, while

almost all people with type 1 diabetes eventually develop some degree of

retinopathy. This suggests that risk factors other than hyperglycemia must be

involved in DKD [20]. Pathogenic pathways induced by high glucose levels and

maintained in the kidney can be enhanced by a number of different factors.

These include several metabolic factors, including fatty acid excess, carbonyl

and oxidative stress, and hemodynamic factors, including shear stress from

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Diabetic Kidney Disease

transmitted systemic hypertension, autoregulatory disturbances, hyper perfusion

and hypoperfusion, and activation of the renin-angiotensin-aldosterone system

(RAAS). These factors themselves do not cause DKD, but rather feed and

reinforce the common pathogenic mechanisms in diabetes, which are increased

levels of growth factors, vasoactive hormones, cytokines and chemokines in the

kidney.

8. IMPORTANT STRUCTURAL CHANGES IN THE GLOMERULI

Despite the importance of the vascular endothelium in microvascular

complications, many researchers suggest that early changes in the glomerulus

are critical for the later development of glomerulosclerosis and nephron loss. The

most important of these changes may be glomerular podocyte dysfunction [21-

23]. They are highly specialized terminally differentiated cells that line the urinary

side of the glomerular basement membrane (GBM). Along with glomerular

endothelial cells, podocytes are responsible for maintaining the shape and

integrity of the GBM, its charge barrier, and the glomerular capillary circuit; all

functions that are impaired in diabetic glomeruli. The diabetic environment

induces "pathoadaptive" changes in podocytes, including cytoskeletal

rearrangements, differentiation, apoptosis and autophagy, manifested by

morphological expansion, retraction and flattening (known as loss), decreased

motility, increased formation of intercellular tight junctions, glomerular

hypertrophy, detachment and disruption.

9. GLOMERULAR BASEMENT MEMBRANE THICKNENING

One of the earliest and most characteristic glomerular changes in diabetes is a

homogeneous thickening of the GBM [24,25]. GBM thickening occurs in most

patients with diabetes usually within a few years of diagnosis. It is unclear

whether GBM thickening is a marker of podocyte or endothelial dysfunction or a

mediator of progressive DKD. Certainly, thickening-related changes in GBM

composition, charge, or architecture may contribute to the development of

albuminuria. GBM stiffening may also reduce pericapillary wall stretch and

compromise the sub podocyte state, facilitating glomerular injury through

hemodynamic mechanisms.

10. RENAL TUBULAR DYSFUNCTION AND FIBROGENESIS

Diabetes also negatively affects the kidney tubules [26]. At the onset of diabetes,

an increased glucose load delivered to the proximal tubule results in cortical

tubular maladaptive hypertrophy and hyperplasia with increased glucose

transport, which may facilitate glucose reabsorption and reduce glucose waste.

However, the consequence of this is that sodium transport in the macula densa is

reduced and tubulo-glomerular feedback is activated, leading to increased

glomerular pressure and hyperfiltration [27]. Chronic hyperglycemia and other

metabolic abnormalities associated with diabetes can cause progressive atrophy

of tubular epithelial cells. Such tubular dysfunction results in deficient uptake,

transcytosis, and/or lysosomal processing of filtered protein, which also

contributes to albuminuria.

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Diabetic Kidney Disease

11. COMPLEX HISTOPATHOLOGY OF DKD

The same clinical presentation of DKD can be associated with a heterogeneous

set of pathological features, including nodular or diffuse glomerulosclerosis,

tubulointerstitial fibrosis, tubular atrophy and renal arteriolar hyalinosis, alone or

in combination [28-30]. A histopathologic staging system has been proposed for

glomerular lesions. However, its prognostic utility is yet to be determined.

Routine renal biopsy is not clinically appropriate in routine practice and DKD

remains the clinical diagnosis for most patients with diabetes.

12. NATURAL COURSE

The classification of clinical stages of diabetic nephropathy is as follows [31]:

Stage 1: Hyperfiltration: From the onset of diabetes, glomerular filtration and

renal blood flow increase, and leads to renal enlargement (renomegaly). Urinary

albumin excretion rate (UAE) is usually less than 30 mg in 24 hours and blood

pressure is also normal. The first pathologic finding is GBM thickening. If the

initial glomerular filtration rate (GFR) is more than 150 ml per minute, it increases

the possibility of diabetic nephropathy.

Stage II: Microalbuminuria: As kidney disease progresses, UAE also develops.

This is also called latent or subclinical nephropathy. A standard strip test is often

negative at this stage. Changes in the degree of albuminuria over time are

associated with different risks of renal decline, so that patients with

microalbuminuria with increased, persistent, or decreased albumin burden are at

very high, moderate, and low risk of GFR decline. In type 1 diabetes, when

albuminuria increases, the incidence of other microvascular complications, such

as retinopathy and neuropathy, also increases. Hyperlipidemia, age, duration of

diabetes are also risk factors for microalbuminuria. Diagnosis at this stage is a

very good chance to avoid progression to clinical nephropathy or even back to

normoalbuminuric. However, without treatment, the risk of developing clinical

nephropathy is high in type 1 diabetes after 10-15 years (more than 75%) and in

type 2 diabetes after 15-20 years (20-40%).

Stage III: Macroalbuminuria: This stage is also called clinical nephropathy,

which appears about 10-20 years after the onset of diabetes (about 5-10 years

after the onset of microalbuminuria). Coronary artery disease and

cerebrovascular events also clearly increase in this stage compared to the

previous stage. About 75 percent of patients at this stage have high blood

pressure. Controlling blood pressure in type 2 diabetics with a history of

hypertension is more difficult. At this stage, a standard dipstick is positive for

proteinuria, and urinary albumin excretion is greater than 300 mg in 24 hours.

After that, the GFR decreases, about 10-12 ml per year. When clinical

nephropathy appears and in the absence of therapeutic measures, kidney

function gradually deteriorates and proteinuria increases, which can reach the

nephrotic range. Diabetic retinopathy is very useful in confirming the diagnosis of

diabetic nephropathy. Hypertension and proteinuria independently lead to

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decreased GFR and progression to ESRD. 20% of patients with type 2 diabetes

before the development of clinical nephropathy and 40% of patients with clinical

nephropathy have renal vascular disease. Tubulointerstitial fibrosis also begins at

this stage, and if its extent and severity are greater, kidney damage and

prognosis are worse.

Stage IV: End stage kidney disease Almost 20-30 years after the onset of

diabetes, about 10 years after the onset of clinical nephropathy, the patient

reaches this stage [32]. The risk with type 1 diabetes is higher than type 2

diabetes. However, the prevalence of type 2 diabetes is 9 times higher than type

1 diabetes, so most diabetics with ESRD have type 2 diabetes. Under these

conditions, the death rate of diabetic patients is higher than that of non-diabetic

patients [33-35]. In addition, cardiovascular diseases are higher in these patients.

At this stage, the incidence of diabetic foot ulcers is higher, sometimes up to

25% [36,37]. In the UKPDS report, the annual chance of diagnosis from diabetes

to microalbuminuria, from microalbuminuria to overt nephropathy, and from overt

nephropathy to elevated serum creatinine or conversion to renal replacement

therapy are 2%, 2.8%, and 2.3%, respectively.

13. RISK FACTORS FOR DKD

Several different factors contribute to the development of CKD in diabetics. Some

of these factors, including hyperglycemia, hypertension, weight gain, and

dyslipidemia, are potentially modifiable with optimized diabetes treatment [38]. In

addition, extensive clinical data show that intensive diabetes management

significantly reduces the incidence of albuminuria, renal failure as well as ESRD.

Indeed, the significant reduction in the incidence of CKD over the past 30 years

is largely due to improvements in diabetes management.

14. POOR GLYCEMIC CONTROL

The most important risk factor for CKD is hyperglycemia. Although there are

structural similarities to other kidney diseases, the DKD phenotype is essentially

only observed in the presence of elevated glucose levels [39, 40]. A definitive

prospective clinical study by Jean Pirart and colleagues in Belgium showed

unequivocally that the degree and duration of hyperglycemia were associated

with microvascular complications, including CKD. Subsequent randomized

controlled trials have confirmed this causal relationship in both type 1 and type 2

diabetes. However, although normal glucose levels, such as glycated

hemoglobin (HbA1c), are associated with microalbuminuria, it is also clear that

many patients with poor blood glucose levels do not develop kidney

complications, while others do despite intensive interventions and dedicated

control measures. Previous episodes of poor glucose balance, even before

diagnosis, can also have a long-term effect in the kidney, and therefore DKD risk

may not be represented by current or recent HbA1c levels. This phenomenon

was known as "metabolic memory", "metabolic karma" or the "inheritance effect"

[41]. The physiological mechanism or mechanisms responsible for metabolic

karma remain poorly defined, but may involve epigenetic programming,

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remodeling, and permanent post-translational modifications such as enhanced

glucose end products. Understanding the molecular basis of the metabolic

inheritance of diabetes will certainly add new targets for intervention to reduce

the burden of CKD in diabetics.

15. HIGH BLOOD PRESSURE

Increased blood pressure is a major risk factor for CKD in both type 1 and type 2

diabetes. In people with type 1 diabetes, blood pressure levels are usually normal

at diagnosis, but increase near microalbuminuria [42]. In type 2 diabetes, other

factors influence the appearance and severity of hypertension, which can

precede or follow chronic kidney disease for several years. The importance of

hypertension in the pathogenesis of renal injury can be partially explained by the

loss of renal autoregulation in diabetes, in which systemic pressure is transmitted

directly to the vulnerable glomerular capillaries. Thus, there is no specific

threshold above which the specific risk of CKD can be expressed or below which

the therapeutic effect of blood pressure control on the development of

albuminuria can be ignored in diabetic patients.

16. LIPID ABNORMALITIES

Dyslipidemia is another important risk factor for the development of chronic

diseases of diabetes [43]. Specifically, high levels of triglycerides, low-density

lipoprotein cholesterol, apolipoprotein-B-100, or low high- density lipoprotein

(HDL) cholesterol are independently associated with the development of CKD in

both type 1 and type 2 diabetes. However, conventional lipid and lipoprotein

measurements do not fully account for the complex lipid and lipoprotein changes

associated with diabetes and/or CKD. For example, not only can HDL lose its

vascular protective, antioxidant, and anti-inflammatory properties in CKD, but

dysfunctional HDL can also be directly pathogenic. Lipidomics has been used to

create a "lipid fingerprint" linked to diabetes complications. However, it remains

unclear which lipids or lipoproteins are most important in the pathogenesis of

diabetic CKD.

17. INSULIN RESISTANCE

Insulin resistance is also independently associated with CKD, in addition to

indirect associations with glucose, blood pressure, body weight, and lipid

regulation [44]. Insulin-sensitizing measures (eg, thiazolidinedione therapy,

exercise, and weight loss) reduce albuminuria in addition to metabolic control.

Decreased insulin sensitivity also causes changes in glucose metabolism in

kidney cells. At the same time, increased insulin signaling due to compensatory

hyperinsulinemia in the setting of selective insulin resistance can contribute to

vasoreactivity, angiogenesis, fibrogenesis and other pathways involved in

progressive kidney disease and atherogenesis.

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18. OBESITY

CKD occurs more frequently and progresses more rapidly in obese diabetics

than in their normal-weight counterparts [45]. This is one of the main reasons

why the cumulative incidence of CKD is higher in type 2 diabetes than in type 1

diabetes. Obesity adversely affects key risk factors associated with CKD,

including lipid, blood pressure, and glucose balance, and promotes insulin

resistance. Obesity also has direct effects on the kidney, including changes in

intraglomerular hemodynamics, increased sympathetic activity, hypertension,

systemic inflammation, endothelial dysfunction, altered expression of growth

factors, and renal compression associated with visceral obesity. Indeed, even

in the absence of diabetes, obesity can be associated with increased albuminuria

and its severity, and obesity-related glomerulopathy has been widely described.

19. HEPATITIS C VIRUS (HCV) INFECTION AND CKD

HCV infection is more common among CKD patients than in the general

population [46,47]. According to recent research, CKD patients with HCV

infection had a faster loss of renal function and a higher chance of developing

ESRD. The important question of whether treating to achieve a sustained

virologic response, defined as an undetectable viral load 12 weeks after

completion of treatment (SVR12), would slow the rate of decline in GFR was

raised by a study which demonstrated that HCV-infected patients with CKD had

an increased mortality and an accelerated rate of progression to ESRD [48].

Most patients with mixed cryoglobulinemia and many histological types of

glomerular damage, including membranoproliferative and membranous GN, have

been linked to HCV infection as the underlying cause of these conditions [49-55].

20. ESRD IN DIABETES

Globally, 80% of ESRD cases are caused by diabetes, hypertension or a

combination of these [56]. Compared to adults without diabetes, the incidence of

ESRD is up to 10 times higher in diabetics. However, only a limited number of

patients with CKD associated with diabetes ever receive renal replacement

therapy, as 78% of these individuals live in low- and middle-income countries

with limited resources, coverage, and access to dialysis and kidney

transplantation. The proportion of diabetes related ESRD varies greatly in

different parts of the world. In 2014, between 5% and 66% of new cases of

ESRD were mainly due to diabetes [57-59]. The highest proportion was in

Singapore, Malaysia and the Jalisco region of Mexico, and the lowest in Norway,

Romania and Iceland. In most countries at the upper end of this distribution, the

incidence of diabetes related ESRD has increased dramatically over the past

decade. Between 2001 and 2015, the highest growth was in Thailand at 1,448%,

Russia at 981% and the Philippines at 378% [60]. Because these figures are

reported for the entire state- based population, they primarily reflect the

increasing prevalence of diabetes in those populations, partly due to a shift in the

burden of disease from infections to chronic lifestyle diseases and increased life

expectancy. The prevalence of treated ESRD was highest, ranging from 1568 to

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3219 per million inhabitants, in some of the Asian countries such as Japan,

Singapore, and in the United States [60]. Although the incidence of treated ESRD

has been fairly stable or declining in many countries in recent years, the

incidence has steadily increased in all 32 countries that reported data between

2001 and 2014. In the United States, 44% of new cases of ESRD are due to

diabetes (either type 1 or type 2), highest in non-Hispanic blacks and lowest in

non-Hispanic whites [61-63]. Detailed quantitative data on the trend of diabetes-

related ESRD and its association with other complications of diabetes in the

United States are presented in an analysis of several nationally representative

databases (NHIS, National Hospital Discharge Survey, US Renal Data System,

and National Vital Statistics System) in the years 1990-2010. Deaths from heart

attack, stroke, amputation, end-stage disease and hypoglycemia were reduced in

the diabetic population (primarily type 2 diabetes). The greatest reduction is for

cardiovascular events and the least for ESRD. In the 1990s, the incidence of

diabetes related ESRD was low because CVD morbidity and mortality were

important competing events. The decline in these competing causes over the

next decade allowed people with diabetes to live long enough to develop ESRD,

which explains why the decline in ESRD is smaller. However, the study found a

statistically significant decrease in diabetes related ESRD in all age groups after

2000, consistent with significant progress in the adoption of reno-protective

therapies nationwide.

21. SCREENING

Annual screening of all diabetic patients is recommended to detect abnormal

and/or variable levels of albuminuria and renal function (ie, eGFR) so that early

renoprotective therapy can be initiated [64]. Early morning spot urine is sufficient

for screening and monitoring and is convenient for the patient. To account for the

large intraday variability (30-40%), 2 of the 3 spot urine samples must be

collected within 3-6 months to confirm the diagnosis. A 24-hour urine collection

has been considered the gold standard for evaluating albuminuria and can

provide additional information on sodium and protein intake, but a complete

urine collection is often difficult for the patient, so this method is usually limited to

patients with established diabetic kidney disease. It should be noted that urinary

albumin excretion may increase independently of kidney disease due to factors

such as heavy exercise within 24 hours, severe UTI, menstruation, heart failure,

and marked hyperglycemia [65]. Another clinical variable assessed in diabetic

kidney disease screening is eGFR using creatinine-based formulas such as the

Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The

"natural" course of untreated diabetic nephropathy shows a continuous annual

decline in eGFR of 2-20 ml/min/1.73 m2 (average 12 ml/min/1.73 m2), but

effective treatment focuses on glycemic, blood pressure control, renin-

angiotensin system (RAS) inhibition, lowering blood cholesterol and improving

lifestyle factors can limit progression to 2-5 mL/min/1.73 m2 per year, indicating

the importance of screening and interventions.

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22. MANAGEMENT

Treatment of hypertension: Observational studies in the general population

have shown a strong and linear association between blood pressure and

cardiovascular disease risk, with the risk of cardiovascular events doubling for

every 20/10 mmHg increase in systolic/diastolic blood pressure above 115/75

mmHg [66]. In addition to directly affecting CV risk, hypertension contributes to

kidney damage in diabetes and albuminuria; therefore, it is an important target

for management. According to the Kidney Disease Outcomes Initiative clinical

practice guidelines for blood pressure control in CKD, a goal of less than 140/90

mmHg was recommended in those diabetic patients without significant

albuminuria (30 mL/min/1.73 m2).

23. RAAS INHIBITION AND ALBUMINURIA

By opposing the renin-angiotensin-aldosterone system (RAAS); angiotensin-

converting enzyme inhibitors (ACEs) and angiotensin receptor blockers lower

blood pressure and albuminuria [67]. The Irbesartan Diabetic Nephropathy Trial

(IDNT) showed that irbesartan protects against the progression of nephropathy in

patients with type 2 diabetes regardless of the drop in blood pressure [68].

The Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial

(ONTARGET) in diabetic and non-diabetic patients showed that although the

combination of ramipril and telmisartan reduced proteinuria compared with either

agent alone, the time to initiation of dialysis was not delayed [69,70]. There are

enough studies to compare the effectiveness of ACE inhibitors and angiotensin

receptor blockers in this situation. These results are already a cornerstone of the

treatment of diabetic nephropathy and can be used to support the routine use of

RAAS inhibitors in the treatment of patients with type 2 diabetes, regardless of

baseline albuminuria.

24. TREATMENT OF HYPERGLYCEMIA

Hyperglycemia, a hallmark of diabetes, is an important therapeutic goal in all

diabetic patients. As shown in important studies such as Epidemiology of

Diabetes Interventions and Complications (EDIC) and UKPDS, tight glycemic

control reduces the risk of microvascular complications, including nephropathy, in

patients with type 1 and type 2 diabetes [71]. Current evidence supports therapy

with a target HbA1c of 7.0% to slow the onset of microvascular complications,

including nephropathy. Of note, no prospective randomized clinical trial has

evaluated the effect of glycemic control on health outcomes in patients with CKD

stages 3-5. Because patients with CKD are more prone to hypoglycemia than

patients with preserved eGFR, it remains unclear whether the same HbA1c

target is optimal for this population.

25. METFORMIN

Metformin remains the first-line antihyperglycemic treatment for most patients

with T2D because of its low cost, high efficacy, and low risk of hypoglycemia [72].

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In addition, it has weight- and lipid-lowering properties, as well as beneficial

effects on CV mortality. Metformin is mainly excreted by the kidneys. Despite

limited data, the increased risk of lactic acidosis in patients with lower eGFR has

limited its use to patients with eGFR >30 mL/min/1.73 m2.

26. INHIBITORS OF SODIUM-GLUCOSE COTRANSPORTER-2

(SGLT-2I)

SGLT2i is now a widely used antihyperglycemic drug for type 2 diabetes [73].

Several CV outcome studies, including the Empagliflozin Cardiovascular

Outcome Event (EMPA-REG OUTOME) study and the Canagliflozin

Cardiovascular Assessment Study (CANVAS), have shown that SGLT2i provides

significant renal benefits in addition to CV benefits [74]. The CANVAS Renal

study reported a corresponding 40% reduction in the renal composite outcome

(persistent decline in eGFR, need for renal replacement therapy, or death from

renal causes) [75,76]. SGLT2i reduces renal glucose reabsorption, resulting in

osmotic diuresis and plasma volume depletion. Approximately one-third of

SGLT2i-treated patients experience a reversible decline in eGFR of more than

10%. Although they are relatively weak glucose-lowering agents, they have the

added benefit of lowering blood pressure and weight and do not cause

hypoglycemia. Possible side effects include an increased risk of fluid depletion,

genital and urinary tract infections, perineal necrotizing fasciitis, and euglycemic

ketoacidosis.

27. GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS

In T2D, GLP-1 RA represents a family of injectable antihyperglycemic drugs [77].

In particular, liraglutide, semaglutide and dulaglutide have shown significant CV

and renal benefits in large CV outcome trials, particularly in patients with

established CVD or at high risk. In the LEADER (Liraglutide Effect and Action in

Diabetes: Evaluation of Cardiovascular Outcome Results) trial, liraglutide

reduced cardiovascular death by 22% and all-cause death by 15% compared to

placebo [78]. Long-term follow-up data in patients with DKD also showed a 22%

reduction in combined nephritis, mainly due to a lower incidence of severely

elevated albuminuria. Several GLP-1 receptor agonists, including liraglutide,

semaglutide have low renal clearance and hence are safer to use even in

patients with advanced diabetic kidney disease. Major guidelines, including those

of the American Diabetes Association (ADA) and the European Association for

the Study of Diabetes, now recommend the use of GLP-1 RAs to reduce

cardiovascular risk in T2D, regardless of glucose control. In clinical practice, the

most common side effects of GLP-1 RA are gastrointestinal symptoms, injection

site reactions, and increased heart rate. GLP-1 RAs should also be avoided in

patients at risk of developing medullary thyroid tumors or with a history of acute

pancreatitis.

28. TREATMENT OF DYSLIPIDEMIA

Dyslipidemia, a highly modifiable risk factor for CV events in the general

population, is common in patients with diabetes and CKD [79]. Data showing a

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reduction in cardiovascular events due to low-density lipoprotein (LDL)

cholesterol lowering by in CKD patients was originally derived from multiple post

hoc analysis of large randomized controlled trials with enough CKD patients. It

used to be recommended for diabetics and people with CKD stages 1-4, with

statins as first-line agents, to achieve serum LDL cholesterol levels below 100

mg/dL or optionally below 70 mg/dL. However, some targets of LDL cholesterol

treatment were omitted from the recent recommendations for lipid management

in patients with CKD in the 2013 Clinical Practice Global Outcomes for the

Improvement of Kidney Disease. These recommendations are consistent with

recent prevention guidelines from the American Heart Association and the

American College of Cardiology, which recommended that the decision to initiate

cholesterol-lowering therapy (especially statin therapy) be based on the absolute

risk of coronary events [80]. Thus, statin therapy should be considered in almost

all patients with diabetes and chronic diseases due to their high CVD risk and the

pleiotropic effects of statins. It is not clear whether patients using statins should

stop using them when starting dialysis.

29. LIFESTYLE CHANGES

All patients with diabetic nephropathy should receive recommendations for

lifestyle changes that can reduce their risk of progression and development of

cardiovascular disease [81]. For patients who smoke, tobacco cessation is

essential, as it not only significantly and directly reduces the risk of

cardiovascular disease but can also slow the progression of early diabetic

nephropathy. In addition to following a diabetic diet, patients with nephropathy

have traditionally been advised to limit salt and protein intake. Reducing salt

intake by 8.5 g per day has been shown to lower blood pressure by 7/3 mmHg,

similar to monotherapy [82]. However, it should be noted that a recent

prospective observational study in patients with type 1 diabetes who did not have

ESRD showed that the relationship between salt intake and mortality as

assessed by urinary sodium excretion is non- linear, with decreased survival in

patients with the highest and lowest levels of excretion regardless of kidney

disease. Clinical trials are needed to assess the effect of dietary salt restriction

on mortality in this setting. Dietary protein restriction may improve eGFR in

patients with diabetic kidney disease, although the quality of the evidence is not

high. Finally, combining lifestyle changes with intensive treatment can

significantly reduce the risk of cardiovascular disease and prevent the

progression of microvascular disease.

30. MANAGEMENT OF CVD

Prevention and treatment of diabetic nephropathy and reduction of risk of

cardiovascular diseases Considering the high mortality rate of patients with

diabetic nephropathy, primary prevention of its development and efforts to

prevent the progression of the disease after detection are extremely important

[83]. Unfortunately, CKD is often unrecognized by patients and providers. In

addition, patients diagnosed with CKD are less likely to achieve an adequate

change in CVD risk factor than the general population. The key to improving

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outcomes in this vulnerable patient population is simply to increase awareness of

these issues and intervene as early as possible.

31. CONCLUSION AND FUTURE RECOMMENDATIONS

Despite significant advances in the pharmacological management of patients

with diabetes, available DKD therapies can slow the decline in GFR, and a

significant CV risk remains. Research into potential new therapeutic targets for

diabetic kidney disease is currently active and brings a lot of expectation and

optimism to this field. New targets for therapeutic interventions include drugs that

inhibit the formation and function of Advanced Glycation End Products (AGEs) or

AGE receptors, drugs that target oxidative stress, inflammatory cytokines or

fibrosis. The role of microRNAs in the pathogenesis of DKD is an emerging field

and may also provide new therapeutic approaches. Cell therapies for

regenerating blood vessels within the kidney are in the early stages of clinical

trials. New insights into the molecular mechanisms underlying the origin and

progression of DKD are emerging from extensive genetic and molecular studies in

experimental models and humans.

COMPETING INTERESTS

Authors have declared that no competing interests exist.

REFERENCES

1. Digsu N Koye, Dianna J Magliano, Robert G Nelson, Meda E Pavkov. The

Global Epidemiology of Diabetes and Kidney Disease. Adv Chronic

Kidney Dis. 2018;25(2)121-132.

2. Palleti, Sujith Kumar, Sreekant Avula, and Sandesh Dewan. Kidney: A

Review on End Stage Renal Disease, Dialysis and Transplant. Int Clinc

Med Case Rep Jour. 2023;2(10):1-8.

3. Darin E Olson, Mary K Rhee, Kirsten Herrick, David C Ziemer, Jennifer G

Twombly, Lawrence S Phillips. Screening for Diabetes and Pre-Diabetes

with Proposed A1C-Based Diagnostic Criteria. Diabetes Care.

2010;33(10):2184-9.

4. Raza A Khan, Nidhi Patel, Atunde Folajimi, Bansari Raveena Bai, Vrushak

Patel, Praveen Kumar Komminni, et al. Comparison of the Efficacy and

Safety of Metformin-Based Combination Therapy Versus Metformin

Alone in Children and Adolescents With Type 2 Diabetes Mellitus: A Meta-

Analysis. Cureus. 2023;15(2):e35014.

5. Forouhi, Nita Gandhi, and Nicholas J. Wareham. Epidemiology of

Diabetes. Medicine (Abingdon). 2014;42(12):698-702.

6. Lena M Thorn, Daniel Gordin, Valma Harjutsalo, Stefanie Hägg, Robert

Masar, Markku Saraheimo, et al. The Presence and Consequence of

Nonalbuminuric Chronic Kidney Disease in Patients with Type 1 Diabetes.

Diabetes Care. Diabetes Care. 2015;38(11):2128-33.

7. Palleti, Sujith, et al. “Int Clinc Med Case Rep Jour (ICMCRJ) 2023 |

Volume 2 | Issue 11 Citation: Sujith Kumar Palleti, Sreekant Avula, Roopa

Advances in Renal Diseases and Dialysis

Diabetic Kidney Disease

Naik. Chronic Kidney Disease.” International Clinical and Medical Case

Reports Journal Review Article. 2023;2(11):1–15,

8. Keith P McCullough, Hal Morgenstern, Rajiv Saran, William H

Herman, Bruce M Robinson. Projecting ESRD Incidence and Prevalence

in the United States through 2030. J Am Soc Nephrol. 2019;30(1):127-

135.

9. Rakesh Pilla, Sujith Kumar Palleti, Renuka Rayana, Satish Reddy Skss,

Aminah Abdul Razzack, Sruti Kalla. Glycated haemoglobin (HbA1c)

variations in nondiabetics with nutritional anemia. Cureus.

2020;12(11):e11479.

10. Paul Muntner, Barry R Davis, William C Cushman, Sripal Bangalore,

David A Calhoun, Sara L Pressel, et al. Treatment-Resistant

Hypertension and the Incidence of Cardiovascular Disease and End-

Stage Renal Disease. Hypertension. 2014;64(5):1012-21.

11. Muhammad Ali Sameer, Bilal Aziz Malik, Muhammad Obaid Ullah

Choudry, Muhammad Shoaib Anwar, Muhammad A Nadeem, Fizza

Mahmood, et al. Comparison of Coronary Artery Bypass Grafting

Combined With Mitral Valve Repair Versus Coronary Artery Bypass

Grafting Alone in Patients With Moderate Ischemic Mitral Regurgitation: A

Meta-Analysis. Cureus. 2023;15(4). e37238.

12. Hans-Joachim Anders, Tobias B Huber, Berend Isermann, Mario Schiffer.

CKD in Diabetes: Diabetic Kidney Disease versus Nondiabetic Kidney

Disease. Nat Rev Nephrol. 2018;14(6):361-377.

13. Duran-Salgado, Montserrat B, and Alberto F Rubio-Guerra.

Diabetic Nephropathy and Inflammation. World J Diabetes. 2014;5(3):

393-8.

14. Sungmi Park, Hyeon-Ji Kang, Jae-Han Jeon, Min-Ji Kim, In-Kyu Lee.

Recent Advances in the Pathogenesis of Microvascular Complications in

Diabetes. Arch Pharm Res. 2019;42(3):252-262.

15. Jithin Karedath, FNU Avanteeka, Muhammad Nouman Aslam, Ahmad

Nadeem, Rao Ahmed Yousaf, Sandesh Shah, et al. Comparison of

Effectiveness and Safety of Low-Dose Versus Standard-Dose Intravenous

Recombinant Tissue Plasminogen Activator in Patients With Acute

Ischemic Stroke: A Meta-Analysis. Cureus. 2023;15(2).

16. Dung V Nguyen, Lynn C Shaw, Maria B Grant. Inflammation in the

Pathogenesis of Microvascular Complications in Diabetes. Front

Endocrinol (Lausanne). 2012;3:170.

17. Mona Sedeek, Rania Nasrallah, Rhian M Touyz, Richard L Hébert.

NADPH Oxidases, Reactive Oxygen Species, and the Kidney: Friend and

Foe. J Am Soc Nephrol . 2013;24(10):1512-8.

18. Abshiro H Mayow, Fatima Ahmad, Muhammad Sohaib Afzal,

Muhammad Usama Khokhar, Daneyal Rafique, et al. A Systematic

Review and Meta-Analysis of Independent Predictors for Acute

Respiratory Distress Syndrome in Patients Presenting With Sepsis.

Cureus. 2023;15(4).

19. Matthew T James, Brenda R Hemmelgarn, Marcello Tonelli. Early

Recognition and Prevention of Chronic Kidney Disease. Lancet.

2010;375(9722):1296-309.

Advances in Renal Diseases and Dialysis

Diabetic Kidney Disease

20. Toth-Manikowski, Stephanie, and Mohamed G. Atta. Diabetic Kidney

Disease: Pathophysiology and Therapeutic Targets. J Diabetes Res.

2015;2015:697010.

21. Luigi Gnudi, Richard J M Coward, David A Long. Diabetic Nephropathy:

Perspective on Novel Molecular Mechanisms. Trends Endocrinol Metab.

2016;27(11):820-830.

22. Sai Kiran Kondabolu, Yasitha Kakarlapudi, Haider Malik, Hamza Malik,

Saima Khan, Praveen Kumar Komminni, et al. Beneficial Impacts of

Fenoldopam on Patients With or at Risk for Acute Renal Failure and

Undergoing Surgery: A Meta-Analysis of Randomized Clinical Trials.

Cureus. 2023;15(2):e34584.

23. Mohsen Pourghasem, Hamid Shafi, Zahra Babazadeh. Histological

Changes of Kidney in Diabetic Nephropathy. Caspian J Intern Med.

2015;6(3):120-7.

24. Behzad Najafian, Charles E Alpers, Agnes B Fogo. Pathology of Human

Diabetic Nephropathy. Contrib Nephrol. 2011;170:36-47.

25. Marshall, Caroline B. Rethinking Glomerular Basement Membrane

Thickening in Diabetic Nephropathy: Adaptive or Pathogenic? Am J

Physiol Renal Physiol. 2016;311(5):F831-F843.

26. Suyan Duan, Fang Lu, Dandan Song, Chengning Zhang, Bo Zhang,

Changying Xing, et al. Current Challenges and Future Perspectives of

Renal Tubular Dysfunction in Diabetic Kidney Disease. Front Endocrinol

(Lausanne). 2021;12:661185.

27. M C Thomas, W C Burns, M E Cooper. Tubular Changes in

Early Diabetic Nephropathy. Adv Chronic Kidney Dis. 2005;12(2):177-

86.

28. Paola Fioretto, Michael Mauer. Histopathology of Diabetic Nephropathy.

Semin Nephrol. 2007;27(2):195-207.

29. Sujith K. Palleti, Hanna Larson, Sreekant Avula, Maria M. Picken,

Anuradha Wadhwa. Subarachnoid Hemorrhage in Autoimmune Vasculitis:

A Rare Presentation of Systemic Lupus Erythematosus- Antineutrophil

Cytoplasmic Autoantibody-Associated Vasculitis Overlap Syndrome.

Cureus. 2023;15(5):2023.

30. Sujith K. Palleti, Maria M. Picken, Anuradha Wadhwa. Sjögren’s

Syndrome Overlap with Lupus Nephritis: A Case Report and Literature

Review of a Rare Entity. Cureus. 2023;15(5).

31. C E Mogensen, C K Christensen, E Vittinghus. The Stages in Diabetic

Renal Disease: With Emphasis on the Stage of Incipient Diabetic

Nephropathy. Diabetes. 1983;32 Suppl 2:64-78.

32. F L Brancati, P K Whelton, B L Randall, J D Neaton, J Stamler, M J Klag.

Risk of End-Stage Renal Disease in Diabetes Mellitus: A Prospective

Cohort Study of Men Screened for MRFIT. Multiple Risk Factor

Intervention Trial. JAMA. 1997;278(23):2069-74.

33. Caroline S Fox, Kunihiro Matsushita, Mark Woodward, Henk J G Bilo,

John Chalmers, Hiddo J Lambers Heerspink,, et al. Associations of

Kidney Disease Measures with Mortality and End-Stage Renal Disease

in Individuals with and without Diabetes: A Meta-Analysis. Lancet.

2012;380(9854):1662-73.

Advances in Renal Diseases and Dialysis

Diabetic Kidney Disease

34. Sujith K Palleti, Santhoshi R Bavi, Margaret Fitzpatrick, Anuradha

Wadhwa. First case report of Sphingobium lactosutens as a human

pathogen causing peritoneal dialysis-related peritonitis. Cureus.

2022;14(7):e27293.

35. Sujith K. Palleti, Santhoshi R. Bavi, Margaret Fitzpatrick, Anuradha

Wadhwa. Study about Sphingobium Lactosutens: A Human Pathogen

Causing Peritoneal Dialysis Related Peritonitis. Perspective of Recent

Advances in Medical Research. BP International. 2023:31-35.

36. Jeffcoate William J, Keith G Harding. Diabetic Foot Ulcers. Lancet

(London, England). 2003; 361(9368):1545-51.

37. Zaid Munir, Muhammad Akash, Fnu Jaiprada, Bilal Abu Tarboush, Osama

Ijaz, Anan Bseiso, et al. Evaluation of the Effects of Extracorporeal

Shockwave Therapy in Patients With Peripheral Arterial Disease:

A Meta-Analysis of Randomized Control Trials. Cureus. 2023;

15(2):e34729.

38. Kazancioğlu Rumeyza. Risk Factors for Chronic Kidney Disease: An

Update. Kidney Int Suppl (2011). 2013;3(4):368-371.

39. K Sharma, F N Ziyadeh. Hyperglycemia and Diabetic Kidney Disease: The

Case for Transforming Growth Factor–β as a Key Mediator. Diabetes.

1995;44(10):1139-46.

40. Benaicha, Karima, et al. Efficacy of Molnupiravir for the Treatment of

Mild or Moderate COVID-19 in Adults: A Meta-Analysis. Cureus.

2023;15(5).

41. Kato Mitsuo, Rama Natarajan. Epigenetics and Epigenomics in Diabetic

Kidney Disease and Metabolic Memory. Nat Rev Nephrol.

2019;15(6):327-345.

42. Bruce Horowitz, Dana Miskulin, Philip Zager. Epidemiology of

Hypertension in CKD. Adv Chronic Kidney Dis. 2015;22(2):88-95.

43. Kaysen GA. Hyperlipidemia in Chronic Kidney Disease. Int J Artif Organs.

2007;30(11):987-992.

44. Luigi Gnudi, Richard J M Coward, David A Long. Diabetic Nephropathy:

Perspective on Novel Molecular Mechanisms. Trends Endocrinol Metab.

2016;27(11):820-830.

45. Christine Maric, John E Hall. Obesity, Metabolic Syndrome and Diabetic

Nephropathy. Contrib Nephrol. 2011;170:28-35.

46. Marco Ladino, Fernando Pedraza, David Roth. Hepatitis c Virus Infection

in Chronic Kidney Disease. J Am Soc Nephrol. 2016;27(8):2238-2246.

47. Fareeha Naseer Syed, Nadia Kashif, Mubashir Razzaq Khan, Fayaz

Ahmed Memon, Muhammad Zubair Jabbar, Sujith Kumar Palleti. Hepatitis

C Virus Infection in Patients with Beta Thalassemia after Multiple

Transfusions at a Tertiary Care Hospital. Pakistan Journal of Medical &

Health Sciences 2023;17(1):363-363.

48. Marco Ladino, Fernando Pedraza, David Roth. Hepatitis c Virus Infection

in Chronic Kidney Disease. J Am Soc Nephrol. 2016;27(8):2238-46.

49. Ron T Gansevoort, Ricardo Correa-Rotter, Brenda R Hemmelgarn,

Tazeen H Jafar, Hiddo J Lambers Heerspink, Johannes F Mann, et al.

Chronic Kidney Disease and Cardiovascular Risk: Epidemiology,

Mechanisms, and Prevention. Lancet. 2013;382(9889):339-52.

Advances in Renal Diseases and Dialysis

Diabetic Kidney Disease

50. Kashyap Kela, Chaitanya Rojulpote, Ajinkya Buradkar, Sreekant Avula,

Vijay Pratap Singh, Sujithraj Dommaraju, et al. AN UNUSUAL CAUSE of

ABNORMAL ECHODENSITY in the RIGHT ATRIUM. J Am Coll Cardiol.

2021;77(18_Supplement_1) 2698.

51. Daniel E Weiner, Sayed Tabatabai, Hocine Tighiouart, Essam Elsayed,

Nisha Bansal, John Griffith, et al. Cardiovascular Outcomes and All-Cause

Mortality: Exploring the Interaction between CKD and Cardiovascular

Disease. Am J Kidney Dis. 2006;48(3):392-401.

52. Karthik Gonuguntla, Komal Ejaz, Chaitanya Rojulpote, Ayesha Shaik,

Abhijit Bhattaru, Tapan Buch, et al. A nationwide cohort analysis to

determine the prevalence of sinus node dysfunction and rates of

pacemaker implantation in systemic lupus erythematosus. Am J

Cardiovasc Dis . 2021;11(4):478-483.

53. Collins Allan J. Cardiovascular Mortality in End-Stage Renal Disease. Am

J Med Sci. 2003;325(4):163-7.

54. Abdulmaleek Idanesimhe Sado, Muhammad S Afzal, Lavanya

Kannekanti, Hrushikesh Reddy Pamreddy, Jorge Pimentel Campillo,

Vaishnavi Kandukuri, et al. A Meta-Analysis on Predictors of Mortality

Among Patients Hospitalized for Acute Exacerbation of Asthma. Cureus.

2023;15(2):e35225.

55. John M Flack, Bemi Adekola. Blood Pressure and the New ACC/AHA

Hypertension Guidelines. Trends Cardiovasc Med. 2020;30(3):160-164.

56. Seyed Bahman Ghaderian, Fatemeh Hayati, Shokouh Shayanpour, Seyed

Seifollah Beladi Mousavi. Diabetes and End-Stage Renal Disease; a

Review Article on New Concepts. J Renal Inj Prev. 2015;4(2):28-33.

57. Digsu N Koye, Dianna J Magliano, Robert G Nelson, Meda E Pavkov. The

Global Epidemiology of Diabetes and Kidney Disease. Adv Chronic Kidney

Dis. 2018;25(2):121-132.

58. Sujith K Palleti, Anuradha Wadhwa, Abdul H Rasheed. The First Case of

Ceftazidime-Induced Antibiomania: A Case Report and Literature Review

Cureus. 2022;14(12):e32904.

59. Keith P McCullough, Hal Morgenstern, Rajiv Saran, William H

Herman, Bruce M Robinson. Projecting ESRD Incidence and Prevalence

in the United States through 2030. J Am Soc Nephrol. 2019;30(1):127-

135.

60. Maria Narres, Heiner Claessen, Sigrid Droste, Tatjana Kvitkina, Michael

Koch, Oliver Kuss, et al. The Incidence of End-Stage Renal Disease in the

Diabetic (Compared to the Non-Diabetic) Population: A Systematic

Review. PLoS One. 2016;11(1):e0147329.

61. Patrick Albertus, Hal Morgenstern, Bruce Robinson, Rajiv Saran. Risk of

ESRD in the United States. Am J Kidney Dis . 2016;68(6):862-872.

62. Palleti Sujith K, Anuradha Wadhwa, Abdul H. Rasheed. Ceftazidime-

induced Antibiomania: A Rare Case Study and Review of Literature.

Research Highlights in Disease and Health Research Vol. 2023:56-61.

63. Bethany J Foster, Mark M Mitsnefes, Mourad Dahhou, Xun Zhang,

Benjamin L Laskin. Changes in Excess Mortality from End Stage Renal

Disease in the United States from 1995 to 2013. Clin J Am Soc Nephrol.

2018;13(1):91-99.

Advances in Renal Diseases and Dialysis

Diabetic Kidney Disease

64. Jorge L Gross, Mirela J de Azevedo, Sandra P Silveiro, Luís Henrique

Canani, Maria Luiza Caramori, Themis Zelmanovitz. Diabetic

Nephropathy: Diagnosis, Prevention, and Treatment. Diabetes Care.

2005;28(1):164-76.

65. Samsu Nur. Diabetic Nephropathy: Challenges in Pathogenesis,

Diagnosis, and Treatment. Biomed Res Int. 2021;2021:1497449.

66. Elaine Ku, Benjamin J Lee, Jenny Wei, Matthew R Weir. Hypertension in

CKD: Core Curriculum 2019. Am J Kidney Dis. 2019;74(1):120-131.

67. Hala Yamout, Ivana Lazich, George L Bakris. Blood Pressure,

Hypertension, RAAS Blockade, and Drug Therapy in Diabetic Kidney

Disease. Adv Chronic Kidney Dis. 2014;21(3):281-6.

68. Lawrence G Hunsicker, Robert C Atkins, Julia B Lewis, Gregory Braden,

Paul J Champion de Crespigny, Giacomo DeFerrari, et al. Impact of

Irbesartan, Blood Pressure Control, and Proteinuria on Renal Outcomes in

the Irbesartan Diabetic Nephropathy Trial. Kidney Int Suppl.

2004;(92):S99-101.

69. Peter Sleight, Josep Redon, Paolo Verdecchia, Giuseppe Mancia, Peggy

Gao, Robert Fagard, Helmut Schumacher, et al. Prognostic Value of

Blood Pressure in Patients with High Vascular Risk in the Ongoing

Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial

Study. J Hypertens. 2009;27(7):1360-9.

70. Robin Rauniyar, Rahul Rauniyar, Ankita Agrawal, Shikha Yadav, Sreekant

Avula. Severe late‐onset neutropenia induced by ocrelizumab in a multiple

sclerosis patient: A case report. Clin Case Rep. 2022;10(1):e05299.

71. Trial, The Diabetes Control and Complications. Epidemiology of Diabetes

Interventions and Complications (DCCT/EDIC) Study Research Group

Intensive Diabetes Treatment and Cardiovascular Disease in Patients with

Type 1 Diabetes. N Engl J Med. 2005;353(25):2643-2653.

72. Flory James, Kasia Lipska. Metformin in 2019. JAMA. 2019;321(19):1926-

1927.

73. Brendon L Neuen, Tamara Young, Hiddo J L Heerspink, Bruce Neal,

Vlado Perkovic, Laurent Billot, et al. SGLT2 Inhibitors for the Prevention of

Kidney Failure in Patients with Type 2 Diabetes: A Systematic Review and

Meta-Analysis. Lancet Diabetes Endocrinol . 2019;7(11):845-854.

74. Marcel H A Muskiet, Daniël H van Raalte, Erik J M van Bommel, Mark M

Smits, Lennart Tonneijck. Understanding EMPA-REG OUTCOME Lancet

Diabetes Endocrinol. 2015;3(12):928-9.

75. Ashu Rastogi, Anil Bhansali. SGLT2 Inhibitors through the Windows of

EMPA-REG and CANVAS Trials: A Review. Diabetes Ther.

2017;8(6):1245-1251.

76. Wajeeha Aiman, Ayesha Anwar, Danish Iltaf Satti, Mohammad Hamza,

Alynna Mariz Perez, Arslan Ahmad Khan, et al. MM-082 Addition of

Daratumumab to Drug Regimens in the Treatment of Multiple Myeloma: A

Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Clinical Lymphoma Myeloma and Leukemia. 2022;22:S405.

77. Dilip Sharma, Suril Verma, Shivani Vaidya, Kiran Kalia, Vinod Tiwari.

Recent Updates on GLP-1 Agonists: Current Advancements &

Challenges. Biomed Pharmacother. 2018;108:952-962.

Advances in Renal Diseases and Dialysis

Diabetic Kidney Disease

78. Arne Astrup, Stephan Rössner, Luc Van Gaal, Aila Rissanen, Leo

Niskanen, Mazin Al Hakim, et al. Effects of Liraglutide in the Treatment of

Obesity: A Randomised, Double-Blind, Placebo-Controlled Study. Lancet.

2009;374(9701):1606-16.

79. Chen, Szu-chi, and Chin-Hsiao Tseng. Dyslipidemia, Kidney Disease,

and Cardiovascular Disease in Diabetic Patients. Rev Diabet Stud. 2013

Summer-Fall;10(2-3):88-100.

80. Rosario Rey F, Sharma Prabhakar. Lipids and Diabetic Nephropathy. Curr

Diab Rep. 2006;6(6):455- 62.

81. Tziomalos, Konstantinos, and Vasilios G. Athyros. Diabetic Nephropathy:

New Risk Factors and Improvements in Diagnosis. Rev Diabet Stud.

2015;12(1-2):110-8.

82. Locatelli, F. The Importance of Diabetic Nephropathy in Current

Nephrological Practice. Nephrol Dial Transplant. 2003;18(9):1716-25.

83. Aso Yoshimasa. Cardiovascular Disease in Patients with Diabetic

Nephropathy. Current Molecular Medicine. 2008;8(6):533-543.

___________________________________________________________________________________

DISCLAIMER

This chapter is an extended version of the article published by the same author(s) in the following journal.

Int Clinc Med Case Rep Jour., 2(11): 1-4, 2023. DOI: https://doi.org/10.5281/zenodo.7974808

________________________________________________________________________

a Department of Internal Medicine/Nephrology, Geisinger Wyoming Valley Medical Center, Wilkes-Barre,

Pennsylvania, USA.

b Department of Internal Medicine, Lovelace Medical Center, Albuquerque, New Mexico, USA.

c Department of Internal Medicine, Geisinger Commonwealth School of Medicine, Scranton, PA,

Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA, USA.

d Department of Internal Medicine, MNR Medical College and Hospital, Telangana, India.

e Department of Internal Medicine/Gastroenterology, Brooklyn Hospital Center, Brooklyn, New York,

USA.

*Corresponding author: E-mail: drmaheshwarikata@gmail.com;

Chapter 4

Print ISBN: 978-81-19491-84-1, eBook ISBN: 978-81-19491-85-8

Continuous Renal Replacement Therapy

Atul Bali a, Harkesh Arora b, Roopa Naik c,

Maheshwari Kata d* and Rajeshwari Ramachandran e

DOI: 10.9734/bpi/mono/978-81-19491-84-1/CH4

ABSTRACT

Continuous renal replacement therapy (CRRT) is commonly used for acute

kidney injury (AKI) in intensive care units (ICU) for renal support, especially in

hemodynamically unstable patients in much of the developed world. However,

despite its widespread use, there is no formal evidence regarding the

improvement in patient related outcomes when CRRT is used instead of

intermittent hemodialysis (IHD). Various techniques can be used that differ in the

mode of solute removal, including continuous venous hemofiltration with primarily

convective solute removal, continuous venous hemodialysis with primarily

diffusional solute removal, and continuous venous hemodiafiltration, which is a

combination of both dialysis and hemofiltration methods. In this review, we

compare CRRT with other renal support modalities and examine the indications

for initiation of renal replacement therapy, as well as dosage and technical

considerations for administering CRRT. We also describe some of the

controversies and questions that remain to be answered regarding the use of

CRRT.

Keywords: Renal failure; hemodialysis; renal replacement therapy; acute kidney

injury.

1. INTRODUCTION

Acute kidney injury (AKI) is a common complication of critically ill patients and is

associated with significant morbidity and mortality [1,2]. About 5-10% of patients

with AKI require renal replacement therapy during their ICU stay, with a mortality

rate of 30-70%. Over the past two decades, the incidence of AKI requiring renal

replacement therapy has increased by approximately 10% per year [3]. Risk

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

factors for AKI requiring active treatment include older age, male sex, African-

American race, disease severity, sepsis, decompensated heart failure, cardiac

surgery, liver failure, and use of mechanical ventilation.

Continuous renal replacement therapy includes spectrum of dialysis techniques

developed in the 1980s that were developed specifically for the treatment of

critically ill patients with acute kidney injury who could not undergo traditional

intermittent hemodialysis due to hemodynamic instability or whose volume or

metabolic abnormalities could not be controlled with intermittent hemodialysis [4].

Slower solute clearance and fluid removal per unit time with continuous renal

replacement therapy compared with intermittent hemodialysis is thought to allow

for better hemodynamic tolerance. Although once considered an extraordinary

procedure, the provision of RRT care has become routine, even in the setting of

significant hemodynamic instability [5,6]. However, considerable uncertainty

remains regarding many key aspects of active care management, including the

optimal timing of initiation and termination and the choice of treatment modalities.

This article provides an overview of key issues in critical care management of

critically ill patients, with a primary focus on the use of continuous renal

replacement therapy (CRRT).

2. RRT MODALITIES

Several modalities of renal replacement therapy can be used in the treatment of

critically ill patients with renal failure [7]. These include CRRT, conventional

intermittent hemodialysis (IHD), and prolonged intermittent renal replacement

therapy (PIRRT), which is a combination of CRRT and IHD. All of them use

relatively similar extracorporeal circulation and differ mainly in the duration of

treatment and thus in net ultrafiltration rate and solute removal. IHD ensures

rapid removal and ultrafiltration of the solute during a relatively short (4 hour)

treatment; continuous therapy provides more gradual fluid removal and solute

clearance over a longer treatment period (optimally 24 hours per day, but often

interrupted by systemic coagulation or diagnostic or therapeutic procedures).

Different forms of PIRRT are characterized by treatments that typically last 8-16

hours, solute absorption and ultrafiltration are slower than IHD but faster than

CRRT. PIRRT is most often delivered by IHD-like devices, but with lower blood

and dialysate flow rates [8]. PIRRT can also be performed with equipment

designed for CRRT, but with higher rates of dialysate and/or ultrafiltration to

achieve a similar treatment response in shorted period of time. Peritoneal dialysis

offers an effective alternative to extracorporeal renal replacement therapies

[9,10].

3. CHOICE OF RRT MODALITY

Although CRRT and PIRRT are most commonly used in hemodynamically

unstable patients, there is considerable variation in practice. Some centers use

CRRT (or PIRRT) in most patients with renal failure, regardless of hemodynamic

status, while others may use intermittent hemodialysis even in some patients

who are vasopressor- dependent. Although the benefit of slow, continuous renal

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

support in hemodynamically unstable patients may seem self-evident,

randomized trials have failed to show any significant differences in terms of

important outcomes such as mortality or recovery of renal function comparing

CRRT with IHD or PIRRT [11,12]. However, it should be appreciated that to

provide IHD in hemodynamically unstable patients, the dialysis prescription may

require modifications, such as increasing the treatment time to allow more

gradual ultrafiltration, using higher sodium dialysate concentrations and lowering

dialysis temperatures. Although the Kidney Disease: Improving Global Outcomes

(KDIGO) Clinical Practice Guidelines for AKI recommend the use of CRRT in

hemodynamically unstable patients, the strength of this recommendation is low.

However, observational data indicate that CRRT is more effective than IHD in

achieving negative fluid balance. Furthermore, in brain-damaged patients with

acute liver failure or increased intracranial pressure, CRRT is associated with

better preservation of cerebral perfusion than IHD [13,14].

Although CRRT was originally developed as arteriovenous therapy, it is now

performed using pump-driven veno- venous circuits. Pump-driven venous

circulation provides greater and more consistent blood flow and eliminates the

hazards associated with long-term arterial cannulation with a large-bore catheter.

Several techniques have been developed to deliver CRRT. If the treatment is

used only for volume control, it is called slow continuous ultrafiltration (SCUF).

When CRRT is delivered as continuous venovenous hemofiltration (CVVH),

continuous venovenous hemodialysis (CVVHD), or continuous venovenous

hemodiafiltration (CVVHDF), it provides both solute clearance and volume

removal, and the differences between these methods relate to solute clearance.

In CVVH, the hydrostatic gradient across the semipermeable hemofilter

membrane creates a high ultrafiltration rate, and solute transport occurs by

convection. Dissolved substances are carried by the water flow through the

membrane, often referred to as "solvent drag" [15]. High ultrafiltration rates are

required to achieve sufficient solute uptake, and a volume of ultrafiltrate greater

than that required to remove the desired fluid is replaced with balanced IV

crystalloid solutions. These replacement solutions can be infused into the

extracorporeal circulation either before or after the hemofilter. Because the high

ultrafiltration rate hemoconcentrates the blood as it passes through the hemofilter

fibers, the risk of contamination and clogging of the fibers increases. An infusion

of prefilter replacement fluid dilutes the blood entering the hemofilter, thereby

reducing the hemoconcentration [16,17]. However, administration of a

replacement fluid prefilter dilutes the blood solute, reducing the effective solute

clearance at a fixed ultrafiltration rate. A post-filter infusion has no such effects.

In CVVHD, the dialysate is perfused through the outer surface of the dialysis

membrane and solutes are removed from the blood by diffusion of the dialysate

along its concentration gradient. Ultrafiltration rates are relatively low compared

to CVVH levels, allowing negative fluid balance without the need for IV

replacement fluids [18]. CVVHDF is a hybrid that combines CVVHD dialysis flow

with high ultrafiltration rates and the use of CVVH replacement fluids. The

different solute removal mechanisms provided by CVVH and CVVHD result in

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

different solute removal profiles for each method. Diffusion ensures effective

removal of low molecular weight solutes (< 500-1500 daltons); however, diffusion

clearance decreases rapidly as the molecular weight of the solute increases

[19,20]. In contrast, the solute movement in convection is largely limited by the

pore size of the hemofilter membrane. Removal of lower and higher molecular

weight solutes is similar until the molecular radius of the solute approaches the

membrane pore size. Thus, at equivalent outlet flow rates, CVVH provides

greater clearance than CVVHD for solutes ranging from 1000 to 20,000 daltons,

or even greater when larger pore membranes are used. Independent of

diffusion and convection, solute adsorption in the CRRT chain can also

contribute to complete solute uptake, depending on the saturation of membrane

binding sites. Thus, the choice of CRRT modality (CVVH, CVVHD, or CVVHDF)

depends primarily on provider preference rather than patient characteristics or

objective outcome data.

4. INITIATION OF RENAL REPLACEMENT THERAPY

Indications for starting renal replacement therapy Indications for initiation of

CRRT generally correspond to the general indications for the dialysis, including

volume overload, severe metabolic acidosis and electrolyte imbalance, and overt

uremic symptoms [21-24].

Volume overload: Volume overload in AKI occurs when the kidney's ability to

maintain fluid balance is compromised when IV fluids, blood products, and/or

other medications are administered to resuscitate and support a critically ill

patient. Renal replacement therapy is usually indicated when volume overload

impairs organ function and is resistant to diuretics.

Nawal et al. [25] Although observational data from both pediatric and adult

populations show a strong association between the severity of volume overload

at the start of intensive care and the risk of mortality, causality has not been

established.

Acid-base abnormalities: Progressive metabolic acidosis is an inevitable

consequence of renal failure that develops due to impaired renal acid secretion

[26-28]. Either intermittent or continuous RRT is effective in patients with severe

acidosis unresponsive to therapy, such as a fluid overloaded patient who cannot

tolerate alkali therapy. The generally recommended threshold values for starting

RRT are pH < 7.1 to 7.2 or serum bicarbonate < 12 to 15 mmol/L. Earlier

initiation of RRT may be necessary in patients with acute lung injury receiving

lung protective ventilation, as the combination of metabolic and respiratory

acidosis may lead to severe acidemia. Although RRT increases lactate

clearance, there is little evidence that initiation of active therapy to increase

lactate clearance changes clinical outcomes in patients with lactic acidosis

unrelated to drug toxicity (eg, metformin) [29-31].

Severe electrolyte imbalance: Severe hyperkalemia is the most life-threatening

and requires prompt treatment to prevent cardiotoxicity and arrhythmias [32-34].

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

Initiation of RRT is appropriate when hyperkalemia is refractory to medical

therapy or recurs after initial therapy. Although no rigid thresholds based on

serum potassium can be given, active treatment of hyperkalemia alone is rarely

appropriate when potassium levels are < 6 mmol/l. Conversely, RRT is generally

indicated if potassium level is > 6.5mmol/L despite treatment [35,36].

Other electrolyte disturbances, such as severe hyponatremia or hypernatremia

and severe hyperphosphatemia, may be associated with AKI and can lead to the

initiation of RRT [37,38]. In patients with severe hyponatremia associated with

AKI, CRRT may allow a slower and more controlled correction of sodium

concentration, which is necessary to prevent the neurological consequences of

osmotic demyelination, compared to IHD.

Uremia and progressive azotemia: The use of RRT in overt uremic symptoms

such as encephalopathy and pericarditis is well established. Although these are

relatively late complications of AKI, other manifestations of uremia such as

platelet dysfunction, nutritional disorders, increased susceptibility to infection

and sepsis, heart failure, and pulmonary edema may be difficult to distinguish in

the critically ill patients with multiple organ dysfunction [39-41]. In the absence of

specific indications for active therapy, it is much more common to initiate it

prophylactically in response to persistent or progressive azotemia before the

onset of uremic manifestations. The appropriate timing of such an initiation is still

a matter of debate.

Elimination of drugs and toxins: Many toxins and drugs, such as toxic

alcohols, lithium, salicylate, valproic acid and metformin, are dialyzable, and the

timely use of RRT for poisoning and drug poisoning can prevent serious

complications [42,43]. The ability of an RRT to remove a particular drug or toxin

from the bloodstream depends on its size, volume of distribution, and protein

binding [44,45]. Thus, RRT is effective in removing smaller non-protein bound

molecules with a volume of distribution < 1 L/kg body weight. The role of RRT in

the treatment of hyperammonemia is uncertain. As in the treatment of drug

intoxication, IHD also reduces the concentration of ammonia in the blood more

quickly. However, in small case series, high-dose CRRT has been shown to be

effective in the acute treatment of severe hyperammonemia (> 400 μmol/L) in

infants with congenital metabolic disorders [46,47]. The role of CRRT in adults

with hyperammonemia as a consequence of liver failure is still less certain.

Timing of RRT initiation: In the absence of specific indications, the optimal time

of initiation of RRT for AKI is uncertain [48,49]. Early initiation of RRT allows

optimization of volume status, early correction of acid-base and electrolyte

disturbances, and control of azotemia before the development of serious

metabolic disturbances, which are objective indications. However, these potential

benefits of early initiation must be balanced against the risks and burdens

associated with active treatment, including vascular access (eg: hemorrhage,

thrombosis, vascular injury, infection), intra-dialysis hypotension, and resource

use, as well as potential worries that active treatment may prevent the

subsequent recovery of renal function [50,51].

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

Several observational studies have shown improved survival associated with

earlier initiation of RRT. However, these studies only included patients who

ultimately received RRT and did not consider patients with AKI who did not

receive early RRT and who either recovered renal function or died without RRT.

Excluding these patients from the analysis introduces a potential bias, as the real

clinical question is not early versus late initiation of RRT, but rather early versus

non-early RRT in patients without an urgent indication.

5. CRRT DOSE

Solute Control: The CRRT dose is calculated from the sum of the total flow

rates of effluent, dialysate and ultrafiltrate. Although several studies published 15

to 20 years ago suggested that higher flow rates of effluent were associated with

improved survival, the results were inconsistent and this association was not

confirmed in two large multicenter randomized controlled trials [52]. Based on the

available data, the KDIGO clinical practice guidelines recommend a CRRT target

dose of 20 to 25 mL/kg per hour, noting that a higher prescribed dose may be

necessary to achieve this target dose.

Volume management: Another important aspect of RRT prescription is volume

control. Net ultrafiltration can be regulated independently of solute clearance

[53]. As previously noted, the severity of volume overload is strongly associated

with mortality risk in both children and adults with AKI who require RRT.

However, optimal volume management strategies are uncertain. Treatment must

be individualized for each patient, and ultrafiltration goals must be frequently

reevaluated. It should be noted that short-term blood pressure variability is not

usually related to volume status, and that transient hypotension during CRRT

should be carefully evaluated for non-volume-mediated factors and often requires

therapy regardless of changes in ultrafiltration goals.

The role of CRRT in sepsis: Although cytokine modulation with CVVH has been

proposed as an adjunctive therapy for sepsis, clinical trials have not shown any

significant benefit [54,55]. In a study of 80 patients randomized to isovolumic

hemofiltration or standard therapy, hemofiltration did not improve clinical

parameters or mortality. Current data do not support the use of CRRT as

adjunctive therapy for sepsis in addition to renal support.

Drug dosing during CRRT: Drug dosing during CRRT can be challenging

because drug dosing must consider many factors in addition to extracorporeal

drug elimination, including non-renal elimination, residual renal function, and

changes in volume of distribution and protein binding [56,57]. Medication dosing

errors can lead to both toxicity due to insufficient dose reduction and treatment

failure due to underdosing. The latter is particularly important for antibiotic dosing

in patients with sepsis associated with AKI.

Medications with a noticeable clinical effect, such as analgesics, sedatives and

vasopressors, should be titrated according to the desired clinical response

[58,59]. Drugs with high molecular weight, strong protein binding, or very large

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

volume of distribution are poorly eliminated by CRRT, and no dose adjustment is

necessary for active therapy. Extracorporeal elimination of nonprotein-bound

small molecule drugs approximates effluent flow. Estimated clearance of protein-

bound drugs must be adjusted for the percentage of unbound fraction. For all

drugs whose blood levels are easily measured, dosage adjustments should be

made based on pharmacokinetic monitoring. Finally, it should be recognized that

although published guidelines provide dosing estimates for many agents, they

only provide general parameters that may not correspond to the specific form and

dose of CRRT used.

Nutritional management: AKI patients undergoing CRRT usually have a

markedly negative nitrogen balance due to high protein catabolism [60,61]. In

addition, CRRT causes a loss of amino acids and water-soluble vitamins and

other micronutrients. Caloric intake should be around 35 kcal/kg per day, aim for

a protein intake of 1.5 g/kg and supplement with water soluble vitamins. Although

enteral feeding is preferred, parenteral support may be necessary.

Complications of CRRT: As with all medical procedures, CRRT is not without

risks. Initiation of CRRT requires placement of a large-bore central venous

catheter, which may require long-term maintenance. Known complications of

catheter placement include vascular or visceral injury causing hemorrhage,

pneumothorax, hemothorax, and arteriovenous fistula formation [62,63].

Prolonged use of the catheter is associated with venous blockage or stenosis.

Exposure to blood in the extracorporeal circulation can induce immediate allergic

or delayed immunological responses due to cytokine activation. Bradykinin-

mediated membrane reactions have been associated with certain synthetic

membranes when angiotensin-converting enzyme inhibitors are used. Air

embolism can occur during catheter insertion or removal and at any time during

therapy if air enters the circuit outside the return line air detector.

Circuit clotting and anticoagulation: The most common complication during

CRRT is clotting of dialysis circuit, and the most common cause is inadequate

catheter function, leading to flow restrictions and pressure towers that interrupt

blood flow [64]. If the blood flow cannot be maintained at 200-300 ml/min, a quick

catheter change may be necessary. An excessive filter fraction can cause

hemoconcentration in the hemofilter, which also contributes to filter coagulation

[65, 66]. If there is no catheter failure, blood flow is maximized and the filtration

fraction is < 20%, initiation or intensification of anticoagulant therapy should be

considered. Complications of heparin anticoagulant therapy may include bleeding

and heparin-induced thrombocytopenia. Citrate anticoagulation can cause citrate

toxicity due to citrate accumulation, overt hypocalcemia due to insufficient

calcium replacement, and both metabolic acidosis and metabolic alkalosis as a

result.

Electrolyte abnormalities: One of the most common electrolyte imbalances

observed during CRRT is hypophosphatemia [67]. Hypophosphatemia may

result from continued removal in the circulation and may potentially lead to delay

in weaning from mechanical ventilation. Hypophosphatemia can be prevented by

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

prophylactic enteral or parenteral phosphate supplementation or the use of

phosphate-containing dialysate or replacement fluids.

Hemodynamic instability: Dialysate and replacement fluids are not often

warmed up, in contrast to traditional hemodialysis. Thermal losses during CRRT

can mask the onset of fever, but they may trigger vasoconstriction and

supposedly increase hemodynamic stability. Significant hypothermia may

develop from more severe thermal loss, necessitating extensive external

rewarming. In certain studies, more than one third of patients have hypotension

during CRRT; nevertheless, this condition is typically unrelated to the actual

CRRT process [68,69]. Ultrafiltration, which exacerbates hemodynamic instability,

is the most common cause of hypotension [70]. Hypotension can also be

observed at the beginning of treatment, especially if the circulation is not

reinfused; this result was of particular concern in children and can be alleviated

by the use of albumin in priming the circuit [71,72]. If hypotension is associated

with fluid depletion, treat with fluid re-infusion and adjust ultrafiltration targets; in

other cases, alternative causes should be considered and hypotension treated

with vasopressors.

6. TERMINATION OF CRRT

There are no specific criteria for discontinuation of CRRT due to recovery of renal

function or switching to other forms of RRT [73]. The first manifestation of

recovery of renal function is usually increased urine output, although specific

criteria are rare. In a study titled, observational Beginning and Ending Supportive

Therapy for the Kidney (BEST Kidney), urine output > 400 mL/d without

concomitant diuretic therapy predicted successful discontinuation of CRRT [74].

In this observational cohort, patients who successfully discontinued CRRT

without restarting it were more likely to survive to hospital discharge compared

with patients who required restarting CRRT. Another study proposed urine output

> 500 mL/d as a criterion for discontinuation of renal replacement therapy in

patients with AKI. Although these strategies may aid in clinical decision-making,

there are no precise criteria for stopping RRT. Patients with improved

hemodynamic status but persistent AKI also have a very different transition to

other forms of RRT [75]. Based on the clinical context, PIRRT can be utilized as a

transitional therapy, or patients can be referred directly to IHD. Converting from

CRRT to PIRRT or IHD may make it simpler to begin physical therapy and bed

mobilization. In general, patients with persistent ICU-dependent AKI should be

transferred to IHD before ICU discharge.

7. CONCLUSIONS

CRRT remains the mainstay of therapy for AKI in critically ill patients. In practice,

the provision of CRRT in the ICU remains highly variable. In patients without

objective indications for initiation of renal therapy, the optimal time of RRT

remains controversial. Although the use of continuous regimens may facilitate the

management of hemodynamically unstable patients, the available data do not

show that the use of CRRT improves survival or recovery of renal function

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

compared with alternatives such as conventional IHD and PIRRT. Large, well-

designed clinical trials have shown that in most patients, increasing solute

clearance at effluent flow rates >20–25 mL/kg/h is not associated with improved

outcomes. however, optimal volume management strategies remain to be

defined. Other aspects of CRRT management also vary considerably in

practice, including anticoagulant strategies. Finally, the role of CRRT in setting

overall treatment goals and the use of other life-sustaining treatment strategies

must be considered.

COMPETING INTERESTS

Authors have declared that no competing interests exist.

REFERENCES

1. Eric A J Hoste, Sean M Bagshaw, Rinaldo Bellomo, Cynthia M Cely, Roos

Colman, Dinna N Cruz, et al. Epidemiology of Acute Kidney Injury in

Critically Ill Patients: The Multinational AKI-EPI Study. Intensive Care

Med. 2015;41(8):1411-23.

2. Palleti, Sujith Kumar, Sreekanth Avula, Sandesh Dewan. Kidney: A

Review on End Stage Renal Disease, Dialysis and Transplant. Int Clinc

Med Case Rep Jour. 2023;2(10):1-8.

3. Muhammad O Hanif, Atul Bali, Kamleshun Ramphul. Acute Renal Tubular

Necrosis. StatPearls. 2021.

4. Anne-Sophie Truche, Michael Darmon, Sébastien Bailly, Christophe

Clec'h, Claire Dupuis, Benoit Misset, et al. Continuous Renal Replacement

Therapy versus Intermittent Hemodialysis in Intensive Care Patients:

Impact on Mortality and Renal Recovery. Intensive Care Med.

2016;42(9):1408-17.

5. Max Bell, SWING, Fredrik Granath, Staffan Schön, Anders Ekbom, Claes-

Roland Martling. Continuous Renal Replacement Therapy Is Associated

with Less Chronic Renal Failure than Intermittent Haemodialysis after

Acute Renal Failure. Intensive Care Med . 2007;33(5):773-780.

6. Palleti, Sujith Kumar, Sreekant Avula, Roopa Naik. Chronic Kidney

Disease. Int Clinc Med Case Rep J. 2023;2(11):1-15.

7. Gianluca Villa, Zaccaria Ricci, Claudio Ronco. Renal Replacement

Therapy. Critical Care Clinics. 2015;31(4):839-848.

8. Fahad Edrees, Tingting Li, Anitha Vijayan. Prolonged Intermittent Renal

Replacement Therapy. Adv Chronic Kidney Dis. 2016;23(3):195-202.

9. Rajnish Mehrotra, Olivier Devuyst, Simon J Davies, David W Johnson.

The Current State of Peritoneal Dialysis. J Am Soc Nephrol.

2016;27(11):3238-3252.

10. Sujith K Palleti, Santhoshi R Bavi, Margaret Fitzpatrick, Anuradha

Wadhwa. First case report of Sphingobium lactosutens as a human

pathogen causing peritoneal dialysis-related peritonitis. Cureus.

2022;14(7):e27293.

11. Vladimir Gasparović, Ina Filipović-Grcić, Marijan Merkler, Zoran Pisl.

Continuous Renal Replacement Therapy (CRRT) or Intermittent

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

Hemodialysis (IHD)—What Is the Procedure of Choice in Critically Ill

Patients? Ren Fail. 2003;25(5):855-62.

12. Palleti Sujith K, et al. Study about Sphingobium Lactosutens: A Human

Pathogen Causing Peritoneal Dialysis Related Peritonitis. Perspective of

Recent Advances in Medical Research. BP International 9 (2023):31-35.

13. Davenport Andrew. Continuous Renal Replacement Therapies in Patients

with Liver Disease. Semin Dial . 2009;22(2):169-72.

14. Jithin Karedath, FNU Avanteeka, Muhammad Nouman Aslam, Ahmad

Nadeem, Rao Ahmed Yousaf, Sandesh Shah, et al. Comparison of

Effectiveness and Safety of Low-Dose Versus Standard-Dose

Intravenous Recombinant Tissue Plasminogen Activator in Patients With

Acute Ischemic Stroke: A Meta- Analysis. Cureus. 2023;15(2).

15. William R Clark, Joseph E Turk, Michael A Kraus, Dayong Gao. Dose

Determinants in Continuous Renal Replacement Therapy. Artif Organs.

2003;27(9):815-20.

16. Raghavan Murugan , Eric Hoste, Ravindra L Mehta, Sara Samoni,

Xiaoqiang Ding, Mitchell H Rosner, et al. Precision Fluid Management in

Continuous Renal Replacement Therapy. Blood Purif. 2016;42(3):266-78.

17. Zaid Munir, Muhammad Akash, Fnu Jaiprada, Bilal Abu Tarboush,

Osama Ijaz, Anan Bseiso, et al. Evaluation of the Effects of

Extracorporeal Shockwave Therapy in Patients with Peripheral Arterial

Disease: A Meta-Analysis of Randomized Control Trials. Cureus.

2023;15(2):e34729.

18. P Saudan, M Niederberger, S De Seigneux, J Romand, J Pugin, T

Perneger, et al. Adding a Dialysis Dose to Continuous Hemofiltration

Increases Survival in Patients with Acute Renal Failure. Kidney Int.

2006;70(7):1312-7.

19. Winchester James F, Patrick F Audia. UNRESOLVED ISSUES in

DIALYSIS: Extracorporeal Strategies for the Removal of Middle

Molecules. Seminars in Dialysis. 2006;19(2,3):110-114.

20. Atul Bali, John Kevin Hix, Peter Kouides. Safe and effective use of chronic

transdermal estradiol for life- threatening uremic bleeding in a patient with

coronary artery disease. Nephron Extra. 2014;4(2):134-7.

21. Noel Gibney, Eric Hoste, Emmanuel A Burdmann, Timothy Bunchman,

Vijay Kher, Ravindran Viswanathan, et al. Timing of Initiation and

Discontinuation of Renal Replacement Therapy in AKI: Unanswered Key

Questions. Clin J Am Soc Nephrol. 2008;3(3):876-80.

22. Sujith K Palleti, Anuradha Wadhwa, Abdul H Rasheed. The First Case of

Ceftazidime-Induced Antibiomania: A Case Report and Literature Review.

Cureus. 2022;14(12):e32904.

23. Bali Atul. Pseudo Metabolic Acidosis in the Setting of Hypertriglyceridemia:

A Case Report. 2020.

24. Palevsky Paul M. Renal Replacement Therapy I: Indications and Timing.

Crit Care Clin. 2005;21(2):347- 56.

25. Nawal Salahuddin, Mustafa Sammani, Ammar Hamdan, Mini Joseph,

Yasir Al-Nemary, Rawan Alquaiz, et al. Fluid Overload Is an Independent

Risk Factor for Acute Kidney Injury in Critically Ill Patients: Results of a

Cohort Study. BMC Nephrol. 2017;18(1):45.

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

26. S Lim. Metabolic Acidosis. Acta Medica Indonesiana. 2007;39(3):145-

50.

27. Sai Kiran Kondabolu, Yasitha Kakarlapudi, Haider Malik, Hamza Malik,

Saima Khan, Praveen Kumar Komminni, et al. Beneficial Impacts of

Fenoldopam on Patients with or at Risk for Acute Renal Failure and

Undergoing Surgery: A Meta-Analysis of Randomized Clinical Trials.

Cureus. 2023;15(2):e34584.

28. Jiachang Hu, Yimei Wang, Xuemei Geng, Rongyi Chen, Xialian Xu,

Xiaoyan Zhang, et al. Metabolic Acidosis as a Risk Factor for the

Development of Acute Kidney Injury and Hospital Mortality. Exp Ther Med.

2017;13(5):2362-2374.

29. Lalau Jean-Daniel. Lactic Acidosis Induced by Metformin. Drug Saf.

2010;33(9):727-40.

30. Raza A Khan, Nidhi Patel, Atunde Folajimi, Bansari Raveena Bai,

Vrushak Patel, Praveen Kumar Komminni, et al. Comparison of the

Efficacy and Safety of Metformin-Based Combination Therapy Versus

Metformin Alone in Children and Adolescents with Type 2 Diabetes

Mellitus: A Meta-Analysis. Cureus. 2023;15(2):e35014.

31. Rakesh Pilla, Sujith Kumar Palleti, Renuka Rayana, Satish Reddy Skss,

Aminah Abdul Razzack, Sruti Kalla. Glycated haemoglobin (HbA1c)

variations in nondiabetics with nutritional anemia. Cureus.

2020;12(11):e11479.

32. J Ahmed, L S Weisberg. Weisberg. Hyperkalemia in Dialysis Patients.

Semin Dial. 2001;14(5):348-56.

33. Gowrishankar K, Anurag Rawat, Pratibha Singh, Sujith Palleti. Study on

Recognition of Heart Arrhythmias by Deep Learning Approach of the ECG

Signals using Edge Devices. 2023.

34. Muhammad Ali Sameer, Bilal Aziz Malik, Muhammad Obaid Ullah

Choudry, Muhammad Shoaib Anwar, Muhammad A Nadeem, Fizza

Mahmood, et al. Comparison of Coronary Artery Bypass Grafting

Combined with Mitral Valve Repair Versus Coronary Artery Bypass

Grafting Alone in Patients With Moderate Ischemic Mitral Regurgitation: A

Meta-Analysis. Cureus. 2023;15(4):e37238.

35. Ho-Jung Kim, Sang-Woong Han. Therapeutic Approach to Hyperkalemia.

Nephron. 2002;92 Suppl 1:33- 40.

36. Karthik Gonuguntla, Komal Ejaz, Chaitanya Rojulpote, Ayesha Shaik,

Abhijit Bhattaru, Tapan Buch, et al. A nationwide cohort analysis to

determine the prevalence of sinus node dysfunction and rates of

pacemaker implantation in systemic lupus erythematosus. Am J

Cardiovasc Dis. 2021;11(4):478-483.

37. Lenar Yessayan, Jerry Yee, Stan Frinak, Balazs Szamosfalvi. Continuous

Renal Replacement Therapy for the Management of Acid-Base and

Electrolyte Imbalances in Acute Kidney Injury. Adv Chronic Kidney Dis.

2016;23(3):203-10.

38. Abdulmaleek Idanesimhe Sado, Muhammad S Afzal, Lavanya

Kannekanti, Hrushikesh Reddy Pamreddy, Jorge Pimentel Campillo,

Vaishnavi Kandukuri, et al. A Meta-Analysis on Predictors of Mortality

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

Among Patients Hospitalized for Acute Exacerbation of Asthma. Cureus.

2023;15(2):e35225.

39. Timothy W Meyer, Thomas H Hostetter. Uremia. New England Journal of

Medicine. 2007;357(13): 1316- 1325.

40. Abshiro H Mayow, Fatima Ahmad, Muhammad Sohaib Afzal, Muhammad

Usama Khokhar, Daneyal Rafique, Sai Krishna Vallamchetla, et al. A

Systematic Review and Meta-Analysis of Independent Predictors for

Acute Respiratory Distress Syndrome in Patients Presenting with Sepsis.

Cureus. 2023;15(4):e37055.

41. Palleti Sujith K, Anuradha Wadhwa, Abdul H. Rasheed. Ceftazidime-

induced Antibiomania: A Rare Case Study and Review of

Literature. Research Highlights in Disease and Health Research.

2023;6:56-61.

42. Winchester James F. Dialysis and Hemoperfusion in Poisoning. Adv Ren

Replace Ther. 2002;9(1):26-30.

43. Karima Benaicha, Raja Ram Khenhrani, Maha Veer, Sapna Devi, Usman

Shahbaz, Qais M. Salah, et al. Efficacy of Molnupiravir for the Treatment

of Mild or Moderate COVID-19 in Adults: A Meta-Analysis. Cureus.

2023;15(5).

44. Bert Bammens, Pieter Evenepoel, Kristin Verbeke, Yves Vanrenterghem.

Removal of Middle Molecules and Protein-Bound Solutes by Peritoneal

Dialysis and Relation with Uremic Symptoms. Kidney Int.

2003;64(6):2238-43.

45. Wajeeha Aiman, Ayesha Anwar, Danish Iltaf Satti, Mohammad Hamza,

Alynna Mariz Perez, Arslan Ahmad Khan, et al. MM-082 Addition of

Daratumumab to Drug Regimens in the Treatment of Multiple Myeloma: A

Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Clinical Lymphoma Myeloma and Leukemia. 2022;22:S405.

46. Ari Auron, Patrick D Brophy. Brophy. Hyperammonemia in Review:

Pathophysiology, Diagnosis, and Treatment. Pediatr Nephrol.

2012;27(2):207-22.

47. Atul D Bali, Akiva Rosenzveig, William H Frishman, Wilbert S Aronow.

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Causation

or Association. Cardiol Rev. 2023;e000537.

48. Susan P Y Wong, Elizabeth K Vig, Janelle S Taylor, Nilka R Burrows,

Chuan-Fen Liu, Desmond E Williams, et al. Timing of Initiation of

Maintenance Dialysis. JAMA Intern Med. 2016;176(2):228-35.

49. Kar Saikat, et al. A two-center, retrospective cohort trial of a tumor

necrosis factor inhibitor coupled with intravenous immunoglobulin and

heparin for the treatment of recurrent spontaneous abortion. 2023.

50. Maher JF, GE Schreiner. Hazards and Complications of Dialysis. N Engl J

Med. 1965;273(7):370-7.

51. Vaillant Angel A Justiz, Roopa Naik. HIV-1 associated opportunistic

infections. StatPearls [Internet]. 2021.

52. Robin Rauniyar, Rahul Rauniyar, Ankita Agrawal, Shikha Yadav, Sreekant

Avula. Dosing Patterns for Continuous Renal Replacement Therapy at a

Large Academic Medical Center in the United States. J Crit Care.

2002;17(4):246-50.

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

53. Daugirdas John T. Pathophysiology of Dialysis Hypotension: An Update.

American Journal of Kidney Diseases. 2001;38(4):S11-S17.

54. C Ronco, Z Ricci, R Bellomo. Importance of Increased Ultrafiltration

Volume and Impact on Mortality: Sepsis and Cytokine Story and the Role

for CVVH. EDTNA ERCA J. 2002;Suppl 2:13-8.

55. Syed, Fareeha Naseer, et al. Hepatitis C Virus Infection in Patients with

Beta Thalassemia after Multiple Transfusions at a Tertiary Care

Hospital. Pakistan Journal of Medical & Health Sciences. 2023;17(1):363-

363.

56. Gordon Choi, Charles D Gomersall, Qi Tian, Gavin M Joynt, Ross

Freebairn, Jeffrey Lipman, et al. Principles of Antibacterial Dosing in

Continuous Renal Replacement Therapy. Crit Care Med.

2009;37(7):2268-82.

57. Palleti Sujith K, Maria M. Picken, Anuradha Wadhwa. Sjögren’s Syndrome

Overlap with Lupus Nephritis: A Case Report and Literature Review of a

Rare Entity. Cureus. 2023;15(5).

58. Scoville Bridget A, Bruce A Mueller. Medication Dosing in Critically Ill

Patients with Acute Kidney Injury Treated with Renal Replacement

Therapy. Am J Kidney Dis. 2013;61(3):490-500.

59. Robin Rauniyar, Rahul Rauniyar, Ankita Agrawal, Shikha Yadav, Sreekant

Avula. Severe late‐onset neutropenia induced by ocrelizumab in a multiple

sclerosis patient: A case report. Clin Case Rep. 2022;10(1):e05299.

60. Marlies Ostermann, Nuttha Lumlertgul, Ravindra Mehta. Nutritional

Assessment and Support during Continuous Renal Replacement Therapy.

Semin Dial. 2021;34(6):449-456.

61. Bali Atul, Roopa Naik. The Impact of a Vegan Diet on Many Aspects of

Health: The Overlooked Side of Veganism. Cureus. 2023;15(2).

62. Sigwalt Florent, et al. Clinical Complications of Continuous Renal

Replacement Therapy. Contrib Nephrol. 2018;194:99-108.

63. Palleti SK, Larson H, Avula S, et al. Subarachnoid Hemorrhage in

Autoimmune Vasculitis: A Rare Presentation of Systemic Lupus

Erythematosus-Antineutrophil Cytoplasmic Autoantibody-Associated

Vasculitis Overlap Syndrome. Cureus. 2023;15(5).

64. Davies Hugh, Gavin Leslie. Maintaining the CRRT Circuit: Non-

Anticoagulant Alternatives. Aust Crit Care . 2006;19(4):133-8.

65. Joannidis Michael, Heleen M Oudemans-van Straaten. Clinical Review:

Patency of the Circuit in Continuous Renal Replacement Therapy. Crit

Care. 2007;11(4):218.

66. Rohit Sharma, Tristan Nguyen-Luu, Pragya Dhaubhadel, Amit Sharma,

Roopa Naik. A Rare Co- occurrence of Monkeypox Encephalitis and

Neurosyphilis. Cureus. 2023;15(3):e35945.

67. Young-Hye Song, Eun-Hye Seo, Yang-Sook Yoo, Young-Il Jo. Phosphate

Supplementation for Hypophosphatemia during Continuous Renal

Replacement Therapy in Adults. Ren Fail. 2019;41(1):72-79.

68. Adrianna Douvris, Khalid Zeid, Swapnil Hiremath, Sean M Bagshaw, Ron

Wald, William Beaubien- Souligny, et al. Mechanisms for Hemodynamic

Instability Related to Renal Replacement Therapy: A Narrative Review.

Intensive Care Med. 2019;45(10):1333-1346.

Advances in Renal Diseases and Dialysis

Continuous Renal Replacement Therapy

69. Eyth Emily, Roopa Naik. Hemoglobin A1c. StatPearls Publishing.

2022.

70. Sreekant Avula, Sandesh Dewan, Bushra Firdous Shaik, Atul Bali.

Diabetic Kidney Disease. International Clinical and Medical Case Reports

Journal. 2023;2(11).

71. Maria J Santiago, Jesús López-Herce, Javier Urbano, María José Solana,

Jimena del Castillo, Yolanda Ballestero, et al. Complications of

Continuous Renal Replacement Therapy in Critically Ill Children: A

Prospective Observational Evaluation Study. Crit Care. 2009;13(6):R184.

72. Zineb Barkhane, FNU Nimerta, Sualeha Zulfiqar, Saleha Dar, Muhammad

Sohaib Afzal, Amna Zaree, et al. Independent Predictors of Mortality in

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: A

Systematic Review and Meta-Analysis. Cureus. 2023;15(5).

73. S Katayama, S Uchino, M Uji, T Ohnuma, Y Namba, H Kawarazaki, et al.

Factors Predicting Successful Discontinuation of Continuous Renal

Replacement Therapy. Anaesth Intensive Care. 2016;44(4):453-7.

74. Shigehiko Uchino, Rinaldo Bellomo, Hiroshi Morimatsu, Stanislao

Morgera, Miet Schetz, Ian Tan, et al. Continuous Renal Replacement

Therapy: A Worldwide Practice Survey. Intensive Care Med.

2007;33(9):1563-70.

75. S Uchino, R Bellomo, J A Kellum, H Morimatsu, S Morgera, M R Schetz,

et al. Patient and Kidney Survival by Dialysis Modality in Critically Ill

Patients with Acute Kidney Injury. Int J Artif Organs. 2007;30(4):281-92.

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May 2023

The kidney is probably the most important target of microvascular damage in diabetes. A significant proportion of people with diabetes develop kidney disease because of their disease and/or other comorbidities, including hypertension and age-related kidney loss. The presence and severity of chronic kidney disease (CKD) identifies individuals at increased risk for adverse health outcomes and premature mortality. Therefore, the prevention and treatment of CKD in diabetics is now a central goal of their general care. Intensive care of diabetic patients includes blood sugar and blood pressure control and blockade of the renin-angiotensin-aldosterone system; these approaches reduce the incidence of diabetic kidney disease and slow its progression. In fact, the significant reduction in the incidence of diabetic kidney disease (DKD) over the past 30 years and the improvement in patient prognosis is largely due to improvements in diabetes management. However, there is a need for innovative treatment strategies to prevent and control the progression of DKD. In this review, we summarize what is currently known about the pathogenesis of CKD in patients with diabetes and the key pathways and targets involved in its progression. In addition, we discuss the current evidence that supports the prevention and treatment of DKD and some of the controversies. Finally, we will explore ways to develop new interventions by making urgently needed investments in targeted and focused research.

Efficacy of Molnupiravir for the Treatment of Mild or Moderate COVID-19 in Adults: A Meta-Analysis

Article

Full-text available

May 2023

The aim of this meta-analysis is to evaluate the efficacy of molnupiravir among mild or moderate COVID-19 patients. This meta-analysis was reported according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Two authors independently performed a comprehensive search for relevant studies in PubMed, Cochrane Library, and Web of Science. The keywords used to search for relevant records were “Molnupiravir,” “COVID-19,” and “efficacy.” This meta-analysis included studies that compared the effectiveness of molnupiravir with a placebo for COVID-19 treatment. The primary outcome assessed in this meta-analysis was the composite of hospitalization and all-cause mortality (30 days). In addition, we assessed all-cause mortality and hospitalization separately and the number of patients who tested negative for viral RNA on day five. A total of 10 studies were included in the meta-analysis. Among the 10 studies, five were randomized controlled trials and five were observational studies. Based on the results presented in the meta-analysis, it can be concluded that molnupiravir has a significant impact on reducing all-cause mortality and improving the proportion of patients who test negative for viral RNA on day five. The risk of hospitalization and composite outcome was also lower in molnupiravir-treated patients, although the difference was statistically insignificant. The subgroup analysis showed consistent results across all subgroups, indicating that the effect of molnupiravir is consistent regardless of patient characteristics.

Comparison of Coronary Artery Bypass Grafting Combined With Mitral Valve Repair Versus Coronary Artery Bypass Grafting Alone in Patients With Moderate Ischemic Mitral Regurgitation: A Meta-Analysis

Article

Full-text available

Apr 2023

The aim of this meta-analysis was to compare clinical outcomes between those who underwent coronary artery bypass grafting (CABG) alone and CABG with mitral valve repair (MVR) in patients with moderate ischemic mitral regurgitation. The present study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two authors performed a comprehensive search of international databases, including PubMed, EMBASE, and the Cochrane Library, for relevant studies published from inception to March 1, 2023. The search was performed again before the submission of the manuscript on March 20, 2023. Primary outcomes assessed in the present meta-analysis included early mortality and long-term mortality. Secondary outcomes assessed in the present meta-analysis included change in New York Heart Association (NYHA) score from baseline, change in ejection fraction (EF) from baseline (%), and major cardiovascular events (MACE). A total of 13 studies were included in the present meta-analysis. Out of 13 included studies, four were randomized control trials (RCTs) and nine were retrospective cohort studies. The pooled analysis showed that early mortality was significantly lower in patients in the CABG group compared to the CABG+MVR group (risk ratio [RR]: 0.47, 95% confidence interval [CI]: 0.31, 0.70). Long-term mortality was also lower in patients who underwent CABG compared to patients in the CABG+MVR group. However, the difference was statistically insignificant (RR: 0.88, 95% CI: 0.77, 1.02). No significant differences were reported in the EF score between patients who underwent CABG and patients who underwent CABG plus MVR (mean difference [MD]: 0.40, 95% CI: -1.90, 2.69). NYHA score was significantly lower in patients in the CABG+repair group compared to the CABG alone group (MD: 0.39, 95% CI: 0.06, 0.72). In conclusion, our meta-analysis suggests that concomitant MVR during CABG may not improve clinical outcomes in patients with moderate ischemic mitral regurgitation. Further clinical trials are needed to investigate this intervention in more detail.

Comparison of Effectiveness and Safety of Low-Dose Versus Standard-Dose Intravenous Recombinant Tissue Plasminogen Activator in Patients With Acute Ischemic Stroke: A Meta-Analysis

Article

Feb 2024

Rao Ahmed Yousaf

Study on Recognition of Heart Arrhythmias by Deep Learning Approach of the ECG Signals using Edge Devices

Article

May 2023

The identification of heart arrhythmias is critical for timely and accurate diagnosis and treatment of cardiac diseases. Electrocardiogram (ECG) signals provide valuable information for detecting and diagnosing heart arrhythmias. However, the interpretation of ECG signals requires specialized medical knowledge and experience. In present years, deep learning techniques have shown promising results in ECG signal analysis for heart arrhythmia detection. This paper proposes a deep learning suggest to the identification of heart arrhythmias by utilizing ECG signals on edge devices. The proposed approach employs a convolutional neural network (CNN) framework to analyze the ECG signals and identify different types of heart arrhythmias. The CNN architecture is optimized for edge devices, ensuring that the proposed approach can be implemented in resource-constrained environments. To assess the effectiveness of the suggested strategy, a dataset containing ECG signals from patients with different types of heart arrhythmias Study on Recognition of Heart Arrhythmias by Deep Learning Approach of the ECG Signals using Edge Devices Section A-Research paper 6652 Eur. Chem. Bull. 2023, 12(Special Issue 4),6651-6658 is used. The experimental findings show that the suggested method successfully detects heart arrhythmias with high accuracy, up to 99.83%.Moreover, the proposed approach shows significant advantages in terms of execution time and energy consumption when compared to traditional ECG signal analysis techniques

A two-center, retrospective cohort trial of a tumor necrosis factor inhibitor coupled with intravenous immunoglobulin and heparin for the treatment of recurrent spontaneous abortion A two-center, retrospective cohort trial of a tumor necrosis factor inhibitor coupled with intravenous immunoglobulin and heparin for the treatment of recurrent spontaneous abortion

Article

May 2023

This retrospective cohort study investigates the effectiveness of combining tumor necrosis factor inhibitor (TNFi), intravenous immunoglobulin (IVIG), & heparin in the treatment of recurrent spontaneous abortion (RSA). The study was conducted at two centers and included 60 patients with a history of RSA who received the combination therapy. The major outcome measure was the live birth rate, with pregnancy problems and adverse events as secondary outcomes. The study found that the combination therapy was connected through a major enhancement in live birth rates differentiate to previous pregnancies (70% vs. 27.5%). The pregnancy complication rate was 16.7%, and no serious adverse events were reported. The results suggest that combining TNFi, IVIG, and heparin may be a promising treatment option for patients with RSA, but more research is needed to corroborate these findings. This retrospective, two-center cohort study explores the use of a combination recurrent spontaneous abortion is treated with a necrosis factor inhibitor, intravenous immunoglobulin, and heparin. The research start that this combo A two-center, retrospective cohort trial of a tumor necrosis factor inhibitor coupled with intravenous immunoglobulin and heparin for the treatment of recurrent spontaneous abortion Section: Research Paper 6377 Eur. Chem. Bull. 2023, 12(Special Issue 4),6376-6385 therapy was implied on better pregnancy outcomes & reducing the risk of recurrent miscarriage in women who have had a history of recurrent spontaneous abortion. The study highlights the importance of individualized treatment plans for women with this condition.

Sjögren's Syndrome Overlap With Lupus Nephritis: A Case Report and Literature Review of a Rare Entity

Article

May 2023

Overlap syndrome is a connective tissue disorder that satisfies the diagnostic criteria for at least two well-known autoimmune diseases. In this report, we describe a rare case of lupus overlap in an elderly woman with primary Sjögren's syndrome who presented with features of nephritic-nephrotic syndrome and renal biopsy results typical of lupus nephritis combined with multiple positive autoantibodies. The kidney biopsy results were assigned the highest weightage based on the revised 2019 systemic lupus erythematosus (SLE) classification criteria developed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). The patient's condition significantly improved after appropriate immunosuppressive therapy was initiated. With the revised ACR/EULAR-2019 criteria, we anticipate that more SLE patients with typical lupus nephritis biopsy findings will be diagnosed accurately.

Subarachnoid Hemorrhage in Autoimmune Vasculitis: A Rare Presentation of Systemic Lupus Erythematosus-Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis Overlap Syndrome

Article

Mar 2023

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), though they share similar clinical characteristics, are distinguishable based on specific characteristics. The concomitant presentation of SLE and AAV as overlap syndrome is rare and makes the diagnosis challenging. Here, we describe a rare case of SLE and AAV overlaps presenting with hemorrhagic stroke as initial presentation, which has been reported only once before. The presence of several positive autoantibodies made the diagnosis challenging, but a kidney biopsy provided the definitive diagnosis and aided in initiating immunosuppressive therapy. The patient did not respond to standard initial surgical measures to lower elevated intracranial pressure and showed significant improvement to immunosuppressive therapy proving the temporal relationship. The authors of this case study aim to highlight the importance of considering SLE-AAV overlap in patients presenting with features similar to those described in the case report and intervening early, as delays in diagnosis can be fatal.

Ceftazidime-induced Antibiomania: A Rare Case Study and Review of Literature

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Apr 2023

The aim of this article is to highlight the importance of recognizing the psychiatric side effects of antibiotics early and formulating effective management options to prevent detrimental effects on a patient's clinical condition. Antibiomania is a rare kind of secondary mania caused by antibiotics. We present the first case of antibiomania in a peritoneal dialysis patient caused by ceftazidime, a cephalosporin antibiotic. Manic symptoms were noticed in the patient mentioned here a few days after starting the antibiotic and worsened over the course of a few weeks of antibiotic treatment. In this instance, there is a close correlation between the start of antibiotic treatment and the emergence of manic symptoms. Antibiotics from various classes have been implicated as the causative agents in a few case reports of antibiomania. Several hypotheses have been proposed regarding the underlying mechanism of antibiomania.

Advances in Renal Diseases and Dialysis

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