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Faculty of Pharmacy, Bahuddin Zakariya University Multan, Pakistan
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INTRODUCTION:
Chronic renal failure, or end stage renal disease, is
a progressive and irreversible deterioration in
renal function in which the body unable to
maintain metabolic, fluid and electrolyte balance,
resulting in retention of urea and other
nitrogenous wastes in the blood. Chronic kidney
disease (CKD) is permanent damage to the
kidneys, if kidneys keep getting worse and can
lead to kidney failure (ESRD) (Brimble et al,
2012).The most common causes of ESRD are
diabetes, obesity, hypertension, cardiovascular
diseases and smoking. ESRD almost always
comes after chronic kidney disease (Gutiérrez et al,
2008).
Obesity
Excess weight is independent risk factor for end
stage renal disease. Obesity is associated with
increased insulin resistance and diabetes type 2
which is a major risk factor for ESRD(Siener
et,2004; Hallan et al, 2006). The most common
cause of end stage renal disease is the diabetes
mellitus. The average expectancy life of diabetic
dialysis patients is about five to six years. Because
these are at the high risk of cardiovascular
diseases. The dialyzed patients die due to cardiac
disease before their kidney diseases become
severe. This can be prevented by the strict
hyperglycemic control. When oral
antihyperglycemic therapy not suitable then
insulin is the best therapeutic option in these
patients.
Hypertension
It is one of the leading causes of chronic kidney
disease due to the deleterious effects on kidney
vasculature. Long-term, hypertension leads to
high intra glomerular pressure, impairing
Muhammad Hanif*1, Hina Javed1, Nazar Muhammad Ranjha1, Umair Jillani1
Prevalence of end stage renal disease in diabetic obese
and hypertensive patients and cardiovascular risk in
dialysis patients
Research Article
ABSTRACT
Chronic Kidney Disease (CKD) is cause of irreversible deterioration in renal function which leads to
end stage renal disease (ESRD). Incidence of end-stage renal disease has increased dramatically during
the last 30 years and screening for early stages of chronic kidney disease is often suggested as a
preventive measure. The main causes of end stage renal disease are diabetes, high blood pressure,
hyperlipidemia and obesity. Obesity and increased BMI are the cause of kidney stone and chronic
kidney disease. This report aims to determine the prevalence of end stage renal disease in diabetic obese
individuals and other problems that are more likely to be encountered in end stage renal disease are
cardiovascular risks in dialysis patients. GFR and Creatinine clearance are used as major diagnostic
tool to determine kidney function. Calcium level is also used as the predictive factor to determine the
vascular calcification.
Received: May 25, 2015
Revised: Dec 21, 2015
Accepted: Jan 11, 2016
Online: Jan 27, 2016
1Faculty of Pharmacy, Bahauddin Zakariya University, Multan, 60000 Pakistan
Keywords: Chronic kidney disease, ESRD, obesity, hypertension, GFR, creatinine clearance, cardiac vascular
death
*Corresponding Author : Muhammad Hanif,
Address:
Faculty of Pharmacy, Bahuddin Zakaryia
University, Multan, Pakistan
e-mail:
Muhammad.hanif@bzu.edu.pk
Ph: +92 3336103668
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glomerular filtration. Damage to the glomeruli
lead to an increase in protein filtration, resulting
in abnormally increased amounts of protein in the
urine (micro albuminuria or proteinuria). Micro
albuminuria is the presentation of small amounts
of albumin in the urine and is often the first sign
of chronic kidney disease. The relationship
between chronic kidney disease and hypertension
is cyclic, as chronic kidney disease can contribute
to or cause hypertension. Elevated blood pressure
leads to damage of blood vessels within the
kidney, as well as throughout the body. This
damage impairs the kidney's ability to filter fluid
and waste from the blood, leading to an increase
of fluid volume in the blood thus causing
hypertension (Brow et al.,1971; Gao et al
,2004).Adequate blood pressure control is the most
important factor for the preservation of renal
function, so every drug that effectively lowers
hypertension is believed to be renoprotective
(Wright et al,2002). The reason for the prevalence
of hypertension may be due to the inadequate
dialysis. There is evidence that the blood pressure
can be improved by long (more than 6 hours,
slower dialysis time.
Vascular calcification
It is known to be a risk factor for ischemic heart
disease in non-uremic individuals. Patients with
end stage renal disease experience accelerated
vascular calcification, due to dysregulation of
mineral metabolism. Vascular calcification is a
well-known complication of chronic kidney
disease and one of the main predictors for
increased cardiovascular morbidity and mortality
in these patients. It may happen in two main types
of intimal calcification, as a part of diffuse
atherosclerosis, and medial calcification, which is
generally focal in distribution, unrelated to
atherosclerotic risk factors, and seen in younger
hemodialysis patients. The extent of coronary
calcification was more pronounced with older age
male, gender, white race, diabetes, longer dialysis
vintage and higher serum concentrations of
calcium and phosphorus. Only dialysis vintage
was significantly associated with the prevalence
of vascular calcification (Bakris et al,2000) .
Cardiovascular disease is the major killer in end
stage renal disease. Left ventricular abnormalities
are present at initiation of dialysis in about 80% of
dialysis patients (Foley and Parfery,2012). Chronic
volume overload and anemia leading to left
ventricular hypertrophy and altered the calcium-
phosphate metabolism with vascular and coronary
calcification contribute to the pathogenesis of
IHD. Other risk factors that have been implicated
include oxidative stress, homocysteine, and
myocardial stunning while undergoing dialysis
treatment. Additional risk factors include
erythropoietin use for treating anemia, as well as
use of calcium-based phosphate binders
(Ariyamuthu et al,2012).
Hyperlipidemia
It is increased in patients having the chronic renal
disease. In end stage renal disease patients, the
low density lipoprotein level is high. Lipid
lowering drugs should be given to these patients.
Others risk factors for the end stage renal disease
are smoking which cause increase in blood
pressure release of vasopressin and renovascular
resistance.
PATHOPHYSIOLOGY
The basic pathophysiology of ESRD are Diabetes
and hypertension leads to the loss of nephron
mass which cause structural and functional
hypertrophy of remnant nephrons. This causes the
sclerosis of remnant nephrons and ultimately
leads to further loss of nephron mass and
permanent kidney damage (Coladonato, 2005). The
prevalence of glomerular hyperfiltration increased
with increasing stages of pre-diabetes and pre-
hypertension, glomerular hyperfiltration leads to
kidney damage (Taylor et al, 2005). Relationship
between obesity and kidney disease increases. The
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cause of renal damage due to obesity is not clearly
defined. Hyperlipidemias, hyperfilteration,
increased in sympathetic activity, increased
activity of rennin angiotensin system are the
contributing factors for the end stage renal
disease. ESRD is more prevalent in diabetic
patients. Diabetic nephropathy leads to RFD(renal
function decline) and thus reduced GFRs and
micro albuminuria and proteinuria which is the
major diagnostic tool in determining the end stage
renal disease stages (Pavkov et al, 2012; Taylor et
al,2012).
The major problems detected in the End Stage
Renal Disease were hypertension and the
cardiovascular diseases. Cardiovascular death is
the most frequent cause of dying in peritoneal
dialysis (PD) patients. Hypertension is the most
important general risk factor in PD patients, while
obesity remains controversial. Inflammation,
malnutrition, calcifications and probably
endothelial dysfunction and oxidative stress are
all cardiovascular risk factors present in ESRD
that contribute to mortality in PD patients.
Additional cardiovascular risk factors in PD are
related to the glucose load, leading to increasing
insulin resistance and a more atherogenic lipid
profile. Loss of residual renal function and ultra
filtration failure promote over hydration, which is
the most important PD-related risk factor for
cardio vascular disease ( Harnett et al,1995).
EPIDEMOLOGY
30% approximately patients having Diabetic
nephropathy progress to End-stage Renal failure
and rest population usually die due to
cardiovascular diseases before reach to End stage.
All these have developed microalbuminuria and
proteinuria. Albuminuria is the important risk
factor in all these Patients. The diabetic patients
must have to assess the microalbuminuria yearly.
(Diabetic nephropathy. Diabetes Care, 2002) The
renal diseases are strongly associated with
albuminuria. The cardiovascular event are the
prediction in the diabetic patients and also in the
general population (Verhave et al,2002). So the
patient having combination of hypertension,
diabetes, and the chronic kidney diseases are now
the most commonly cause of End-stage Kidney
failure. In the year 1996, there were the 100
Patients/million populations beginning Dialysis in
the Hong Kong. In 2000, this was increased to
122 Patients, and in the 2003, the 140
Patients/million population began treatments for
End-stage Renal failure. Similarly, these rates
have been increasing in United States, and with
the increasing in prevalence, it is predicted that by
the year 2010, this will be the almost 700,000.
There is costing an about US$30 millions in year
for the Dialysis treatments in United states.
(Lysaght,2002) Obviously, the treatment of such is
ever increasing the burden of End-stage renal
failure cannot be afforded, even in wealthiest
countries. In Hong Kong, renal Registry show
progressive increase in number of diabetics
beginning dialysis, which now represents 38% of
incident in Patients, while the only 23% were due
to the glomerulonephritis. In other countries
throughout the Asia also have large percentage of
their incidents End-stage renal failure Patients due
to the diabetes: the Pakistan 42%, the Taiwan
35%, the Philippines 25% and the Japan 37%
(USRDS 2003). It is also demonstrated that
relatively the steady acceptance rate of Type 1
Diabetes over this time, but progressively
increases in number of Type 2 Diabetic patients
have been accepted into Dialysis program over
past two decades. The diabetes is now major
cause of End-stage renal failure world widely in
the both developed countries and as well in the
emerged countries.
The risk of cardiovascular disease in patients with
chronic renal disease appears to be far greater
than in the general population. For example,
among patients treated by hemodialysis or
peritoneal dialysis, the prevalence of coronary
artery disease is approximately 40% and the
prevalence of left ventricular hypertrophy is
approximately 75%. Cardiovascular mortality has
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been estimated to be approximately 9% per year.
Even after stratification by age, gender, race, and
the presence or absence of diabetes,
cardiovascular mortality in dialysis patients is 10
to 20 times higher than in the general population.
Patients with chronic renal disease should be
considered in the highest risk group for
subsequent cardiovascular events. Cardiac failure
is more common in chronic renal disease patients
than in the general population, and is an
independent predictor of death in chronic renal
disease. Among hemodialysis and peritoneal
dialysis patients, the prevalence of cardiac failure
is approximately 40%. Both coronary artery
disease and left ventricular hypertrophy are risk
factors for the development of cardiac failure. In
practice, it is difficult to determine whether
cardiac failure reflects left ventricular dysfunction
or extracellular fluid volume overload. Patients
who develop clinical manifestations of cardiac
failure should be evaluated for cardiovascular
disease.
Symptoms of ESRD:
A patient having ESRD may experience these
symptoms:
Decrease in urine output
Difficulty to urinate
Fatigue
Headache
Weight loss
Appetite loss
Nausea
Vomiting
Dry skin
Itching
Bone pain
Skin color changed
Numbness
Excessive thirst
frequent hiccups
absence of menstrual cycles
obstructive sleep apnea
restless leg syndrome (RLS)
low libido or impotence
edema
DIAGNOSIS
To determine the prevalence of ESRD with
different diseases various diagnostic tests are
utilized to determine the RFD (renal function
decline) in patients. Blood and urine samples are
tested and radiographical imaging study
techniques are utilized to diagnose and determine
the stage of various comorbidities. The major
diagnostic tool to determine the kidney function is
GFR and creatinine clearance.
Glomerular filtration rate (GFR) Test
It is used to check how well the kidneys are
working. Specifically, it estimates how much
blood passes through the glomeruli each minute.
Glomeruli are the tiny filters in the kidneys that
filter waste from the blood. Increased GFR also
called hyper filtration is a proposed mechanism
for renal injury in several clinical conditions. A
GFR of 120–149 mL/min/1.73 m² may be
considered normal in Young adults (<30 years), in
whom a level that exceeds 150 mL/min/1.73 m²
may reflect hyperfiltration. Older people will have
lower normal GFR levels, because GFR decreases
with age. GFR of the 120–149 mL/min/ 1.73 m²
may thus represent the hyperfiltration in elderly
patients, whom have GFR of the 60-89
mL/min/1.73 m² is then considered normal.(
Okada et al,2012) Levels below mL/min/1.73 m2
for 3 or more months are a sign of chronic kidney
disease. GFR result lower than 15 mL/min/1.73
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m2 is a sign of kidney failure requires immediate
medical attention (Brimble et al, 2012).
Estimated glomerular filtration rate eGFR is
determined by formula:
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-
0.203 × (0.742 if female) × (1.212 if African
American)
The creatinine clearance Test
It involves a 24-hour urine collection, can also
provide an estimate of kidney function. It is also
major diagnostic tool of kidney function. The
creatinine clearance test helps provide
information about how well the kidneys are
working. The test compares the creatinine level in
urine with the creatinine level in blood. The
normal creatinine level is 50-110µmol/L or 0.6-
1.2mg/dL in serum and normal level of creatinine
in urine in males is 8.8- 17.6µmol/L or 1.0-2.0
g/24h and in females is 7.0-15.8µmol/L or 0.8-1.8
g/24h. Decreased Creatinine clearance is marker
of RFD (renal function decline) (Blacher et al,
1998).
It is calculated by various formulas as:
CL (cr) = (U× V)/S (2)
Where; U= urine creatinine clearance (µmol/L) ,
V is the urine flow rate (mL/min) , S is the serum
creatinine concentration (µmol/L).
The urine albumin-to-creatinine ratio
The albumin to creatinine ratio is determined
between albumin and the creatinine level in urine.
The Creatinine is waste material in blood which is
filtered through the both kidneys and then
excreted from the urine. Albumin Creatinine ratio
(ACR) is more than 30mg is the indicator of
chronic kidney disease (C O, 2012).
Normoalbuminuria = <30mg albumin/g Creatinine
Microalbuminuria =30 - 300 mg albumin/g Creatinine
Macroalbuminuria= > 300 mg/g Creatinine
The Dipstick test for albumin
The dipstick test is performed on urine sample
which detect the presence of albumin in urine.
Albumin is passed into urine when both kidneys
are damaged. The urine samples of patient are
collected in special container and then send it to
lab for the analysis. For this test, a technician
places a strip, called dipstick, into the urine
sample. The patches on the dipstick change the
color when there is protein or blood present in the
urine. Albuminuria is marker of progression of
CKD (Rao PK,,2008).
Renal ultrasound (sonography)
The sonography is used to determine the size and
shape of kidney and also used to detect the mass,
cyst, kidney stone, or any other obstruction or
abnormalities.
Kidney biopsy
This procedure involves the removal of tissue
samples (with a needle or during surgery) from
the body for examination under a microscope; to
determine if cancer or other abnormal cells are
present ( Mendelssohn D,1995).
Computed tomography scan (CAT scan)
A computed tomography scan shows the detail
images of any part of body, including bones, fat,
muscles and organs. The CT scans are more
detailed than the general X-rays. The contrast CT
cannot be done when there is renal
failure. (Herman, G. T, 2009)
Histological examination of the arterial
specimens
The gold standard for diagnosis of vascular
calcification would be histological examination of
the arterial specimens, which is not clinically
feasible. The other recommended diagnostic
techniques are electron beam computed
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tomography, which is more of research interest
and not accessible in most centers of the world;
ultrasonographic measurement of pulse wave
velocity or carotid intima-media thickness; and
plain radiography of the abdominal aorta ( Blacher
et al, 1999; Persson et al ,1994; Kauppila et al,1997;
Bellasi et al, 2006).
Determination of serum calcium level
Calcium level is also predictive factor to
determine the vascular calcification which is the
risk factor for ischemic heart diseases. A normal
serum calcium level is 8-10 mg/dL (2-2.5
mmol/L). Hypercalcemia is defined as a serum
calcium level greater than 10.5 mg/dL (>2.5
mmol/L). A high calcium level and phosphorus
was determined in patients with ESRD who
undergo dialysis ( Moe & Chen ,2004).
RESULTS AND DISCUSSION
End stage renal disease (ESRD) is more prevalent
in diabetic hypertensive patients and risk of
cardiovascular diseases is more in end stage renal
disease patients. The treatment of end stage renal
disease is only the dialysis and kidney transplant
but the cardiovascular death is more prevalent in
dialyzed patients due to increased serum
phosphate and calcium level in dialyzed patient.
Obesity has been identified as a risk factor for
single nephron hyperfiltration, increased
prevalence of chronic kidney disease (CKD), and
higher odds for end-stage renal disease (ESRD).
CKD and ESRD in obese individuals develop in
an incremental fashion directly proportional to
body mass index (BMI), independent of
hypertension and diabetes comorbidities. Obese
individuals with CKD seem to consume an
equivalent amount of daily protein and even fewer
total calories compared with obese non-CKD
controls; however, their leisure activity is
significantly less and they do not pursue weight
loss similar to their counterparts. These findings
highlight the importance of lifestyle and behavior
modification as risks for CKD in obese
individuals, although we cannot downplay the role
of prevalent comorbidities such as diabetes,
hypertension, dyslipidemia, and heart disease in
this population. End stage renal disease always
comes after chronic kidney disease whose stages
are determined by the GFR as given in the Table 1.
Table 1: Estimated values of GFR of renal disease
Stage
description
GFR(mL/min/1.73m²)
1
Kidne damage with
normal or ↑ GFR
≥90
2
Kidney damage with
mild ↓ GFR
60-89
3
Moderate ↓ GFR
30-59
4
Severe ↓ GFR
15-29
5
Kidney failure
<15(or dialysis)
CONCLUSION
Earlier stages of CKD are defined based on the
combination of kidney damage (most often
quantified using albuminuria) and decreased
kidney function (quantified as glomerular
filtration rate [GFR] estimated from the serum
creatinine concentration). Estimation of GFR
from serum creatinine is the recommended
approach for CKD staging at this time and
increasing evidence shows a strong association
with risk even when applied to the general
population. Because individuals with early stages
of CKD have a higher risk of cardiovascular
disease morbidity and mortality than their risk of
progression to kidney failure, cardiovascular risk
factor management is critical. The high
prevalence of CKD overall, and particularly
among older individuals and persons with
hypertension and diabetes, suggests that CKD
needs to be a central part of future public health
planning.
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