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Epidemic of end-stage renal disease in people with diabetes in the United States population: Do we know the cause?
Abstract
The number of individuals initiating renal replacement therapy in the United States population grew exponentially over the past two decades. Cases of end-stage renal diseae (ESRD) attributed to diabetes accounted for most of this increase. In this report we examined factors that may account for the increase to determine whether it truly represents an epidemic of ESRD due to diabetes.
We reviewed time trends in data of the United States Renal Data system, the Diabetes Surveillance Program of the Centers for Disease Control and Prevention, and diabetes literature.
Recent growth of the number of individuals with diabetes accounted for less than 10% of the increase in the number of diabetes-related ESRD. Instead, most of it was due to a threefold increase in risk of ESRD in people with diabetes and, therefore, qualifies as an epidemic. Curiously, this epidemic occurred despite widening implementation of effective renoprotective therapies. Individuals with type 2 diabetes, regardless of gender, age, or race, experienced the greatest increase in risk. There is no evidence that diabetic patients have been surviving longer, so the increased risk was not attributable to the high risk associated with long duration diabetes.
We hypothesize that an epidemic of ESRD has occurred in people with diabetes in the United States population over the last two decades. The nature of the factor responsible for the epidemic and the reasons it affects patients with type 2 diabetes particularly are unknown. Research efforts to identify the putative factor deserve high priority, as does a commitment of resources to provide care for the burgeoning number of patients with ESRD and type 2 diabetes.
... In most cases, the risk of developing complications can be reduced by following the principles of a healthy diet or targeted drug therapy associated with the optimization of blood sugar levels and lipids, undertaking a recommended amount of daily physical activity for weight control or the effective treatment of comorbid diabetes mellitus type 2 (T2DM) disorders such as hypertension [3,4]. Clinical observations provide evidence that not all people suffering from T2DM develop diabetic angiopathy, which is a major cause of morbidity and mortality during the course of T2DM [4,5]. In clinical practice, there is a group of patients without complications, despite having diabetes for many years or not having the best glycemic control. ...
... The VEGF is currently considered to be the main factor in regulating angiogenesis [20,21,24]. There are evidences that VEGF is a risk factor for different diabetes-associated microvascular and macrovascular complications in T2DM patients [1,4,5]. In recent years, several polymorphisms in the VEGF gene have been extensively studied in both type 1 and type 2 diabetes [27][28][29]. ...
Purpose:
Diabetes mellitus type 2 (T2DM) and its vascular complications are a serious world health problem. For this reason it is important to look for new diabetes complication risk factors. The aim of this study was to determine whether 18-bp insertion/deletion (I/D) polymorphism at -2549 position of the vascular endothelial growth factor (VEGF) gene is associated with diabetic vascular complications (DVC).
Material and methods:
Caucasian subjects (n = 100) with T2DM were recruited for this study. Genotyping of the VEGF gene I/D polymorphism was done by the polymerase chain reaction (PCR) method. The results were correlated with laboratory and clinical data.
Results:
In our population heterozygous of the VEGF gene polymorphism was observed most frequently (57%). DVC were observed in 53 patients. Heterozygous T2DM patients significantly more often suffered from heart failure (HF) and stroke (p = 0.05). Amongst all the DVC, D allele of the VEGF polymorphism had a significantly increased risk of diabetic retinopathy (DR) (OR = 1.31; p = 0.033) irrespective of the duration of diabetes, BMI, the glycemia control expressed by HbA1c, renal function, lipid values or applied treatment. The studied polymorphism did not correlate with coronary heart disease, peripheral vascular disease, cardiovascular death, diabetic kidney disease or applied treatment.
Conclusions:
The multivariate logistic regression analysis showed that the D allele in the promoter region of the VEGF gene is an independent risk factor of DR irrespective of other laboratory and clinical variables in T2DM patients. Our study suggests that I/D allele in the studied gene is associated with HF and strokes.
... Diabetic kidney disease (DKD), also known as diabetic nephropathy, affects nearly 40% of all patients with diabetes [1][2][3]. Despite improved management of DKD, including near universal implementation of renoprotective therapies, DKD remains the leading cause of end-stage renal disease (ESRD) worldwide and is associated with excess morbidity and premature mortality in patients with diabetes [1][2][3]. ...
... Diabetic kidney disease (DKD), also known as diabetic nephropathy, affects nearly 40% of all patients with diabetes [1][2][3]. Despite improved management of DKD, including near universal implementation of renoprotective therapies, DKD remains the leading cause of end-stage renal disease (ESRD) worldwide and is associated with excess morbidity and premature mortality in patients with diabetes [1][2][3]. As the incidence of diabetes continues to rise globally, so too has the incidence of DKD. ...
Diabetic kidney disease (DKD) is a devastating complication of Type 1 and Type 2 diabetes and leads to increased morbidity and mortality. Earlier work in families has provided strong evidence that heredity is a major determinant of DKD. Previous linkage analyses and candidate gene studies have identified potential DKD genes; however, such approaches have largely been unsuccessful. Genome-wide association studies (GWAS) have made significant contribution in identifying SNPs associated with common complex diseases. Thanks to advanced technology, new analytical approaches, and international research collaborations, many DKD GWASs have reported unique genes, highlighted novel biological pathways and suggested new disease mechanisms. This review summarizes the current state of GWAS technology; findings from GWASs of DKD and its related traits conducted over the past 15 years and discuss the future of this field.
... Это обусловлено главным образом фактическим ростом заболеваемости, в том числе ассоциированной с сердечно-сосудистой патологией и сахарным диабетом 2-го типа, а также увеличением продолжительности жизни больных [2]. В свою очередь диабетическая нефропатия -одно из наиболее тяжёлых сосудистых осложнений сахарного диабета 2-го типаприводит к развитию хронической почечной недостаточности, занимающей в развитых странах мира 1-2-е место по распространённости в структуре заболеваний почек различной этиологии [3] и угрожающей ранней инвалидизацией и гибелью пациентов. Несмотря на имеющиеся терапевтические стандарты ведения больных диабетической нефропатией и артериальной гипертензией, связанные преимущественно с приёмом лекарственных препаратов, позволяющих замедлить прогрессирование хронической болезни почек, данные подходы не способствовали существенному снижению уровня заболеваемости и частоты осложнений [4]. ...
BACKGROUND: In recent decades, there has been a progressive increase in the number of patients with chronic kidney disease worldwide, which is associated with both an actual increase in the incidence of the disease, associated with cardiovascular pathology and type 2 diabetes mellitus, among other things, and an increase in the life expectancy of patients. AIM: To assess hemodynamics of renal vessels during a course of magnetic laser therapy with the patients suffering from diabetic nephropathy caused by arterial hypertension against the background of the standard of care for this category of patients. MATERIALS AND METHODS: There has been carried out a randomized controlled trial on 100 patients with diabetic nephropathy caused by arterial hypertension. Their average age was 61,7 [52,8; 69,7] years old, the duration of arterial hypertension ― 24,1 [14,5; 36,1], type 2 diabetes mellitus ― 16,6 [14,9; 19,1] and diabetic nephropathy ― 6,1 [4,2; 8,9] years. In addition to general clinical studies, the patients in the control group (49 people) before and after prescribing the standard medication, and in the main group (51 people) with additional use of magnetic laser therapy, had their renal blood flow examined by Doppler ultrasound. RESULTS: The obtained data indicate the positive effect of magnetic laser therapy with the patients suffering from diabetic nephropathy caused by arterial hypertension on the hemodynamics of renal vessels with improved blood flow in arteries of both medium and small caliber, which, in turn, apparently should contribute to the normalization of the function of the capillary system of the renal parenchyma. CONCLUSION: The results of the given study allow us to recommend the use of magnetic laser therapy in the complex rehabilitation treatment of the patients with diabetic nephropathy caused by arterial hypertension taking into account the criteria for their strict selection.
... The major causes of ESRD have shifted towards diabetes, hypertension, and peripheral vascular diseases. In recent reports coming from Asia, these conditions now account for about 40-50% of all cases with ESRD, as well as established causes of CKD [13][14][15]. ...
The inevitable reality of today is that the world population is aging, and the elderly (above 65 years) are more prevalent among the dialysis population worldwide. Objectives: The purpose of this review is to do a literature search on issues related to dialysis in the elderly Asian population, such as vascular access outcomes, complication rates, and survival data by modality on hemodialysis (HD) and peritoneal dialysis (PD). Methods: A literature search on key topic areas was done on articles published in English between January 1, 2005 and December 31, 2015. Results: Although incidences of elderly dialysis patients are increasing in Asia, we found that large-scale data is lacking. Further research is needed to assess dialysis outcomes among the elderly. Available studies suggest acceptable outcomes in vascular access, primary and secondary patency rates, and similar intervention rates compared to non-elderly. Survival data suggests superior outcomes in HD in elderly. Due to significant differences in dialysis practices in Asia, a proper comparison is difficult. Conclusion: Age alone is not a contraindication for dialysis.
... 35% of patients treated with Hemodialysis stay alive after five years. 7, 8 Only limited publishedresearch is available from Pakistan focusing on the financial hardships of these patients. This study explores different categories of expenses and its impact on their life. ...
ABSTRAC Background:- Dialysis is the process of removing waste products and excess fluid from the body. Dialysis allows the patient with kidney failure a chance to live a productive life. Government Hospitals in Punjab providing free treatment to all Hemodialysis patients, Government introduced Sehat Sahoolat card for citizen of Pakistan for their family by providing 1 million rupees per year for every family. Most of the patients spending out of pocket expenditures to meet their medical demand and due to this burden some time they can’t continue their routine visit for Hemodialysis to sustain their daily life, the impact of this out pocket expenditure disturb the home budget as well as their treatment continuity. The purpose of this study to find out different categories of expenses and its impact on their treatment, Of patients being treated with dialysis about 10% receive peritoneal dialysis and the remainders receive Hemodialysis. Pakistan is among the lower middle income countries. It is reported that the cost of dialysis per patient is approximately international $4,003.03 per year. Dialysis is exhausting for patients and fraught with morbidity and eventual mortality. While out-of-pocket expenditure remains the major source of health care financing in Pakistan (two-thirds of the total health spending), the financial burden varies enormously across diseases and by the economic wellbeing of the households.1 Objectives: To assess out of pocket expenditures and health facility charges among patients undergoing dialysis at Services Hospital, Lahore. Study design: It was a descriptive Cross section study. Study setting: Dialysis unit of Services Hospital, Lahore. Sample size: The sample size was estimated by using WHO SS (Sample Size) software by using formula of estimating a population proportion with specific relative precision at confidence level of 75%, anticipated population proportion of 75% and relative precision of 10%. The maximum sample size is 130. Result: We audited records Mean out of pocket incurred both medical and non medical 4950/week while mean out of pocket charges on lab investigation were 10300/ during one year of dialysis, Study shows that those with co-morbidity but they lost the regularity treatment were 69.2% and having only renal dialysis 8.4% and lost the regular treatment due to out of pocket expenditures either expending from their own pocket or support from family. Highly significant with df=1 Chi squire=14.0793 P value=0.0001. Reason to lost continuity of treatment from 33 cases 90.9% due to out of pocket expenditures while 9.09% says due to other reason ,their source of income was personal and from family support respectively. df=1 Chi squire= 0.0143478 P value=0.90 Conclusion: Our research concluded that health facilities provided by the dialysis unit of Services hospital to the patients were considered to be average. Majority of patients who spent money on medicines and transport, were financially supported by their families. Government hospitals were preferred because medical facilities were affordable. Key words: Out of Pocket. Hemodialysis,Financial burden ,Co-Morbidity
... [1][2][3][4][5][6][7] Among patients with type 1 or 2 DM, 30%-40% develop diabetic kidney disease (DKD), with ~50% subsequently progressing to end-stage kidney disease that is associated with a high mortality rate. [8][9][10][11] Several factors can enhance the pathogenetic pathways initiated and sustained in the kidney by elevated glucose levels in DKD. These include metabolic factors, such as excess fatty acids, carbonyl and oxidative stress, as well as hemodynamic factors, shear stress induced by transmitted systemic hypertension, impaired autoregulation, hyperperfusion, hypoperfusion, and activation of the renin-angiotensin-aldosterone system. ...
Diabetic kidney disease (DKD) develops in ~40% of patients with diabetes and is the leading cause of chronic kidney disease worldwide. We used single‐cell RNA‐sequencing and spatial transcriptomic analyses of kidney specimens from patients with DKD. Unsupervised clustering revealed distinct cell clusters, including epithelial cells and fibroblasts. We also identified differentially expressed genes (DEGs) and assessed enrichment, and cell–cell interactions. Specific enrichment of DKD was evident in venous endothelial cells (VECs) and fibroblasts with elevated CCL19 expression. The DEGs in most kidney parenchymal cells in DKD were primarily enriched in inflammatory signaling pathways. Intercellular crosstalk revealed that most cell interactions in DKD are associated with chemokines. Spatial transcriptomics revealed that VECs co‐localized with fibroblasts, with most immune cells being enriched in areas of renal fibrosis. These results provided insight into the cell populations, intercellular interactions, and signaling pathways underlying the pathogenesis and potential targets for treating DKD.
... As of 2013, the prevalence of diabetes in China was 11.6%, with nearly 113.9 million adults suffering from diabetes [1]. Diabetic nephropathy (DN) is a serious microvascular complication that is often associated with type 1 and type 2 diabetes and is the leading cause of renal failure [2]. DN is often characterized by an increase in urinary albumin excretion rates (AERs) and a decrease in glomerular filtration rates (GFRs). ...
Diabetic nephropathy (DN) is a major microvascular complication in diabetic patients. It has become the leading cause of end-stage renal disease (ESRD) in individuals living in urban areas undergoing dialysis. DN diagnosis primarily depends on the course of diabetes and the detection of albuminuria. However, the onset of DN is obscure, and many patients have already developed ESRD when they are diagnosed with DN. Hence, early diagnosis of DN progression and early interventional strategies are essential. Noncoding RNAs (ncRNAs) are a class of RNA transcripts that are transcribed from DNA but are not translated into proteins. They play an important role in regulating gene expression and protein synthesis. Several studies have demonstrated that ncRNAs are abundantly present in the blood, urine, and tissues and have the potential to aid in the diagnosis and treatment of DN. This review focuses on the role of microRNAs, long ncRNAs, and circular RNAs in DN and their potential value as biomarkers and therapeutic targets.
... However, many studies reported that the male sex is still a risk factor for the development of renal disease in DM [40][41][42][43]. In contrast, Orchard et al. [44] reported that the female sex appears to accelerate the renal disease progression in DM. ...
... Due to the dependence of exogenous insulin complement on blood glucose control and poor adherence of children, the blood glucose of children with T1D tends to fluctuate greatly and have severe complications, including microangiopathy and cardiovascular disease. Diabetic microvascular lesions can invade patients' retina, kidney, nerves and other important organs, when serious can cause blindness, kidney failure, neuropathy, and even life-threatening [2][3][4]. Early diagnosis and treatment of microvascular complications of T1DM are extremely important to improve the quality of life and prolong the life span of patients [5,6]. ...
Background:
Fibroblast growth factor 19 (FGF19) takes part in maintaining the balance of glycolipids and may be involved in complications of type 1 diabetes(T1D) in children. This study aimed at at evaluating the relationship among the levels of serum FGF19 and vascular endothelial growth factor(VEGF)and soluble klotho protein(sklotho) in type 1 diabetic children.
Methods:
In a cross-section single center study samples were obtained from 96 subjects: 66 T1D and 30 healthy children.Serum FGF19 and VEGF and sklotho concentrations were measured by ELISA. And 66 type 1 diabetes participants were divided into two groups according to T1D duration or three groups according to HbA1c.Furthermore,we compared the serum levels of FGF19 and VEGF and sklotho in different groups.
Results:
The concentration of FGF19 was lower in T1D than in the controls(226.52 ± 20.86pg/mu vs.240.08 ± 23.53 pg/L, p = 0.03),while sklotho was also lower in T1D than in the controls (2448.67 ± 791.92pg/mL vs. 3083.55 ± 1113.47pg/mL, p = 0.011). In contrast, VEGF levels were higher in diabetic patients than in controls (227.95 ± 48.65pg/mL vs. 205.92 ± 28.27 pg/mL, p = 0.016). In T1D, FGF19 and VEGF and sklotho was not correlated with the duration of diabetes. FGF19 and VEGF and sklotho were correlated with HbA1c (r=-0.349, p = 0.004 and r = 0.302, p = 0.014 and r=-0.342, p = 0.005, respectively), but not with blood glucose and lipid. Among subjects in the T1D group, concentrations of FGF19,VEGF and sklotho protein were different between different groups according to the degree of HbA1c(P < 0.005).Furthermore, there was a positive correlation between the serum FGF19 concentration and sklotho levels (r = 0.247,p = 0.045), and a negative correlation between the serum FGF19 concentration and VEGF level(r=-0.335,P = 0.006).
Conclusions:
The serum FGF19 levels have a close relation with serum VEGF levels and sklotho levels among T1D subjects. FGF19 may be involved in the development of complications in children with type 1 diabetes through interaction with VEGF and sklotho.
... Thus, the public health burden from DNP is enormous. Current evidence suggests that both genetic and environmental factors determine susceptibility to develop DNP and the risk for and rate of progression of DNP (4) . The decrease in renal function in diabetic nephropathy is characterized by glomerular dysfunction, which is closely related to elevated urinary albumin excretion. ...
... La diabetes mellitus (DM) afecta tempranamente al riñón. Puede finalizar en enfermedad renal crónica (ERC) severa y constituir el principal motivo de terapia de remplazo renal (TRR) que demanda un control exhaustivo endocrino-metabólico en los pacientes que dializan 1,2 . La DM como causa mayor de muerte (enfermedad no transmisible) en el mundo varía por región 3 . ...
La pandemia por enfermedad por coronavirus 2019 (COVID-19) aumentó la mortalidad mundial, más en poblaciones vulnerables como pacientes bajo terapia de remplazo renal (TRR). Se propuso evaluar la mortalidad de pacientes en TRR y si hubo diferencias entre las personas con o sin diabetes (DM). Métodos: Estudio retrospectivo, observacional de pacientes en TRR con SARS-CoV-2 por prueba de la reacción en cadena de la polimerasa transcriptasa reversa (RT-PCR) ingresados con distrés respiratorio para asistencia respiratoria al Hospital IESS Quito Sur (Ecuador, abril-diciembre 2020). Resultados: población de 93 pacientes bajo TRR con COVID-19 y dificultad respiratoria; media de edad de 65.6 años; hombres el 80.6%. La mortalidad fue del 36%, 38% con DM y 34.9% sin DM (χ2: 0.098; p = 0.75). Se observó que con mayor compromiso tomográfico pulmonar (3.1%; intervalo de confianza del 95% [IC95%]: –23.2 a 17.0%) aumentó la mortalidad (χ2: 3.409; p = 0.492), pero el único factor de riesgo de muerte fue la edad mayor a 60 años (odds ratio [OR]: 6.92; IC95%: 1.212-39.505). Conclusiones: Los pacientes internados en un Hospital de Quito bajo TRR tuvieron más dificultad respiratoria y mayor mortalidad por COVID-19 que la población general (más elevada que lo informado en el resto del mundo). No hubo diferencia de mortalidad entre pacientes con o sin diabetes (otras etiologías de enfermedad renal). La edad constituyó el mayor factor de riesgo de muerte por COVID-19 en pacientes bajo TRR.
... Diabetic nephropathy is the commonest etiology of end-stage renal disease (ESRD) worldwide. The number of patients suffering from DM and associated CKD is increasing and is said to be epidemic in distribution with poor prognosis [6] . So CKD is commonly associated with abnormal metabolism of carbohydrate, resistance to insulin and infection by HCV [7] . ...
Background: Hepatitis C virus infection has strong relationship with insulin resistance in general population. Insulin resistance increases risk of cardiovascular events in chronic kidney disease patients.This work is intended to study the interrelation between Hepatitis C virus infection and insulin resistance among end stage renal disease patients on regular hemodialysis. Methods: It included a total number of 90 subjects. They were divided into two groups: Group 1 (45 subjects Hepatitis C viruspositivepatientson regular hemodialysis), Group 2 (45 subjects Hepatitis C virusnegative patients on regular hemodialysis).All patients included in this study were subjected to the following: Full clinical assessment,Complete blood picture, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea, fasting plasma glucose, Coagulation profile, serum calcium, serum phosphorus, serum parathyroid hormone, Hepatitis C virusantibodies, human immunodeficiency virus antibodies, hepatitis surface antigen, fasting serum insulin and fasting serum C-peptide. Results: Our study reported that no statically significant difference in Homeostatic model assessment of insulin resistance between the two studied groups. Homeostatic model assessment of insulin resistance has significant correlation to age, weight, body mass index,serum parathyroid hormone, serum creatinine, urea reduction ratio and serum ferritin. Conclusion: We couldn't detect any strong correlation between Hepatitis C virus seropositivity and insulin resistance in hemodialysis patients, but we detected strong relationship of insulin resistance to age, weight, body mass index, serum parathyroid hormone, serum creatinine, urea reduction ratio and serum ferritin in hemodialysis patients.
... One of the reasons should be effective pediatric diabetes education with the support of the project of Standardized Management of Children with Diabetes and the Chinese Children's Diabetes Collaborative Group (22). The growing burden of T2DM-related CKD may be due to the increasing burden of T2DM in China, which accounts for 90% of all diabetes and has an increasing trend mainly due to dietary changes and physical inactivity brought by urbanization (24); moreover, CKD is more prevalent in T2DM patients due to their prolonged life expectancy (4,(25)(26)(27). The age-standardized rates of both T1DM-and T2DM-related CKD were declined over decades, contrary to the rates globally which increased in 2019 compared to 1990 (3), indicating that the overall increase in the numbers in China might have been partly driven largely by population growth. ...
Objective
To analyze the trends in disease burden of diabetes-related chronic kidney disease (CKD) by year, age, gender and types of diabetes in China from 1990 to 2019.Methods
Data on prevalence, deaths and disability-adjusted life years (DALYs) for diabetes-related CKD were extracted from the Global Burden of Disease (GBD) 2019 study. Analyses were performed by year, age, gender and types of diabetes.ResultsIn China, the numbers of deaths and DALYs of diabetes-related CKD continuously increased but the age-standardized rates (per 100,000 population) decreased over 30 years, in which the numbers of deaths and DALYs attributable to type 1 diabetes mellitus (T1DM)-related CKD barely changed and the age-standardized rates decreased over the years; and the number of deaths and DALYs attributable to type 2 diabetes mellitus (T2DM)-related CKD continuously increased, but the age-standardized rates also decreased. In 2019, 76.03 (58.24-95.61) thousand deaths and 2.13 (1.65–2.67) million DALYs were attributable to diabetes-related CKD, of which, T2DM accounted for 83.32% and 77.0% respectively, and T1DM accounted for the rest. Increasing gender disparity was seen, with males being more heavily impacted. The burden of diabetes-related CKD varied among different age groups, with the numbers of deaths and DALYs attributable to T1DM-related CKD peaking between 45 and 54 years of age and T2DM-related CKD peaking between 75 and 79 years of age; and the crude rates of deaths and DALYs attributable to T1DM-related CKD peaking between 70 and 79 years of age and 40 to 54 years of age, respectively, and T2DM-related CKD peaking over 90 years of age. Among neighboring and G20 countries, the burden of diabetes-related CKD in China was relatively controlled reflected by the ranking of adjusted death and DALYs rates.Conclusions
The burden of diabetes-related CKD in China worsens and shows gender disparities and different age distribution. Greater efforts are needed to improve the health outcomes of these patients, especially among males.
... Diabetic nephropathy (DN), namely, diabetic kidney disease (DKD), is known to be a prevalent microvascular complication of diabetes mellitus (7,90). It was estimated that more than 40% of individuals with T1DM or T2DM will suffer from DN in their lifespan, Moreover, half of these patients could progress to endstage renal disease (ESRD), which would significantly increase the mortality rate of patients with diabetes (5,183,184). DN is characterized by glomerulosclerosis, epithelial-mesenchymal transition (EMT) of tubular cells, hypertrophy and proliferation of mesangial cells, apoptosis of podocytes, renal vascular disease and so on (185,186). ...
Diabetes mellitus (DM) and its related complications are among the leading causes of disability and mortality worldwide. Substantial studies have explored epigenetic regulation that is involved in the modifications of DNA and proteins, but RNA modifications in diabetes are still poorly investigated. In recent years, posttranscriptional epigenetic modification of RNA (the so-called ‘epitranscriptome’) has emerged as an interesting field of research. Numerous modifications, mainly N6 -methyladenosine (m6A), have been identified in nearly all types of RNAs and have been demonstrated to have an indispensable effect in a variety of human diseases, such as cancer, obesity, and diabetes. Therefore, it is particularly important to understand the molecular basis of RNA modifications, which might provide a new perspective for the pathogenesis of diabetes mellitus and the discovery of new therapeutic targets. In this review, we aim to summarize the recent progress in the epitranscriptomics involved in diabetes and diabetes-related complications. We hope to provide some insights for enriching the understanding of the epitranscriptomic regulatory mechanisms of this disease as well as the development of novel therapeutic targets for future clinical benefit.
... However, data from a review study confirmed that the risk of incidence of non-diabetic renal disease was higher among men than among age-matched women without diabetes. It suggested that a possible mechanism for the deficiency of the distinct sex discrepancy in the status of diabetes might be due to the imbalance of sex hormone levels with diabetes 29 . This finding was consistent with that of the current study. ...
Objective:
The metabolic score for insulin resistance(METS-IR) is a novel noninsulin-based metabolic index used as a substitution marker of insulin resistance. However, whether METS-IR is associated with the urinary albumin-creatinine ratio(UACR) is not well known. Therefore, we explored the associations between METS-IR and UACR and compared the discriminative ability of METS-IR and its components for elevated UACR.
Methods:
This study included 37,290 subjects. METS-IR was calculated as follows:(Ln[2×fasting blood glucose(FBG)+fasting triglyceride level(TG0 )]×body mass index(BMI))/[Ln(high-density lipoprotein cholesterol(HDL-C))]. Participants were divided into four groups on the basis of METS-IR:<25%, 25%-49%, 50%-74%, and≥75%. Logistic regression analyses were conducted to determine the associations between METS-IR vs. its components (FBG, TG0 , BMI, and HDL-C) with UACR.
Results:
Participants with the highest quartile METS-IR presented a more significant trend towards elevated UACR than towards its components(odds ratio[OR]:1.260, 95%CI:1.152-1.378, P<0.001 in all subjects; OR:1.321, 95%CI:1.104-1.579, P=0.002 in men; OR:1.201, 95%CI:1.083-1.330, P<0.001 in women). There were significant associations between METS-IR and UACR in younger participants(<65 years for women and 55-64 years for men). Increased METS-IR was significantly associated with UACR in men with FBG≥5.6 or postprandial blood glucose≥7.8, mmol/L and systolic blood pressure≥120 or diastolic blood pressure≥80, mmHg. The relationships were significant in women with diabetes and hypertension.
Conclusions:
Increased METS-IR was significantly associated with elevated UACR, its discriminative power for elevated UACR was superior to that of its components.
... Diabetic kidney disease (DKD) is the most important chronic kidney disease (CKD), requiring renal replacement therapy [2]. Moreover, the prevalence of dialysis due to DKD-induced end-stage renal disease (ESRD) has exceeded that of glomerulonephritis-related ESRD in the U.S., and the number is increasing [3]. Several large clinical studies such as the action in diabetes and vascular disease: Preterax and Diamicron modified release controlled evaluation (ADVANCE) study, the UK prospective diabetes study (UKPDS), and the action to control cardiovascular risk in diabetes (ACCORD) trial indicated that intensive glycemic control could reduce the risk of DKD [4][5][6][7]. ...
Diabetes-induced endothelial pathologies are hypothesized to lead to the progression of diabetic kidney disease (DKD). The endothelial to mesenchymal transition (EndMT) possibly induces fibrosis, leading to glomerulosclerosis in the kidney. Furthermore, this could lead to albuminuria in diabetic nephropathy due to glomerular endothelial dysfunction. Eicosapentaenoic acid (EPA), purified from fish oil, decreases inflammatory cytokine levels in glomerulonephritis. Here, we aimed at finding whether ethyl eicosapentaenoate (EPA-E) exerts renal protective effects via EndMT inhibition. To find out whether EPA inhibits EndMT in vitro, the changes in CD31 expression were studied in cultured mouse endothelial cells. The addition of the conditioned medium from the adipocyte culture significantly decreased the protein levels of CD31, while the addition of EPA-E partially reversed this inhibition. Further, EndMT inhibition by EPA-E treatment might occur via the inhibition of the protein kinase Cβ (PKCβ)/transforming growth factor-β (TGF-β)/plasminogen activator inhibitor-1 (PAI-1) signaling and not via microRNAs. Streptozotocin-induced diabetic mice fed a high-fat diet (60% from fat) exhibited mesangial expansion and albuminuria. Induction of EPA-E ameliorated the mesangial expansion and decreased albuminuria without affecting blood pressure, triglyceride and free fatty acid levels, and intraperitoneal glucose. These findings suggest that EPA-E exerts renal protective effects on endothelial cells, by normalizing EndMT followed by the PKCβ/TGF-β/PAI-1 signaling. Thus, EPA-E has the potential for imparting renal protection by regulating EndMT in DKD.
... Hypertension is a growing public health concern worldwide and is a major risk factor for increasing morbidity and mortality from strokes, cardiovascular diseases, and renal failure [1]. However, it often remains clinically silent until complications arise. ...
The thiazide-sensitive sodium chloride cotransporter (NCC) in the distal convoluted tubule is responsible for reabsorbing up to one-tenth of the total filtered load of sodium in the kidney. The actin cytoskeleton is thought to regulate various transport proteins in the kidney but the regulation of the NCC by the actin cytoskeleton is largely unknown. Here, we identify a direct interaction between the NCC and the cytoskeletal protein filamin A in mouse distal convoluted tubule (mDCT15) cells and in the native kidney. We show that the disruption of the actin cytoskeleton by two different mechanisms downregulates NCC activity. As filamin A is a substrate of the Ca2+/calmodulin-dependent protein kinase II (CaMKII), we investigate the physiological significance of CaMKII inhibition on NCC luminal membrane protein expression and NCC activity in mDCT15 cells. The pharmacological inhibition of CaMKII with the compound KN93 increases the active form of the NCC (phospho-NCC) at the luminal membrane and also increases NCC activity in mDCT15 cells. These data suggest that the interaction between the NCC and filamin A is dependent on CaMKII activity, which may serve as a feedback mechanism to maintain basal levels of NCC activity in the distal nephron.
... It is histologically defined by renal glomerular hypertrophy, expansion of mesangial and tubular compartments, accumulation of mesangial extracellular matrix proteins, and podocytopenia associated with foot process effacement. 2 DN is a complex multifactorial disease caused by multiple genetic and environmental factors. Genetics alone cannot fully explain the variability in the incidence of nephropathy and the uneven distribution and graveness of complications in diabetic patients. ...
Diabetic nephropathy (DN) is a lethal microvascular complication associated with Type 1 and Type 2 diabetes mellitus, and is the leading single cause of end-stage renal disease. Although genetic influences are important, epigenetic mechanisms have been implicated in several aspects of the disease. The current therapeutic methods to treat DN are limited to slowing disease progression without repair and regeneration of the damaged nephrons. Replacing dying or diseased kidney cells with new nephrons is an attractive strategy. This review considers the genetic and epigenetic control of nephrogenesis, together with the epigenetic mechanisms that accompany kidney development and recent advances in induced reprogramming and kidney cell regeneration in the context of DN.
... Diabetic nephropathy (DN) is a devastating diabetic microvascular complication in the diabetic patients and the main cause of end stage renal disease (ESRD) and renal failure [1][2][3]. In China about 21.3% of all diabetic patients suffer from diabetic kidney diseases [4]. ...
PurposeDiabetic nephropathy (DN), one of severe diabetic complications in the diabetes, is the main cause of end stage renal disease (ESRD). Notably, the currently available medications used to treat DN remain limited. Here, we determined whether berberine (BBR) could enhance the anti-diabetic nephropathy activities of metformin (Met) and explored its possible mechanisms.Method
The anti-diabetic nephropathy properties were systematically analyzed in the diabetic db/db mice treated with Met, BBR or with combination of Met and BBR.ResultsWe found that both single Met and BBR treatments, and combination therapy could lower blood glucose, and ameliorate insulin resistance. The improvement of lipids metabolism by co-administration was more evident, as indicated by reduced serum cholesterol and less fat accumulation in the liver. Further, it was found that Met and BBR treatments, and co-administration could attenuate the progression of DN. However, anti-diabetic nephropathy activities of Met were enhanced when combined with BBR, as evidenced by improved renal function and histological abnormalities of diabetic kidney. Mechanistically, BBR enhanced renal-protective effects of Met primarily through potently promoting expression of Trib1, which subsequently downregulated the increased protein levels of CCAAT/enhancer binding protein α (C/EBPα), and eventually inhibited fatty synthesis proteins and nuclear factor kappa-B (NF-κB) signaling.Conclusion
Our data provide novel insight that co-administration of BBR and Met exerts a preferable activity of anti-diabetic nephropathy via collectively enhancing lipolysis and inhibiting inflammation. Combination therapy with these two drugs may provide an effective therapeutic strategy for the medical treatment of diabetic nephropathy.
... The worldwide prevalence of type 2 diabetes mellitus has rapidly increased over the past 30 years as a result of changes in the population distribution, namely, aging of the general population (Worldwide trends in diabe, 2016), indicating that the prevalence of microvascular complications, such as diabetic nephropathy (DN) and neuropathy and macrovascular complications, such as cardiovascular diseases, has also increased (Liyanage et al., 2015;Shah and Brownlee, 2016;Yoshida et al., 2020). In particular, DN has been a social issue in that the number of people requiring hemodialysis for end-stage renal disease (ESRD) has been increasing rapidly, and diabetic nephropathy is the most common indication for maintenance hemodialysis (System (2019)., 2019; Jones et al., 2005). However, the mechanisms underlying DN pathogenesis are still not fully understood, and no specific treatment is currently available for DN. ...
Recently, epigenetic alterations have been shown to be involved in the pathogenesis of diabetes and its complications. Kidney podocytes, which are glomerular epithelial cells, are important cells that form a slit membrane-a barrier for proteinuria. Podocytes are terminally differentiated cells without cell division or replenishment abilities. Therefore, podocyte damage is suggested to be one of the key factors determining renal prognosis. Recent studies, including ours, suggest that epigenetic changes in podocytes are associated with chronic kidney disease, including diabetic nephropathy. Furthermore, the association between DNA damage repair and epigenetic changes in diabetic podocytes has been demonstrated. Detection of podocyte DNA damage and epigenetic changes using human samples, such as kidney biopsy and urine-derived cells, may be a promising strategy for estimating kidney damage and renal prognoses in patients with diabetes. Targeting epigenetic podocyte changes and associated DNA damage may become a novel therapeutic strategy for preventing progression to end-stage renal disease (ESRD) and provide a possible prognostic marker in diabetic nephropathy. This review summarizes recent advances regarding epigenetic changes, especially DNA methylation, in podocytes in diabetic nephropathy and addresses detection of these alterations in human samples. Additionally, we focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes. Furthermore, epigenetic memory in diabetes is discussed. Understanding the role of epigenetic changes in podocytes in diabetic nephropathy may be of great importance considering the increasing diabetic nephropathy patient population in an aging society.
... Diabetes mellitus type 1 and type 2 will inevitably result in diabetic nephropathy (DN) at some point, which features a progressive leak of circulating albumin into the urine and thus can be empirically staged according to the severity of the leakage, i.e., normal albuminuria, moderately increased albuminuria (previously known as microalbuminuria), and severely increased albuminuria (previously known as macroalbuminuria) [1][2][3]. Although long-term epidemiologic studies have shown that not all diabetic patients will progress to DN, it has been estimated that approximately 25-40% of diabetic patients eventually develop kidney disease [4]. ...
One of the major complications of diabetes mellitus is diabetic nephropathy (DN), the pathogenesis of which is primarily driven by oxidative stress. As a major regulator of antioxidant responses, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has recently attracted much interest. NRF2 is a primary defense mechanism against the cytotoxic effects of oxidative stress, involving heterogeneous detoxification, the production of antioxidants and anti-inflammatory molecules, DNA repair, nuclear chaperones, and proteasome systems. A myriad of studies in pre-clinical models of DN have consistently demonstrated a beneficial effect of NRF2 activation, suggesting that NRF2 is likely a promising target for treating DN. This has been further supported by findings from clinical trials of bardoxolone methyl, an activator of NRF2, despite the unexpected adverse cardiovascular effects. This review summarizes the support for therapeutic targeting of NRF2 in DN and emphasizes the need for the optimization of NRF2-based treatment with the minimization of potential adverse effects.
... However, this renoprotective effect was only evident in premenopausal female (19,20). Once patients suffer from diabetes, the renoprotective effect of female is generally considered lost, even in premenopausal female (21). Accumulating evidence A B FIGURE 2 | Sex difference and ESKD. ...
Background:
To investigate the association between sex differences and end-stage kidney disease (ESKD) in patients with biopsy-confirmed diabetic kidney disease (DKD).
Method:
We performed a retrospective cohort study. A total of 336 patients with biopsy-confirmed DKD who were followed up for at least 12 months were enrolled. Baseline clinical and pathological data at the time of biopsy were collected. ESKD was defined by an estimated glomerular filtration rate of <15 ml/min/1.73 m2 or initiation of renal replacement therapy. The association between sex differences and ESKD was assessed using the log-rank test and Cox regression.
Result:
There were 239 (71%) male and 97 (29%) female patients in our cohort. Female patients had higher systolic blood pressure, total cholesterol and low-density lipoprotein cholesterol levels compared with male. There were a lower proportion of female patients in the very high risk grade according to the chronic kidney disease categories (37% of female vs. 44% of male). During a median follow-up time of 20 months, 101 (57.7%) male and 43 (44.3%) female entered into ESKD, with no significant difference by the log-rank test (P >0.05). Univariate [male: hazard ratio (HR) [95% confidence interval (CI)], 1.005, (0.702-1.439)] and multivariable ([male: HR (95%CI), 1.164, (0.675-2.007)]. Cox regression further showed that sex difference was not significantly associated with ESKD.
Conclusion:
Female patients had the higher systolic blood pressure, total cholesterol, LDL-C, compared with male patients. However, there was no significant association observed between sex difference and ESKD in our study.
... e variation could be the fact that men have more muscle mass than women, and the differences in hormone metabolism and glomerular structure are assumed to play a role in the differences in prevalence of CKD observed between male and female genders [68]. Additionally, in the setting of diabetes, it is generally believed that female sex as a protective factor is lost even before menopause [69], possibly due to the imbalance in sex hormone levels and activity. e present study revealed that age>60 years leads to a three times greater likelihood of developing CKD. is finding is in support of previous studies conducted in Nigeria [11] and a systematic review of diabetic nephropathy in Africa [70]. ...
Background. Though different primary studies have reported the burden of chronic kidney disease among diabetes patients, their results have demonstrated substantial variation regarding its prevalence in Ethiopia. Therefore, this study aimed to estimate the pooled prevalence of chronic kidney disease and its associated factors among diabetes patients in Ethiopia. Method. PubMed, African Journals Online, Google Scholar, Scopus, and Wiley Online Library were searched to identify relevant studies. The I² statistic was used to check heterogeneity across the included studies. A random-effects model was applied to estimate the pooled effect size across studies. A funnel plot and Egger’s regression test were used to determine the presence of publication bias. All statistical analyses were performed using STATA™ version 14 software. Result. In this meta-analysis, a total of 12 studies with 4,075 study participants were included. The estimated prevalence of CKD among diabetes patients was found to be 35.52% (95% CI: 25.9–45.45, I² = 96.3%) for CKD stages 1 to 5 and 14.5% (95% CI: 10.5–18.49, I² = 91.1%) for CKD stages 3 to 5. Age greater than 60 years (OR = 2.99; 95% CI: 1.56–5.73), female sex (OR = 1.68; 95% CI: 1.04–2.69), duration of diabetes >10 years (OR = 2.76; 95% CI: 1.38–5.51), body mass index >30 kg/m² (OR = 2.06; 95% CI: 1.41–3.00), type 2 diabetes (OR = 2.54; 95% CI: 1.73–3.73), poor glycemic control (OR = 2.01; 95% CI: 1.34–3.02), fasting blood glucose >150 mg/dl (OR = 2.58; 95% CI: 1.79–3.72), high density lipoprotein >40 mg/dl (OR = 0.48; 95% CI: 0.30–0.85–25), systolic blood pressure>140 mmHg (OR = 3.26; 95% CI: 2.24–4.74), and diabetic retinopathy (OR = 4.54; CI: 1.08–25) were significantly associated with CKD. Conclusion. This study revealed that the prevalence of chronic kidney disease remains high among diabetes patients in Ethiopia. This study found that a long duration of diabetes, age>60 years, diabetic retinopathy, female sex, family history of kidney disease, poor glycemic control, systolic blood pressure, overweight, and high level of high-density lipoprotein were associated with chronic kidney disease among diabetic patients. Therefore, situation-based interventions and context-specific preventive strategies should be developed to reduce the prevalence and risk factors of chronic kidney disease among diabetes patients.
1. Background
Chronic kidney disease (CKD) is defined as structural/functional abnormalities of the kidney or decreased GFR <60 ml/min/1.73 m² for 3 months [1]. It is an emerging global public health problem [2]. Globally, in 2017, there were 697.5 million cases of all-stage CKD, and 1.2 million people died each year due to high economic cost treatment [3]. In addition, it has been estimated that, by the year 2030, approximately 2.3–7.1 million adults have died prematurely from lack of access to renal replacement therapy [4]. The burden of CKD has been increasing, particularly in Oceania, sub-Saharan Africa, and Latin America [3]. Hence, developing countries have insufficient resources to address the CKD epidemic and its serious long-term complications. It has a significant economic burden, with treatment costs far exceeding preventive costs. For instance, a study performed in London revealed that the total yearly cost for the treatment of CKD was £1.44 to £1.45 billion, and more than half spent on renal replacement therapy, which was provided for 2% of the CKD population [5].
Although there is still uncertainty about the root cause of CKD, studies suggest that numerous risk factors are responsible for CKD, such as obesity [6–11], old age [7–9, 11–14], hypertension [3, 7, 9–13, 15–17], diabetes mellitus [3, 7, 8, 10–12, 16, 18], male gender [12, 17], hyperlipidemia [7], use of nephrotoxic medications [7], family history of kidney disease [9, 11, 13], smoking [19], heavy drinking [19], HIV infection [13], electrolyte and acid-base disturbances [13], low-income occupation, use of traditional medication, and low hemoglobin [11]. Early detection and treatment of possible risk factors are readily available and often inexpensive. Patients with CKD often suffer from an increased risk of cardiovascular mortality [20], ischemic heart disease [21], stroke [22], peripheral vascular disease [23], gout [24], depression and anxiety [25, 26], and reductions in patients’ quality of life and markedly increases health care costs [27]. Patients with CKD may eventually progress to end-stage kidney disease (ESKD), which is associated with a high burden of disease and significant costs of treatment [28].
Large differences have been reported in terms of the prevalence of CKD based on available studies. For instance, the prevalence of CKD among diabetes patients is 38.5% in Palestine [29], 34.7% in Morocco [30], 18.2% in Ethiopia [31], and 24.6% in South Africa [32]. Evidence suggests that early detection and treatment of diabetes, hypertension, and other chronic diseases can improve renal outcomes and slow or prevent the progression of CKD [33]. Despite the availability of such interventions, the burden of CKD and its related risk factors remain understudied in developing countries. This would be due to low awareness among the public, health care workers, and government and other funders and may lead to the false perception that CKD is not an important problem in sub-Saharan Africa [34].
Although different primary studies have shown that the burden of CKD among diabetes patients is high and treatment options are expensive, their results have demonstrated substantial variation regarding its prevalence in Ethiopia. Given this, there is a strong imperative to fully understand the burden of CKD in the region. Therefore, this study aimed to estimate the pooled prevalence of CKD and its associated factors among diabetes patients in Ethiopia. This finding provides a scientific basis for a better understanding of the burden of CKD among diabetes mellitus patients and helps to design appropriate preventive strategies.
2. Methods
2.1. Data Source and Search Strategy
We conducted this systematic review and meta-analysis according to the protocol registered in PROSPERO (CRD42020204239), available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020204239. The Preferred Reporting Items for Systematic Review and Meta-Analysis statement (PRISMA) guideline was used to report the pooled prevalence of CKD in patients with DM [35]. The literature was searched using PubMed, Scopus, Google Scholar, African Journals Online, and Wiley Online Library to identify published reports of kidney disease among diabetes patients in Ethiopia up to May 18, 2020. A manual search was performed for grey literature available on local university shelves and institutional repositories. Moreover, the reference lists of all retrieved articles were conducted to identify additional relevant research to minimize publication bias to possible levels. The search was restricted to full texts, free articles, human studies, and English language publications. Endnote X 8.1 reference manager software was used to search, collect, organize search outcomes, and remove duplicate articles. During the search, medical subheading (MeSH) as well as plain text was used for the following keywords: “chronic kidney disease,” “diabetic nephropathy,” “chronic renal failure,” “renal impairment,” “proteinuria,” “end-stage kidney/renal disease,” “renal insufficiency,” “diabetes mellitus,” “type 2 diabetes mellitus,” “type 1 diabetes mellitus,” “insulin dependent diabetes,” “non-insulin dependent diabetes”, and “Ethiopia”. We have followed the search protocol described in the previous publication [36], and we also used Boolean operators such as “AND” and “OR” which were used to combine search terms (Table 1).
Search
Search terms
Hits
1
Diabetes[tw] OR diabetes mellitus[tw] OR type 1 diabetes[tw] OR type 1 diabetes mellitus[tw] OR T1DM[tw] OR type 2 diabetes[tw] OR type 2 diabetes mellitus[tw] OR T2DM[tw]
623,574
2
Chronic kidney disease [tw] OR diabetic nephropathy[tw] OR chronic renal failure [tw] OR renal impairment [tw] OR proteinuria [tw] OR end-stage kidney/renal disease[tw] OR renal insufficiency [tw]
191,757
3
#1 and #2
168,020
4
Ethiopia[tw] OR ethio[tw]
18, 268
5
#3 and #4
127
6
Limits: studies done in humans, English language, and full text
48
... Despite the effectiveness of known physiological interventions to decrease the T2DM-CKD progression (Campbell, Ruggenenti, & Remuzzi, 2002;Rachmani, Levi, Slavachevski, Avin, & Ravid, 2002;Ruggenenti, Perna, & Remuzzi, 2001), African-Americans have the highest rates among ethnic groups of T2DM-CKD and progression to end-stage renal disease (ESRD). While African-Americans comprise only 13.2% of the U.S. population, they comprise 35% of the population receiving hemodialysis, the prominent renal replacement therapy (Eggers, 2011;Jones et al., 2005;USRDS, 2018). ...
African-Americans have the highest rates of chronic kidney disease due to type 2 diabetes (T2DM-CKD) and of progression to end-stage renal disease. The purpose of this study was to describe African-American's perceptions of T2DM-CKD: specifically, perceptions of cause, risk, severity, self-management of T2DM-CKD before and after diagnosis, and overall effect on their lives. Informed by the Common Sense Model of Illness, a cross-sectional qualitative study using purposive sampling was conducted. Findings were that participants did not take T2DM seriously until they had CKD and they also had misperceptions about the cause of T2DM. Participants believed that a family history of diabetes meant nothing could prevent a T2DM onset. In addition, participants viewed primary care providers as not explicitly informing them of their status/risks regarding CKD. The study results identified factors among African-Americans that contribute to the T2DM-CKD progression. This may enhance primary care providers' ability to educate African-Americans, which may lead to more accurate perceptions.
... The loss of female sex as protective factor against nondiabetic CKD after menopause led to the belief that ovarian hormones are renoprotective. 16 In the setting of diabetes, it is generally believed that female sex as protective factor is lost even before menopause, 73 possibly due to the imbalance in sex hormone levels and activity. Indeed, studies have suggested that both T1DM and T2DM are associated with an imbalance of sex hormone levels. ...
While the global prevalence of both type 1 and type 2 diabetes mellitus is similar in men and women, the consequences of diabetes on associated end-organ complications, including diabetic kidney disease appear to be more sex-specific. Particularly, women with diabetes have higher mortality rates for diabetes-related deaths, and higher prevalence of diabetic kidney disease risk factors such as hypertension, hyperglycemia, obesity, and dyslipidemia. However, the evidence for the impact of sex on diabetic kidney disease prevalence and disease progression is limited and inconsistent. Although most studies agree that the protective effect of the female sex against the development of kidney disease is diminished in the setting of diabetes, the reasons for this observation are unclear. Whether or not sex differences exist in the risk of diabetic kidney disease is also unclear, with studies reporting either higher risk in men, women, or no sex differences. Despite the remaining controversies, some of the factors that associate with sex differences in the risk of diabetic kidney disease are age at onset, and type and duration of diabetes. There is growing appreciation of the importance of sex hormones in the regulation of renal function, with estrogens generally considered to be renoprotective. Although some progress has been made towards better understanding of the mechanisms by which sex hormones play a role in the pathophysiology of diabetic kidney disease, the translational potential of this knowledge is still underappreciated. A better understanding of sex differences in diabetic kidney disease may provide basis for personalized and sex-specific treatment of diabetic kidney disease.
... It is reported that the global morbidity of DM was 8.3% in 2012, affecting 371 million people [2]. Diabetic nephropathy (DN) is a severe microvascular complication of DM and the leading cause of renal failure [3]. DN is also the major cause for the preference of alternative treatment once DM aggravates into the end-stage renal disease (ESRD) [4]. ...
To uncover the role of NORAD in the progression of diabetic nephropathy (DN) and the underlying mechanism. Relative levels of NORAD and TLR4 in db/m mice and db/db mice were tested. Meanwhile, their levels in glomerular mesangial cells undergoing high-level (H-MC group) or low-level (L-MC) glucose treatment were determined. Regulatory effects of NORAD and TLR4 on proliferative ability and apoptosis in SV40-MES-13 cells were assessed. The interaction in the regulatory loop NORAD/miR-520h/TLR4 was verified through dual-luciferase reporter gene assay, determination of subcellular distribution and RIP (RNA Immunoprecipitation) assay. At last, potential role of the regulatory loop NORAD/miR-520h/TLR4 in regulating DN was clarified. NORAD and TLR4 were upregulated in db/db mice and SV40-MES-13 cells in H-MC group. Overexpression of them promoted proliferative ability and inhibited apoptosis in SV40-MES-13 cells. MiR-520h was confirmed to bind NORAD and TLR4. NORAD, miR-520h and TLR4 were mainly distributed in cytoplasm, which were enriched in anti-Ago2. The regulatory loop NORAD/miR-520h/TLR4 has been demonstrated to promote the progression of DN. The regulatory loop NORAD/miR-520h/TLR4 promotes the proliferative ability and inhibits apoptosis in glomerular mesangial cells, thus aggravating the progression of DN.
... About 20-40% of diabetic patients eventually develop DN within 15-20 years after the onset of diabetes [2]. About a half of patients with all end-stage renal disease (ESRD) is due to diabetes, and they have to be conducted the painful and costly dialysis often [3]. ...
The current treatment for diabetic nephropathy (DN) is still limited. NaoXinTong Capsule (NXT) is a Chinese Medicine prescribed to patients with cardiovascular disease. It can also ameliorate metabolic syndromes in patients indicating its anti-diabetic properties. Herein we report the therapeutic effects of NXT on the developed DN. The db/db diabetic mice at ˜12 weeks old, the age with DN at middle/advanced stages, were treated with NXT for 12 weeks. We found NXT treatment reduced diabetes-induced hyperglycemia and dyslipidemia, thereby substantially reduced DN progress. In the kidney, NXT reduced mesangial matrix expansion and glomerulosclerosis by inhibiting extracellular matrix accumulation through activation of matrix metalloproteinase 2/9 and inactivating transforming growth factor β1 expression. NXT reduced podocyte injury by reducing renal inflammation and expression of adhesion molecules. Mechanically, NXT potently activated AMPKα in multiple tissues thereby enhancing energy metabolism. In the liver, NXT increased glucokinase expression and insulin sensitivity by increasing insulin receptor substrate 1/2 and protein kinase B (AKT) 1/2 expression/phosphorylation. In skeletal muscle, NXT activated expression of glucose transporter type 4, AKT, glycogen synthase and peroxisome proliferator activated receptor α/γ. In adipose tissue, NXT reduced fatty acid synthase while activating hormone-sensitive lipase expression. Taken together, our study demonstrates that NXT reduced progress of the developed DN by ameliorating glucose, lipid and energy metabolism, maintaining renal structural and functional integrity. Our study also indicates the potential application of NXT for DN treatment in clinics.
... Epidemiological studies show that improvements in diabetes management have led to reductions in diabetes-associated cardiovascular morbidity over recent decades; however, the impact of these strategies on rates of end-stage renal disease (ESRD) have been minimal 8 . Approximately 30-40% of patients with diabetes mellitus (T1DM and T2DM) develop DKD, and about 50% of them can progress to ESRD [9][10][11][12] . Current therapies to manage DKD include control of blood pressure and glucose levels, and treatment with angiotensin-receptor blockers (ARBs) and angiotensin-converting-enzyme inhibitors; however, these modalities show limited efficacy in preventing the progression of DKD. ...
The development and progression of diabetic kidney disease (DKD), a highly prevalent complication of diabetes mellitus, are influenced by both genetic and environmental factors. DKD is an important contributor to the morbidity of patients with diabetes mellitus, indicating a clear need for an improved understanding of disease aetiology to inform the development of more efficacious treatments. DKD is characterized by an accumulation of extracellular matrix, hypertrophy and fibrosis in kidney glomerular and tubular cells. Increasing evidence shows that genes associated with these features of DKD are regulated not only by classical signalling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation and non-coding RNAs. These mechanisms can respond to changes in the environment and, importantly, might mediate the persistent long-term expression of DKD-related genes and phenotypes induced by prior glycaemic exposure despite subsequent glycaemic control, a phenomenon called metabolic memory. Detection of epigenetic events during the early stages of DKD could be valuable for timely diagnosis and prompt treatment to prevent progression to end-stage renal disease. Identification of epigenetic signatures of DKD via epigenome-wide association studies might also inform precision medicine approaches. Here, we highlight the emerging role of epigenetics and epigenomics in DKD and the translational potential of candidate epigenetic factors and non-coding RNAs as biomarkers and drug targets for DKD.
... T2DM is associated with multiple complications, with diabetic kidney disease (DKD) being the most prevalent [2]. DKD is the leading cause of end-stage renal disease (ESRD) in patients with diabetes [3]. The incidence of DKD has increased by almost twofold annually in the past few decades and currently accounts for almost 50% of all cases of ESRD requiring renal transplantation [4,5]. ...
Background
Diabetic kidney disease (DKD) can result in end-stage kidney disease and renal failure. This study aimed to examine the expression of serum microRNAs (miRNAs), miR-20a, miR-99b, miR-122-5p, and miR-486-5p, and to use bioinformatics data to investigate the pathways involved in DKD.
Material/Methods
Serum miRNAs were obtained from 25 healthy volunteers, 50 patients with non-complicated type 2 diabetes mellitus (T2DM), and 42 patients with T2DM and DKD. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of serum miRNAs. Specificity and sensitivity of the association between serum miRNAs in DKD were evaluated by analysis of the receiver operating characteristic (ROC) area under the curve (AUC). Serum miRNAs and clinical parameters of the patients were compared. Bioinformatics data analysis accessed the miRNA targets involved in the pathways related to the pathogenesis of DKD.
Results
Serum levels of miR-99b and miR-122 significantly increased, and mir-20a and miR-486 decreased in the DKD group compared with healthy controls. Serum levels of miR-20a, miR-99b, miR-486-5p, and miR-122-5p were significantly correlated with albuminuria, estimated glomerular filtration rate (eGFR), blood glucose and lipid profiles. ROC curve analysis showed that diagnostic accuracy of serum levels of miR-99b for DKD was superior to miR-486-5p, miR-122-5p, and miR-20a, resulting in AUCs of 0.895, 0.853, 0.80, and 0.697, respectively. These four miRNAs regulate several genes affecting oxidative stress, inflammation, and apoptosis.
Conclusions
Serum miR-99b, miR-486-5p, miR-122-5p, and miR-20a were differentially expressed in patients with T2DM and DKD and should be evaluated further as potential biomarkers for DKD.
... Diabetic kidney disease (DKD), also known as diabetic nephropathy, is one of the major microvascular complications of diabetes, affecting nearly 50% of all patients with diabetes [1]. ...
Purpose of Review
Epigenetic variations have been shown to reveal vulnerability to diabetes and its complications. Although it has become clear that metabolic derangements, especially hyperglycemia, can impose a long-term metabolic memory that predisposes to diabetic complications, the underlying mechanisms remain to be understood. It has been suggested that epigenetics (e.g., histone modification, DNA methylation, and non-coding RNAs) help link metabolic disruption to aberrancies related to diabetic kidney disease (DKD). In this review, we discuss the key findings and advances made in the epigenetic risk profile of DKD and provide perspectives on the emerging topics that implicate epigenetics in DKD.
Recent Findings
Epigenetic profiles can be profoundly altered in patients with diabetes, in circulating blood cells as well as in renal tissues. These changes provide useful insight into the mechanisms of diabetic kidney injury and progressive kidney dysfunction.
Summary
Increasing evidence supports the role of epigenetic regulation in DKD. More studies are needed to elucidate the mechanism and importance of epigenetic changes in the initiation and progression of DKD and to further explore their diagnostic and therapeutic potential in the clinical management of patients with diabetes who have a high risk for DKD.
... The incidence of bacteremia in the HD patients in our population was found to be similar to that of previous studies [19,20]. Compared to other hemodialysis patients in Asia, Europe, and the USA, our patients had a higher percentage of comorbidities (DM, HTN, CAD), a higher rate of dialysis catheter use, and were younger on average [21][22][23][24][25]. Mortality from sepsis in bacteremic patients in our study was similar to previous studies, with 7-day mortality of 3.6% and 28-day mortality of 9.8% [16]. ...
Background:
Infectious disease is the second most common cause of death in patients receiving hemodialysis (HD). When presenting to the emergency department (ED) with fever, it remains a diagnostic challenge to distinguish patients with potentially life-threatening bacterial infections from those with less significant causes of fever. The primary goal of this study was to determine the rate of bacteremia in HD patients presenting to the ED with fever. The secondary goal of this study was to identify any independent risk factors associated with bacteremia in the febrile HD patient.
Methods:
This is a retrospective medical record review of all HD patients who presented to the ED with either subjective fever as primary complaint or with a documented triage temperature of 38 °C or higher during the 3-year period between September 1, 2014, and September 1, 2017. Patient visits were included in the study if blood cultures were ordered in the ED. Data related to demographic information, clinical parameters, diagnostic test results in the ER, final diagnosis, and results of microbiology cultures were collected from each patient encounter. Univariate analysis was performed to identify risk factors associated with bacteremia.
Results:
We identified 353 patient visits from 138 unique patients that met inclusion criteria. Fifty-eight percent of these were women, and the average age was 54.6 years. The rate of bacteremia was 31.7%, and the main microorganisms isolated in blood culture were non-MRSA Staphylococcus aureus (40.7%), MRSA (13.3%), Pseudomonas aeruginosa (11.5%), and Enterobacter spp. (11.5%). Independent prognostic factors associated with bacteremia were use of dialysis catheter, prior history of bacteremia, and > 5% neutrophilic band cells (OR 6.55 [95% CI 3.96-10.8; p < 0.0001]; OR 8.87 [95% CI 5.32-14.8; p < 0.0001]; OR 3.32 [95% CI 1.90-5.80; p < 0.0001] respectively).
Conclusion:
HD patients presenting to the ED with fever have high rates of bacteremia, with a significantly higher rate in patients using dialysis catheters or those with a history of bacteremia. Other clinical data available in the ED is minimally useful in predicting bacteremia.
... A multitude of studies have demonstrated the rising prevalence of diabetic nephropathy (DN), which has become one of the most common causes of morbidity and mortality in type 2 diabetes worldwide [1][2][3][4]. DN has been proven to be associated with abnormal renal lipid depositions (renal steatosis) so far [4][5][6][7][8][9][10][11]. Animal studies [5,6,9,12] have shown that lipid-mediated changes in renal cells, termed lipotoxicity, were responsible for the pathological changes to the renal parenchyma, including glomerular sclerosis, tubular damage and interstitial fibrosis [6,8,9,11,13], with subsequent impaired renal function. ...
Objective:
To investigate the renal fat fraction and water molecular diffusion features in patients with early-stage DN using Dixon imaging and diffusion tensor imaging (DTI).
Methods:
Sixty-one type 2 diabetics (normoalbuminuria: n = 40; microalbuminuria: n = 21) and 34 non-diabetic volunteers were included. All participants received three-point Dixon imaging and DTI using a 3.0-T magnetic resonance imager. The fat fraction [FF] and DTI features [fractional anisotropy (FA), apparent diffusion coefficient (ADC), tract counts and length from DTI tractography] were collected. All image features were compared between cohorts using one-way ANOVA with Bonferroni post-hoc analysis.
Results:
Renal FF in the microalbuminuric group was significantly higher than in the normoalbuminuric and control groups (5.6% ± 1.3%, 4.7% ± 1.1% and 4.3% ± 0.5%, respectively; p < 0.001). Medullary FA in the microalbuminuric group was the lowest (0.31 ± 0.06) in all cohorts. The tract counts and length in the renal medulla were significantly lower in the microalbuminuric group than in the other two groups.
Conclusions:
Dixon imaging and DTI are able to detect renal lipid deposition and water molecule diffusion abnormalities in patients with early-stage DN. Both techniques have the potential to noninvasively evaluate early renal impairment in type 2 diabetes.
Key points:
• Dixon imaging demonstrated renal fat deposition in early-stage DN; • Renal fractional anisotropy decreased in patients with early-stage DN; • Renal tractography demonstrated reduced track counts and length in early-stage DN.
... Diabetic nephropathy is the commonest etiology of end-stage renal disease (ESRD) worldwide. The number of patients suffering from DM and associated CKD is increasing and is said to be epidemic in distribution with poor prognosis [6] . So CKD is commonly associated with abnormal metabolism of carbohydrate, resistance to insulin and infection by HCV [7] . ...
... La totalidad de ellos se encuentran en estadios avanzados de la IRCT, es decir, en estadios 3b en adelante. Necesitan un manejo especial en la mayoría de áreas de la HD, como son las pautas de diálisis, el AV o el control de la diabetes, la anemia, la vasculopatía y la retinopatía, enfermedades que suelen tener asociadas estos pacientes 47,48 . ...
Introducción: Diabetes Mellitus considerada hoy una verdadera epidemia, quienes la padecen presentan alto riesgo de desarrollar nefropatía diabética, entre el 20 y 50% tienen riesgo de llegar a Insuficiencia Renal Crónica Terminal y necesitar de diálisis o trasplante de riñones.Objetivos: evaluar comportamiento diferencial del paciente diabético en relación al no diabético en Hemodiálisis del Hospital Universitario Manuel Ascunce Domenech de Camagüey durante agosto 2009 hasta enero 2014.Metodología: Estudio descriptivo de cohorte de 174 pacientes en hemodiálisis (estadíos 3b, 4 y 5), la muestra fue de 90 pacientes estratificadamente entre diabéticos y no diabéticos, siguiendo criterios de inclusión, exclusión y salida. La fuente primaria de información la constituyó la encuesta, confeccionada según criterios de objetivos trazados. La fuente secundaria, la conformaron Historias Clínicas y Pancartas de los pacientes en Hemodiálisis. Variables estudiadas: edad, sexo, comorbilidad, tiempo en hemodiálisis, estado nutricional, el tipo y el número de intentos de acceso vascular, complicaciones asociadas a hemodiálisis; así como las principales causas que invalidan a dichos pacientes para el trasplante renal. Resultados: Predominaron pacientes mayores de 60 años, masculinos, con menos de 1 año en Hemodiálisis. Las comorbilidades mayormente encontradas fueron Hipertensión Arterial, Cardiopatía Isquémica y Hepatopatías, por ese orden. En diabéticos prevalecieron los bajopeso y sobrepeso ligeros.Conclusiones: Las comorbilidades mayormente fueron la Hipertensión Arterial, la Cardiopatía Isquémica y las Hepatopatías por ese orden en ambos grupos. Se encontraron en mayor número los catéteres doble luz así como más intentos de acceso vascular en población diabética. Las complicaciones que más se presentaron en Hemodiálisis fueron: hipotensión, hipoglucemia y las infecciones. Contraindicaron principalmente el trasplante renal, la enfermedad cardiovascular y las edades extremas de la vida.
Background:
The prevalence of ferroptosis in diabetic kidney tubules has been documented, yet the underlying mechanism remains elusive. The aim of this study was to ascertain the pivotal gene linked to ferroptosis and establish a novel target for the prevention and management of diabetic kidney disease (DKD).
Methods:
Transcriptomics data (GSE184836) from DKD mice (C57BLKS/J) were retrieved from the GEO database and intersected with ferroptosis-related genes from FerrDb. Then, differentially expressed genes associated with ferroptosis in the glomeruli and tubules were screened. Gene ontology analysis and protein-protein interaction network construction were used to identify key genes. Western blotting and real-time quantitative polymerase chain reaction were employed to validate the expression in the same model. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) expression in patients and mice with DKD was assessed using immunohistochemistry staining. ARNTL knockdown in C57BLKS/J mice was established and plasma malonaldehyde, superoxide dismutase, and renal pathology were analyzed. The efficacy of ARNTL knockdown was evaluated using proteomics analysis. Mitochondrial morphology was observed using transmission electron microscopy.
Results:
ARNTL was screened by bioinformatics analysis and its overexpression verified in patients and mice with DKD. ARNTL knockdown reduced oxidative stress in plasma. Kidney proteomics revealed that ferroptosis was inhibited. The reduction of the classic alteration in mitochondrial morphology associated with ferroptosis was also observed. Gene set enrichment analysis demonstrated that the downregulation of the TGFβ pathway coincided with a decrease in collagen protein and TGFβ1 levels.
Conclusions:
The ferroptosis-associated gene ARNTL is a potential target for treating DKD.
It is common for diabetic kidney disease (DKD) to be complicated by abnormal blood glucose, blood lipids, and blood pressure rhythms. Thus, it is essential to examine diagnostic and treatment plans from the perspective of circadian disruption. This brief review discusses the clinical relevance of circadian rhythms in DKD and how the core clock gene encoding brain and muscle arnt-like protein 1 (BMAL1) functions owing to the importance of circadian rhythm disruption processes, including the excretion of urinary protein and irregular blood pressure, which occur in DKD. Exploring Bmal1 and its potential mechanisms and signaling pathways in DKD following contact with Sirt1 and NF-κB is novel and important. Finally, potential pharmacological and behavioral intervention strategies for DKD circadian rhythm disturbance are outlined. This review aids in unveiling novel, potential molecular targets for DKD based on circadian rhythms.
Background
Despite not being frequently recognized, malnutrition, a consequence of chronic kidney disease, negatively affects morbidity, mortality, functional activity, and patient’s quality of life. Management of this condition is made more difficult by the dearth of knowledge regarding the symptom burden brought on by inadequate nutritional status. Additionally, there are multiple tools to evaluate nutritional status in CKD; but, Pt-Global web tool/PG-SGA used in oncology, has not been investigated in chronic kidney disease patients. This study aimed to explore the nutritional status, symptom burden and also investigate the predictive validity of Pt-Global web tool/PG-SGA among pre-dialysis diabetic and non-diabetic chronic kidney disease patients.
Methodology
This cross-sectional study was carried out at a renal clinic of a tertiary care public teaching hospital. Nutritional status and symptom burden was evaluated by employing a ‘Pt-Global web tool/PG-SGA’ which is considered as a preeminent interdisciplinary tool in oncology and other chronic catabolic conditions. The predictive validity of the Pt-Global web tool/PG-SGA, referred as overall score for malnutrition was ascertained using Receiver Operating Curves (ROC). The conclusions were drawn using descriptive statistics, correlation, and regression analysis.
Results
In a sample of 450 pre-dialysis CKD patients, the malnutrition was present in 292(64.9%) patients. Diabetic CKD patients exhibit higher proportion of malnutrition 159(35.3%). The prevalence of malnutrition was exacerbated by eGFR reduction. The overall Pt-Global web tool/PGA-SGA score was significantly influenced by the symptoms of fatigue (81.5%), appetite loss (54.8%), physical pain (45.3%), constipation (31.78%), dry mouth (26.2%), and feeling full quickly (25.8%). The ROC analysis showed that the AUC for the total PG-SGA score was 0.988 (95% CI: 0.976–1.000), indicating that it is a reliable indicator of malnutrition. The sensitivity (84.2%) for identifying malnutrition was low when using the conventional tool cut off score of ≥9. Instead, it was discovered that a score of ≥3 had a greater sensitivity (99.3%) and specificity (44.3%) and was therefore recommended.
Conclusions
This study not only presents empirical evidence of poor nutritional status in CKD patients but also reveals that it is worse in patients with diabetes, hypoalbuminemia, and poorer kidney function (well recognized risk factors for cardiovascular disease). Early diagnosis and management of symptoms contributing malnutrition will reduce mortality and CKD progression. The Pt-Global web tool/PG-SGA total score of 3 or more appears to be the ideal cut off score for identifying malnutrition, which can be utilized by dietician for improving malnutrition.
Objective
This study aimed to determine the neutrophil–lymphocyte ratio (NLR) as an inflammatory biomarker among type 2 diabetes mellitus (T2DM) patients with diabetic nephropathy (DN).
Methods
A comparative cross-sectional study design was conducted on 199 T2DM patients attending Bole 17 Health Center, Addis Ababa, Ethiopia. The urine albumin test was done by the MICRAL-II test strip. Fasting blood sugar was measured by a glucometer. Complete blood count was analyzed using an automated hematology analyzer (HUMAN GmbH, Wiesbaden, Hesse, Germany). The student’s t-test, a chi-square test, and Pearson correlation were applied to analyze the data.
Results
Out of the 199 diabetes mellitus patients, 45 (22.6%) and 154 (77.4%) were found with DN and without DN, respectively. Interestingly, the mean NLR value (2.66 ± 0.49) was found significantly higher in diabetic patients with DN compared to the mean NLR (1.65 ± 0.20) in diabetes patients without DN ( p < 0.0001). The NLR showed positive significant correlation with variables such as age ( r = 0.162, p = 0.023), duration of disease ( r = 0.52, p < 0.0001), absolute neutrophil count ( r = 0.712, p < 0.0001), total white blood cell count ( r = 0.162, p = 0.022), systolic blood pressure ( r = 0.338, p < 0.0001), and diastolic blood pressure ( r = 0.731, p < 0.0001). On the other hand, negatively significant correlation was found between NLR and absolute lymphocyte count ( r = −0.770, p < 0.000).
Conclusion
The NLR was significantly increased in T2DM patients with DN, suggesting that inflammation and endothelial dysfunction could be an integral part of the pathogenesis of DN, and therefore, this ratio may be considered as a predictor and a prognostic biomarker of DN.
Background
The metabolic score for insulin resistance (METS-IR) is a novel noninsulin-based metabolic index used as a substitution marker of insulin resistance. However, whether METS-IR is associated with the urinary albumin–creatinine ratio (UACR) is not well known. Therefore, we explored the associations between METS-IR and UACR and compared the discriminative ability of METS-IR and its components for elevated UACR. Methods
This study included 37,290 subjects. METS-IR was calculated as follows: (Ln [2 × fasting blood glucose (FBG) + fasting triglyceride level (TG 0 )] × body mass index (BMI))/[Ln (high-density lipoprotein cholesterol (HDL-C))]. Participants were divided into four groups on the basis of METS-IR: <25%, 25%–49%, 50%–74%, and ≥75%. Logistic regression analyses were conducted to determine the associations between METS-IR vs. its components (FBG, TG 0 , BMI, and HDL-C) with UACR. ResultsParticipants with the highest quartile METS-IR presented a more significant trend towards elevated UACR than towards its components (odds ratio [OR]: 1.260, 95% CI: 1.152–1.378, P < 0.001 in all subjects; OR: 1.321, 95% CI: 1.104–1.579, P = 0.002 in men; OR: 1.201, 95% CI: 1.083–1.330, P < 0.001 in women). There were significant associations between METS-IR and UACR in younger participants (<65 years for women and 55–64 years for men). Increased METS-IR was significantly associated with UACR in men with FBG ≥ 5.6 mmol/L or postprandial blood glucose ≥ 7.8 mmol/L and systolic blood pressure ≥ 120 mmHg or diastolic blood pressure ≥ 80 mmHg. The relationships were significant in women with diabetes and hypertension.Conclusions
Increased METS-IR was significantly associated with elevated UACR, and its discriminative power for elevated UACR was superior to that of its components. This findings support the clinical significance of METS-IR for evaluating renal function damage.
Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. In this review, we present an overview of the methodological sources of selection bias inherent in survivorship research (selection of those with early-onset diabetes, incidence–prevalence bias and bias from losses to follow-up in cohort studies) and the breadth and depth of literature focusing on this special study population. We focus on the learnings from the study of longstanding type 1 diabetes on discoveries about the natural history of insulin production loss and microvascular complications, and mechanisms associated with them that may in future offer therapeutic targets. We detail descriptive findings about the prevalence of preserved insulin production and resistance to complications, and the putative mechanisms associated with such resistance. To date, findings imply that the following mechanisms exist: strategies to maintain or recover beta cells and their function; activation of specific glycolytic enzymes such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin–angiotensin–aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint proteins. Among the many clinical and public health insights, research into this special study population has identified putative mechanisms that may in future serve as therapeutic targets, knowledge that likely could not have been gained without studying long-term survivors.
Graphical abstract
Despite increasing research efforts, there is not yet a final cure for diabetes, whether insulin‐ or non‐insulin‐dependent. On the other hand, the most intensive treatment programs to correct hyperglycemia can decrease the incidence of diabetic nephropathy (DN), but are not easy to put into practice. Tight metabolic control is particularly difficult to achieve in type 2 diabetes, and therefore the current epidemic of type 2 diabetes, paralleled by obesity, is likely to generate in perspective a steep increase of cases of DN. As a consequence of the above, DN has rapidly and progressively become the first cause of end‐stage renal failure on a worldwide basis. Based on these premises, this chapter aims to describe the clinical protocols presently applied to treat DN and the research studies meant to identify new ways to prevent, cure, and, ideally, induce the regression of this life‐threatening complication of diabetes.
The epithelial-mesenchymal transition (EMT) plays an important role in diabetic renal fibrosis. The ARAP1 gene is located near risk alleles for Type 2 diabetes, and its function has been linked to cytoskeleton rearrangement, Golgi apparatus remodeling, and endocytic trafficking of membrane receptors. The role of ARAP1 and its antisense RNA, ARAP1-AS2, in the pathogenesis of diabetes is unclear. To clarify the roles of ARAP1 and its antisense RNA in diabetes and related complications, we examined if the expression of these transcripts changed under high glucose (HG) conditions. To do this, we examined transcript levels in HK-2 cells, and explored the roles of ARAP1 and ARAP1-AS2 in the EMT process in HK-2 cells. We found increased expression of ARAP1-AS2 and ARAP1 in HK-2 cells under HG condition, and observed that the overexpression of ARAP1-AS2 significantly increased the EMT process. In addition, HG upregulated Cdc42-GTP levels in HK-2 cells, and increased cytoskeleton rearrangement, cell viability, and migration. After knockdown of ARAP1, the level of Cdc42-GTP was decreased; cytoskeleton reorganization, cell viability, and migration processes were decreased; and EMT and expression of fibrosis marker protein. Overall, our results indicated that ARAP1-AS2/ARAP1 may participate in cytoskeleton rearrangement and EMT processes in HK-2 cells through increased Cdc42-GTP levels.
The review describes a conception of chronic kidney disease (CKD) in contemporary nephrology. Recent data on risk factors of renal dysfunction development and cardiorenal relations are discussed. It is emphasized the need of combine prevention of cardiovascular disease and CKD progression.
Familial aggregation of diabetic nephropathy (DN) in type 1 and type 2 diabetes and the heritability of DN-related traits provide compelling evidence that genetic factors contribute to their susceptibility. Motivated by these studies, researchers have been working for the past 20 years to identify the causal genes responsible for the development of DN. During this period, advances in genomics and evolving technologies have revolutionized our ability to interrogate genetic variation across the genome and have aided in improving our understanding of the genetic basis of DN. Significant progress has been made in this area of research; however, much work remains. To advance this area of research and further drive discovery of genes for DN, studies need to take advantage of improved gene mapping strategies, including next-generation sequencing and renewed interest in family-based studies, and our increased understanding of the course of kidney disease in patients with diabetes. As the field moves forward, approaches that incorporate these advances should greatly facilitate efforts to identify variants in genes that have a major effect on the risk of DN. In this chapter, we review evidence supporting a genetic basis for DN, discuss the efforts to identify the genes that underlie its risk, and present the major findings of this area to research to date.
Diabetic kidney disease (DKD) is a major renal complication of diabetes that leads to renal dysfunction and end-stage renal disease (ESRD). Major features of DKD include accumulation of extracellular matrix proteins and glomerular hypertrophy, especially in early stage. Transforming growth factor-β plays key roles in regulation of profibrotic genes and signal transducers such as Akt kinase and MAPK as well as endoplasmic reticulum stress, oxidant stress, and autophagy related to hypertrophy in diabetes. Many drugs targeting the pathogenic signaling in DKD (mostly through protein-coding genes) are under development. However, because of the limited number of protein-coding genes, noncoding RNAs (ncRNAs) including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are attracting more attention as potential new drug targets for human diseases. Some miRNAs and lncRNAs regulate each other (by hosting, enhancing transcription from the neighbor, hybridizing each other, and changing chromatin modifications) and create circuits and cascades enhancing the pathogenic signaling in DKD. In this short and focused review, the functional significance of ncRNAs (miRNAs and lncRNAs) in the early stages of DKD and their therapeutic potential are discussed.
Early detection of chronic kidney diseases such as diabetic nephropathy is an area of emerging research interest. To date, most efforts focused on either histological analysis of biopsied renal tissue or investigation of protein, mRNA, or microRNA levels in kidney or urine. Urine contains small microvesicles (40-100 nm in size), commonly called exosomes, that are released by cells lining the inner walls of nephron segments. It is becoming clear that exosomes released into the urine may provide valuable information for identifying biomarkers of kidney damage, particularly under conditions of renal dysfunction and injury. Several methods have been developed to isolate exosomes from urine, including ones based on ultracentrifugation, nanomembrane concentration and precipitation techniques. We have previously compared different methods for the extraction of urinary exosomes for downstream applications involving analysis of protein, mRNA, and miRNA. In this chapter, we outline the basic principles, as well as the strengths and weaknesses, of each method for the isolation of exosomes from human urine. The goal of this chapter is to provide a foundation upon which researchers may select the method of urinary exosome extraction most suitable for their specific downstream needs. © Springer Science+Business Media Dordrecht 2015. All rights reserved.
Introduction of Diabetic Nephropathy Mogensen Staging and TCM Typing of DN The Metabonomics Study of DN Condition of Metabolism after Treatment with TangShen Formula (TSF) Genomics Study of Diabetic Neuropathy The Integrated Biomarker System of DN Conclusions References
Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes. Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and Vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. Findings The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) brood pressures, ramipril stilt lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004). Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.
To project the number of people with diagnosed diabetes in the U.S. through 2050, accounting for changing demography and diabetes prevalence rates.
We combined age-, sex-, and race-specific diagnosed diabetes prevalence rates-predicted from 1980-1998 trends in prevalence data from the National Health Interview Survey-with Bureau of Census population demographic projections. Sensitivity analyses were performed by varying both prevalence rate and population projections.
The number of Americans with diagnosed diabetes is projected to increase 165%, from 11 million in 2000 (prevalence of 4.0%) to 29 million in 2050 (prevalence of 7.2%). The largest percent increase in diagnosed diabetes will be among those aged > or =75 years (+271% in women and +437% in men). The fastest growing ethnic group with diagnosed diabetes is expected to be black males (+363% from 2000-2050), with black females (+217%), white males (+148%), and white females (+107%) following. Of the projected 18 million increase in the number of cases of diabetes in 2050, 37% are due to changes in demographic composition, 27% are due to population growth, and 36% are due to increasing prevalence rates.
If recent trends in diabetes prevalence rates continue linearly over the next 50 years, future changes in the size and demographic characteristics of the U.S. population will lead to dramatic increases in the number of Americans with diagnosed diabetes.
Summary Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes. Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. Findings The study was stopped 6 months early (after 4·5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0·0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0·027). After adjustment for the changes in systolic (2·4 mm Hg) and diastolic (1·0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (12-36, p=0·0004). Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.
To describe the prevalence of, and trends in, overweight and obesity in the US population using standardized international definitions.
Successive cross-sectional nationally representative surveys, including the National Health Examination Survey (NHES I; 1960-62) and the National Health and Nutrition Examination Surveys (NHANES I: 1971-1974; NHANES II: 1976-1980; NHANES III: 1988-94). Body mass index (BMI:kg/m2) was calculated from measured weight and height. Overweight and obesity were defined as follows: Overweight (BMI > or = 25.0); pre-obese (BMI 25.0-29.9), class I obesity (BMI 30.0-34.9), class II obesity (BMI 35.0-39.9), and class III obesity (BMI > or = 40.0).
For men and women aged 20-74 y, the age-adjusted prevalence of BMI 25.0-29.9 showed little or no increase over time (NHES I: 30.5%, NHANES I: 32.0%, NHANES II: 31.5% and NHANES III: 32.0%) but the prevalence of obesity (BMI > or = 30.0) showed a large increase between NHANES II and NHANES III (NHES I: 12.8%; NHANES I, 14.1%; NHANES II, 14.5% and NHANES III, 22.5%). Trends were generally similar for all age, gender and race-ethnic groups. The crude prevalence of overweight and obesity (BMI > 25.0) for age > or = 20 y was 59.4% for men, 50.7% for women and 54.9% overall. The prevalence of class III obesity (BMI > or = 40.0) exceeded 10% for non-Hispanic black women aged 40-59 y.
Between 1976-80 and 1988-94, the prevalence of obesity (BMI > or= 30.0) increased markedly in the US. These findings are in agreement with trends seen elsewhere in the world. Use of standardized definitions facilitates international comparisons.
The increasing prevalence of obesity is a major public health concern, since obesity is associated with several chronic diseases.
To monitor trends in state-specific data and to examine changes in the prevalence of obesity among adults.
Cross-sectional random-digit telephone survey (Behavioral Risk Factor Surveillance System) of noninstitutionalized adults aged 18 years or older conducted by the Centers for Disease Control and Prevention and state health departments from 1991 to 1998.
States that participated in the Behavioral Risk Factor Surveillance System.
Body mass index calculated from self-reported weight and height.
The prevalence of obesity (defined as a body mass index > or =30 kg/m2) increased from 12.0% in 1991 to 17.9% in 1998. A steady increase was observed in all states; in both sexes; across age groups, races, educational levels; and occurred regardless of smoking status. The greatest magnitude of increase was found in the following groups: 18- to 29-year-olds (7.1% to 12.1%), those with some college education (10.6% to 17.8%), and those of Hispanic ethnicity (11.6% to 20.8%). The magnitude of the increased prevalence varied by region (ranging from 31.9% for mid Atlantic to 67.2% for South Atlantic, the area with the greatest increases) and by state (ranging from 11.3% for Delaware to 101.8% for Georgia, the state with the greatest increases).
Obesity continues to increase rapidly in the United States. To alter this trend, strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority.
Utilization and costs of prescription drugs were investigated in diabetic and nondiabetic patients.
The study was carried out in Tayside, Scotland, U.K. A validated population-based diabetes register was used to identify patients with type 1 and type 2 diabetes, and a database of all prescriptions dispensed in the community was used to investigate drug utilization in 1995.
In a population of 406,526, there were 974 (0.2%) with type 1 diabetes and 6,869 (1.7%) with type 2 diabetes. The mean dispensed prescribing rates for all drugs (excluding antidiabetic medication) were higher across all age-groups for diabetic patients. After adjusting for age, patients with type 1 diabetes were 2.07 times (95% CI 2.03-2.11) more likely and patients with type 2 diabetes were 1.70 times (1.69-1.71) more likely to be dispensed a drug item than people without diabetes. This likelihood was increased in every drug category, even those not directly related to diabetes, and the proportion and cost of drug items dispensed to diabetic patients was therefore higher than expected given the prevalence of diabetes. Upon projecting these results to the U.K. population, it was discovered that nearly 8% of the U.K. drug budget (Pound Sterling 350 million) is accounted for by patients with diabetes (90% of that by patients with type 2 diabetes).
This study highlights the increased usage and cost of prescription drugs in diabetes, with type 2 diabetes constituting a particular burden. It was discovered that 1.4% of drug usage in the entire population can be accounted for by the increased prescribing rate of diabetic patients compared with that of nondiabetic patients.
This study investigates temporal trends in the prevalence and incidence of persistent proteinuria among people with adult-onset diabetes (age > or =40 years).
The complete community-based medical records of all Rochester, Minnesota, residents with a diagnosis of diabetes or diabetes-like condition from 1945 through 1989 were reviewed to determine whether they met National Diabetes Data Group (NDDG) criteria. All confirmed diabetes cases residing in Rochester on 1 January 1970 (n = 446), 1980 (n = 647), and/or 1990 (n = 940) were identified. The medical records of these prevalence cases were reviewed from the time of the first laboratory urinalysis value to the last visit, death, or 1 April 1992 (whichever came first) for evidence of persistent proteinuria (two consecutive urinalyses positive for protein, with no subsequent negative values). Similarly, the medical records of all 1970-1989 diabetes incidence cases (n = 1,252) were reviewed to investigate temporal changes in 1) the likelihood of having persistent proteinuria before the date NDDG criteria was met, i.e., baseline; 2) the risk of persistent proteinuria after baseline; and 3) the relative risk of mortality associated with persistent proteinuria.
The proportion of diabetes prevalence cases with persistent proteinuria on or before the prevalence date declined from 20% in 1970 to 11% in 1980 and 8% in 1990. Among the 1970-1989 diabetes incidence cases, 77 (6%) had persistent proteinuria on or before baseline; the adjusted odds declined by 50% with each 10-year increase in baseline calendar year (P<0.001). Among individuals free of persistent proteinuria at baseline, 136 subsequently developed persistent proteinuria; the estimated 20-year cumulative incidence was 41% (95% CI 31-59); the adjusted risk did not differ as a function of baseline calendar year. Survival of individuals with persistent proteinuria relative to those without was reduced but did not differ by baseline calendar year.
The prevalence of persistent proteinuria among people with adult-onset diabetes in Rochester, Minnesota, declined 60% between 1970 and 1990. The decline appears because of a decrease in the proportion of diabetes incidence cases with persistent proteinuria before baseline rather than secular declines in the risk of persistent proteinuria after baseline or secular increases in the risk of mortality associated with persistent proteinuria. Similarity over time in age and fasting glucose at baseline, and at prevalence dates, is evidence that earlier detection of diabetes is not the sole explanation for the decline.
The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective randomized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications. The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy, retinopathy, and neuropathy.
The 470 hypertensive subjects, defined as having a baseline diastolic blood pressure of > or = 90 mmHg, were randomized to intensive blood pressure control (diastolic blood pressure goal of 75 mmHg) versus moderate blood pressure control (diastolic blood pressure goal of 80-89 mmHg).
The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group. During the 5-year follow-up period, no difference was observed between intensive versus moderate blood pressure control and those randomized to nisoldipine versus enalapril with regard to the change in creatinine clearance. After the first year of antihypertensive treatment, creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria. In contrast, patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5-6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy. There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria (25% intensive therapy vs. 18% moderate therapy, P = 0.20) or microalbuminuria to overt albuminuria (16% intensive therapy vs. 23% moderate therapy, P = 0.28). Intensive therapy demonstrated a lower overall incidence of deaths, 5.5 vs. 10.7%, P = 0.037. Over a 5-year follow-up period, there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy. In addition, the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy.
Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period. The more intensive blood pressure control decreased all-cause mortality.
Increasing obesity within the general population has been accompanied by rising rates of diabetes. The extent to which obesity has increased among people with diabetes is unknown, as are the potential consequences for diabetes outcomes.
Community medical records (hospital and ambulatory) of all Rochester, Minnesota, residents aged > or =30 years who first met standardized research criteria for diabetes from 1970 to 1989 (n = 1,306) were reviewed to obtain data on BMI and related characteristics as of the diabetes identification date (+/-3 months). Vital status as of 31 December 1999 and date of death for those who died were obtained from medical records, State of Minnesota death tapes, and active follow-up.
As of the identification date, data on BMI were available for 1,290 cases. Of the 272 who first met diabetes criteria in 1970-1974, 33% were obese (BMI > or =30), including 5% who were extremely obese (BMI > or =40). These proportions increased to 49% (P < 0.001) and 9% (P = 0.012), respectively, for the 426 residents who first met diabetes criteria in 1985-1989. BMI increased significantly with increasing calendar year of diabetes identification in multivariable regression analysis. Analysis of survival revealed an increased hazard of mortality for BMI > or =41, relative to BMI of 23-25 (hazard ratio 1.60, 95% CI 1.09-2.34, P = 0.016).
The prevalence of obesity and extreme obesity among individuals at the time they first met criteria for diabetes has increased over time. This is disturbing in light of the finding that diabetic individuals who are extremely obese are at increased risk of mortality compared with their nonobese diabetic counterparts.
Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy.
A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).
Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
Purpose:
To determine whether response of albumin excretion rate to angiotensin-converting enzyme (ACE) inhibitors has a threshold in patients with type 1 diabetes mellitus and microalbuminuria and to examine treatment effect according to covariates.
Data sources:
Studies were identified by searching MEDLINE and related bibliographies.
Study selection:
Selected studies included at least 10 normotensive patients with type 1 diabetes mellitus and microalbuminuria, had a placebo or nonintervention group, and included at least 1 year of follow-up.
Data extraction:
Raw data were obtained for 698 patients from the 12 identified trials. Analysis of treatment effect at 2 years was restricted to trials with at least 2 years of follow-up (646 patients from 10 trials).
Data synthesis:
In patients receiving ACE inhibitors, progression to macroalbuminuria was reduced (odds ratio, 0.38 [95% CI, 0.25 to 0.57]) and the odds ratio for regression to normoalbuminuria was 3.07 (CI, 2.15 to 4.44). At 2 years, albumin excretion rate was 50.5% (CI, 29.2% to 65.5%) lower in treated patients than in those receiving placebo (P < 0.001). Estimated treatment effect varied by baseline albumin excretion rate (74.1% and 17.8% in patients with a rate of 200 microg/min and 20 microg/min, respectively [P = 0.04]) but not by patient subgroup. Adjustment for change in blood pressure attenuated the treatment difference in albumin excretion rate at 2 years to 45.1% (CI, 18.6% to 63.1%; P < 0.001).
Conclusions:
In normotensive patients with type 1 diabetes mellitus and microalbuminuria, ACE inhibitors significantly reduced progression to macroalbuminuria and increased chances of regression. Beneficial effects were weaker at the lowest levels of microalbuminuria but did not differ according to other baseline risk factors. Changes in blood pressure cannot entirely explain the antiproteinuric effect of ACE inhibitors.
Background:
Two new classes of antihypertensive agents were introduced in the 1980s, but their effectiveness in preventing heart disease and stroke has not been demonstrated. Lack of evidence of their efficacy might reasonably be expected to discourage their widespread use in management of hypertension.Methods:
Use of various classes of antihypertensive agents was estimated from published drug use information in an effort to estimate trends in antihypertensive drug use and evaluate the impact of these trends on costs of antihypertensive therapy in the United States.Results:
Proportionate use of the five major antihypertensive drug classes shifted markedly between 1982 and 1993. Diuretics accounted for 56% of all hypertensive drug mentions in 1982 but only 27% in 1993, a relative decline of 52%. Use of β-blockers and central agents also declined during this period. Proportionate use of calcium antagonists showed the greatest gains, increasing from 0.3% to 27%, while the use of angiotensin-converting enzyme inhibitors increased from 0.8% to 24%. Given the higher costs of the newer agents, and assuming an estimated total cost of antihypertensive medications in 1992 of $7 billion, approximately $3.1 billion would have been saved had 1982 prescribing practices remained in effect in 1992.Conclusions:
Use of calcium antagonists and angiotensin-converting enzyme inhibitors in hypertension has increased dramatically in the past 10 years. Without convincing evidence of the advantages of these agents, it is difficult to explain the continued decline in the use of less expensive agents, such as diuretics and β-blockers, which are the only antihypertensive agents proved to reduce stroke and coronary disease in hypertensive patients.(Arch Intern Med. 1995;155:829-837)
Context Mortality from coronary heart disease has declined
substantially in the United States during the past 30 years. However,
it is unknown whether patients with diabetes have also experienced a
decline in heart disease mortality.
Objective To compare adults with diabetes with those without
diabetes for time trends in mortality from all causes, heart disease,
and ischemic heart disease.
Design, Setting, and Participants Representative cohorts of
subjects with and without diabetes were derived from the First National
Health and Nutrition Examination Survey (NHANES I) conducted between
1971 and 1975 (n=9639) and the NHANES I Epidemiologic
Follow-up Survey conducted between 1982 and 1984
(n=8463). The cohorts were followed up prospectively
for mortality for an average of 8 to 9 years.
Main Outcome Measure Changes in mortality rates per 1000
person-years for all causes, heart disease, and ischemic heart disease
for the 1982-1984 cohort compared with the 1971-1975 cohort.
Results For the 2 periods, nondiabetic men experienced a 36.4%
decline in age-adjusted heart disease mortality compared with a 13.1%
decline for diabetic men. Age-adjusted heart disease mortality declined
27% in nondiabetic women but increased 23% in diabetic women. These
patterns were also found for all-cause mortality and ischemic heart
disease mortality.
Conclusions The decline in heart disease mortality in the general
US population has been attributed to reduction in cardiovascular risk
factors and improvement in treatment of heart disease. The smaller
declines in mortality for diabetic subjects in the present study
indicate that these changes may have been less effective for people
with diabetes, particularly women.
Objectives.
—To study the effect of angiotensin converting enzyme inhibition on the rate of progression to clinical proteinuria and the rate of change of albumin excretion rates in patients with insulin-dependent diabetes mellitus and persistent microalbuminuria.Design and Setting.
—Randomized, double-blind, placebo-controlled clinical trial of 2 years' duration at 12 hospital-based diabetes centers.Patients.
—Ninety-two patients with insulin-dependent diabetes mellitus and persistent microalbuminuria but no hypertension.Intervention.
—The patients were randomly allocated in blocks of two to receive either captopril, 50 mg, or placebo twice per day.Measurements.
—Albumin excretion rate, blood pressure, glycosylated hemoglobin level, and fructosamine level every 3 months; urinary urea nitrogen excretion every 6 months; and glomerular filtration rate every 12 months.Results.
—Twelve patients receiving placebo and four receiving captopril progressed to clinical proteinuria, defined as an albumin excretion rate persistently greater than 200 μg/min and at least a 30% increase from baseline (P=.05). The probability of progression to clinical proteinuria was significantly reduced by captopril therapy (P=.03 by log-rank test). Albumin excretion rate rose from a geometric mean (95% confidence interval) of 52 (39 to 68) to 76 (47 to 122) μg/min in the placebo group but fell from 52 (41 to 65) to 41 (28 to 60) μg/min in the captopril group, a significant difference (P<.01). Mean blood pressure was similar at baseline in the two groups and remained unchanged in the placebo group but fell significantly, by 3 to 7 mm Hg, in the captopril group. Glycosylated hemoglobin levels and glomerular filtration rate remained stable in the two groups.Conclusions.
—Captopril therapy significantly impeded progression to clinical proteinuria and prevented the increase in albumin excretion rate in nonhypertensive patients with insulin-dependent diabetes mellitus and persistent microalbuminuria.(JAMA. 1994;271:275-279)
Context:
The increasing prevalence of obesity is a major public health concern, since obesity is associated with several chronic diseases.
Objective:
To monitor trends in state-specific data and to examine changes in the prevalence of obesity among adults.
Design:
Cross-sectional random-digit telephone survey (Behavioral Risk Factor Surveillance System) of noninstitutionalized adults aged 18 years or older conducted by the Centers for Disease Control and Prevention and state health departments from 1991 to 1998.
Setting:
States that participated in the Behavioral Risk Factor Surveillance System.
Main outcome measures:
Body mass index calculated from self-reported weight and height.
Results:
The prevalence of obesity (defined as a body mass index > or =30 kg/m2) increased from 12.0% in 1991 to 17.9% in 1998. A steady increase was observed in all states; in both sexes; across age groups, races, educational levels; and occurred regardless of smoking status. The greatest magnitude of increase was found in the following groups: 18- to 29-year-olds (7.1% to 12.1%), those with some college education (10.6% to 17.8%), and those of Hispanic ethnicity (11.6% to 20.8%). The magnitude of the increased prevalence varied by region (ranging from 31.9% for mid Atlantic to 67.2% for South Atlantic, the area with the greatest increases) and by state (ranging from 11.3% for Delaware to 101.8% for Georgia, the state with the greatest increases).
Conclusions:
Obesity continues to increase rapidly in the United States. To alter this trend, strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority.
Several case-control studies suggest an association between analgesic use and increased risk of chronic renal disease, but few cohort studies have examined this association.
To determine whether analgesic use is associated with risk of renal dysfunction.
Cohort study of analgesic use data from the Physicians' Health Study, which lasted 14 years from September 1982 to December 1995 with annual follow-up.
A total of 11 032 initially healthy men who provided blood samples and self-report of analgesic use.
Elevated creatinine level defined as 1.5 mg/dL (133 micromol/L) or higher and a reduced creatinine clearance defined as 55 mL/min (0.9 mL/s) or less, and self-reported use of acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (never [<12 pills]; 12-1499 pills; 1500-2499 pills; and >/=2500 pills).
A total of 460 men had elevated creatinine levels (4.2%) and 1258 had reduced creatinine clearance (11.4%). Mean creatinine levels and creatinine clearances were similar among men who did not use analgesics and those who did, even at total intakes of 2500 or more pills. In multivariable analyses adjusted for age; body mass index; history of hypertension, elevated cholesterol, and diabetes; occurrence of cardiovascular disease; physical activity; and use of other analgesics, the relative risks of elevated creatinine level associated with intake of 2500 or more pills were 0.83 (95% confidence interval [CI], 0.50-1.39; P for trend =.05) for acetaminophen, 0.98 (95% CI, 0.53-1.81; P for trend =.96) for aspirin, and 1.07 (95% CI, 0.71-1.64; P for trend =.86) for other nonsteroidal anti-inflammatory drugs. No association was observed between analgesic use and reduced creatinine clearance.
Moderate analgesic use in this cohort study of initially healthy men was not associated with increased risk of renal dysfunction.
BackgroundRenal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known.MethodsWe carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20–59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm hg diastolic, and no more than 155 mm hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months.FindingsThere were no differences in baseline characteristics by treatment group; mean AER was 8.0 μg/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 μg/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2·0–32·7, p=0·03), adjusted for baseline AER and centre, absolute difference 2.2 μg/min. In people with normoalbuminuria, the treatment difference was 1·0 μg/min (12·7% [−2·9 to 26·0], p=0·1). In those with microalbuminuria, however, the treatment difference was 34.2 μg/min (49·7% [−14·5 to 77·9], p=0·1; for interaction, p=0·04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38·5 μg/min in those with microalbuminuria at baseline (p=0·001), and 0·23 μg/min in those with normoalbuminuria at baseline (p=0·6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin.InterpretationLisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER ≥20 μg/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM.
Data from the Michigan Kidney Registry and the US Renal Data System (USRDS) show that the number of patients receiving treatment for end-stage renal disease (ESRD) increased sevenfold following the introduction of Medicare coverage for ESRD in 1973. The number of new patients added per year has also increased dramatically--approximately fourfold. Initial selection criteria for acceptance into the ESRD Program included age less than 65 years and absence of systemic diseases such as diabetes. During the past 18 years, the gradual acceptance of older patients and of diabetic patients has led to an increase in the median age of new patients from 46 to 61 years and a 12-fold increase in the incidence of treatment in patients with ESRD due to diabetes. Given the broad acceptance of sicker and older patients, withdrawal from dialysis has become a consideration when dialysis no longer benefits the patient. Treatment modalities have also changed, and increasing numbers of patients undergo successful renal transplantation or receive continuous ambulatory peritoneal dialysis (CAPD). During the 1980s, hemodialysis treatment times and dialysis staffs decreased; however, several improvements in the care of patients on dialysis occurred during this period.
We studied the entry of elderly uremic patients to chronic dialysis in the U.S. in 1979. We also reviewed long-term survival, causes of death, and risk factors for death in old patients on dialysis at one center for the period 1966 to 1983.
A comparison of the number of patients at risk with the number entering dialysis in the United States in 1979 indicates that 80% of the patients aged 25-45 years, 30% of patients over the age of 65 years, and 6% of those over the age of 75 years entered dialysis during that period. Of 239 patients over the age of 70 years followed at the Regional Kidney Disease Program at Hennepin County Medical Center in Minneapolis, the seven-year cumulative survival was 17%. In this program withdrawal from dialysis was the commonest cause of death, accounting for 40% of all deaths. Age groups over 75 years, sex, time period, duration of dialysis, eight pre-existing degenerative diseases, living situation, family support, and site and type of dialysis were not risk factors for termination of dialysis, but living in a nursing home was. When compared to the young, total deaths and deaths from discontinuation were much higher, and this decision was made earlier. Half of the patients who died because dialysis was discontinued were competent and decided for themselves; the other half were incompetent and families and physicians made the decision. Thus, old patients do not live as long, and they withdraw from dialysis more frequently than the young. Qualitatively, though, the decisions to stop dialysis are no different from those decisions made by or for younger patients.
Population studies indicate that hypertension occurs with greater frequency in diabetic than in nondiabetic subjects. The hypertension associated with diabetes may be of three types: (1) essential hypertension usually complicating diabetes of late onset, (2) systolic hypertension secondary to atherosclerosis, and (3) “diabetic hypertension” which is a form of renal hypertension accompanying the clinical syndrome of diabetic nephropathy most commonly observed in patients with diabetes of juvenile onset. Surgically curable forms of hypertension including renal vascular hypertension are probably no more frequent in patients with diabetes than in the general population.
Evidence is presented suggesting that there is suppression of the renin-angiotensin system accompanied by hypertension in uncontrolled diabetes in the rat treated with alloxan. Additionally, suppression of this system has been observed in patients with long-term diabetes and evidence of diabetic renal disease and hypertension, a finding that may explain the rarity of malignant hypertension in long-term diabetes. Possible mechanisms involved in both the suppression of the renin-angiotensin system and in the “diabetic hypertension” are discussed. Since “diabetic hypertension” may be a form of hyporeninemic hypertension, elucidation of the mechanism involved may yield valuable information concerning the large group of patients with essential hypertension with suppression of the renin-angiotensin system.
The agents used for antihypertensive therapy in the diabetic patient are similar to those used in other hypertensive patients, but certain considerations must be given to their use, especially in the diabetic patient with complications.
Two distinct patterns of response of blood pressure to achievement of dry weight (no clinical evidence of edema and optimal body sodium content and volume of water), antihypertensive drugs and bilateral nephrectomy were documented in 40 unselected patients with end-stage renal disease. Group 1, 35 of 40 patients, was characterized by an excellent response of blood pressure to dry weight and the ability to remain normotensive without antihypertensive drugs as long as dry weight was maintained. Group 2, five of 40 patients, had persistent hypertension in spite of dry weight, a poor response to antihypertensive drugs and a prompt reduction of blood pressure after bilateral nephrectomy. A further important difference between these two groups was seen in the serum renin values obtained at the initiation of therapy. In Group 1 values ranged from 0 to 1.02 Goldblatt units × 10–4 per milliliter of serum (mean, 0.31) whereas those in Group 2 ranged from 1.88 to 4.60 (mean of 3.37 units). Serum renin level...
The effect of early aggressive antihypertensive treatment on kidney function in diabetic nephropathy was studied prospectively in ten insulin-dependent diabetics (mean age 29 years). During the mean pretreatment period of 29 (range 23-38) months the glomerular filtration rate (GFR) decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the 39 month (range 28-48) period of antihypertensive treatment with metoprolol, hydralazine, and frusemide (furosemide) or thiazide, arterial blood pressure fell from 144/97 mm Hg (mean of all pretreatment values) to 128/84 mm Hg (mean of all post-treatment values), urinary albumin excretion from 977 micrograms/min to 433 micrograms/min, and GFR from 80 to 62 ml/min/1 . 73 m2. The rate of decline in GFR decreased from 0.91 ml/min/month before treatment to 0.39 ml/min/month (range 0.08 to 0.68 ml/min/month) during treatment.
Six men aged 26-35 years with proteinuria due to insulindependent juvenile-onset diabetes were treated for moderate hypertension (mean blood pressure 162/103 mm Hg) and studied for a mean of 73 months for the effect on the progression of nephropathy. All patients were of normal weight. During a mean control period of 28 months before treatment the mean glomerular filtration rate (three or four measurements) was 86.1 ml/min and mean 24-hour urinary albumin excretion (also three or four measurements) 3.9 g (range 0.5-8.8 g).During antihypertensive treatment the mean systolic blood pressure fell to 144 mm Hg and mean diastolic pressure to 95 mm Hg. In the control period five patients had shown a mean monthly decline in glomerular filtration rate of 1.23 ml/min; with antihypertensive treatment, however, this decline fell to 0.49 ml/min (2p=0.042). In the remaining patient the glomerular filtration rate was 137 ml/min before treatment and 135 ml/min at the end of the treatment period. In all patients the mean yearly increase in albumin clearance (expressed as a percentage of the glomerular filtration rate) fell from 107% before treatment to 5% during treatment (2p=0.0099).This small study indicates that antihypertensive treatment slows the decline in renal function in diabetic nephropathy. Clinical trials beginning treatment in the incipient phase of diabetic nephropathy will define the optimal modality of treatment in this large patient population.
In 6 male insulin-dependent proteinuric long-term diabetics aged 26-35 years the rate of progression of nephropathy was followed for an initial control period of 2.0 years and subsequently for 4.1 years during antihypertensive therapy with a beta-receptor blocker combined with Hydralazine and Furosemide. GFR and urinary albumin excretion was measured 3-4 times before and 9-14 times during treatment. Systolic blood pressure was reduced significantly from 162 +/- 14 (SD) mm Hg before treatment to 146 +/- 9 (SD) as a mean during the whole treatment period (2p = 0.002). Diastolic pressure was also reduced significantly, from 103 +/- 9 (SD) mm Hg to 95 +/- 8 (SD), (2p = 0.025). After 49 days of treatment there was a significant fall in albumin clearance as a per cent of GFR from 0.243 +/- 0.28 (SD) to 0.170 +/- 0.20 (SD), (2p < 0.001 for percentage change) with no change in GFR. In five patients the fall rate of GFR was in the initial control period 1.24 ml/min/month +/- 0.8 (SD). In the period when antihypertensive therapy was given it was reduced to 0.45 ml/min/month +/- 0.5 (SD) (2p = 0.037). In the 6th patient there was no decline in GFR neither before, nor during treatment. Before treatment there was a mean yearly percentage increase in albumin excretion of 107 per cent. During treatment this yearly increase was reduced to--7 per cent (2p = 0.002 for differences in slope). The results indicate that the state of renal insufficiency in diabetic patients with nephropathy and moderately increased blood pressure can be postponed by antihypertensive treatment. Other trials should be carried out to define the optimal scheme of treatment.
To determine whether angiotensin-converting enzyme (ACE) inhibition with captopril reduces the progression of microalbuminuria to overt proteinuria in normotensive patients with insulin-dependent diabetes mellitus (IDDM).
This study was a prospective randomized, double-blind, placebo-controlled trial involving 26 centers in the United States and Canada. One hundred forty-three subjects, 14 to 57 years of age, with IDDM for 4 to 33 years, blood pressure < 140/90 mm Hg in the absence of antihypertensive therapy, and persistent albumin excretion 20 to 200 micrograms/min were randomized to double-blind treatment with captopril 50 mg or placebo BID. Albumin excretion rate (AER), blood pressure, and glycohemoglobin were determined every 3 months, and creatinine clearance (CrCl) and urea excretion were measured every 6 months.
Within 24 months, 6.0% (4/67) of captopril-treated subjects and 18.6% (13/70) of placebo-treated subjects progressed to clinical proteinuria, defined as AER > 200 micrograms/min and at least 30% above baseline (risk reduction = 67.8%, P = 0.037). AER increased at an annual rate of 11.8% (95% confidence interval [CI] -3.3% to 29.1%) in the placebo group, while it declined by 17.9% (CI -29.6% to -4.3%) in the captopril group (P = 0.004). CrCl decreased by 4.9 mL/min per 1.73 m2 per year in the placebo group, while it remained stable in the captopril group (0.9 mL/min per 1.73 m2 per year, P = 0.039 between groups). Ten subjects required treatment for hypertension; 8 in the placebo group and 2 in the captopril group. There was little correlation between the 24-month changes in mean arterial blood pressure and AER in either group. Glycohemoglobin and urinary urea excretion did not differ between groups.
After 24 months of therapy with captopril, compared with placebo, normotensive subjects with IDDM experienced significantly less progression of microalbuminuria to clinical proteinuria, reduced albumin excretion, and preserved CrCl rate. The ACE inhibitor, captopril, was well tolerated.
Two new classes of antihypertensive agents were introduced in the 1980s, but their effectiveness in preventing heart disease and stroke has not been demonstrated. Lack of evidence of their efficacy might reasonably be expected to discourage their widespread use in management of hypertension.
Use of various classes of antihypertensive agents was estimated from published drug use information in an effort to estimate trends in antihypertensive drug use and evaluate the impact of these trends on costs of antihypertensive therapy in the United States.
Proportionate use of the five major antihypertensive drug classes shifted markedly between 1982 and 1993. Diuretics accounted for 56% of all hypertensive drug mentions in 1982 but only 27% in 1993, a relative decline of 52%. Use of beta-blockers and central agents also declined during this period. Proportionate use of calcium antagonists showed the greatest gains, increasing from 0.3% to 27%, while the use of angiotensin-converting enzyme inhibitors increased from 0.8% to 24%. Given the higher costs of the newer agents, and assuming an estimated total cost of antihypertensive medications in 1992 of $7 billion, approximately $3.1 billion would have been saved had 1982 prescribing practices remained in effect in 1992.
Use of calcium antagonists and angiotensin-converting enzyme inhibitors in hypertension has increased dramatically in the past 10 years. Without convincing evidence of the advantages of these agents, it is difficult to explain the continued decline in the use of less expensive agents, such as diuretics and beta-blockers, which are the only antihypertensive agents proved to reduce stroke and coronary disease in hypertensive patients.
This report is a summary of the discussion on the United States Renal Data System and its data contents, as presented at the Symposium on World Renal Registries on December 10, 1993. The United States Rental Data System is a national database that collects and analyzes information on the incidence, prevalence, morbidity, and mortality, as well as the modalities of therapy of patients with end-stage renal disease (ESRD) in the United States. The database is funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Data on the patients are provided by the Health Care Financing Administration Medicare Program. The coordinating center for the database, operated through a contract mechanism, was formerly at the Urban Institute in Washington, DC, but is currently located at the University of Michigan, Ann Arbor, MI. The data system contains information on over 462,000 patients with more than 4 million dialysis records, 2.3 million inpatient records, 94,000 transplant reports, and more than 290,000 follow-up reports. The incidence rate of ESRD is approximately 180 per million population. However, the rate is higher in African-Americans (430) and Native Americans (281) than in whites (153) and Asian/Pacific Islanders (133). The gross mortality rate of the entire ESRD population is approximately 168 deaths per 1,000 patient-years at risk. The death rate is higher in diabetic than in nondiabetic ESRD patients. It is also higher in ESRD patients older than 65 years (357) than in patients in the 45- to 64-year-old age group (158) or those in the 20- to 44-year-old age group (62).
To study the effect of angiotensin converting enzyme inhibition on the rate of progression to clinical proteinuria and the rate of change of albumin excretion rates in patients with insulin-dependent diabetes mellitus and persistent microalbuminuria.
Randomized, double-blind, placebo-controlled clinical trial of 2 years' duration at 12 hospital-based diabetes centers.
Ninety-two patients with insulin-dependent diabetes mellitus and persistent microalbuminuria but no hypertension.
The patients were randomly allocated in blocks of two to receive either captopril, 50 mg, or placebo twice per day.
Albumin excretion rate, blood pressure, glycosylated hemoglobin level, and fructosamine level every 3 months; urinary urea nitrogen excretion every 6 months; and glomerular filtration rate every 12 months.
Twelve patients receiving placebo and four receiving captopril progressed to clinical proteinuria, defined as an albumin excretion rate persistently greater than 200 micrograms/min and at least a 30% increase from baseline (P = .05). The probability of progression to clinical proteinuria was significantly reduced by captopril therapy (P = .03 by log-rank test). Albumin excretion rate rose from a geometric mean (95% confidence interval) of 52 (39 to 68) to 76 (47 to 122) micrograms/min in the placebo group but fell from 52 (41 to 65) to 41 (28 to 60) micrograms/min in the captopril group, a significant difference (P < .01). Mean blood pressure was similar at baseline in the two groups and remained unchanged in the placebo group but fell significantly, by 3 to 7 mm Hg, in the captopril group. Glycosylated hemoglobin levels and glomerular filtration rate remained stable in the two groups.
Captopril therapy significantly impeded progression to clinical proteinuria and prevented the increase in albumin excretion rate in nonhypertensive patients with insulin-dependent diabetes mellitus and persistent microalbuminuria.
Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy.
We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was < or = 2.5 mg per deciliter (221 mumol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration.
Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0.007). The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine concentration of 2.0 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a concentration of 1.5 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a concentration of 1.0 mg per deciliter (88.4 mumol per liter). The mean (+/- SD) rate of decline in creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per year in the placebo group (P = 0.03). Among the patients whose base-line serum creatinine concentration was > or = 1.5 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25 percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group (P = 0.01). Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups.
Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone.
The relationship between the delivered dose of hemodialysis and patient mortality remains somewhat controversial. Several observational studies have shown improved patient survival with higher levels of delivered dialysis dose. However, several other unmeasured variables, changes in patient mix or medical management may have impacted on this reported difference in mortality. The current study of a U.S. national sample of 2,311 patients from 347 dialysis units estimates the relationship of delivered hemodialysis dose to mortality, with a statistical adjustment for an extensive list of comorbidity/risk factors. Additionally this study investigated the existence of a dose beyond which more dialysis does not appear to lower mortality. We estimated patient survival using proportional hazards regression techniques, adjusting for 21 patient comorbidity/risk factors with stratification for nine Census regions. The patient sample was 2,311 Medicare hemodialysis patients treated with bicarbonate dialysate as of 12/31/90 who had end-stage renal disease for at least one year. Patient follow-up ranged between 1.5 and 2.4 years. The measurement of delivered therapy was based on two alternative measures of intradialytic urea reduction, the urea reduction ratio (URR) and Kt/V (with adjustment for urea generation and ultrafiltration). Hemodialysis patient mortality showed a strong and robust inverse correlation with delivered hemodialysis dose whether measured by Kt/V or by URR. Mortality risk was lower by 7% (P = 0.001) with each 0.1 higher level of delivered Kt/V. (Expressed in terms of URR, mortality was lower by 11% with each 5 percentage point higher URR; P = 0.001). Above a URR of 70% or a Kt/V of 1.3 these data did not provide statistical evidence of further reductions in mortality. In conclusion, the delivered dose of hemodialysis therapy is an important predictor of patient mortality. In a population of dialysis patients with a very high mortality rate, it appears that increasing the level of delivered therapy offers a practical and efficient means of lowering the mortality rate. The level of hemodialysis dose measured by URR or Kt/V beyond which the mortality rate does not continue to decrease, though not well defined with this study, appears to be above current levels of typical treatment of hemodialysis patients in the U.S.
Significant improvements were made during the last two decades in the treatment of IDDM patients. To assess the risk of ESRD in a population that was exposed to these improvements, we determined the cumulative incidence of ESRD in a cohort of 142 white patients who were aged less than 21 years when they came to the Joslin Diabetes Center in 1959 with recently diagnosed IDDM. The first case of ESRD occurred after 13 years of IDDM, and a total of 25 cases have developed by 35 years' duration (cumulative incidence 21.3%). Median survival after the diagnosis of ESRD for the 16 patients who began dialysis was only 3.5 years. A strong predictor of the development of ESRD was the level of glycemic control during the first two decades of IDDM. ESRD developed in 36.3% of patients in the worst tertile for glycemic control but only in 14.4% and 9.2% of those in the middle and best tertiles. In comparison with two population based studies, the onset of ESRD in the Joslin Cohort was postponed by about five years. This advantage is more plausibly attributable to differences arising after the diagnosis of diabetes than to referral of less severe cases of IDDM to the Joslin Diabetes Center. What differences in diabetes care accounted for the postponement of ESRD cannot be discerned from comparisons among published studies, but likely candidates include Joslin's long-term advocacy of good glycemic control and the prompt implementation of new clinical interventions, such as antihypertensive treatment.
The past decade has seen substantial improvements in end-stage renal disease (ESRD) outcomes, especially mortality, in the United States. Incidence rates for treated ESRD have doubled for most age groups, probably because of improved survival among high-risk populations, such as patients with diabetes and hypertension. The ESRD patient population is becoming older and has a greater incidence of diabetes because of changes in the types of patients starting treatment. The number of patients added to the waiting list each year for transplants has increased dramatically, whereas the number of transplantations performed annually has remained relatively constant. Although transplantation is consequently less available than before, transplant survival, both of the patient and the graft, has improved dramatically. Length of stay for hospitalizations has decreased. Both dialysis mortality and all ESRD mortality have decreased. It is important to monitor such statistics to try and modify adverse trends in outcomes for patients with ESRD. The ability to monitor patient outcomes through national databases has improved greatly during the last decade. Large-scale population-based studies of practices and outcomes for patients with ESRD offer a potent addition to the previously available arsenal of research tools, which was previously dominated by studies from single or few institutions and more expensive randomized clinical trials.
Mortality from coronary heart disease has declined substantially in the United States during the past 30 years. However, it is unknown whether patients with diabetes have also experienced a decline in heart disease mortality.
To compare adults with diabetes with those without diabetes for time trends in mortality from all causes, heart disease, and ischemic heart disease.
Representative cohorts of subjects with and without diabetes were derived from the First National Health and Nutrition Examination Survey (NHANES I) conducted between 1971 and 1975 (n = 9639) and the NHANES I Epidemiologic Follow-up Survey conducted between 1982 and 1984 (n = 8463). The cohorts were followed up prospectively for mortality for an average of 8 to 9 years.
Changes in mortality rates per 1000 person-years for all causes, heart disease, and ischemic heart disease for the 1982-1984 cohort compared with the 1971-1975 cohort.
For the 2 periods, nondiabetic men experienced a 36.4% decline in age-adjusted heart disease mortality compared with a 13.1% decline for diabetic men. Age-adjusted heart disease mortality declined 27% in nondiabetic women but increased 23% in diabetic women. These patterns were also found for all-cause mortality and ischemic heart disease mortality.
The decline in heart disease mortality in the general US population has been attributed to reduction in cardiovascular risk factors and improvement in treatment of heart disease. The smaller declines in mortality for diabetic subjects in the present study indicate that these changes may have been less effective for people with diabetes, particularly women.
The incidence of patients with end-stage renal failure and diabetes mellitus type 2 as a comorbid condition has increased progressively in the past decades, first in the United States and Japan, but subsequently in all countries with a western lifestyle. Although there are explanations for this increase, the major factor is presumably diminishing mortality from hypertension and cardiovascular causes, so that patients survive long enough to develop nephropathy and end-stage renal failure. This review summarizes the striking differences between countries against the background of a similar tendency of an increasing incidence in all countries. Survival on renal replacement therapy continues to be substantially worse for patients with type 2 diabetes. A major reason for this observation is that patients enter renal replacement programs with cardiovascular morbidity acquired in the preterminal phase of renal failure. It is argued that the challenge for the future will be better patient management in earlier phases of diabetic nephropathy to attenuate or prevent progression, as well as cardiovascular complications.
To evaluate access and utilization of medical care, and health status and outcomes that would be influenced by recent medical care, in a representative sample of patients with type 2 diabetes.
A national sample of 733 adults with type 2 diabetes was studied from 1991 to 1994 in the Third National Health and Nutrition Examination Survey. Structured questionnaires and clinical and laboratory assessments were used to determine the frequencies of physician visits, health insurance coverage, screening for diabetes complications, treatment for hyperglycemia, hypertension, and dyslipidemia; and the proportion of patients who met treatment goals and established criteria for health outcome measures including hyperglycemia, albuminuria, obesity, hypertension, and dyslipidemia.
Almost all patients had 1 source of primary care (95%), 2 or more physician visits during the past year (88%), and health insurance coverage (91%). Most (76%) were treated with insulin or oral agents for their diabetes, and 45% of those patients taking insulin monitored their blood glucose at least once per day The patients were frequently screened for retinopathy (52%), hypertension (88%), and dyslipidemia (84%). Of those patients with hypertension, 83% were diagnosed and treated with antihypertensive agents and only 17% were undiagnosed or untreated; most of the patients known to have dyslipidemia were treated with medication or diet (89%). Health status and outcomes were less than optimal: 58% had HbA1c >7.0, 45% had BMI >30, 28% had microalbuminuria, and 8% had clinical proteinuria. Of those patients known to have hypertension and dyslipidemia, 60% were not controlled to accepted levels. In addition, 22% of patients smoked cigarettes, 26% had to be hospitalized during the previous year, and 42% assessed their health status as fair or poor.
Rates of health care access and utilization, screening for diabetes complications, and treatment of hyperglycemia, hypertension, and dyslipidemia in type 2 diabetes are high; however, health status and outcomes are unsatisfactory. There are likely to be multiple reasons for this discordance, including intractability of diabetes to current therapies, patient self-care practices, physician medical care practices, and characteristics of U.S. health care systems.
To establish a relationship between angiotensin-converting enzyme (ACE) inhibitor therapy and renal outcomes in Medicaid patients with diabetes, and compare the use of ACE inhibitors between 1994 and 1998.
One thousand patients with either type 1 or type 2 diabetes were randomly selected from the Iowa Medicaid database and followed retrospectively from 1994 through 1998. Data on medication use (insulin, oral antidiabetic agents, or both) and medical services were collected from prescription claims and diagnostic codes. Differences were evaluated with nonparametric statistics.
Overall, 402 patients (40.2%) were prescribed an ACE inhibitor during the study period before any adverse renal outcomes occurred; 25 of the patients in this group (6.2%) had a subsequent adverse renal outcome. One hundred patients (16.7%) not receiving an ACE inhibitor had an adverse renal outcome (p = 0.006). We evaluated four subgroups and found that patients with hypertension had fewer adverse renal outcomes if they were receiving ACE inhibitors whether they were taking (p = 0.0006) or not taking insulin (p = 0.047). There was no difference in adverse renal outcomes and ACE inhibitor use in normotensive patients who were taking (p = 0.15) or not taking insulin (p = 0.96). The pattern of use of ACE inhibitors in this population increased more than twofold between 1994 and 1998 (38.1% vs. 80.1%; p < 0.001). Of those patients who had adverse renal outcomes, almost one-half (43.2%) were not taking an ACE inhibitor in 1998.
ACE inhibitors were renoprotective in patients with diabetes in the Iowa Medicaid population. All patients with diabetes who had hypertension had fewer renal outcomes when taking an ACE inhibitor. ACE inhibitors were used more frequently in 1998 than in 1994. The use of ACE inhibitors in this population is improving, but remains less than optimal.
This study assessed trends from 1980 to 1995 in ambulatory patients' antihypertensive drug therapy by US office-based physicians for visits in which hypertension was the principal diagnosis and compared these trends with the respective guidelines given in 5 Joint National Committee (JNC) Reports on Detection, Evaluation, and Treatment of High Blood Pressure published around the same time period. Data from the National Center for Health Statistics' National Ambulatory Medical Care Surveys for 1980, 1985, 1990, and 1995 were used. From 1980 to 1995, there was no significant trend in the percentage of hypertension visits that did not mention any antihypertensive drug (20% to 27%). Further analyses focused on those hypertension visits in which at least 1 antihypertensive drug was used. Across the years, antihypertensive drug visits mentioning calcium channel blockers or ACE inhibitors significantly increased; those noting diuretics significantly decreased. However, in 1995, antihypertensive drug visits that included a diuretic and/or a beta-adrenergic blocker equalled 53%; these are the antihypertensive drug classes preferred by the JNC V. Physician antihypertensive drug prescribing was generally consistent with the basic antihypertensive drug guidelines of the JNC reports.
Hemodialyzer reuse is commonly practiced in the United States. Recent studies have raised concerns about the mortality risk associated with certain reuse practices. We evaluated adjusted mortality risk during 1- to 2-year follow-up in a representative sample of 12,791 chronic hemodialysis patients treated in 1,394 dialysis facilities from 1994 through 1995. Medical record abstraction provided data on reuse practice, use of bleach, dialyzer membrane, dialysis dose, and patient characteristics and comorbidity. Mortality risk was analyzed by bootstrapped Cox models by (1) no reuse versus reuse, (2) reuse agent, and (3) dialyzer membrane with and without the use of bleach, while considering dialysis and patient factors. The relative risk (RR) for mortality did not differ for patients in reuse versus no-reuse units (RR = 0.96; 95% confidence interval [CI], 0.86 to 1.08; P > 0.50), and similar results were found with different levels of adjustment and subgroups (RR = 1.01 to 1.05; 95% CI, lower bound > 0.90, upper bound < 1.19 each; each P > 0.40). The RR for peracetic acid mixture versus formalin varied significantly by membrane type and use of bleach during reprocessing, achieving borderline significance for synthetic membranes. Among synthetic membranes, mortality was greater with low-flux than high-flux membranes (RR = 1.24; 95% CI, 1.02 to 1.52; P = 0.04) and without than with bleach during reprocessing (RR = 1.24; 95% CI, 1.01 to 1.48; P = 0.04). Among all membranes, mortality was lowest for patients treated with high-flux synthetic membranes (RR = 0.82; 95% CI, 0.72 to 0.93; P = 0.002). Although mortality was not greater in reuse than no-reuse units overall, differences may exist in mortality risk by reuse agent. Use of high-flux synthetic membrane dialyzers was associated with lower mortality risk, particularly when exposed to bleach. Clearance of larger molecules may have a role.
A pharmacy prescription database was used to identify patients at high risk for drug-related problems. Of the 1054 patients in the study, 687 had a diagnosis of hypertension. The utilization of antihypertensive medications was captured at three periods over 24 months (12 months before enrollment, at enrollment, and 12 months after enrollment). The diagnosis of hypertension and coexisting diseases were identified at enrollment. There were 238 (34.6%) with diabetes, 333 (48.5%) with coronary artery disease, 64 (9.3%) with congestive heart failure, and 244 (35.5%) with none of these coexisting conditions. At Period 3, 44.7% of patients without coexisting diseases received calcium channel blockers, followed closely by diuretics (41.4%). Calcium channel blockers were used significantly more frequently than any other drug category for these patients (p less than 0.05). For patients with hypertension and diabetes, ACE inhibitors were used by 62%, and this was significantly more frequently than any other category (p less than 0.03). Diuretics (52.1%) were utilized significantly more frequently than calcium channel blockers (42.9%) (p less than 0.043). For patients with hypertension and congestive heart failure, diuretics were utilized significantly more than any other category (70.3%, p less than 0.03), and ACE inhibitors were utilized significantly more often than any other category except diuretics (68.8%, p less than 0.0001). This study examined antihypertensive utilization in specific patients (rather than as a function of total drugs), making the results different from those of previous reports. This study demonstrates better adherence to recommended guidelines than previous studies have suggested. While Beta blockers and diuretics were utilized frequently in these patients, statistics suggest that there is still room for improvement in the utilization of these important drugs. This paper describes the utilization of antihypertensive medications in nine Veterans Affairs Medical Centers. (c)2000 by Le Jacq Communications, Inc.
Diabetic nephropathy is a chronic, progressive kidney disease with a mean rate of decline of in glomerular filtration rate (GFR) of 10 to 12 mL/min/year (natural history). The introduction of aggressive antihypertensive treatment has improved the renal prognosis during the last decades. To examine whether remission and regression of diabetic nephropathy are possible in type 1 diabetic patients, we analyzed data from a prospective observational cohort study that was started in 1983.
We measured GFR with a 51Cr-EDTA plasma clearance technique every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 microg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. Blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol were measured every three to four months during the study. In total, 271 patients received antihypertensive treatment, 179 patients predominantly with angiotensin-converting enzyme inhibitors. Remission was defined as albuminuria <200 microg/min sustained for at least one year and a decrease of at least 30% from preremission levels (surrogate endpoint), and regression as a rate of decline in GFR (DeltaGFR) equal to the natural aging process: < or =1 mL/min/year during the entire observation period (principal end point).
The total number of patients who obtained remission was 92 (31%), with a duration of remission of [median (range)] 3.4 (1.0 to 14.1) years, and regression 67 (22%). The patients were stratified in quintiles by the average value of office mean arterial blood pressure (mean +/- SE): 93 +/- 0.5, 99 +/- 0.2, 103 +/- 0.1, 107 +/- 0.2, and 113 +/- 0.4 mm Hg. The prevalence of patients obtaining remission/regression was 58/42, 33/32, 25/11, 20/20, and 17/7% in each quintile, respectively. Spontaneous remission and regression occurred in 10 and 14 patients from the persistent normotensive group (N = 30), none of whom had ever received antihypertensive treatment. In all 301 consecutive patients, the (mean +/- SE) DeltaGFR was 4.0 +/- 0.2 mL/min/year during the investigation period.
Our study suggests that aggressive antihypertensive treatment in type 1 diabetic patients can induce remission and regression in a sizable fraction of patients with diabetic nephropathy. Lower arterial blood pressure, reduced albuminuria, and better glycemic control were predictors of regression of diabetic nephropathy.
Microalbuminuria and hypertension are risk factors for diabetic nephropathy. Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes, but similar data are lacking for hypertensive patients with type 2 diabetes. We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria.
A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 mg daily or 300 mg daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level.
The base-line characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2 percent) and 19 of the 195 patients in the 150-mg group (9.7 percent) reached the primary end point, as compared with 30 of the 201 patients in the placebo group (14.9 percent) (hazard ratios, 0.30 [95 percent confidence interval, 0.14 to 0.61; P< 0.001] and 0.61 [95 percent confidence interval, 0.34 to 1.08; P=0.081 for the two irbesartan groups, respectively). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P=0.02).
Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.
It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure.
We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point.
The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point.
The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.