Nephropathy In Insulin-dependent Diabetes Mellitus Research Articles

Negative Impact of Underlying Non–Insulin-dependent Diabetes Mellitus Nephropathy on Long-term Allograft Survival in Kidney Transplantation: A 10-Year Analysis From a Single Center

IntroductionWe analyzed the relationship between underlying nephropathy and long-term outcomes in kidney transplant recipients. MethodsWe retrospectively analyzed data from 678 patients who underwent kidney transplantation (KTx) between 1998 and 2011. Recipients with 13 major nephropathies were evaluated for graft and patient survival, and causes of graft loss. ResultsThe best 10-year graft survival rates (100%) were in the patients with autosomal-dominant polycystic kidney disease, preeclampsia, Alport syndrome, and purpura nephritis. The worst rate (50.8%) was in patients with non–insulin-dependent diabetes mellitus nephropathy (NIDDMN; P = .039). Causes of graft-loss in the NIDDM patients included chronic rejection (6 cases), acute rejection (3 cases), infection (2 cases), and cardiovascular event (2 cases). Significant risk factors for graft loss were donor age (P < .01) and NIDDMN (P < .01). ConclusionUnderlying NIDDMN before KTx was a significant risk factor for long-term graft function. Immunologic factors and nonimmunologic factors influenced the long-term outcomes in patients with underlying NIDDMN.

Occurrence of microalbuminuria among children and adolescents with insulin-dependent diabetes mellitus

Microalbuminuria precedes the onset of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) pediatric patients. Its prevention is among the most important challenges in managing IDDM. We attempted to determine the occurrence of microalbuminuria among IDDM Saudi children and adolescents and its associated risk factors. This is a retrospective cross-sectional study conducted on 409 IDDM children and adolescents attending the pediatric clinic at King Abdul-Aziz University Hospital from 2006 to 2010. Their ages ranged from 1 to 18 years and the mean ± standard deviation (mean ± SD) was 12.3 ± 4.1 years. Twenty-four-hour urinary albumin excretion (on two separate occasions or more, 3 - 6 months apart each), HbA1c, duration of IDDM, Tanner staging and body mass index (BMI) were reviewed. Prevalence of microalbuminuria in our cohort was 11.3%. IDDM duration was ≥2 years in 55.8% of our patients; of them, 15.6% had microalbuminuria while 45.2% had IDDM duration <2 years (6% had microalbuminuria) (P <0.01). The prevalence of microalbuminuria was higher among the post-pubertal subjects (50%) than that among the pre-pubertal (8.7%) and pubertal (41.5%) subjects. Furthermore, microalbuminuria was present in 16.7% of those with elevated blood pressure, but only in 8.5% among those with normal blood pressure (P <0.05). The enrolled overweight and obese subjects showed a higher prevalence of microalbuminuria (14%) when compared with that among those with a normal BMI (6.6%) (P <0.05). In our cohort, duration of IDDM, pubertal status, hypertension and BMI affected the prevalence of microalbuminuria. Annual screening for microalbuminuria in IDDM children and adolescents is imperative.

Microvascular and macrovascular complications associated with diabetes in children and adolescents

Department of Pediatrics, Ulleval University˚Hospital, and Faculty of Medicine, University of Oslo, NorwayCorresponding author:Assoc. Prof. Kim DonaghueThe Children’s Hospital at Westmead, Locked Bag 4001,Westmead, NSW 2145, Australia.Tel: C61 2 9845 3172;fax: C61 2 9845 3170;e-mail: kimd@chw.edu.auAcknowledgments: Esko Wiltshire, Gisela Dahlquist, KennethLee Jones, Edna Roche, Amina Balafrej and Riccardo Bonfanti.Conflicts of interest: The authors have declared no conflictsof interest.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

The C825T polymorphism in the G-protein beta3 subunit gene and diabetic complications in IDDM patients.

Complications of insulin-dependent diabetes mellitus (IDDM) are a major cause of morbidity and mortality; however, the mechanisms of their development are still to be elucidated. Genetic susceptibility contributes to the pathogenesis of nephropathy in IDDM. Enhanced G-protein activation, a cellular phenotype observed in cultured cells from patients with essential hypertension, was recently documented in IDDM subjects with nephropathy. A C825T polymorphism was recently described in GNB3, the gene encoding the beta 3 subunit of heterotrimeric G-proteins. This genetic variant has been associated with enhanced G-protein activation. The 825T allele was observed more frequently in a group with essential hypertension. We analyzed the role of the C825T polymorphism in the predisposition to diabetic complications in IDDM. In this study, we investigated the frequency of this polymorphism in a large case-control study and found no association of the 825T allele with diabetic nephropathy, retinopathy, and neuropathy.

Glycosaminoglycans: use in treatment of diabetic nephropathy.

Glycosaminoglycans: use in treatment of diabetic nephropathy.

Methylenetetrahydrofolate Reductase Gene Polymorphism as a Risk Factor for Diabetic Nephropathy in IDDM Patients

A missense mutation in the methylenetetrahydrofolate reductase gene (MTHFR), C677T, results in a thermolabile variant with reduced activity. Elevated levels of homocysteine have been recognized as a risk factor for vascular disease. Insulin-dependent diabetes mellitus (IDDM) is characterized by a higher prevalence of vascular complications. We analyzed the frequency of C677T MTHFR in IDDM and control groups. The genotype distribution did not differ between control subjects (n = 297) and IDDM patients (n = 392) (χ2 = 5.413, df = 2, P > 0.05). The MTHFR T677T genotype was found significantly more frequently in IDDM patients with diabetic nephropathy (0.216) compared with the IDDM patients without nephropathy (0.056); the odds ratio was 2.635 (95% CI 1.768–3.927). Thus, we suggest that the T677T genotype of the MTHFR gene is an independent risk factor for diabetic nephropathy in IDDM.

Angiotensin-converting enzyme gene polymorphism: is there a link to nephropathy in patients with type 1 diabetes?

To evaluate the association between the angiotensin-converting enzyme (ACE) gene polymorphism and diabetic nephropathy in patients with type 1 diabetes. Citations were selected using the MEDLINE database. Only those citations involving human subjects and available in English were selected. Key search words included angiotensin-converting enzyme (ACE), polymorphism, nephropathy, and type 1 diabetes. Selection criteria consisted of all MEDLINE-referenced clinical trials, review articles, and editorial comments assessing the potential link between the ACE gene polymorphism and diabetic nephropathy in insulin-dependent diabetes mellitus published between January 1990 and February 1998. Because diabetic nephropathy is a serious complication of type 1 diabetes, focus has been placed on the early identification of and intervention with patients genetically susceptible to this complication. Because the ACE gene polymorphism has an effect on plasma ACE concentration variations among individuals, it has been investigated as a potential genetic marker for diabetic nephropathy. The best studies to date are reviewed in order to assess the utility of the ACE polymorphisms as a genetic marker of diabetic nephropathy in patients with type 1 diabetes, and to determine what implications this holds for drug treatment. Although the ACE gene polymorphism's potential link to diabetic nephropathy in patients with type 1 diabetes has been debated, the most definitive studies show that an association exists. Large epidemiologic studies must now be conducted to determine the implications this polymorphism holds for the best treatment strategies in the care of these patients.

Diabetic nephropathy is associated with AGT polymorphism T235: results of a family-based study.

Diabetic nephropathy is a serious and frequent complication of insulin-dependent diabetes mellitus (IDDM) that has a strong genetic component. Several case-control studies have reported conflicting results with regard to the role of angiotensinogen gene polymorphisms, specifically the M235T T allele, in the development of diabetic nephropathy. The primary limitation of the case-control approach is that bias may be introduced by unrecognized differences in the populations selected for cases and control subjects. In contrast, family-based approaches, such as the transmission/disequilibrium test, assess whether a particular variant, or allele, is transmitted preferentially from a parent having a single copy of that allele. Thus each family provides its own control, thereby eliminating spurious results caused by mismatched population samples. To take advantage of this study design for further investigation of M235T, we collected from the Joslin Diabetes Center in Boston 148 IDDM patients with diabetic nephropathy, 62 nephropathy-free patients with long-duration IDDM, and, very importantly, parents of all these individuals. We found that among males (but not females) the T allele of the M235T polymorphism was transmitted preferentially to those with nephropathy compared with IDDM patients without nephropathy (P=.05). Moreover, the T allele was transmitted preferentially to patients with the most severe manifestation of nephropathy, end-stage renal disease (P=.04). In conclusion, results obtained in our family-based study support a role of the angiotensinogen gene M235T polymorphism, and specifically the T allele, in the development of diabetic nephropathy in IDDM.

Prevention and slowing down the progression of the diabetic nephropathy through antihypertensive therapy

Diabetic nephropathy is the major cause of illness and premature death in people with diabetes, largely through accompanying cardiovascular disease and end-stage renal failure. Diabetic patients are several times as prone to kidney disease as nondiabetic people and the accumulative risk of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) is about 30%–50% after 25 years of disease. Diabetic nephropathy is a progressive disease that takes several years to develop, ending in chronic renal insufficiency. Proteinuria heralds the onset of diabetic nephropathy, and the worsening of proteinuria parallels the progression of renal disease. The main risk factors for the frequency, severity, and progression of diabetic nephropathy are the degree of hyperglycemia and associated metabolic disturbances, hypertension, protein overload, cigarette smoking, as well as the duration of diabetes. Interventional strategies for primary, secondary, and tertiary prevention of diabetic nephropathy therefore include meticulous glycemic control, appropriate treatment of associated lipid abnormalities, rigorous control of the blood pressure, reduction in dietary protein intake, in particular animal protein, and of fat intake, and stopping cigarette smoking. Randomized clinical trials indicate that antihypertensive therapy is beneficial in preventing and slowing down the progression of diabetic nephropathy. There is now increasing evidence that angiotensin-converting enzyme inhibitors and certain calcium antagonists produce a more beneficial effect on diabetic nephropathy in terms of reducing proteinuria and slowing the progression to diabetic renal failure. These drugs are attributed nephroprotective capacity beyond their blood pressure lowering capacity and initial clinical trials with combinations have revealed even additive protective effects on end organs.

Lack of association between cystopathy and progression of diabetic nephropathy in insulin-dependent diabetes mellitus.

Whether an association exists between cystopathy and progression of diabetic nephropathy has never been clarified. The aim of the present study was to measure the degree of cystopathy in relation to the rate of progression of diabetic nephropathy. To that end, 17 insulin-dependent diabetic patients with diabetic nephropathy but without voiding symptoms were investigated urodynamically. The median age of the patients was 45 years (range 27-67 years), diabetes duration 23 years (range 14-44 years) and the serum creatinine level was 162 mumol/L (median, range 65-449 mumol/L) at the time of the study. The progression rate of diabetic nephropathy was analysed retrospectively by measuring changes in yearly mean values of Log10 serum creatinine for a period of 13 years (3-15 years) before the investigation. The progression rate was 0.028 mumol/L/year (median). Patients with a progression rate above and below the median rate were considered to be rapid (n = 8) and slow (n = 9) progressors, respectively. More women than men had a rapid progression rate of nephropathy. Rapid progressors were found to have smaller volume or residual urine (90 vs 165 ml; p < 0.05), larger volume voided (440 vs 270 ml; p < 0.05), lower opening pressure (18 vs 48 cm H2O; p < 0.05) and lower pressure at maximum flow (37 vs 64 cm H2O; p < 0.05) compared to slow progressors. However, these variables were not related to the progression rate of nephropathy (MANOVA). Furthermore, these results should be interpreted with caution because of the natural gender differences in pressure conditions. In conclusion, rapid progression of diabetic nephropathy does not seem to be associated with dysfunction of the urinary bladder measured with cystometry and pressure flow.

Report on a workshop to develop management recommendations for the prevention of progression in chronic renal disease.

EVERAL large clinical trials on the management/prevention of progressive renal disease have been published within the last year.‘” Three of these trials relate to diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM), and a fourth relates to renal disease of diverse etiologies (excluding IDDM). These studies show that the incidence of chronic renal disease can be decreased by approximately 50%, that the rate of progression of proteinuria can be decreased by a similar percentage, and that these favorable results also apply to patients with advanced nephropathy. Thus, for the first time, it has been conclusively shown that chronic progressive renal disease is amenable to both prevention and treatment. There had not been a consensus as to the implications of these studies for general patient care. For this reason, a conference was held on April 4 and 5, 1994, for the purpose of developing practical management recommendations. The conference was composed of several panels of nephrology experts drawn from around the world. The panels reviewed the existent literature, listened to presentations on the published studies, and reviewed manuscripts in press from secondary analyses of the Modification of Diet in Renal Disease (MDRD) study data. The panels developed initial recommendations and presented them to an audience of more than 150 physicians who provided a critique of the recommendations. A draft of the recommendation report was then read to the audience participants for final comments. The final recommendations were agreed upon and are the subject of this report.

Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I--converting enzyme gene.

In search of genetic determinants of susceptibility to diabetic nephropathy, we examined the association between DNA sequence differences at the locus of angiotensin I-converting enzyme (ACE) and renal complications in 151 insulin-dependent diabetes mellitus (IDDM) patients with a diabetes duration of 16-21 years. This nested case-control study included 77 normoalbuminuric control subjects (albumin excretion rate < 30 micrograms/min) and 74 cases with evidence of nephropathy ranging from microalbuminuria to overt proteinuria. DNA from each of these patients was genotyped at the ACE locus by a three-allele restriction fragment-melting polymorphism (RFMP) (Dde I), which we described recently, and a two-allele insertion/deletion recognized as an Xba I restriction fragment-length polymorphism, which has been shown by other investigators to be associated with serum levels of ACE and with risk of myocardial infarction. The least common allele of the Dde I RFMP was significantly more frequent among cases with nephropathy than among normoalbuminuric control subjects (12.8 vs. 4.5%, P < 0.05). The deletion in the ACE gene was also more frequent in case than in control subjects (56.1 vs. 47.4%), but the difference was not statistically significant (P < 0.25) with this sample size. To determine the independence of these associations, the two polymorphisms were analyzed jointly to identify Xba I/Dde I haplotypes. As might be expected, carriers of the Xba I/Dde I '+ =' haplotype had a fourfold risk of developing diabetic nephropathy (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.5-11.0). However, this did not explain all of the excess Xba I '+' allele among cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Current therapeutic management of diabetic nephropathy.

Roughly 40% of all patients with insulin-dependent diabetes mellitus (IDDM) develop diabetic nephropathy with proteinuria, hypertension and a decrease in glomerular filtration rate 10 to 20 years after the onset of the disease, and 5 years later most patients suffer from end-stage renal disease. Microalbuminuria, defined as an urinary albumin excretion rate (UAER) between 30 and 300 mg/day, strongly predicts the development of nephropathy in IDDM. Nearly all patients with IDDM, a decreasing glomerular filtration rate and a UAER > 300 mg/day have coexisting hypertensive disease additionally worsening renal function. We review the results of recent long-term studies of the current therapeutic management in diabetic patients by means of better blood pressure control, low-protein diet and near-normal blood glucose control in the early microalbuminuric phase as well as in the later phases of the disease characterized by diabetic nephropathy with a UAER > 300 mg/day. Since the large majority of studies have been performed on IDDM, our conclusions with regard to therapy are only valid in this subgroup of diabetic patients.

Changes of albumin concentrations in the first morning urine according to age and sex in 2990 healthy children and adults

This study was performed to clarify the changes in urinary albumin excretion according to age and sex in healthy subjects, for the appropriate judgment of microalbuminuria in insulin-dependent diabetes mellitus (IDDM). Concentrations of albumin in the first morning urine from 2990 healthy individuals (1713 males, 1277 females) aged from 6 to 39 years were measured by turbidimetry immunoassay. Reference values of the concentrations for each age group were obtained from the 95% confidence limits from the distribution simulated by the x 2-test ( k = 1). Reference values were 1.3–2.2 mg/dl in children aged 6–11 years. Values for females increased significantly from 22 mg/dl at age 11 years to 3.9 mg/dl at age 12 years ( P < 0.0001) and those of males increased gradually from 1.7 mg/dl at age 11 years to 3.9 mg/dl at age 16 years. There were significant differences between males and females at the ages of 12 ( P < 0.0001), 13 ( P < 0.0001), and 14 ( P < 0.0007). After 17 years, the values decreased from 3.9 mg/dl to 3.3 mg/dl in females, and to 2.9 mg/dl in males. We conclude that reference values of urinary albumin excretion change according to age and sex, which should be taken into consideration in the assessment of diabetic nephropathy in IDDM.

Molecular genetic approaches to the identification of genes involved in the development of nephropathy in insulin-dependent diabetes mellitus.

Genetic factors contribute significantly to the development of diabetic nephropathy in patients with insulin-dependent diabetes mellitus. This report discusses some models of diabetic nephropathy that incorporate genetic susceptibility and presents strategies for identifying the responsible genes. To identify variation at a locus, newly developed methods are discussed that employ denaturing gradient gel electrophoresis to study sequence differences in both polymerase chain reaction-amplified DNA fragments and genomic DNA. These techniques are illustrated with studies of the angiotensinogen gene and the insulin receptor gene. In preliminary data from a comparison between individuals with and without diabetic nephropathy, no DNA sequence difference in that part of the angiotensinogen gene that codes for angiotensin I was found. However, with a probe corresponding to exons 7 and 8 of the insulin receptor gene and denaturing gradient gel electrophoresis of Rsal digestions of genomic DNA, different distributions of a DNA polymorphism were found in patients with fast as compared with slowly progressing nephropathy. The interpretation of this finding and the need for further studies are discussed. In conclusion, the advent of methods of molecular genetics makes possible studies on genetic determinants of diabetic nephropathy. However, more clinical and epidemiologic data are needed to find out how many genes are involved and how they interact with exposure to diabetes. Foremost, DNA from families with two or more siblings with diabetic nephropathy must be collected to permit the necessary genetic studies.

Von Willebrand Factor and Development of Diabetic Nephropathy in IDDM

We tested the hypothesis that dysfunction of vascular endothelium, indicated by an increase in plasma level of von Willebrand factor (vWF), is present in patients with insulin-dependent diabetes mellitus (IDDM) who develop diabetic nephropathy (DN). DN was classified as absent (urinary albumin excretion [UAE] rate less than 15 microgram/min), incipient (UAE rate 15-200 micrograms/min), or clinical (UAE rate greater than 200 micrograms/min). We followed a cohort of 59 patients for a median of 3 yr. At baseline, 52 patients had no DN, 6 had incipient DN, and 1 had clinical DN. At follow-up, 38 patients had no DN (group 1). Incipient DN had developed in 14 patients and worsened in 3 patients. Clinical DN had worsened in 1 patient. Together, these 18 patients comprised group 2. A decrease in UAE was observed in the remaining three patients with incipient DN at baseline (group 3). In group 1, vWF--measured by immunoelectrophoresis and expressed as a percentage of normal--increased slightly (median 10%, range -43 to 145, P = 0.009). In group 2, vWF increased in all patients (median 80%, range 14 to 206 [corrected], P = 0.0002 vs. baseline and group 1). In group 3, vWF decreased (median -19%, range -44 to -18). After correction for possible confounders, i.e., age, varying duration of follow-up, and initial level of vWF, the difference in vWF change between groups 1 and 2 remained significant (P = 0.009). Poor glycemic control at baseline, estimated by glycosylated hemoglobin, was a significant predictor of increases in vWF in both group 1 and groups 1 and 2 combined.(ABSTRACT TRUNCATED AT 250 WORDS)

‘Microalbuminuria’ and Diabetes: A Critique—Assessment of Urinary Albumin Excretion and Its Role in Screening for Diabetic Nephropathy

Abnormal albumin excretion in the range not previously detectable by routine clinical methods can now be readily quantified, and has been shown to predict the development of clinically significant nephropathy in insulin-dependent diabetes mellitus (IDDM) and to predict excess mortality in non-insulin-dependent diabetes mellitus (NIDDM). Albuminuria of this degree has been inappropriately called "microalbuminuria," a misleading term which should be abandoned. In IDDM, persistent minimal elevation of albumin excretion predicts the development of more severe proteinuria and clinical diabetic nephropathy, which frequently progresses to renal failure. In NIDDM, the predictive value for renal failure remains to be established, but excess mortality occurs in those with abnormal albumin excretion, suggesting that it is an indicator of generalized vascular disease. However, the normal range of albumin excretion in older subjects is not well established. The relationship of glomerular injury to mildly elevated albumin excretion is uncertain. Several means of reducing the excretion rate have been described, but whether these can halt or prevent progression of glomerular injury is unknown. Thus, at the present time detection of mildly elevated albumin excretion and intervention to reduce the incidence of diabetic nephropathy or other diabetes-related complications fail to meet generally accepted criteria for prescriptive screening. However, such measurements of albumin excretion provide an important tool for research into the natural history and pathogenesis of diabetic nephropathy.