Clinical Manifestations Of Diabetic Nephropathy Research Articles

Analisis Interaksi Obat Secara Farmakokinetik dan Farmakodinamik Terhadap Pasien Nefropati Diabetik di Rumah Sakit X Kota Jambi Tahun 2022

Diabetic nephropathy (ND) is a complication of diabetes in the kidney. Nephropathy, or kidney disease, is the leading cause of death and disability in diabetes. The first clinical manifestation of diabetic nephropathy is microalbuminuria. If a patient is diagnosed with microalbuminuria, the development of end-stage renal and cardiovascular disease can be prevented by controlling blood pressure, glucose, and lipids. This study aimed to determine pharmacokinetic and pharmacodynamic drug interactions, determine drug interactions and severity in patients, determine the relationship between age and drug severity and gender relationship with drug severity in patients with diabetic nephropathy at X Hospital Jambi City in 2022. The method used in this research is descriptive method. The data collected in this study came from the medical records of diabetic nephropathy patients at X Hospital Jambi City in 2022. The total population in this study was 67 patients with a total sample of 46 patients. The results showed that the highest prevalence in the sample was female (56.52%), elderly patients aged 46-55 years (47.83%), drugs that interact with lantus ˃˂ novorapid (8.43%), patients experiencing drug interactions (71.74%), pharmacodynamic interactions (92.77%), pharmacokinetic interactions (4.82%), minor (10.84%), moderate (78.31%), and major severity (10.84%). The conclusions drawn from this study were based on the interaction mechanism, namely there were 6 cases (7.23%) of pharmacokinetic interactions and 77 cases of pharmacodynamic interactions (92.77%). Based on interactions with 9 cases of minor severity (10.84%), 65 cases of moderate severity (78.31%), and 9 cases of major severity (10.84%). And there is no relationship between the severity of the drug and age and gender.

Study of Neutrophil–Lymphocyte Ratio, Interleukin-6 (IL-6) and Tumor Necrosis Factor-Alpha (TNF-α) in Type 2 Diabetes with Diabetic Nephropathy

Abstract Background Diabetic kidney disease is defined by characteristic structural and functional changes. The predominant structural changes include mesangial expansion, glomerular basement membrane thickening, podocyte injury, and, ultimately, glomerular sclerosis. The major clinical manifestations of diabetic nephropathy are albuminuria, hematuria (less often), and, in many patients, progressive chronic kidney disease, which can be slowed with optimal therapy. Objective to assess the Neutrophil-lymphocyte Ratio, Interleukin- 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in Type 2 Diabetes with Diabetic Nephropathy. Patients and Methods In Our study We collect 90 subjects with their ages ranging from 35-70, selected from Internal Medicine and Endocrinology outpatient clinics and the inpatient department at Ain Shams University Hospitals. Results As regards NLR, there were statistically significant and direct correlations between NLR and IL6, TNF, serum BUN, serum creatinine and albumin to creatinine ratio, while significant and indirect correlation with EGFR. As regards IL6, there were statistically significant and direct correlations between IL6 and TNF, serum BUN, serum creatinine and albumin to creatinine ratio, while significant and indirect correlation with BMI and EGFR. As regards TNF, there were statistically significant and direct correlations between TNF and serum BUN and albumin to creatinine ratio. There is no statistical difference between the studied groups as regard sex, age, BMI, SBP, DBP. Conclusion The current study could find that NLR, IL-6 and TNF-α were significantly associated with albuminuria in Type 2 Diabetic patients with DN and that they can be used as evident biomarkers in assessing the progression of deteriorating renal function and different stages of renal disease in patients with DN.

Non-Diabetic Nephrotic Syndrome in Patients with Diabetes Mellitus

Abstract Type 2 diabetic nephropathy may be the consequence of some non-diabetic form of renal disease, unlike type 1 diabetes mellitus (DM) of long duration (≥10 years) in which severe proteinuria is always related to a well -defined pattern of diabetic nephropathy. The clinical manifestations of diabetic nephropathy are similar in type 1 and type 2 diabetes, while the renal lesions may differ. Diabetic glomerulopathy is the predominant renal lesion in type 1 diabetes, although tubular, interstitial and arteriolar lesions are also present in the advanced stages of renal disease. In contrast, in type 2 diabetes renal lesions are heterogeneous and several patients who fall into this category and who also suffer from diabetic kidney disease have mild or absent glomerulopathy with tubulointerstitial and/or arteriolar abnormalities. In addition, a high prevalence of non-diabetic renal diseases (NDRD), isolated or superimposed on classic diabetic nephropathy lesions have been reported in patients with type 2 diabetes, often reflecting the bias of selecting patients for unusual clinical presentations for renal biopsy. In this case report is illustrated that the nephrotic syndrome in patients with diabetes mellitus is not always associated with diabetic nephropathy non-diabetic renal disease.

Connexin 43‑autophagy loop in the podocyte injury of diabetic nephropathy.

The reduction of podocyte injury is a key strategy in controlling proteinuria, which is the main early clinical manifestation of diabetic nephropathy (DN). Impaired autophagic flux is the primary mechanism responsible for podocyte injury in DN. The aim of the present study was to elucidate the effect of connexin 43 (Cx43) on impaired autophagic flux in podo-cyte injury and to explore its molecular mechanism of action in DN. Sprague-Dawley rats were administered streptozocin (STZ) to construct a DN animal model. Podocytes were incubated in media containing either buffer or high glucose (HG; 30 mM) for variable time periods. The podocytes were then examined and the mechanism of injury was investigated using an Annexin V/PI assay, immunofluorescence staining, western blotting, and RNA interference. In vivo, STZ-induced DN rats with or without Cx43 knockdown were established to observe the role of Cx43 in autophagic flux and podocyte injury. We observed that HG induced podocyte injury, accompanied by increases in Cx43 expression and impaired autophagic flux, as evidenced by the accumulation of LC3II/LC3I and p62. Interestingly, the silencing of Cx43 expression ameliorated autophagic flux impairment and reduced podocyte injury via suppression of the mammalian target of rapamycin pathway. Furthermore, impaired autophagic flux also blocked the degradation of Cx43. In vitro studies indicated that higher numbers of Annexin V/PI-positive podocytes, impaired autophagic flux and increased Cx43 expression were observed in HG-induced podocyte injury relative to the control group. The pathogenic effect of Cx43 on impaired autophagic flux and podocyte injury was also confirmed by Cx43 knockdown. The present study provided preliminary evidence indicating that the interdependence of Cx43 and impaired autophagic flux represents a novel mechanism of podocyte injury in DN. Hence, the Cx43-autophagy loop is a potentially relevant therapeutic target for the treatment of DN.

The role of nicotinamide in the correction of renal function in diabetic nephropathy

Hyperglycemia of diabetes mellitus leads to the activation of the polyol way of oxidation of glucose with the activation of the enzymes of aldose reductase and sorbitol dehydrogenase and of their coenzymes NADPH and NAD, which triggers the mechanism of formation of sorbitol. The consequences of these changes lead to microangiopathy of the tissues of the kidneys, which may be one of the pathogenetic mechanisms of diabetic nephropathy. In an accessible literature, the role of coenzymes of sorbitol pathway in the development of diabetic nephropathy is not sufficiently defined. The purpose of the study was to study the content of NAD and NADPH coenzymes, their correlation, and their role in the mechanism of kidney damage in diabetes mellitus and to predict the possible correction of these changes with the NAD-nicotinamide derivative. The study was conducted on a model of streptotrozectinic diabetes mellitus (single administration of streptozotocin in a dose of 60 mg per 1 kg of body weight). Four weeks after induction of diabetes, nicotinamide (100 mg per 1 kg body weight) was injected. The level of glucose was determined by the Accu-chek (Roshe Diagnostics, Switzerland) glucose meter. The content of NAD and NADH was determined in the non-protein extracts. The statistical analysis was carried out using the Microsoft Excel statistical analysis program. The difference between the indicators was considered statistically significant (p<0.05). The NAD level was reduced by 31%, the NAD/NADN ratio was 32%. The dependence of the ratio of NADP/NADPN in conditions of hyperglycemia of diabetes mellitus with clinical manifestations of diabetic nephropathy is determined. A decrease in the ratio of NADP/NADPN to 38% in the rat kidney in the cortical layer was detected. The introduction of nicotinamide normalized the reduced content of NAD diabetic rats. These results provide perspectives for further research in which nicotinamide can be used as a renal protector.

HLA-DRB1*03 as a risk factor for microalbuminuria in same duration of type 1 diabetes: a case control study.

BackgroundIncreased urinary albumin excretion rate is the earliest clinical manifestation of diabetic nephropathy. The development of microalbuminuria in patients with type 1 diabetes mellitus (T1D) usually begins 5 to 15 years after the onset of diabetes. The rate of progression of diabetic nephropathy varies considerably among patients and not always can be explained solely by glycaemic control. The evidence suggests that genetic susceptibility may play a role in the development of diabetes microvascular complications, besides the presence of such risk factors as hyperglycaemia, hypertension, dyslipidaemia and smoking. The aim of the study was to evaluate a link between known genetic risk factors for type 1 diabetes mellitus (HLA-DR3/DR4) and microalbuminuria among patients with the same durations of diabetes.MethodsNinety-nine patients with T1D at the age 18–35 years were recruited for the study. The urine albumin excretion rate was normal when <30 mg/24 h; microalbuminuria 30–300 mg/24 h. Genotypes were investigated in 39 patients with normal albumin excretion rate and duration of diabetes 13.46 ± 3.72 years and in 60 patients with microalbuminuria and duration of diabetes 15.28 ± 4.08 years (p = 0.11). Genetic typing of DR3 and DR4 antigens successfully was performed for 99 subjects. Statistical analysis was performed using SPSS v. 20.0.ResultsGenotyping of 99 patients with T1D was performed: no DR3 and DR4 risk alleles were found in 22 (22.22 %) cases, DR3 alleles were present in 47 (47.48 %) cases, DR4 alleles in 25 (25.25 %) cases, and DR3/DR4 alleles in 5 (5.05 %) cases. The highest 24 h albumin excretion rate was found in patients with DRB1 gene expressed DR3 risk alleles group, the lowest - in patients with DRB1 gene with no expression of both DR3 and DR4 antigen. We confirmed the 1.87 (p = 0.021) increased relative risk for microalbuminuria in patients with DR3/DR3 alleles and same duration of diabetes. The distribution of DR3 and DR4 risk alleles was not associated with cardiovascular autonomic neuropathy both in patients with normal albumin excretion rate and microalbuminuria (1.6 vs 2.1; p = 0.21).ConclusionsThe 1.87 (p = 0.021) increased relative risk for microalbuminuria was found in patients with DR3/DR3 alleles and the same duration of diabetes.

HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice.

Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease–induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy in a type 1 diabetic animal model, OVE26. YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole], an HIF-1 inhibitor, reduced whole kidney glomerular hypertrophy, mesangial matrix expansion, extracellular matrix accumulation, and urinary albumin excretion as well as NOX4 protein expression and NADPH-dependent reactive oxygen species production, while blood glucose levels remained unchanged. The role of NOX oxidases in HIF-1–mediated extracellular matrix accumulation was explored in vitro using glomerular mesangial cells. Through a series of genetic silencing and adenoviral overexpression studies, we have defined GLUT1 as a critical downstream target of HIF-1α mediating high glucose–induced matrix expression through the NADPH oxidase isoform, NOX4. Together, our data suggest that pharmacological inhibition of HIF-1 may improve clinical manifestations of diabetic nephropathy.

A label-free approach by infrared spectroscopic imaging for interrogating the biochemistry of diabetic nephropathy progression

Routine histology, the current gold standard, involves staining for specific biomolecules. However, untapped biochemical information in tissue can be gathered using biochemical imaging. Infrared spectroscopy is an emerging modality that allows label-free chemical imaging to derive biochemical information (such as protein, lipids, DNA, collagen) from tissues. Here we employed this technology in order to better predict the development of diabetic nephropathy. Using human primary kidney biopsies or nephrectomies, we obtained tissue from 4 histologically normal kidneys, 4 histologically normal kidneys from diabetic subjects, and 5 kidneys with evidence of diabetic nephropathy. A biochemical signature of diabetic nephropathy was derived that enabled prediction of nephropathy based on the ratio of only 2 spectral frequencies. Nonetheless, using the entire spectrum of biochemical information, we were able to detect renal disease with near-perfect accuracy. Additionally, study of sequential protocol biopsies from 3 transplanted kidneys showed biochemical changes even prior to clinical manifestation of diabetic nephropathy. Thus, infrared imaging can identify critical biochemical alterations that precede morphologic changes, potentially allowing for earlier intervention.

266 Patients' Trust in Their Physician Associated with Satisfaction with ESRD Providers

ARE PATIENTS BEING SCREENED APPROPRIATELY FOR MICROALBUMINURIA? Rhoda Lyn Rojas, Pranay Kathuria Department of Internal Medicine, University of Oklahoma, Tulsa Oklahoma Microalbuminuria is not only the earliest clinical manifestation of diabetic nephropathy, but also an important risk factor for development of cardiovascular disease. The National Kidney Foundation has provided recommendations on screening of microalbuminuria. Testing should be performed only when blood pressure is close to goal and hyperglycemia corrected. Our clinical observations suggested the hypothesis that patients are not screened appropriately for microalbuminuria according to the guidelines provided by the National Kidney Foundation. Charts of all diabetic patients with no known kidney disease seen at the University of Oklahoma – Tulsa Internal Medicine and Family Medicine clinics from November 1, 2008 to October 31, 2009 were reviewed. Each chart was checked whether diabetics were screened for microalbuminuria. In those who had microalbuminuria, we checked if this screening was done according to guidelines provided by the National Kidney Foundation. Charts were also reviewed for documentation of the diagnosis and if an angiotensin converting enzyme inhibitor or angiotensin receptor blocker was prescribed. In the scheduled time duration, four hundred ninety-nine diabetic patients were seen in the out patient clinics. Forty-two per cent (210/499) were tested for microalbuminuria. Fifty-five patients (55/210) had microalbuminuria and 5 (5/210) had macroalbuminuria. Of the 55 patients with microalbuminuria, 4 patients had repeat testing, of which 3 were negative, and 1 was positive. Only 1 out of the 5 patients with macroalbuminuria was started on an angiotensin converting enzyme inhibitor. None of the patients with confirmed microalbuminuria had the diagnosis added to their problem list. Patients are not being screened appropriately for the presence of microalbuminuria according to the National Kidney Foundation guidelines.

Rationale and Strategies for Early Detection and Management of Diabetic Kidney Disease

Rationale and Strategies for Early Detection and Management of Diabetic Kidney Disease

From Fibrosis to Sclerosis

Progression of diabetic nephropathy to end-stage kidney disease is mediated by a host of processes, but none is as important as the gradual, inexorable scarring of the renal glomerulus, known as glomerulosclerosis. Hence, a host of studies over the decades have attempted to elucidate the molecular mechanisms that lead to this chronic sclerosing condition so that effective therapies and preventative strategies can be developed. Over the past several years, the general understanding of the pathogenic factors that lead to this important feature of diabetic nephropathy has improved considerably. Glomerulosclerosis in diabetic nephropathy is caused by accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space, resulting in fibrosis manifested by either diffuse or nodular changes (1). The most common matrix proteins detected are collagen types I, III, and IV and fibronectin (2). These accumulate both due to increased synthesis by mesangial cells and reduced degradation by mesangial matrix metalloproteinases (3). Over 20 years ago, Mauer et al. (4) established the clear link between mesangial matrix expansion and progression of diabetic kidney disease by demonstrating that measures of mesangial expansion strongly predicted the clinical manifestations of diabetic nephropathy. Since then, the critical charge to investigators has been to elucidate the mechanisms that promote glomerulosclerosis in diabetic nephropathy. In this brief perspective, we will review pathogenic processes that appear to be critical in the development of diabetic glomerulosclerosis, emphasizing newer findings and insights. During the 1990s, a general consensus emerged about major signaling mechanisms involved in stimulating mesangial cell synthesis of ECM proteins (Fig. 1). In this consensus view, high extracellular glucose induces an increase in glucose uptake via increased expression of the facilitative glucose transporter GLUT1 (5,6). The resultant enhancement in glucose metabolic flux leads to activation of a number of metabolic pathways that result in increased advanced …

Diabetic nephropathy: An update on renal structure

Abstract The renal lesions underlying renal dysfunction differ in type 1 and type 2 diabetes, although the clinical manifestations of diabetic nephropathy, proteinuria, decreased glomerular filtration rate and increasing blood pressure are similar. Indeed, in type 1 diabetes, although also tubular, interstitial and arteriolar lesions are present, the most important structural changes involve the glomerulus, while several type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulo-interstitial and arteriolar abnormalities. The clinical manifestations of diabetic nephropathy are strongly related with the structural changes, especially with the degree of mesangial expansion in both type 1 and type 2 diabetes. In the last years it has been demonstrated that also changes in the structure and number of podocytes may be involved in the progression of diabetic nephropathy. Previous studies using light and electron microscopic morphometric analysis described the renal structural changes and the renal structural–functional relationships, documenting the contribution of kidney biopsy studies in understanding the pathogenesis of diabetic nephropathy and in identifying the patients with higher risk to progress to end stage renal disease. Finally this review will summarize studies in pancreas transplant recipients demonstrating that the lesions of diabetic nephropathy in humans are reversible, if normoglycemia is achieved and maintained for a long period of time.

Histopathology of Diabetic Nephropathy

The clinical manifestations of diabetic nephropathy, proteinuria, increased blood pressure, and decreased glomerular filtration rate, are similar in type 1 and type 2 diabetes; however, the renal lesions underlying renal dysfunction in the 2 conditions may differ. Indeed, although tubular, interstitial, and arteriolar lesions are ultimately present in type 1 diabetes, as the disease progresses, the most important structural changes involve the glomerulus. In contrast, a substantial subset of type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulointerstitial and/or arteriolar abnormalities. The clinical manifestations of diabetic nephropathy are strongly related with the structural changes, especially with the degree of mesangial expansion in both type 1 and type 2 diabetes. However, several other important structural changes are involved. Previous studies, using light and electron microscopic morphometric analysis, have described the renal structural changes and the structural-functional relationships of diabetic nephropathy. This review focuses on these topics, emphasizing the contribution of research kidney biopsy studies to the understanding of the pathogenesis of diabetic nephropathy and the identification of patients with a higher risk of progression to end-stage renal disease. Finally, evidence is presented that the reversal of established lesions of diabetic nephropathy is possible.

Disappearance of Nephrotic Syndrome in Type 1 Diabetic Patients Following Pancreas Transplant Alone

Diabetic nephropathy affects approximately 40% of diabetic patients and is the leading cause of kidney disease in patients starting renal replacement therapy (1, 2). It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion in the absence of other renal diseases (1, 2). Nephrotic syndrome, characterized by massive proteinuria (≥2.5–3.0 g/24h), dysproteinemia/hypoalbuminemia, hyperlipidemia and edema, may be a devastating clinical manifestation of diabetic nephropathy (3). Pancreas transplant alone (PTA) can be effective in significantly improving the quality of life of type 1 diabetic patients, and can also eliminate diabetes acute complications, such as hypoglycemic and/or hyperglycemic episodes (4). In addition, evidence is growing to show that pancreas transplantation alone may have positive effects on chronic diabetes complications (4). We have recently observed that this procedure reduced urinary protein excretion in a group of type 1 diabetic patients (5). Here we describe the effects of pancreas transplant alone on the course of nephrotic syndrome in six type 1 diabetic patients (four females and two males, aged 35.3±3.7 years at the time of transplantation, with a diabetes duration of 24.1±7.5 years) with histologically documented diabetic nephropathy. Patients were evaluated before and after successful PTA (28.0±6.9 months of follow-up, with a range of 3–36 months), and results were compared with those obtained from a group of five matched type 1 diabetic patients (four females and one male, aged 26±5 years, with a diabetes duration of 18±3 years, and 28.0±5.6 months of follow-up, with a range of 3–36 months), who were evaluated for pancreas transplantation but did not accept to undergo the procedure. All the transplanted patients received portal drainage of endocrine pancreas secretions. Induction immunosuppression therapy consisted of basiliximab and steroids, and maintainance therapy consisted of tacrolimus (given at doses to achieve blood through levels of 10–15 ng/ml during the first month posttransplant, and 8–12 ng/ml thereafter), mycophenolate mophetil and steroids (tapered to 5 mg per day after 3 months) (6). Pancreas transplantation restored sustained normoglycemia, without exogenous insulin administration (plasma glucose levels: from 238±123 to 98±1.5 mg/dl; A1c values: from 9.52±2.26% to 5.6±0.41%, both P<0.01 of last posttransplant control vs. pretransplant measurements). Under these conditions, edema disappeared in all the patients, and urinary protein excretion decreased (Fig. 1A), with values from 6.3±3.5 before transplantation to 0.50±0.18 g/24h at the end of follow-up (P<0.01). Conversely, no significant change occurred in non-transplanted patients (Fig. 1B). As shown in Table 1, serum protein levels normalized in transplanted patients, whereas, again, no major change was observed in the control group (Table 1). Furthermore, in PTA patients serum total and LDL cholesterol decreased significantly (Table 1) in the absence of antidyslipidemic therapy modifications. These improvements occurred without any significant change of creatinine clearance values (from 84±19 ml/min pretransplantation to 78±28 ml/min posttransplantation, P=0.47).FIGURE 1.: Course of proteinuria in transplanted (A) and nontransplanted (B) patients.TABLE 1: Some biochemical parameters of transplanted and nontransplanted patientsThis study demonstrates for the first time that in type 1 diabetic patients, successful pancreas transplant alone determines the disappearance of nephrotic syndrome, as documented by disappearance or significant improvement of the clinical signs of this condition. These effects were accompanied by no change of creatinine clearance. Routine native kidney biopsies of pancreas transplant alone recipients are not performed in our centre for ethical reasons. Nevertheless, the beneficial actions of PTA that we observed are unlikely to be due to anatomical changes in the kidneys, because it has been previously demonstrated that reversal of diabetic renal lesions occurred many years after pancreas grafting (7). Rather, diabetes “curing” by PTA is likely to have played the major role, by normalization of circulating glucose levels and restoration of endogenous insulin and C-peptide secretion. These data suggest that the beneficial effects of PTA may be more evident than currently appreciated. Alberto Coppelli Rosa Giannarelli Ugo Boggi Stefano Del Prato Gabriella Amorese Fabio Vistoli Franco Mosca Piero Marchetti Department of Endocrinology and Metabolism University of Pisa Pisa, Italy

Diabetic nephropathy: renal structural studies in type 1 and type 2 diabetic patients

The clinical manifestations of diabetic nephropathy, proteinuria, decreasing glomerular filtration rate and increasing blood pressure are similar in type 1 and type 2 diabetes, while the renal lesions differ. Indeed, in type 1 diabetes, although also tubular, interstitial and arteriolar lesions are present, the most important structural changes involve the glomerulus, in contrast several type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulo-interstitial and arteriolar abnormalities. The renal functional parameters are strongly related with the structural changes, especially with the degree of mesangial expansion in both type 1 and type 2 diabetes. Previous studies using light and electron microscopic morphometric analyses described the renal structural changes and the structural–functional relationships of diabetic nephropathy. This review focuses on these topics, documenting the contribution of renal biopsy studies in understanding the pathogenesis of diabetic nephropathy and in identifying the patients with higher risk to progress to end-stage renal disease.

Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide.

Clinical manifestations of diabetic nephropathy are an expression of diabetic microangiopathy. This review revisits the previously proposed Steno hypothesis and advances our hypothesis that development of endothelial cell dysfunction represents a common pathophysiological pathway of diabetic complications. Specifically, the ability of glucose to scavenge nitric oxide is proposed as the initiation phase of endothelial dysfunction. Gradual accumulation of advanced glycated end products and induction of plasminogen activator inhibitor-1, resulting in the decreased expression of endothelial nitric oxide synthase and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for the maintenance phase of endothelial dysfunction. The proposed conceptual shift toward the role of endothelial dysfunction in diabetic complications may provide new strategies for their prevention.

Molecular biology of diabetic glomerulosclerosis.

Diabetic nephropathy is one of the leading causes of renal failure in Western countries, where diabetic patients account for nearly half of all patients on haemodialysis. Progressive expansion of the mesangial matrix, and thickening of the glomerular and tubular basement membranes without signs of major cell proliferation are hallmarks of human and experimental diabetic nephropathy. These lesions eventually lead to glomerular fibrosis, a central pathological feature in many human acute and chronic kidney diseases, which progressively destroys the renal filtration unit, and may finally cause renal failure. Indeed, structure function relationship studies have shown that mesangial matrix expansion is strongly related to the clinical manifestation of diabetic nephropathy.

Extracellular matrix and its interactions in the diabetic kidney: A molecular biological approach

Increased extracellular matrix (ECM) is the ultrastructural hallmark of diabetic microangiopathy. Its accumulation within the kidney is directly linked to the clinical manifestations of diabetic nephropathy, namely proteinuria and declining renal function. The pathogenesis of ECM changes in diabetes is not well understood, but is likely to involve interaction between cells, growth factors, structural proteins, and cell receptors for these molecules. Molecular biological techniques may offer the necessary tools for gaining insight into the pathogenetic processes that eventually lead to renal failure in diabetes.

Structural-functional relationships in diabetic nephropathy.

Renal biopsies in 45 patients with insulin-dependent diabetes mellitus (IDDM) were examined by semiquantitative light microscopy and quantitative electron microscopic stereologic morphometry. In these 14 males and 31 females, aged 13-52 yr, who had had IDDM for 2.5-29 yr there was no strong relationship between either glomerular basement membrane (GBM) thickness or mesangial expansion and duration of IDDM. There was only a weak relationship between the thickness of the GBM and expansion of the mesangium. Thus, GBM thickening and mesangial expansion in IDDM occur at rates that often differ from one another and that vary greatly among patients. The clinical manifestations of diabetic nephropathy, albuminuria, hypertension, and decreased glomerular filtration rate related poorly or not at all to GBM thickening. In contrast, all light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions. Mesangial expansion had strong inverse correlations with capillary filtering surface area density. It is hypothesized that mesangial expansion could lead to glomerular functional deterioration in IDDM by restricting the glomerular capillary vasculature and its filtering surface. However, capillary closure, glomerular sclerosis, and interstitial fibrosis could also contribute to the clinical manifestations of this disorder.