Diabetic nephropathy

Diabetic nephropathy is the leading cause of end-stage renal disease in the United States and the largest contributor to the total cost of diabetic care. In addition to the development of diabetic nephropathy and end-stage renal failure, diabetic patients with evidence of albuminuria have a much higher risk of developing myocardial infarctions, cerebrovascular accidents, severe progressive retinopathy, and neuropathy. This article characterizes the clinical and pathologic features of diabetic nephropathy and reviews the major pathogenetic theories that underlie the development of this dreaded complication of diabetes. Widespread screening for this condition and aggressive treatment of diabetic nephropathy at early stages of disease are critical to diminish the risk of costly late complications.     

Renal functional reserve in patients with Type 1 diabetes mellitus

AIM: Decreased renal functional reserve might precede incipient diabetic nephropathy in patients with Type 1 diabetes. The aim of this study was to assess the relationship between renal functional reserve and easily assessable estimates of systemic endothelial dysfunction in normoalbuminuric patients with Type 1 diabetes and diabetic retinopathy. METHODS: Renal functional reserve was calculated as the relative change in glomerular filtration rate after protein ingestion. Glomerular filtration rate was measured using pharmacokinetic compartmental analysis of single-shot plasma sinistrin clearance. We measured the activity of von Willebrand factor and concentrations of C-reactive protein and apolipoprotein B, as easily assessable estimates of systemic endothelial dysfunction. RESULTS: Twenty-two patients were studied. Renal functional reserve was inversely associated with activity of von Willebrand factor (R=-0.431, p=0.045) and, in a multivariate model, with concentration of C-reactive protein (R=0.652, p=0.031). CONCLUSION: Renal functional reserve is inversely associated with concentration of C-reactive protein in normoalbuminuric patients with Type 1 diabetes and diabetic retinopathy. This finding provides evidence that decreased renal functional reserve might reflect endothelial dysfunction. We speculate that decreased renal functional reserve might possibly show as an early marker of diabetic nephropathy.     

Clinical features and health-care costs of diabetic nephropathy

The nephropathy complicating insulin-dependent diabetes mellitus (IDDM) has been well studied, but that complicating non-insulin-dependent diabetes mellitus (NIDDM) is less well defined. In patients with IDDM, the glomerular filtration rate is often increased early in the course of the disease, approaches normal with insulin therapy, but tends to remain slightly elevated throughout the ensuing 10-15 yr of insulin dependency. After the onset of overt azotemia, end-stage renal disease (ESRD) develops in approximately 5 yrs. Proteinuria may be intermittently positive in the earliest stages of diabetes, evolving into intermittent and then persistent microalbuminuria, which in turn blossoms into macroalbuminuria. Because 40-50% of IDDM patients develop proteinuria and two-thirds of this subpopulation develop ESRD, some 20-30% of any given cohort of IDDM patients eventually need dialysis or transplantation. Evidence indicates that diabetic nephropathy is associated with a greater incidence of eye, nerve, heart, and peripheral vascular disease. Nondiabetic renal disease complicating IDDM and NIDDM is associated with a lesser frequency and severity of these extrarenal manifestations. The prevalence of retinopathy increases with advancing nephropathy. Roughly two-thirds of the deaths from IDDM are related to renal failure, and most of the remainder are caused by associated cardiovascular disease. Transplantation from living relatives carries the best prognosis for survival, and little difference is seen between hemodialysis, peritoneal dialysis, and cadaver transplantation. The health-care costs of treating diabetic nephropathy are also reviewed.     

Pancreas transplantation for the prevention of diabetic nephropathy

Diabetic nephropathy is the leading cause of kidney failure in the United States. Poor glycemic control, hypertension, and smoking have been implicated as risk factors for the development and progression of diabetic nephropathy in patients with type 1 diabetes mellitus. Improved medical therapy including angiotensin-converting enzyme inhibitors and tight glycemic control with use of intensive insulin therapy have been shown to reduce the progression of diabetic nephropathy substantially based on albumin excretion rates. Despite these improvements in medical management, many patients still experience progression from early diabetic nephropathy to end-stage renal disease. Successful pancreas transplantation leads to normal glycemic control in patients with type 1 diabetes, but historically it has generally been limited to patients with both kidney failure and diabetes. In this review of the current treatment of diabetic nephropathy, we examine the potential role of preemptive pancreas transplantation in patients with diabetic nephropathy.     

Early diabetic nephropathy: assessment and potential therapeutic interventions

End-stage renal failure secondary to diabetes has increasingly become a health and socioeconomic issue. Diabetic nephropathy is the major cause of death in type I insulin-dependent diabetic patients and accounts for approximately 25% of all patients beginning hemodialysis in the United States. Once diabetic nephropathy is well established, attempts to modify the relentless downward progression of the disease have been essentially unsuccessful. We focus on the early structural and functional changes that occur as a consequence of diabetic renal disease and examine the evidence for microalbuminuria as an early marker and predictor for future overt diabetic nephropathy. The rationale for different therapeutic interventions to alter the course of early diabetic nephropathy are discussed.     

The care of patients with diabetic nephropathy: audit, feedback, and improvement

Diabetic nephropathy is the commonest cause of end-stage renal failure in the developed world. The quality of care of 152 patients with diabetic nephropathy was assessed at the time of referral to a single nephrologist. The type II diabetics (62%) were older than the type I diabetics (38%) (mean 65 years vs. 48 years). The mean duration of diabetes was 17 years. Significant cardiovascular disease was present in 52%. There was diabetic retinopathy in 84% of the type I diabetics and 53% of the type II diabetics. Overall, 63% had hypertension at referral (St Vincent Declaration criteria), untreated in 25%. ACE inhibitors were not prescribed in 48% when no contraindications to their use were present. Glycosylated haemoglobin was > 9.1% in 29%. Twenty were prescribed medications inappropriate to their renal function. Of patients with ischaemic heart disease and serum cholesterol > 5.5 mmol/l, 82% were untreated; 82% of patients with secondary hyperparathyroidism were also untreated. At initial referral, many patients' care was sub-optimal. Referral was too late for adequate preparation for renal replacement therapy in 33%. Following a process of education and feedback of the results to referring practitioners, the timing of referral improved. We emphasize the need for closer co-operation between those managing diabetic patients with nephropathy to optimize their care.     

Diabetic hypertensive patients. Is this a group in need of particular care and attention?

Morbidity and mortality in diabetes are caused mainly by its vascular complications, both in the microcirculation and in the large vessels. Diabetic nephropathy and retinopathy are the clinical hallmarks of microangiopathy, which may lead to end-stage renal failure and blindness. The cardiovascular complications in diabetes consist mainly of an accelerated form of atherosclerosis. Systemic hypertension is an early and frequent phenomenon. Nocturnal hypertension is also more frequent in people with diabetes compared with the nondiabetic population. Capillary hypertension has been demonstrated in type 1 diabetic patients. Poor metabolic control may induce elevation in blood pressure, but data are conflicting. The prevalence of white-coat hypertension in the diabetic population is comparable with that in the nondiabetic population. Prospective observational studies in type 1 and type 2 patients have revealed that abnormally increased urinary albumin excretion and other potentially modifiable risk factors--such as hypertension, smoking, poor metabolic control, and social class--predict increased all-cause mortality and cardiovascular mortality. Arterial hypertension is a risk factor in the initiation and progression of diabetic micro- and macroangiopathy. Diabetes, hypertension, and smoking are the three most important risk factors for fatal and nonfatal stroke. A randomized, double-blind, parallel study has revealed that the 5-year major cardiovascular disease rate was lowered by 34% for antihypertensive treatment compared with placebo. Furthermore, the study found a trend for lower all-cause mortality for low-dose antihypertensive-treated diabetic patients. Effective blood pressure reduction with ACE inhibitors and/or non-ACE inhibitors, frequently in combination with diuretics, reduces albuminuria, delays the progression of nephropathy, postpones end-stage renal failure, and improves survival in diabetic nephropathy.     

Anaemia is common and predicts mortality in diabetic nephropathy

BACKGROUND: Diabetes is the single largest cause of chronic renal failure, accounting for 18% of patients on renal replacement therapy in the UK. AIM: To investigate the chronic kidney disease stage at which patients with diabetic nephropathy are referred to renal services, determine the prevalence of anaemia in patients with diabetic nephropathy, examine patient outcome and identity prognostic factors. DESIGN: Retrospective review. METHODS: Patients with diabetic nephropathy referred to our renal services between 1989 and 2004 were identified from electronic records. Estimated glomerular filtration rate (calculated using the MDRD formula) and haemoglobin at referral were collected. Times to renal replacement therapy and death were noted. RESULTS: We identified 508 patients. At referral, mean eGFR was 34 ml/min/1.73 m(2) and 48% of patients were at CKD stages 4 and 5. Mean haemoglobin was 11.7 g/dl; 21% had a haemoglobin <10 g/dl at referral. Median survival was 37.9 months (95%CI 33.2-42.6); median survival independent of renal replacement therapy (RRT) was 21 months (95%CI 17.8-24.6). Of patients starting RRT, 38% did so within 1 year of referral. Older age (RR 1.02, 95%CI 1.01-1.04) and lower haemoglobin (RR 0.9, 95%CI 0.85-0.99) at referral predicted death on multivariate analysis. DISCUSSION: At referral to renal services, almost 50% of patients with diabetic nephropathy were at CKD stages 4 and 5. Anaemia was common and predicted mortality. All diabetic patients from CKD stage 3 should be screened for anaemia. We believe that patients with diabetic nephropathy should be discussed with renal services when they reach CKD stage 3 with evidence of progression of renal disease.     

Renal outcome in type 2 diabetic patients with or without coexisting nondiabetic nephropathies

OBJECTIVE: To determine the risk factors for adverse renal outcome in type 2 diabetic patients who underwent renal biopsy and were followed-up longitudinally. RESEARCH DESIGN AND METHODS: We examined 68 consecutive patients with type 2 diabetes during the period of 1985-1999 who underwent renal biopsy for proteinuria > or =1 g/day, renal involvement (proteinuria or renal impairment) at the absence of retinopathy, renal involvement with duration of diabetes < 5 years, or unexplained hematuria of glomerular origin. Their clinical features and underlying renal lesion were correlated with the renal outcome after longitudinal follow-up. Three groups of patients were defined based on their renal pathology: group I consisted of 24 patients (35%) with diabetic glomerulosclerosis (DGS) alone, group II consisted of 13 patients (19%) with nondiabetic nephropathy (NDN) superimposed on DGS, and group III consisted of 31 patients (46%) with NDN alone without evidence of DGS. RESULTS: After a mean follow-up of 123 months from the diagnosis of type 2 diabetes (74 months from the time of renal biopsy), univariate analysis showed that risk factors for reaching end-stage renal disease (requiring maintenance dialysis, or a serum creatinine [SCr] > or =700 micromol/l) included proteinuria > or = 2g/day (P = 0.0087), SCr >120 micromol/l (P = 0.0005), presence of retinopathy (P < 0.00001) at the time of biopsy, and biopsy showing DGS (groups I and II) (P = 0.035). On multivariate analysis, retinopathy was the only independent variable correlated with end-stage renal failure. This study also showed that the association of hematuria or proteinuria with the absence of retinopathy constitutes the strongest indication for a nondiabetic lesion (positive predictive values of 94%). CONCLUSIONS: Patients with type 2 diabetes undergoing renal biopsy constitute a heterogeneous group by their clinical presentations and underlying pathology, but longitudinal studies on the renal outcome of these patients remain limited. Our study showed that renal biopsy is indicated in selective diabetic patients because of potentially treatable nephropathy and of a better prognosis than DGS.     

不同肾脏功能状态对糖尿病足部溃疡疗效及预后的影响

目的探讨肾脏功能对糖尿病足部溃疡疗效及预后的影响。方法采用前瞻性研究的方法，对126例Ⅰ～Ⅴ期糖尿病足部溃疡患者在治疗前检查肾脏功能后，进行全身综合治疗及溃疡局部彻底清创，外敷黄芪提取液加适量短效胰岛素，观测溃疡部位肉芽组织出现时间（GT）、溃疡愈合时间（HT）及溃疡治愈率、截肢率。结果糖尿病肾病从Ⅰ期逐渐过渡到Ⅴ期，相同程度糖尿病足部溃疡患者的GT和HT逐渐延长，其中糖尿病肾病Ⅰ～Ⅲ期相同程度足部溃疡患者GT和HT均显著短于糖尿病肾病Ⅳ期（临床蛋白尿期）和Ⅴ期（终末期肾病）相同程度足部溃疡患者的GT和HT（P〈0．05或P〈0．01）；糖尿病足部溃疡患者的GT和HT与糖尿病肾病病情程度问呈显著正相关（r1=2．344和r2=2．563，P均〈0．05）；糖尿病肾病Ⅰ～Ⅲ期糖尿病足部溃疡患者的截肢率显著少于糖尿病肾病Ⅳ期和Ⅴ期相应程度的足部溃疡患者（P〈0．05），治愈率也显著高于后者（P〈0．05）。结论糖尿病肾病病情的轻重在很大程度上影响了糖尿病足部溃疡的治疗效果及预后，提示对糖尿病足部溃疡患者注重和尽可能改善肾功能状态是非常必要的。     

Dealing with diabetic nephropathy

Nephropathy may develop in patients with type 1 diabetes because poor glycemic control produces effects that eventually lead to glomerular scarring and renal failure. The worse and more prolonged the hyperglycemia, the greater the risk of diabetic nephropathy. In patients with type 2 diabetes, hyperglycemia, as well as insulin resistance and generalized vascular disease, is involved in the pathogenesis of nephropathy. The glomerular changes of early diabetic nephropathy can be identified only by renal biopsy or by testing for microalbuminuria. Once macroalbuminuria occurs (albumin excretion rate, > 300 mg/day), usually after type 1 diabetes has been present for 10 to 15 postpubertal years, end-stage renal disease is almost inevitable. However, aggressive control of hypertension in diabetic patients without microalbuminuria helps avoid nephropathy, and tight glycemic control in those with microalbuminuria can avoid or delay its onset. Even when macroalbuminuria is present, treatment can prolong renal function. Aggressive antihypertensive therapy, especially with ACE inhibitors, can reduce renal decline by half. Avoiding circumstances that may damage the kidneys (e.g., use of radiocontrast materials or nephrotoxic drugs, dehydration, hyperlipidemia, urinary tract infection, buildup of AGEs) is critical. Some treatment methods are controversial (dietary protein restriction) or still under investigation (use of injected or oral heparin) but may help delay renal transplantation or dialysis.     

Platelet antioxidant enzymes in insulin-dependent diabetes mellitus.

BACKGROUND: The measurement of the peroxidase scavenging system represented by the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) in blood cells of diabetic patients has, in the past, given equivocal results. Likewise, the role of these intracellular enzymatic scavengers against the oxidative stress of diabetes-associated microangiopathic complications is unknown. METHODS: Choosing platelets as cell model (as commonly done in previous studies), the aim of this study was to relate the platelet content of SOD, catalase and GSH-Px to the presence of diabetes, as well as to the presence of nephropathy and retinopathy in 35 insulin-dependent diabetic patients, as compared to 10 age-matched control subjects. RESULTS: The enzymatic activities were not changed in diabetic patients in comparison with healthy controls. After stratifying patients according to presence of nephropathy (24-h urinary albumin excretion rate persistently > or =20 microg min(-1)) or retinopathy, the group of albuminuric patients was characterized by a significant decrease in SOD activity as compared to those in the normoalbuminuric range (4.36+/-1.06 vs. 6.81+/-2.26 mU 10(-9) platelets; p=0.01). Catalase and GSH-Px did not change. No modification in platelet enzyme activities has been found in diabetic subjects with retinopathy. CONCLUSIONS: These results suggest that diabetic nephropathy, at least in its early stage, may be related to an altered redox state of platelets, as tested by the reduction in SOD activity, thus, indicating that the renal damage in these patients may be associated to a selective increase in platelet susceptibility to variation in the redox state.     

Comparison of the prevalence and associated features of abnormal albumin excretion in insulin-dependent and non-insulin-dependent diabetes

Overnight albumin excretion rates were measured in 940 diabetic patients, 416 with insulin dependent and 524 with non-insulin dependent diabetes, and in 106 healthy volunteers. A significantly higher number of non-insulin dependent diabetic patients had abnormal albumin excretion compared with the insulin-dependent group (X2 = 15.2, p less than 0.002). Ten per cent of non-insulin-dependent and 7 per cent of insulin-dependent diabetic patients had albumin excretion rates in the range 30-150 micrograms/min and thus were at risk of the cardiovascular and renal complications of diabetes. Six per cent of non-insulin-dependent and 5 per cent of insulin-dependent diabetic patients had albumin excretion rates above 150 micrograms/min and thus were entering the phase of clinical diabetic nephropathy. Multivariate analysis revealed that male sex and retinopathy in insulin-dependent diabetes, and systolic blood pressure and retinopathy and peripheral vascular disease in non-insulin-dependent diabetes, were significantly related to albumin excretion. Only one patient with insulin-dependent diabetes of less than 5 years known duration had an albumin excretion rate in the range 30-150 micrograms/min, whereas such an excretion rate indicating patients at risk was observed at all durations of non-insulin-dependent diabetes. It is possible that during the long silent phase of non-insulin-dependent diabetes, before diagnosis, significant renal damage occurred.     

Anemia with erythropoietin deficiency occurs early in diabetic nephropathy

OBJECTIVE: The normochromic normocytic anemia of erythropoietin (EPO) deficiency is recognized in advanced renal failure but not in early renal disease. The aim of this study was to determine whether anemia with EPO deficiency is found in type 1 diabetic patients with diabetic nephropathy in the absence of advanced renal failure and to compare them with patients with nondiabetic renal disease of similar severity. RESEARCH DESIGN AND METHODS: A total of 27 type 1 diabetic patients with diabetic nephropathy (DN), defined as having persistent proteinuria (mean 1,086 mg/day [CI 120-5,1901), a serum creatinine < or = 180 micromol/l, and retinopathy, were compared with 26 nondiabetic patients with glomerulonephritis (GN) and persistent proteinuria (1,874 mg/day [349-5,005]). The Hb concentration, red cell indexes, and serum EPO levels were measured, and other causes for the anemia were excluded. The EPO values were compared with a normal reference range obtained from nondiabetic patients with a microcytic anemia. The DN patients were tested for signs of diabetic peripheral and autonomic neuropathy. RESULTS: We found that 13 of the 27 DN patients were anemic (Hb 10.6 +/- 0.9 g/dl) in marked contrast to none of the GN patients (Hb 13.7 +/- 1.4 g/dl, P < 0.005). In the DN group, serum EPO concentrations failed to increase in response to anemia compared with the response seen in patients with microcytic anemia. Thus, the anemia of the DN group was associated with EPO deficiency. The anemic DN patients showed evidence of more severe proteinuria and diabetic neuropathy than the nonanemic DN patients. CONCLUSIONS: Anemia associated with EPO deficiency can occur early in DN before the onset of advanced renal failure, but does not normally occur in nondiabetic renal disease of similar severity. The pathogenesis requires elucidation.     

Different patterns of insulin resistance in relatives of type 1 diabetic patients with retinopathy or nephropathy: the Genesis France-Belgium Study

OBJECTIVE: Insulin resistance may be a risk factor for diabetic microangiopathy, which may have a familial component. We carried out a family-based study to determine which components of the insulin resistance syndrome are associated with diabetic retinopathy and nephropathy in type 1 diabetes. RESEARCH DESIGN AND METHODS: The Genesis France-Belgium Study is a multicenter binational study designed to investigate the genetic factors involved in the microvascular complications of type 1 diabetes using a family-based design. Probands were type 1 diabetic patients with diabetic retinopathy (classified as background, preproliferative, or proliferative) and possibly diabetic nephropathy (absent, incipient, established, or advanced). The insulin resistance score of their first-degree relatives was calculated according to their BMI and history of arterial hypertension, lipid disorders, and type 2 diabetes. RESULTS: The insulin resistance score of relatives was positively correlated with the albumin excretion rate (P = 0.0009) and fasting plasma glucose (P = 0.0003) and HbA(1c) (P < 0.0001) concentrations. This score was higher in the relatives of probands with than in those without diabetic nephropathy (P = 0.0370). Similarly, it was higher in relatives of subjects with proliferative diabetic retinopathy than in those of probands without, even after controlling for subjects with versus without diabetic nephropathy (P = 0.0379). However, the components of the insulin resistance score in relatives differed according to the severity of diabetic retinopathy or nephropathy in the probands. Obesity and history of arterial hypertension were most common in relatives of probands with proliferative diabetic retinopathy, whereas obesity and history of lipid disorders were most common in the relatives of probands with diabetic nephropathy. CONCLUSIONS: Familial insulin resistance segregates with diabetic complications: lipid disorders and obesity segregate with diabetic nephropathy, whereas arterial hypertension and obesity segregate with diabetic retinopathy.     

Heterogeneity of causes of proteinuria in patients with non-insulin dependent diabetes mellitus

AIM: To make a retrospective clinicomorphological (autopsy) study of proteinuria causes. MATERIAL AND METHODS: The records have been analysed for 231 patients with non-insulin-dependent diabetes mellitus (NIDDM) over 60 years of age who died in a general hospital between 1990 and 1999. The choice of patients with diabetic nephropathy (DN) for a further morphological investigation was based on the presence of proteinuria (> 0.5 g/day), normal renal function. 72 patients met the above criteria. Of them 26 were women. RESULTS: Proteinuria occurred more frequently in men (63.4%). A morphological examination of the kidneys revealed diabetic glomerulosclerosis (diffuse and focal) in 48(67%) patients. In 24(33%) patients proteinuria resulted from non-diabetic affection of the kidneys: amyloidosis, atherosclerotic and/or hypertensive nephroangiosclerosis, membraneous and myelomic nephropathy, mesangioproliferative glomerulonephritis. Glomerular changes were not registered in 4 patients. 35(72%) DN patients had diabetic retinopathy which was not found in patients with non-diabetic renal affection. CONCLUSION: Diabetic retinopathy in patients with NIDDM and proteinuria allows to conclude that the latter is consequent to DN. The absence of diabetic retinopathy in such patients promotes a search for other causes of proteinuria.     

Complement activation and diabetic vascular complications

Diabetes mellitus is a major and increasing health problem worldwide. One of the most serious consequences of diabetes is the development of diabetic angiopathy, which includes cardiovascular disease, neuropathy, retinopathy and nephropathy. Diabetic nephropathy alone affects 15-25% of patients with type 1 diabetes and 30-40% of patients with type 2 diabetes and is the single-most important cause of end-stage renal failure in the Western World. Existing research has demonstrated the involvement of glycation factors, growth factors/cytokines, hemodynamic factors and intracellular changes in the pathogenesis of diabetic kidney disease. An emerging amount of recent data suggests that the complement system, especially the MBL pathway, plays an important role in the pathogenesis of diabetic vascular complications. Although the numerous therapeutic interventions available today may delay the development and progression of diabetes vascular complications, there is an ongoing need for new therapeutic strategies. In this article the evidence for a connection between the complement system and vascular dysfunction will be reviewed, with a special focus on the relation to diabetic kidney disease. Several ways of specifically manipulating the complement system already exist. However, whether or not these drugs provide new targets for intervention on diabetic vascular complications is still unknown.     

Diabetic microvascular complications: can patients at risk be identified? A review

People with diabetes have an increased risk of developing microvascular complications, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, which, if undetected or left untreated, can have a devastating impact on quality of life and place a significant burden on health care costs. In addition, diabetic microvascular complications can reduce life expectancy. The strongest risk factors are glycaemic control and diabetes duration; however, other modifiable risk factors such as hypertension, hyperlipidaemia and smoking, and unmodifiable risk factors including age at onset of diabetes and genetic factors may all play a part. Along with the presence of external risk factors, some associations have also been noted between diabetic microvascular complications themselves. There is evidence that diabetic retinopathy in association with increased blood pressure is an important risk factor for diabetic nephropathy progression. Significant correlations have also been shown between the presence of diabetic peripheral neuropathy and the presence of background or proliferative diabetic retinopathy. Clinical trials are currently in progress looking at a number of approaches to designing treatments to prevent the adverse effects of hyperglycaemia. It is essential however, that risk factors associated with the progression and development of diabetic microvascular complications are detected and treated at an early stage in order to further reduce morbidity and mortality. Considering all three complications as interrelated may well facilitate early detection of microvascular disease. Despite good long-term glycaemic and blood pressure control, diabetes remains a major cause of blindness, renal failure and amputations. As the incidence of diabetes continues to rise, the burden of diabetic microvascular complications will increase in future, hence the need for early detection. Considering the microvascular complications of diabetes as related, and enquiring proactively about complications, may well facilitate early detection of microvascular disease.     

Measurement of soluble thrombomodulin in sera from various clinical stages of diabetic nephropathy

The levels of soluble thrombomodulin (TM) in serum samples were measured by one-step sandwich enzyme immunoassay. The aim of the present study was to determine if levels of soluble TM in sera might correlate with disease activity in patients with diabetic nephropathy. Three hundred and twenty patients with diabetic nephropathy were examined. Patients with diabetic retinopathy were excluded from the present study. This study showed an increase of soluble TM levels in sera from patients with diabetic nephropathy. The levels of soluble TM in sera from the macroalbuminuric stage with renal dysfunction were significantly increased compared with those from the normo-, micro-, or macroalbuminuric stage of diabetic nephropathy without renal dysfunction. The increase of soluble TM in sera paralleled levels of urinary albumin, blood urea nitrogen (BUN), s-creatinine (Cr), and duration of noninsulin-dependent diabetes mellitus (NIDDM). Furthermore, a decrease of TM staining in the glomerular capillary walls was observed in both microalbuminuric and macroalbuminuric stages by immunofluorescence. It appears that the measurement of soluble TM in sera is useful in evaluating the degree of glomerular endothelial injuries in patients with diabetic nephropathy. © 1996 Wiley-Liss, Inc.     

In vitro culture of cells exfoliated in the urine by patients with diabetes mellitus.

As an approach to facilitate the understanding of the progression of diabetic renal disease, we assessed the urine of diabetic patients and normal volunteers for the presence of cells that could be cultured in vitro. The results suggest that both normal control subjects and diabetic patients, without clinically detectable microangiopathy, exfoliate few culturable cells into the urine. In contrast, diabetics with documented retinopathy but without nephropathy exfoliate substantially higher numbers of culturable cells (5.2 cells/100 ml urine), whereas diabetics with both retinopathy and advanced nephropathy exfoliate even greater numbers of culturable cells (50.8 cells/100 ml urine). The cells that are exfoliated and culturable can be divided into five distinct cell types based on morphology at the light microscope level. The exfoliated cells proliferate at clonal density after isolation from urine and are epithelial in appearance. These data suggest that the culture of cells from urine might have diagnostic value as an early indicator of diabetic renal disease and provide a convenient, noninvasive new source of human kidney epithelial cells.