Lesions Of Diabetic Nephropathy Research Articles

Does antihypertensive treatment prevent progression of microalbuminuria to overt proteinuria in insulin-dependent diabetic patients?

Prospective studies in insulin-dependent diabetic patients have shown that microalbuminuria is a strong predictor of clinical nephropathy. Because this syndrome is associated with a dramatic excess in mortality, different types of intervention have been proposed for insulin-dependent diabetic patients with microalbuminuria to prevent or postpone clinical nephropathy. The effects of antihypertensive treatment are being extensively investigated. Beta-blockers, calcium antagonists, and angiotensin-converting enzyme inhibitors have proved effective in reducing albumin excretion and postponing overt proteinuria in hypertensive and normotensive insulin-dependent diabetic patients with microalbuminuria. However, many problems remain to be solved. A decrease in albumin excretion may not be an adequate endpoint for intervention trials, because it has been shown that patients with normal albumin excretion can develop diabetic nephropathy lesions, whereas patients with microalbuminuria alone may have little or no pathology. The patients included in these trials all had incipient diabetic nephropathy but exhibited different functional, and probably morphological, forms of the disease. For insulin-dependent diabetic patients with microalbuminuria, the real aim of antihypertensive treatment is not to reduce urinary albumin excretion or to prevent its progression but to preserve renal function and to reduce the incidence of premature cardiovascular deaths. To achieve this, we have to improve our knowledge of the natural history of the early pathology of diabetic nephropathy and of the mechanisms of action of antihypertensive treatment. New large-scale intervention trials will have to be designed in which the patients will have to be carefully characterized on the basis of functional and morphological data.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal structure and function in insulin-dependent diabetes mellitus in man

To review renal pathological changes in diabetes, which include thickening of all renal extracellular basement membranes and the mesangial matrix and, to a lesser extent, mesangial cell expansion. Two renal lesions appear critical in diabetic nephropathy. Mesangial expansion out of proportion to the size of the glomerulus is inversely related to proteinuria, hypertension and a declining glomerular filtration rate. Arteriolar hyalinosis is related to global glomerulosclerosis and both are correlated with the clinical features of nephropathy. By the time renal dysfunction is clinically detectable, these lesions tend to be advanced. Interstitial volume may be increased in insulin-dependent diabetes mellitus, particularly in areas containing sclerotic glomeruli or marked tubular atrophy. Longitudinal studies of renal structure and function and a simultaneous study of potential risk factors and pathways of injury are necessary to develop more refined predictors and clearer pathogenic concepts of this important diabetic complication.

Mesangial cells in diabetes

The glomerular mesangium is the site of prominent structural lesions in diabetic nephropathy, including excess deposition of extracellular matrix in a focal, nodular pattern. Increased single-nephron blood flow and filtration are early signs of glomerular involvement in diabetes, and may initiate or contribute to mesangial damage. Vasodilatation results from arteriolar insensitivity to vasoconstrictors. In turn, this may reflect primary metabolic defects of glomerular smooth muscle, including the afferent arteriole and mesangial cells themselves. Parallel alterations in the glomerular basement membrane and related structures, such as mesangial matrix, are likely to result from glycosylation of intrinsic proteins, or accumulation of advanced glycosylation end-products. Structural and haemodynamic changes account for (micro)-albuminuria, with additional possible overloading of the measangium. Mesangial proliferative changes eventually ensue, with excess matrix deposition and progressive fibrosis. Recent evidence that long-standing hyperglycaemia modifies mesangial metabolism, sensitivity to vasoconstrictors and matrix biosynthesis in vitro is reviewed here, in the light of its potential implications for experimental and human diabetic nephropathy.

Should There Be an Expanded Role for Kidney Biopsy in the Management of Patients With Type I Diabetes?

Diabetic nephropathy is the single most important cause of end-stage renal disease (ESRD) in the United States. Further, the increased risk of mortality from type I diabetes is almost entirely confined to patients developing clinical diabetic nephropathy. Nonetheless, kidney biopsy has had little role in the clinical assessment of diabetic patients or in the design of clinical research in diabetic nephropathy. The development of dipstick-positive proteinuria in patients with type I diabetes of more than 10 years' duration is regularly associated with advanced structural changes of diabetic nephropathology; in these patients, clinical parameters, especially the rate of decline of glomerular filtration rate (GFR), are accurate monitors of disease progression. Microalbuminuria indicates a very high risk of overt proteinuria and thus ESRD. This increased risk is associated with levels of urinary albumin excretion (UAE; greater than 30 micrograms/min [45 mg/24 h]), which are frequently accompanied by hypertension and reduced or decreasing GFR. At this stage, lesions of diabetic nephropathy are usually already well established. Thus, microalbuminuria is more a marker of early nephropathy than a predictor of later renal injury. Before these clinical stages of nephropathy, there are no accurate predictors of renal risk. Renal biopsy may serve this role by indicating those patients who are developing significant lesions during the "silent" phase of the disease. In large measure, this value of the biopsy derives from evidence that the lesions tend to develop linearly over time and can be measured by techniques that are relatively easily established in standard surgical pathology environments. Renal biopsies can serve to assure the majority of diabetic patients that they are developing serious lesions slowly, if at all.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term study of normal kidneys transplanted into patients with type I diabetes.

We examined the rate of development of the lesions of diabetic nephropathy in transplanted kidneys residing for 6-14 yr in type I (insulin-dependent) diabetic kidney-allograft recipients. Although each recipient had end-stage diabetic nephropathy with his/her own kidneys, there was marked variability in the rate of development of mesangial expansion observed in the transplanted kidneys. The progression of glomerular pathology, including widening of the glomerular basement membrane and expansion of the mesangium, did not correlate significantly with several potential risk factors (e.g., donor source--cadaver or living related, histocompatibility match, age of the recipient or donor, age at onset of diabetes, duration of diabetes before renal failure, immunosuppressive drug dose, blood pressure, and severity of lesions of chronic rejection). However, there was a direct albeit imprecise relationship between the index of mesangial expansion at the final biopsy and the index of glycemic control (r = .61, P less than .01). These observations suggest that currently unknown factor(s) may modulate the progression of diabetic renal disease, even in a population that had uniformly demonstrated nephropathy risk. Our data support the hypothesis that in addition to glycemic control per se, there are risk factors intrinsic to the kidney itself.

Renal transplantation in diabetic patients is confirmed therapy while pancreas transplantation should be performed only in an investigational setting

Kidney transplantation is now firmly established as the standard treatment for all diabetic patients with end-stage renal fallure. In an analysis of all renal transplants at the University of Minnesota between June 1, 1980 and May 31, 1987, there were no differences in renal allograft functional survival rates for diabetic and nondiabetic recipients. At one year the survival rates were 84% (n=151) and 86% (n=260) for those treated with azathioprine, prednisone and ALG; 86% (n=101) and 87% (n=104) for those treated with cyclosporine-prednisone, and 92% (n=165) and 89% (n=191) for those treated with triple therapy (cyclosporine, azathioprine, and prednisone). Pancreas transplantation remains an investigational procedure for nonuremic diabetic patients but may be considered therapeutic in diabetic renal allograft recipients because such patients are obligated to immunosuppression and only the surgical risks of pancreas transplantation need to be considered, which are now aceptably low. Recipients of pancreas transplants performed simultaneous with the kidney have patient and pancreas graft survival rates of >90% and ±60% at several institutions, including our own. The potential for benefit of pancreas transplantation, however, is greater in the nonuremic nonkidney transplant patient, and pancreas transplantations are being performed in such patients at a few institutions. An early beneficial effect of pancreas transplantation preexisting proliferative retinopathy has not been discerned, although long-term retinopathy has been stable in patients with functioning grafts. Preliminary studies have shown a beneficial effect on neuropathy and on microscopic lesions of diabetic nephropathy, but at the expense of cyclosporine toxicity. Pancreas transplantation as a solitary procedure will not realize its full potential until nontoxic, immunosuppressive regimens are available. At this time, pancreas transplatation is appropriate in selected patients with complications of diabetes that would otherwise progress to a stage more serious than the potential side effects of chronic immunosuppression, but it should be performed only in an investigational setting at institutions committed to long-term, formal protocol follow-up studies.

The development of lesions in the glomerular basement membrane and mesangium after transplantation of normal kidneys to diabetic patients.

Renal allograft biopsies at the time of transplantation (baseline) and 2 yr later were obtained in 6 type I diabetic and 12 nondiabetic patients and studied for glomerular basement membrane (GBM) and mesangial changes. Diabetic patients had significantly greater GBM thickness compared with nondiabetics at 2 yr (P = 0.05, rank sum test), and the increase in GBM thickness comparing baseline and 2-yr biopsies was greater in the diabetic compared with nondiabetic patients (P = 0.005, rank sum test). Similarly, diabetic patients developed significant mesangial thickening by light microscopy while no changes were observed in nondiabetic patients (P = 0.001). Electron microscopic morphometric analysis of the percentage of total mesangium was not different on comparing diabetic and nondiabetic patients at 2 yr. There was an increase in the matrix component of the mesangium in the diabetics at this time, although this did not reach statistical significance (P = 0.06). In addition, the surface density of the peripheral glomerular capillary wall, presumably reflecting mesangial expansion, was decreased in the diabetic and unchanged in the nondiabetic patients (P = 0.005). These studies document, for the first time, the development of GBM and mesangial lesions of diabetic nephropathy in normal living related donor and cadaver kidneys transplanted into diabetic patients and support the hypothesis that these lesions are secondary to the diabetic state.

Immunological evaluation on the reactivation of EB virus in a patient with diabetes mellitus and membranous glomerulonephrilis

One case of membranous glomerulonephritis (MGN) associated with primary diabetes mellitus has been followed for more than 5 years. Peripheral blood lymphocyte, lymphocytotoxins, immune complexes, and EB virus antibodies were serially assayed. These studies demonstrated that the patient had 50% of B cells (C3 receptor, Fc receptor and/or IF positive cell), 3% of Tγ cells, positive lymphocytotoxins, increased lymphocyte blastogenesis with decreased Ig secretion less than 50% of control lymphocytes, and VCA (IgG) 320×, VCA (IgM) <10×, EA. DR (IgG) 20×, and EBNA<10× that suggested latent EB virus infection. Renal histology was the typical MGN in addition to diffuse lesion of diabetic nephropathy diagnosed by LM, IF, and EM. However, no positive immunofluorescent findings for insulin, anti-insulin antibody, and EB virus antigens were found. During the long term observation, the nephrotic syndrome disappeared spontaneously and it was paralleled wih the association of Tγ cell increment to 17%, raised lymphocytotoxins to 50% accompanied by positive anti-Tγ cell antibody, and increased EB virus antibodies such as VCA (IgG) to 640×, VCA (IgM) to<10×, EA. DR (IgG) to 80×, and EBNA to 40×, which were considered as the reactivation of EB virus. The possibie pathogenetic relationships between diabetes mellitus, MGN, and EB virus infection were discussed.