The development, enhancement and reversibility of diabetic glomerulopathy.
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Biomedical subjects
Publications and source records attributed to S M Mauer.
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Diabetic glomerulopathy continues as a major problem in the management of the patient with diabetes mellitus; however, evidence in man and in animals underlines the fact that good control of diabetes favorably alters the course of this complication. Islet transplantation in the diabetic rat returns plasma glucose and insulin levels to normal. In parallel mesangial matrix thickening, mesangial deposition of immunoglobulin and urinary excretion of albumin markedly improve following islet transplantation. Although amelioration of diabetes affects the course of glomerulopathy, other factors (most notably measures that increase glomerular capillary pressure) enhance the development of the diabetic renal lesions. Following uninephrectomy or clipping of a renal artery, the remaining (in the case of uninephrectomy) or unclipped diabetic kidney develops the morphologic and functional changes of diabetic nephropathy at a rate greater than in kidneys in an intact diabetic rat. The clipped kidney demonstrates diminished diabetic changes, suggesting a protective effect with decreased glomerular capillary pressures. In addition to measures improving the control of diabetes, procedures reducing factors accelerating diabetic complications may improve the prognosis in diabetic glomerulopathy.
Glomerular basement membrane (GBM) thickness was measured in diabetic rats prior to and following islet transplantation. Over the course of the experiment (from 7 to 13 months of diabetes) GBM thickness in diabetic animals exceeded that of littermate controls. After 7 months of diabetes a group of animals received successful intraportal transplants of neonatal pancreatic tissue. GBM thickness at 2 and 6 months following islet transplantation matched the thickness in nontransplanted diabetic rats and exceeded that in control animals. Failure to reverse GBM thickening in diabetic rats following islet transplantation may be due to very slow rates of GBM tunover in the rat. Previous work has demonstrated normalization of urinary albumin excretion after islet transplantation, suggesting that GBM thickening, per se, is not a significant factor causing albuminuria in rats with longstanding diabetes.
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The uptake and processing of colloidal carbon by the glomerular mesangium was studied in an attempt to determine whether abnormal mesangial function occurs in rats with longstanding streptozotocin-induced diabetes mellitus. The chronically diabetic rats were considerably smaller than their normal littermates receiving a similar dose of colloidal carbon based upon body weight. Thus, further control groups, animals weight-matched with the diabetic rats (younger rats) and littermates of the diabetic rats given the mean quantity of colloidal carbon administered to the diabetic rats, were included. Quantitative evaluation of renal tissues indicated that younger rats have more avid mesangial uptake of colloidal carbon from the circulation and more rapid processing of these macromolecules through the mesangium than the other groups studied. These quantitative studies did not demonstrate any marked impairment in diabetic rats in the over-all capacity of their mesangium to take up and process colloidal carbon when compared with the two groups of littermate nondiabetic animals. However, in those areas of the mesangium thickened by the diabetic process large aggregated of carbon accumulated and persisted over the 6-week period of the study. It appears, therefore, that those areas of the mesangium in diabetic rats with pathologic changes consequent to the diabetic state have significant functional impairment.
Fifty-three children, ages one day to 15 years, were treated with hemodialysis for acute renal failure between 1968 and 1977. Twenty-three had acute tubular necrosis. Nine had ATN associated with catastrophic medical illnesses; all died. Fourteen had ATN following major surgical procedures; ten died. Thirty had ARF due to primary nephrologic disorders; 27 survived. Thus it was not the ARF per se but the underlying and concomitant disorders which had the major influences on survival. As prognostic indications of survival in patients with postoperative ATN cannot be clearly defined, these patients almost always deserve aggressive management, including dialysis therapy. Patients with ATN associated with severe medical illness often have fatal underlying conditions which cannot be influenced by presently available technologies.
After several hemodialysis treatments, neutrophil chemotactic responsiveness is commonly depressed. The median chemotactic index of 34 patients was 21, compared with 47 for 21 controls tested simultaneously. The depressed chemotactic responsiveness was not restored to normal when leukocytes were washed and resuspended in normal plasma, neither did plasma from patients with depressed chemotaxis affect control neutrophils.
Renal transplantation was carried out in 21 children ages 1 to 5 years. Eighteen received grafts from a living, related donor (LRD). Four children died, one following rejection, and three because of infection. Five children lost their initial grafts and two have received new transplants. Cumulative patient survival two and four years following LRD transplantation was 94% and 76%, respectively. This was similar to results found in children ages 6 to 14 years. Accelerated growth rates were seen in the first posttransplant year in those small children who were severely growth-retarded at the same time of transplantation and who achieved normal graft function. However, only one of these children ultimately reached the tenth percentile for height for chronological age. We conclude that renal transplantation is warranted in the very young child with renal failure.
One month following induction of diabetes with streptozotocin, one half of diabetic and control rats underwent unilateral nephrectomy. Subsequently, all animals were studied with respect to renal function and glomerular alterations of diabetes. Blood pressure levels were similar in all animals. Diabetic and control animals with unilateral nephrectomy had similar but elevated serum creatinine levels and lower creatinine clearance values as compared with the intact rats. However, on a per kidney basis the creatinine clearance levels were higher in the animals with unilateral nephrectomy. At both three and six months following nephrectomy, markedly increased mesangial matrix thickening and mesangial deposition of IgG and C3 were observed in diabetic rats with unilateral nephrectomy as compared with intact diabetic animals. Nephrectomy had no detectable effects on glomerular morphology or immunohistochemistry of nondiabetic rats. Thus, unilateral nephrectomy in the rat increases, at as early as three months, the severity of diabetic glomerular lesions.
Antisera to rat smooth muscle actomyosin (AMY) and myosin localize in the rat glomercular mesangium. The width of mesangial staining for AMY is increased in rats diabetic for four months (p less than 0.01) and seven months (p less than 0.0005) compared with age-matched controls. Mesangial AMY staining of unilaterally nephrectomized control animals was moderately increased after seven months, whereas unilaterally nephrectomized diabetic rats had prominently increased AMY mesangial width at four months, when they were compared with intact diabetic animals (p less than 0.05). Thus, a distinctive alteration that is found in human diabetic nephropathy also occurs in experimental (streptozotocin) diabetes in the rat. Further, this alteration appears to be accelerated by the changes in nephron hemodynamics resulting from unilateral nephrectomy. While the function of mesangial AMY is unknown, it may be related to intrarenal regulation of glomerular ultrafiltration, which appears to be altered in diabetic nephropathy in man.
Rats with classic Goldblatt (two-kidney) hypertension had diabetes induced by streptozotocin. After four months of diabetes, glomeruli of the unclipped kidney of hypertensive diabetic rats had markedly increased diabetic changes, including mesangial matrix thickening and mesangial immunoglobulin (IgG and IgM) and complement (C3) localization, when compared with glomeruli of the contralateral-clipped kidneys. Further, glomeruli of the unclipped kidneys of hypertensive diabetic animals had more mesangial thickening and IgG and IgM staining than glomeruli of normotensive diabetic rats. Although glomeruli of clipped kidneys in hypertensive diabetic rats had less mesangial thickening than glomeruli of normotensive diabetic rats, this did not reach statistical significance. However, these glomeruli did have significantly less IgG, IgM, and C3 staining compared with glomeruli of normotensive diabetic animals. Mesangial thickness in glomeruli of clipped and unclipped nondiabetic hypertensive rats did not differ from that in normal animals. However, there was less mesangial IgG staining in clipped than in unclipped kidneys of nondiabetic hypertensive rats or in kidneys of normal animals. We have interpreted these results to imply that alterations in nephron hemodynamics combine with the diabetic state to influence the rate of development of diabetic glomerulopathy in rats.
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It is difficult to determine which pediatric hemodialyzer to use in a given clinical situation since there is no comprehensive comparison of pediatric hemodialyzers. We evaluated five currently available disposable pediatric hemodialyzers in vitro and in vivo during treatment of pediatric patients. Two dialyzers, Gambro Mini-Minor and Viva Cell 0.2 are well suited to small pediatric patients weighing less than 10 kg. Three of the dialyzers are well suited to the pediatric patients weighing greater than 10 kg (Gambro Minor, Cordis Dow 0.6, Viva Cell 0.5). By considering the clinical status of the child and the performance characteristics of the dialyzer (solute removal, priming volume, ultrafiltration, etc.) it is possible to employ a hemodialyzer which more precisely meets the needs of the child without increasing risk factors associated with pediatric hemodialysis.
Skeletal muscle from 34 insulin-dependent diabetic patients and 20 age-matched controls was examined by immunofluorescent microscopy. Significantly increased staining of capillary and muscle basement membranes of diabetics was seen for IgG, albumin, and fibrin. The immunofluorescent pattern was identical with that observed using heterologous antibasement membrane antiserum, indicating that these proteins were present within these basement membranes. No differences were detected between males and females or between kidney-transplanted and nontransplanted diabetics. No correlation was noted between intensity of staining and duration of diabetes. The presence of certain serum proteins within vascular and nonvascular basement membranes in diabetics is not restricted to the kidney and may reflect widespread alterations in extracellular membranes that permit entrapment of these proteins.