Advanced Diabetic Nephropathy Research Articles

Serum concentrations of laminin P1 in diabetics with advanced nephropathy.

In 97 patients with type I diabetes mellitus, 155 patients with type II diabetes mellitus, and two matched control groups, serum concentrations of laminin P1, a non-collagenous component of basement membranes, were determined by radioimmunoassay to see whether laminin P1 might be a valuable indicator of microangiopathic complications in diabetics. Independent of the type of diabetes, serum laminin concentrations in patients without nephropathy or with early renal damage as assessed by microalbuminuria were comparable with those of the control subjects. Patients with macroproteinuria or with renal insufficiency had significantly increased serum laminin P1 concentrations. Diabetic retinopathy was not found to influence serum laminin P1 concentrations. These data indicate that serum laminin P1 concentrations are increased in advanced diabetic nephropathy.

The cortical distribution pattern of diabetic glomerulopathy.

In advanced diabetic nephropathy, all nephrons are affected. However, glomerulopathy shows some variation in severity. The aim of this study was to see whether the distribution of glomerular lesions bears any relationship to known renal anatomical/functional organization. Autopsy material from 12 long-term Type 1 (insulin-dependent) diabetic patients was collected retrospectively. Sections presenting the whole depth of cortex were subdivided into 3 zones of equal width. Two parameters were estimated in the deep and the superficial zones separately: in open glomeruli, the volume of red-stained (PAS-positive) material as a fraction of the total glomerular volume, and the number of occluded glomeruli as a fraction of the total number. The results show that the volume fraction of red-stained (PAS-positive) material, as well as the frequency of occluded glomeruli, are similar in the superficial and the deep zone. In addition, the spatial distribution of occluded glomeruli was tested for randomness. The occluded glomeruli are not randomly distributed, but show clustering. Furthermore, they tend to be located in columns perpendicular to the kidney surface, a tendency which cannot be explained by the general tendency for glomeruli to show such an arrangement. We conclude that it is unlikely that the combined structural and functional differences that exist between the superficial and deep glomeruli play a major role in the development of diabetic glomerulopathy. The kidney topology influences the process of glomerular occlusion. Several a priori, plausible mechanisms for the process are discussed.

Effect of captopril on heavy proteinuria in azotemic diabetics.

We investigated whether captopril, an angiotensin-converting-enzyme inhibitor, would reduce proteinuria in patients with advanced diabetic nephropathy. Captopril (37.5 mg given in divided doses three times daily) was administered to 10 azotemic diabetics with heavy proteinuria. Urinary protein decreased promptly within two weeks (from 10.6 +/- 2.2 to 6.1 +/- 1.4 g per day [mean +/- S.E.M.]; P less than 0.01). The decrease in proteinuria did not coincide with a fall in systemic blood pressure or in the blood glucose concentration. Serum creatinine and potassium values did not change in any of the patients except one. We suggest that captopril caused a decrease in intrarenal hypertension, which contributed to the reduction of urinary protein excretion. The therapeutic value of this intervention remains to be established.

The Pathophysiology of Experimental Insulin-Deficient Diabetes in the Monkey

In an 11-year study of experimental insulin-deficient diabetes (IDDM) induced in rhesus monkeys by streptozotocin or total pancreatectomy, the authors have found that pathophysiologic changes occur in eye and kidney, which closely resemble the early stages of human insulin deficient diabetes mellitus (IDDM). In addition, morphologic changes of thickening of glomerular capillary basement membrane and expansion of mesangial matrix (by light microscopy) appear within 3 years of onset of hyperglycemia. However, progression to irreversible complications of advanced diabetic nephropathy or proliferative retinopathy, have not occurred. This animal model resembles human disease in that the animals tend to become ketotic unless maintained with exogenous insulin; C-peptide production is low to absent, and large amounts of glycosylated hemoglobin develop within a month of onset. The monkeys differ from humans in the absence of hypertension and hyperlipidemia. The authors suggest that the abnormalities in basement membrane form and function caused by hyperglycemia form the necessary background upon which other factors, such as hypertension and hyperlipidemia, then act to cause irreversible complications. The role of pancreatic transplantation is in prevention of these background changes.

The Pathophysiology of Experimental Insulin-Deficient Diabetes in the Monkey

In an 11-year study of experimental insulin-deficient diabetes (IDDM) induced in rhesus monkeys by streptozotocin or total pancreatectomy, the authors have found that pathophysiologic changes occur in eye and kidney, which closely resemble the early stages of human insulin deficient diabetes mellitus (IDDM). In addition, morphologic changes of thickening of glomerular capillary basement membrane and expansion of mesangial matrix (by light microscopy) appear within 3 years of onset of hyperglycemia. However, progression to irreversible complications of advanced diabetic nephropathy or proliferative retinopathy, have not occurred. This animal model resembles human disease in that the animals tend to become ketotic unless maintained with exogenous insulin; C-peptide production is low to absent, and large amounts of glycosylated hemoglobin develop within a month of onset. The monkeys differ from humans in the absence of hypertension and hyperlipidemia. The authors suggest that the abnormalities in basement membrane form and function caused by hyperglycemia form the necessary background upon which other factors, such as hypertension and hyperlipidemia, then act to cause irreversible complications. The role of pancreatic transplantation is in prevention of these background changes.

Renin Secretion in Advanced Diabetic Nephropathy.

Low basal and stimulated plasma renin activity (PRA) levels have been reported in patients witn diabetic nephropathy (DN). We have measured PRA before and after stimulation with captopril in 28 patients with DN and in 25 control patients. Renal function impairment was similar in both groups. Most patients were treated with furosemide. In 19 patients with DN the PRA-response to dihydralazine was also studied. PRA before and after captopril were higher in the DN than in the control group (P < 0.001). PRA increased from 4.6 ± 3.6 to 6.3 ± 5.3 in the DN, and from 1.8 ± 2.7 to 2.7 ± 3.4 in the control patients. The increases in PRA, caused by decreased angiotensin II feed-back inhibition, were comparable. PRA did not increase after dihydralazine despite a pronounced blood-pressure reduction. The difference in response to these stimuli indicate selective lesions involving both the sympathetic innervation and the renal baroreceptor function in DN. Overhydration is a plausible explanation to the low PRA earlier reported in DN. The results thus indicate that a preserved renin secretion capacity is present in DN. Differences in PRA between the both groups can only partly be explained by other factors than DN. Our findings indicate a role for the reninangiotensin-system in hypertension in DN.

Fetal-neonatal uremia in advanced maternal diabetes.

A symmetrically growth retarded premature infant was born to a mother with advanced diabetic nephropathy, chronic renal failure, and hypertension, and managed with aggressive medical therapy without the use of dialysis. The neonatal course was uncomplicated, except for cord blood creatinine and BUN concentrations of 4.7 mg/dl and 116 mg/dl, respectively, that fell to 1.1 mg/dl and 44 mg/dl by 2 days of age. Strict glucose control, careful management of the metabolic abnormalities of uremia, and periodic surveillance of fetal well-being led to a successful pregnancy.

Successful Pregnancy in a Diabetic Patient Treated with Continuous Ambulatory Peritoneal Dialysis

In this article we describe the successful management of pregnancy and delivery in a 26-yr-old patient with advanced diabetic nephropathy and chronic renal failure. Targets for control of blood urea and hemoglobin were achieved with the aid of continuous ambulatory peritoneal dialysis (CAPD). Peritoneal dialysis did not interfere with normal recovery from cesarean section. With CAPD, successful pregnancy is now possible in this group of patients, among whom fetal loss would otherwise be high.

Glomerular function in advanced human diabetic nephropathy

Intrinsic membrane properties of the glomerular capillary wall were evaluated in 20 diabetic patients, who had heavy proteinuria and reduced GFR, and in 15 healthy control subjects. The glomerular sieving coefficients were determined for narrow dextran fractions with molecular radii between 20 and 64 A. GFR determinants were directly measured or indirectly estimated. These quantities were then subjected to a theoretical analysis based upon (1) a mathematical model of glomerular ultrafiltration and (2) a pore model of transmembrane solute transport. The results indicated that in patients with diabetic nephropathy and glomerular ultrafiltration coefficient (0.02 vs. 0.16 ml . sec-1 . mm Hg-1 . 1.73m-2), effective pore area-to-pore length (2.6 x 10(6) vs. 20.0 x 10(6) cm), and mean pore radius (56.8 vs. 58.0 A) are all reduced relative to normal control subjects. It is suggested that (1) hypofiltration in advanced diabetic nephropathy results, in part, from reduction of the surface area available for filtration, while (2) proteinuria is a consequence of either loss of electrostatic barrier function, of isolated focal disruptions within the glomerular filtration barrier, or a combination thereof.

Mechanisms of proteinuria in diabetic nephropathy: A study of glomerular barrier function

The fractional clearance of neutral dextrans (theta D) with Einstein-Stokes radii between 30 and 64 A was determined in normal subjects (controls, N = 15) and in diabetic patients with heavy proteinuria (advanced nephropathy, N = 16) or trace proteinuria (early nephropathy, N = 8). When plotted on log normal probability coordinates, the correlation between theta D and radius in controls and in early diabetic nephropathy was linear, suggesting that glomerular pores form one population with a normal distribution. In advanced diabetic nephropathy, however, theta D for large molecules (radius greater than 46 A) was elevated and departed from linearity suggesting a bimodal pore size distribution within the glomerular membrane. A mathematical model was devised, which revealed the mean fraction of glomerular filtrate permeating the upper pore mode to be 0.009 +/- 0.002, and the pores to be totally nondiscriminatory toward molecules with radii up to 64 A. We conclude that the development of large pores (or defects) within the glomerular membrane in advanced diabetic nephropathy permits the unrestricted passage of large plasma proteins into the urine.

High Density Lipoproteins in Diabetes

The concentration of high density lipoproteins (HDL) in patients with diabetes mellitus is highly variable. Subnormal HDL cholesterol levels are present in untreated patients with insulin-deficient juvenile diabetes, but the values return to the normal range after beginning insulin therapy. During conventional subcutaneous insulin treatment the diabetic patients often exhibit increased mean HDL cholesterol concentrations, even in the presence of poor diabetic control. HDL concentration is not related to blood glucose or fast hemoglobin levels. However, in the presence of overt ketoacidosis and upon development of advanced diabetic nephropathy, HDL levels fall. In noninsulin-dependent diabetes low HDL cholesterol values are common, but they are associated more with obesity and hypertriglyceridemia than with the diabetic state itself. Thus, when diabetic and nondiabetic subjects are compared at similar relative body weight and serum triglyceride levels, there seems to be no difference in the mean HDL cholesterol values. The possible effects on HDL of treatment by diet and particularly by oral antidiabetic agents are not yet clear; published results are controversial in this respect. Alterations of HDL in diabetes are probably based on the presence of insulin deficiency or, more commonly, on hyperinsulinemia and insulin resistance. HDL (particularly the subfraction HDL2) concentration is regulated by two endothelial lipolytic enzymes, lipoprotein lipase and hepatic lipase, both of which are insulin sensitive. Peripheral hyperinsulinemia is produced in insulin-dependent diabetics by insulin treatment. This results in an increase of tissue lipoprotein lipase activity, which in turn augments HDL levels. In obese diabetic patients the peripheral tissues are resistant to insulin and, accordingly, the lipoprotein lipase activity is subnormal. Furthermore, the hepatic lipase activity is often increased and may contribute to the lowering of HDL by increased removal of HDL cholesterol. It is not known whether the alterations of HDL play any role in the increased atherosclerosis of diabetic patients.

Proteinuria and functional characteristics of the glomerular barrier in diabetic nephropathy

Fractional clearances of uncharged dextran 40 and anionic proteins were performed in an attempt to elucidate the defect in glomerular barrier function responsible for heavy proteinuria in diabetic nephropathy. Notwithstanding urinary albumin excretion (UalbV) at 3634 +/- 608 microgram/min, the fractional clearance for dextran molecules with Einstein-Stokes radii (r) between 22 and 36 A was depressed in 12 patients with advanced diabetic nephropathy, which suggests a reduction in mean glomerular pore size or density. Equivalent restriction to transglomerular passage of dextrans with a r < 36 A in 7 patients with minimal change nephropathy was associated with a similarly enhanced proteinuria (UalbV, 3333 +/ 759 microgram/min). The dissociation between fractional clearances for neutral and anionic macromolecules in both disorders is consistent with loss of glomerular electrostatic charge. In diabetic nephropathy, however, the fractional clearances for large dextrans and test proteins considerably exceeded corresponding values in minimal change nephropathy when r greater than or equal to 36 A. Furthermore, the fractional clearances for test proteins were two orders of magnitude smaller than that for equivalent-sized dextrans in minimal change nephropathy, whereas this difference was much less in diabetic nephropathy. Thus, a selective increase in transglomerular passage of large molecules and a progressive loss of ability to discriminate between large molecules of different configuration distinguish the glomerular capillary wall in diabetic nephropathy from that in minimal change nephropathy.

Hypertension, hyperkalaemia and abnormalities of the renin-angiotensin system in diabetes mellitus.

BLOOD pressure levels are higher and hypertension is commoner among diabetics, compared with the nondiabetic population. Hypertension further increases mortality in diabetes, although it is not clear whether the effect is more marked than in normoglycaemic hypertensive subjects. Hypertension in the diabetic patient requires effective treatment. High levels of renin and angiotensin II occur in ketoacidosis, while low levels are seen in advanced diabetic nephropathy. There are conflicting data on renin levels in other diabetic conditions, including uncomplicated diabetes and diabetes associated with hypertension. We have shown that plasma angiotensin II falls with improved blood sugar control, and varying control might explain some of the differences between series. Isolated hypoaldosteronism in adults commonly results from a decreased production of renin and angiotensin II. Hypoaldosteronism presents with unexplained hyperkalaemia and appears to be associated with diabetes mellitus, especially in cases where renal function has been impaired, although a few such patients with normal renal function have been described. Our data indicate that overt hypoaldosteronism is rare among diabetics. In normal subjects plasma potassium usually falls following a glucose load. However, in some diabetic patients plasma potassium rises and this paradoxical response has been attributed to combined insulin-aldosterone deficiency. We report paradoxical hyperkalaemia in insulin-requiring diabetics without evidence of aldosterone deficiency. We also report paradoxical hyperkalaemia in a diabetic patient subsequently controlled by dietary restriction alone.

Human glomerular basement membrane: chemical composition in diabetes mellitus.

Abstract.Glomerular basement membrane (GBM) was isolated from human kidneys obtained at autopsy or nephrectomy in preparation for transplantation. Kidneys from 22 patients were used: 10 patients without a history of diabetes mellitus or kidney disease and with normal kidney morphology, 5 with a short history of diabetes and minimal pathological changes in the kidneys, and 7 with very advanced diabetic nephropathy. The GBM preparations were individually analysed for amino acids, carbohydrates, phospholipids and cholesterol. The cystine concentration was found to be lower both in early diabetic nephropathy and advanced diabetic nephropathy than in normal kidneys. In advanced diabetic nephropathy a significant decrease in the content of sialic acid was found. Contrary to other reports there was no increase in the amounts of hydroxylysine or glucosyl‐galactosyl‐hydroxylysine. The influence of technical factors on the chemical composition of GBM preparations is discussed.