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Query: UMLS:C0011860 (type 2 diabetes)
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Not all patients with diabetes develop clinically significant nephropathy and, for this reason, attention has begun to focus on the risk factors for development of this serious complication. These risk factors have not been quantified to the same degree as those factors associated with more common progressive vascular diseases, such as atherosclerosis. However, studies of pathogenesis and clinical and epidemiological surveys of diabetic nephropathy point to numerous risk categories. Glycemic control, genetic and familial predispositions, renal and glomerular enlargement, glomerular hyperfiltration, and capillary and systemic hypertension can be invoked as contributors to this disease process. This review focuses on hemodynamic alterations and their role in the development and progression of diabetic nephropathy. Increases in GFR, largely driven by increases in plasma flow and capillary pressure, appear in early IDDM and NIDDM. This abnormality of renal vascular control probably is derived from alterations in several vasoactive control systems. In addition, the elevations in capillary pressure may be damaging to the glomerular capillaries. Arterial hypertension is not necessarily present before clinical nephropathy appears; however, it is a usual concomitant of progressive diabetic renal disease. The strongest evidences for the roles of altered systemic and renal hemodynamics in the progression of diabetic renal disease are clinical and experimental studies demonstrating attenuation of the disease process by lowering systemic and capillary pressures with antihypertensive agents, and dietary and glycemic modifications. Thus, although multiple factors probably interact to determine risk for the development of diabetic nephropathy, hemodynamic forces are a particularly important contributor and are especially amenable to therapeutic intervention.
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PMID:Diabetic nephropathy. Metabolic versus hemodynamic considerations. 139 17

To clarify the problem in the measurement of renal plasma flow and glomerular filtration rates in diabetes, the effect of glucose on the determination of para-aminohippuric acid (PAH) and inulin was examined. The concentration of urinary PAH in glucosuric diabetic subjects decreased after the storage of urine samples because of the glycation of PAH. Therefore, glucose must be removed by the acid treatment before the determination of the concentrations of urinary PAH. Since glucose can interfere with the assay of inulin, the sample must be treated with NaOH prior to the determination of the inulin concentration. GFR of the subjects with type 2 diabetes was next examined. GFR in the subjects with a duration of diabetes less than 10 years was significantly higher than that in the subjects with a duration of diabetes more than 10 years. Thus, the subjects with short-term type 2 diabetes may present with hyperfiltration similar to the subjects with short-term type 1 diabetes.
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PMID:[Measurement of renal plasma flow and glomerular filtration rates in diabetic subjects]. 150 86

Diabetic nephropathy, clinically defined by overt albuminuria, hypertension and declining GFR, affects 25-35% of IDDM patients. The risk of nephropathy peaks during the second decade of IDDM and declines thereafter, suggesting that only a subset of IDDM patients is at risk for nephropathy. A role for hypertension in the progression of established renal damage in IDDM is now accepted; however the role of hypertension in the genesis of diabetic nephropathy is not yet clear. Mesangial expansion is a characteristic lesion of diabetic nephropathology and correlates with renal function. Functional studies are not indicative of underlying renal pathology except relatively late, when glomerular injury is advanced. Microalbuminuria in the 'predictive' range (greater than 30 micrograms/min) and associated with hypertension and/or declining GFR is a marker of established diabetic glomerulopathy. Only carefully designed longitudinal studies of renal morphology and function with accurate blood pressure monitoring beginning early in the course of IDDM will clarify the relationships between blood pressure and renal damage in IDDM. In NIDDM the frequent presence of non-diabetic renal lesions, of hypertension at or before the onset of diabetes, and the relative paucity of clinical-pathological correlations currently make it difficult to understand the role of hypertension in the genesis and progression of nephropathy. Again, longitudinal studies of blood pressure and renal structure and function are required in NIDDM patients. Finally, animal models of hypertension and diabetes may aid progress in these areas.
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PMID:Hypertension and diabetic renal disease. 179 13

Hyperfiltration is a very characteristic feature in insulin-dependent diabetes. Hyperfiltration is to some extent associated with long-term glycemic control but the correlation is not very strong. Long-term hyperfiltration may play a role in the genesis of late diabetic nephropathy, but it is difficult to distinguish effects of hyperfiltration per se from effects of poor metabolic control. Long-term hyperfiltration without diabetes does not produce nephropathy. It is hypothesized that IDDM patients who do not show considerable hyperfiltration in spite of poor metabolic control may be those who are to some extent protected against late diabetic nephropathy, but other mechanisms may also be involved in the renal protection of these patients, who survive long-term diabetes without nephropathy. On the other hand, those with poor metabolic control combined with hyperfiltration are likely to develop nephropathy. In addition, it is suggested that the metabolic aberrations in diabetes, with the subsequent changes in the biochemistry of the glomerular wall, are permissive and absolutely required for the development of diabetic nephropathy. Of note, diabetic glomerulopathy in NIDDM occurs without significant hyperfiltration and extreme hyperfiltration in the one-kidney-model (without diabetes) does not produce nephropathy. Nonglycemic modalities of intervention, resulting in reduced hyperfiltration, e.g., low-protein diet or administration of somatostatin analogues, deserves interest as new potential ways of preventing or postponing diabetic nephropathy. Also intervention with aldose-reductase inhibitors may be an important therapeutic modality for those patients in whom good metabolic control is not obtainable. It is now well-established that antihypertensive treatment, including ACE-inhibition, reduces rate of decline in GFR in patients with already established nephropathy. In addition, protein excretion is diminished in IDDM patients with incipient diabetic nephropathy by antihypertensive treatment where GFR is well-preserved during treatment. No data are available for NIDDM.
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PMID:Comparative renal pathophysiology relevant to IDDM and NIDDM patients. 306 56

103 Indians (74 females, 29 males) with NIDDM diagnosed before age 30 yr on the basis of the revised WHO diagnostic criteria were studied in order to assess the prevalence of microvascular complications. The mean duration of NIDDM in the subjects was 11 yr (range 2-38 yr). 24 patients (23%) eventually required insulin therapy for control after a mean interval of 11.8 yr (range 5-38 yr). Diabetic retinopathy was present in 37 patients (35.9%), of whom 6 had proliferative retinopathy. Nephropathy was found in 16 patients (15.5%). The mean GFR of these patients was 46.8 ml/min, compared to a mean of 97.1 ml/min in 12 of the patients without nephropathy who had a similar mean duration of disease. The mean duration of disease in patients with retinopathy and nephropathy was 14.9 yr and 14.8 yr respectively. In the patients who eventually required insulin therapy both retinopathy (75%) and nephropathy (41%) were more common but the mean duration of disease in these patients was longer (16 yr vs 9 yr). This study has underlined the heterogeneity of NIDDM in the young, as microvascular complications are by no means uncommon in South African Indians with the disease.
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PMID:Microvascular complications and non-insulin-dependent diabetes of the young in South African Indians. 382 87

Diabetic nephropathy is a progressive renal disease and represents a serious late complication of diabetes. There are familial clustering and huge ethnic differences in the occurrence of diabetic nephropathy, which point to a genetic predisposition. Diabetic nephropathy is defined by persistent albuminuria (albumin excretion rate [AER] > 300 mg/day), declining glomerular filtration rate and rising blood pressure. Several years of incipient nephropathy, characterized by worsening microalbuminuria (AER 30 to 300 mg/day or 20 to 200 micrograms/min), which is Albustix-negative and detectable by special assays only, are followed by established nephropathy. The natural history of nephropathy differs between insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. In IDDM, nephropathy develops in 30 to 40% of cases. The incidence peaks after 15 to 16 years of diabetes. In NIDDM, estimates of prevalence range from 15 to 20%, and nephropathy often supervenes after a shorter known duration of diabetes than in IDDM. GFR is often increased above normal (hyperfiltration) from the onset of IDDM due to increased renal blood flow, glomerular capillary hypertension and increased filtration surface. The glomeruli are hypertrophied and the kidneys enlarged. In both IDDM and NIDDM, GFR begins to decline irreversibly, when AER has risen to 100 to 300 mg/day at an average rate of 10 ml/min. per year. This is due to progressive reduction of the filtration surface area through mesangial expansion. Serum creatinine levels begin to rise when GFR falls below 50 ml/min, and then end-stage renal failure follows after an average of five years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Diabetic nephropathy: significance of microalbuminuria and proteinuria in Type I and Type II diabetes mellitus]. 749 50

The detection of overt albuminuria (> 300 mg/g creatinine) in the absence of azotemia was used to diagnose early nephropathy in 34 Pima Indians with NIDDM of 16 +/- 1 years duration. Differential solute clearances were performed serially to define the course of the glomerular injury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtration fraction and sieving coefficients of relatively permeant dextrans (< 52 A) were all depressed below corresponding values in 20 normoalbuminuric Pima Indians with a similar duration of NIDDM. Over the ensuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of large, nearly impermeant dextrans (> 56 A radius) increased selectively and fractional clearances of albumin and IgG increased correspondingly by > 10-fold. Analysis of the findings with pore theory revealed: (1) a progressive decline in pore density and the ultrafiltration coefficient (Kf); and (2) broadening of glomerular pore-size distribution that resulted in greater prominence of large pores (> 70 A radius). We conclude that increasing loss of intrinsic ultrafiltration capacity is the predominant cause of the early and progressive decline in GFR that follows the development of nephropathy in NIDDM. We speculate that progressive impairment of barrier size-selectivity contributes to but does not fully account for the increasingly heavy proteinuria that is observed early in the course of this disorder.
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PMID:Progression of overt nephropathy in non-insulin-dependent diabetes. 754 61

We studied renal function of 194 black subjects with duration of diagnosed NIDDM from 1 month to 36 years to determine the interaction of hypertension and diabetes on nephropathy. Renal function was assessed by isotopic GFR and RPF studies, and serum creatinine. One hundred seventeen of the 194 subjects had 24-hour urinary albumin excretion (AER). AER > 300 mg/24 h correlated with longer duration of NIDDM, decrease in GFR and RPF, and rise in serum Cr, and all subjects were hypertensive. AER 30 to 300 mg/24 h also correlated with a longer duration of NIDDM and 80% had hypertension. When 194 subjects were grouped according to duration of NIDDM and the presence or absence of hypertension, subjects who remained normotensive had normal renal function. In hypertensive subjects a decrease in GFR occurred with duration of NIDDM > 1 year and decrease in RPF with duration of NIDDM > 5 years. In hypertensive subjects with NIDDM > 10 years, 36% had impaired renal function (GFR < 80 ml/min/1.73 m2 or serum creatinine > 1.4 mg/dl) and 75% had microalbuminuria or clinical proteinuria. Within this group, those subjects who developed hypertension after their diagnosis of diabetes were likely to have evidence of nephropathy as compared to those subjects whose hypertension was diagnosed prior to or simultaneous with their diabetes: 17 of 20 (85%) versus 7 of 13 (54%), respectively (P = 0.05). These data provide insight into the relationship between hypertension and diabetes in the development of nephropathy in black NIDDM individuals.
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PMID:Interaction of hypertension and diabetes on renal function in black NIDDM subjects. 764 39

Lithium is the best available marker of proximal tubular reabsorption of fluid. The first part of the present thesis reviews the background for the use of the lithium clearance (CLi) method. Micropuncture studies on proximal reabsorption of lithium, showed that CLi is a reasonably correct measure of end-proximal fluid delivery rate, even during osmotic diuresis. During severe salt restriction, distal reabsorption of lithium renders the CLi method inappropriate in animals, but this problem does probably not occur in humans. The major current issue is whether a quantitatively significant reabsorption of lithium occurs in the loop of Henle. Available evidence is in accord with the interpretation that it does not occur. The interpretation of results form CLi studies depends to a surprising degree on the investigators beliefs about renal physiology. In the evaluation of proximal tubular function, the relevant parameter is the absolute proximal reabsorption rate of fluid and sodium. In the evaluation of integrated distal tubular reabsorption of sodium, the relevant parameter is the fractional distal reabsorption rate of sodium. The fractional CLi does not give meaningful information, and calculated absolute distal reabsorption rate of sodium is inherently not suited to detect modest changes in distal reabsorption leading to large changes in sodium excretion. Results from the use of the CLi method in relation to diabetes are reviewed in the second section. Even in IDDM patients with early diabetic nephropathy, the proximal reabsorption rate is elevated, resulting in a normal CLi despite glomerular hyperfiltration. Overnight euglycemia did not change GFR in IDDM patients, but during maintained euglycemia, GFR was normalized. A few hours of hyperglycemia prevented the decline in GFR, whereas CLi was unchanged. Thus hyperglycemia produced changes in renal function similar to those observed previously, but the time-course of the effect of euglycemia on kidney function is delayed. Plasma levels of atrial natriuretic peptide, renin and glucagon were not importantly affected by plasma glucose. In NIDDM patients CLi was normal, despite slight hyperfiltration, although this observation must be confirmed in a study with larger sample size. Prompted by the clinical observation of a marked decline in the GFR induced by carbonic anhydrase inhibitors, we studied the renal effects of acetazolamide in a controlled study.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lithium clearance in the evaluation of segmental renal tubular reabsorption of sodium and water in diabetes mellitus. 818 64

Growth retardation is a common feature in children with end-stage renal failure (ESRF). Medical management of renal insufficiency rarely normalizes growth and optimistic reports on the effect of rhGH treatment on growth velocity may presage more extensive use of rhGH in pediatric nephrology. Ample evidence has shown beneficial effects of GH replacement therapy in both childhood and adolescent hypopituitarism. However, the remarkably few side effects of treatment reported in these conditions cannot necessarily be extrapolated to children with ESRF. Uremia is associated with a wide range of metabolic and hormonal derangements including decreased glucose tolerance. This is mainly due to impaired insulin-stimulated glucose disposal in peripheral tissues and insufficient insulin-induced suppression of hepatic glucose production. Insulin-stimulated glucose uptake in skeletal muscle in ESRF is reduced by 30-50% as compared to that in healthy subjects, and a reduction may be detected even in subjects with a more moderate reduction in renal function (GFR around 25 ml/min). Dialysis therapy improves the disturbed insulin action significantly. The cause of the insulin resistance in ESRF is multifactorial. Impaired physical fitness, accumulation of uremic toxins, raised levels of GH and glucagon, metabolic acidosis, dyslipidemia and the medication applied may all contribute. If exogenous GH administration is added to the already marked uremic insulin resistance, insulin action may be severely disturbed and the secondary hyperinsulinism further magnified. However, frank diabetes mellitus does not develop unless the beta cells fail to meet the enhanced demands. This will probably occur only in patients with a beta-cell genotype pivotal for the phenotypic expression of non-insulin dependent diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose metabolism in chronic renal failure with reference to GH treatment of uremic children. 837 90


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