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M W Steffes

Publications and source records attributed to M W Steffes.

At least 19 recordsLinked to original sources
PubMed1992

An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics.

Clinical diabetic nephropathy in man is the consequence of the development of a specific constellation of glomerular, tubular, vascular, and interstitial structural abnormalities accompanied by highly characteristic immunohistochemical alterations that, together, are unique to diabetes. Because changes resembling the specific pathology of diabetes do not develop in patients with conditions that lead to long-standing glomerular hyperfunction (such as unilateral nephrectomy), it is unlikely that glomerular hemodynamic abnormalities per se can be the cause of diabetic nephropathy. Whether hemodynamic abnormalities represent a risk factor that, in the presence of the diabetic state, can accelerate the rate of development of the basic lesions of diabetic nephropathy is currently unclear. However, there is considerable evidence that when the renal lesions of diabetes are far advanced, factors such as systemic hypertension can determine the rate of renal functional deterioration in diabetes as in other disorders. Although the diabetic rat may be a useful model for the study of aspects of the pathogenesis of diabetic nephropathy, much confusion has resulted from the inclusion of focal segmental glomerular sclerosis as a diabetic lesion. Similarly, the acceptance of all increases in urinary protein excretions in this model as resulting from or reflecting of diabetic nephropathology can be misleading. It is concluded that treatment aimed at manipulating renal hemodynamics in diabetic patients without evidence of renal disease should remain in the realm of clinical research.

Animals↗
PubMed1992

Relationship of systemic blood pressure to nephropathology in insulin-dependent diabetes mellitus.

Although hypertension is an important complication of diabetes it is unclear whether its association with other diabetic complications represents cause or consequence. Our study is a cross sectional evaluation of the relationship of blood pressure to renal structural and functional parameters. In 139 patients with insulin dependent diabetes for 18.9 +/- 7.4 years (mean +/- SD), we divided the patients into those with markedly increased mesangial volume fraction [Vv(mes/glom) greater than or equal to 0.37] and those with less [Vv(mes/glom) less than 0.37]. Hypertension (systolic BP greater than or equal to 160 and/or diastolic BP greater than 90 mm Hg or receiving BP medications) occurred in 29/40 with Vv(mes/glom) greater than or equal to 0.37. All 40 had clinical nephropathy with urinary albumin excretion (UAE) greater than 200 mg/24 hr. By two-way ANOVA creatinine clearance was lower and albuminuria was increased with both hypertension and the expanded mesangium. Also other measures of renal structure including filtration surface, index of interstitial fibrosis and index of arteriolar hyalinosis were increased by hypertension and mesangial expansion. Most patients with hypertension had other criteria for clinical nephropathy. Since, in these studies, we could not determine if hypertension contributed to or resulted from the renal lesions, we developed an estimate of the rate of mesangial expansion. We found that patients with normal BP (119 +/- 11/78 +/- 7 mm Hg) can be rapidly developing mesangial expansion. These studies support the view that the development of serious renal lesions can be independent of hypertension in IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Heparan sulfate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus.

Heparan sulfate proteoglycans (HSPG) are negatively charged constituents of the renal extracellular matrix including the glomerular basement membrane (GBM) and mesangial matrix. Biochemical and functional studies of patients with type-1 insulin dependent diabetes mellitus (IDDM) suggest that alterations of HSPG may occur in diabetic nephropathy. We have utilized a specific cytochemical method and electron microscopy to quantitate the distribution of HSPG in the GBM of 10 normal people and in 16 IDDM patients with a spectrum of clinical and structural changes. Enzyme incubation studies of normal infant kidney demonstrated that heparitinase removed 94% of the stainable anionic sites in the lamina rara externa (LRE) and 77% of the sites in the lamina rara interna (LRI) of the GBM. In contrast, incubation in the enzyme chondroitinase ABC did not reduce the number of sites in the LRE but reduced the number of sites in the LRI by 26%. The HSPG anionic sites in normal subjects were distributed in the LRE as 20.9 +/- 1.3, and in the LRI as 13.1 +/- 2.2 per micron GBM length. Anionic sites were slightly reduced (19.6 +/- 1.3, P less than 0.04) in the LRE of IDDM patients with normal urinary albumin excretion rates (UAE), or microalbuminuria, and were reduced in both the LRE and LRI of IDDM patients with clinical proteinuria (13.1 +/- 2.3, P less than 0.001 and 8.9 +/- 2.1, P less than 0.001, respectively). The number of anionic sites in the LRE and LRI, respectively, correlated with UAE (r = +0.78, P less than 0.001, r = +0.58, P less than 0.02), with GBM thickness (LRE, r = +0.81, P less than 0.001; LRI, r = +0.67, P less than 0.01) and with the volume fraction of mesangium (LRE, r = +0.59, P less than 0.02; LRI, r = +0.58, P less than 0.03). These data confirm earlier biochemical findings of a reduction of HSPG in the GBM in advanced diabetic nephropathy but do not provide evidence for the loss of HSPG in the GBM as a mechanism for early microalbuminuria.

Adolescent↗
PubMed1992

Estimation of glomerular volume: a comparison of four methods.

Methods for estimating glomerular volume were compared in Zenker-fixed, paraffin-embedded biopsies from 10 patients with insulin-dependent diabetes mellitus and 6 normal kidney donors. Two methods of measurement of individual glomerular volumes were used: the Cavalieri method (considered the "gold standard") and the maximal profile area (MPA) method. Also studied were the method of Weibel and Gomez and a method based on the disector principle; both estimate mean volume (VG). MPA and Cavalieri showed strong correlation (r = 0.93; P less than 0.001), although the MPA method consistently overestimated the true volume; six glomeruli were necessary for a reliable estimate of VG. The disector method did not correlate with VG determined by Cavalieri. Weibel-Gomez did correlate with Cavalieri (r = 0.68; P less than 0.05), but overestimated VG. At least 15 profiles were needed to provide a dependable estimate of VG by Weibel-Gomez. The Cavalieri, MPA, and Weibel-Gomez methods all can provide reliable estimates of VG, the latter two with appropriate correction factors. The individual glomerular volume methods, while more time consuming, provide information on variation and distribution of the glomerular population and are the methods of choice for studies of glomerular volume.

Adult↗
PubMed1992

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

PURPOSE: 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. CRITICAL RENAL LESIONS IN DIABETIC NEPHROPATHY: 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. FUTURE RESEARCH: 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.

Diabetes Mellitus, Type 1↗
PubMed1992

Renal structure and function in insulin-dependent diabetes mellitus and type I membranoproliferative glomerulonephritis in humans.

Renal pathological changes of diabetes 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 related to proteinuria, hypertension, and declining GFR. 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. Parallel findings were documented for type I membranoproliferative glomerulonephritis in which the increased mesangial volume fraction was related to decreased GFR, increased glomerular permeability to protein, and hypertension. As in diabetes, the cortical interstitial volume fraction is correlated with functional abnormalities in type I membranoproliferative glomerulonephritis. Thus, in both of these chronic glomerular disorders, mesangial expansion and interstitial expansion are associated with disordered renal function. Thus, it is not true that glomerular structural changes correlate poorly with glomerular function. Whether it is the glomerular or interstitial pathology or both that is causally responsible for the dysfunction requires further study.

Diabetes Mellitus, Type 1↗
PubMed1992

Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion.

Eight women with insulin-dependent diabetes mellitus (IDDM) with low creatinine clearance rate (CCR) and normal urinary albumin excretion (UAE) were compared with three other groups of diabetic women: 19 with normal creatinine clearance rate (CCR) and UAE, 7 with normal CCR and microalbuminuria, and 7 with low CCR and microalbuminuria. The four groups were similar in age, duration of diabetes, HbA1, incidence of urinary tract infection, prevalence of bladder neuropathy, and urinary urea nitrogen excretion rate. The prevalence of hypertension was similar among the groups, although mean arterial pressure was higher in the low CCR and microalbuminuria group. Renal area index was lower in the low CCR and normal UAE groups than in the other groups of diabetic patients, but was not different from normal. Morphometric measures of mesangial expansion and estimates of arteriolar hyalinosis and global glomerulosclerosis were increased to a similar degree in the low CCR and normal UAE, normal CCR and microalbuminuria, and low CCR and microalbuminuria groups compared with the group without abnormalities of renal function. Therefore, it is likely that diabetic glomerulopathy is, at least in part, responsible for the loss of glomerular filtration rate seen in the low CCR and normal UAE patients. Thus, the definition of incipient nephropathy may have to be expanded beyond the concept of microalbuminuria if longitudinal study of such patients reveals an increased risk of the subsequent development of overt nephropathy. Finally, screening for diabetic kidney disease among IDDM patients should include determination of glomerular filtration rate and measurement of UAE and blood pressure, especially among women.

Adult↗
PubMed1992

Cell and matrix components of the glomerular mesangium in type I diabetes.

In a cross-sectional study, glomerular basement membrane (GBM) width, the volume fractions of the mesangium (VvMes), its cell (VvCell) and matrix (VvMatx) components, and surface density of the peripheral capillary surface (SvPGBM) were measured in renal biopsies from 187 nondiabetic living related and cadaveric donors of kidneys for transplantation and from 150 patients with insulin-dependent (type I) diabetes mellitus of 1-41 yr duration. In the diabetic patients, the matrix was the major factor in the expansion of the mesangium. However, both VvCell (0.11 +/- 0.04) and VvMatx (0.20 +/- 10) in diabetic patients exceeded the same measurements in nondiabetic subjects (0.07 +/- 0.02 for each component) (P less than 0.001 in each case). Linear regression analysis demonstrated significant correlations (P less than 0.001 for all) between GBM width, VvMes, VvCell, VvMatx, or SvPGBM and either urinary albumin excretion and creatinine clearance, with the higher correlation coefficients in all cases with albuminuria. Of the structural parameters, VvMatx correlated best with either functional measure by stepwise regression, with GBM as an added factor only with albuminuria. Therefore, although models of diabetic glomerulopathy must consider enlargement of both mesangial cells and matrix, the predominant factor in the progression of structural and functional renal disease is mesangial matrix expansion.

Adult↗
PubMed1991

Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes.

We studied the lesions of global glomerular sclerosis and arteriolar hyalinosis in 43 (29 females) insulin-dependent diabetes mellitus (IDDM) patients whose creatinine clearance (CCr) was greater than or equal to 45 ml/min/1.73 m2 and whose renal biopsies had at least 20 glomeruli available for study. These patients, ages 17 to 55 years, had IDDM for 7 to 32 (20 +/- 6, means +/- SD) years. CCr ranged from 47 to 139 (91 +/- 25) ml/min/1.73 m2 and urinary albumin excretion (UAE) from 5 to 3386 (median = 127) mg/24 hrs. Eighteen patients were hypertensive. Thus, these patients represented a broad clinical range from normal renal function through overt diabetic nephropathy. The percent of glomeruli which were globally sclerosed was strongly correlated with CCr (r = -0.64, P less than 0.0001) and log UAE (r = +0.67, P less than 0.001). Hypertension was more common in patients with more than 10% sclerosed glomeruli (chi square = 9.5, P less than 0.002). Percent sclerosed glomeruli was highly significantly correlated with the index of severity of the arteriolar hyalinosis lesion (r = +0.66, P less than 0.0001) and mesangial volume fraction (r = +0.61, P less than 0.0001). We hypothesize that arteriolar hyalinosis could contribute to global glomerular sclerosis through severe compromise of glomerular blood flow. Alternately, global glomerular sclerosis may result from marked mesangial expansion and capillary occlusion. However, in this broad range of patients it appeared that global glomerular sclerosis and mesangial expansion were not infrequently independent diabetic renal lesions which could contribute separately to the ultimate development of overt diabetic nephropathy.

Adolescent↗
PubMed1991

An overview of role of matrix components.

The glomerular filtration barrier consists of complex matrix constituents interposed between the glomerular endothelial and epithelial cells, which constitute the lining of the glomerular capillaries. The matrix components include collagen and noncollagenous molecules such as laminin and proteoglycans. This review describes herein the metabolic consequences of diabetes mellitus to which increased permeability of the filtration barrier may be attributed by altering matrix molecules.

Animals↗
PubMed1991

Hypertension and diabetic renal disease.

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.

Animals↗
PubMed1991

Diabetic nephropathy: a disease causing and complicated by hypertension.

In examining the pathophysiology underlying the development of hypertension in diabetes mellitus, it is important to draw clear distinctions between Type I and Type II diabetes. In patients with Type I diabetes, with a peak onset of disease early in the second decade of life, hypertension clearly represents the sequelae to the development of substantial renal lesions, especially in the glomerulus. Thus the prevalence of hypertension in those patients without substantial glomerular lesions approximates the incidence of hypertension in the general population (approximately 4%). In patients with Type II diabetes mellitus and onset generally later in adult life, an increase in blood pressure can often be demonstrated early after or even before diagnosis of the disease (most readily demonstrated in the Pima Indians). Furthermore, clear familial tendencies towards the development of nephropathic complications of diabetes can be shown. In patients with Type I disease, the fall in glomerular filtration rate parallels the fall in glomerular capillary surface available for filtration. This reduction in the peripheral glomerular capillary surface correlates well with the expansion of the mesangium, strongly implicating the mesangial expansion in the demise in renal function. For both Type I and Type II diabetes mellitus, the increase in albuminuria may reflect an opening of large pores in the glomerular basement membrane, thereby allowing serum proteins to cross into the filtration space.

Albuminuria↗
PubMed1990

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)

Albuminuria↗
PubMed1990

Studies of renal autoregulation in pancreatectomized and streptozotocin diabetic rats.

We studied renal autoregulation in pancreatectomized Munich-Wistar diabetic rats and in their sham-operated controls. In a second experiment we studied renal autoregulation in untreated and insulin treated streptozotocin diabetic Munich-Wistar rats and their nondiabetic controls. In the first experiment the diabetic rats had higher baseline renal blood flows (RBF). There was a fall in renal vascular resistance (RVR) and sustained RBF in both diabetic and control rats as renal perfusion pressures (RPP) was reduced from 130 and 110 mm Hg. As RPP was reduced from 110 and 80 mm Hg, there was no significant Change in RVR in control rats and RBF began to fall. Below RPP of 80 mm Hg RVR rose and RBF fell sharply in these rats. In contrast, there was a progressive fall in RVR as RPP was lowered to 60 mm Hg in the diabetic rats and, thus, RBF was much better sustained in these animals. In the second experiment the plasma glucose level was 502 +/- 52 mg/dl (X +/- SD) in the untreated diabetic rats and only modestly reduced to 411 +/- 49 mg/dl in the insulin treated animals. Untreated streptozotocin diabetic rats had moderately reduced and insulin-treated diabetic rats had mildly reduced baseline RVR and RBF. However, in these animals as in the pancreatectomized rats the increases in RVR noted in control rats at subautoregulatory RPPs were not seen. Thus, regardless of whether baseline RBFs were increased or decreased, diabetic rats sustained RBF at markedly reduced RPPs far more efficiently than did nondiabetic rats. The pathogenesis of these abnormalities in diabetic rats was not learned in these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.

The microvascular complications of diabetes mellitus may be caused, in part, by poor glycemic control. Diabetic patients who have received renal allografts may have new glomerular lesions that are manifested structurally by increases in mesangial and glomerular volume. Successful pancreas transplantation produces long-term normoglycemia and provides a unique opportunity to evaluate the impact of the normalization of the blood glucose level on the development of the renal lesions typical of diabetes mellitus in transplanted kidneys. We obtained biopsy specimens from the functioning renal allografts of 12 patients with insulin-dependent (Type I) diabetes before successful pancreas transplantation (performed one to seven years after renal transplantation) and repeated the biopsy at least 1.9 years later. In renal biopsy specimens obtained before pancreas transplantation, the mesangial volume was normal or modestly increased and the glomerular basement membrane was moderately thickened. At follow-up, no progression could be detected in any structural measure in the glomerulus. Furthermore, the recipients of pancreas transplants had smaller glomerular volumes than 13 matched diabetic patients who were recipients of renal allografts but who did not undergo pancreas transplantation (mean +/- SD, 1.80 +/- 0.55 vs. 2.47 +/- 0.73 x 10(6) microns 3; P = 0.02) and showed markedly less mesangial expansion (mesangial-volume fraction, 0.19 +/- 0.07 vs. 0.31 +/- 0.10 microns 3 per cubic micrometer; P = 0.004). We conclude that successful pancreas transplantation is associated with significantly less severe diabetic glomerulopathy in kidneys previously transplanted into diabetic patients. These data support the hypothesis that normoglycemia can prevent the progression of diabetic glomerulopathy in humans.

Adult↗
PubMed1989

Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria.

Since several studies have suggested that a slight increase in urinary albumin excretion (microalbuminuria) is predictive of nephropathy in patients with diabetes mellitus, we studied the relation of albumin excretion to renal structure in patients with insulin-dependent (Type I) diabetes. Renal biopsy specimens were evaluated with light- and electron-microscopical morphometric techniques in 48 patients who had had diabetes for 5 to 40 years and who excreted less than 200 mg of urinary albumin per 24 hours. Patients in Group I (n = 26) had normal urinary albumin excretion, creatinine clearance, and blood pressure; those in Group II (n = 10) had increased urinary albumin excretion but normal creatinine clearance and blood pressure; those in Group III (n = 12) had increased urinary albumin excretion and hypertension, decreased creatinine clearance, or both. Glomerular structure varied similarly, ranging from normal to abnormal in Groups I and II, but was consistently abnormal in Group III. The thickness of the glomerular basement membrane, the fractional volume of the mesangium, and the mesangial volume per glomerulus in Group III exceeded the corresponding values in the other groups significantly. Thus, microalbuminuria, when present with hypertension, decreased creatinine clearance, or both, indicates established abnormalities of glomerular structure. Normal albumin excretion, or microalbuminuria without these other functional abnormalities, does not accurately predict the severity of the underlying glomerular lesions in patients with Type I diabetes.

Adolescent↗