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Biomedical subjects

M W Steffes

Publications and source records attributed to M W Steffes.

At least 109 records · Page 6Linked to original sources
PubMed1983

Diabetic nephropathy. A perspective.

The earliest manifestations of clinical diabetic nephropathy, including proteinuria, hypertension, and declining GFR, represent very advanced diabetic glomerulopathy with especially prominent mesangial expansion. Mesangial expansion, by restricting glomerular capillary filtration surface and lumenal volume, stimulates compensatory mechanisms analogous to those resulting from a marked reduction in nephron number. These compensatory mechanisms involve alterations in glomerular hemodynamics designed to maintain glomerular filtration but which ultimately injure the kidney. These hemodynamic perturbations are not specific to diabetes but represent a final common pathway toward endstage renal failure that also characterizes the remnant kidney. This thesis concludes that the onset of clinical diabetic nephropathy augurs inevitable decline in kidney function, and that only studies and interventions exercised before clinical nephropathy develops can influence understanding and outcome of diabetic nephropathy.

Basement Membrane↗
PubMed1983

Quantitative glomerular morphology of the normal human kidney.

We determined glomerular basement membrane (GBM) width (as the harmonic mean) and relative volumes of the glomerular mesangium and of its cellular and matrix components in 59 male (73% living-related) and 59 female (93% living-related) donors of kidneys for transplantation. The GBM, consistently wider in male (mean, 373 nm.) versus female (mean, 326 nm.) donors, increased in width in all donors until the fourth decade of life when it appeared to decrease in width. The relative volume of the mesangium did not differ as to sex or age (mean, 14.2% of the glomerular volume), nor did either of its components (mean cellular mesangium, 7.1%; mean matrix mesangium, 7.1%). We found no correlations among renal index, GBM width, or the mesangium. No parameter differed in diabetic-related compared with nondiabetic-related donors. Results in cadavers for GBM width and the mesangium were no different from those of living-related donors. These observations yield insights into the development of the human kidney and its glomerular components, and in addition the GBM and mesangial measures will serve as normative values to which surgical or biopsy specimens can be related.

Adolescent↗
PubMed1982

Diabetic glomerulopathy in the uninephrectomized rat resists amelioration following islet transplantation.

Uninephrectomy is known to accelerate the development of both functional and morphological changes seen with experimental diabetic nephropathy in the rat. The present experiments utilized electron and light microscopic morphometric techniques to assess glomerular basement membrane width and the volumes of the total mesangium and its cellular and matrix components of inbred Lewis rats made diabetic at 6 weeks of age and uninephrectomized 9 days later. Immunofluorescent microscopy was used to evaluate IgG and C3 in the mesangium. The reversibility of established diabetic glomerular lesions in uninephrectomized diabetic rats after 7 months of diabetes was studied by performing intraportal transplant of neonatal pancreatic tissue. Renal biopsies were taken 2 months later in transplanted and non-transplanted animals. Islet transplantation lowered plasma glucose to normal levels (29.6 to 7.3 mmol/l) and raised plasma insulin values (6.3 to 53 muU/I). Glomerular basement membrane width in transplanted rats (268 nm) still exceeded the same measure (226 nm) in nondiabetic uninephrectomized rats. In transplanted animals volumes of the mesangium (0.51 x 10(6) micrometers 3) and of its cellular (0.27 x 10(6) micrometers 3) and matrix (0.24 x 10(6) micrometers 3) components remained higher than similar measures in control rats (0.32 x 10(6), 0.17 x 10(6) and 0.15 x 10(6) micrometers 3, respectively). Mesangial IgG in treated animals approached normal, but mesangial C3 remained similar to levels in non-transplanted diabetic control animals. These observations in uninephrectomized-diabetic rats contrast with previous observations in intact diabetic rats in which mesangial volumes and localization of immunoglobulins and complement returned to normal levels following islet transplantation.

Animals↗
PubMed1982

Diabetic nephropathy in the uninephrectomized dog: microscopic lesions after one year.

Carefully age-matched, purebred male beagle dogs that underwent uninephrectomy one month after they were made diabetic with alloxan were used to establish a model of rapidly developing diabetic nephropathy in a large animal. The diabetic animals, all requiring insulin, were divided into two groups: one group with control by insulin injections permitting elevated fasting and postprandial serum glucose values and substantial glycosuria; the other with better control and with near-normal serum glucose levels and less glycosuria. By 1 year of diabetes both diabetic groups had renal lesions different from the uninephrectomized control animals but differing only slightly from one another. With light microscopy, diabetic dogs had increased mesangial thickening. With electron microscopic morphometry, glomeruli of diabetic subjects demonstrated increased fractional volumes of the total mesangium and of its cellular and matrix components and increased width of the GBM. These quantitative measures of diabetic nephropathy in the dog within 1 year of onset of the disease describe a model potentially useful in evaluating the efficacy of improved diabetic control in preventing or ameliorating diabetic nephropathy.

Animals↗
PubMed1982

Islet transplantation in mice differing in the I and S subregions of the H-2 complex. Effects of presensitization with skin allografts.

Pancreatic islets from A.TH mice were transplanted into the spleen of streptozotocin (SZ)-diabetic A.TL mice. The two strains of mice are congenic inbred strains, differing only in the I and S subregions of the H-2 complex. The allogeneic islet grafts decreased blood glucose temporarily, but the islets were rejected after 21 +/- 7 days (mean +/- SD). The effect of skin presensitization was tested by giving both allogeneic and syngeneic skin grafts to each of a second set of A.TL mice before streptozotocin treatment and islet transplantation. The time course of rejection of the allogeneic islets in animals that received initial skin grafts was decreased to 8 +/- 3 days. In both skin-presensitized and non-presensitized mice syngeneic islet grafts were able to restore normoglycaemia, even in animals that had previously rejected an islet allograft. These observations demonstrate that transplantation of pancreatic islet allografts across the I and S subregions of the H-2 complex is sufficient to induce rejection of the islets. The islet rejection was markedly accelerated by prior sensitization with allogeneic skin grafting. It is suggested that elements in allogeneic skin grafts serve as inducers of cytotoxic T-cell responses directed against gene products of the I and/or S subregions present on cells in the allogeneic islets.

Animals↗
PubMed1982

Preservation of mesangium and immunohistochemically defined antigens in glomerular basement membrane isolated by detergent extraction.

To define the characteristics of isolated glomerular basement membrane (GBM), immunohistochemical and morphometric analyses have been carried out on rat and human tissues. Site-specific arrays of antigens were identified in detergent-isolated GBM in a distribution similar to that observed in intact kidney. In the human, fibronectin, procollagen IV, and collagen V were observed along the internal aspect of GBM continuous with antigenic sites in the mesangium. Another array of antigens was identified in the GBM but not within the mesangium--Goodpasture's antigen, bovine lens capsule type IV collagen, and amyloid P component. In addition, sites reactive with rabbit antiserum to laminin were present on both sides of the lamina densa as well as within the mesangial region. Actomyosin, a presumed mesangial cell antigen persisted in the mesangium of isolated GBM. Mesangial matrix was identified in detergent-isolated GBM in an amount equivalent to that present in intact glomeruli. Sonicated GBM contained the same antigens but it was not possible to quantitate the amount of mesangial material by immunofluorescence or morphometric analysis. The thickness of the lamina densa was greater in sonicated and detergent-treated rat GBM preparations than in native rat kidney. These studies demonstrated that isolated GBM is heterogeneous with respect to its antigenic constituents and in addition contains mesangial matrix, which is morphologically and immunohistochemically distinct from peripheral GBM.

Actomyosin↗
PubMed1982

A double balloon catheter technique for alloxan diabetogenesis in the dog.

Venous injection of alloxan monohydrate is a standard method to produce a canine model of diabetes. Others have reported mortalities greater than 45 per cent and yields of diabetic dogs of less than 36 per cent with this technique. In this study, a new method for alloxan diabetogenesis is reported upon: alloxan monohydrate is injected intravenously with protection of the renal arteries at the time of injection by a 7F, triple lumen double balloon catheter placed in the abdominal aorta. The balloons are inflated under fluoroscopic control to occlude the renal arteries at the time of injection. Forty-three age-matched beagle dogs were initially injected with 60 milligrams per kilogram of alloxan monohydrate: 26 or 61 per cent became diabetic-defined as persistently doubled fasting serum glucose and glucosuria; ten failed to become diabetic, 23 per cent, and seven died, 16 per cent. The ten initial failures were reinjected with 65 milligrams per kilogram of alloxan monohydrate: six or 60 per cent then became diabetic, three were persistent failures, 30 per cent, and one dog died, 10 per cent. Thus, the over-all yield of diabetic dogs was 74 per cent, with an 18 per cent mortality. Minimal renal damage occurred, as evidenced by creatinine clearance, blood urea nitrogen and renal biopsy studies. These results suggest a significantly improved method--a twofold improvement over standard success rates with a twofold less mortality--of producing diabetic dogs by alloxan injection.

Alloxan↗
PubMed1981

The kidney in diabetes.

The kidneys as a target organ for secondary microvascular complications of diabetes mellitus represents a health problem of enormous social cost. Recent studies in man and animals strongly support the concept that the primary responsibility for diabetic nephropathy rests with the metabolic derangements of the diabetic state. However, these metabolic derangements have complex biological effects; it is unlikely that hyperglycemia, per se, produces all of the nephropathic influences of diabetes. Alterations in microvascular hemodynamics in diabetes probably contribute to glomerular pathology. These alterations may be based upon disturbed vasoactive control mechanisms regulating angiotensin and prostaglandin secretion and metabolism. Although much remains to be learned about the pathogenesis of glomerular basement membrane and mesangial thickening in diabetes, these central structural abnormalities appear separable. Mesangial thickening is reversible by cure of the diabetic state in rats whereas glomerular basement membrane thickening is not. Treatment for the diabetic patient with end-stage renal failure has recently improved markedly. Although presently, kidney transplants from living related donors appear best, cadaver transplants and long-term hemodialysis are reasonable options.

Basement Membrane↗
PubMed1981

Islet transplantation in mice differing in the I and S subregions of the H-2 complex.

Diabetic A.TL and A.TH mice, congenic inbred strains differing only in the I and S (non-K, non-D) regions of the major histocompatibility (H-2) complex, received intrasplenic allogeneic and isogeneic pancreatic islet transplants. The isografts were uniformly accepted, while approximately 60% of the recipients receiving allografts rejected the islets, most within 4 weeks of transplantation. With either strain the animals accepting the allografts had higher blood glucose values than normal mice or isografted recipients. After a minimum of 13 weeks of nearly normal glucose levels, successfully allografted mice received skin grafts and spleen cells. None of the A.TH recipients rejected the A.TL islets, but two of four A.TL recipients of A.TH islets became diabetic after the skin grafts. These observations suggest a variable response to islet transplanted across this isolated difference of the H-2 complex. Furthermore, allografted islets resisting rejection did not provide normal glucose levels in the recipients.

Animals↗
PubMed1981

A major loss in islet mass and B-cell function precedes hyperglycemia in mice given multiple low doses of streptozotocin.

Streptozotocin (SZ) given in five low doses causes diabetes and an associated lymphocytic infiltration of the pancreatic islets. Using C57BL/KsJ-mice, we demonstrate a reduction in islet number (--38%) and volume (--64%) within 1 day following the last injection of SZ. A substantial fall of insulin secretory capacity (--84%) in the in vitro perfused pancreas matches the reduction in islet cell volume. The parameters of decreased islet function seem to precede the peak of lymphocytic infiltration, occurring 3 days after the last dose of SZ. These functional changes are readily demonstrable before a rise in fasting blood glucose, but they seem to be reflected more readily by a rise in nonfasting blood glucose levels. With development of overt diabetes, as measured by elevated fasting and nonfasting glucose levels, the measures of islet volume and function are reduced to levels only 1--2% of those found in control mice. Taken together, these observations reflect a rapid, islet-toxic effect of SZ that substantially decreases insulin secretory capacity. When islet function falls more than 90%, blood glucose levels begin to reflect the pathophysiologic process. In many aspects, the low-dose SZ model of diabetes parallels the development of diabetes in man. If so, measures other than blood sugar must be developed to identify at an early stage processes reducing islet volume and function.

Animals↗
PubMed1981

Factitious hypophosphatemia related to mannitol therapy.

We observed factitious hypophosphatemia in a patient who was receiving large amounts of intravenous mannitol. Mannitol concentrations as low as 25 mmol/L inhibited phosphorus measurement by the Dupont aca endpoint method; a kinetic method was unaffected. The mechanism of the mannitol interference was binding to molybdate in the reaction, decreasing both the rate of color development and the endpoint measurement. We conclude that the molybdate concentration in the DuPont method is suboptimal for measuring phosphorus in specimens containing mannitol.

Brain Edema↗
PubMed1980

Urine C-peptide, beta-cell function, and insulin requirement.

Urinary C-peptide excretion was investigated as a method for monitoring beta-cell function in diabetic patients and for studying the contribution of endogenous insulin production to diabetic control. Control subjects had variations in serum and urine C-peptide immunoreactivity that correlated with basal and meal-related insulin secretion. In a group of well-controlled juvenile diabetic patients, those receiving high doses of insulin had low or negligible C-peptide excretion, whereas most patients with low exogenous insulin requirements had near-normal urinary C-peptide excretion. Patients treated for diabetic ketoacidosis had recovery of beta-cell function as measured by C-peptide immunoreactivity in serial urine specimens. Thus, measurement of urinary C-peptide excretion is a simple technique that may be useful in assessing endogenous insulin production in juvenile diabetic patients.

Adolescent↗