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Biomedical subjects

R L Vernier

Publications and source records attributed to R L Vernier.

At least 19 recordsLinked to original sources
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

Explantation of mesangial cell 'hillocks': a method for obtaining human mesangial cells in culture.

A simple method is presented for selective cell culture of human mesangial cells using explantation of mesangial cell hillocks. Glomeruli which had been incubated with collagenase were explanted on plastic tissue culture flasks. Three to 6 weeks after explantation, a rapidly growing multilayer of elongated mesangial cells was observed to grow over the previously established monolayer of glomerular epithelial cells, ultimately forming multiple nodular foci of mesangial cells or 'mesangial cell hillocks'. By explanting mesangial cell hillocks selectively, pure mesangial cell cultures were easily obtained. When compared with mesangial cells grown in mixed cultures from glomerular explants, the hillock-derived cells were identical in morphology, growth characteristics, cell markers and synthesis of extracellular matrix. This system provides a simple method for the isolation of human mesangial cells in culture.

Adolescent↗
PubMed1992

Acute serum sickness in normal and C6 deficient rabbits: role of membrane attack complex.

Acute serum sickness was induced in New Zealand White (NZW) and in C6 deficient (C6D) rabbits, to compare the histology, immunofluorescence, especially distribution of poly C9 (MAC), and electron microscopic characteristics of the disease in each strain. Glomerulonephritis and albuminuria of comparable extent occurred in 13/17 NZW and 4/8 C6D rabbits. In NZW rabbits with albuminuria an early intense glomerular infiltration by mononuclear cells was associated with focal small fine granular glomerular basement membrane (GBM) deposits of IgG and BSA and more diffuse and larger deposits of C3 and MAC. After the disappearance of monocytes and decrease in mesangial cell proliferation, development of large subepithelial GBM deposits rich in all immune reactants was observed in NZB rabbits. In C6D rabbits with albuminuria a similar monocytic infiltrate occurred, but no association with IgG and C3 GBM immune deposits was noted. No deposits of MAC and no large subepithelial GBM 'humps' were observed in C6D rabbits. We conclude that the exudative (monocytic) phase of glomerular injury and albuminuria in acute serum sickness nephritis are not dependent upon terminal complement components, but the subsequent formation of large subepithelial GBM deposits does not occur in this model in the absence of MAC.

Albuminuria↗
PubMed1979

Immunofluorescence studies of dense deposit disease. The presence of railroad tracks and mesangial rings.

Immunopathologic analysis was carried out on renal tissue from patients with membranoproliferative glomerulonephritis, nine with type I and nine with type II (dense deposit disease). A specific finding in all patients with type II, but not type I, was the presence of C3 along the margin but not within the central portion of dense deposit material in the glomerular basement membrane giving a double linear appearance (railroad tracks); C3 was also present within the mesangium, outlining numerous circular structures (mesangial rings). By phase contrast, electron microscopy, and dual label fluorescence studies, the railroad tracks and mesangial rings were shown to outline dense deposit material. Mesangial rings contained properdin (four of nine patients); railroad tracks contained properdin (five of nine patients) and C4 (four of nine patients); no other complement components or immunoglobulins were present. Studies using rhodamine-conjugated rabbit antibody to human glomerular basement membrane demonstrated no reactivity with the dense deposit material itself. In type I and to a lesser extent in type II, granular deposits of C3, C4, properdin, IgM, and IgG were present along the glomerular basement membrane, suggesting that immune complexes play a role in both diseases. Dense deposit transformation of the glomerular basement membrane may be a consequence of a highly specific injury.

Autoantibodies↗
PubMed1979

Tamm-Horsfall glycoprotein: ultrastructural immunoperoxidase localization in rat kidney.

Tamm-Horsfall urinary glycoprotein (TH) is the primary constituent of urinary casts. The intracellular distribution of TH in normal rat kidney was determined by immunoelectron microscopy using horseradish peroxidase-labeled antibodies and compared with morphologic localization of TH by immunofluorescence and light immunoperoxidase microscopy. Electron microscopy revealed an intracellular localization of TH restricted to the thick ascending limb of the loop of Henle (ALH). In this nephron segment, TH was distributed on and between adjacent intercellular membranes and infolding intracellular membranes at the base of these cells, within Golgi vacuoles, apical vesicles, and on the luminal membranes. Macula densa cells were negative, although typical ALH cells across the lumen of the same tubular segment were positive. Other renal segments were negative for intracellular TH. The unique distribution of TH is consistent with the known function of the ALH as the diluting segment of the nephron. We speculate that the aggregation and gel formation of TH on and between ALH surface membranes may restrict water movement across the ALH. This influence on permeability would be an important role for TH in the generation of concentration gradients for the countercurrent multiplier system of the kidney.

Animals↗
PubMed1978

Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens. V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis.

In heterologous immune complex glomerulonephritis glomerular deposition of immune complexes occurs immediately after an injection with heterologous antibody directed against antigen, derived from the brush border of the tubules. The injected antibody is thought to combine with circulating Fx1A antigen to form immune complexes which subsequently are deposited in the glomeruli. However, perfusion of rat kidneys in absence of this antigen likewise resulted in prompt localization of immune complexes along the glomerular basement membrane. Further, Fx1A antigen was shown to be present in the capillary wall, especially in the filtration slits and on the cell membrane of epithelial cells. From these findings it was concluded that in this model of glomerulonephritis the deposited immune complexes are formed locally instead of being deposited from the circulation. This concept of "fixed antigen" may also be relevant to the pathogenesis of other forms of experimental glomerulonephritis and probably also for human glomerulonephritis.

Antigen-Antibody Complex↗
PubMed1978

Tamm-Horsfall protein. Abnormal localization in renal disease.

Interstitial deposits of periodic acid-Schiff positive fibrillar material have been detected in a variety of diseases associated with tubulointerstitial pathology. This material has been shown to be Tamm-Horsfall protein by immunofluorescent, immunochemical, and electron microscopic studies. Prospective evaluation of 133 kidneys revealed deposits in 11 per cent. These deposits included medullary cystic disease (50 per cent), obstructive uropathy and vesicoureteral reflux (21 per cent), and tubulointerstitial disease (29 per cent). Tamm-Horsfall protein was also detected in Bowman's space in four cases of obstructive uropathy. It is proposed that these deposits result from severe tubular damage with release of Tamm-Horsfall protein from its normal intracellular and intralumenal locations into the renal interstitium. We speculate that the intersitial deposition of this sequestered protein may result in a continued inflammatory response and progressive renal damage.

Fluorescent Antibody Technique↗
PubMed1977

Systemic lupus erythematosus within the first two decades of life.

Forty-nine patients with systemic lupus erythematosus (SLE) during childhood and adolescence presenting over a period of 17 years were followed during treatment with prednisone and azathioprine. The average period of follow-up was 5.7 years. Detailed analyses of clinical parameters of renal function and sequential changes in glomerular abnormalities by percutaneous renal biopsy are reported. Therapy was directed towards normalizing the results of urinalysis and renal function, eliminating proteinuria and maintaining normal serology (normal serum complement and negative antiDNA titers). The 10 year survival of the entire group was 86 per cent. A survival of 73 per cent and 87 per cent over this interval in patients with diffuse and focal proliferative lupus nephritis, respectively, was achieved. The major cause of mortality in this series was infection. It appears that intensive observation and monitoring of serologic parameters in SLE, along with aggressive steroid and immunosuppressive therapy, lead to a prognosis in SLE more favorable than previously reported.

Adolescent↗
PubMed1977

The association of familial liver disease, subepidermal immunoproteins, and membranoproliferative glomerulonephritis.

Herein we report a new familial form of hepatic disease. Each of the four patients had splenomegaly, hypersplenism, a small liver, biochemical evidence of hepatic excretory dysfunction and hepatocellular damage, kidneys without demonstrable cysts, and normal blood pressue. An evaluation of serum immunoproteins, autoantibodies, histocompatibility antigens, and mixed lymphocyte reactivity further defined the immunologic features of this syndrome. Extrahepatic manifestations included a papulosquamous dermatitis with deposition of immunoglobulins and complement in both normal and abnormal skin, a membranoproliferative glomerulonephritis with subendothelial deposits, arthritis, and pericardial, pleural, and synovial effusions.

Adolescent↗
PubMed1977

Postpubertal evaluation of gonadal function following cyclophosphamide therapy before and during puberty.

Evaluation of pituitary gonadotropins, gonadal steroids, spermatogenesis, and menstrual function was undertaken in 32 patients (19 males and 13 females) treated with cyclophosphamide because of nephrotic syndrome. Patients were treated before, during, or after puberty. Evaluations took place after or in very late puberty. Spermatogenic dysfunction occurred in six of 15 boys who received the entire course before and during puberty and was probably dose related. Menstrual dysfunction did not occur following treatment of six prepubertal or pubertal girls, though only low total doses were used. Therapy after puberty was associated with spermatogenic dysfunction in all four boys, but did not cause menstrual dysfunction in any of seven women. Tentative guidelines are suggested that many minimize gonadal toxicity when cyclophosphamide is used in children with nephrotic syndrome. Factors of particular importance in the interpretation of gonadotropin determinations and of sperm counts in young cyclophosphamide-treated patients are discussed.

Cyclophosphamide↗
PubMed1976

Development of diabetic vascular lesions in normal kidneys transplanted into patients with diabetes mellitus.

We examined renal-transplant tissue from 12 diabetic and 28 nondiabetic patients who had had a renal graft for at least two years. In 10 diabetic patients arteriolar hyalinosis lesions developed in the graft. In six these lesions involved both afferent and efferent limbs of glomerular arterioles - a pathological finding virtually diagnostic of diabetes mellitus. In all cases these lesions were present within five years of transplantation. Only three of the 28 nondiabetic patients had hyaline vascular changes (P less than 0.001), which occurred only in rare vessels, did not appear within the first five years after transplantation and did not involve both afferent and efferent arterioles, One diabetic patient had nodular glomerulosclerosis. Thus, the first clearly distinguishable lesion of diabetes to occur with frequency in normal kidneys transplanted into diabetic patients is arteriolar hyalinosis.

Adolescent↗
PubMed1976

Natural remission of nephrotic syndrome in a dog with immune-complex glomerular disease.

A nephrotic syndrome caused by immune-complex glomerular disease was diagnosed in a 4-year-old male Great Dane. The syndrome was characterized by proteinuria, hypoproteinemia, hypoalbuminemia, hypercholesterolemia, and subcutaneous edema. Renal biopsy revealed segmental membranous glomerular disease. The edema underwent complete remission 18 days after admission. Two months after admission, there was no clinical or laboratory evidence of glomerular disease. Periodic reevaluation of the dog during the next 2 years revealed recurrence of proteinuria, but no other clinical or laboratory abnormalities. Serial renal biopsies revealed persistence, but no appreciable increase, in the severity of the segmental membranous glomerular disease. The natural course of the nephrotic syndrome and immune-complex glomerular disease has been associated with unpredictable variability. It was concluded that the widespread use of corticosteroid or immunosuppressant therapy in dogs with immune complex glomerular disease should be withheld until the natural course of the disease has been evaluated in a significant number of patients and until the results of well-controlled clinical studies confirm or deny their therapeutic value.

Animals↗
PubMed1976

Recurrence of membranoproliferative glomerulonephritis following kidney transplantation. Serum complement component studies.

Sixteen patients with membranoproliferative glomerulonephritis who required kidney transplantation because of renal failure were evaluated for evidence of recurrence of the original disease by serologic and morphologic studies. Of the 12 patients with transplant tissue available for study, seven showed membranoproliferative glomerulonephritis by light morphology. Four of these seven also had hypocomplementemia, and this hypocomplementemia was characterized by decreased serum CH50, C3 beta1A or C3-C9 but norma serum C1, C4 and C2 by hemolytic assay. Immunofluorescent microscopy demonstrated more intense glomerular deposition of C3 and properdin in the hypocomplementemic patients. Ultrastructural studies demonstrated intramembranous deposits typical of dense deposit disease in one patient who also had marked hypocomplementemia. One patient who had two transplant biopsies and persistent hypocomplementemia showed progression from predominantly mesangial glomerular changes to both capillary wall and mesangial abnormalities. This study has shown a high rate of recurrence of membranoproliferative glomerulonephritis in the transplanted kidneys. A high death rate was noted in persistently hypocomplementemic patients. The serum C profile in hypcomplementemic patients who received translants was similar to that seen before transplantation, but the signficance of this finding remains unknown.

Adolescent↗
PubMed1976

Extramembranous glomerulonephritis in childhood: relationship to systemic lupus erythematosus.

Extramembranous glomerulonephritis is an uncommon but distinct pathologic lesion in children. The diagnosis is established by the characteristic light, immunofluorescent, and ultrastructural abnormalities in renal biopsy specimens. This report describes seven of the ten children with this lesion studied in the past 11 years. Emphasis is given to the comparison of four children with idiopathic membranous glomerulonephritis with three others who presented with a nephrotic syndrome but subsequently developed evidence of systemic lupus erythematosus. Two of the latter three children, and three others with SLE and MGN not described in detail, demonstrated deposition of IgA by immunofluorescence along glomerular capillaries. Five of six children with SLE and MGN had microtubular structures in glomerular endothelial cells demonstrable by electron microscopy. These observations suggest that children with MGN require careful and continuing study for evidence of SLE.

Adolescent↗
PubMed1976

The glomerular mesangium: uptake and transport of intravenously injected colloidal carbon in rats.

Collodial carbon, 70 mg/100 g, was injected into rats which were sacificed for histologic study of the kidneys at intervals of five minutes to seven weeks. Transient thrombocytopenia and albuminuria were observed. Uptake of carbon by the mesangium of glomeruli was maximal at 32 hr and gradually decreased thereafter. Semiquantitative analysis of the distribution of carbon particles within glomeruli revealed a predominately peripheral localization during early time periods, and increased relative concentration of particles within more central zones and in the lacis area at the vascular pole of the glomerulus at two to seven weeks, indicating that one of the mechanisms for clearance of materials from the mesangium was movement of particles in the direction of the lacis area. Sequential electron microscopic studies showed that carbon particles moved through fenestrae in the endothelium covering the mesangium into channels between mesangial cells. Observations at later intervals suggested that carbon eventually reached the vascular pole by being passed on from one mesangial cell to the next. Vasoactive amines or other substances derived from platelets may play an important role in initiating the process of mesangial uptake.

Albuminuria↗