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Biomedical subjects

M C Gubler

Publications and source records attributed to M C Gubler.

At least 19 recordsLinked to original sources
PubMed1992

Alport syndrome: a genetic study of 31 families.

Thirty one families with Alport syndrome including 3 families with associated syndromes were studied. The location of the COL4A5 gene, responsible for the Alport syndrome, was determined by linkage analysis with eight probes of the Xq arm and by a radiation hybrid panel. Concordant data indicated the localization of the Alport gene between DXS17 and DXS11. Four deletions and one single base mutation of the COL4A5 gene were detected. Homogeneity tests failed to show any evidence of genetic heterogeneity superimposed on clinical heterogeneity for ophthalmic signs and end-stage renal disease age.

Adolescent↗
PubMed1992

Effects of epidermal growth factor on calf renal glomerular cells in vitro.

Epidermal growth factor (EGF) stimulates the mitosis and differentiation of a variety of cellular types. It also delays the cell senescence in vitro. Because of its multiple functions, the effects of EGF on cells from isolated, explanted calf renal glomeruli have been studied. The cell types emerging from glomeruli cultured with and without EGF were compared and identified by morphological, immunofluorescence and electron microscopy criteria. Two cell types: visceral epithelial cells or podocytes (type I) and mesangial cells (type II) emerged from glomeruli cultivated without EGF. A third cell type, called type III cells, appeared only in the presence of EGF. These cells divided, were mobile and had prolonged lifespan in culture. They appeared pavement-like, and acquired progressively the morphological features and cytoskeletal components of type I cells. They also showed certain characteristics of podocytes in vivo. We suggest that type III epithelial-like cells are precursor cells of podocytes, that EGF triggers their emergence from glomeruli and their subsequent proliferation and differentiation in vitro. EGF also prolongs their lifetime in culture.

Animals↗
PubMed1992

Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.

A large kindred with adult-type X-linked Alport syndrome was studied with regard to a defect in the recently described COL4A5 collagen gene. Southern blot analysis with COL4A5 cDNA probes showed loss of a MspI restriction site. Direct sequencing of cDNA amplified from lymphoblast mRNA demonstrated a single-base substitution converting a glycine codon to arginine at position 325 in the alpha 5 chain of type IV collagen. The triple-helical collagenous domain of alpha 5(IV), characterized by a Gly-X-Y repeat sequence, is interrupted 22 times by noncollagenous sequences. The mutation creates an additional interruption in the Gly-X-Y repeat motif, between interruptions 4 and 5. It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of osteogenesis imperfecta. This gly325-to-arg substitution presumably alters the triple-helix formation, and, in turn, modifies the ultrastructural and functional characteristics of the type IV collagen network inside the glomerular basement membrane.

Adult↗
PubMed1992

Changes in thickness and anionic sites of the glomerular basement membrane after subtotal nephrectomy in the rat.

Rats progressively develop proteinuria and glomerular sclerosis with age. These physiologic and histologic changes are accelerated by subtotal renal mass ablation. Alterations in the glomerular basement membrane (GBM), such as thickening and decreased anionic site density, occur during senescence. This study examines the ultrastructural alterations of the GBM affecting remnant glomeruli. Six week-old male Wistar rats underwent a subtotal nephrectomy (70%) and were compared with sham operated rats. Rats were fed a standard diet, and physiologic measurements were performed every 3 weeks. Rats were killed 6 and 12 weeks after surgery. Anionic sites were labeled by polyethyleneimine perfusion before killing. Kidneys were processed for light and electron microscopy. Nephrectomized rats had higher protein-uria than the controls and developed glomerular sclerosis. The GBM of nephrectomized rats were significantly thinner and anionic sites were less numerous 12 weeks after nephrectomy, especially in the lamina densa (LD) of the GBM. The number and distribution of anionic sites were similar to those observed in sham operated rats killed 6 weeks after surgery. These results indicate that glomerular sclerosis and GBM thickening are unrelated phenomena. They also suggest that the number and density of anionic sites in LD are not a prominent factor for increasing proteinuria after subtotal nephrectomy.

Aging↗
PubMed1991

[Renal artery pathology and its therapeutic indications in the child].

Between September 1955 and January 1990, 94 pediatric patients were managed for renovascular hypertension caused by renal artery occlusive disease. Patients (50 boys and 44 girls) were aged 4 days to 17 years (median age: 7 years). At initial evaluation, 34 patients had symptoms of hypertensive encephalopathy or acute heart failure, 36 had moderate symptoms, and 24 were symptom-free. Sixty-five cases were classified on the basis of clinical, radiological, and histological features, as follows: neurofibromatosis (17), fibromuscular dysplasia (11), diffuse arterial calcified elastopathy (11), renal artery thrombosis (10), Williams syndrome (4), Takayashu disease (3), and miscellaneous diseases (9). In the 29 remaining patients, classification was based only on radiological features: causes included unilateral renal artery stenosis (15), bilateral renal artery stenosis with or without aortic stenosis (11), and miscellaneous disorders (3). Surgical treatment consisted in 47 renal revascularization, procedures (14 aortorenal bypasses, 8 aortorenal reimplantations, 9 anastomoses in the upper mesenteric arterial system, 7 autotransplantations, 4 resection-reanastomosis procedures, and 5 miscellaneous procedures). Renal revascularization failed in 15 cases (32%) (because of thrombosis in 14 cases and dehiscence in one). Residual or recurrent stenosis was seen in 7 arteries, whereas the anatomic result was satisfactory in 25 arteries (53%). Blood pressures returned to normal in 16 of 40 (40%) patients successfully treated by revascularization. An additional 25 patients recovered normal blood pressure values after primary nephrectomy (21), partial nephrectomy (4) or nephrectomy after failed renal revascularization.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Immunogold studies of monomeric elements from the globular domain (NC1) of type IV collagen in renal basement membranes during experimental diabetes in the rat.

The protein A-gold immunocytochemical technique was applied to reveal the monomeric elements M1, M2* and M3 from the non-collagenous globular domain (NC1) of type IV collagen over various renal basement membranes from control and long-term streptozotocin-induced diabetic rats. This study includes the basement membranes of the proximal tubule, the Bowman's capsule and the glomerulus as well as the extracellular matrix of the mesangium. The labellings obtained were confined to basement membrane material. The quantitative analysis demonstrated changes in labelling intensities and distribution between tissues from normal and diabetic animals. Increased labelling intensities were observed for M1 and M2* monomers in all the basement membranes studied except for the mesangial matrix which remained unchanged. In addition, the labelling for M1 monomers, present on the endothelial side of the glomerular basement membrane of control animals, was found to be distributed throughout the entire thickness of the basement membrane of diabetic animals. In contrast, neither the intensity of the labelling, nor the distribution of M3 monomers were altered in diabetic animals. Since M1 monomers are markers of the alpha 1(IV) and alpha 2(IV) chains of type IV collagen while M2* and M3 mark alpha 3(IV) and alpha 4(IV) chains respectively, the present results demonstrate changes in the nature of the collagenous elements of basement membranes during diabetes. Furthermore, the results indicate that the alpha 3(IV) and the alpha 4(IV) chains are not necessarily present in the same molecule. The modifications of the collagenous elements of the basement membranes during diabetes must alter the structural characteristics of these matrices which in turn might influence their functional properties.

Animals↗
PubMed1990

Renal amyloidosis in juvenile chronic arthritis: evolution after chlorambucil treatment.

Over a 22-year period, eight patients affected with severe systemic or polyarticular juvenile chronic arthritis (JCA) developed systemic amyloidosis with nephrotic syndrome. They were treated with chlorambucil over 5-192 months (mean = 44 months). With treatment, an abrupt decrease in the severity of JCA was observed in six patients but two patients were chlorambucil resistant. After a mean follow-up period of 10 years from onset of renal symptoms, one chlorambucil-resistant patient died of end-stage renal failure; two patients have a persistent nephrotic syndrome; and five patients are free from proteinuria, of whom one has developed hypertension. A good correlation was observed between the response of the rheumatic disease to chlorambucil treatment and the clinical course of renal symptoms. Fourteen renal biopsies were performed in these eight patients. In all, amyloid deposits were of the AA type, which persisted on repeat biopsies. In addition, 15%-60% of glomeruli had become globally sclerotic by the second or third biopsies. At the ultrastructural level, modifications in the structure of amyloid deposits and reparative changes of the glomeruli, characterized by partial restoration of glomerular architecture, were observed in three patients with a favourable clinical course.

Amyloidosis↗
PubMed1990

Heterogeneous distribution of monomeric elements from the globular domain (NC1) of type IV collagen in renal basement membranes as revealed by high resolution quantitative immunocytochemistry.

Heterogeneity in the distribution of major components, namely laminin, entactin/nidogen, heparan sulfate proteoglycan and type IV collagen among renal basement membranes, was previously demonstrated (Desjardins and Bendayan, J Histochem Cytochem 37:885-897, 1989). To further investigate the nature of basement membranes, we applied high resolution immunocytochemistry to reveal monomers M1, M2* and M3 composing the NC1 domain of type IV collagen of various rat renal basement membranes. Labeling for the three monomers was confined to basement membranes. Quantitative morphometrical analysis demonstrated that the labeling for each monomer was not evenly distributed among the various basement membranes. Labeling for M1 was intense over the proximal tubule and the Bowman's capsule basement membranes. In the glomerulus, the mesangial matrix was highly labeled, whereas the glomerular basement membrane was labeled with a lower intensity. In contrast, labeling for M2* and M3 were high in the glomerular basement membrane, while very low in the mesangial matrix. Labeling intensities were intermediate in the other renal basement membranes. The ultrastructural distribution analysis made over the glomerular basement membrane showed a preferential subendothelial localization of M1 monomers. M2 and M3 on the other hand, were found throughout the entire thickness of the basement membrane. M1 monomers being associated to alpha 1(IV) and alpha 2(IV) chains of type IV collagen, and M2* and M3 to alpha 3(IV) and alpha 4(IV) chains respectively, our results thus demonstrate the existence of an heterogeneity in the collagenous nature of renal basement membranes, particularly the glomerular one. This heterogeneity must reflect variations in the structural arrangement of basement membranes and therefore in their functional properties.

Animals↗
PubMed1990

[Congenital or childhood nephrotic syndrome with diffuse mesangial sclerosis].

Diffuse mesangial sclerosis (DMS) has been described as a distinct morphological pattern observed in patients presenting with a congenital or infantile nephrotic syndrome (NS) leading to end stage renal failure (ESRF) before the age of 3 years (Habib & Bois: Helv. Peadiat. Acta 28: 91-107, 1973). In recent years, we diagnosed this entity in 36 infants and we wish to report our findings which extend our previous observations. The nephropathy was discovered before 1 year of age in 26 patients. In one of these the onset was neonatal. Five additional children were between 1 and 2 years of age at onset of the disease and the remaining 5 were between 24 and 42 months old. Thirty-three patients presented with a NS often preceded by a proteinuria and associated with renal failure in 6 of them. The 3 remaining patients presented with renal failure. Thirty-one patients reached ESRF before the age of 4 years. Progression was slower in 5 patients who were respectively 5, 5, 6, 8 and 11 years old at ESRF. Thirteen patients were transplanted and none recurred their original disease. Seven patients in 4 families had similarly affected siblings. In 16 patients (6 boys and 10 girls) the nephropathy was isolated. In the remaining 20 several associated findings were noted. In 14 infants a diagnosis of Drash syndrome was made on the basis of the association of a male pseudo-hermaphroditism (PsH) and Wilms tumour (WT) in 5, of a male PsH in 5 additional infants and of a WT in 4 female patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1990

[Nail-patella syndrome without extra-renal lesions. A new hereditary glomerular nephropathy].

We observed an unusual glomerular disease in eight pediatric patients. Clinical features of this early, progressive renal disease included increased blood pressure in many cases, extrarenal hematologic and pulmonary symptoms, and, in one of our patients and two genetically related children, hemolytic uremic syndrome with thrombotic microangiopathy resulting in permanent renal failure. Histologic studies showed major and complex modifications of glomerular capillary walls and electron microscopy disclosed numerous bundles of fibrillar collagen within the extracellular glomerular matrix. Clinical and genetic investigations out-ruled hereditary osteo-onychodysplasia, a condition in which fibrillar collagen is found within glomerular basement membranes. In addition results of family studies were consistent with autosomal recessive transmission of this new entity.

Adolescent↗
PubMed1990

Hemolytic uremic syndrome in patients with Behçet's disease treated with cyclosporin A: report of 2 cases.

Hemolytic uremic syndrome (HUS) has been reported in patients treated with cyclosporin A (CsA) following bone, hepatic and kidney transplantation. We report two patients with Behçet's disease (BD) under CsA treatment because of severe uveitis, who developed HUS several months after the initiation of treatment. Renal biopsies showed lesions consistent with the diagnosis of the arterial form of thrombotic microangiopathy: vascular thrombosis with extensive glomerular ischemia. Renal failure persisted after withdrawal of CsA: one patient is in chronic renal failure (CRF) with a 4-year follow-up; the other died after refusal of chronic hemodialysis. In our two patients, excessive doses of CsA with high trough levels are likely to have contributed to the development of HUS. A rapid adjustment of CsA doses and an early detection of signs of the microangiopathic process might have prevented this severe complication of CsA treatment.

Adult↗
PubMed1989

Dark cells of cystinosis: occurrence in renal allografts.

Twenty-four biopsies of renal allografts, generally cadaveric, from 20 patients with cystinosis were examined by light, polarization, phase contrast, and electron microscopy. The unusual dark cells previously reported in the native kidneys and livers of patients with cystinosis were observed in 12 of the 24 biopsies. The cells were present in the interstitium in all of these 12 biopsies, in glomeruli in one biopsy, and in the tubular lumen in two biopsies. They were evident by light and electron microscopy in stained and unstained ultrathin sections, and could be discerned solely in Epon sections. The dark appearance resulted from the presence of dark, fine granular material in the cytoplasm and nucleus and in cytoplasmic inclusions. The cells were judged to be macrophages. They were present as early as 3 months following transplantation and bore no relationship to interstitial crystals or inflammation. The dark cells have two important implications: cystine storage may not be limited to lysosomes, and dark cells are a morphologic alternative to the traditional identifying configuration of cystine in tissues, namely crystals.

Adolescent↗
PubMed1989

Delayed renal failure with extensive mesangiolysis following bone marrow transplantation.

Within two years we have had the opportunity of observing seven leukemic children who were referred to our Pediatric Nephrology Unit for delayed renal failure following bone marrow transplantation (BMT). These children (3 to 12 years old), six with acute lymphoblastic leukemia (ALL) and one with acute non-lymphoblastic leukemia (ANLL), underwent BMT (4 autologous BMT, 3 allogeneic BMT) after the first remission in two, and after the second remission in five. Preparative regimen for BMT included cyclosphosphamide in three, cyclosphosphamide, vepeside and cytosine A in four, and a total body irradiation in a single dose of 10 grays (1000 R) in all of them. Three children were treated immediately after grafting with low dose cyclosporine for four to six months. Five to 10 months after BMT, four patients developed a hemolytic uremic syndrome with severe hypertension. The remaining three were found to have isolated renal insufficiency several months post-BMT. In the seven patients, renal biopsy showed a uniform pattern of severe glomerular involvement characterized by extensive lesions of mesangiolysis associated with severe arteriolonecrosis. A repeat biopsy performed one year later, in two patients showed severe scarring of the renal parenchyma with minor lesions of mesangiolysis. The similarity of the pathologic features observed suggests that the same mechanism might have been operative in the seven patients. It is very likely that the nephropathy is related to total body irradiation enhanced by chemotherapy. We conclude that current treatments of high risk leukemia might become a new cause of chronic renal failure. Further investigations are needed to know the exact incidence of this complication.

Bone Marrow Transplantation↗
PubMed1989

Inherited defects of renal basement membranes.

For 15 to 20 years, electron microscopy studies have shown that some hereditary renal diseases are characterized by various abnormalities of the basement membranes. In the nail-patella syndrome, in Alport's syndrome and variants, and in benign familial hematuria, the changes involve the glomerular basement membrane (GBM). In nephronophthisis, the tubular basement membrane (TBM) is affected. These histopathologic features are not uniform. The progress afforded by biochemistry, immunology, and molecular biology allows us to compare these various lesions, to analyze their biochemical characteristics and their antigenicity, and to hypothesize as to the mechanisms involved.

Anemia↗
PubMed1989

Renal allografts in cystinosis and mesangial demography.

Twenty-four biopsies of generally cadaveric renal allografts from 20 patients with cystinosis were examined by light, polarization, phase contrast and electron microscopy. Cystine crystals, or cytoplasmic crystalline spaces compatible with cystine, were observed in interstitial cells in 23 of the 24 biopsies and in glomeruli in six. Among the six, crystalline spaces were identified by electron microscopy in cells compatible with macrophages in the mesangium in two, and, in one of the latter, dark, presumably cystine-containing cells were also present in the mesangium. On the premise that cystine-containing cells derive from the host, these findings support the thesis that in man cells of the mononuclear phagocyte system of extrarenal origin may exist in the mesangium. However, in comparison with infiltration of the interstitium, infiltration of the glomerulus by macrophages from extrarenal sources is scant, as studied under conditions of renal transplantation.

Adolescent↗
PubMed1988

De novo membranous glomerulonephritis in renal allografts in children.

The incidence of de novo membranous glomerulonephritis (MGN) in transplanted kidneys is around 1 to 2%. In our series, of the 310 grafts that were examined by immunofluorescence microscopy (IF), 29 (9.3%) showed subepithelial IgG deposits, a pattern consistent with the diagnosis of MGN. Transplant biopsy had been performed because of the occurrence of proteinuria in 8 patients (pts), for suspected rejection in 16 and systematically in the remaining 9 who had no proteinuria and a normal renal function. In all cases the lesions were identified by IF and were confirmed by electron microscopy (EM) in 14 pts. Granular deposits of IgG were diffuse in 22 cases and segmental in 7. Sequential specimens were available in 17 pts and showed the persistence or the increase of the IgG deposits in all patients but one in whom they had disappeared. Age at transplantation (Tx) ranged from 2 years 3 months to 16 years. Grafts were from cadaveric donors in 27 pts and from living related donors in 2 pts. In none of the recipients was MGN the nephropathy of the native kidneys. With a follow-up of 18 to 74 months, 6 pts never developed a proteinuria. In the remaining 23, proteinuria developed 1 to 70 months after Tx, associated with a nephrotic syndrome (NS) in 6 pts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗