Juvenile renal disease in the Doberman Pinscher: Ultrastructural changes of the glomerular basement membrane

Background: There is an increasing appreciation that variants of the COL4A genes may be associated with the development of focal segmental glomerulosclerosis (FSGS). On electron microscopy, such variants may produce characteristic changes within the glomerular basement membrane (GBM). These changes may be missed if glomerular lesions histologically diagnosed as FSGS on light microscopy are not subjected to electron microscopy. Methods: We conducted a retrospective cohort analysis of all patients presenting to two hospitals who received a primary histological diagnosis of FSGS to see if these samples underwent subsequent electron microscopy. Each such sample was also scrutinised for the presence of characteristic changes of an underlying type IV collagen disorder Results: A total of 43 patients were identified. Of these, only 30 underwent electron microscopy. In two samples there were histological changes detected that might have suggested the underlying presence of a type IV collagen disorder. Around one in three biopsy samples that had a histological diagnosis of FSGS were not subjected to electron microscopy. Conclusion: Renal biopsy samples that have a histological diagnosis of primary FSGS not subjected to subsequent electron microscopy may potentially miss ultrastructural changes in the GBM that could signify an underlying type IV collagen disorder as the patient’s underlying disease process. This could potentially affect both them and their families’ investigative and management decisions given potential for implications for transplant, heritability and different disease pathogenesis. This represents a gap in care which should be reflected upon and rectified via iterative standard care and unit-level quality assurance initiatives.

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Danaparoid sodium lowers proteinuria in diabetic nephropathy.

Journal of the American Society of Nephrology ◽

10.1681/asn.v83456 ◽

1997 ◽

Vol 8 (3) ◽

pp. 456-462 ◽

Cited By ~ 4

Author(s):

J W van der Pijl ◽

F J van der Woude ◽

P H Geelhoed-Duijvestijn ◽

M Frölich ◽

F J van der Meer ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Side Effects ◽

Basement Membrane ◽

Renal Disease ◽

Heparan Sulfate ◽

Crossover Study ◽

Glomerular Basement Membrane ◽

Diabetic Patients ◽

Danaparoid Sodium ◽

Urinary Creatinine

Diabetic nephropathy is a progressive renal disease with thickening of the glomerular basement membrane and mesangial expansion and proliferation as histological hallmarks. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in diabetic nephropathy proportionally to the degree of proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate. The study presented here involved performing a randomized placebo-controlled crossover study with danaparoid sodium in diabetic patients with overt proteinuria. The aim of the study was to evaluate the effect on proteinuria and safety/tolerability. Nine patients completed the study, without major side effects; the crossover study consisted of two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once-daily or placebo. Following danaparoid sodium, significant declines of both albuminuria and proteinuria were found. After danaparoid sodium, the albumin excretion ratio standardized for urinary creatinine reduced with 17% in comparison with an increase of 23% after placebo (95% confidence interval of the difference,-75.9-3.9%; P = 0.03). The percentage change of the urinary protein excretion corrected for urinary creatinine differed at 8 wk significantly between both treatment arms (P = 0.001). Additional parameters for safety as hematological, hemostasis, biochemical parameters, and fundusphotography did not show any clinically significant difference for both groups. Only two patients had minor skin hematomas at the injection site while using danaparoid sodium. In conclusion, the supplementation was found to be feasible and was not associated with side effects. A significant decline of proteinuria was found. More prospective dose-finding and long-term studies must be performed to see whether danaparoid sodium could not only induce a reduction of proteinuria but also halt the progression of renal disease.

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Thin glomerular basement membrane nephropathy and other collagenopathies

10.1093/med/9780199592548.003.0325_update_001 ◽

2018 ◽

Author(s):

Laurence Heidet ◽

Bertrand Knebelmann ◽

Marie Claire Gubler

Keyword(s):

Basement Membrane ◽

Renal Disease ◽

Renal Biopsy ◽

Glomerular Basement Membrane ◽

Alport Syndrome ◽

Autosomal Dominant ◽

Increased Risk ◽

Autosomal Dominant Fashion ◽

Nail Patella Syndrome

The discovery of a thin glomerular basement membrane in a renal biopsy without any other abnormalities can be explained in a number of ways. This could be an early biopsy in a patient with Alport syndrome, or it could be an individual who is a carrier for an Alport gene. These carriers are at increased risk of significant renal disease in their lifetime and some have proteinuria as well as haematuria, so they can no longer be equated with the historic label of benign familial haematuria. Some families with a thin glomerular basement membrane and haematuria inherited in an autosomal dominant fashion do not appear to have linkage to COL4 genes. Others have variable renal disease that has sometimes given rise to a label of mild but autosomal dominant Alport syndrome. This territory might also attract the label basement membrane 345 collagenopathy. Other uncommon conditions affecting the glomerular basement membrane include nail patella syndrome.

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Relationship of Proteinuria to Glomerular Basement Membrane Deposits in Serum-Sickness Glomerulonephritis in Rabbits

Veterinary Pathology ◽

10.1177/030098587701400508 ◽

1977 ◽

Vol 14 (5) ◽

pp. 482-489 ◽

Cited By ~ 1

Author(s):

J. R. Easley ◽

W. H. Halliwell

Keyword(s):

Electron Microscopy ◽

Bovine Serum Albumin ◽

Basement Membrane ◽

Light Microscopy ◽

Glomerular Basement Membrane ◽

Serum Sickness ◽

Ultrastructural Changes ◽

Mesangial Matrix ◽

Foot Process ◽

Relationship Of

Fifteen rabbits were injected with one dose of 250 milligrams per kilogram of bovine serum albumin intravenously to induce acute serum sickness. The kidneys were removed from groups of five rabbits each at 10, 12 and 14 days after injection and examined by light, electron and immunofluorescent microscopy for evidence of immune complex glomerulonephritis. Urine was examined for protein when rabbits died. Glomerulonephritis was found in eight rabbits by light microscopy and in 10 rabbits by electron microscopy. Only one rabbit had positive immunofluorescence for immunologic components and only two rabbits had proteinuria. Hypercellularity was the primary change seen by light microscopy. Ultrastructural changes were numerous and various, and the major changes recognized were irregularity of the glomerular basement membrane, increased mesangial matrix, hypercellularity, endothelial hypertrophy, mesangial deposits, epithelial foot process fusion and mesangial circumferential interposition. Subepithelial humps were seen in only four rabbits; none of these rabbits had proteinuria. We concluded that increased permeability followed the deposition of immune complexes and development of ultrastructural lesions.

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Nephrotic tunnels in glomerular basement membrane as revealed by a new electron microscopic method.

Journal of the American Society of Nephrology ◽

10.1681/asn.v4121965 ◽

1994 ◽

Vol 4 (12) ◽

pp. 1965-1973

Author(s):

Z Ota ◽

K Shikata ◽

K Ota

Keyword(s):

Nephrotic Syndrome ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Three Dimensional ◽

Minimal Change Nephrotic Syndrome ◽

Renal Tissue ◽

Honeycomb Structure ◽

Ultrastructural Changes ◽

Electron Microscopic ◽

Transmission Electron

To clarify the ultrastructure in situ of the normal human glomerular basement membrane and ultrastructural changes of the glomerular basement membrane in patients with nephrotic syndrome, specimens of normal renal tissue and specimens from patients with membranous nephropathy, lupus nephritis, minimal change nephrotic syndrome, diabetic nephropathy, and Alport's syndrome were obtained. Specimens were examined by transmission electron microscopy by the newly devised "tissue negative staining method." Normal glomerular basement membrane showed a three-dimensional lattice-like meshwork of fibrils measuring 1.9 +/- 0.4 nm in diameter that formed numerous uniform, round, oval, or polygonal pores 2.5 +/- 0.4 nm in short diameter and 2.8 +/- 0.5 nm in long dimension. The nephrotic glomerular basement membrane revealed varying degrees of ultrastructural defects, the most prominent being tunnels and cavities. Tortuous tunnels measuring approximately 15 to 50 nm in diameter penetrated the entire glomerular basement membrane. Cavities of various shapes measuring 15 to 200 nm in diameter were diffusely scattered in the glomerular basement membrane and occasionally aggregated to form a honeycomb structure that occupied the whole thickness of the glomerular basement membrane. These defects appeared to be the pathway for protein leakage.

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Effect of Angiotensin-Converting Enzyme Inhibition on Glomerular Basement Membrane Permeability and Distribution of Zonula Occludens-1 in MWF Rats

Journal of the American Society of Nephrology ◽

10.1681/asn.v113477 ◽

2000 ◽

Vol 11 (3) ◽

pp. 477-489

Author(s):

DANIELA MACCONI ◽

MARINA GHILARDI ◽

MARIA ENRICA BONASSI ◽

EHAB I. MOHAMED ◽

MAURO ABBATE ◽

...

Keyword(s):

Epithelial Cells ◽

Basement Membrane ◽

Angiotensin Converting Enzyme ◽

Glomerular Basement Membrane ◽

Ace Inhibitors ◽

Ultrastructural Changes ◽

Converting Enzyme ◽

Filtration Barrier ◽

Zonula Occludens ◽

Zonula Occludens 1

Abstract. The mechanism(s) by which angiotensin-converting enzyme (ACE) inhibitors prevent glomerular membrane loss of permselective function is still not understood. In male MWF rats, which develop spontaneous proteinuria with age, ACE inhibitors prevent proteinuria and increase glomerular ultrafiltration coefficient. These renoprotective effects are not associated with ultrastructural changes of capillary wall components. This study was undertaken to investigate whether ACE inhibitors modulate functional properties of glomerular basement membrane (GBM) and/or of epithelial cells, both of which have been suggested to play a role in the maintenance of the glomerular filtration barrier. The hydraulic and macromolecular permeability of the GBM were determined, by an in vitro filtration system, in untreated or lisinopril-treated rats and in Wistar rats taken as controls. By indirect immunofluorescence and immunoelectron microscopy, glomerular distribution of the tight junction protein zonula occludens-1 (ZO-1), a component of the slit diaphragm, was also studied. Results document that spontaneous proteinuria in MWF rats develops without significant changes in the permeability of the GBM to water and albumin, or in the ultrastructure of the podocyte foot processes, but is associated with an important alteration in the distribution of ZO-1 at the glomerular level. Lisinopril, which prevented proteinuria, also prevented glomerular redistribution of the protein. Thus, renoprotective effects of ACE inhibitors are not associated with changes in intrinsic functional properties of GBM, or ultrastructural changes of the epithelial cells, but rather with preservation of glomerular ZO-1 distribution and slit diaphragm function, which are essential for maintaining the filtration barrier.

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