Membranous Nephropathy with Lambda Light Chain Restriction: A Rare Form with Serum Negative and Tissue Positive PLA2R Ab

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Subepithelial polyclonal immunoglobulin deposits and >70% M-type phospholipase A2 receptor antibody positivity are typical findings in idiopathic MN. A 58-year-old female patient was admitted with clinical presentation of nephrotic syndrome. Autoimmune diseases, infections, and malignancies were ruled out after clinical and laboratory evaluations. Diagnostic work-up revealed serum PLA2R antibody negativity and diffuse thickening of glomerular capillary wall on biopsy, while glomerular capillary wall IgG, C3, and Lambda monotypic light chain deposition and PLA2R1 positivity were detected by immunofluorescence and immunohistochemical examination, respectively. Following prednisolone treatment, creatinine and proteinuria were markedly regressed. The MN cases with a light chain deposits are rare and experience regarding their treatment are insufficient.

The role of TRPC6 calcium channels and P2 purinergic receptors in podocyte mechanical and metabolic sensing

Podocyte calcium (Ca2+) signaling plays important roles in the (patho)physiology of the glomerular filtration barrier. Overactivation of podocyte transient receptor potential canonical (TRPC) channels including TRPC6 and purinergic signaling via P2 receptors that are known mechanosensors can increase podocyte intracellular Ca2+ levels ([Ca2+]i) and cause cell injury, proteinuria and glomerular disease including in diabetes. However, important mechanistic details of the trigger and activation of these pathways in vivo in the intact glomerular environment are lacking. Here we show direct visual evidence that podocytes can sense mechanical overload (increased glomerular capillary pressure) and metabolic alterations (increased plasma glucose) via TRPC6 and purinergic receptors including P2Y2. Multiphoton microscopy of podocyte [Ca2+]i was performed in vivo using wild-type and TRPC6 or P2Y2 knockout (KO) mice expressing the calcium reporter GCaMP3/5 only in podocytes and in vitro using freshly dissected microperfused glomeruli. Single-nephron intra-glomerular capillary pressure elevations induced by obstructing the efferent arteriole lumen with laser-induced microthrombus in vivo and by a micropipette in vitro triggered >2-fold increases in podocyte [Ca2+]i. These responses were blocked in TRPC6 and P2Y2 KO mice. Acute elevations of plasma glucose caused >4-fold increases in podocyte [Ca2+]i that were abolished by pharmacological inhibition of TRPC6 or P2 receptors using SAR7334 or suramin treatment, respectively. This study established the role of Ca2+ signaling via TRPC6 channels and P2 receptors in mechanical and metabolic sensing of podocytes in vivo, which are promising therapeutic targets in conditions with high intra-glomerular capillary pressure and plasma glucose, such as diabetic and hypertensive nephropathy.

An Investigation of the Antigenic Characteristics of the Renal Glomerulus in the Rat

<p>The finding of a granular deposition of immunoglobulin in the kidney in experimental animal models of glomerulonephritis has been been interpreted as resulting from the random deposition of immune complexes in the glomeruli. Recent data suggests that although immune complex deposition may be an important factor in some forms of glomerulonephritis, the in situ formation of immune complexes between circulating anti-kidney antibodies and fixed glomerular capillary wall antigens may also be a significant factor in the pathogenesis of some animal models of glomerulonephritis. To examine the characteristics of discontinuously represented glomerular capillary wall antigens in the rat, monoclonal antibodies were generated against a glomerular plasma membrane fraction, depleted of glomerular basement membrane, prepared from isolated Lewis rat glomeruli. A total of 17 hybridomas, generated from the fusion of splenocytes obtained from mice immunised with the glomerular membrane fraction produced monoclonal antibodies which reacted with discontinuously represented antigens in the glomerulus and renal tubules. One further hybridoma secreted a monoclonal antibody which reacted with an antigen present on glomerular and tubular nuclear membranes. No hybridomas were produced which secreted a monoclonal antibody which reacted with linearly arrayed glomerular basement membrane antigens. Two of these monoclonal antibodies, both of the IgM subclass and code-named PH7 and SC5, produced a heavy granular glomerular staining pattern when examined by indirect immunofluorescence microscopy. Neither monoclonal antibody was kidney specific, with reactivity being demonstrated with a number of non-renal tissues. When administered intravenously to normal Lewis rats both SC5 and PH7 induced a mild proteinuric lesion. The proteinuria was not associated with histopathological changes at the light or electron microscope level. Immunoblotting experiments revealed that SC5 reacted predominantly with a protein band of 96 kDa present in detergent extracts of isolated glomeruli and glomerular plasma membranes. PH7 was shown to react with three low molecular weight proteins of 14, 13 and 11 kDa The findings of this study demonstrate the potential for a nephritogenic response to occur following the in situ formation of immune complexes between circulating anti-kidney antibodies and discontinuously arrayed non-glomerular, basement membrane glomerular capillary wall antigens characterised by granular immunofluorescence patterns,in animal models of glomerulonephritis.</p>

An Investigation of the Antigenic Characteristics of the Renal Glomerulus in the Rat

<p>The finding of a granular deposition of immunoglobulin in the kidney in experimental animal models of glomerulonephritis has been been interpreted as resulting from the random deposition of immune complexes in the glomeruli. Recent data suggests that although immune complex deposition may be an important factor in some forms of glomerulonephritis, the in situ formation of immune complexes between circulating anti-kidney antibodies and fixed glomerular capillary wall antigens may also be a significant factor in the pathogenesis of some animal models of glomerulonephritis. To examine the characteristics of discontinuously represented glomerular capillary wall antigens in the rat, monoclonal antibodies were generated against a glomerular plasma membrane fraction, depleted of glomerular basement membrane, prepared from isolated Lewis rat glomeruli. A total of 17 hybridomas, generated from the fusion of splenocytes obtained from mice immunised with the glomerular membrane fraction produced monoclonal antibodies which reacted with discontinuously represented antigens in the glomerulus and renal tubules. One further hybridoma secreted a monoclonal antibody which reacted with an antigen present on glomerular and tubular nuclear membranes. No hybridomas were produced which secreted a monoclonal antibody which reacted with linearly arrayed glomerular basement membrane antigens. Two of these monoclonal antibodies, both of the IgM subclass and code-named PH7 and SC5, produced a heavy granular glomerular staining pattern when examined by indirect immunofluorescence microscopy. Neither monoclonal antibody was kidney specific, with reactivity being demonstrated with a number of non-renal tissues. When administered intravenously to normal Lewis rats both SC5 and PH7 induced a mild proteinuric lesion. The proteinuria was not associated with histopathological changes at the light or electron microscope level. Immunoblotting experiments revealed that SC5 reacted predominantly with a protein band of 96 kDa present in detergent extracts of isolated glomeruli and glomerular plasma membranes. PH7 was shown to react with three low molecular weight proteins of 14, 13 and 11 kDa The findings of this study demonstrate the potential for a nephritogenic response to occur following the in situ formation of immune complexes between circulating anti-kidney antibodies and discontinuously arrayed non-glomerular, basement membrane glomerular capillary wall antigens characterised by granular immunofluorescence patterns,in animal models of glomerulonephritis.</p>

Mathematical model of solute transfer in a permeable channel with effect of variable viscosity

This paper describes a mathematical model of solute transfer in fluid flow across a permeable channel with variable viscosity, with applications to glomerular capillary blood flow. Solute transfer through the glomerular capillary wall is controlled by the difference in transcapillary hydrostatic pressure and the analogous difference in colloid osmotic pressure (Starling’s law). Using appropriate analytical and numerical approaches, the solutions of coupled equations regulating fluid flow and solute transport are found. The current study’s hydrostatic and osmotic pressure curves are qualitatively in excellent agreement with the experimental data. The effects of variable viscosity on velocity profiles, concentration profiles, and total solute clearance are seen to be substantial, and the findings are graphically depicted.

Case Report. Cryoglobulin Hyaline-thrombi Associated Acute Jejunitis in A Patient with Type 2 Cryoglobulinemic Glomerulonephritis

Introduction/Objective Only one prior case report indicates that mixed positive cryoglobulin in serum can be associated with intestinal vasculitis (Annals of Internal Medicine, 1974). Methods/Case Report We report a 63-year old man with history of positive serum cryoglobulin and hepatitis-C 4 years ago and membranoproliferative pattern of glomerulonephritis with possible cryoglobulin type of deposits by electron microscopy on renal biopsy. After treatment, his hepatitis C became negative. But he was recently found to have monoclonal IgM-kappa and positive cryoglobulin in his serum, and the concurrent renal biopsy showed membranoproliferative pattern of glomerulopathy with many hyaline-thrombi (eosinophilic vascular occlusions with no lamination, inflammatory cells or nuclear debris) in the glomerular capillary loops (Figure, left panel). Both immunofluorescent and electron microscopy confirmed a mixed IgG polyclonal and IgM monoclonal type 2 cryglobulinemic glomerulonephritis. The patient also developed abdominal pain and underwent intestinal endoscopy with biopsy. His jejunal biopsy revealed neutrophil infiltration into glands and surface epithelium, with superficial sloughed epithelial cells, consistent with acute jejunitis with features of ischemic etiology. In addition, hyaline-thrombi were identified in the submucosal vessels with surrounding vasculitis (Figure, right panel); the central part of thrombi was morphologically similar to that found in glomerular capillary loops. Therefore, we conclude that cryoglobulin associated hyaline-thrombi were the most likely etiology to cause the acute ischemic jejunitis in this patient. Results (if a Case Study enter NA) NA Conclusion NA