Development Of Membranoproliferative Glomerulonephritis Research Articles

Overexpression of toll-like receptor 9 correlates with podocyte injury in a murine model of autoimmune membranoproliferative glomerulonephritis

Toll-like receptors (Tlrs) are sensors of danger signals which promote the activation of immune cells and intrinsic renal cells. Podocytes, the intrinsic cells of glomerulus, are continuously exposed to various plasma solutes and danger signals due to their unique location in the glomerulus. Herein, we show that Tlr9 is overexpressed in podocytes and the mechanisms which cause its injury and development of membranoproliferative glomerulonephritis (MPGN) in model BXSB/MpJ-Yaa (Yaa) mice. Yaa mice developed typical lesions of MPGN and showed strong expression of Tlr9 mRNA throughout the glomerulus particularly toward the periphery of the glomerulus. However, BXSB/MpJ (BXSB) mice showed no lesion for MPGN but a very weak expression of Tlr9 mRNA. Relative mRNA expression of Tlr9 and its downstream cytokines, including interleukin 1 beta (Il1b), Il6, interferon gamma (Ifng) and tumour necrosis factor alpha (Tnfa) was markedly increased in glomeruli isolated from Yaa mice. Tlr9 protein expression was almost absent in BXSB mice but intense expression was found in Yaa mice. Podocyte protein expression was normal in BXSB mice but decreased in Yaa mice and colocalized with Tlr9 protein. Furthermore, electron microscopy examination revealed podocyte injury and electron-dense materials in thickened glomerular basement membrane of Yaa mice. Glomerular Tlr9 mRNA expression was significantly correlated with anti-dsDNA antibody, proteinuria, renal function indices (sBUN and sCr), glomerular histopathology indices, downstream factors of Tlr family (Ilb and Tnfa), podocyte injury parameters (p < .05 and p < .01). In conclusion, overexpression of TLR9 correlates with podocyte injury and development of MPGN.

Membranoproliferative glomerulonephritis Type 3 associated with Kabuki syndrome

First described in Japanese patients, Kabuki syndrome (KS) is a congenital condition associated with multiple anomalies and mental retardation. Although urological and immune abnormalities are common in KS, immune complex nephritis such as membranoproliferative glomerulonephritis (MPGN) has not yet been reported. We describe the first reported case of a KS patient with common variable immunodeficiency (CVI) and recurrent otitis media who developed severe proteinuria and hematuria due to MPGN Type 3 detected during the school urinary screening program in Japan. The patient was intravenously treated with methylprednisolone pulses followed by alternate-day prednisolone and an angiotensin receptor blocker. The patient showed remarkable improvement in both histological and urinary analyses. This case report suggests that immune abnormalities associated with KS can play an important role in the development of MPGN. Urinalysis should be regularly performed in KS patients with hypogammaglobulinemia and/or recurrent infection.

Primary Sjogren and #8217;s Syndrome with Concurrent Presentation of Membranoproliferative Glomerulonephritis in A Child: Review of the Literature

Primary Sjogren syndrome (PSS) with concurrent membranoproliferative glomerulonephritis (MPGN) has not been reported in children previously. Reported cases are usually adults and development of MPGN is after a long duration of PSS. In this case report we presented a six-year-old boy with bilateral parotid swelling. During the evaluation of parotid swelling, he developed macroscopic hematuria with nephrotic range proteinuria (44.8 mg/m2/h), low serum albumin (2.9 g/dl), low serum complement C3 (57 mg/dl) and C4 (5.5 mg/dl). He was treated with prednisone. Ten months later, parotid swelling and nephrotic range proteinuria (51 mg/m2/h) relapsed concurrently. He went into remission with prednisone and he is now in remission with cyclosporine A therapy. Concurrent presentation of MPGN and PSS in a child is worthy of presentation.

Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation

The development of membranoproliferative glomerulonephritis (MPGN) is associated with uncontrolled activation of the complement alternative pathway. This dysregulation is related either to C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase, or to homozygous loss-of-function mutation of the complement regulatory protein factor H. Heterozygous mutations in the genes coding for factor H, or for the other alternative pathway inhibitory proteins factor I and membrane cofactor protein, have recently been identified in a small number of patients with MPGN with exclusive C3 deposits. We report three hypocomplementemic children with dense deposit disease (n=1) or immune-complex-mediated MPGN type I (n=2), associated with both C3NeF activity and heterozygous mutation of factor H or factor I. These observations highlight the possible combination of genetic and acquired defect in complement control in various subtypes of MPGN, a finding that may influence the treatment strategy in some patients.

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice

The inflammatory kidney disease membranoproliferative glomerulonephritis type II (MPGN2) is associated with dysregulation of the alternative pathway of complement activation. MPGN2 is characterized by the presence of complement C3 along the glomerular basement membrane (GBM). Spontaneous activation of C3 through the alternative pathway is regulated by 2 plasma proteins, factor H and factor I. Deficiency of either of these regulators results in uncontrolled C3 activation, although the breakdown of activated C3 is dependent on factor I. Deficiency of factor H, but not factor I, is associated with MPGN2 in humans, pigs, and mice. To explain this discordance, mice with single or combined deficiencies of these factors were studied. MPGN2 did not develop in mice with combined factor H and I deficiency or in mice deficient in factor I alone. However, administration of a source of factor I to mice with combined factor H and factor I deficiency triggered both activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated that C3 deposited along the GBM was derived from plasma. Together, these findings provide what we believe to be the first evidence that factor I–mediated generation of activated C3 fragments in the circulation is a critical determinant for the development of MPGN2 associated with factor H deficiency.

Membranoproliferative glomerulonephritis in a patient with X-linked agammaglobulinemia

Immune complex and complement systems play an important role in membranoproliferative glomerulonephritis (MPGN). X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by severe hypogammaglobulinemia. We report the case of an XLA patient who developed MPGN during an intravenous immunoglobulin (IVIG) treatment. In this patient, the serum IgG level was maintained at more than 400 mg/dl of regular IVIG administration (2.5 g/dose/month). The patient presented with microscopic hematuria, proteinuria (U-pro/Cr: 4.0-4.2) and low serum complement levels (C3: 57.8 mg/dl) 3 years after IVIG treatment and was diagnosed histopathologically as having MPGN type III. Both hematuria and proteinuria significantly improved, and the serum complement level returned to a normal level following methylprednisolone pulse therapy. To our knowledge, this is the first case report of MPGN associated with XLA. Although it is unclear how MPGN occurred in this XLA patient, we suggest that residual humoral immunity in the patient could be associated with the development of MPGN.