Factor H autoantibodies in membranoproliferative glomerulonephritis

Factor H autoantibodies are found in ∼10% of aHUS patients. Most are associated with complete deficiency of factor H related proteins 1/3 and bind to the C terminal recognition domain. MPGN, like aHUS, is characterised by complement activation. In this study we, therefore, examined the hypothesis that factor H autoantibodies are associated with MPGN. We screened sera from 16 MPGN patients and 100 normal controls using ELISA and detected strongly positive IgG factor H autoantibodies in 2 patients. One patient had type II (DDD) MPGN (male aged 24 yrs) with C3NeF and the other type I (female aged 26 yrs) with no detectable C3NeF. We identified the binding site of the autoantibodies using small SCR domain fragments in the ELISA and showed that the autoantibodies in both patients bound predominately to the N terminal complement regulatory domain of factor H. We measured CFHR 1/3 copy number using MLPA and showed that both patients had 2 copies of CFHR1 and 3. Finally, we examined the functionality of detected factor H autoantibodies using purified patient IgG and observed increased haemolysis when purified IgG from both patients was added to normal human sera prior to incubation with rabbit red blood cells. Thus, in a cohort of MPGN patients we have found a high titre of functionally significant factor H autoantibodies in two patients with MPGN. Antibody depleting therapy may have a role in such patients and we suggest that screening for factor H autoantibodies should be undertaken in all patients with MPGN.     

Complement studies in membranoproliferative glomerulonephritis

Detailed studies of the complement system were carried out in fifteen patients with membranoproliferative glomerulonephritis. The findings of reduced levels of C3 and C7 and of circulating breakdown products of C3 in fresh plasma suggested in vivo complement activation. Low C3 levels were associated with the presence of a serum factor (the C3 nephritic factor C3NeF) which was capable of breaking down C3 in normal serum in vitro. Metabolic studies using radioactive iodine labelled C3 showed no evidence of accelerated in vivo breakdown of parenterally administered C3 suggesting that hypocomplementaemia is either maintained by diminished C3 synthesis or that accelerated catabolism is occurring in a pool that does not freely exchange with parenterally given C3. The C3 nephritic factor has so far only been identified in patients with membranoproliferative nephritis and is therefore of major diagnostic significance in patients with glomerular disease.     

Major-histocompatibility-complex extended haplotypes in membranoproliferative glomerulonephritis

Membranoproliferative glomerulonephritis is often associated with evidence of immune derangement, especially hypocomplementemia. We studied genetic markers for membranoproliferative glomerulonephritis within the major histocompatibility complex in 34 patients and their families and in 29 normal families. We examined the frequencies of extended haplotypes (combinations of alleles that tend to occur together) in patients and controls. The extended haplotype HLA-B8,DR3,SC01,GLO2(glyoxalase I 2) was observed in 9 of 68 disease-associated haplotypes (13 percent), but in only 3 of 205 controls (1 percent) (relative risk, 14.79; P less than 0.001). An extended haplotype similar except for a different glyoxalase allotype (B8,DR3,SC01,GLO1) did not occur with increased frequency, nor did any other extended haplotypes. Patients with the extended haplotype B8,DR3,SC01,GLO2 had a higher incidence of renal insufficiency than those without it (P less than 0.01). The data support the hypothesis that a specific extended haplotype of the major histocompatibility complex is associated with susceptibility to membranoproliferative glomerulonephritis, and that patients with glomerulonephritis who have this extended haplotype have a poorer prognosis for kidney survival than those without the haplotype.     

Basement membrane changes in membranoproliferative glomerulonephritis

Summary In a previous study on membranoproliferative glomerulonephritis (MPGN) we reported the preliminary result that a basement membrane (b.m.) lesion incompatible with the criteria of subendothelial deposits (type I) or intramembranous dense deposits (type II) can be recognized by silver impregnation (s.i.) of ultra-thin sections. This technique has been further evaluated and applied firstly to control cases with normal b.m., perimembranous GN, diffuse proliferative (MPGN-like) lupus nephritis and, secondly to additional cases of idiopathic MPGN comprising 10 biopsies with doubtful findings as judged by electron microscopy with conventional impregnation. S.i. of ultra-thin sections proved to be a reliable method, of particular value in the visualization of fine structural details of b.m. changes in the field of MPGN. The light microscopic (l.m.) equivalent of the new lesion is defined. Accordingly, the series of 31 patients with idiopathic MPGN has been subdivided into three groups: Type I (19), type II (3), type III (9 patients). Type III is understood to be an intermediate type lesion, distinguished from type I by true membranous changes (discontinuity of the lamina densa) and from type II by the lack of the intramembranous electrondense (argyrophilic) material. It resembles in part, however, perimembranous GN due to segmental spike formation and little proliferation.The clinical course of the patients with the type III lesion did not significantly differ from that of the other groups. The details are given in short case reports. Serum C3 was persistently depressed in 6, initially depressed in 2 patients and normal in one. As in type II, a predominant or isolated presence of C3 can be seen by immunofluorescence microscopy. Therefore, type III is likely to be mistaken for type II on the basis of immunological and l.m. data, and for type I on the basis of e.m. with conventional impregnation. The resultant inconsistencies so far inherent in the dual subclassification concept of MPGN can probably be solved — at least in part — by the acceptance of the type III lesion as defined by its appearance in silver impregnated ultra-thin sections.Both lesions, type II and type III, are understood to be conditions in which the notional difference between deposits and a substantial alteration of the b.m. is poorly defined.Part I is identical with previous paper: D. Anders and W. Thoenes (1975), see referencesTechnical assistance     

Long-term immunosuppressive therapy of idiopathic membranoproliferative glomerulonephritis

Summary Fifty cases of idiopathic membranoproliferative glomerulonephritis were followed up for an average of 10±0.9 (SE) years. Forty of them, who presented a nephrotic syndrome, were treated by immunosuppressive drugs (prednisone, azathioprine, chlorambucil, cyclophosphamide) for 79±9.7 (SE) months. Cumulative survival ratio for 5, 10 and 15 years after enrolment was 0.90, 0.82 and 0.77 and after appearance of first symptoms or signs of kidney disease as determined by anamnestic data 0.97, 0.91 and 0.90 accordingly.Triple-drug therapy (prednisone and azathioprine combined with chlorambucil or cyclophosphamide) was more effective in improving proteinuria than other immunosuppressive regimens. No serious side effects were encountered.Abbreviations MPGN membranoproliferative glomerulonephritis - IgG immunoglobulin G - C₃ complement C₃ - FU curve Follow-up curve - DD curve Disease duration curve Supported by Ministry of Health Grant, 10 MZ XIIINachtrag zu den Hauptreferaten des 19. Kongresses der Gesellschaft für Nephrologie in Göttingen (Klin Wochenschr 66/18)     

Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis

Age-related macular degeneration (AMD) and membranoproliferative glomerulonephritis type II (MPGN2) are dense deposit diseases that share a genetic association with complement genes and have complement proteins as important components of the dense deposits. Here, we present the case of a 64-year-old smoker male who developed both AMD and MPGN2 in his late 50s. The patient presented persistent low plasma levels of C3, factor H levels in the lower part of the normal range and C3NeF traces. Genetic analyses of the CFH, CFB, C3, CFHR1-CFHR3 and LOC387715/HTRA1 genes revealed that the patient was heterozygote for a novel missense mutation in exon 9 of CFH (c.1292 G > A) that results in a Cys431Tyr substitution in SCR7 of the factor H protein. In addition, he was homozygote for the His402 CFH allele, heterozygote for the Ser69 LOC387715 allele, homozygote for the Arg32 (BFS) CFB allele, heterozygote for the Gly102 (C3F) C3 allele and carried no deletion of the CFHR1/CFHR3 genes. Proteomic and functional analyses indicate absence in plasma of the factor H allele carrying the Cys431Tyr mutation. As a whole, these data recapitulate a prototypical complement genetic profile, including a partial factor H deficiency and the presence of major risk factors for AMD and MPGN2, which support the hypothesis that these dense deposit diseases have a common pathogenic mechanism involving dysregulation of the alternative pathway of complement activation.     

Kidney tubule basement membrane alterations in type II membranoproliferative glomerulonephritis

Summary Fourteen kidney biopsy specimens from nine patients with type II membranoproliferative glomerulonephritis (MPGN) were examined by electron microscopy for tubular basement membrane (TBM) alterations. In all biopsies, laminal densities, characteristic for type II MPGN, were present in the glomerular basement membranes.The TBM alterations observed included: 1) the presence of laminal, and/ or discrete, and/or aggregated densities; 2) focal thickening; 3) multilamination; and, 4) vesicular structures. Laminal densities occurred in 6 of the 9 cases examined. All biopsies had TBM densities representative of at least one of the three forms.The occurrence of electron densities in or near the TBM in type II MPGN may have diagnostic value. In those biopsies where tissue is insufficient for immunofluorescence microscopy and where glomeruli are not found on electron microscopy, an electron microscopic search for densities associated with TBMs would be warranted. Although TBM-associated densities are not pathognomonic for type II MPGN, the observation of such densities, especially laminal densities, would be useful in complementing light microscopic and clinical findings.     

Mixed cryoglobulinemia-associated membranoproliferative glomerulonephritis, disclosing gastric MALT lymphoma

We report a case of a mixed cryoglobulinemia-associated membranoproliferative glomerulonephritis, disclosing gastric lymphoma of MALT-type. In the reported case, glomerulonephritis was associated with joint and skin symptoms related to type II mixed cryoglobulinemia. MALT lymphoma diagnosis was made by gastric biopsy. Renal pathological examination showed relatively uncommon findings, ie mesangioproliferative glomerulonephritis lacking usual intraluminal thrombi. Although classical, renal manifestations of malignant lymphomas are uncommon, and rarely allow lymphoma diagnosis. The renal biological function improves as the lymphoma regresses with appropriated treatment. This case underlines the benefit of gastroscopy in cryoglobulinemia etiological research.     

A case of membranoproliferative glomerulonephritis associated with a hydatidiform mole

We treated a 54-year-old woman who was suffering from membranoproliferative glomerulonephritis associated with a complete type of hydatidiform mole. The renal manifestations were proteinuria and hematuria. A renal biopsy, performed before gynecologic management, disclosed focal and segmental subendothelial deposits with a proliferation of the mesangial cell and showed irregularly thickened capillary loops by light and electronmicroscoy. Genralized edema, proteinuria and hematuria were completely recovered by suction and curettage of the hydatidiform mole with prophylactic chemotherapy. The clinical manifestation of earlier presented 3 cases have been the nephrotic syndrome. The common feature of them was a complete remission of the nephropathy after the removal of the hydatidiform mole. The relationship between the hydatidiform mole and glomerulonephritis remains unresolved at present. But we concluded that the hydatidiform mole might be a cause of glomerulonephritis in this case.     

Atrial fibrillation due to oral methylprednisolone in a patient with membranoproliferative glomerulonephritis

Cardiac adverse effects of intravenous pulse methylprednisolone administration are well known, but there is little information about the cardiac side effects of oral methylprednisolone in the literature. We present a 41 year-old man with membranoproliferative glomerulonephritis in whom developed atrial fibrillation after oral methylprednisolone therapy.