Mesangiocapillary glomerulonephritis associated with meningococcal meningitis,C3 nephritis factor and persistently low complement C3 and C5

We report two unusual cases in which mesangiocapillary glomerulonephritis occurred in association with meningococcal infection. C3 nephritic factor, an autoantibody to alternate pathway C3 convertase, was present. Low serum complement C3 and C5 levels were also noted. The depressed complement levels, in conjuction with terminal complement complexes at the upper limit of normal, suggest activation of the early and late complement cascade. We suggest that children presenting with meningococcal infection should have a regular urine examination, as well as full complement measurements performed, in view of the association with hypocomplementaemic mesangiocapillary glomerulonephritis. Similarly, prophylactic penicillin should be prescribed for patients with mesangiocapillary glomerulonephritis and persistently low C5 levels to prevent meningococcal complications.     

Gaucher's disease and mesangiocapillary glomerulonephritis in childhood — a coincidence?

A 6-year-old boy, presenting with a nephritic syndrome, was diagnosed as suffering from Gaucher's disease (GD) and mesangiocapillary glomerulonephritis (MCGN). GD was suspected because of aseptic necrosis of the femoral heads on X-ray and later confirmed by bone marrow aspiration and a lack of glucocerebrosidase activity in white blood cells; MCGN was documented on renal biopsy. The child was treated with prednisone, dipyridamole and aspirin, and recovered completely clinically. A second biopsy was not performed. The connection between these two rare diseases, and between nephritis and GD in general, is discussed.     

Hypocomplementaemia of poststreptococcal acute glomerulonephritis is associated with C3 nephritic factor (C3NeF) IgG autoantibody activity

We have observed that decreased plasma levels of C3 in the serumof three children with poststreptococcal acute glomerulonephritis(PSAGN) at the time of presentation were associated with thepresence of C3NeF activity in purified serum IgG from the patients.C3NeF activity was determined using a sensitive assay measuringthe ability of patients’ IgG to stabilize a preformedcell-bound alternative pathway convertase complex. C3NeF activityof patients’ IgG decreased within weeks as plasma levelsof C3 progress ively returned to normal values. C3NeF activitybecame undetectable within 1–4 months following normalizationof plasma C3 levels. Our observations suggest that early alternativepathway-dependent hypo complementaemia, a cardinal feature ofPSAGN, is mediated by the transient expression of C3NeF autoantibody activity by patients’ IgG.     

Activated C3 (C3b) in the nephritic glomerulus

An autoradiographic technique was developed to assess in the nephritic glomerulus the relative amount of C3 which is in the activated form, C3b, compared with the inactivated form, iC3b. Frozen renal biopsy sections from children and young adults with glomerulonephritis were assessed for the C3b fraction of total C3, using a radiolabeled monoclonal anti-C3c. Grain counts with this antibody, before and after reacting the section with 0.0002% typsin, gave the relative amounts of total C3 and C3b, respectively. C3b was found in all diseases studied. To explain its presence, glomerular C3b acceptors which would restrict C3b inactivation were sought by immuno-fluorescence studies. C3b acceptor candidates were: igG in aggregated form, IgA as found in the IgA nephropathies and the C3/C5 convertase, C4b,2a,3b. In acute post-streptococcal glomerulonephritis and membranoproliferative glomerulonephritis type III, diseases in which these acceptors were lacking, it is postulated that the nephritis strain-associated protein and absence of membrane cofactor protein, respectively, may be responsible for C3b deposition. The phlogistic effect of C3b is mediated largely by one of its products, C5b-9. However, the C3b: total C3 ratio failed to correlate with indices of glomerular inflammation. probably in part because the ratio is not a measure of total glomerular C3b.     

C3肾小球肾炎的诊断和中西医结合治疗

C3肾小球肾炎(C3GN)是指免疫荧光仅见C3沉积而免疫球蛋白和C1q阴性,电镜下见内皮下和(或)系膜区电子致密物沉积的一种肾小球病。随着病理学、免疫学的逐步发展,我们对C3GN的认识不断提高。目前临床医生主要通过临床表现、实验室检查(补体成分异常)及病理三方面来对C3GN进行诊断。C3GN作为一种最近提出的疾病,现有资料有限,在诊断上需要慎重鉴别。C3GN尚无特效的治疗方法,作用于C5的人造单克隆抗体依库丽单抗、补体调节剂CR1以及以雷公藤甲苷为代表的中西医结合对症治疗有望获得良好的疗效。本病预后呈多样性,在对症支持的基础上,中西医结合治疗通过免疫抑制等机制有望控制疾病的进展,而更加有效的药物亟待研发。     

A case of autoimmune thyroiditis and membranoproliferative glomerulonephritis

Thyroid hormones play an important role in the growth of the kidney and maintenance of its functions. Prolonged hypothyroidism is known to be accompanied by changes in renal morphology such as thickening of the glomerular and tubular basement membranes as well as increased mesangial matrix. Increased transcapillary leakage of plasma proteins leading to proteinuria and generalized edema is also a known complication of hypothyroidism. In particular, autoimmune thyroiditis is associated with proteinuria. Most previous reports of autoimmune thyroiditis with nephrotic syndrome have demonstrated mixed pathological morphology marked by predominant membranous glomerulopathy. Here we present a patient whose initial presentation with profound hypothyroidism and autoimmune thyroiditis was dominated by nephrotic syndrome secondary to type 1 membranoproliferative glomerulonephritis (MPGN). The association of MPGN and autoimmune thyroiditis is very rare.     

Hepatitis C and glomerulonephritis

Summary: Several systemic viral infections have been associated with the development of glomerular lesions. of the viruses that cause liver disease hepatitis B was the first to be recognized. the recent availability of serologic tests for the hepatitis C virus (HCV) has uncovered an association between HCV infection and renal disease. the principal glomerular lesion that develops is that of a membranoproliferative glomerulonephritis (MPGN), usually in association with antigenaemia and circulating immune complexes that have the characteristics of mixed cryoglobulinaemia represented by polyclonal IgG and monoclonal IgM with rheumatoid factor activity. the presence of a very high percentage of anti-HCV seropositivity in cryoglobulinaemic forms of MPGN suggests that the virus plays an important role in the pathogenesis of the associated immune complex glomerulonephritis. Precipitates containing HCV-RNA and circulating anti-HCV IgG and IgM have been found in the majority of such cases. the course of the renal disease that develops is progressive. Treatment with interferon alpha appears to attenuate the progression of the renal lesions, and the response to treatment appears to be closely related to the clearance of hepatitis C viraemia. Renal lesions also occur in the absence of clinical evidence of liver disease or mixed cryoglobulinaemia. In addition to MPGN, membranous glomerulonephropathy, IgA nephropathy and focal segmental glomerulosclerosis have been reported in these cases of HCV infection. the prevalence of glomerular lesions in patients with HCV infection remains to be determined. the available serologic tests for HCV are still in evolution. In the meantime, all patients presenting with glomerular disease should be screened for HCV.     

Novel estimation of histologic activity in human glomerulonephritis by detection of complement component C3 messenger RNA

Background The histologic diagnosis and clinical findings of glomerulonephritis are very important for determining the treatment strategies. Contrary to expectation, some patients with glomerulonephritis get worse and progress into endstage renal disease. Renal deposition of C3 cleavage products are significant in the pathogenesis and development of glomerulonephritis. Recently, some investigators have reported local C3 synthesis in human renal tissue, and have suggested that it contributes to local inflammatory disorders. The purpose of this study was to explore further the clinicopathologic significance of renal C3 mRNA expression. Methods We examined C3 mRNA expression in kidney tissues (2 normal and 18 diseased) by using nonradioactive, in situ hybridization, and compared results with clinicopathologic findings. Results In all diseased kidney specimens, proximal tubules had C3 mRNA-positive cells. In some cases of minimal-change nephrotic syndrome, lupus nephritis, and membranoproliferative glomerulonephritis, C3 mRNA-positive cells were found in the glomerulus. Specimens from patients with lupus nephritis showed C3 mRNA expression not only in in their tubules and glomeruli, but also in invasive, inflammatory cells. However, no signal was observed in the normal kidney specimens Cases with severe nephrotic conditions and/or with tubular injury showed strong expression. Conclusions These data indicate that renal C3 mRNA that could not been detected by routine immunohistologic methods is, in fact, detectable during the active stage of disease. Therefore detection of renal C3 mRNA may give us new information for assessing pathologic activities, and may be an effective means for determining the prognosis of patients with glomerulonephritis.     

Pathogenesis of hepatitis C virus-associated glomerulonephritis

Summary: Hepatitis C virus (HCV), in addition to causing both acute and chronic liver disease, may also be associated with several immunologically-mediated syndromes, particularly cryoglobulinaemia and membranoproliferative glomerulonephritis. Although the glomerulonephritis may be a feature of a systemic cryoglobulinaemic syndrome, it may also present as a primary renal disease without evidence of vasculitis or liver disease. Most of these latter patients, however, will have detectable cryoglobulinaemia either at the time of presentation or with continued observation. In this review, we discuss the pathogenesis of the glomerular disease. Most evidence supports the hypothesis that HCV associated glomerular disease results from the deposition of circulating immune complexes that are usually cryoprecipitable and which contain HCV, anti-HCV IgG, and rheumatoid factors. However, HCV antigens have yet to be identified in glomerular biopsies. This has raised the possibility that other pathogenic mechanisms may be involved, including auto-antibodies directed against glomerular antigens and factors related to chronic liver disease. Further studies are necessary to fully elucidate the pathogenesis of this recently recognized disease.     

Selective disappearance of C3NeF IgG autoantibody in the plasma of a patient with membranoproliferative glomerulonephritis following renal fransplantation

The serum of patients with membranopro-liferative glomerulonephritis(MPGN) often exhibits C3 nephritic factor activity (C3NeF) associatedwith autoantibodies directed against the C3bBb alternative complementpathway C3 convertase. In the present study, we have sequentiallyassessed C3NeF activity in the purified IgG fraction of theserum of a patient with MPGN type II and end-stage renal diseaseevery month for 1 year following renal transplantation and bilateralnephrectomy. C3NeF activity in the patient's purified serumIgG decreased with time from the first month after transplantationand became undetectable after forty-five weeks. At that time,plasma levels of C3 and factor B had returned to normal values.The disappearance of C3NeF activity in patient's IgG was selectivein that no change in activity of two other autoantibodies andof one antibody against a non-self antigen was observed withtime, indicating that the decrease in C3NeF activity was notrelated to a non specilic effect of immunosuppressive therapy.Loss of C3NeF activity was not related to the generation ofanti-idiotypic antibodies against C3NeF. This study documentsfor the first time the selective disappearance of C3NeF activityfollowing renal transplantation and bilateral nephrectomy. Theresults suggest that the autoantibody represents an antigen-drivenexpansion of self reactive B cell clones in response to a specificdisease process in the kidney of patients with MPGN.     

Long-term prognosis of diffuse proliferative glomerulonephritis associated with infection in adults.

BACKGROUND: Infection-associated glomerulonephritis is rare in adults and its long-term prognosis is undefined. METHODS: We retrospectively evaluated the clinical course of 50 adults (30 men, 20 women) with infection-associated glomerulonephritis diagnosed in our department from 1979 to 1999. The mean follow-up was 90+/-78 months. Patients were subdivided into two groups: group 1 included those without underlying disease and group 2 included those with severe underlying disease. RESULTS: At presentation, the median age was 54 years, and 33 patients were hypertensive, 31 had nephritic syndrome, eight had nephrotic syndrome and 11 had non-nephrotic proteinuria. Patients in group 2 were significantly older and had a significantly higher proteinuria than patients of group 1. Of the 21 patients in group 2, nine had liver cirrhosis, four cancer, five diabetes, three bronchiectasis, one thalassaemia intermedia, one polymyositis and one had anti-phospholipid antibodies syndrome. At the last follow-up, five patients had died, 21 patients were in complete remission, ten had partial remission, ten had renal insufficiency and three were on chronic dialysis. Multivariate analysis showed that an underlying disease (P=0.04) and interstitial infiltration at biopsy (P=0.036) were predictors of incomplete recovery. A correlation analysis between the year of diagnosis and the clinical/ histological characteristics at presentation showed that age (P=0.05), atypical infections (P=0.01), underlying disease (P=0.01) and interstitial infiltration at biopsy (P=0.02) increased over time, while the number of patients with complete remission significantly decreased (P=0.001). CONCLUSIONS: Infection-associated glomerulonephritis may progress to chronic renal failure in a consistent number of adult hospitalized patients, particularly in those with an underlying disease and when associated with interstitial infiltration at biopsy.     

Nephritic factor and recurrence in the renal transplant of membranoproliferative glomerulonephritis type II

Animal models suggest a role for nephritic factor in the pathogenesis of glomerular disease, but evidence for a role in human disease is lacking. To assess its role, we applied a recently developed method that allows measurement of low levels of nephritic factor activity to stored serum specimens from three patients who had membranoproliferative glomerulonephritis (MPGN) type II. All three had had renal transplants, and one lost two of three transplants from recurrent disease. Evidence for a role for nephritic factor in human disease was a positive correlation between the level of nephritic factor activity and both the severity of recurrence and an increase in serum creatinine concentration. However, the hypocomplementemia was never severe; C3 levels of 49-76 mg/dl and nephritic factor levels of 89 U/ml were associated with severe recurrences. We have previously seen severe disease with mild hypocomplementemia. In contrast, patients with partial lipodystrophy often have severe hypocomplementemia and, presumably, high levels of nephritic factor yet have a mild glomerulonephritis. Disease severity and nephritic factor levels thus appear to be inversely related. The disease is progressive when only moderate amounts of nephritic factor have been circulating and C3 only mildly depressed.     

Complement profiles in acute post-streptococcal glomerulonephritis

It is well known that the hypocomplementemia of acute post-streptococcal glomerulonephritis (APSGN) is characterized by markedly reduced serum concentrations of C3 and moderately reduced levels of C5 and properdin (P). However, the extent of the activation of the classical pathway is not well defined and only limited data are available concerning serum concentrations of terminal components other than C5. In serial serum specimens from 14 children with APSGN, the presence and extent of C4 activation was directly assessed by measurement by rocket immunoelectrophoresis for C4 and C4 (C4d/C4 ratio). Elevated values for this ratio, indicating C4 activation, were found in 8 of 14 of the initial serum specimens, and in some patients the ratio remained elevated for several weeks. In contrast, the serum C4 level was low in only 1 specimen (the specimen with the highest C4d/C4 ratio). However, in 10 patients C4 concentrations within the normal range rose in serial serum specimens. Serum C2 concentrations were depressed in the initial specimens from 5 patients. The concentrations of 13 other complement component and control proteins were also measured in these specimens. Levels of terminal components, other than C5, in the initial serum specimens were normal except for depressed C8 in 3 of 13 patients and depressed C6 in 1 of 14. Of these 4 individuals, 3 had the lowest C3 levels in the study. It is concluded that the classical complement pathway is frequently activated in patients with APSGN early in the condition and that subtle abnormalities in C6 and C8 levels occasionally occur.Supported by National Institutes of Health Grants AM 00777, AI 10386 and RR 05374.