Familial membranoproliferative glomerulonephritis

Four and two male sibs of two separate families who had biopsy-provenmembranoproliferative glomerulonephritis (MPGN) are presented.In the first family four sibs of the first-degree consanguineousmarriage showed the clinical picture of nephrotic syndrome withouthypocomplementaemia at initial laboratory findings. In the secondfamily two affected sibs showed nephrotic and nephritic syndromeson admission. Family investigations showed normal serum complement,immunoglobulins, T-cell subsets, urine analysis, and serum biochemistry.HLA typing in the two families revealed a common antigen HLAA2 in all affected sibs. Some other reports give suggestiveevidence of MPGN in siblings but this is the first report thatshowed the occurrence of MPGN in four sibs. Our data strengthenedthe concept that genetic factors are involved in the developmentof MPGN but additional immunogenetic studies will shed lighton the genetic aspects of the disease.     

Malignancy-associated membranoproliferative glomerulonephritis

An 11-year-old girl with an abdominal desmoplastic round cell tumor, treated with chemotherapy, presented with gross hematuria and proteinuria. Renal biopsy revealed type I membranoproliferative glomerulonephritis (MPGN). The association of a malignant tumor and MPGN is extremely unusual in children, and the pathogenesis of the renal lesion under these circumstances is unknown. Received June 23, 1994; accepted in revised form July 10, 1996; accepted July 11, 1996     

Idiopathic membranoproliferative glomerulonephritis in childhood

Membranoproliferative glomerulonephritis (MPGN), recognized since 1965, is now known to have three forms, designated types I, II, and III. The types are similar in the frequency of hypocomplementemia and clinical course but are dissimilar in glomerular ultrastructure, pathogenesis, mechanisms of complement activation, predisposition to recur in the renal transplant, and, to some extent, in clinical presentation. Although glomerular proliferation is usually diffuse, it may be focal and segmental particularly in mild cases of MPGN I. Hypocomplementemia, present in about 80% of patients, is the result of hypercatabolism of C3 by three mechanisms as well as of diminished C3 synthesis. The hypocomplementemia is unrelated to clinical course or prognosis. Although MPGN I and III both have a high frequency of an extended haplotype on chromosome 6, which has known associations with autoimmune phenomena, and both have a high frequency of inherited complement defects, they are nevertheless dissimilar in glomerular ultrastructure, complement profile, and immunohistology in ways which suggest a wide difference in pathogenesis. Abnormalities in humoral immunity appear not to be involved in MPGN III. Treatment with anticoagulant, antiplatelet and cytotoxic drugs have, in controlled trials, been either ineffective or marginally effective. Long-term use of alternate-day prednisone in high dosage appears to be the most efficacious regimen in both controlled and uncontrolled studies.     

Pathogenic mechanisms in membranoproliferative glomerulonephritis

PURPOSE OF REVIEW: This review considers new information on the pathogenesis of a long recognized and poorly understood form of glomerular injury, membranoproliferative glomerulonephritis. This disease has received growing attention as it is the principal renal manifestation of hepatitis C virus infection, which has become pandemic worldwide. RECENT FINDINGS: This review briefly describes three murine models of membranoproliferative glomerulonephritis suitable for pathogenesis studies. We consider recent evidence implicating innate immune mechanisms in immune and autoimmune-mediated glomerulonephritis, and recent data pointing to the alternative pathway of complement activation in the amplification of glomerulonephritic injury. SUMMARY: Understanding the contribution of complement activation and innate immunity to the evolution of membranoproliferative glomerulonephritis promises to provide new therapeutic targets for this disease. Inhibitors of the complement cascade are already being tested in clinical trials as therapeutic interventions for some human glomerular diseases. Successful tests of this approach in membranoproliferative glomerulonephritis are still awaited. Our understanding of how the innate immune system modulates glomerulonephritis is still in an early stage, and future studies should be directed at identifying targets and specific interventions that may also benefit patients with this disease.     

A patient with membranoproliferative glomerulonephritis diagnosed by the third biopsy via endocapillary proliferative glomerulonephritis and focal membranoproliferative glomerulonephritis

We present a girl with type I membranoproliferative glomerulonephritis (MPGN) diagnosed by the third renal biopsy. The first renal biopsy was performed at age 11.2 years after microscopic hematuria (which was revealed by school urinary screening) had persisted for 3 months, along with a low level of serum C₃. Pathological examination of the biopsied specimen revealed endocapillary proliferative glomerulonephritis with multiple humps. The serum C₃ level increased to within the normal range 2 months after the first renal biopsy, and the microscopic hematuria disappeared at age 12.3. However, microscopic hematuria, proteinuria, and the low serum complement level reappeared at age 12.8. Pathological examination of a further renal biopsy that was performed at age 13.2 revealed focal MPGN with humps. Prednisolone therapy was subsequently initiated. Fluvastatin was added to her treatment regime when she developed hypercholesterolemia at age 13.6 and was continued even after normal cholesterol levels were reestablished. Pathological examination of the third renal biopsy, which was performed at age 15.2, revealed type I MPGN with humps. Serum C₃ normalized 6 months after the cessation of prednisolone at age 15.9. It is clinically important that patients with nontypical acute glomerulonephritis should be observed over a long period and repeated renal biopsies should be performed.     

Clinicopathologic study of adult-onset membranoproliferative glomerulonephritis

We analyzed clinicopathologic characteristics of adult-onset membranoproliferative glomerulonephritis (MPGN) by comparing two tentatively-classified subgroups. Group A consisted of 9 patients in whom more than 50% of glomeruli showed mixed segmental and global duplication of glomerular basement membrane (GBM), and Group B 9 patients with global duplication of GBM. Group A showed a tendency for more favorable clinical course and outcome than Group B. Nephrotic syndrome was present in 33% of Group A and 100% in Group B, hypertension in 22% and 44%, hypocomplementemia in 44% and 67% at the time of renal biopsy. Deterioration of renal function, at comparable durations of follow-up of 62 +/- 12 (M +/- SE) and 53 +/- 13 months, was observed in 22% of Group A and 56% in Group B, respectively. Histologically, mesangial proliferation and tubulointerstitial change were more pronounced and frequency of sclerosing glomeruli was greater in Group B. There was also a negative correlation between the extent of global double contour and renal function as assessed by creatinine clearance at the time of renal biopsy (r = -0.55, P less than 0.05). These results indicate that the high incidence of global double contour, in addition to the presence of marked tubulointerstitial change and sclerosing glomeruli, may relate to progressive deterioration of renal function in MPGN. That outcomes for Group A and Group B may be different when clinical parameters, including the durations from onset of symptoms to the time of biopsy and length of follow-up periods, are comparable also indicates that these two groups should be considered separate entities, at least on the basis of clinical results.     

Focal segmental membranoproliferative glomerulonephritis in children

Eight patients with focal segmental membranoproliferative glomerulonephritis (FSMPGN) were followed for 5–16 years. Their urinary abnormalities were detected by school urinary screening in seven, and one patient presented with nephrotic syndrome. All but one patient were treated with alternate-day (ALD) prednisolone. With time, urinalysis became normal in six and two continued to have proteinuria with or without hematuria. Serum albumin, cholesterol, and creatinine levels were normal at the last follow-up. Serum C3 returned to normal levels in six, but remained persistently decreased in two. Mesangial proliferation and matrix changes in glomeruli without MPGN lesions were mild. Subendothelial and mesangial electron-dense deposits and deposits containing C3 along capillary walls and mesangium were observed. MPGN lesions and mesangial proliferation improved. No severe growth retardation was observed, but the duration and dosage of ALD prednisolone could be reduced further, since the patients with FSMPGN seemed to have an excellent prognosis.     

Apoptosis and proliferating cell nuclear antigen in lupus nephritis (class IV) and membranoproliferative glomerulonephritis

BACKGROUND: The role of apoptosis in the pathogenesis of renal diseases has not been clearly established. Proliferating cell nuclear antigen (PCNA) is also a proliferation marker. In this study, we investigated the relationship between clinical course and PCNA apoptosis on baseline renal biopsy in patients with Lupus nephritis (LN) and membranoproliferative glomerulonephritis (MPGN). METHODS: Thirty-nine patients with proliferative glomerulonephritis [lupus nephritis (LN)[21] and MPGN[18]] were included in this study. PCNA and apoptosis on renal biopsies were detected by immunohistochemical and terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) methods, respectively. We calculated the ratios of intraglomerular apoptotic cells and PCNA positive cells per glomeruli, and total numbers of apoptotic tubular cells and PCNA positive tubular cells among the 100 tubular cells, and PCNA positive cell and apoptotic cell on two different tubulointerstitial areas (40 x 10). RESULTS: In LN: Apoptotic indexes of glomerulus and tubulus were 1.08+/-0.49 and 3.71+/-1.38, respectively. PCNA positivities were found at 16.76+/-11.34%, 46.57+/-22.54%, and 40.28+/-23.14% on glomerulus, tubulus, and interstitium, respectively. The activity index was 11.23+/-3.41, and the chronicity index was 3.81+/-1.99. In MPGN: Apoptotic indexes were found at 0.83+/-0.25 and 3.55+/-1.75 on glomerulus and tubulus, respectively. PCNA positivities were found at 21.33+/-18.42%, 35.5+/-25.99%, and 34.66+/-26.84% on glomerulus, tubulus, and interstitium, respectively. In controls, apoptosis was not found. In LN: PCNA positivity on tubulus and interstitium were correlated with the activity index (r = 0.768, p < 0.001, r = 0.721, and p < 0.001, respectively). Glomerular PCNA and apoptosis on interstitium and glomerulus were not correlated with the activity index. The activity index also was not correlated with creatinine clearance and daily proteinuria (p = 0.35 for both). At the end of the first year, patients with recovered or stabilized renal function had higher interstitial and tubular PCNA than others in G1 and G2. CONCLUSION: It can be said that expression of PCNA on renal biopsy was correlated with activity indexes in LN. PCNA may be a prognostic indicator in MPGN and LN. However, apoptosis does not have a predictive value for MPGN and LN.     

Circulating immune complexes in membranoproliferative glomerulonephritis

Circulating immune complexes (CIC), measured by the solid-phase Clq method, were found to be in abnormal concentration in about half of 39 patients with membranoproliferative glomerulonephritis (MPGN). In contrast, they were present, usually in higher concentration, in nearly all patients with active lupus nephritis. Correlations between clinical course and CIC levels in patients with MPGN showed that complexes were always present when the disease was mild or "silent," but when renal impairment developed or was incipient, complexes were nearly always absent. In patients with disease of intermediate severity, characterized by definite proteinuria but without renal impairment, 50% had complexes. The presence of complexes when glomerular abnormality is relatively slight could be interpreted as indicating that the complexes measured were not nephritogenic, or that they program subsequent events that augment glomerular injury in the absence of complexes. The measurement of CIC in MPGN appears to have minimal value both in diagnosis and in determining prognosis.     

Idiopathic membranoproliferative glomerulonephritis in Japanese children

The course of idiopathic membranoproliferative glomerulonephritis (MPGN) in 41 Japanese children (21 boys, 20 girls) is reported. The mean follow-up period was 8 years, 9 months; 29 children with MPGN (71%) were identified by school urinary screening; 32 patients had type I MPGN, 2 type II and 7 type III; 10 patients were treated with multiple low-dose cocktail therapy (MLD), 8 with MLD followed by high-dose alternate-day (ALD) prednisolone and 21 with high-dose ALD prednisolone alone. In 1 patient, MPGN progressed to end-stage renal failure. The serum creatinine level in all of the remaining 40 patients was ≤ 1.3 mg/dl at the last follow-up. Urinalysis was normal in 24 (59%). Of the 17 patients who still had urinary abnormalities, 4 had nephrotic syndrome. The incidence of remission of urinary abnormalities was highest in the patients treated with high-dose ALD prednisolone. Rebiopsy was performed in 33 patients, and revealed slight histological improvement in 11 (33%) patients, moderate improvement in 8 (24%), marked improvement in 5 (15%) and deterioration or no improvement in 9 patients (27%). Relatively few side effects of treatment were observed. The superior outcome of the MPGN patients in this compared with other studies may be the result of earlier detection and treatment.     

Inherited complement component deficiencies in membranoproliferative glomerulonephritis

Anecdotal reports of complement component deficiencies in patients with immune complex disease led to a systematic study of the levels of seven complement components in serum specimens from 178 patients with glomerulonephritis and 163 normal subjects. Deficiencies were found with significantly higher frequency (22.7%) among 44 patients with membranoproliferative glomerulonephritis (MPGN) types I and III, than among the normal subjects (6.7%, P less than 0.002) or among 134 patients with other glomerulonephritides (5.2%, P less than 0.001). The component deficiencies in MPGN were partial in nine patients and subtotal in one. They could not be ascribed to acquired hypocomplementemia or to a nephrotic syndrome. They were present over long periods, were found in family members, and involved C2, C3, factor B, C6, C7, and C8. Six were presumably the result of null structural genes, two were associated with a structurally abnormal component, and two were of unknown cause. The results give evidence that partial deficiency of one or more complement components is a factor predisposing to MPGN.     

Focal and diffuse membranoproliferative glomerulonephritis in children

Characteristic deposition of C3 has been reported in type I membranoproliferative glomerulonephritis (MPGN). Immunofluorescence microscopy shows diffuse granular deposition of C3 along the majority of capillary loops with lobular pattern. To determine the specificity of this immunofluorescence finding which might aid in distinction between type 1 MPGN, particularly focal MPGN, and the other glomerulopathies, 530 renal biopsies from 437 children were studied retrospectively. Nineteen patients showed diffuse granular deposits of C3 along the capillary walls with lobular distribution. Three patients had lupus nephritis. Nine patients showed the light microscopic changes of diffuse type I MPGN with the characteristic double-walled capillaries. Six patients showed the changes of focal MPGN, and 1 had diffuse mesangial proliferation but without double contours, and they were regarded as examples of a mild or early form of MPGN. A similar deposition of C3 was not seen in the 418 patients with other conditions. We concluded that diffuse granular deposits of C3 along the capillary walls with a lobular distribution appear to be confined to type I MPGN and lupus nephritis and are seen in all patients with diffuse and focal type I MPGN.