Clinicopathological survey of persistent hypocomplementemic glomerulonephritis in children; correlation of DPGN and MPGN type I]

We studied clinicopathologically 19 patients with abnormal urinary findings accompanying with persistent hypocomplementemia under age 15. They consisted of 6 patients with membranoproliferative glomerulonephritis (MPGN) type I, 2 with MPGN type II, 2 with focal MPGN, 8 with diffuse proliferative glomerulonephritis (DPGN), 1 with focal glomerulonephritis (FGN). 17 cases were treated with steroid. In 2 patients with MPGN type I and 1 patient with DPGN, the treatment resulted in normalization of serum C3 level and urinary abnormalities and improvement of histological findings. In 3 patients with DPGN, urinary abnormalities and hypocomplementemia have been persisted and histological findings changed to those of MPGN type I. Thus, DPGN with hypocomplementemia seems to be an early stage of MPGN type I.     

Nucleosomes and histones are present in glomerular deposits in human lupus nephritis

Background. Recently we showed that antinuclear autoantibodies Complexed to nucleosomes can bind to heparan sulphate (HS) in the glomerular basement membrane (GBM) via the histone part of the nucleosome. Histones have been identified in glomerular deposits in human and murine lupus nephritis. In addition, a decreased HS staining in the GBM was found, most probably due to masking by deposition of antibodies complexed to nucleosomes. Methods. In this study we first investigated whether histones or nucleosomes could be identified in glomerular deposits in human lupus nephritis, and secondly whether the presence of these nuclear components was correlated with absence of HS staining. Kidney biopsies of SLE patients (11 with diffuse proliferative glomerulonephritis (DPGN) and six with membranous glomerulonephritis (MGN)) and of non-SLE glomerular diseases were stained for histones, DNA, nucleosomes, IgG and HS. Results. Using a polyclonal anti-H3 1-21 antiserum, histones were detected in all patients with DPGN and in two of six patients with SLE-MGN (P <0.01(. Using a monoclonal antihistone antibody, histones were stained in three patients with DPGN, but in none of the biopsies with MGN. Using nucleosome specific monoclonal antibodies, nucleosomes were detected in five patients with DPGN, in two patients with MGN, but in none of the biopsies with non-SLE glomerulonephritis. HS staining was nearly absent in DPGN, whereas staining was only moderately reduced in patients with MGN and controls (P=0.001). Conclusion. Using polyclonal and monoclonal antihistone antisera, histones were identified in all patients with DPGN and their presence was associated with a decrease of HS staining. Nucleosomes were identified in five of 11 patients with DPGN and in two of six patients with MGN. This is the first demonstration of nucleosomes in glomerular deposits in SLE nephritis.     

Asymptomatic haematuria and proteinuria: Renal pathology and clinical outcome in 54 children

In a mass screening programme, 54 children with haematuria and proteinuria were detected and evaluated by clinical findings and renal histology. IgA glomerulonephritis (GN) occurred in 29 patients, diffuse mesangial proliferative GN (DPGN) in 16, membranous GN (MGN) in 4, membranoproliferative GN (MPGN) in 3, and focal segmental glomerular sclerosis (FSGS) was seen in 2. Of the 35 children with proteinuria less than or equal to 1 g/m² per day, 21 with IgA GN and 14 with DPGN had only mild to moderate glomerular changes. None of these children had developed renal impairment after a mean period of 6.5 years (range 5–10 years). On the other hand, 8 children with IgA GN, 2 with DPGN, 4 with MGN, 3 with MPGN, and 2 with FSGS had proteinuria that exceeded 1 g/m² per day. The biopsy specimens from these children showed moderate to severe glomerular changes, and 7 of these children had hypertension or renal impairment during the period of evaluation. This study suggests that a poor outcome correlates with the level of proteinuria and the severity of renal pathology in children with haematuria and proteinuria.     

A case of fibrillary glomerulonephritis with unusual IgM deposits and hypocomplementemia

Fibrillary glomerulonephritis (FGN) is rare immune-mediated GN with predominant immunoglobulin (Ig) G deposits, normal serum complement levels, and poor prognosis. The incidence of FGN is less than 1% in the adult population, and only six pediatric cases have been reported in the English literature. A 12-year-old girl presented with acute nephrotic-nephritic syndrome mimicking atypical clinical features of acute poststreptococcal GN (APSGN). Clinical features had completely resolved in 2 weeks, but the serum complement levels remained low. Renal biopsy was done 6 months later, and she was diagnosed as having FGN with unusual IgM deposits. Despite persistently low serum complement levels during the subsequent 3 years, clinical relapse did not develop. This case was an atypical form of FGN characterized by unusual IgM deposits, persistent hypocomplementemia, and good prognosis, which suggests that childhood FGN is not necessarily a disease with poor prognosis.     

Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features

BACKGROUND: The clinical relevance of distinguishing two types of glomerulonephritis (GN) with non-amyloid organized immunoglobulin (Ig) deposits-fibrillary GN (FGN) and immunotactoid (microtubular) GN (IT/MTGN)-on the basis of ultrastructural organization, is debated. METHODS: Twenty-three patients with organized glomerular Ig deposits were classified into two groups based on the fibrillar or microtubular ultrastructural appearance of the deposits. Kidney biopsy samples were studied by immunofluorescence microscopy, using anti-light chain conjugates (all cases) and anti-IgG subclass conjugates (13 patients). In each group, we studied clinicopathological features, associated monoclonal gammapathy (detected by immunoelectrophoresis and/or immunoblot) or B-cell lymphoproliferative disease, effects of chemotherapy and long-term renal outcome. RESULTS: In 14 IT/MTGN and 9 FGN patients, clinical symptoms [hypertension, nephrotic syndrome (NS) and hematuria] and the mean diameters of the substructures were similar. In 13 IT/MTGN patients, glomerular (IgG1, 2 or 3) deposits were monotypic (kappa, 7 cases; lambda, 6 cases). Glomerular deposits were associated with a monoclonal Ig of the same isotype in eight patients, detected in the serum (5 cases), and/or in the cytoplasm of lymphocytes (4 cases), and with lymphoproliferative disease in seven patients. The ultrastructural features of monoclonal Ig inclusions in lymphocytes were similar to those of glomerular microtubular deposits. In contrast, none of the FGN patients presented lymphoplasmocytic proliferation or paraproteinemia. Glomerular Ig deposits were polyclonal in eight cases and contained IgG4 in all three cases studied. Although patient and renal survival did not differ significantly between the two groups, chemotherapy led to remission of NS in ten IT/MTGN patients, with parallel improvement in hematological parameters. CONCLUSIONS: The identification of ultrastructural patterns in these nephropathies is important. GN with organized microtubular monoclonal deposits (GOMMID) probably accounts for a large proportion of immunotactoid (microtubular) GN cases.     

The pathology and clinical features of early recurrent membranous glomerulonephritis

We assessed the earliest manifestations of recurrent membranous glomerulonephritis (MGN) in renal allografts. Clinical, laboratory and pathologic data were reviewed in 21 patients at the initial biopsy within 4 months post-transplant with evidence of MGN and on follow-up biopsies, compared to a biopsy control group of eight transplants without recurrent MGN. The mean time of first biopsy with pathologic changes was 2.7 months. In each earliest biopsy, immunofluorescence (IF) showed granular glomerular basement membrane (GBM) staining for C4d, IgG, kappa and lambda. IF for C3 was negative or showed trace staining in 16/21. On each MGN biopsy positive by IF, 14/19 showed absence of deposits or rare tiny subepithelial deposits by electron microscopy (EM). At the earliest biopsy, the mean proteinuria was 1.1 g/day; 16 patients had <1 g/day proteinuria. Follow-up was available in all patients (mean 35 months posttransplant). A total of 13 patients developed >1 g/day proteinuria; 12 were treated with: rituximab (n = 8), ACEI and increased prednisone dose (n = 2), ACEI or ARB only (n = 2). All patients showed reduction in proteinuria after treatment. A total of 11/16 patients showed progression of disease by EM on follow-up biopsy. Recognition of early allograft biopsy features aids in diagnosis of recurrent MGN before patients develop significant proteinuria.     

Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3κ (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.Among dysproteinemia-related renal diseases, those manifesting monoclonal glomerular deposits of IgG are relatively uncommon. Renal diseases caused by monoclonal IgG deposition include light- and heavy-chain deposition disease (LHCDD),¹ type 1 cryoglobulinemic glomerulonephritis,² immunotactoid glomerulonephritis (IT),³ light- and heavy-chain amyloidosis,⁴ and rarely fibrillary glomerulonephritis (FGN).³ LHCDD is characterized by the presence of nodular sclerosing glomerulopathy by light microscopy (LM); diffuse, linear staining of glomerular basement membranes (GBMs) and tubular basement membranes (TBMs) for a single heavy chain and a single light chain by immunofluorescence (IF); and nonfibrillar, “powdery” electron-dense deposits in GBMs and TBMs by electron microscopy (EM).¹ Type 1 cryoglobulinemic glomerulonephritis exhibits a membranoproliferative or diffuse proliferative glomerulonephritis pattern on LM, usually with prominent intracapillary infiltrating monocytes and large, glassy intraluminal immune deposits.² Ultrastructurally, the deposits commonly show an annular-tubular or fibrillar substructure. The glomerular deposits in IT are composed of microtubular structures with a diameter of 30 to 50 nm and a tendency for parallel alignment, whereas in FGN they are composed of Congo red–negative, randomly oriented fibrils measuring 16 to 24 nm in diameter.³ Light- and heavy-chain amyloidosis is extremely rare and, similar to light chain amyloidosis, is characterized by the presence of Congo red–positive deposits composed of haphazardly oriented fibrils that measure 8 to 14 nm in diameter.⁴In 2004, we reported 10 patients with a novel form of glomerular injury related to monoclonal IgG deposition that could not be assigned to any of these conditions, which we termed “proliferative glomerulonephritis with monoclonal IgG deposits” (PGNMID).⁵ On IF, the glomerular deposits were monoclonal, staining for a single light-chain isotype and a single γ heavy-chain subclass. LM exhibited endocapillary proliferative or membranoproliferative glomerulonephritis, and EM revealed granular electron-dense deposits, mimicking ordinary immune-complex glomerulonephritis. Clinical presentations included proteinuria in 100% of patients (mean 24-h urine protein 5.8 g/d), renal insufficiency in 80% (mean serum creatinine 2.8 mg/dl), and micohematuria in 60%. A monoclonal serum or urine protein was identified in 50% of patients, although none of them had evidence of multiple myeloma (MM) or B cell lymphoproliferative disorder.⁵ The follow-up on these 10 patients was of short duration, and the treatment details were limited.This report enlarges our experience with PGNMID to 37 cases, representing the largest series to date. Our aim was to define better the natural history, presenting features, treatment, and outcome of this enigmatic disease.     

Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis

BACKGROUND: Renal disease related to the deposition of monoclonal immunoglobulins containing both heavy and light chains can occur in type 1 cryoglobulinemia, Randall type light and heavy chain deposition disease (LHCDD), and immunotactoid glomerulonephritis. We report a novel phenotype of glomerular injury that does not conform to any of the previously described patterns of glomerular involvement by monoclonal gammopathy. METHODS: Ten cases of unclassifiable proliferative glomerulonephritis manifesting glomerular monoclonal immunoglobulin G (IgG) deposits were identified retrospectively from the archives of the Renal Pathology Laboratory of Columbia University over the past 3 years (biopsy incidence 0.21%). RESULTS: The monoclonal immunoglobulins formed granular electron dense deposits in mesangial, subendothelial, and subepithelial sites, mimicking ordinary immune complex-mediated glomerulonephritis and producing a diffuse endocapillary proliferative or membranoproliferative glomerulonephritis. However, by immunofluorescence, the deposits were monoclonal, staining for a single light chain isotype and a single gamma subclass (including two IgG1kappa, one IgG1lambda, one IgG2lambda, four IgG3kappa, and one IgG3lambda). All cases stained for the three constant domains of the gamma heavy chain (CH1, CH2, and CH3), suggesting deposition of a nondeleted immunoglobulin molecule. Tissue fixation of complement was observed in 90% of cases, and 40% of patients had hypocomplementemia. Clinical presentations included renal insufficiency in 80% (mean serum creatinine 2.8 mg/dL, range 0.9 to 8.0), proteinuria in 100% (mean urine protein 5.8 g/day; range 1.9 to 13.0), nephrotic syndrome in 44%, and microhematuria in 60%. A monoclonal serum protein with the same heavy and light chain isotype as that of the glomerular deposits was identified in 50% of cases (including three IgGkappa and two IgGlambda); however, no patient had clinical or laboratory features of type 1 cryoglobulinemia. No patient had overt myeloma or lymphoma at presentation or over the course of follow-up (mean 12 months). CONCLUSION: Glomerular deposition of monoclonal IgG can produce a proliferative glomerulonephritis that mimics immune-complex glomerulonephritis by light and electron microscopy. Proper recognition of this entity requires confirmation of monoclonality by staining for the gamma heavy chain subclasses.     

Outcome of renal transplantation in fibrillary glomerulonephritis

Fibrillary glomerulonephritis (FGN) is a rare but progressive glomerular disease usually with end-stage renal disease (ESRD) developing within months or few years following the diagnosis. Little is known about the outcome of renal transplantation in patients with ESRD due to FGN. We report four patients with FGN who received renal allografts. Two patients developed recurrent FGN in their grafts. One patient was diagnosed to have recurrent FGN 9 years post-transplant, and lost his graft 4 years thereafter. Another patient had recurrent disease 2 years post-transplant but has stable graft function after 7 years. One patient died with normal renal allograft function 7 years following transplantation. The fourth patient has chronic transplant nephropathy 34 months post-transplant without evidence of recurrent FGN. A literature review revealed 10 additional patients who received 11 renal allografts due to ESRD caused by FGN. Four of these 10 patients had biopsy-proven recurrence (one patient in two subsequent grafts), but this caused graft loss only in 2 patients 56 months and 7 years post-transplant, respectively. The earliest recurrence was diagnosed 2 years post-transplant. We conclude that although the recurrence rate of FGN in renal transplants is high (around 50%), the recurrent disease has a relatively benign course and prolonged graft survival is possible.     

Differences between membranoproliferative glomerulonephritis types I and III in clinical presentation, glomerular morphology, and complement perturbation

Data for 26 patients with membranoproliferative glomerulonephritis, type I (MPGN I) and 22 with membranoproliferative glomerulonephritis, type III (MPGN III), as distinguished by glomerular ultrastructure, were analyzed to determine differences in presentation, complement perturbation, and glomerular morphology by light microscopy. MPGN III was detected with greater frequency by the chance discovery of hematuria and proteinuria in the otherwise healthy individual (MPGN III, 63%; MPGN I, 30%; P = .01) and never, in the absence of renal failure, presented with systemic symptoms such as ease of fatigue, weight loss, and pallor, as may patients with MPGN I. The more frequent detection of MPGN III by chance is evidence that its onset is insidious and that for long periods it produces no symptoms or signs. Glomerular proliferation is also less than in MPGN I. Further, in MPGN III, the complement perturbation and glomerular immunofluorescence give no evidence of classical pathway activation, for which there is abundant evidence in MPGN I. Even with severe hypocomplementemia in MPGN III, C3 nephritic factor, another cause of hypocomplementemia, is rarely detectable and then in very low concentration. The cause of the complement perturbation in MPGN III has so far escaped identification. Although these observations give evidence that MPGN III is distinct from MPGN I, there is compelling evidence from other studies that a predisposition to both types is inherited and that similar genetic factors are operative in the two types. Because their genetic basis appears to be the same, it must be concluded that despite their differences, types I and III are variants of the same disease.     

Ultrastructural study on membranoproliferative glomerulonephritis with special reference to subepithelial deposits

The distribution of electron dense deposits in the glomerulus was scrutinized by electron microscopy in 34 cases of membranoproliferative glomerulonephritis (MPGN). Seven cases underwent serial biopsies. Results are summarized as follows. (1) Mesangial deposits (MD) and subendothelial deposits (SEND) were demonstrated in nearly all biopsy specimens. Intramembranous deposits (IMD) and subepithelial deposits (SEPD), which had hitherto been considered uncommon in MPGN, were also seen in over three- fourths of the specimens. (2) According to these findings, Burkholder's Type III MPGN, characterized by the frequent presence of SEPD, seems not to be essential in the classification of MPGN. In contrast, Strife's type III MPGN, defined by the disruption of the glomerular basement membrane (GBM), appears to be appropriate for the classification, because the cases diagnosed as Strife's type III showed quite peculiar histology among the MPGN. (3) In most cases having undergone serial biopsies, cellular proliferation in the glomeruli was more improved at the second biopsy than at the first, which probably resulted from intensive medications such as the combined therapy of corticosteroids, immunosuppressants, and anticoagulants. On electron microscopy, however, electron dense deposits were not decreased, and SEPD was rather increased. Furthermore, the GBM was more thickened and showed more irregular structure in the second biopsy. (4) Humps were observed in 14 out of 41 biopsy specimens of MPGN. They were seen not only in the acute but also in the chronic stage of the disease, especially in the cases with persistent hypocomplementemia. These results suggest that the subepithelial deposits are more common in MPGN than considered previously, and are more closely related to the morphological changes and the progression of MPGN. In particular, humps should be a marker indicating the activity of the disease associated with hypocomplementemia, whether it is acute or chronic.     

The alternative pathway C3 convertase and glomerular deposits

Five conditions in which the alternative pathway C3 convertase, C3b,Bb, circulates in excess as a result of factor H dysfunction are frequently accompanied by nephritis. These convertase-related nephritides are seen in association with heterozygous absence of a binding site for factor H on C3b (Marder disease), homozygous factor H deficiency, circulating factor H inhibitor, and with the nephritic factors, one of the amplification loop and the other of the terminal pathway, found in membranoproliferative glomerulonephritis (MPGN) types II and III, respectively. Observations which relate convertase to glomerular deposits are: (1) in MPGN type II, subepithelial deposits on the paramesangial segments of the glomerular basement membrane are with high frequency present in patients hypocomplementemic at biopsy, but not in those normocomplementemic; (2) in MPGN type III paramesangial deposits are similarly found with hypocomplementemia but are present for up to 1 year after normocomplementemia is achieved; (3) in MPGN type III, subendothelial deposits are present only with hypocomplementemia. The principal deposits foundin factor H deficiency and in Marder disease are also paramesangial. Differences in the incidence, severity, and morphology of the nephritides accompanying convertase in excess may relate to the characteristics of the circulating convertase and/or to the C3 conversion products formed by it. Received: 17 September 1998 / Accepted: 3 November 1998     

De novo membranous glomerulonephritis in renal allografts in children

The incidence of de novo membranous glomerulonephritis (MGN) in transplanted kidneys is around 1 to 2%. In our series, of the 310 grafts that were examined by immunofluorescence microscopy (IF), 29 (9.3%) showed subepithelial IgG deposits, a pattern consistent with the diagnosis of MGN. Transplant biopsy had been performed because of the occurrence of proteinuria in 8 patients (pts), for suspected rejection in 16 and systematically in the remaining 9 who had no proteinuria and a normal renal function. In all cases the lesions were identified by IF and were confirmed by electron microscopy (EM) in 14 pts. Granular deposits of IgG were diffuse in 22 cases and segmental in 7. Sequential specimens were available in 17 pts and showed the persistence or the increase of the IgG deposits in all patients but one in whom they had disappeared. Age at transplantation (Tx) ranged from 2 years 3 months to 16 years. Grafts were from cadaveric donors in 27 pts and from living related donors in 2 pts. In none of the recipients was MGN the nephropathy of the native kidneys. With a follow-up of 18 to 74 months, 6 pts never developed a proteinuria. In the remaining 23, proteinuria developed 1 to 70 months after Tx, associated with a nephrotic syndrome (NS) in 6 pts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Idiopathic nephrotic syndrome of the adult with asymptomatic thrombosis of the renal vein

Twenty-six adult patients with idiopathic nephrotic syndrome, ages ranging from 16 to 62 years, were prospectively evaluated with selective renal venogram for the presence of renal vein thrombosis (RVT). Ten patients had membranoproliferative glomerulonephritis (MPGN); 5, membranous nephropathy (MGN); 3, diffuse proliferative glomerulonephritis (DGPG), and 1 focal glomerulonephritis (FPG). Renal vein thrombosis was observed in 11 patients. The primary nephropathies in these patients were: MPGN in 4, MGN in 3, FGS in 2, FPG in 1, and DGPG in 1. All patients were asymptomatic. The clinical and renal pathology features were similar in patients with and without RVT. Other thromboembolic complications were observed in 4 patients. In conclusion, renal vein thrombosis was observed in 42% of our patients and MPGN was the most frequent nephropathy associated with RVT.     

Natural killer activity and antibody-dependent cell-mediated cytotoxicity in primary glomerular diseases

This study was performed to investigate the role of cell-mediated immunity in primary glomerular diseases (PGD), by estimating natural killer (NK) activity from peripheral blood mononuclear cells (PBMC) assayed against K562 cells, and antibody-dependent cell-mediated cytotoxicity (ADCC) activity from PBMC assayed against chicken red blood cells. The proportion of PBMC was examined by flow cytometry using the monoclonal antibodies OKT and Leu series. NK activity in patients with nephrotics of minimal change nephrotic syndrome (MCNS), membranous glomerulonephritis (MGN) and membranoproliferative glomerulonephritis (MPGN) was significantly lower compared to those of the normal controls. In addition, ADCC activity in patients with nephrotics of MPGN was significantly lower compared to the normal controls. The sera from patients with diminished NK activity inhibited NK activity of PBMC from healthy individuals. Furthermore, OKM1 positive lymphocytes were significantly higher in the MCNS, MGN and MPGN patients and Leu7 positive lymphocytes were significantly higher in the MPGN patients. These data suggest that several mechanisms contribute to the defects of NK and ADCC activities in patients with PGD, and the defects in NK and killer cells are common in patients with nephrotics of MCNS, MGN and MPGN, and may be important in the pathogenesis of PGD.     

Membranoproliferative glomerulonephritis type III: association of glomerular deposits with circulating nephritic factor-stabilized convertase

Deposits in the glomerular ultrastructure of 44 renal biopsy specimens from 21 patients with membranoproliferative glomerulonephritis (MPGN) type III have been compared with those in the ultrastructure of 34 biopsy specimens from 19 patients with MPGN type I. Previous studies have concluded that subepithelial deposits on the paramesangial portion of the glomerular basement membrane in MPGN types II and III are closely associated with circulating nephritic factor-stabilized convertase. In the present study, subendothelial deposits in MPGN type III were also found to be closely associated with nephritic factor; they were present in 14 of 26 (54%) biopsy specimens obtained during hypocomplementemia but in none of the 18 biopsy specimens obtained during normocomplementemia (P < 0.001). Subepithelial loop deposits in type III were also more frequent in biopsy specimens obtained during hypocomplementemia and are probably in some way also associated with circulating stabilized convertase. Taken together, the results of this and previous studies are compatible with the hypothesis that an excess of the C3b-dependent convertase in the circulation is basic to the pathogenesis of MPGN types II and III as well as of several other nephritides associated with factor H dysfunction. The half-life, structural complexity, and size of the convertases circulating in these nephritides increase in the following order: native convertase, convertase stabilized by the nephritic factor of the amplification loop (NFa), and convertase stabilized by nephritic factor of the terminal pathway (NFt). In the same order, the nephritides associated with these convertases more frequently manifest and have increasing amounts of glomerular deposit. This relationship of glomerular deposits with circulating convertase, however, is only circumstantial. There is no evidence that the convertase or a part thereof is a constituent of the deposits. The lesion that is the hallmark of MPGN type III is one in which interruptions of lamina densa are associated with subendothelial and subepithelial deposits, often confluent, and interspersed with multiple layers of new lamina densa-like material. This "type III lesion," which by implication is also associated with circulating nephritic factor, is the most persistent of the glomerular deposits. For reasons that are not yet clear, the type III lesion was absent in three patients who were severely hypocomplementemic, and the diagnosis of type III was made only after this lesion appeared in biopsy specimens obtained later. In MPGN type I, differing from type III, subendothelial deposits were present in 100% of biopsy specimens obtained during hypocomplementemia and in 47% of those obtained during normocomplementemia. Their persistence in type I may reflect rearrangement and condensation of the deposited material, shown by other investigators to be dependent on the presence of immunoglobulin G, which is largely absent from the deposits in type III. The comparison of deposits in types I and III indicates that relating the presence of subendothelial and paramesangial deposits to the C3 level at the time of biopsy can be helpful in distinguishing types I and III when the type III lesion is not present.     

Long-term benefits of therapy with cyclophosphamide and prednisone in patients with membranous glomerulonephritis and impaired renal function.

Long-term follow-up data are provided for a previously reported study of patients with membranous glomerulonephritis (MGN), nephrotic syndrome, and renal function impairment. Nine patients were treated with cyclophosphamide (1 to 2 mg/kg) and six of these received concurrent prednisone; they are compared with 17 concurrent controls (14 of whom had received prednisone at some time). The mean follow-up is 83 +/- 13 months in the treated patients and 64 +/- 7 months in the controls. Of the nine treated patients, four achieved a complete remission from the nephrotic syndrome (proteinuria less than 0.5 g/d), and five a partial remission (proteinuria decreased by at least 50% and to less than 3.5 g/d). One of the nine treated patients and 10 of the 17 controls have reached end-stage renal disease (ESRD) (P less than 0.05). Nine of the controls reaching ESRD had persistent nephrotic syndrome, whereas of the seven controls who have not yet reached ESRD, only two have persistent nephrotic syndrome (chi 2, P less than 0.02). There have been four relapses in three treated patients, and three of the four have responded to repeat therapy. One patient refused full therapy and remains nephrotic. Life-table analysis demonstrates significantly increased survival from ESRD in treated patients as compared with controls (P = 0.04).     

A case of idiopathic membranoproliferative glomerulonephritis with a transient glomerular deposition of nephritis-associated plasmin receptor antigen

The differential diagnosis of acute poststreptococcal glomerulonephritis (APSGN) and idiopathic membranoproliferative glomerulonephritis (MPGN) is sometimes difficult, as they share several key features in their laboratory and histological findings, especially during the acute phase of the diseases. We herein report an idiopathic case of MPGN in which the glomerular deposition of nephritis-associated plasmin receptor (NAPlr), a recently identified nephritic antigen for APSGN, was demonstrated. A 24-year-old postpartum woman developed nephrotic syndrome and hypocomplementemia. Although she showed no apparent findings of a prior infection, her serum titer of antistreptolysin O antibody was elevated. Renal biopsies were performed twice at intervals of 6 months, both of which showed findings fully consistent with those of MPGN. Of note, fluorescent immunostaining for NAPlr was positive in the glomeruli of the first biopsy but not in the second. Despite the use of a corticosteroid, hypocomplementemia persisted for more than 1 year. It was therefore suggested that a streptococcal infection may have influenced the development of glomerular injury in this idiopathic case of MPGN.     

IgA deficiency and membranous glomerulonephritis presenting as nephrotic syndrome

Selective IgA deficiency associated with glomerulonephritis is rare and no previous reports in childhood have been made of the association of IgA deficiency and membranous glomerulonephritis (MGN). We report a 5-year-old boy with selective IgA deficiency and MGN. He presented with nephrotic syndrome. Percutaneous renal needle biopsy showed diffuse global thickening on light microscopy and heavy IgG and moderate C3 deposits were found on immunofluorescence. Electron microscopy detected extensive global subepithelial deposition of electron-dense material with frequent intramembranous extension and spike formation. The pathological diagnosis was diffuse MGN stage 1. Oral prednisolone (1 mg kg^–1 day^–1), angiotensin-converting enzyme inhibitors (ACEI), and angiotensin II receptor blocker (ARB) were given resulting in reduction of proteinuria. The prednisolone dose was gradually tapered and discontinued after 2 months. At present the patient has been in complete remission for 10 months despite the discontinuance of prednisolone. In conclusion, our treatment with corticosteroid, ACEI and ARB reduced proteinuria and was effective for our case with selective IgA deficiency and MGN.     

De novo membranoproliferative glomerulonephritis III in a renal transplant patient: case report and review of the literature

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare cause of renal failure with a cumulative incidence of 0.3% of all ESRD and 4% of all primary glomerulonephritis for types I and II. Membranoproliferative glomerulonephritis type III is more uncommon and idiopathic de novo MPGN III in a renal transplant patient has not been reported. We present the case of a 57-year old white female patient with a diagnosis of lithium toxicity as cause of end stage renal disease (ESRD) who developed MPGN III in her allograft 6 years after a renal transplant. Despite treatment, she progressed to ESRD within four and a half years from the time of diagnosis.