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Objectives: Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN) is considered "pauci-immune" with absent or mild glomerular tuft staining for immunoglobulin (Ig) and/or complement. However, it is not unusual to see some immune deposits (ID) within glomeruli on immunofluorescence (IF). We determined to evaluate the prevalence and clinical significance of immune deposits in ANCA-associated GN., Methods: We included all patients with ANCA associated vasculitis with renal biopsies between January 2002 and May 2014: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis and renal limited vasculitis. Patients were divided into Group A: biopsy without ID (≤2+ intensity of immunostaining) and Group B: biopsy with ID (>2+ intensity of immunostaining). Serum creatinine, estimated glomerular filtration rate (eGFR) at time of the biopsy, amount of proteinuria and hematuria, requirement of dialysis and extra renal involvement were recorded., Results: Fifty-three patients (75.4% females) were included. Mean age at biopsy was 66.3 years. Typical pauci-immune GN was found in 39 patients (73.5%, group A). In 14 patients (26.4%, group B) examination revealed substantial deposition of Ig or complement in the mesangium and/or along the glomerular capillary wall. The only difference comparing both groups was significantly higher proteinuria in group B (mean 1.6/24 h (SD: 10.7) vs. 0.8/24 h (SD: 7.6), p=0.0036)., Conclusions: In ANCA GN at least a quarter of patients were not "pauci-immune" (26.4%). In this subgroup, immune deposits were only associated with a significantly higher proteinuria. Further basic and clinical research is needed to elucidate the significance of immune deposition in ANCA GN.

C1q nephropathy (C1qN) is defined by conspicuous C1q deposits in the glomerular mesangial regions of patients who do not have any evidence of systemic lupus erythematosus (SLE). We present our experience with C1qN over the last three years. In total, 1775 native renal biopsies were reviewed and dominant/co-dominant C1q mesangial deposits in patients with absence of clinical and/or serological evidence of SLE were considered as C1qN. Their clinical profile and renal function status were studied and correlated. C1qN was observed in 11 patients (0.61%), and included eight males and three females; the mean age was 36.6 years. The most common presentation was nephrotic syndrome. Hematuria was noted in eight patients (72%). The mean serum creatinine was 2.78 mg/dL. Hypertension was seen in two patients (18%). Mesangial proliferative glomerulonephritis (MePGN) was the most common histological pattern, followed by focal and segmental glomerulosclerosis and other lesions. The common codeposits along with C1q were IgM, followed by C3 and others. MePGN had better prognosis than others. To conclude, C1qN was noted in 0.61% of all renal biopsies with bimodal age distribution and may present as podocytopathy or non-podocytopathy. The prognosis depends on the morphological pattern and C1q deposits per se are not prognostic indicators.

Introduction: There is no data specifically on the clinical and immunopathologic features of Immunoglobulin M nephropathy (IgMN) in adults with kidney diseases in Pakistan., Materials and Methods: We retrospectively reviewed our adult native renal biopsy records from May 2001 to April 2010 and identified 57 cases out of a total of 1,753 records labeled as IgMN on final histopathological analysis. Among these, 41 cases were included in the present analysis. Their relevant data items were collected from the case files and biopsy reports., Results: The mean age of this cohort was 30.21 ± 10.12 years. The male-female ratio was 1.15:1. The most common presentation was idiopathic nephrotic syndrome. Hematuria and hypertension at presentation were noted in 24 (58.5%) and 10 (24.4%) patients, respectively. The most common morphologic change was glomerular mesangial cell proliferation, found in 28 biopsies (68.3%). Mesangial matrix expansion was noted in 16 (39%). Minor glomerular alterations were noted in 5 cases (12.2%) and focal segmental glomerulosclerosis in 4 (9.8%). Immunofluorescence microscopy showed diffuse mesangial positivity of IgM in all specimens. Subdominant IgA was noted in 6 cases (14.6%). Complements C3 and C1q were found in 28 (68.3%) and 21 (51.2%) patients, respectively., Conclusions: Our results show that IgMN is not very common in adults. Its clinicopathological spectrum is similar to that described from the neighboring countries, showing a spectrum of morphologic changes ranging from minor changes to focal segmental glomerulosclerosis.

C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.

Background and Objectives: Only rare cases of concurrent membranous glomerulonephritis (MGN) and antineutrophil cytoplasmic antibody (ANCA)-associated necrotizing and crescentic glomerulonephritis (NCGN) have been reported., Design, Setting, Participants, & Measurements: The authors report the clinical and pathologic findings in 14 patients with MGN and ANCA-associated NCGN., Results: The cohort consisted of eight men and six women with a mean age of 58.7 yr. ANCA positivity was documented by indirect immunofluorescence or ELISA in all patients. Indirect immunofluorescence was positive in 13 patients (seven P-ANCA, five C-ANCA, one atypical ANCA). ELISA was positive in nine of 10 patients (five MPO-ANCA, three PR3-ANCA, one MPO- and PR3-ANCA). Clinical presentation included heavy proteinuria (mean 24-hr urine protein 6.5 g/d), hematuria, and acute renal failure (mean creatinine 4.4 mg/dl). Pathologic evaluation revealed MGN and NCGN, with crescents involving a mean of 32% of glomeruli. On ultrastructural evaluation, the majority of cases showed stage I or II membranous changes. Follow-up was available for 13 patients, 12 of whom were treated with steroids and cyclophosphamide. At a mean follow-up of 24.3 mo, five patients progressed to ESRD, seven had stabilization or improvement in renal function, and one had worsening renal function. Five patients, including three with ESRD, died during the follow-up period. The only independent predictor of progression to ESRD was serum creatinine at biopsy., Conclusions: MGN with ANCA-associated NCGN is a rare dual glomerulopathy seen in patients with heavy proteinuria, acute renal failure, and active urine sediment. Prognosis is variable, with 50% of patients reaching endpoints of ESRD or death.

Objective: Recent studies have revealed a potential implication of CD8+ T lymphocytes in the pathogenesis of systemic lupus erythematosus (SLE) through their ability to induce tissue damage. The aim of the present study was to analyze the localization of CD8+ cells in the kidneys of patients with class III and class IV lupus nephritis and to establish correlations with histologic, biologic, and clinical features of SLE., Methods: Twenty-five consecutive SLE patients with class III or class IV lupus nephritis were enrolled. Phenotype analyses of blood lymphocytes and renal immunohistochemistry studies were performed., Results: CD8+ T cells were the predominant kidney-infiltrating subset of cells. The mean +/- SD numbers of CD8+ T cells and CD4+ T cells were 66.2 +/- 65.2/mm(2) and 19.3 +/- 29.4/mm(2), respectively. There was a significant correlation between the percentage of blood CD3+,CD8+,DR+ cells and the total number of renal CD8+ T cells (r = 0.42, P = 0.039). Renal CD8+ T cell infiltration correlated well with the renal activity index (r = 0.63, P = 0.0007) and with high serum creatinine levels (r = 0.75, P = 0.0001). This CD8+ T cell infiltrate, which was predominantly in the periglomerular area, was correlated with cellular crescents and Bowman's capsule rupture and was associated with a poor response after conventional induction therapy., Conclusion: CD8+ T lymphocytes infiltrate the periglomerular area in patients with severe (class III and class IV) lupus nephritis and are linked to a poor outcome after induction therapy. These results reveal a new potential effector pathway operant in lupus nephritis.

Typical features of IgA-associated nephritis were found in renal biopsies from 16 of 355 consecutive patients. Generalized segmental mesangial proliferation was noted in biopsies from most patients, and dense deposits were detected by electron microscopy in mesangial regions of approximately 50% of biopsies. Immunofluorescent studies showed IgA to be the predominant immunoglobulin in glomueruli; IgG was present in less than 50% of biopsies and IgM in only 12%. The serum IgA value was significantly increased (P les than 0.001) in 50% of patients and the mean IgA/IgG ratio was significantly increase (P less than 0.001) for the patient group as a whole, which suggests a selective increase in IgA. Mesangial deposits of C3 were present in 15 of 16 biopsies and properdin was noted in all biopsies tested; C4 was not demonstrated in any biopsy. This suggests activation of the alternative complement pathway. The results of this study support the concept that IgA-associated nephritis is a unique condition that in some patients gives rise to idiopathic recurrent hematuria. Although the prognosis is good in the majority of patients, the renal disease may progress.

Characteristic ultrastructural alterations of the glomerular basement membrane (GBM) have been reported in hereditary nephritis and in children without a family history of renal disease. The clinical features, renal biopsy findings, and subsequent course were studied retrospectively in 48 children with such GBM changes to compare findings in those with and without a family history of nephritis and to determine the significance of the GBM changes in patients with nonfamilial disease. All 48 patients had hematuria. For 30, there was hematuria in at least one other member of the family (familial hematuria group); for 18, there was no familial incidence. There were no differences between the two groups with regard to clinical and pathologic findings. At the latest follow-up six boys with familial hematuria and three boys with nonfamilial hematuria had reduced renal function, and nine boys with familial hematuria and four boys and one girl with nonfamilial hematuria had neurosensory deafness. Our study results show that children with these GBM changes, with or without a family history of hematuria, tend to have a progressive course, with frequent occurrence of neurosensory deafness, and that the prognosis is more severe in boys. These observations suggest that such GBM changes in patients with nonfamilial hematuria may represent new mutations for hereditary nephritis.

We reviewed 222 renal biopsies performed on patients with nonurologic hematuria alone or hematuria and proteinuria. This review revealed 31 patients who presented minor glomerular abnormalities with granular mesangial C3 deposition without any immunoglobulin or other complement component deposits. These patients presented with gross hematuria in five cases, microscopic hematuria alone in 12 cases, and proteinuria and microscopic hematuria in 14 cases. Light microscopy disclosed a segmentally increased mesangial matrix, sometimes associated with a segmental and focal mesangial hypercellularity. Focal tubulointerstitial and arteriolar lesions occurred in seven cases. In all cases, immunofluorescence showed diffuse granular mesangial deposition of C3. However, the deposits were not observed along the glomerular and tubular basement membranes. We should point out the high frequency of arteriolar C3 deposits (27 of 31). They were either isolated or associated with IgM or other complement components. Using electron microscopy, an increase of mesangial matrix and/or a proliferation of mesangial cells was observed. In two cases, electron-dense deposits were present in the mesangium. Glomerular basement membranes were normal in all but five cases, where they appeared segmentally thickened. After a 3-year follow-up study the clinical features remained unchanged.

The authors describe a patient with focal-segmental glomerulonephritis with a benign progress, induced by antibodies to glomerular basement membrane. Clinically the disease advanced in the course of 10 years with painless macroscopic hematuria and persisting microscopic hematuria during the intervals. Histologically, a focal-segmental glomerulonephritis was established, with crescents in certain glomeruli and immunomorphologically with linear depositis of IgG, C3 and febrin.

Eighty patients had idiopathic renal hematuria and normal renal function. Renal biopsy showed minimal changes or focal glomerulonephritis in two thirds of the patients. The remainder exhibited diffuse proliferative glomerulonephritis and included nine patients with segmental glomerular sclerosis. Electron microscopy disclosed alterations of the capillary loop in 23 biopsy specimens and electron-dense deposits in 11. Immunofluorescent microscopy identified glomerular-bound immunoglobulins, C3, or fibrinogen in 58% in a generalized distribution. IgG was the immunoglobulin seen most commonly. IgA and IgM were present in 14 and 13 biopsy specimens, respectively. These findings suggest that idiopathic renal hematuria is a clinical syndrome rather than a single disease with varying underlying renal findings. Both immunologic and nonimmunologic mechanisms may be involved, and the prognosis is favorable even in patients followed up for 11 years.

The mesangial egress, but not the uptake of radiolabeled aggregated human immunoglobulin G (AHIgG125I) (macromolecular proteins biologically akin to immune complexes), deviated markedly from normal in rats with preexisting ferritin-antiferritin immune complexes in the mesangium. Sprague-Dawley rats, given daily intraperitoneal ferritin, 8 mg. per 100 gm. of body weight, for 6 weeks (Ferritin rats), uniformly developed intense mesangial staining for IgG and C3 by immunofluorescence microscopy but minimal glomerular proliferation by light microscopy. With electron microscopy, ferritin was seen in mesangial channels and also in mesangial cells. These rats had normal serum creatinine, no hematuria or proteinuria. AHIgG125I, 50 mg. per 100 gm of body weight, was given intravenously to control and to Ferritin rats; groups of five control and five Ferritin rats were sacrificed at 2, 4, 8, 16, and 24 hours after injection. AHIgG125I was measured in preparations of isolated glomeruli and compared with simultaneous spleen, liver, and blood levels. At all time intervals, blood levels of > 7 S AHIgG125I were similar in control and Ferritin rats. Initial, 2-hour mesangial uptake of AHIgG125I was similar in control and Ferritin rats. During the 2- to 16-hour interval, the disappearance of AHIgG125I from glomeruli of Ferritin rats was delayed; glomerular AHIgG125I concentration decreased 85 per cent in control but only 38 per cent in Ferritin rats. After the administration of AHIgG125I, hematuria (2 to 3+) developed in 60 per cent of Ferritin rats but not in control rats. These studies suggest that immune complexes of different antigen-antibody systems may influence the kinetics of each other locally, at the glomerular level. This impaired mesangial clearance of immune complexes may favor the development of glomerular injury. The experimental model described may be relevant to some forms of human glomerulonephritis in which mesangial pathology and immunopathology are characteristic, and may explain some of the pathogenetic mechanisms operative in these diseases in man.

Six patients are described in whom recurrent haematuria was associated with IgA deposits in the glomerular mesangium. These patients conform closely to the nephropathy described by Berger. The condition can only be definitely diagnosed by immunofluorescence techniques. These six patients were diagnosed in one renal unit within 18 months and, despite the absence of reports from British units, this nephropathy is probably not uncommon. No treatment for it is known at present but the prognosis appears to be good in most patients. Renal failure and hypertension have been reported and long-term follow up is necessary to clarify the natural history of the disease.