Autophagy in Immune-Related Renal Disease.

Autophagy is an important biology process, central to the maintenance of biology process in both physiological and pathological situations. It is regarded as a "double-edged sword"-exerting both protective and/or detrimental effects. These two-way effects are observed in immune cells as well as renal resident cells, including podocytes, mesangial cells, tubular epithelial cells, and endothelial cells of the glomerular capillaries. Mounting evidence suggests that autophagy is implicated in the pathological process of various immune-related renal diseases (IRRDs) as well as the kidney that underwent transplantation. Here, we provide an overview of the pathological role of autophagy in IRRDs, including lupus nephritis, IgA nephropathy, membrane nephropathy, ANCA-associated nephritis, and diabetic nephropathy. The understanding of the pathogenesis and regulatory mechanisms of autophagy in these renal diseases may lead to the identification of new diagnostic targets and refined therapeutic modulation.

Murine Models of Human IgA Nephropathy.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. IgAN is characterized by mesangial deposits of IgA1-containing immune complexes. IgA1 usually co-deposits with complement C3 and variable IgG and/or IgM. Exactly 50 years have passed since IgAN was described, however, the pathogenesis of disease onset and progression have not been fully clarified. Animal models can re-create the complex immunologic microenvironments that foster human autoimmunity and nephritis and provide access to tissue compartments not readily examined in patients. Thus, multiple models that may be helpful in studies of specific aspects of IgAN have been developed. A unique spontaneous animal model of IgAN, the ddY mouse, was reported in 1985. These mice show mild proteinuria and glomerular IgA deposits, with a highly variable incidence and degree of glomerular injury owing to a heterogeneous genetic background. Thus, we intercrossed an early onset group of ddY mice in which the development of IgAN resulted in the establishment of a novel 100% early onset-grouped ddY mouse model with increased levels of aberrantly glycosylated IgA and immune complexes. Although the molecular features of human IgA1 are different from rodent IgA, human IgA1 knock-in (α1KI)-CD89 transgenic mice, which express both human IgA1 and CD89, show circulating and mesangial deposits of IgA1-soluble CD89 complexes that result in kidney inflammation, hematuria, and proteinuria. In this review, we introduce several murine models of IgAN that can be useful tools for the analysis of multiple aspects of the pathogenesis of IgAN, which may aid in the assessment of approaches for the treatment of IgAN.

Activated natural killer T cells in mice induce acute kidney injury with hematuria through possibly common mechanisms shared by human CD56+ T cells.

Although activation of mouse natural killer T (NKT) cells by α-galactosylceramide (α-GalCer) causes failure of multiple organs, including the kidneys, the precise mechanisms underlying kidney injury remain unclear. Here, we showed that α-GalCer-activated mouse NKT cells injured both kidney vascular endothelial cells and tubular epithelial cells in vitro, causing acute kidney injury (AKI) with hematuria in middle-aged mice. The perforin-mediated pathway was mainly involved in glomerular endothelial cell injury, whereas the TNF-α/Fas ligand pathway played an important role in the injury of tubular epithelial cells. Kidney injury in young mice was mild but could be significantly exacerbated if NKT cells were strongly activated by NK cell depletion alone or in combination with IL-12 pretreatment. When stimulated by a combination of IL-2 and IL-12, human CD56+ T cells, a functional counterpart of mouse NKT cells, also damaged both glomerular endothelial cells and tubular epithelial cells, with the former being affected in a perforin-dependent manner. These data suggest that both mouse NKT cells and human CD56+ T cells are integral to the processes that mediate AKI. Targeting CD56+ T cells may, therefore, be a promising approach to treat AKI.

Treatment of Immunoglobulin A Nephropathy Recurrence Post-Renal Transplant.

Immunoglobulin A nephropathy (IgAN) is the most commonly occurring glomerulonephritis. Recurrence of disease in the transplanted kidney can significantly reduce allograft survival rates. Currently, there is no definitive management plan for IgAN recurrence in a transplant that reduces the rate of decline of allograft function and prolongs time to dialysis or re-transplantation. Herein we present a 48-year-old man who had received a renal transplantation in 2006 following his diagnosis of IgAN. In 2015, the patient was noted to have an elevated blood pressure and proteinuria (urinary protein:creatinine ratio [uPCR] 170 mg/mmol). A transplant biopsy confirmed recurrent IgAN. A year later, he presented with dipstick hematuria, nephrotic-range proteinuria (uPCR 820 mg/mmol), and a serum creatinine of 90 to 140 µmol/L. A second biopsy revealed mesangioproliferative glomerulopathy consistent with crescentic IgAN. An optimal management plan is currently unknown for recurrent crescentic IgAN in the transplanted kidney. We decided to treat this patient with oral cyclophosphamide daily and high-dose prednisolone. The treatment has so far yielded a positive response and managed to preserve allograft function without significant adverse effects for our patient. Our case illustrates the importance of timely biopsies to identify recurrence of disease and highlights an effective therapeutic option for recurrent IgAN with crescent formation in a transplant.

The Utility of Urinalysis in Determining the Risk of Renal Relapse in ANCA-Associated Vasculitis.

BACKGROUND AND OBJECTIVES: The significance of persistent hematuria or proteinuria in patients with ANCA-associated vasculitis who are otherwise in clinical remission is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis was conducted using participants enrolled in two randomized, placebo-controlled clinical trials who had active GN due to ANCA-associated vasculitis, had positive ANCA, and achieved remission by month 6. Dipstick and microscopic urinalyses were performed at each visit. Persistent hematuria or proteinuria for at least 6 months and the cumulative duration of hematuria were examined. Renal relapse was defined as new or worsening red blood cell casts and/or worsening kidney function according to the Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis. RESULTS: There were 149 patients included in this study: 42% had persistent hematuria, and 43% had persistent proteinuria beyond 6 months. Persistent hematuria was associated with a significantly higher risk of relapse, even after adjusting for potential confounders (subdistribution hazard ratio, 3.99; 95% confidence interval, 1.20 to 13.25; P=0.02); persistent proteinuria was not associated with renal relapse (subdistribution hazard ratio, 1.44; 95% confidence interval, 0.47 to 4.42; P=0.53). Furthermore, greater cumulative duration of hematuria was significantly associated with a higher risk of renal relapse (adjusted subdistribution hazard ratio, 1.08 per each month; 95% confidence interval, 1.03 to 1.12; P<0.01). The median time to renal relapse was 22 months. CONCLUSIONS: In patients with ANCA-associated vasculitis and kidney involvement who achieve remission after induction therapy, the presence of persistent hematuria, but not proteinuria, is a significant predictor of future renal relapse.

ANCA-associated pauci-immune glomerulonephritis: always pauci-immune?

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.

Clinicopathological significance of monoclonal IgA deposition in patients with IgA nephropathy.

BACKGROUND: Clinicopathological significance of monoclonal IgA deposition and its relation to bone marrow abnormalities in IgA nephropathy (IgAN) remains unclear. METHODS: We retrospectively investigated the prevalence and clinicopathological significance of monoclonal IgA deposition in 65 patients with IgAN. Serum-free light chain ratio, and urinary Bence Jones protein were also measured. RESULTS: Thirty-nine percent of patients were men, median age was 40 and median observation period was 31 months. Five patients (Group M) showed monoclonal IgA lambda deposition and one showed monoclonal IgA kappa deposition. Fifty-nine patients (Group P) showed polyclonal IgA deposition. There were no significant differences in the degree of proteinuria, hematuria and renal function between Group M and Group P. Total protein and albumin were significantly lower in Group M than in Group P. According to the Oxford classification, the percentage of patients with M1 was significantly higher in Group M than in Group P. One patient in Group P showed serum monoclonal IgG lambda. No patient showed abnormal serum-free light chain ratio. Seventy-five percent in Group M and 42 % in Group P were treated with steroid. Three patients in Group P progressed to end-stage renal disease (ESRD). The frequency of disappearance of proteinuria or hematuria and progression to ESRD was not different between the groups. CONCLUSIONS: The prevalence of monoclonal IgA deposition was 9.2 %. Although some parameters differed between the groups, renal outcome were similar. Thus, IgAN with monoclonal IgA deposition seems not to be different entity from those with polyclonal IgA deposition.

CMV disease complicating induction immunosuppressive treatment for ANCA-associated vasculitis.

We present a case of a 71-year-old woman who initially presented with renal-limited antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Following standard therapy with cyclophosphamide, steroids and plasma exchange, her renal function began to improve. However, despite appropriate treatment, her renal function subsequently deteriorated and she suffered haemoptysis. Owing to diagnostic uncertainty, bronchoscopy and a repeat renal biopsy were performed. The bronchoscopy washings demonstrated positivity for cytomegalovirus (CMV) DNA, and in combination with a positive serum CMV PCR, immunosuppression was withheld. Treatment with ganciclovir was started. Repeat renal biopsy demonstrated active vasculitis and, following successful treatment of CMV disease, immunosuppression was re-started alongside prophylactic valganciclovir. This resulted in a successful outcome for the patient. Pulmonary CMV disease may mimic pulmonary disease associated with vasculitis, posing a diagnostic challenge to clinicians. We recommend a low threshold when testing for CMV in these patients.

C1q nephropathy in India: a single-center study.

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.

Choreito formula for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (P = .018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P = .037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P = .0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.

Immunoglobulin M nephropathy in adults: a clinicopathological study.

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: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.

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.

Proliferative glomerulonephritis with monoclonal IgM deposits without Waldenström's macroglobulinemia: case report and review of the literature.

A 38-year-old man was presented with nephrotic syndrome associated with hematuria and mild hypocomplementemia. Renal biopsy revealed lobular mesangial proliferation, thickened capillary walls, and intraluminal protein thrombi. Immunofluorescence showed marked and mild depositions of immunoglobulin (Ig) M heavy chains and complement C3, respectively, in a peripheral lobular pattern. On light chain staining, only kappa (κ) light and IgM heavy chains showed a similar pattern. Electron microscopy showed fine granular electrondense deposits in subendothelial areas and numerous globular deposits (varying size and density) in glomerular capillary lumens. Serum levels of Ig κ, but not of free κ, light chains were significantly increased. Bone marrow aspiration revealed a normocellular marrow. Waldenström's macroglobulinemia and cryoglobulinemia were ruled out. Clinically, steroid therapy was ineffective and proteinuria persisted. This report demonstrates that glomerular deposition of monoclonal IgM-κ can produce membranoproliferative- like changes in the glomeruli. This condition may be recognized as proliferative glomerulonephritis with monoclonal IgM deposits similar to the recently recognized proliferative glomerulonephritis with monoclonal IgG deposits.

Incidence and features of dual anti-GBM-positive and ANCA-positive patients.

AIMS: Goodpasture's syndrome, glomerulonephritis and pulmonary haemorrhage, may be due to a variety of causes. Rarely, patients with Goodpasture's syndrome present with both anti-glomerular basement membrane (GBM) and antineutrophil cytoplasmic antibody (ANCA). The aim of this report was to determine the incidence, clinical features, management and outcomes of patients presenting with concurrent ANCA and anti-GBM disease in Auckland. METHODS: Potential patients were identified by an electronic search of serology for ANCA and anti-GBM antibody, diagnostic renal biopsy, or in-hospital admissions using ICD9 and ICD10 codes between 1998 and 2008. A retrospective case-note review of all potential cases was performed. RESULTS: Six cases were identified: two women and four men. The incidence was estimated at 0.47 cases per million people per year. The mean age of presentation was 59 years (range 25-85 years). One patient was a smoker and two patients were ex-smokers. All subjects were anaemic, had haemoptysis and an abnormal chest X-ray at presentation. The mean creatinine at presentation was 225 µmol/L (range 126-406 µmol/L); all patients had haematuria and proteinuria. All patients received corticosteroids and cyclophosphamide. Two patients were not plasma exchanged and died. Four patients received plasma exchange and are alive. One patient had a clinical relapse 6 years after their initial presentation and is on renal replacement therapy. CONCLUSION: Concurrent ANCA and anti-GBM disease is rare. The mortality rate is high. Aggressive immunosuppression with steroids, cyclophosphamide and plasma exchange can induce remission and preserve renal function. Long-term monitoring for relapses should occur.

Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.

BACKGROUND AND OBJECTIVES: Complement factor H and related proteins (CFHR) are key regulators of the alternative complement pathway, where loss of function mutations lead to a glomerulopathy with isolated mesangial C3 deposits without immunoglobulins. Gale et al. (12) reported on 26 patients with the first familial, hematuric glomerulopathy caused by a founder mutation in the CFHR5 gene in patients of Cypriot descent living in the United Kingdom. CFHR5 nephropathy is clinically characterized by continuous microscopic hematuria whereas some patients present with additional episodes of synpharyngitic macrohematuria, associated with infection and pyrexia. A subgroup of patients, particularly men, develop additional proteinuria, hypertension, and chronic renal disease or ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We herewith expand significantly on the study by Gale et al., reporting on histologic, molecular, and clinical findings in 91 patients from 16 families with the same founder mutation. RESULTS: Eighty-two patients (90%) exhibited microscopic hematuria; 51 (62%), exhibited only microscopic hematuria, whereas the remaining 31 additionally had proteinuria (38%); 28 proteinuric patients developed chronic renal failure (CRF). Among carriers of CFHR5 mutation aged >50 years, 80% of the men and 21% of the women developed CRF; 18 developed ESRD (14 men [78%], 4 women [22%]). CONCLUSIONS: The diagnosis of CFHR5-related, isolated C3 glomerulopathy was established in 2009 using newly described mutation analysis after decades of follow-up with unclear diagnoses, occasionally confused with IgA nephropathy. This larger patient cohort establishes the clinical course, significant variable expressivity, and marked gender difference regarding the development of CRF and ESRD.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis with rheumatoid arthritis: a comparison of patients without rheumatoid arthritis.

BACKGROUND: Several cases of rheumatoid arthritis (RA) with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated crescentic glomerulonephritis (CrGN) have been reported. However, its clinical characteristics are not clear. METHODS: We summarized 3 patients of concurrent RA and MPO-ANCA-associated CrGN, diagnosed in our hospital from 1992 to 2006, and compared their clinicopathological data with those of 10 MPO-ANCA-associated CrGN patients without RA in the same period. RESULTS: All three RA patients were middle-aged or young adult women with 7-14 years of RA history. The initial clinical symptom was microhematuria, and mean duration from hematuria onset to histological confirmation of CrGN was 17 months. At renal biopsy, serum creatinine concentration (sCr) was modestly elevated, with the mean value of 3.4 mg/dl. Crescents were detected in 30% of glomeruli, whereas advanced glomerular sclerosis, tubular atrophy, and interstitial fibrosis were also observed. In comparison with patients without RA, patients with RA were significantly younger and showed a longer duration from the onset to histological confirmation of CrGN. Serum creatinine concentration at referral was significantly lower; however, estimated glomerular filtration rate (eGFR) was comparable. The Birmingham Vasculitis Activity Score and the Disease Extent Index were significantly lower, and pathological examination showed less crescent formation and a tendency to advanced glomerular sclerosis in patients with RA. CONCLUSIONS: In patients with RA, MPO-ANCA-associated CrGN appeared to develop at younger ages and often showed a slowly progressive deterioration of the renal function with slight extrarenal manifestations. These smoldering clinical features may result in late referral from rheumatologists to nephrologists and therefore poor prognosis.

IgG glomerulonephritis: a morphologic study of a rare entity.

Mesangial IgG glomerulonephritis (MesIgGN) is recently recognized as a distinct type of glomerulonephritis. In our renal biopsy series, two patients with MesIgGN were identified. The morphologic criteria detected in these patients included mesangial dense deposits by ultrastructural studies, which were predominantly positive for IgG by immunofluorescence. Both patients were young boys, one presented with hematuria and the other with the nephrotic syndrome. Similar cases have been reported in other studies from around the world; however, this is the first report of MesIgGN from Saudi Arabia.

The prevalence of Th17 cells and FOXP3 regulate T cells (Treg) in children with primary nephrotic syndrome.

The aim of this study was to investigate the prevalence of interleukin (IL)-17-producing CD4+ T cells (Th17) and regulatory T (Treg) cells in children with primary nephrotic syndrome. The study cohort consisted of 62 children who were randomly divided into control, primary nephrotic syndrome, and isolated hematuria groups. Flow cytometric analysis revealed the presence of Th17 cells in the peripheral blood mononuclear cells (PBMCs) of 35 children and Tregs in the PBMCs of all children. In addition, mRNA expression of Th17-related factors [IL-17, -23p19 and retinoid orphan nuclear receptor (RORc)] and the concentration of plasma inflammatory mediators such as IL-6 and IL-1beta were consistently detected in all children. Protein expression of IL-17 and transforming growth factor-beta1 were also detected in renal biopsy tissue and compared between different groups. Patients with PNS were found to have an increased number of Th17 cells and decreased numbers of Tregs in their PBMCs, and there was significant difference in the prevalence of Th17 and Tregs between the patients with PNS and those with isolated hematuria. Our data show that among our study cohort, there was a dynamic equilibrium between Th17 and Treg cells in children with PNS following the development of PNS with apparent renal tubular epithelial cell and interstitium lesions. The dynamic interaction between Th17 and Treg cells may be important in the development of PNS.

A case of immunotactoid glomerulopathy exhibiting nephrotic syndrome successfully treated with corticosteroids and antihypertensive therapy.

We report a case of immunotactoid glomerulopathy (ITG) with cerebral hemorrhage and hypocomplementemia, with successful therapeutic outcome following the corticosteroids and antihypertensive treatment. A 70-year-old man presented with facial edema in October 2006. One day prior to his referral, he experienced speech disturbance, headache, and vomiting, and on the next day he was referred to our hospital. The laboratory examination revealed massive proteinuria (11.3 g/day) and hematuria. The total serum hemolytic complement (CH50) was decreased to 23 U/ml and C4 component was decreased to 7.5 mg/dl, whereas C3 component remained within normal limits (82 mg/dl). Brain computed tomography scan showed high-density lesions in the left parieto-occipital area suggesting subcortical cerebral hemorrhage. Renal biopsy revealed diffuse subendothelial PAS-positive depositions. Immunofluorescence studies revealed intensive deposition of IgG, IgA, C3, C1q, Fibrinogen, and kappa light chain with granular pattern in the capillary and mesangial area. Electron microscopic examination revealed regularly arranged microtubular deposits, appearing as 21-33 nm in diameter. Based on these findings, this patient was diagnosed as ITG complicated with cerebral hemorrhage and hypocomplementemia. He received oral prednisolone (30 mg/day), resulting in reduction of proteinuria, improvement of hypocomplementemia, and prevention of renal functional deterioration. This case demonstrates that accurate diagnosis of ITG may result in successful therapeutic outcome.