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Immunoglobulin A nephropathy (IgAN) is characterized by mesangial IgA and IgG co-deposition. As the clinical course of IgAN is highly variable, a lot of patients will eventually develop to end-stage renal disease (ESRD) within years. Hirudin, a potent and specific thrombin inhibitor, has been reported to treat IgAN with hematuria, but the mechanism is unclear. Our study aims to explore the potential of hirudin and the underlying mechanism in the treatment of IgAN. The establishment of IgAN model was set up in rats through oral and intravenous immunization with bovine gamma-globulin (BGG). Results suggested that hirudin could reduce the increased level of proteinuria, serum creatinine and urea nitrogen in IgAN models. Besides that, hirudin ameliorated the elevated number of apoptotic bodies and expressions of apoptosis-related proteins (caspase-3 and caspase-9) in IgAN model. The fibrosis indexes (transforming growth factor β-1 (TGF-β1), Collagen-IV (CoI-IV) and Fibronectin-1) of kidney were remarkably suppressed in IgAN rats treated with hirudin compared with IgAN rats with no further treatment. IgAN rats exhibited remarkably increased inflammatory factors (IL-1β, IL-6, and IL-18), while hirudin treatment significantly alleviated these alterations. Moreover, the reduced levels of CD4 + CD25 + Foxp3 + Treg and CD4 + IFN-γ + Th1/CD4 + IL-4 + Th2 could be reversed by hirudin in IgAN model. Furthermore, in the process of IgAN, hirudin could inactivate various pathways (IκBα, NF-κB, TNF-α, and VCAM-1) compared with IgAN model group. Taken together, our study indicated that hirudin could ameliorate IgAN through suppressing fibrosis and inflammatory response. These findings provide a new therapeutic method to treat IgAN.

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.

Background: Henoch-Schönlein purpura (HSP) is a multisystemic vasculitis of unknown etiology. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and CD28 have been reported to be important candidate genes for conferring susceptibility to autoimmunity. In this study, we investigated the correlation of CTLA-4 and CD28 gene polymorphisms with HSP in children with and without renal involvement., Methods: The CTLA-4 exon 1 +49A/G, promoter -318C/T and CD28 IVS3 +17T/C single nucleotide polymorphisms (SNPs) were genotyped in 110 children with HSP and 90 ethnically matched healthy controls through restriction fragment-length polymorphism (RFLP)., Results: The CTLA-4 (+49) GG genotype and G allele (GG + AG genotype) were more common in HSP patients with renal involvement (n = 52) than in HSP patients without renal involvement (n = 58) (P = 0.019 and 0.001, respectively). There were no significant differences in the prevalence of CTLA-4 (+49 A/G), (-318C/T) and CD28 IVS3 (+17 /T/C) polymorphisms between HSP patients and controls., Conclusions: Our findings suggest that the CTLA-4 +49 GG genotype and G allele may contribute to increased risk for the development of renal damage in HSP patients.

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.

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.

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.

Background: As previously reported, the membrane-bound complement regulator at the C3 level (Crry/p65) is important in maintaining normal integrity of the kidney in rats. However, the role of a complement regulator at the C8/9 level (CD59) is not clear, especially when activation of complement occurs at the C3 level. The aim of this work was to elucidate the in vivo role of CD59 under C3 activating conditions., Methods: Two monoclonal antibodies, 5I2 and 6D1, were used to suppress the function of Crry and CD59, respectively. In order to activate alternative the pathway of complement, the left kidney was perfused with 5I2 and/or 6D1 and was recirculated., Results: In the kidneys perfused with 5I2 alone, deposition of C3 and membrane attack complex (MAC) was observed in the peritubular capillaries, vasa recta, and tubular basement membranes. Cast formation, tubular dilation and degeneration, and cellular infiltration were observed at days 1 and 4, and they recovered by day 7. Further suppression of CD59 by 6D1 significantly enhanced the deposition of MAC and worsened the already exacerbated tubulointerstitial injury. These effects of 6D1 were dose dependent. Perfusion with 6D1 alone did not induce histologic damage or MAC deposition in the tubulointerstitium., Conclusions: In rats, CD59 maintains normal integrity of the kidney in collaboration with Crry in rats against complement-mediated damage in vivo.

To determine the physiological function(s) of uteroglobin (UG), a steroid-inducible, homodimeric, secreted protein, we have generated transgenic mice that either are completely UG-deficient due to UG gene-knockout (UG-KO) or are partially UG-deficient due to the expression of UG antisense RNA (UG-AS). Both the UG-KO and UG-AS mice develop immunoglobulin A (IgA) nephropathy (IgAN), characterized by microhematuria, albuminuria, and renal glomerular deposition of IgA, fibronectin (Fn), collagen, and C3 complement. This phenotype of both UG-KO and UG-AS mice is virtually identical to that of human IgAN, the most common primary glomerulopathy worldwide. The molecular mechanism by which UG prevents this disease in mice appears to center around UG's interaction with Fn. Since Fn, IgA, and UG are present in circulation and high plasma levels of IgA-Fn complex have been reported in human IgAN, we sought to determine whether UG interacts with Fn and prevents Fn-Fn and/or IgA-Fn interactions, essential for abnormal tissue deposition of Fn and IgA. Our coimmunoprecipitation studies uncovered the formation of Fn-UG heteromers in vitro and these heteromers are detectable in the plasma of normal mice, but not UG-KO mice. Further, high plasma levels of IgA-Fn complex, a characteristic of human IgAN patients, were also found in UG-KO mice. Finally, coadministration of UG + Fn or UG + IgA to UG-KO mice prevented glomerular deposition of Fn and IgA, respectively. Our results define a possible molecular mechanism of IgAN and provide insight into at least one important physiological function of UG in maintaining normal renal function in mice.

Urinary system was examined in 35 hemophiliacs. 25 of them had in the past 2 to 6 episodes of hematuria. The examinees had also depressed cellular immunity. Their humoral immunity, on the contrary, was activated. In the absence of clinical and x-ray evidence of urinary abnormalities, renal affections were registered in 88.6% of the examinees. According to the data obtained all hemophiliacs suffer from unbalance of cellular and humoral immunity, abnormal clearance of immune complexes, probable renal damage. Therefore, it is desirable to make ultrasonic investigation of the kidneys in all hemophiliacs to check latent renal affection and take therapeutic measures.

Kidney biopsies from ten children with recurrent macroscopic haematuria, showed mesangial deposition of IgG, IgA and complement. Eight of these ten biopsies also showed disposition of properdin, a basic euglobulin intimately involved in the alternate pathway of complement activation. Serum haemolytic complement activity was normal in the eight patients tested. Incubation of the serum at 4 degrees C for 24 dours did not result in any change in complement activity. Theses data suggest that the mesangial inflammatory process in these patients may be medicated in part by the alternate pathway of complement activation and that the mechanism is activated locally.

An immunologic study and a renal biopsy were performed in 64 patients with isolated hematuria. Fifty of them had macroscopic hematuria and 14 microscopic hematuria. The kidney was normal in 66% by light microscopy; in the remaining 34% glomerular lesions were moderate: thickening of the mesangial matrix, diffuse or segmentary mesangial proliferation. Four patterns were observed by immunofluorescence: C3 located either in the mesangium, or at the level of the vascular pole, mesangial IgA, mesangial IgM and lack of deposits. According to our experience IgA nephropathy presenting as isolated hematuria has a better prognosis than the other symptomatic forms of this glomerulonephritis. No patient with the other renal pathological changes so far developed hypertension or renal failure. We prefer to perform biopsies on patients with isolated hematuria, considering the frequency of IgA nephropathy and the possibility of finding mesangial deposits of IgM and C3 whose significance is so far poorly known.

Deposition of C3 without immunoglobulins ("isolated C3") was found in 9.8% of 540 renal biopsies performed between 1976 and 1982. Thirty-two of these samples were from patients with systemic diseases (16), well defined forms of glomerulonephritis (9), other renal diseases (4) or renal allografts (4). The remaining 22 patients are described. Five had nephrotic syndrome, three of them with minimal changes on light microscopy and good response to corticosteroids. We were left with a group of 17 patients who presented with gross (4) or microscopic (12) hematuria or asymptomatic proteinuria (1) whose biopsies showed mesangial proliferation or/and hyperplasia and who followed a benign course over the mean 3 years of follow-up, with the exception of one whose renal function is declining. This clinicopathological picture is similar to that described in two previous publications suggesting that "Isolated C3 mesangial proliferative nephritis" is a recognizable sub-group within the spectrum of glomerulonephritis.

Among sixty-four patients with primary haematuria, immunofluorescence methods revealed seven cases (11%) with isolated C3 deposits in the 'vascular pole'. Serum complement were normal and the follow-up after 20-41 months indicate a benign course. In patients with C3 deposits in the 'vascular pole' light microscopy was normal. We never observed C3 deposits in specimens of normal kidney which were processed by the same methods using mono-specific antisera confirmed by immunoelectrophoresis. This entity defined by immunofluorescence methods, can be called 'vascular pole disease'.