FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy.

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

Long-term outcomes of patients with end-stage kidney disease due to membranoproliferative glomerulonephritis: an ANZDATA registry study.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of end stage kidney disease (ESKD) and the clinical outcomes of patients with MPGN who commence kidney replacement therapy have not been comprehensively studied. METHODS: All adult patients with ESKD due to glomerulonephritis commencing kidney replacement therapy in Australia and New Zealand from January 1, 1996 to December 31, 2016 were reviewed. Patients with ESKD due to MPGN were compared to patients with other forms of glomerulonephritis. Patient survival on dialysis and following kidney transplantation, kidney recovery on dialysis, time to transplantation, allograft survival, death-censored allograft survival and disease recurrence post-transplant were compared between the two groups using Kaplan Meier survival curves and Cox proportional hazards regression. RESULTS: Of 56,481 patients included, 456 (0.8%) had MPGN and 12,660 (22.4%) had another form of glomerulonephritis. Five-year patient survival on dialysis and following kidney transplantation were similar between patients with ESKD from MPGN and other forms of glomerulonephritis (Dialysis: 59% vs. 62% p = 0.61; Transplant: 93% vs. 93%, p = 0.49). Compared to patients with other forms of glomerulonephritis, patients with MPGN had significantly poorer 5-year allograft survival (70% vs. 81% respectively, p = 0.02) and death censored allograft survival (74% vs. 87%, respectively; p < 0.01). The risk of disease recurrence was significantly higher in patients with MPGN compared to patients with other glomerulonephritidites (18% vs. 5%; p < 0.01). In patients with MPGN who had allograft loss, patients with MPGN recurrence had a significantly shorter time to allograft loss compared to patients with MPGN who had allograft loss due to any other cause (median time to allograft loss 3.2 years vs. 4.4 years, p < 0.01). CONCLUSIONS: Compared with other forms of glomerulonephritis, patients with MPGN experienced comparable rates of survival on dialysis and following kidney transplantation, but significantly higher rates of allograft loss due to disease recurrence.

IgA-dominant glomerulonephritis with a membranoproliferative pattern of injury.

Immunoglobulin A (IgA)-dominant membranoproliferative glomerulonephritis (MPGN) is a descriptive term for renal biopsies in which differential diagnoses of unusual IgA nephropathy (IgAN), infection-related GN, or other etiologies are considered. We sought to understand clinical and pathologic features of this finding. Native kidney biopsies with IgA-dominant immune deposits and diffuse MPGN features without significant exudative features or subepithelial deposits were retrospectively reviewed. Two groups (n = 27, 33 biopsies) were identified: patients with chronic liver disease and those without. Patients without chronic liver disease (n = 15) were men (73%, age 40) who presented with nephrotic-range proteinuria, hematuria, renal insufficiency, negative serologic studies, and no history of infection. At a median interval of 3 years, 11 had available follow-up information. Three (27%) progressed to end-stage renal disease. One had recurrent IgA-dominant GN in the renal allograft less than 1 year posttransplant. Four of 5 patients with repeat biopsies had persistent IgA-dominant MPGN. Patients with chronic liver disease (n = 12) had similar biopsy findings, but 42% had concurrent infections, some occult. At a median interval of 7 weeks, 8 patients (80% of those with follow-up) had died and 2 were dialysis dependent. In conclusion, IgA-dominant MPGN was seen in 2 clinical cohorts in this study. In patients without chronic liver disease, this appears to represent either a unique clinicopathologic entity with a poorer prognosis than IgAN or an aggressive variant of IgAN. Patients with chronic liver disease often have underlying infection, and regardless of treatment, die within 1 year because of complex medical conditions.

Unraveling the Molecular Mechanisms Underlying Complement Dysregulation by Nephritic Factors in C3G and IC-MPGN.

Membranoproliferative glomerulonephritis (MPGN) was recently classified as C3 glomerulopathies (C3G), and immune-complex (IC) mediated MPGN. Dysregulation of the complement alternative pathway, driven by acquired and/or genetic defects, plays a pathogenetic role in C3G. However, alternative pathway abnormalities were also found in IC-MPGN. The most common acquired drivers are the C3 nephritic factors (C3NeFs), heterogeneous autoantibodies that stabilize the C3 convertase, C3bBb. C3NeFs are traditionally detected by hemolytic assays based on sheep erythrocyte lysis, which however do not provide a direct molecular estimation of C3bBb formation and decay. We set up a microplate/western blot assay that specifically detects and quantifies C3bBb, and its precursor, the C3 proconvertase C3bB, to investigate the complex mechanistic effects of C3NeFs from patients with primary IC-MPGN (n = 13) and C3G (n = 13). In the absence of properdin, 9/26 patients had C3NeF IgGs stabilizing C3bBb against spontaneous and FH-accelerated decay. In the presence of properdin the IgGs of all but one patient had C3bBb-stabilizing activity. Properdin-independent C3NeFs were identified mostly in DDD patients, while properdin-dependent C3NeFs associated with either C3GN or IC-MPGN and with higher incidence of nephrotic syndrome. When we grouped patients based on our recent cluster analysis, patients in cluster 3, with highly electron-dense intramembranous deposits, low C3, and mostly normal sC5b-9 levels, had a higher prevalence of properdin-independent C3NeFs than patients in clusters 1 and 2. Conversely, about 70% of cluster 1 and 2 patients, with subendothelial, subepithelial, and mesangial deposits, low C3 levels and high sC5b-9 levels, had properdin-dependent C3NeFs. The flexibility of the assay allowed us to get deep insights into C3NeF mechanisms of action, showing that: (1) most C3NeFs bind strongly and irreversibly to C3 convertase; (2) C3NeFs and FH recognize different epitopes in C3 convertase; (3) C3NeFs bind rapidly to C3 convertase and antagonize the decay accelerating activity of FH on newly formed complexes; (4) C3NeFs do not affect formation and stability of the C3 proconvertase. Thus, our study provides a molecular approach to detecting and characterizing C3NeFs. The results highlight different mechanisms of complement dysregulation resulting in different complement profiles and patterns of glomerular injury, and this may have therapeutic implications.

C5 nephritic factors drive the biological phenotype of C3 glomerulopathies.

C3 Glomerulopathies, which include Dense Deposit Disease and C3 Glomerulonephritis, are associated with genetic and acquired dysregulation of the C3 convertase alternative pathway of complement. The potential role of the activation of the C5 convertase has not been studied extensively. Here we analyzed IgG samples from patients with C3 Glomerulopathies to identify circulating autoantibodies that stabilize the C3 alternative pathway (C3 Nephritic Factors) as well as C5 convertases (C5 Nephritic Factors), thus preventing decay of these enzyme complexes. Rare variants in alternative pathway genes were found in 28 of 120 tested patients. C3 and C5 Nephritic Factors were found in 76 of 101 (75%) and 29 of 59 (49%) of the patients, respectively. Therefore, we compared the results of the assays for the C3 and C5 nephritic factors functional activity: 29% were positive for C3 Nephritic Factors alone, 39% were positive for both C3 and C5 Nephritic Factors, and 10% were positive for C5 Nephritic Factors alone. We found that the addition of properdin-enhanced stabilization of C3 convertase in the presence of IgG doubly positive for both Nephritic Factors, while it did not modify the stabilization mediated by IgG solely positive for C3 Nephritic Factors. Both C3 and C5 Nephritic Factors correlated with C3 consumption, while only C5 Nephritic Factors correlated with sC5b9 levels. C5 Nephritic Factors-positive patients were more likely to have C3 Glomerulonephritis than Dense Deposit Disease. Thus, dysregulation of the C5 convertase contributes to C3 Glomerulopathies inter-disease differences and may have direct therapeutic implications.

C3 glomerulopathy: clinicopathologic features and predictors of outcome.

BACKGROUND AND OBJECTIVES: The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model. RESULTS: Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD. CONCLUSIONS: Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

Positive C1q staining associated with poor renal outcome in membranoproliferative glomerulonephritis.

BACKGROUND: Pathogenesis and clinical prognosis of membranoproliferative glomerulonephritis (MPGN) has not yet been established. METHODS: We conducted a retrospective study of 41 patients with MPGN (type I and III) and examined the renal survival. In addition, factors contributing to survival time were analyzed. RESULTS: Fourteen patients (34 %) were classified into the renal death group. Patients with nephrotic syndrome and positive C1q staining of glomerular deposits showed a particularly poor prognosis. Significantly higher frequency of nephrotic syndrome and higher urinary protein excretion were observed in the renal death group (p = 0.0002, p = 0.0002) than in the renal survival group. The intensity of C1q staining was positively correlated with the severity of the proteinuria (p = 0.004). Factors that influenced the survival time were positive C1q staining of glomerular deposits (p = 0.003), presence of nephrotic syndrome (p = 0.004), serum albumin (p = 0.02), and proteinuria (p = 0.04). CONCLUSIONS: C1q staining in glomerular deposits and nephrotic syndrome were important factors influencing the prognosis and outcome in MPGN patients. C1q deposition may play a key role in the pathogenesis of MPGN, as evidenced by numerous observations, such as induction of proteinuria.

Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.

Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.

Allograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis.

BACKGROUND: Membranoproliferative glomerulonephritis types I (MPGN-I) and II (MPGN-II) are rare diseases that in limited case series have been reported to recur frequently in kidney transplants and have a negative impact on allograft survival. STUDY DESIGN: Retrospective database review. SETTING & PARTICIPANTS: 189,211 primary kidney transplants in the United Network for Organ Sharing (UNOS) database from September 1987 to May 2007. PREDICTOR OR FACTOR: MPGN-I (811 patients; 0.4%), MPGN-II (179 patients; 0.1%), other GN (58,129 patients; 30.7%), and all other diagnoses (130,092 patients; 68.7%). OUTCOMES: Death-censored and non-death-censored allograft survival. RESULTS: Compared with controls, patients with MPGN-I and MPGN-II were significantly younger at the time of transplant, with a median age of 36 and 27 years compared with 44 years in the GN group and 46 years in all other disease groups, respectively (all P < 0.001). Mortality in patients with MPGN-I (8.8%) was significantly lower compared with the GN (11.3%; P = 0.02) and other disease (16.6%; P < 0.001) populations and lower in those with MPGN-II (9.5%) compared with the other disease (16.6%; P = 0.01) population. Graft failure rates were significantly higher in the MPGN-I (44.5%) cohort, but not in the MPGN-II (45.3%) cohort compared with the GN (38.0%) population (P < 0.001 and P = 0.05, respectively); neither MPGN cohort differed from the other disease (43.0%) population (P = 0.4 and P = 0.5). Overall, 10-year death-censored graft survival was similar for MPGN-I (56.2%) and MPGN-II (57.5%); both were significantly worse than for GN (65.2%; P < 0.001 and P = 0.003, respectively), and only MPGN-I was significantly worse than the other disease (60.0%) population (P = 0.004). Of allograft failures with a reported cause, disease recurrence was the primary cause in 36 (14.5%) MPGN-I and 18 (29.5%) MPGN-II transplant recipients and was significantly higher compared with 879 (6.6%) GN and 1,319 (4.4%) all-other-disease recurrence failures (P < 0.001). LIMITATIONS: Limited pretransplant clinical and biopsy data. CONCLUSIONS: A diagnosis of MPGN-I or MPGN-II has a significant negative impact on overall primary allograft survival compared with other forms of glomerulonephritis, whereas only MPGN-I has a significant, but modest, negative effect compared with other causes of end-stage renal disease.

Influence of tonsillectomy on the progression of mesangioproliferative glomerulonephritis.

BACKGROUND: Little information is available about the efficacy of tonsillectomy on long-term renal survival of patients with primary IgA nephropathy (IgAN). METHODS: In this retrospective cohort study, we considered 61 patients with IgAN who had tonsillectomy (n = 15) or not (n = 46) and compared them with 121 control patients with mesangioproliferative glomerulonephritis (MesGN) free of IgA deposits, who had tonsillectomy (n = 49) or not (n = 72). We evaluated the progression from a normal function [estimated glomerular filtration rate 60-220 mL/min/1.73 m(2), chronic kidney disease (CKD) stage 1 and 2] to a moderate renal dysfunction in CKD stage 3, which was considered the outcome. RESULTS: The mean duration of follow-up was 250 months (12-300 months) in the whole group of 182 patients. The survival to progression to stage 3 was 88% after 10 years, 71% after 20 years and 53% after 25 years. It was 72% after 20 years in both groups. Tonsillectomy was not significantly associated with CKD progression. Significant prognostic factors were age (P = 0.01), initial CKD stage (P = 0.03), proteinuria (P = 0.03), persistent proteinuria (P < 0.001) and diastolic blood pressure (P = 0.01). In the multivariate analysis (Cox model), there was no significant effect of tonsillectomy adjusted for the type of glomerulonephritis, initial CKD stage, persistent proteinuria, diastolic blood pressure and age. Only persistent proteinuria adjusted for the other factors was significantly associated with CKD progression (hazard ratio of 6.2, 95% confidence interval 3.1-12.7, P < 0.001). CONCLUSIONS: Tonsillectomy was not associated with a different progression rate of IgAN nor of MesGN after 20 years of follow-up.

Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.

BACKGROUND AND OBJECTIVES: Dense deposit disease (DDD) is a rare disorder that most commonly affects children. This study reports the largest North American series addressing clinicopathologic and outcome differences in children and adults. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Thirty-two patients with DDD were analyzed from the archives of Columbia University between 1977 and 2007. Characteristic intramembranous electron-dense deposits defined all diagnoses. RESULTS: The cohort included 14 children (<16 yr) and 18 adults, with 39% of adults >60 yr. The female/male ratio was 1.9. At presentation, the mean 24-h urine protein was 4.6 g, nephrotic syndrome was present in 33%, renal insufficiency in 59%, and hematuria in 87% of patients. Compared with adults, children had lower incidence of renal insufficiency and were more likely to have reduced C3. Histologic pattern included membranoproliferative, mesangial, endocapillary, and crescentic glomerulonephritis. Treatment included immunosuppression (IS) alone in seven, renin angiotensin system (RAS) blockade alone in six, and combined IS/RAS blockade in 11. On follow-up (mean 63 mo) available in 27 patients, 26% had complete response, 48% had persistent renal dysfunction, and 26% had ESRD. Correlates of ESRD were older age and higher creatinine at biopsy, the absence of combined IS/RAS blockade therapy and the presence of subepithelial humps, but not histologic pattern. On multivariate analysis, age and creatinine emerged as the only independent predictors of ESRD. CONCLUSIONS: DDD is clinically and pathologically heterogeneous. Adults have worse outcome than children, despite similar treatment. Combined IS/RAS blockade appears superior to either agent alone.

Prognostic factors in children with membranoproliferative glomerulonephritis type I.

The clinical outcome of patients with membranoproliferative glomerulonephritis (MPGN) varies, with some patients progressing to end-stage renal disease. The aim of this retrospective study was to analyze the initial clinical signs and laboratory test results associated with an MPGN prognosis. The study cohort consisted of 47 patients with idiopathic MPGN Type I treated at the National Institute of Pediatrics, Mexico City, between 1971 and 2001. The median follow-up was 3 years. The three different outcomes of interest were death, renal failure, and nephrotic syndrome. The patients' ages ranged between 4 and 16 years. All patients had different degrees of proteinuria, hyperlipidemia, and microscopic/macroscopic hematuria, and 85.1% of them showed hypocomplementemia. Clinical outcomes varied, however, the most common was nephrotic syndrome, either alone or combined with other syndromes, which accounted for 74.5% of all cases. Fifteen patients died. Treatment with methylprednisolone improved the patient's condition, while the use of chloroquine or cyclophosphamide worsened it. Twenty-two patients had some degree of renal failure; glomerular filtration rate (GFR) levels and albumin values were negatively associated to renal failure, while treatment with methylprednisolone decreased the probability of renal failure. Nephrotic syndrome persisted in 18 patients; hemolytic complement and hemoglobin values were negatively associated with nephrotic syndrome, while macroscopic hematuria was positively associated with it. Signs that suggested a poor prognosis during diagnosis were low GFR, low albumin, low hemolytic complement, and macroscopic hematuria. Treatment with methylprednisolone seemed to improve prognosis, however, this needs to be confirmed with randomized studies.

Prognosis, treatment and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis.

BACKGROUND: Prognostic factors and outcome are incompletely known in childhood mesangiocapillary glomerulonephritis (MCGN). This study aimed to correlate renal outcome with clinical and histopathological variables. METHODS: We conducted a two-centre retrospective analysis of children with MCGN. RESULTS: Fifty-three children presented at a mean age of 8.8 years (range: 13 months-15 years). They were followed for a median of 3.5 years (range: 0-17 years). Histological classification identified 31 type 1, 14 type 2, two type 3 and six undetermined type. Mean renal survival [time to end-stage renal failure (ESRF)] was projected to be 12.2 years [confidence interval (CI): 9.7-14.6 years]. Five and 10 year renal survival was 92% (CI: 88-100%) and 83% (CI: 74-92%), respectively. Those with nephrotic syndrome at presentation had mean renal survival of 8.9 years (CI: 7.1-10.7 years) vs 13.6 years for those without (CI: 10.8-16.5 years) (P = 0.047). The mean estimated glomerular filtration rate (eGFR) at 1 year in those who progressed to ESRF was 52 vs 98 ml/min/1.73 m2 in those who did not (P < 0.001). Chronic damage scored on the first biopsy in 31 children (one centre) was positively associated with adverse renal outcome at 5 years: <20% was associated with 100% and > or =20% with 71% 5-year renal survival (P = 0.006). In 29 children treated with steroid there was a higher proportion (76%) with reduced eGFR at presentation and a significantly higher incidence of nephrotic syndrome (P = 0.002) and hypertension (P = 0.037). There were no significant differences in outcome eGFR, hypertension or proteinuria. CONCLUSIONS: Nephrotic syndrome at presentation and subnormal eGFR at 1 year were adverse features. The finding that structural disease at onset predicted poor renal outcome at 5 years has implications for the design of therapeutic trials. Treatment of MCGN was variable and not evidence-based.

Effects of complement factor D deficiency on the renal disease of MRL/lpr mice.

BACKGROUND: The alternative complement pathway (AP) is activated in individuals with lupus nephritis and in murine models of systemic lupus erythematosus, including MRL/lpr mice. A previous study from our laboratory evaluated the development of renal disease in MRL/lpr mice genetically deficient in factor B (Bf-/-), a protein necessary for AP activation. MRL/lpr Bf-/- mice developed less renal disease and had improved survival; however, these mice were also a different major histocompatibility complex (MHC) haplotype (H-2b) than their wild-type littermates (H-2k) due to the gene for Bf being located in the MHC gene complex. We undertook the current study to determine if the decreased renal disease in MRL/lpr Bf-/- mice was due to the lack of AP activation or the H-2b haplotype by studying the effects of factor D (Df) deficiency, a critical protein for AP activation, on disease development in MRL/lpr mice. METHODS: Df-deficient mice were backcrossed with MRL/lpr mice for four to nine generations. MRL/lpr H-2k Df-/-, Df+/-, and Df+/+ littermates were evaluated for disease development. Lack of AP activation in MRL/lpr Df-/- mice was determined by the zymosan assay. Serum creatinine levels were measured using a creatinine kit. Proteinuria and autoantibody levels were determined by enzyme-linked immunosorbent assay (ELISA). Sections from one kidney were stained with fluorescein isothiocyanate (FITC) alpha-murine C3 or alpha-murine IgG to detect C3 and IgG deposition. The remaining kidney was cut in half with one half fixed, sectioned, and stained with hematoxylin and eosin and periodic acid-Schiff (PAS) to evaluate pathology and another half fixed in glutaraldehyde and examined via electron microscopy. RESULTS: MRL/lpr Df-/- mice had similar glomerular IgG deposition, proteinuria and autoantibody levels, as Df+/+ and Df+/- littermates. However, glomerular C3 deposition, serum creatinine levels, and pathologic renal disease were significantly reduced in Df-/- mice. Despite the lack of renal disease in Df-/- mice, life span was not impacted by factor D deficiency. CONCLUSION: The absence of Df and AP activation is protective against the development of proliferative renal disease in MRL/lpr mice suggesting the similar effect of Bf deficiency in MRL/lpr mice was also due to the lack of AP activation.

Deletion of the fcgamma receptor IIb in thymic stromal lymphopoietin transgenic mice aggravates membranoproliferative glomerulonephritis.

Engagement of immunoglobulin-binding receptors (FcgammaR) on leukocytes and other cell types is one means by which immunoglobulins and immune complexes activate effector cells. One of these FcgammaRs, FcgammaRIIb, is thought to contribute to protection from autoimmune disease by down-regulation of B-cell responsiveness and myeloid cell activation. We assessed the role of FcgammaRIIb in a mouse model of cryoglobulin-associated membranoproliferative glomerulonephritis induced by overexpression of thymic stromal lymphopoietin (TSLP). TSLP transgenic mice were crossbred with animals deficient for FcgammaRIIb on the same genetic background (C57BL/6). Renal pathology was assessed in female and male animals (wild-type, FcgammaRIIb-/-, TSLP transgenic, and combined TSLP transgenic/FcgammaRIIb-/- mice) after 50 and 120 days, respectively. FcgammaRIIb-/- mice had no significant renal pathology, whereas overexpression of TSLP induced a membranoproliferative glomerulonephritis, as previously established. TSLP transgenic FcgammaRIIb-/- mice appeared sick with increased mortality. Kidney function was significantly impaired in male mice corresponding to aggravated glomerular pathology with increases in glomerular matrix and cellularity. This resulted from both a large influx of infiltrating macrophages and increased cellular proliferation. These results emphasize the important role of FcgammaRIIb in regulating immune responses and suggest that modulation of Fcgamma receptor activation or expression may be a useful therapeutic approach for treating glomerular diseases.

Plasma exchange treatment improves prognosis of antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis: a case-control study in 26 patients from a single center.

Twenty-six patients with Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (GN) were divided into two groups according to the acute phase treatment: drug therapy consisting of steroids and oral cyclophosphamide plus a plasma exchange (PE) course (group A, 13 patients) or drug therapy alone (group B, 13 patients). Group A patients had a more severe clinical picture and higher serum creatinine than group B (12.7 +/- 6.9 vs. 8.5 +/- 5.3 mg%); nine patients from group A (69%) and five from group B (38%) required dialysis. At follow up (mean 35 months) all patients treated with PE were alive: four of them were in end-stage renal disease. Among group B patients, three (23%) died in the acute phase; 6 (46%) needed renal replacement therapy at follow up. Of the dialysis-dependent patients, five out of nine from group A were free of dialysis, while in group B two out of five patients had died, two had entered a regular dialysis treatment and one had received a cadaver graft. These data suggest that PE may significantly improve the prognosis of patients with ANCA-associated crescentic GN even if they are not dialysis-dependent at the time of diagnosis.

[Idiopathic nephrotic syndrome in children: report of 57 cases]. / Le syndrome nephrotique idiopathique de l'enfant: a propos de 57 observations.

The aim of this study was to analysis epidemiological, clinical, biochemical and histopathological profile of INS in children and to document their management and their final course. A retrospective study of 57 children with INS hospitalized in the pediatric department of Monastir hospital from the 1st of January 1989 to the 31 th of December 1999 was conducted. The annual rate was of 3,2 cases 1000 admissions, sex ratio was of 1,28 with 32 boys and 25 girls. The mean age at the onset of the affection was of 5 years and 3 months. The renal biopsy was performed in 18 children. The histological finding were a minimal change histology in 50% of cases, a focal segmental glomerulosclerosis in 33% of cases and membrano-proliferative glomerulonephritis in 11% of cases. A cortico-therapy was initiated in all children. 87,5% of them were steroid sensitive. 22,4% of patients had steroid dependent nephrotic syndrome and 12,5% of patients had steroid resistant nephrotic syndrome. All children steroid resistant underwent immunosuppressive therapy; however chronic failure was observed in 57% of them. After a mean follow up period of 46 months, recovery was obtained in 48,2%, complete remission in 28,5% and death in 5,3% of cases.

Prognostic factors in mesangioproliferative glomerulonephritis.

BACKGROUND: The aim of our study was to examine patients with mesangioproliferative glomerulonephritis (MPGN), with or without glomerular IgA deposits, and to analyse the effect of different clinical and histopathological variables at the time of biopsy on progression to end-stage renal failure (ESRF) and death. METHODS: We retrospectively examined 273 patients who got this diagnosis in Norway from April 1988 to December 1990 after a renal biopsy. All patients were followed for a median duration of 34.8 months (0.8-68 months). RESULTS: The mean age at the time of biopsy was 40+/-17 years (range 1.1-79 years). Glomerular IgA deposits were present in 45% of the patients; IgA deposits did not affect prognosis. Three years after the time of biopsy, 7% had developed ESRF (chronic dialysis treatment or kidney transplantation) and 8% had died. By Kaplan-Meier analyses, the following clinical variables indicated progression to ESRF: increased serum creatinine, proteinuria > or =1 g/24 h, systolic blood pressure (BP) > or =160 mmHg, diastolic BP > or =90 mmHg, serum albumin <35 g/l, presence of urinary granular casts and age > or =60 years. Morphological variables indicating progression to ESRF were presence of focal mesangial sclerosis, focal glomerular crescents or necroses, benign nephrosclerosis and increased interstitial score. In the multivariable analysis, the following variables indicated progression to ESRF: increased serum creatinine (P<0.001), decreased serum albumin (P<0.05), increased diastolic BP (P<0.05), low age (P<0.05) and increased interstitial score (P<0.001). CONCLUSIONS: It is possible from clinical and histopathological variables to identify low-risk and high-risk patients at the time of biopsy. There is, however, considerable convergence. A major new observation is the finding of young age, decreased serum albumin and the presence of urinary granular casts as important clinical risk factors. Interstitial damage was the most important histopathological predictor of ESRF.

[Long-term follow-up on the treatment of diffuse proliferative glomerulonephritis in patients with systemic lupus erythematosus].

BACKGROUND: Diffuse Proliferative Glomerulonephritis (DPGN) is the most ominous form of lupus nephritis. Treatment according to the "NIH Protocol" is considered by many physicians to be the treatment of choice for this form of disease, but this is not accepted exclusively. OUR AIM: To evaluate the outcome of SLE patients with biopsy proven DPGN diagnosed and treated in our department, between the years 1976-1996, and to compare the results achieved by using the "NIH Protocol" as opposed to other forms of treatment. PATIENTS AND METHODS: The archive of the Department of Pathology was screened for patients with SLE and DPGN. The specimens were re-examined to confirm the diagnosis and calculate the activity and chronicity scores. The pertinent data was extracted from the patients medical records. RESULTS: Twenty-six patients fulfilled the inclusion criteria, 22 females and 4 males. We followed-up on these patients for an average period of 89 +/- 74 months (range 9-255). More than 80% of the patients achieved remission, about a third experienced at least one relapse. Only one patient died during the follow-up period and 4 others developed end stage renal failure necessitating chronic renal replacement therapy. Sixteen patients were treated according to the NIH protocol, the other 10 were treated with high dose Prednisone, either alone or in combination with oral immunosuppressive drugs. At time of diagnosis there was no statistically significant difference between the two groups regarding the age and gender distribution, blood levels of creatinine and C3 and the level of proteinuria. We were unable to demonstrate any statistically significant difference between the two groups in any of the evaluated parameters, regarding neither patient and kidney survival nor the type and rate of complications. CONCLUSION: Following treatment, patient and kidney survival is good. The NIH protocol is the treatment of choice, but the use of high dose steroids for six months with or without oral immunosuppressive drugs may yield comparable results in selected cases.

Membranoproliferative glomerulonephritis.

Glomerulonephritis (GN) encompasses a wide variety of primary and secondary diseases that cause injury to the functioning unit of the kidney, the glomerulus. The many classifications of GN sometimes lead to confusion. This case study describes an individual with membranoproliferative GN and includes discussion of classification, treatment, and prognosis of this disease.