Atypical Anti-Glomerular Basement Membrane Nephritis: A Case Series From the French Nephropathology Group.

RATIONALE & OBJECTIVE: Atypical anti-glomerular basement membrane (GBM) nephritis is characterized by a bright linear immunoglobulin staining along the GBM by immunofluorescence without a diffuse crescentic glomerulonephritis nor serum anti-GBM antibodies by conventional enzyme-linked immunosorbent assay (ELISA). We characterized a series of patients with atypical anti-GBM disease. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients identified by the French Nephropathology Group as having atypical anti-GBM nephritis between 2003 and 2022. FINDINGS: Among 38 potential cases, 25 were included, of whom 14 (56%) were female and 23 (92%) had hematuria. The median serum creatinine at diagnosis was 150 (IQR, 102-203) µmol/L and median urine protein-creatinine ratio (UPCR) was 2.4 (IQR, 1.3-5.2) g/g. Nine patients (36%) had endocapillary proliferative glomerulonephritis (GN), 4 (16%) had mesangial proliferative GN, 4 (16%) had membranoproliferative GN, 2 (8%) had pure and focal crescentic GN, 1 (4%) had focal segmental glomerulosclerosis, and 5 had glomeruli that were unremarkable on histopathology. Nine patients (36%) had crescents, involving a median of 9% of glomeruli. Bright linear staining for IgG was seen in 22 cases (88%) and for IgA in 3 cases (12%). The 9 patients (38%) who had a monotypic staining pattern tended to be older with less proteinuria and rarely had crescents. Kidney survival rate at 1 year was 83% and did not appear to be associated with the light chain restriction. LIMITATIONS: Retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Compared with typical anti-GBM disease, atypical anti-GBM nephritis frequently presents with an endocapillary or mesangial proliferative glomerulonephritis pattern and appears to have a slower disease progression. Further studies are needed to fully characterize its pathophysiology and associated clinical outcomes. PLAIN-LANGUAGE SUMMARY: Atypical anti-glomerular basement membrane (GBM) nephritis is characterized histologically by bright linear immunoglobulin staining along the GBM without diffuse crescentic glomerulonephritis or circulating anti-GBM antibodies. We report a case series of 25 atypical cases of anti-GBM nephritis in collaboration with the French Nephropathology Group. Compared with typical anti-GBM disease, we observed a slower disease progression. Patients frequently presented with heavy proteinuria and commonly had evidence of endocapillary or mesangial proliferative glomerulonephritis. About half of the patients displayed a monotypic immune staining pattern; they tended to be older, with less proteinuria, and commonly without glomerular crescents in biopsy specimens. No concomitant circulating monoclonal gammopathy was detected. Further studies are needed to fully characterize its pathophysiology and associated clinical outcomes.

The role of PLA2R antibody monitoring: what we know and what we do not know.

For a long time, kidney biopsy was the only diagnostic means for membranous nephropathy (MN) and proteinuria and serum creatinine were the only markers of disease activity. The discovery of the phospholipase A2 receptor (PLA2R) antibody in 2009 has induced a paradigm shift in both the diagnosis and monitoring of patients. Two serological tests are routinely used: the enzyme-linked immunosorbent assay (ELISA), which is quantitative, and the immunofluorescence assay (IFA), which is more sensitive. In centres where the two assays are available, the recommendation is to use IFA for screening and diagnosis of immunological remission and ELISA for monitoring the effectiveness of therapy. In patients with positive PLA2R antibody serology, normal kidney function and no evidence of an underlying disease, a kidney biopsy is not mandatory given the almost 100% specificity of the assays. Because MN has different phases, one cannot base a clinical or therapeutic decision on a single measurement of PLA2R antibody at baseline. Risk evaluation of disease progression is a dynamic process that should be performed repeatedly to capture the trajectory of the disease based on both the traditional biomarkers (proteinuria and serum creatinine) and PLA2R antibody levels. The effectiveness of therapy is also evaluated on the PLA2R antibody trajectory, particularly during the first 6 months. Finally, PLA2R antibody monitoring has transformed the management of patients with kidney allografts. Future studies are needed to develop more subtle immunological tests, including monitoring of antigen-specific memory B cells.

The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy.

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.

Organ Transplantation in Hereditary Fibrinogen A α-Chain Amyloidosis: A Case Series of French Patients.

RATIONALE & OBJECTIVE: Fibrinogen A α-chain amyloidosis (AFib amyloidosis) is a form of amyloidosis resulting from mutations in the fibrinogen A α-chain gene (FGA), causing progressive kidney disease leading to kidney failure. Treatment may include kidney transplantation (KT) or liver-kidney transplantation (LKT), but it is not clear what factors should guide this decision. The aim of this study was to characterize the natural history and long-term outcomes of this disease, with and without organ transplantation, among patients with AFib amyloidosis and various FGA variants. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 32 patients with AFib amyloidosis diagnosed by genetic testing in France between 1983 and 2014, with a median follow-up of 93 (range, 4-192) months, were included. RESULTS: Median age at diagnosis was 51.5 (range, 12-77) years. Clinical presentation consisted of proteinuria (93%), hypertension (83%), and kidney failure (68%). Manifestations of kidney disease appeared on average at age 57 (range, 36-77) years in patients with the E526V variant, at age 45 (range, 12-59) years in those with the R554L variant (P<0.001), and at age 24.5 (range, 12-31) years in those with frameshift variants (P<0.001). KT was performed in 15 patients and LKT was performed in 4. In KT patients with the E526V variant, recurrence of AFib amyloidosis in the kidney graft was less common than with a non-E526V (R554L or frameshift) variant (22% vs 83%; P=0.03) and led to graft loss less frequently (33% vs 100%). Amyloid recurrence was not observed in patients after LKT. LIMITATIONS: Analyses were based on clinically available historical data. Small number of patients with non-E526V and frameshift variants. CONCLUSIONS: Our study suggests phenotypic variability in the natural history of AFib amyloidosis, depending on the FGA mutation type. KT appears to be a viable option for patients with the most common E526V variant, whereas LKT may be a preferred option for patients with frameshift variants.

Prevalence of tubulopathy and association with renal function loss in HIV-infected patients.

BACKGROUND: The incidence of chronic kidney disease (CKD) is 10 times higher in human immunodeficiency virus (HIV)-infected patients than in the general population. We explored the prevalence and determinants of proximal tubular dysfunction (PTD) in HIV-infected individuals, and assessed the impact of the tubulopathy on the estimated glomerular filtration rate (eGFR) outcome. METHODS: A cohort study was performed on 694 outpatients followed in a French centre to analyse the prevalence of PTD, the diagnosis performance of screening tools and the associated factors. eGFR was prospectively evaluated to analyse the predictive value of the tubulopathy on eGFR decrease. RESULTS: At inclusion, 14% of the patients presented with PTD and 5% with CKD. No individual tubular marker, including non-glomerular proteinuria, glycosuria dipstick or hypophosphataemia, registered sufficient performance to identify PTD. We found a significant interaction between tenofovir disoproxil fumarate exposure and ethnicity (P = 0.03) for tubulopathy risk. Tenofovir disoproxil fumarate exposure was associated with PTD in non-Africans [adjusted odds ratio (aOR) = 4.71, P < 10-3], but not in patients of sub-Saharan African origin (aOR = 1.17, P = 0.73). Among the 601 patients followed during a median of 4.3 years, 13% experienced an accelerated eGFR decline. Unlike microalbuminuria and glomerular proteinuria, tubulopathy was not associated with accelerated eGFR decline. CONCLUSION: PTD is not rare in HIV-infected individuals but is less frequent in sub-Saharan African patients and is associated with tenofovir disoproxil fumarate exposure only in non-Africans. Its diagnosis requires multiple biochemical testing and it is not associated with an accelerated eGFR decline.

Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1-related stroke.

Mutations in the α1 (COL4A1) or α2 (COL4A2) chains of collagen type IV, a major component of the vascular basement membrane, cause intracerebral haemorrhages with variable expressivity and reduced penetrance by mechanisms that remain poorly understood. Here we sought to investigate the cellular mechanisms of COL4A1-related intracerebral haemorrhage and identify a marker for haemorrhage risk stratification. A combination of histological, immunohistochemical, and electron microscopy analyses were used to analyse the brain parenchyma, cerebrovasculature, and retinal vessels of mice expressing the disease-causing COL4A1 p.G498V mutation. Mutant mice developed cerebral microhaemorrhages and macroscopic haemorrhages (macrohaemorrhages), the latter with reduced penetrance, mimicking the human disease. Microhaemorrhages that occurred in early postnatal life were associated with a transient, generalized increase in blood-brain barrier permeability at the level of capillaries. Macrohaemorrhages, which occurred later in life, originated from deep brain arteries with focal loss of smooth muscle cells. Similar smooth muscle cell loss was detected in retinal arteries, and a time-course analysis of arterial lesions showed that smooth muscle cells are recruited normally in arterial wall during development, but undergo progressive apoptosis-mediated degeneration. By assessing in parallel the extent of these retinal arterial lesions and the presence/absence of macrohaemorrhages, we found that the arterial lesion load in the retina is strongly correlated with the burden of macrohaemorrhages. We conclude that microhaemorrhages and macrohaemorrhages are driven by two distinct mechanisms. Moreover, smooth muscle cell degeneration is a critical factor underlying the partial penetrance of COL4A1-related macrohaemorrhages, and retinal imaging is a promising tool for identifying high-risk patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

HANAC Col4a1 Mutation in Mice Leads to Skeletal Muscle Alterations due to a Primary Vascular Defect.

Collagen IV is a major component of basement membranes (BMs). The α1(IV) chain, encoded by the COL4A1 gene, is expressed ubiquitously and associates with the α2(IV) chain to form the α1α1α2(IV) heterotrimer. Several COL4A1 mutations affecting a conformational domain containing integrin-binding sites are responsible for the systemic syndrome of hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC). To analyze the pathophysiology of HANAC, Col4a1 mutant mice bearing the p.Gly498Val mutation were generated. Analysis of the skeletal muscles of Col4a1G498V mutant animals showed morphologic characteristics of a muscular dystrophy phenotype with myofiber atrophy, centronucleation, focal inflammatory infiltrates, and fibrosis. Abnormal ultrastructural aspects of muscle BMs was associated with reduced extracellular secretion of the mutant α1α1α2(IV) trimer. In addition to muscular dystrophic features, endothelial cell defects of the muscle capillaries were observed, with intracytoplasmic accumulation of the mutant α1α1α2(IV) molecules, endoplasmic reticulum cisternae dilation, and up-regulation of endoplasmic reticulum stress markers. Induction of the unfolded protein response in Col4a1 mutant muscle tissue resulted in an excess of apoptosis in endothelial cells. HANAC mutant animals also presented with a muscular functional impairment and increased serum creatine kinase levels reflecting altered muscle fiber sarcolemma. This extensive description of the muscular phenotype of the Col4a1 HANAC murine model suggests a potential contribution of primary endothelial cell defects, together with muscle BM alterations, to the development of COL4A1-related myopathy.

Minimal change nephrotic syndrome in patients infected with human immunodeficiency virus: a retrospective study of 8 cases.

BACKGROUND: Human immunodeficiency virus (HIV) is associated with diverse glomerular diseases. Characteristics of minimal change nephrotic syndrome (MCNS) in this setting have been little studied, and the specific features of this uncommon association remain to be determined. METHODS: We conduct a retrospective study. Clinical, biological and pathological characteristics of patients with MCNS and HIV infection were assessed. We evaluated HIV infection by in situ hybridization and CMIP expression by immunochemistry on kidney biopsies and compared it to HIV-associated nephropathy (HIVAN) and idiopathic MCNS. RESULTS: Eight patients were identifies. In all but one of these cases, MCNS occurred after HIV diagnosis (mean of 9.5 years). Acute kidney injury was detected in three cases. Mean CD4+ lymphocyte count was 733/mm3 and three patients had a detectable HIV viral load. In situ hybridization for HIV-1 RNA detection yielded a positive signal in a few tubular cells in the renal parenchyma in two of four patients with HIV infection associated with MCNS. Podocytes of these patients presented strong positive immunostaining for CMIP (4/4). Three patients suffered steroid-dependent nephrotic syndrome, and another two patients had at least one relapse. Rituximab treatment was initiated in four cases. After a median follow-up of 20 months, all patients were in remission (complete in 5 cases). CONCLUSIONS: In patients with MCNS occurring in a context of HIV infection, podocyte injury seems to be associated with CMIP induction rather than renal HIV infection but further studies are needed to determine the molecular link between these two conditions.

Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up.

Randomized trials of rituximab in primary membranous nephropathy (PMN) have not been conducted. We undertook a multicenter, randomized, controlled trial at 31 French hospitals (NCT01508468). Patients with biopsy-proven PMN and nephrotic syndrome after 6 months of nonimmunosuppressive antiproteinuric treatment (NIAT) were randomly assigned to 6-month therapy with NIAT and 375 mg/m2 intravenous rituximab on days 1 and 8 (n=37) or NIAT alone (n=38). Median times to last follow-up were 17.0 (interquartile range, 12.5-24.0) months and 17.0 (interquartile range, 13.0-23.0) months in NIAT-rituximab and NIAT groups, respectively. Primary outcome was a combined end point of complete or partial remission of proteinuria at 6 months. At month 6, 13 (35.1%; 95% confidence interval [95% CI], 19.7 to 50.5) patients in the NIAT-rituximab group and eight (21.1%; 95% CI, 8.1 to 34.0) patients in the NIAT group achieved remission (P=0.21). Rates of antiphospholipase A2 receptor antibody (anti-PLA2R-Ab) depletion in NIAT-rituximab and NIAT groups were 14 of 25 (56%) and one of 23 (4.3%) patients at month 3 (P<0.001) and 13 of 26 (50%) and three of 25 (12%) patients at month 6 (P=0.004), respectively. Eight serious adverse events occurred in each group. During the observational phase, remission rates before change of assigned treatment were 24 of 37 (64.9%) and 13 of 38 (34.2%) patients in NIAT-rituximab and NIAT groups, respectively (P<0.01). Positive effect of rituximab on proteinuria remission occurred after 6 months. These data suggest that PLA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety.

Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome.

The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling. SUMMARY STATEMENT: This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition.

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.

Spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN.

Noninfectious mixed cryoglobulinemic GN (MCGN) has been poorly investigated. We analyzed presentation and outcome of 80 patients with biopsy-proven MCGN, which were identified in the retrospective French CryoVas survey. MCGN was related to primary Sjögren's syndrome in 22.5% of patients and to lymphoproliferative disorders in 28.7% of patients, and was defined as essential in 48.8% of patients. At presentation, hematuria, proteinuria ≥1 g/d, hypertension, and renal failure were observed in 97.4%, 84.8%, 85.3%, and 82.3% of cases, respectively. Mean±eGFR was 39.5±20.4 ml/min per 1.73 m(2) Membranoproliferative GN was the predominant histologic pattern, observed in 89.6% of cases. Renal interstitium inflammatory infiltrates were observed in 50% of cases. First-line treatment consisted of steroids alone (27.6%) or in association with rituximab (21.1%), alkylating agents (36.8%) or a combination of cyclophosphamide and rituximab (10.5%). After a mean follow-up of 49.9±45.5 months, 42.7% of patients relapsed with a renal flare in 75% of cases. At last follow-up, mean eGFR was 50.2±26.1 ml/min per 1.73 m(2)with 9% of patients having reached ESRD; 59% and 50% of patients achieved complete clinical and renal remission, respectively. A rituximab+steroids regimen prevented relapses more effectively than steroids alone or a cyclophosphamide+steroids combination did, but was associated with a higher rate of early death when used as first-line therapy. Severe infections and new-onset B-cell lymphoma occurred in 29.1% and 8.9% of cases, respectively; 24% of patients died. In conclusion, noninfectious MCGN has a poor long-term outcome with severe infections as the main cause of death.

Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature.

In patients with infectious cryoglobulinemia vasculitis (CryoVas) in the absence of hepatitis C virus infection, data on presentation, therapeutic management and outcome are lacking. We conducted a nationwide survey that included patients with HCV-negative CryoVas. We describe here the presentation, therapeutic management and outcome of 18 patients with non-HCV infectious CryoVas and 27 additional patients identified form a systematic review of the literature. We included 18 patients, mean age 57.9±13.5 years. Infectious causes were viral infections in 8 patients [hepatitis B virus (HBV) in 4, and cytomegalovirus, Epstein Barr virus, parvovirus B19 and human immunodeficiency virus in one case each], pyogenic bacterial infection in 6 patients, parasitic infection in 2 patients, and leprosy and candidiasis in one case each. Baseline manifestations were purpura (78%), glomerulonephritis (28%), arthralgia (28%), peripheral neuropathy (22%), skin necrosis (22%), cutaneous ulcers (17%), and myalgia (11%). Cryoglobulinemia was type II in 2/3 of cases. Most cases received specific anti-infectious therapy as first-line therapy, sometimes associated with corticosteroids, achieving sustained remission in the majority of cases. Refractory or relapsing patients, frequently related to HBV infection, showed a complete remission after rituximab in addition to antiviral therapy. In contrast, corticosteroids and/or immunosuppressive agents used in the absence of anti-infectious agents were frequently associated with refractory CryoVas. Viral and pyogenic bacterial infections represent the main causes of non-HCV infectious CryoVas. Antimicrobial therapy is commonly associated with sustained remission. Immunosuppressive agents should be considered only as a second-line option in patients with refractory vasculitis.

Improving mutation screening in familial hematuric nephropathies through next generation sequencing.

Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.

INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy.

BACKGROUND: Charcot-Marie-Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot-Marie-Tooth neuropathy associated with FSGS. METHODS: We performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted. RESULTS: We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2-MAL-CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42. CONCLUSIONS: INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. (Funded by the Agence Nationale de la Recherche and others.).

Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey.

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.

Acute metabolic acidosis in a GLUT2-deficient patient with Fanconi-Bickel syndrome: new pathophysiology insights.

Fanconi-Bickel syndrome is a rare autosomal-recessive disorder caused by mutations in the SLC2A2 gene coding for the glucose transporter protein 2 (GLUT2). Major manifestations include hepatomegaly, glucose intolerance, post-prandial hypoglycaemia and renal disease that usually presents as proximal tubular acidosis associated with proximal tubule dysfunction (renal Fanconi syndrome). We report a patient harbouring a homozygous mutation of SLC2A2 who presented a dramatic exacerbation of metabolic acidosis in the context of a viral infection, owing to both ketosis and major urinary bicarbonate loss. The kidney biopsy revealed nuclear and cytoplasmic accumulation of glycogen in proximal tubule cells, a lack of expression of GLUT2, and major defects of key proteins of the proximal tubule such as megalin, cubilin and the B2 subunit of H(+)-ATPase. These profound alterations of the transport systems most likely contributed to proximal tubule alterations and profound bicarbonate loss.

Pemetrexed-induced acute kidney injury leading to chronic kidney disease.

There is little data availableon the nephrotoxicity of pemetrexed, a new generation antifolate agent that is increasingly used in the treatment of numerous malignant tumors. We report the observation of two patients suffering from non-small cell lung cancer who developed acute kidney injury (AKI) after administration of pemetrexed. In one case, pemetrexed was used as a single agent treatment. In the other, pemetrexed was first co-administered with cisplatin, then alone, with AKI worsening 2 months after the discontinuation of cisplatin. The two patients concomitantly developed edema of the face, which is a rare adverse side effect of pemetrexed. Renal biopsies showed acute tubular necrosis and interstitial fibrosis. In both cases, chronic kidney disease (CKD) persisted despite drug discontinuation. Herein, we discuss renal presentation, risk factors, and prognosis of pemetrexed-induced nephrotoxicity.

Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease.

Development of steroid dependency in patients with nephrotic syndrome may require a long-term multi-drug therapy at risk of drug toxicity and renal failure. Rituximab treatment reduces the steroid dosage and the need for immunosuppressive therapy in pediatric patients. Here we retrospectively analyze the efficacy and safety of rituximab in adult patients with steroid-dependent minimal change disease. To do this, we analyzed the outcome of all adult patients treated with rituximab for steroid-dependent minimal change nephrotic syndrome over a mean follow-up of 29.5 months (range 5.1-82 months). Seventeen patients with steroid-dependent or frequently relapsing minimal change nephrotic syndrome, unresponsive to several immunosuppressive medications, were treated with rituximab. Eleven patients had no relapses after rituximab infusion (mean follow-up 26.7 months, range 5.1-82 months) and nine of them were able to come off all other immunosuppressive drugs and steroids during follow-up. Six patients relapsed at least once after a mean time of 11.9 months (mean follow-up 34.5 months, range 16.9-50.1 months), but their immunosuppressive drug treatment could be stopped or markedly reduced during this time. No adverse events were recorded. Thus, rituximab is efficient and safe in adult patients suffering from severe steroid-dependent minimal change disease. Prospective randomized trials are needed to confirm this study.