Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant

Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients along with further NPHS2 mutation analysis in those carrying the variant

Néphropathies tubulo-interstitielles héréditaires, étude rétrospective de 35 familles

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Central Nervous System Complications in Cystinosis: The Role of Neuroimaging

Despite improvement in the specific treatment, clinical and anatomo-functional central nervous system (CNS) abnormalities of various severities are still observed in cystinosis patients. Patients who develop CNS complications today have a worse compliance to cysteamine treatment. Radiological studies have shown that cortical or central (ventriculomegaly) atrophy is observed in more than two thirds of cystinosis patients’ magnetic resonance imaging (MRI) and correlates with the intelligence quotient score. Half of cystinosis patients have marked aspecific white matter hyperintensities. The development of advanced neuroimaging techniques provides new tools to further investigate CNS complications. A recent neuroimaging study using a voxel-based morphometry approach showed that cystinosis patients present a decreased grey matter volume in the left middle frontal gyrus. Diffusion tensor imaging studies have shown white matter microstructure abnormalities in children and adults with cystinosis, respectively in areas of the dorsal visual pathway and within the corpus callosum’s body. Finally, leucocyte cystine levels are associated with decreased resting cerebral blood flow, measured by arterial spin labelling, in the frontal cortex, which could be associated with the neurocognitive deficits described in these patients. These results reinforce the relevance of neuroimaging studies to further understand the mechanisms that underline CNS impairments

Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant

Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients along with further NPHS2 mutation analysis in those carrying the variant

Proliferative lupus nephritis in the absence of overt systemic lupus erythematosus

International audienceSevere lupus nephritis in the absence of systemic lupus erythematosus (SLE) is a rare condition with an unclear clinical presentation and outcome. We conducted a historical observational study of 12 adult (age >18 years) patients with biopsy-proven severe lupus nephritis or lupus-like nephritis without SLE immunological markers at diagnosis or during follow-up. Excluded were patients with chronic infections with HIV or hepatitis B or C; patients with a bacterial infectious disease; and patients with pure membranous nephropathy. Electron microscopy was retrospectively performed when the material was available. End points were the proportion of patients with a complete response (urine protein to creatinine ratio <0.5 g/day and a normal or near-normal eGFR), partial response (≥50% reduction in proteinuria to subnephrotic levels and a normal or near-normal eGFR), or nonresponse at 12 months or later after the initiation of the treatment. The study included 12 patients (66% female) with a median age of 36.5 years. At diagnosis, median creatinine and proteinuria levels were 1.21 mg/dL (range 0.5–11.6) and 7.5 g/day (1.4–26.7), respectively. Six patients had nephrotic syndrome and acute kidney injury. Renal biopsy examinations revealed class III or class IV A/C lupus nephritis in all cases. Electron microscopy was performed on samples from 5 patients. The results showed mesangial and subendothelial dense deposits consistent with LN in 4 cases, and a retrospective diagnosis of pseudo-amyloid fibrillary glomerulonephritis was made in 1 patient. Patients received immunosuppressive therapy consisting of induction therapy followed by maintenance therapy, similar to treatment for severe lupus nephritis. Remission was recorded in 10 patients at 12 months after the initiation of treatment. One patient reached end-stage renal disease. After a median follow-up of 24 months, 2 patients relapsed. Lupus nephritis in the absence of overt SLE is a nosological entity requiring careful etiological investigation, including systematic electron microscopy examination of renal biopsies to rule out fibrillary glomerulonephritis. In this series, most patients presented with severe glomerulonephritis, which was highly similar to lupus nephritis at presentation and in terms of response to immunosuppressive therapy. Abbreviations: CKD = chronic kidney disease, CR = complete response, eGFR = estimated glomerular filtration rate, FHN = Full House nephropathy, LN = lupus nephritis, MMF = mycophenolate mofetil, PR = partial response, SLE = systemic lupus erythematosus

Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of <i>MAFB</i> Gene and Literature Review

Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment

Immunoglobulin A Nephropathy in Association with Inflammatory Bowel Diseases: Results from a National Study and Systematic Literature Review

International audienceAbstract Background Little is known about clinical characteristics and kidney outcomes in patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in a context of inflammatory bowel disease (IBD). Methods We conducted a retrospective multicentre study with a centralized histological review to analyse the presentation, therapeutic management and outcome of 24 patients suffering from IBD-associated IgAN relative to a cohort of 134 patients with primary IgAN without IBD. Results Crohn's disease and ulcerative colitis accounted for 75 and 25% of IBD-associated IgAN cases, respectively. IBD was diagnosed before IgAN in 23 cases (a mean of 9\,years previously) and was considered active at IgAN onset in 23.6% of patients. Hypertension was present in 41.7% of patients. The urinary protein:creatinine ratio exceeded 100\,mg/mmol in 70.8% of patients (mean 254\,mg/mmol). Estimated glomerular filtration rate (eGFR) was &gt;60\,mL/min/1.73\,m2 in 13/24 patients and only 1 patient required dialysis. In the Oxford mesangial hypercellularity, endocapillary cellularity, segmental sclerosis and interstitial fibrosis/tubular atrophy with crescents classification of renal biopsies, 57% were M1, 48% E1, 76% S1, 57% T1\textendash 2 and 38% C1\textendash 2. Steroids were administered in 50% of cases. After a mean follow-up of 7.2\,years, 4 patients (16.7%) had a poor kidney outcome: end-stage renal disease (n\,=\,3) or a &gt;50% decrease in eGFR from initial values (n\,=\,1). A similar evolution was observed in patients with primitive IgAN. Conclusions This first case series suggests that IBD-associated IgAN has frequent inflammatory lesions at onset and variable long-term outcomes

COVID-19 outbreak in vaccinated patients from a haemodialysis unit: antibody titres as a marker of protection from infection

International audienceBackground Patients on maintenance haemodialysis (HD) have an increased risk of severe coronavirus disease 2019 (COVID-19) and a reduced response to vaccines. Data are needed to identify immune correlates of protection in this population. Methods Following a COVID-19 outbreak among vaccinated patients in a HD unit, clinical data and serological response to BNT162b2 vaccine were retrospectively recorded. Results Among 53 patients present in the dialysis room, 14 were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant (COVID_Pos) and 39 were not. Compared with uninfected patients, COVID_Pos patients more frequently had additional causes of immunosuppression (50% versus 21%; P = .046) and were more often scheduled on the Monday–Wednesday–Friday (MWF) shift (86% versus 39%; P = .002). Moreover, COVID_Pos had lower anti-spike (S) immunoglobulin G (IgG) titres than uninfected patients {median 24 BAU/mL [interquartile range (IQR) 3–1163] versus 435 [99–2555]; P = .001} and lower neutralization titres [median 108 (IQR 17–224) versus 2483 (481–43 908); P = .007]. Anti-S and neutralization antibody titres are correlated (r = 0.92, P &lt; .001). In multivariable analysis, an MWF schedule {odds ratio [OR] 10.74 [95% confidence interval (CI) 1.9–93.5], P = .014} and anti-S IgG titres 1 month before the outbreak [&lt;205 BAU/mL: OR 0.046 (95% CI 0.002–0.29), P = .006] were independently associated with COVID-19 infection. None of the patients with anti-S IgG &gt;284 BAU/mL got infected. Ten of 14 COVID_Pos patients were treated with casirivimab and imdevimab. No patient developed severe disease. Conclusions Anti-S IgG titre measured prior to exposure correlates to protection from SARS-CoV-2 infection in HD patients. BNT162b2 vaccination alone or in combination with monoclonal antibodies prevented severe COVID-19