Publications by authors named "Caroline Rousset-Rouviere"

12 Publications

  • Page 1 of 1

Association of kidney biopsy findings with short- and medium-term outcomes in children with moderate-to-severe IgA vasculitis nephritis.

Eur J Pediatr 2021 May 2. Epub 2021 May 2.

Department of Multidisciplinary Pediatrics, Pediatric Nephrology Unit, Assistance Publique des Hôpitaux de Marseille, Marseille, France.

Assessing the initial severity of immunoglobulin A vasculitis nephritis (IgAV-N) is important due to its determining effect on kidney management and outcomes. This paper describes a multicentre paediatric cohort of IgAV-N patients and discusses relationships among clinical presentation, histological features, and kidney outcome. We retrospectively studied a cohort of 170 children with biopsy-proven IgAV-N, diagnosed between 2007 and 2017. One-quarter of the cohort (27%) presented with initial nephrotic syndrome (NS). Kidney biopsy revealed International Study of Kidney Disease (ISKDC) grade II or grade III in 83% of cases. Endocapillary proliferation was observed in 73% of patients, and chronic lesions were observed in 25%. Data analysis showed a significant association between NS at onset and endocapillary proliferation and cellular crescents. After a median follow-up of 21 months (IQR 12-39), 30% of patients had persistent proteinuria or decreased eGFR. At the end of follow-up, kidney impairment was more often observed in patients with NS at onset and those with cellular crescents and chronic lesions on initial kidney biopsy.Conclusion: This study highlights the relationship between the clinical and histological presentation of IgAV-N and the factors that affect kidney outcome. The ISKDC classification may be improved by including lesions that are more discriminating for disease severity and prognosis. What is Known: • Nephrotic syndrome (NS) or kidney failure at diagnosis and cellular crescents in more than 50% of the glomeruli are recognized as risk factors for poor kidney outcome in immunoglobulin A vasculitis nephritis (IgAV-N). • The reference histological classification of the International Study of Kidney Disease in Children (ISKDC) is primarily based on the presence and number of affected glomeruli (mesangial proliferation, cellular crescents). The updated Oxford classification, which emphasizes tubular atrophy and interstitial fibrosis, is also used to group pathological features of IgAV-N. Both classifications have limitations. What is New: • Medical treatment should not be postponed in patients with IgAV-N and NS until after biopsy, as NS at diagnosis is associated with initial histological severity and poorer kidney outcome. This proposal needs to be verified in further studies. • Endocapillary proliferation is associated with the initial severity of IgAV-N at diagnosis, while chronic glomerular changes and interstitial fibrosis are associated with poorer short- and medium-term kidney outcomes.
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http://dx.doi.org/10.1007/s00431-021-04065-4DOI Listing
May 2021

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness.

J Am Soc Nephrol 2021 Apr 2. Epub 2021 Apr 2.

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.

Background: The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na,K-ATPase function but are also involved in potassium and pH sensing. Genetic defects in cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.

Methods: A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.

Results: We identified mutations in the gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in oocytes significantly reduced currents.

Conclusions: Biallelic variants in were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.
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http://dx.doi.org/10.1681/ASN.2020111587DOI Listing
April 2021

mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy.

JIMD Rep 2020 Jul 5;54(1):37-44. Epub 2020 May 5.

Assistance Public Hôpitaux de Marseille Service Multidisciplinaire Timone Marseille France.

Introduction: Primary coenzyme Q10 (CoQ10) deficiencies are a group of mitochondrial disorders that has proven responsiveness to replacement therapy. Mutations in enzymes involved in the biosynthesis of CoQ10 genes are associated with these deficits. The clinical presentation of this rare autosomal recessive disorder is heterogeneous and depends on the gene involved. Mutations in the , and genes are responsible for steroid-resistant nephrotic syndrome (SRNS), which is associated with extra-renal symptoms. Previous studies have reported mutations in 11 patients from five different families presenting with SRNS and sensorineural deafness.

Case Reports: Our study reports the cases of two brothers of Turkish origin with renal failure and sensorineural deafness associated with mutations responsible of CoQ10 deficiency. Optical symptoms were present in the eldest, that improved with Idebenone.

Conclusion/discussion: For the first time, mutation with optical involvement is associated with renal and hearing impairment. Although the response to replacement CoQ10 therapy was difficult to evaluate, we think that this treatment was able to stop the disease progression in both patients, and even to prevent the occurrence/development of optical and neurological impairment in the younger brother. Mitochondrial dysfunction secondary to CoQ10 deficiency should always be suspected in patients with SRNS and extra-renal symptoms. Early recognition of this genetic SRNS is mandatory since SRNS can be avoided by adequate treatment based on CoQ10 supplement or an analogue. All cases of primary CoQ10 deficiency should be treated at an early stage to limit the progression of lesions and prevent the emergence of new symptoms.
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http://dx.doi.org/10.1002/jmd2.12068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358665PMC
July 2020

Anti-Factor B Antibodies and Acute Postinfectious GN in Children.

J Am Soc Nephrol 2020 04 7;31(4):829-840. Epub 2020 Feb 7.

Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France;

Background: The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis.

Methods: This retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia.

Results: All children with acute postinfectious GN had activation of the alternative pathway of the complement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 [91%] versus 4 of 28 [14%], respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity , confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity.

Conclusions: These findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glomerulopathy, and to help determine therapy.
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http://dx.doi.org/10.1681/ASN.2019080851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191928PMC
April 2020

The Invisible Threat of Non-steroidal Anti-inflammatory Drugs for Kidneys.

Front Pediatr 2019 17;7:520. Epub 2019 Dec 17.

Department of Multidisciplinary Pediatrics, Pediatric Nephrology Unit, Assistance Publique des Hôpitaux de Marseille, Marseille, France.

Non-steroidal anti-inflammatory drugs (NSAIDs) are often used as analgesic and antipyretic drugs. Nephrotoxicity is a common side effect and leads in 1-5% of pediatric cases to acute kidney injury (AKI). The nephrotoxic effects of NSAIDs arise mainly from two pathological mechanisms: (1) acute tubulo-interstitial nephritis (ATIN) following immune reaction and (2) prerenal failure because of reduced renal plasma flow. Histological examinations are required to confirm the pathomechanism of AKI after NSAID exposure. The aim of this study was to illustrate the risk of ATIN in children with AKI after NSAID exposure. The medical records of all 100 pediatric patients with biopsy-proven AKI treated between January 2006 and 2016 at La Timone Hospital, Marseille, France, were analyzed retrospectively. Twenty-five of these patients had ATIN, four of which were healthy children who had been treated with NSAIDs. In other words, NSAID side effects accounted for 4% of all cases of biopsy-proven AKI and 16% of all cases of ATIN. None of the patients had hypovolemia when they received NSAIDs. Clinical symptoms were non-specific. All patients had abdominal pain and vomiting but normal urine volume output. Maximum serum creatinine levels ranged from 300 to 512 μmol/l, with estimated minimum creatinine clearances of 12-26 ml/min/1.73 m. None of the patients had significant proteinuria. One child had hyperechogenic enlarged kidneys. Three patients were treated with steroids, one of whom also received intravenous methylprednisolone. Renal function improved gradually in all patients, but the patient who received methylprednisolone developed moderate chronic kidney disease (CKD). Biopsy proven-AKI secondary to NSAID use can be severe and be associated with ATIN. Since NSAID-induced ATIN can lead to CKD, clinicians using NSAIDs should focus on preventing AKI.
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http://dx.doi.org/10.3389/fped.2019.00520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927993PMC
December 2019

Growth Patterns After Kidney Transplantation in European Children Over the Past 25 Years: An ESPN/ERA-EDTA Registry Study.

Transplantation 2020 01;104(1):137-144

Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France.

Background: Improved management of growth impairment might have resulted in less growth retardation after pediatric kidney transplantation (KT) over time. We aimed to analyze recent longitudinal growth data after KT in comparison to previous eras, its determinants, and the association with transplant outcome in a large cohort of transplanted children using data from the European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry.

Methods: A total of 3492 patients transplanted before 18 years from 1990 to 2012 were included. Height SD scores (SDS) were calculated using recent national or European growth charts. We used generalized equation models to estimate the prevalence of growth deficit and linear mixed models to calculate adjusted mean height SDS.

Results: Mean adjusted height post-KT was -1.77 SDS. Height SDS was within normal range in 55%, whereas 28% showed moderate, and 17% severe growth deficit. Girls were significantly shorter than boys, but catch-up growth by 5 years post-KT was observed in both boys and girls. Children <6 years were shortest at KT and showed the greatest increase in height, whereas there was no catch-up growth in children transplanted >12.

Conclusions: Catch-up growth post-KT remains limited, height SDS did not improve over time, resulting in short stature in nearly half of transplanted children in Europe.
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http://dx.doi.org/10.1097/TP.0000000000002726DOI Listing
January 2020

Treatment and outcome of congenital nephrotic syndrome.

Nephrol Dial Transplant 2019 03;34(3):458-467

Hôpital Necker-Enfants malades, Néphrologie pédiatrique, Assistance Publique des Hôpitaux de Paris, Université Paris Descartes-Sorbonne Paris-Cité, Paris, France.

Background: Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France.

Methods: We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS.

Results: The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9-52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year.

Conclusions: Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients.
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http://dx.doi.org/10.1093/ndt/gfy015DOI Listing
March 2019

Rituximab fails where eculizumab restores renal function in C3nef-related DDD.

Pediatr Nephrol 2014 Jun 10;29(6):1107-11. Epub 2014 Jan 10.

Unité de Néphrologie Pédiatrique, Hôpital La Timone, AP-HM, Université de la Méditerranée, Marseille, France,

Background: Dense deposit disease (DDD), a C3 glomerulopathy (C3G), is a rare disease with unfavorable progression towards end-stage kidney disease. The pathogenesis of DDD is due to cytotoxic effects related to acquired or genetic dysregulation of the complement alternative pathway, which is at times accompanied by the production of C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase. Available treatments include plasma exchange, CD20-targeted antibodies, and a terminal complement blockade via the anti-C5 monoclonal antibody eculizumab.

Case-diagnosis/treatment: We report here the case of an 8-year-old child with C3NeF and refractory DDD who presented with a nephritic syndrome. She tested positive for C3NeF activity; C3 was undetectable. Genetic analyses of the alternative complement pathway were normal. Methylprednisolone pulses and mycophenolate mofetil treatment resulted in complete recovery of renal function and a reduction in proteinuria. Corticosteroids were tapered and then withdrawn. Four months after corticosteroid discontinuation, hematuria and proteinuria recurred, and a renal biopsy confirmed an active DDD with a majority of extracapillary crescents. Despite an increase in immunosuppressive drugs, including methylprednisolone pulses and rituximab therapy, the patient suffered acute renal failure within 3 weeks, requiring dialysis. Eculizumab treatment resulted in a quick and impressive response. Hematuria very quickly resolved, kidney function improved, and no further dialysis was required. The patient received bimonthly eculizumab injections of 600 mg, allowing for normalization of renal function and reduction of proteinuria to <0.5 g per day. Since then, she continues to receive eculizumab.

Conclusion: Complement regulation pathway-targeted therapy may be a specific and useful treatment for rapidly progressing DDD prior to the development of glomerulosclerosis. Our data provide evidence supporting the pivotal role of complement alternative pathway abnormalities in C3G with DDD.
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http://dx.doi.org/10.1007/s00467-013-2711-5DOI Listing
June 2014

Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses.

Pediatr Nephrol 2014 Jan 19;29(1):75-83. Epub 2013 Jul 19.

Néphrologie Pédiatrique, Hôpital Necker - Enfants Malades, MARHEA, Assistance Publique Hôpitaux de Paris (APHP), Inserm U983, IMAGINE, Université Paris Descartes-Sorbonne Paris-Cité, Paris, France.

Background: Anti-complement factor H (CFH) autoantibody (Ab)-associated atypical hemolytic uremic syndrome (aHUS) has a poor prognosis, but no consensus exists on its treatment.

Methods: We report the follow-up of four children with anti-CFH Ab (8,000 to >32,000 arbitrary units)-associated aHUS after plasma exchanges (PEs), prednisone, and cyclophosphamide pulse therapy with the evolution of anti-CFH Ab titers and kidney function.

Results: Patient 1 received PEs + prednisone + cyclophosphamide pulses after two relapses following PEs and then PEs + rituximab. The other three patients were treated with PEs + prednisone + cyclophosphamide pulses as a first-line therapy. In our four patients, the induction protocol combining PEs + prednisone + cyclophosphamide pulses led to a rapid and sustained remission up to 6 years, 4 years and 4 months without any maintenance therapy. Kidney function was normal and anti-CFH Ab titer decreased, but remained detectable during remission without any clinical or biological signs of relapse.

Conclusions: We demonstrate the long-term efficiency and safety of cyclophosphamide pulses combined with PEs and prednisone in anti-CFH Ab-associated aHUS leading to a prolonged decrease in anti-CFH Ab titers and prevention of relapses without the need for maintenance therapy.
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http://dx.doi.org/10.1007/s00467-013-2558-9DOI Listing
January 2014

Mutations of NPHP2 and NPHP3 in infantile nephronophthisis.

Kidney Int 2009 Apr 28;75(8):839-47. Epub 2009 Jan 28.

Inserm, Paris, France.

Nephronophthisis is an autosomal recessive chronic tubulointerstitial disease that progresses to end-stage renal disease (ESRD) in about 10% of cases during infancy. Mutations in the INVS (NPHP2) gene were found in a few patients with infantile nephronophthisis. Mutations of NPHP3, known to be associated with adolescent nephronophthisis, were found in two patients with early-onset ESRD. Here we screened 43 families with infantile nephronophthisis (ESRD less than 5 years of age) for NPHP2 and NPHP3 mutations and determined genotype-phenotype correlations. In this cohort there were 16 families with NPHP2 mutations and NPHP3 mutations in seven. Three patients carried only one heterozygous mutation in NPHP3. ESRD arose during the first 2 years of life in 16 of 18 patients with mutations in NPHP2, but in only two patients with mutations in NPHP3. Renal morphology, characterized by hyper-echogenic kidneys on ultrasound and tubular lesions with interstitial fibrosis on histology, was similar in the two patient groups. The kidney sizes were highly diverse and ultrasound-visualized cysts were present in a minority of cases. Extra-renal anomalies were found in 80% of the entire cohort including hepatic involvement (50%), cardiac valve or septal defects (20%) and recurrent bronchial infections (18%). We show that NPHP3 mutations in both infantile and adolescent nephronophthisis point to a common pathophysiological mechanism despite their different clinical presentations.
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http://dx.doi.org/10.1038/ki.2008.662DOI Listing
April 2009