Publications by authors named "Corinne Antignac"

191 Publications

Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice.

Nephrol Dial Transplant 2021 Jul 15. Epub 2021 Jul 15.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Germany.

The overall diagnostic yield of massively parallel sequencing (MPS) based-tests in patients with chronic kidney disease (CKD) is around 30% for pediatric cases and 6-30% for adult cases. These figures should encourage nephrologists to frequently use genetic testing as a diagnostic means for their patients, but in reality several barriers appear to hinder the implementation of NGS diagnostics in routine clinical practice. In this paper, we aim to support the nephrologist to overcome these barriers. After a detailed discussion on the general items that are important to genetic testing in nephrology, namely (1) genetic testing modalities and their indications, (2) clinical information needed for high-quality interpretation of the genetic test, (3) clinical benefit of genetic testing and (4) genetic counselling, we will describe each of these items more specifically for the different groups of genetic kidney diseases and for CKD of unknown origin.
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http://dx.doi.org/10.1093/ndt/gfab218DOI Listing
July 2021

An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis.

Kidney Int 2021 Jul 6. Epub 2021 Jul 6.

Department of Pediatric Nephrology and Development and Regeneration, University Hospitals Leuven, Leuven, Belgium.

Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.
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http://dx.doi.org/10.1016/j.kint.2021.06.019DOI Listing
July 2021

Non-invasive intradermal imaging of cystine crystals in cystinosis.

PLoS One 2021 4;16(3):e0247846. Epub 2021 Mar 4.

Division of Genetics, Department of Pediatrics, University of California, San Diego, La Jolla, California, United States of America.

Importance: Development of noninvasive methodology to reproducibly measure tissue cystine crystal load to assess disease status and guide clinical care in cystinosis, an inherited lysosomal storage disorder characterized by widespread cystine crystal accumulation.

Objective: To develop an unbiased and semi-automated imaging methodology to quantify dermal cystine crystal accumulation in patients to correlate with disease status.

Design, Setting And Participants: 101 participants, 70 patients and 31 healthy controls, were enrolled at the University of California, San Diego, Cystinosis Clinics, Rady Children's Hospital, San Diego and at the annual Cystinosis Research Foundation family conference for an ongoing prospective longitudinal cohort study of cystinosis patients with potential yearly follow-up.

Exposures: Intradermal reflectance confocal microscopy (RCM) imaging, blood collection via standard venipuncture, medical record collection, and occasional skin punch biopsies.

Main Outcomes And Measures: The primary outcome was to establish an automated measure of normalized confocal crystal volume (nCCV) for each subject. Secondary analysis examined the association of nCCV with various clinical indicators to assess nCCV's possible predictive potential.

Results: Over 2 years, 57 patients diagnosed with cystinosis (median [range] age: 15.1 yrs [0.8, 54]; 41.4% female) were intradermally assessed by RCM to produce 84 image stacks. 27 healthy individuals (38.7 yrs [10, 85]; 53.1% female) were also imaged providing 37 control image stacks. Automated 2D crystal area quantification revealed that patients had significantly elevated crystal accumulation within the superficial dermis. 3D volumetric analysis of this region was significantly higher in patients compared to healthy controls (mean [SD]: 1934.0 μm3 [1169.1] for patients vs. 363.1 μm3 [194.3] for controls, P<0.001). Medical outcome data was collected from 43 patients with infantile cystinosis (media [range] age: 11 yrs [0.8, 54]; 51% female). nCCV was positively associated with hypothyroidism (OR = 19.68, 95% CI: [1.60, 242.46], P = 0.02) and stage of chronic kidney disease (slope estimate = 0.53, 95%CI: [0.05, 1.00], P = 0.03).

Conclusions And Relevance: This study used non-invasive RCM imaging to develop an intradermal cystine crystal quantification method. Results showed that cystinosis patients had increased nCCV compared to healthy controls. Level of patient nCCV correlated with several clinical outcomes suggesting nCCV may be used as a potential new biomarker for cystinosis to monitor long-term disease control and medication compliance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247846PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932553PMC
October 2021

Bi-allelic pathogenic variations in DNAJB11 cause Ivemark II syndrome, a renal-hepatic-pancreatic dysplasia.

Kidney Int 2021 02 28;99(2):405-409. Epub 2020 Oct 28.

Laboratoire des Maladies rénales héréditaires, Institut Imagine, Inserm U1163, Université de Paris, Paris, France; APHP, Néphrologie pédiatrique, Centre de Référence MARHEA, Hôpital universitaire Necker-Enfants malades, Paris, France. Electronic address:

DNAJB11 (DnaJ Heat Shock Protein Family (Hsp40) Member B11) heterozygous loss of function variations have been reported in autosomal dominant cystic kidney disease with extensive fibrosis, associated with maturation and trafficking defect involving both the autosomal dominant polycystic kidney disease protein polycystin-1 and the autosomal dominant tubulointerstitial kidney disease protein uromodulin. Here we show that biallelic pathogenic variations in DNAJB11 lead to a severe fetal disease including enlarged cystic kidneys, dilation and proliferation of pancreatic duct cells, and liver ductal plate malformation, an association known as Ivemark II syndrome. Cysts of the kidney were developed exclusively from uromodulin negative tubular segments. In addition, tubular cells from the affected kidneys had elongated primary cilia, a finding previously reported in ciliopathies. Thus, our data show that the recessive disease associated with DNAJB11 variations is a ciliopathy rather than a disease of the autosomal dominant tubulointerstitial kidney disease spectrum, and prompt screening of DNAJB11 in fetal hyperechogenic/cystic kidneys.
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http://dx.doi.org/10.1016/j.kint.2020.09.029DOI Listing
February 2021

Generation of an induced pluripotent stem cell (iPSC) line (IMAGINi007) from a patient with steroid-resistant nephrotic syndrome carrying the homozygous p.R138Q mutation in the podocin-encoding NPHS2 gene.

Stem Cell Res 2020 07 18;46:101878. Epub 2020 Jun 18.

Université de Paris, Imagine Institute, Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Paris, France. Electronic address:

Mutations in the NPHS2 gene, encoding podocin, are responsible for the majority of familial cases of steroid-resistant nephrotic syndrome (SRNS), a rare glomerulopathy that rapidly progresses to end-stage renal disease. We obtained peripheral blood mononuclear cells (PBMCs) from a patient carrying the homozygous c.413G>A substitution (p.R138Q) in NPHS2 gene, which is the most prevalent mutation in the European population. The PBMCs were reprogrammed by non-integrative viral transduction of the Yamanaka's factors. The resulting iPSCs display normal karyotype, express pluripotency hallmarks and are capable of multilineage differentiation, offering a useful tool to study pathological mechanisms of SRNS and perform drug testing.
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http://dx.doi.org/10.1016/j.scr.2020.101878DOI Listing
July 2020

Pseudouridylation defect due to and mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

Proc Natl Acad Sci U S A 2020 06 17;117(26):15137-15147. Epub 2020 Jun 17.

Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC H2X 1Y4, Canada.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in , , or cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with p.Glu206Lys and two children with homozygous p.Thr16Met. Females with heterozygous p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.
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http://dx.doi.org/10.1073/pnas.2002328117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334496PMC
June 2020

Bi-allelic mutations in renin-angiotensin system genes, associated with renal tubular dysgenesis, can also present as a progressive chronic kidney disease.

Pediatr Nephrol 2020 06 20;35(6):1125-1128. Epub 2020 Mar 20.

APHP, Néphrologie pédiatrique, Centre de Référence MARHEA, Hôpital Universitaire Necker-Enfants malades, 149 rue de Sèvres, 75015, Paris, France.

Background: Bi-allelic loss of function variations in genes encoding proteins of the renin-angiotensin system (AGT, ACE, REN, AGTR1) are associated with autosomal recessive renal tubular dysgenesis, a severe disease characterized by the absence of differentiated proximal tubules leading to fetal anuria and neonatal end-stage renal disease.

Case-diagnosis/treatment: We identified bi-allelic loss of function mutations in ACE, the gene encoding angiotensin-converting enzyme, in 3 unrelated cases displaying progressive chronic renal failure, whose DNAs had been sent for suspicion of juvenile hyperuricemic nephropathy, nephronophthisis, and cystic renal disease, respectively. In all cases, patients were affected with anemia whose severity was unexpected regarding the level of renal failure and with important polyuro-polydipsia.

Conclusions: Bi-allelic loss of function mutation of ACE can have atypical and sometimes late presentation with chronic renal failure, anemia (out of proportion with the level of renal failure), and polyuro-polydipsia. These data illustrate the usefulness of next generation sequencing and "agnostic" approaches to elucidate cases with chronic kidney disease of unknown etiology and to broaden the spectrum of phenotypes of monogenic renal diseases. It also raises the question of genetic modifiers involved in the variation of the phenotypes associated with these mutations.
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http://dx.doi.org/10.1007/s00467-020-04524-4DOI Listing
June 2020

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.

J Clin Invest 2020 01;130(1):335-344

Center for Human Genetics, Bioscientia, Ingelheim, Germany.

BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).
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http://dx.doi.org/10.1172/JCI129937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934218PMC
January 2020

Protection of Cystinotic Mice by Kidney-Specific Megalin Ablation Supports an Endocytosis-Based Mechanism for Nephropathic Cystinosis Progression.

J Am Soc Nephrol 2019 11 23;30(11):2177-2190. Epub 2019 Sep 23.

Cell Biology Unit, de Duve Institute and Université Catholique de Louvain, Brussels, Belgium.

Background: Deletions or inactivating mutations of the cystinosin gene lead to cystine accumulation and crystals at acidic pH in patients with nephropathic cystinosis, a rare lysosomal storage disease and the main cause of hereditary renal Fanconi syndrome. Early use of oral cysteamine to prevent cystine accumulation slows progression of nephropathic cystinosis but it is a demanding treatment and not a cure. The source of cystine accumulating in kidney proximal tubular cells and cystine's role in disease progression are unknown.

Methods: To investigate whether receptor-mediated endocytosis by the megalin/LRP2 pathway of ultrafiltrated, disulfide-rich plasma proteins could be a source of cystine in proximal tubular cells, we used a mouse model of cystinosis in which conditional excision of floxed alleles in proximal tubular cells of cystinotic mice was achieved by a Cre-LoxP strategy using . We evaluated mice aged 6-9 months for kidney cystine levels and crystals; histopathology, with emphasis on swan-neck lesions and proximal-tubular-cell apoptosis and proliferation (turnover); and proximal-tubular-cell expression of the major apical transporters sodium-phosphate cotransporter 2A (NaPi-IIa) and sodium-glucose cotransporter-2 (SGLT-2).

Results: -driven ablation in cystinotic mice efficiently blocked kidney cystine accumulation, thereby preventing lysosomal deformations and crystal deposition in proximal tubular cells. Swan-neck lesions were largely prevented and proximal-tubular-cell turnover was normalized. Apical expression of the two cotransporters was also preserved.

Conclusions: These observations support a key role of the megalin/LRP2 pathway in the progression of nephropathic cystinosis and provide a proof of concept for the pathway as a therapeutic target.
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http://dx.doi.org/10.1681/ASN.2019040371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830792PMC
November 2019

Defects in tA tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.

Nat Commun 2019 09 3;10(1):3967. Epub 2019 Sep 3.

Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre de référence de maladies rénales rares, Université de Lyon, Bron, France.

N-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (tA) is a universal modification essential for translational accuracy and efficiency. The tA pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
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http://dx.doi.org/10.1038/s41467-019-11951-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722078PMC
September 2019

Central nervous system complications in adult cystinosis patients.

J Inherit Metab Dis 2020 03 18;43(2):348-356. Epub 2019 Sep 18.

Department of Pediatric Radiology, Necker hospital, APHP, Inserm U1000, Imagine Institute, Paris Descartes University, Paris, France.

Little is known about the long-term progression of adult nephropathic cystinosis patients. Our objective was to study central nervous system complications in cystinosis patients in the era of early cysteamine treatment, using advanced neuroimaging techniques. Neurological examination and multimodal brain 3 Tesla MRI were performed in 21 adult cystinosis patients, including 18 infantile cystinosis patients, 20 controls matched for age and renal function, and 12 healthy controls. Differences in gray matter volume and rest cerebral blood flow (CBF) using arterial spin labeling sequence were investigated using whole-brain voxel-based approach. Median age was 33.8 years (18.7-65.8). Seven patients (38.9%) presented with at least one central nervous system clinical abnormality: two (11.1%) with seizures, three (16.7%) with memory defects, five (27.8%) with cognitive defect, and one (5.5%) with stroke-like episode. These patients had a worse compliance to treatment (compliance score 2 vs 1, P = .03) and received a lower median cysteamine dose (0.9 g/day vs 2.1 g/day, P = .02). Among patients with infantile cystinosis, 13 (72.2%) showed cortical atrophy, which was absent in controls, but it was not correlated with symptoms. Cystinosis patients showed a significant gray matter decrease in the middle frontal gyrus compared with healthy controls and a significant negative correlation between the cystine blood level and rest CBF was observed in the right superior frontal gyrus, a region associated with executive function. Compliance to cysteamine treatment is a major concern in these adult patients and could have an impact on the development of neurological and cognitive complications.
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http://dx.doi.org/10.1002/jimd.12164DOI Listing
March 2020

Urokinase-type plasminogen activator contributes to amiloride-sensitive sodium retention in nephrotic range glomerular proteinuria in mice.

Acta Physiol (Oxf) 2019 12 17;227(4):e13362. Epub 2019 Sep 17.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Aim: Activation of sodium reabsorption by urinary proteases has been implicated in sodium retention associated with nephrotic syndrome. The study was designed to test the hypothesis that nephrotic proteinuria in mice after conditional deletion of podocin leads to urokinase-dependent, amiloride-sensitive plasmin-mediated sodium and water retention.

Methods: Ten days after podocin knockout, urine and faeces were collected for 10 days in metabolic cages and analysed for electrolytes, plasminogen, protease activity and ability to activate γENaC by patch clamp and western blot. Mice were treated with amiloride (2.5 mg kg for 2 days and 10 mg kg for 2 days) or an anti-urokinase-type plasminogen activator (uPA) targeting antibody (120 mg kg /24 h) and compared to controls.

Results: Twelve days after deletion, podocin-deficient mice developed significant protein and albuminuria associated with increased body wt, ascites, sodium accumulation and suppressed plasma renin. This was associated with increased urinary excretion of plasmin and plasminogen that correlated with albumin excretion, urine protease activity co-migrating with active plasmin, and the ability of urine to induce an amiloride-sensitive inward current in M1 cells in vitro. Amiloride treatment in podocin-deficient mice resulted in weight loss, increased sodium excretion, normalization of sodium balance and prevention of the activation of plasminogen to plasmin in urine in a reversible way. Administration of uPA targeting antibody abolished urine activation of plasminogen, attenuated sodium accumulation and prevented cleavage of γENaC.

Conclusions: Nephrotic range glomerular proteinuria leads to urokinase-dependent intratubular plasminogen activation and γENaC cleavage which contribute to sodium accumulation.
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http://dx.doi.org/10.1111/apha.13362DOI Listing
December 2019

APOL1 risk genotype in Europe: Data in patients with focal segmental glomerulosclerosis and after renal transplantation

Nephrol Ther 2019 04;15 Suppl 1:S85-S89

Inserm U1163, 24, boulevard du Montparnasse, 75015 Paris, France; Institut Imagine, 24, boulevard du Montparnasse, 75015 Paris, France; Université Paris Descartes, 24, boulevard du Montparnasse, 75015 Paris, France; Genetic Department, hôpital Necker-Enfants-malades, AP-HP, 149, rue de Sèvres, 75015 Paris, France.

Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis in populations with African ancestry. We determined the frequency of G1/G2 variants in patients with steroid-resistant nephrotic syndrome/focal segmental glomerulosclerosis with African or French West Indies origin in France and its relationships with other steroid-resistant nephrotic syndrome genes. In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped: the two risk allele (high risk) genotype was found in 43.1% of subjects compared to 18.9% in a control population (P < 0.0001). Compared to patients in the low risk group, patients in the high-risk group were more likely to originate from French West Indies than from Africa. APOL1 high-risk genotype was more frequent in young adult patients, but it was also found in children and it was associated with a bad renal prognosis. APOL1 high-risk genotype was usually not associated with other causative mutation in known monogenic steroid-resistant nephrotic syndrome genes and families in which multiple individuals have focal segmental glomerulosclerosis may have APOL1-associated disease. After renal transplantation, recipients of deceased-donor kidney transplantation from individuals with recent African ancestry possessing two APOL1 high-risk variants have slightly shorter allograft survival. Effects of APOL1 are independent of other traditional risk factors. Recently it was shown that black living kidney donors homozygous for APOL1 high-risk alleles have significantly lower glomerular filtration rate and increased risk of end-stage renal disease after donation. However, APOL1 genotype may not summarize by itself the totality of this risk. We showed that living kidney donors of African ancestry in France with low-risk APOL1 genotype have lower postdonation eGFR increase and lower baseline kidney volume compared to Caucasian donors.
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http://dx.doi.org/10.1016/j.nephro.2019.02.005DOI Listing
April 2019

Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Kidney Int 2019 08 6;96(2):350-362. Epub 2019 Mar 6.

Department of Pediatrics, Division of Genetics, University of California, San Diego, La Jolla, California, USA. Electronic address:

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the β-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the CtnsGal3 mice compared to Ctns mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression.
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http://dx.doi.org/10.1016/j.kint.2019.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269416PMC
August 2019

Nephrotic syndrome and mitochondrial disorders: answers.

Pediatr Nephrol 2019 08 12;34(8):1375-1377. Epub 2019 Mar 12.

Unité de néphrologie pédiatrique, CHU de Nice - Hôpital Archet, 151 Route de Saint-Antoine de Ginestière, B.P. 23079, 06202, Nice Cedex 3, France.

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http://dx.doi.org/10.1007/s00467-019-04217-7DOI Listing
August 2019

Nephrotic syndrome and mitochondrial disorders: Questions.

Pediatr Nephrol 2019 08 12;34(8):1373-1374. Epub 2019 Mar 12.

Unité de néphrologie pédiatrique, CHU de Nice - Hôpital Archet 2, 151 Route de Saint-Antoine de Ginestière, B.P. 23079, 06202, Nice Cedex 3, France.

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http://dx.doi.org/10.1007/s00467-019-04216-8DOI Listing
August 2019

TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways.

Am J Hum Genet 2019 02 17;104(2):348-355. Epub 2019 Jan 17.

Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM U1163, Paris Descartes University, 75015 Paris, France; Department of Genetics, Reference center for Hereditary Kidney Diseases (MARHEA), Necker Hospital, APHP,75015 Paris, France. Electronic address:

Steroid-resistant nephrotic syndrome (SRNS) is characterized by high-range proteinuria and most often focal and segmental glomerulosclerosis (FSGS). Identification of mutations in genes causing SRNS has improved our understanding of disease mechanisms and highlighted defects in the podocyte, a highly specialized glomerular epithelial cell, as major factors in disease pathogenesis. By exome sequencing, we identified missense mutations in TBC1D8B in two families with an X-linked early-onset SRNS with FSGS. TBC1D8B is an uncharacterized Rab-GTPase-activating protein likely involved in endocytic and recycling pathways. Immunofluorescence studies revealed TBC1D8B presence in human glomeruli, and affected individual podocytes displayed architectural changes associated with migration defects commonly found in FSGS. In zebrafish we demonstrated that both knockdown and knockout of the unique TBC1D8B ortholog-induced proteinuria and that this phenotype was rescued by human TBC1D8B mRNA injection, but not by either of the two mutated mRNAs. We also showed an interaction between TBC1D8B and Rab11b, a key protein in vesicular recycling in cells. Interestingly, both internalization and recycling processes were dramatically decreased in affected individuals' podocytes and fibroblasts, confirming the crucial role of TBC1D8B in the cellular recycling processes, probably as a Rab11b GTPase-activating protein. Altogether, these results confirmed that pathogenic variations in TBC1D8B are involved in X-linked podocytopathy and points to alterations in recycling processes as a mechanism of SRNS.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369567PMC
February 2019

Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults.

Kidney Int 2018 11;94(5):1013-1022

Inserm U1163, Imagine Institute, Paris Descartes University, Paris, France; Adult Nephrology & Transplantation, Centre de référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Necker Hospital, Paris, France. Electronic address:

Monogenic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) have been widely characterized, but genetic screening paradigms preferentially address congenital, infantile onset, and familial cases. Our aim was to characterize the distribution of disease-causing gene mutations in adults with sporadic SRNS or focal segmental glomerulosclerosis (FSGS). We selected adult patients with non-syndromic, biopsy-proven FSGS or SRNS in the absence of known family history. Strict clinical criteria included lack of response to glucocorticoids and cyclosporine, and no recurrence after kidney transplantation. Mutations in SRNS genes were detected using a targeted gene panel. Sixteen of 135 tested participants (11.8%) carried pathogenic mutations in monogenic SRNS genes, and 14 others (10.4%) carried two APOL1 high-risk alleles. Autosomal recessive disease was diagnosed in 5 participants, autosomal dominant disease in 9, and X-linked disease in 2. Four participants carried a de novo heterozygous mutation. Among the 16 participants with identified mutations in monogenic SNRS genes, 7 (43.7%) had type IV collagen mutations. Mutations in monogenic SNRS genes were identified primarily in participants with proteinuria onset before 25 years of age, while the age at disease onset was variable in those with APOL1 high-risk genotype. Mean age at diagnosis was lower and renal survival was worse in participants with identified mutations in SNRS genes than in those without mutations. We found a significant rate of pathogenic mutations in adults with SRNS, with Type IV collagen mutations being the most frequent. These findings may have immediate impact on clinical practice.
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http://dx.doi.org/10.1016/j.kint.2018.07.024DOI Listing
November 2018

The mutation-dependent pathogenicity of NPHS2 p.R229Q: A guide for clinical assessment.

Hum Mutat 2018 12 22;39(12):1854-1860. Epub 2018 Oct 22.

MTA-SE Lendület Nephrogenetic Laboratory, Budapest, Hungary.

NPHS2, encoding podocin, is the major gene implicated in steroid-resistant nephrotic syndrome. Its c.686G>A, p.R229Q variant is the first human variant with a mutation-dependent pathogenicity; it is only pathogenic when trans-associated to specific mutations. Secondary to its high allele frequency in the European, South Asian, African, and Latino populations, its benign trans-associations can be accidentally identified in affected patients. Distinguishing pathogenic and benign p.R229Q associations can be challenging. In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270-351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:10 ). We show that >15% of the p.R229Q associations identified so far in patients are benign.
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http://dx.doi.org/10.1002/humu.23660DOI Listing
December 2018

Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations.

Am J Med Genet A 2018 11 23;176(11):2470-2478. Epub 2018 Sep 23.

Génétique des Anomalies du Développement, UMR1231, Université de Bourgogne, Dijon, France.

De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C-terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data-sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.
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http://dx.doi.org/10.1002/ajmg.a.40357DOI Listing
November 2018

Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome.

J Clin Invest 2018 10 4;128(10):4313-4328. Epub 2018 Sep 4.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.
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http://dx.doi.org/10.1172/JCI98688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159964PMC
October 2018

Renal tubular dysgenesis and microcolon, a novel association. Report of three cases.

Eur J Med Genet 2019 Apr 31;62(4):254-258. Epub 2018 Jul 31.

Division of Nephrology, Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada. Electronic address:

Renal tubular dysgenesis (RTD) is a developmental abnormality of the nephron characterized by fetal anuria, oligohydramnios, and severe postnatal hypotension. Genetic forms have an autosomal recessive inheritance and are caused by mutations in genes encoding key components of the renin-angiotensin pathway. We report three patients from two unrelated families with RTD due to pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in whom RTD was associated with microcolon. We also detail key variations of the renin-angiotensin system in one of these infants. The severe intestinal developmental abnormality culminating in microcolon and early terminal ileum perforation/necrotizing enterocolitis is a novel finding not previously associated with RTD, which points to a role of the renin-angiotensin system in gut development.
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http://dx.doi.org/10.1016/j.ejmg.2018.07.024DOI Listing
April 2019

APOL1 risk genotype in European steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis patients of different African ancestries.

Nephrol Dial Transplant 2019 11;34(11):1885-1893

Inserm U1163, Institut Imagine, University Paris Descartes, Paris, France.

Background: Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis (FSGS) in populations with African ancestry. We determined the frequency of G1/G2 variants in steroid-resistant nephrotic syndrome (SRNS)/FSGS patients with African or French West Indies ancestry in France and its relationships with other SRNS genes.

Methods: In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped by direct Sanger sequencing and pathogenic mutations were screened by next-generation sequencing with a panel including 35 SRNS genes.

Results: The two risk allele [high-risk (HR)] genotypes were found in 43.1% (66/152) of subjects compared with 18.9% (106/562) in a control population (P < 0.0001): 33 patients homozygous for APOL1 G1 alleles, 4 homozygous for G2 and 29 compound heterozygous for G1 and G2. Compared with patients in the low-risk (LR) group, patients in the HR group were more likely to originate from the French West Indies than from Africa [45/66 (68.2%) versus 30/86 (34.9%); P < 0.0001]. There were more familial cases in the HR group [27 (41.5%) versus 8 (11.4%); P < 0.0001]. However, causative mutations in monogenic SRNS genes were found in only 1 patient in the HR group compared with 16 patients (14 families) in the LR group (P = 0.0006). At diagnosis, patients in the HR group without other mutations were more often adults [35 (53.8%) versus 19 (27.1%); P = 0.003] and had a lower estimated glomerular filtration rate (78.9 versus 98.8 mL/min/1.73 m2; P = 0.02).

Conclusions: The HR genotype is frequent in FSGS patients with African ancestry in our cohort, especially in those originating from the West Indies, and confer a poor renal prognosis. It is usually not associated with other causative mutations in monogenic SRNS genes.
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http://dx.doi.org/10.1093/ndt/gfy176DOI Listing
November 2019

A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

PLoS Genet 2018 05 16;14(5):e1007386. Epub 2018 May 16.

Laboratory of Epithelial Biology and Disease, Institut National de la Santé et de la Recherche Médicale (Inserm) UMR1163, Imagine Institute, Paris, France.

Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders.
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http://dx.doi.org/10.1371/journal.pgen.1007386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973622PMC
May 2018

C-terminal oligomerization of podocin mediates interallelic interactions.

Biochim Biophys Acta Mol Basis Dis 2018 Jul 13;1864(7):2448-2457. Epub 2018 Apr 13.

MTA-SE Lendület Nephrogenetic Laboratory, Budapest, Hungary; Semmelweis University, Ist Department of Pediatrics, Budapest, Hungary; Laboratory of Hereditary Kidney Diseases, INSERM, UMR 1163, Imagine Institute, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France. Electronic address:

Interallelic interactions of membrane proteins are not taken into account while evaluating the pathogenicity of sequence variants in autosomal recessive disorders. Podocin, a membrane-anchored component of the slit diaphragm, is encoded by NPHS2, the major gene mutated in hereditary podocytopathies. We formerly showed that its R229Q variant is only pathogenic when trans-associated to specific 3' mutations and suggested the causal role of an abnormal C-terminal dimerization. Here we show by FRET analysis and size exclusion chromatography that podocin oligomerization occurs exclusively through the C-terminal tail (residues 283-382): principally through the first C-terminal helical region (H1, 283-313), which forms a coiled coil as shown by circular dichroism spectroscopy, and through the 332-348 region. We show the principal role of the oligomerization sites in mediating interallelic interactions: while the monomer-forming R286Tfs*17 podocin remains membranous irrespective of the coexpressed podocin variant identity, podocin variants with an intact H1 significantly influence each other's localization (r = 0.68, P = 9.2 × 10). The dominant negative effect resulting in intracellular retention of the pathogenic F344Lfs*4-R229Q heterooligomer occurs in parallel with a reduction in the FRET efficiency, suggesting the causal role of a conformational rearrangement. On the other hand, oligomerization can also promote the membrane localization: it can prevent the endocytosis of F344Lfs*4 or F344* podocin mutants induced by C-terminal truncation. In conclusion, C-terminal oligomerization of podocin can mediate both a dominant negative effect and interallelic complementation. Interallelic interactions of NPHS2 are not restricted to the R229Q variant and have to be considered in compound heterozygous individuals.
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http://dx.doi.org/10.1016/j.bbadis.2018.04.008DOI Listing
July 2018

Endoplasmic reticulum-retained podocin mutants are massively degraded by the proteasome.

J Biol Chem 2018 03 30;293(11):4122-4133. Epub 2018 Jan 30.

From the Laboratory of Hereditary Kidney Diseases, Inserm UMR 1163, Imagine Institute, Paris 75015, France,

Podocin is a key component of the slit diaphragm in the glomerular filtration barrier, and mutations in the podocin-encoding gene are a common cause of hereditary steroid-resistant nephrotic syndrome. A mutant allele encoding podocin with a p.R138Q amino acid substitution is the most frequent pathogenic variant in European and North American children, and the corresponding mutant protein is poorly expressed and retained in the endoplasmic reticulum both and To better understand the defective trafficking and degradation of this mutant, we generated human podocyte cell lines stably expressing podocin or podocin Although it has been proposed that podocin has a hairpin topology, we present evidence for podocin-glycosylation, suggesting that most of the protein has a transmembrane topology. We find that -glycosylated podocin has a longer half-life than non-glycosylated podocin and that the latter is far more rapidly degraded than podocin Consistent with its rapid degradation, podocin is exclusively degraded by the proteasome, whereas podocin is degraded by both the proteasomal and the lysosomal proteolytic machineries. In addition, we demonstrate an enhanced interaction of podocin with calnexin as the mechanism of endoplasmic reticulum retention. Calnexin knockdown enriches the podocin non-glycosylated fraction, whereas preventing exit from the calnexin cycle increases the glycosylated fraction. Altogether, we propose a model in which hairpin podocin is rapidly degraded by the proteasome, whereas transmembrane podocin degradation is delayed due to entry into the calnexin cycle.
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http://dx.doi.org/10.1074/jbc.RA117.001159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858002PMC
March 2018

Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

Ann Intern Med 2018 01 5;168(2):100-109. Epub 2017 Dec 5.

From Columbia University, New York, New York; VU University Medical Center, Amsterdam, the Netherlands; Nephrology Associates, Newark, Delaware; Krysiewicza Children's Hospital, Poznań, Poland; Poznań University of Medical Sciences and Center for Medical Genetics GENESIS, Poznań, Poland; IRCCS Giannina Gaslini Children's Hospital, Genova, Italy; IRCCS San Raffaele Scientific Institute, Milan, Italy; New York University School of Medicine, New York, New York; University of Texas Southwestern Medical Center, Dallas, Texas; and French Institute of Health and Medical Research (INSERM) U1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, and Necker Hospital, Paris, France.

Background: The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.

Objective: To study the diagnostic utility of WES in a selected referral population of adults with CKD.

Design: Observational cohort.

Setting: A major academic medical center.

Patients: 92 adults with CKD of unknown cause or familial nephropathy or hypertension.

Measurements: The diagnostic yield of WES and its potential effect on clinical management.

Results: Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.

Limitation: The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.

Conclusion: Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.

Primary Funding Source: New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.
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http://dx.doi.org/10.7326/M17-1319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947852PMC
January 2018
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