Publications by authors named "Ali G Gharavi"

132 Publications

Do research participants share genomic screening results with family members?

J Genet Couns 2021 Oct 19. Epub 2021 Oct 19.

Division of Genetics and Genomics and the Manton Center for Orphan Diseases Research, Boston Children's Hospital, Boston, MA, USA.

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6 months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.
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http://dx.doi.org/10.1002/jgc4.1511DOI Listing
October 2021

Generalizability of Polygenic Risk Scores for Breast Cancer Among Women With European, African, and Latinx Ancestry.

JAMA Netw Open 2021 Aug 2;4(8):e2119084. Epub 2021 Aug 2.

Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York.

Importance: Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown.

Objective: To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry.

Design, Setting, And Participants: This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm.

Main Outcomes And Measures: Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components.

Results: This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations.

Conclusions And Relevance: This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.19084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339934PMC
August 2021

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19.

J Clin Invest 2021 07;131(14)

College of Applied Medical Sciences, Taibah University, Madina, Saudi Arabia.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.
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http://dx.doi.org/10.1172/JCI147834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279578PMC
July 2021

Medical Records-Based Genetic Studies of the Complement System.

J Am Soc Nephrol 2021 08 3;32(8):2031-2047. Epub 2021 May 3.

Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York

Background: Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts.

Methods: We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network.

Results: In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; =0.20; 95% CI, 0.14 to 0.25; =1.52x10) and chr.19p13.3 (C3 locus; rs11569470-G; =0.19; 95% CI, 0.13 to 0.24; =1.29x10). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; =0.40; 95% CI, 0.34 to 0.45; =4.58x10). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS (=-0.36; 95% CI, -0.42 to -0.30; =2.98x10) and C4-AL-BS (=0.25; 95% CI, 0.21 to 0.29; =8.11x10). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation.

Conclusions: We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans.
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http://dx.doi.org/10.1681/ASN.2020091371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455263PMC
August 2021

Improving data quality in observational research studies: Report of the Cure Glomerulonephropathy (CureGN) network.

Contemp Clin Trials Commun 2021 Jun 17;22:100749. Epub 2021 Feb 17.

NYU Langone Health, Department of Pediatrics, Division of Nephrology, New York, NY, USA.

Background: High data quality is of crucial importance to the integrity of research projects. In the conduct of multi-center observational cohort studies with increasing types and quantities of data, maintaining data quality is challenging, with few published guidelines.

Methods: The Cure Glomerulonephropathy (CureGN) Network has established numerous quality control procedures to manage the 70 participating sites in the United States, Canada, and Europe. This effort is supported and guided by the activities of several committees, including Data Quality, Recruitment and Retention, and Central Review, that work in tandem with the Data Coordinating Center to monitor the study. We have implemented coordinator training and feedback channels, data queries of questionable or missing data, and developed performance metrics for recruitment, retention, visit completion, data entry, recording of patient-reported outcomes, collection, shipping and accessing of biological samples and pathology materials, and processing, cataloging and accessing genetic data and materials.

Results: We describe the development of data queries and site Report Cards, and their use in monitoring and encouraging excellence in site performance. We demonstrate improvements in data quality and completeness over 4 years after implementing these activities. We describe quality initiatives addressing specific challenges in collecting and cataloging whole slide images and other kidney pathology data, and novel methods of data quality assessment.

Conclusions: This paper reports the CureGN experience in optimizing data quality and underscores the importance of general and study-specific data quality initiatives to maintain excellence in the research measures of a multi-center observational study.
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http://dx.doi.org/10.1016/j.conctc.2021.100749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039553PMC
June 2021

Medical records-based chronic kidney disease phenotype for clinical care and "big data" observational and genetic studies.

NPJ Digit Med 2021 Apr 13;4(1):70. Epub 2021 Apr 13.

Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA.

Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate ("A-by-G" grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.
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http://dx.doi.org/10.1038/s41746-021-00428-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044136PMC
April 2021

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

J Am Soc Nephrol 2021 Feb 17. Epub 2021 Feb 17.

Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.

Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.

Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry.

Results: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; =6.35×10) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract ( and ). In particular, 3.3% of VUR patients were homozygous for an intronic variant in (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; =1.86×10). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis.

Conclusions: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.
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http://dx.doi.org/10.1681/ASN.2020050681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017540PMC
February 2021

Familial Aggregation of CKD: Gene or Environment?

Am J Kidney Dis 2021 06 11;77(6):861-862. Epub 2021 Feb 11.

Division of Nephrology, Department of Medicine, Columbia University, New York, New York. Electronic address:

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http://dx.doi.org/10.1053/j.ajkd.2020.12.010DOI Listing
June 2021

Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy.

J Autoimmun 2021 03 25;118:102593. Epub 2021 Jan 25.

University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Background: IgA nephropathy is thought to be an autoimmune disease wherein galactose-deficient IgA1 (Gd-IgA1) is recognized by IgG autoantibodies, resulting in formation and renal accumulation of nephritogenic immune complexes. Although this hypothesis is supported by recent findings that, in renal immunodeposits of IgA nephropathy patients, IgG is enriched for Gd-IgA1-specific autoantibodies, experimental proof is still lacking.

Methods: IgG isolated from sera of IgA nephropathy patients or produced as a recombinant IgG (rIgG) was mixed with human Gd-IgA1 to form immune complexes. IgG from healthy individuals served as a control. Nude and SCID mice were injected with human IgG and Gd-IgA1, in immune complexes or individually, and their presence in kidneys was ascertained by immunofluorescence. Pathologic changes in the glomeruli were evaluated by quantitative morphometry and exploratory transcriptomic profiling was performed by RNA-Seq.

Results: Immunodeficient mice injected with Gd-IgA1 mixed with IgG autoantibodies from patients with IgA nephropathy, but not Gd-IgA1 mixed with IgG from healthy individuals, displayed IgA, IgG, and mouse complement C3 glomerular deposits and mesangioproliferative glomerular injury with hematuria and proteinuria. Un-complexed Gd-IgA1 or IgG did not induce pathological changes. Moreover, Gd-IgA1-rIgG immune complexes injected into immunodeficient mice induced histopathological changes characteristic of human disease. Exploratory transcriptome profiling of mouse kidney tissues indicated that these immune complexes altered gene expression of multiple pathways, in concordance with the changes observed in kidney biopsies of patients with IgA nephropathy.

Conclusions: This study provides the first in vivo evidence for a pathogenic role of IgG autoantibodies specific for Gd-IgA1 in the pathogenesis of IgA nephropathy.
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http://dx.doi.org/10.1016/j.jaut.2021.102593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997636PMC
March 2021

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Am J Hum Genet 2021 02 27;108(2):357-367. Epub 2021 Jan 27.

Division of Pediatric Neurology and Developmental Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895901PMC
February 2021

Assessing Genetic Risk for IgA Nephropathy: State of the Art.

Clin J Am Soc Nephrol 2021 02 18;16(2):182-184. Epub 2021 Jan 18.

Division of Nephrology, Department of Medicine, Columbia University, New York, New York

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http://dx.doi.org/10.2215/CJN.19491220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863648PMC
February 2021

Cases in Precision Medicine: Genetic Testing to Predict Future Risk for Disease in a Healthy Patient.

Ann Intern Med 2021 04 19;174(4):540-547. Epub 2021 Jan 19.

Columbia University Irving Medical Center, New York, New York (H.M.R., A.G.G.).

Genetic testing is performed more routinely in clinical practice, and direct-to-consumer tests are widely available. It has obvious appeal as a preventive health measure. Clinicians and their healthy patients increasingly inquire about genetic testing as a tool for predicting diseases, such as cancer, heart disease, or dementia. Despite demonstrated utility for diagnosis in the setting of many diseases, genetic testing still has many limitations as a predictive tool for healthy persons. This article uses a hypothetical case to review key considerations for predictive genetic testing.
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http://dx.doi.org/10.7326/M20-5713DOI Listing
April 2021

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19.

medRxiv 2020 Dec 21. Epub 2020 Dec 21.

Laboratory Department, Security Forces Hospital, General Directorate of Medical Services, Ministry of Interior, Clinical Laboratory Sciences, Taibah University, Madina, Saudi Arabia.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.
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http://dx.doi.org/10.1101/2020.12.18.20248226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781338PMC
December 2020

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy.

PLoS One 2020 28;15(12):e0244131. Epub 2020 Dec 28.

Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States of America.

Introduction: A large proportion of patients with COVID-19 develop acute kidney injury (AKI). While the most severe of these cases require renal replacement therapy (RRT), little is known about their clinical course.

Methods: We describe the clinical characteristics of COVID-19 patients in the ICU with AKI requiring RRT at an academic medical center in New York City and followed patients for outcomes of death and renal recovery using time-to-event analyses.

Results: Our cohort of 115 patients represented 23% of all ICU admissions at our center, with a peak prevalence of 29%. Patients were followed for a median of 29 days (2542 total patient-RRT-days; median 54 days for survivors). Mechanical ventilation and vasopressor use were common (99% and 84%, respectively), and the median Sequential Organ Function Assessment (SOFA) score was 14. By the end of follow-up 51% died, 41% recovered kidney function (84% of survivors), and 8% still needed RRT (survival probability at 60 days: 0.46 [95% CI: 0.36-0.56])). In an adjusted Cox model, coronary artery disease and chronic obstructive pulmonary disease were associated with increased mortality (HRs: 3.99 [95% CI 1.46-10.90] and 3.10 [95% CI 1.25-7.66]) as were angiotensin-converting-enzyme inhibitors (HR 2.33 [95% CI 1.21-4.47]) and a SOFA score >15 (HR 3.46 [95% CI 1.65-7.25).

Conclusions And Relevance: Our analysis demonstrates the high prevalence of AKI requiring RRT among critically ill patients with COVID-19 and is associated with a high mortality, however, the rate of renal recovery is high among survivors and should inform shared-decision making.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244131PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769434PMC
January 2021

GeneLiFT: A novel test to facilitate rapid screening of genetic literacy in a diverse population undergoing genetic testing.

J Genet Couns 2021 06 26;30(3):742-754. Epub 2020 Dec 26.

Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

With the broader introduction of genomic medicine in research and clinical care, an increasing number of persons are offered genetic testing. Many factors, including genetic literacy, may impact the utilization of genetic results by patients and their families. We developed a rapid, self-administered measure of genetic literacy, called Genetic Literacy Fast Test (GeneLiFT). We next evaluated the association of GeneLiFT scores with the comprehension of limitations of genomic medicine in participants undergoing genetic testing in the NIH-sponsored eMERGE III study at Columbia University Irving Medical Center, New York. All participants underwent genetic screening for variants in 74 actionable genes associated with adult-onset disorders. A diverse cohort of 724 participants completed the survey (60% women, 45% less than 40 years old, and 53% self-reported White non-Hispanic ancestry). The GeneLiFT was validated using known group differences based on education, health literacy, and numeracy, and with questions assessing genetic knowledge. GeneLiFT identified multiple standard genetics terms, that is, jargon, not recognized by more than 50% of participants (including actionability and pathogenicity). Low genetic literacy, identified in 210 participants (29%), was significantly associated with poor understanding of the limitations of genetic testing (p-values < 10 ). This association was independent of education, health literacy, and numeracy levels, highlighting the importance of directly measuring genetic literacy. Low genetic literacy was also associated with low satisfaction with the informed consent process. GeneLiFT is a practical tool for rapid assessment of genetic literacy in large studies or clinical care. GeneLiFT will allow future research to efficiently assess the role of genetic literacy on the clinical impact of genetic testing.
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http://dx.doi.org/10.1002/jgc4.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246865PMC
June 2021

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

Hum Mol Genet 2020 12;29(22):3662-3678

Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G1X3, Canada.

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.
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http://dx.doi.org/10.1093/hmg/ddaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823106PMC
December 2020

COVID-19-Associated Glomerular Disease.

J Am Soc Nephrol 2021 01 19;32(1):33-40. Epub 2020 Nov 19.

Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Studies have documented AKI with high-grade proteinuria in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In some patients, biopsies have revealed collapsing glomerulopathy, a distinct form of glomerular injury that has been associated with other viruses, including HIV. Previous patient reports have described patients of African ancestry who developed nephrotic-range proteinuria and AKI early in the course of disease.

Methods: In this patient series, we identified six patients with coronavirus disease 2019 (COVID-19), AKI, and nephrotic-range proteinuria. COVID-19 was diagnosed by a positive nasopharyngeal swab RT-PCR for SARS-CoV-2 infection. We examined biopsy specimens from one transplanted kidney and five native kidneys. Three of the six patients underwent genetic analysis of , the gene encoding the APOL1 protein, from DNA extracted from peripheral blood. In addition, we purified genomic DNA from paraffin-embedded tissue and performed genotype analysis of one of the native biopsies and the donor kidney graft.

Results: All six patients were of recent African ancestry. They developed COVID-19-associated AKI with podocytopathy, collapsing glomerulopathy, or both. Patients exhibited generally mild respiratory symptoms, and no patient required ventilator support. Genetic testing performed in three patients confirmed high-risk genotypes. One high-risk patient developed collapsing glomerulopathy in the engrafted kidney, which was transplanted from a donor who carried a low-risk genotype; this contradicts current models of APOL1-mediated kidney injury, and suggests that intrinsic renal expression of APOL1 may not be the driver of nephrotoxicity and specifically, of podocyte injury.

Conclusions: Glomerular disease presenting as proteinuria with or without AKI is an important presentation of COVID-19 infection and may be associated with a high-risk genotype.
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http://dx.doi.org/10.1681/ASN.2020060804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894674PMC
January 2021

Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program.

Circulation 2020 10 28;142(17):1633-1646. Epub 2020 Sep 28.

Faculty of Medicine and Health Sciences (A.H.S., L.T., M.E.G., K.H., J.B.N.), Norwegian University of Science and Technology, Trondheim, Norway.

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability.

Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease.

Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; =1.6×10), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; =0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratio, 1.26 [95% CI, 1.18-1.36]; =2.7×10 per SD increase in PRS), independent of family history and smoking risk factors (odds ratio, 1.24 [95% CI, 1.14-1.35]; =1.27×10). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines.

Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580856PMC
October 2020

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Am J Hum Genet 2020 10 4;107(4):727-742. Epub 2020 Sep 4.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536580PMC
October 2020

Rare genetic causes of complex kidney and urological diseases.

Nat Rev Nephrol 2020 11 17;16(11):641-656. Epub 2020 Aug 17.

Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY, USA.

Although often considered a single-entity, chronic kidney disease (CKD) comprises many pathophysiologically distinct disorders that result in persistently abnormal kidney structure and/or function, and encompass both monogenic and polygenic aetiologies. Rare inherited forms of CKD frequently span diverse phenotypes, reflecting genetic phenomena including pleiotropy, incomplete penetrance and variable expressivity. Use of chromosomal microarray and massively parallel sequencing technologies has revealed that genomic disorders and monogenic aetiologies contribute meaningfully to seemingly complex forms of CKD across different clinically defined subgroups and are characterized by high genetic and phenotypic heterogeneity. Investigations of prevalent genomic disorders in CKD have integrated genetic, bioinformatic and functional studies to pinpoint the genetic drivers underlying their renal and extra-renal manifestations, revealing both monogenic and polygenic mechanisms. Similarly, massively parallel sequencing-based analyses have identified gene- and allele-level variation that contribute to the clinically diverse phenotypes observed for many monogenic forms of nephropathy. Genome-wide sequencing studies suggest that dual genetic diagnoses are found in at least 5% of patients in whom a genetic cause of disease is identified, highlighting the fact that complex phenotypes can also arise from multilocus variation. A multifaceted approach that incorporates genetic and phenotypic data from large, diverse cohorts will help to elucidate the complex relationships between genotype and phenotype for different forms of CKD, supporting personalized medicine for individuals with kidney disease.
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http://dx.doi.org/10.1038/s41581-020-0325-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772719PMC
November 2020

Dashboards to Facilitate Nephrology Disaster Planning in the COVID-19 Era.

Kidney Int Rep 2020 Aug 3;5(8):1298-1302. Epub 2020 Jul 3.

Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332958PMC
August 2020

Genetic testing for kidney disease of unknown etiology.

Kidney Int 2020 09 24;98(3):590-600. Epub 2020 Apr 24.

Department of Medicine, Division of Nephrology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Institute for Genomic Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Center for Precision Medicine and Genomics, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA. Electronic address:

In many cases of chronic kidney disease, the cause of disease remains unknown despite a thorough nephrologic workup. Genetic testing has revolutionized many areas of medicine and promises to empower diagnosis and targeted management of such cases of kidney disease of unknown etiology. Recent studies using genetic testing have demonstrated that Mendelian etiologies account for approximately 20% of cases of kidney disease of unknown etiology. Although genetic testing has significant benefits, including tailoring of therapy, informing targeted workup, detecting extrarenal disease, counseling patients and families, and redirecting care, it also has important limitations and risks that must be considered.
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http://dx.doi.org/10.1016/j.kint.2020.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784921PMC
September 2020

Kidney Biopsy Findings in Patients with COVID-19.

J Am Soc Nephrol 2020 Sep 17;31(9):1959-1968. Epub 2020 Jul 17.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York

Background: Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury by a variety of mechanisms. To date, pathologic analyses have been limited to patient reports and autopsy series.

Methods: We evaluated biopsy samples of native and allograft kidneys from patients with COVID-19 at a single center in New York City between March and June of 2020. We also used immunohistochemistry, hybridization, and electron microscopy to examine this tissue for presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Results: The study group included 17 patients with COVID-19 (12 men, 12 black; median age of 54 years). Sixteen patients had comorbidities, including hypertension, obesity, diabetes, malignancy, or a kidney or heart allograft. Nine patients developed COVID-19 pneumonia. Fifteen patients (88%) presented with AKI; nine had nephrotic-range proteinuria. Among 14 patients with a native kidney biopsy, 5 were diagnosed with collapsing glomerulopathy, 1 was diagnosed with minimal change disease, 2 were diagnosed with membranous glomerulopathy, 1 was diagnosed with crescentic transformation of lupus nephritis, 1 was diagnosed with anti-GBM nephritis, and 4 were diagnosed with isolated acute tubular injury. The three allograft specimens showed grade 2A acute T cell-mediated rejection, cortical infarction, or acute tubular injury. Genotyping of three patients with collapsing glomerulopathy and the patient with minimal change disease revealed that all four patients had high-risk gene variants. We found no definitive evidence of SARS-CoV-2 in kidney cells. Biopsy diagnosis informed treatment and prognosis in all patients.

Conclusions: Patients with COVID-19 develop a wide spectrum of glomerular and tubular diseases. Our findings provide evidence against direct viral infection of the kidneys as the major pathomechanism for COVID-19-related kidney injury and implicate cytokine-mediated effects and heightened adaptive immune responses.
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http://dx.doi.org/10.1681/ASN.2020060802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461665PMC
September 2020

Clinical Genetic Screening in Adult Patients with Kidney Disease.

Clin J Am Soc Nephrol 2020 10 9;15(10):1497-1510. Epub 2020 Jul 9.

Division of Nephrology and Center for Precision Medicine and Genomics, Department of Medicine, Columbia University, New York, New York

Expanded accessibility of genetic sequencing technologies, such as chromosomal microarray and massively parallel sequencing approaches, is changing the management of hereditary kidney diseases. Genetic causes account for a substantial proportion of pediatric kidney disease cases, and with increased utilization of diagnostic genetic testing in nephrology, they are now also detected at appreciable frequencies in adult populations. Establishing a molecular diagnosis can have many potential benefits for patient care, such as guiding treatment, familial testing, and providing deeper insights on the molecular pathogenesis of kidney diseases. Today, with wider clinical use of genetic testing as part of the diagnostic evaluation, nephrologists have the challenging task of selecting the most suitable genetic test for each patient, and then applying the results into the appropriate clinical contexts. This review is intended to familiarize nephrologists with the various technical, logistical, and ethical considerations accompanying the increasing utilization of genetic testing in nephrology care.
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http://dx.doi.org/10.2215/CJN.15141219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536756PMC
October 2020

Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy.

Kidney Dis (Basel) 2020 May 16;6(3):168-180. Epub 2020 Apr 16.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Objectives: IgA nephropathy (IgAN) is thought to involve an autoimmune process wherein galactose-deficient IgA1 (Gd-IgA1), recognized as autoantigen by autoantibodies, forms pathogenic immune complexes. Mounting evidence has implicated abnormal activation of some protein-tyrosine kinases (PTKs) in IgAN. Furthermore, genome-wide association studies (GWAS) of IgAN provided insight into disease pathobiology and genetics. A GWAS locus on chromosome 22q12 contains genes encoding leukemia inhibitory factor (LIF) and oncostatin M, interleukin (IL)-6-related cytokines implicated in mucosal immunity and inflammation. We have previously shown that IL-6 mediates overproduction of Gd-IgA1 through aberrant STAT3 activation. Here, we show that LIF enhanced production of Gd-IgA1 in IgA1-secreting cells of patients with IgAN and provide initial analyses of LIF signaling.

Methods: We characterized LIF signaling that is involved in the overproduction of Gd-IgA1, using IgA1-secreting cell lines derived from peripheral blood of patients with IgAN and healthy controls (HC). We used global PTK activity profiling, immunoblotting, lectin ELISA, and siRNA knock-down.

Results: LIF stimulation did not significantly affect production of total IgA1 in IgA1-secreting cells from patients with IgAN or HC. However, LIF increased production of Gd-IgA1, but only in the cells from patients with IgAN. LIF stimulation enhanced phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN to a higher degree than in the cells from HC. siRNA knock-down of STAT1 blocked LIF-mediated overproduction of Gd-IgA1. Unexpectedly, this abnormal phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN was not mediated by JAK, but rather involved activation of Src-family PTKs (SFKs).

Conclusion: Abnormal LIF/STAT1 signaling represents another pathway potentially leading to overproduction of Gd-IgA1 in IgAN, providing possible explanation for the phenotype associated with chromosome 22q12 GWAS locus. Abnormal LIF/STAT1 signaling and the associated SFKs may represent potential diagnostic and/or therapeutic targets in IgAN.
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http://dx.doi.org/10.1159/000505748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265702PMC
May 2020

Persistent Disease Activity in Patients With Long-Standing Glomerular Disease.

Kidney Int Rep 2020 Jun 20;5(6):860-871. Epub 2020 Mar 20.

Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York, USA.

Introduction: Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease.

Methods: Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort,  = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy <5 years before enrollment drawn from the Cure Glomerulonephropathy Network (CureGN cohort,  = 1182; CUMC-CureGN cohort,  = 362). Disease activity was defined by (i) Kidney Disease: Improving Global Outcomes-recommended threshold criteria for initiation of immunosuppression in primary glomerulonephropathy (GN) and (ii) CureGN's Disease Activity Working Group definitions for activity.

Results: No significant differences were detected among the 3 cohorts in terms of age, sex, serum creatinine, and urinary protein-to-creatinine ratio. For each GN subtype, disease activity in the OLD cohort was comparable with disease activity in the entire CureGN and the CUMC-CureGN cohort. When limiting our comparisons to disease activity in incident CUMC-CureGN patients (first diagnostic biopsy within 6 months of enrollment), OLD patients demonstrated similar activity rates as incident patients.

Conclusion: Disease activity did not differ among patients with shorter versus longer duration of disease. Such survivor patients, with long-term but persistent disease, are potentially highly informative for understanding the clinical course and pathogenesis of GN and may help identify factors mediating more chronic subtypes of disease.
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http://dx.doi.org/10.1016/j.ekir.2020.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270998PMC
June 2020

Presentation and Outcomes of Patients with ESKD and COVID-19.

J Am Soc Nephrol 2020 07 28;31(7):1409-1415. Epub 2020 May 28.

Division of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York

Background: The relative immunosuppression and high prevalence of comorbidities in patients with ESKD on dialysis raise concerns that they may have an elevated risk of severe coronavirus disease 2019 (COVID-19), but outcomes for COVID-19 in such patients are unclear.

Methods: To examine presentation and outcomes of COVID-19 in patients with ESKD on dialysis, we retrospectively collected clinical data on 59 patients on dialysis who were hospitalized with COVID-19. We used Wilcoxon rank sum and Fischer exact tests to compare patients who died versus those still living.

Results: Two of the study's 59 patients were on peritoneal dialysis, and 57 were on hemodialysis. Median age was 63 years, with high prevalence of hypertension (98%) and diabetes (69%). Patients who died were significantly older than those still living (median age, 75 versus 62 years) and had a higher median Charlson comorbidity index (8 versus 7). The most common presenting symptoms were fever (49%) and cough (39%); initial radiographs most commonly showed multifocal or bilateral opacities (59%). By end of follow-up, 18 patients (31%) died a median 6 days after hospitalization, including 75% of patients who required mechanical ventilation. Eleven of those who died had advanced directives against intubation. The remaining 41 patients (69%) were discharged home a median 8 days after admission. The median initial white blood cell count was significantly higher in patients who died compared with those still living (7.5 versus 5.7×10/l), as was C-reactive protein (163 versus 80 mg/L).

Conclusions: The association of COVID-19 with high mortality in patients with ESKD on dialysis reinforces the need to take appropriate infection control measures to prevent COVID-19 spread in this vulnerable population.
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http://dx.doi.org/10.1681/ASN.2020040470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350989PMC
July 2020

Pilot Study of Return of Genetic Results to Patients in Adult Nephrology.

Clin J Am Soc Nephrol 2020 05 16;15(5):651-664. Epub 2020 Apr 16.

Division of Nephrology, Department of Medicine, Columbia University, New York, New York

Background And Objectives: Actionable genetic findings have implications for care of patients with kidney disease, and genetic testing is an emerging tool in nephrology practice. However, there are scarce data regarding best practices for return of results and clinical application of actionable genetic findings for kidney patients.

Design, Setting, Participants, & Measurements: We developed a return of results workflow in collaborations with clinicians for the retrospective recontact of adult nephrology patients who had been recruited into a biobank research study for exome sequencing and were identified to have medically actionable genetic findings.

Results: Using this workflow, we attempted to recontact a diverse pilot cohort of 104 nephrology research participants with actionable genetic findings, encompassing 34 different monogenic etiologies of nephropathy and five single-gene disorders recommended by the American College of Medical Genetics and Genomics for return as medically actionable secondary findings. We successfully recontacted 64 (62%) participants and returned results to 41 (39%) individuals. In each case, the genetic diagnosis had meaningful implications for the patients' nephrology care. Through implementation efforts and qualitative interviews with providers, we identified over 20 key challenges associated with returning results to study participants, and found that physician knowledge gaps in genomics was a recurrent theme. We iteratively addressed these challenges to yield an optimized workflow, which included standardized consultation notes with tailored management recommendations, monthly educational conferences on core topics in genomics, and a curated list of expert clinicians for patients requiring extranephrologic referrals.

Conclusions: Developing the infrastructure to support return of genetic results in nephrology was resource-intensive, but presented potential opportunities for improving patient care.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_16_12481019.mp3.
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http://dx.doi.org/10.2215/CJN.12481019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269209PMC
May 2020
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