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Multicenter Study
. 2023 Dec 1;34(12):2039-2050.
doi: 10.1681/ASN.0000000000000249. Epub 2023 Oct 5.

The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease

Neera K Dahl  1 , Michelle S Bloom  2 , Fouad T Chebib  3 , Dinah Clark  2 , Maggie Westemeyer  2 , Sara Jandeska  2 , Zhiji Zhang  2 , Hila Milo-Rasouly  4 , Victoria Kolupaeva  4 , Maddalena Marasa  4 , Varshasb Broumand  5 , Richard A Fatica  6 , Dominic S Raj  7 , Zachary P Demko  2 , Kyle Marshall  2 , Sumit Punj  2 , Hossein Tabriziani  2 , Sangeeta Bhorade  2 , Ali G Gharavi  4
Affiliations
Multicenter Study

The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease

Neera K Dahl et al. J Am Soc Nephrol. .

Abstract

Significance statement: Accurate diagnosis of a patient's underlying cause of CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, and Evaluation study assessed the utility of genetic testing with a 385 gene kidney disease panel on the diagnosis and management of 1623 patients with CKD. Among 20.8% of patients who had positive genetic findings, half resulted in a new or reclassified diagnosis. In addition, a change in management because of genetic testing was reported for 90.7% of patients with positive findings, including treatment changes in 32.9%. These findings demonstrate that genetic testing has a significant effect on both CKD diagnosis and management.

Background: Genetic testing in CKD has recently been shown to have diagnostic utility with many predicted implications for clinical management, but its effect on management has not been prospectively evaluated.

Methods: Renasight Clinical Application, Review, and Evaluation RenaCARE (ClinicalTrials.gov NCT05846113 ) is a single-arm, interventional, prospective, multicenter study that evaluated the utility of genetic testing with a broad, 385 gene panel (the Renasight TM test) on the diagnosis and management of adult patients with CKD recruited from 31 US-based community and academic medical centers. Patient medical history and clinical CKD diagnosis were collected at enrollment. Physician responses to questionnaires regarding patient disease categorization and management were collected before genetic testing and 1 month after the return of test results. Changes in CKD diagnosis and management after genetic testing were assessed.

Results: Of 1623 patients with CKD in 13 predefined clinical disease categories (ages, 18-96; median, 55 years), 20.8% ( n =338) had positive genetic findings spanning 54 genes. Positive genetic findings provided a new diagnosis or reclassified a prior diagnosis in 48.8% of those patients. Physicians reported that genetic results altered the management of 90.7% of patients with a positive genetic finding, including changes in treatment plan, which were reported in 32.9% of these patients.

Conclusions: Genetic testing with a CKD-focused 385 gene panel substantially refined clinical diagnoses and had widespread implications for clinical management, including appropriate treatment strategies. These data support the utility of broader integration of panels of genetic tests into the clinical care paradigm for patients with CKD.

Clinical trial registry name and registration number: ClinicalTrials.gov, NCT05846113 .

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Conflict of interest statement

S. Bhorade reports Employer: Natera and Veracyte; Ownership Interest: Natera and Veracyte; and Patents or Royalties: Veracyte. S. Bhorade, M.S. Bloom, D. Clark, Z.P. Demko, S. Jandeska, K. Marshall, S. Punj, H. Tabriziani, M. Westemeyer, and Z. Zhang are employees of Natera, Inc. and own or have the option to own stock. V. Broumand reports Consultancy: Bayer, Outset Medical, and Vifor Pharma; Ownership Interest: ADR, Ardelyx, Outset Medical, Precigen, Renalytx, and US Renal Care; Research Funding: AMAG Pharmaceuticals, Astra Zenca, Fibrogen, Kind Pharmaceuticals, and Pathalys Pharma; Honoraria: Bayer, Outset Medical, and Vifor Pharma; Advisory or Leadership Role: Chief Medical Officer, Christus Santa Rosa Westover Hills Hospital, and Health System Dialysis Medical Director; and Speakers Bureau: Bayer, Outset Medical, Natera, and Vifor Pharma. F.T. Chebib has received research and educational fellowship grant funding from Otsuka Pharmaceuticals. F.T. Chebib also reports Patents or Royalties: Patent no US20200368191A1; and Advisory or Leadership Role: PKD Foundation—Chair of Education Advisory Panel. N.K. Dahl reports Consultancy: Otsuka Pharmaceuticals; Research Funding: PI for clinical trials sponsored by Reata, and Vertex; Honoraria: Natera and Otsuka Pharmaceuticals; Advisory or Leadership Role: Natera Scientific Advisory Board and PKD Foundation; Speakers Bureau: on the unbranded speakers bureau for Otsuka until December 2022; and Other Interests or Relationships: Medical Advisory Board and NKF NE Chapter. R.A. Fatica reports Research Funding: Natera and Reata. A.G. Gharavi receives a research grant from Natera and has served on advisory boards for Natera through a service agreement with Columbia University. A.G. Gharavi has served on advisory boards for Actio Biosciences, Alnylam, Novartis, and Travere and has stock options for Actio Biosciences. A.G. Gharavi also reports Consultancy: Actio Biosciences, Alnylam, Novartis, and Travere; Research Funding: Renal Research Institute; Honoraria: Alnylam and Sanofi; and Advisory or Leadership Role: Editorial board: JASN, Journal of Nephrology, and Science Advances. S. Jandeska reports Employer: BioCryst Pharmaceuticals, Inc., Blue Comet Medical Solutions, LLC, Natera, Inc., and University Anesthesiologists, SC; and Ownership Interest: BioCryst Pharmaceuticals, Inc. and Natera, Inc. S. Punj reports Employer: LabCorp, Myriad Genetics, and Natera Inc.; and Ownership Interest: LabCorp, Myriad Genetics, and Natera Inc. D.S. Raj reports Consultancy: Novo Nordics; Research Funding: NIH; Honoraria: Novo Nordics; Advisory or Leadership Role: NIDDK, NHLBI, and Novo Nordics; and Other Interests or Relationships: American Association of Kidney Patients. H.M. Rasouly reports Research Funding: Natera. H. Tabriziani reports Consultancy: Natera; Patents or Royalties: Natera; Advisory or Leadership Role: Natera; Speakers Bureau: Natera; and Other Interests or Relationships: HossMed, Inc. Because A.G. Gharavi is an editor of the JASN, he was not involved in the peer review process for this manuscript. A guest editor oversaw the peer review and decision-making process for this manuscript. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Positive genetic findings according to pretest clinical diagnosis. (A) The frequency of positive genetic findings across 54 genes identified in 338 patients. A total of 362 positive findings were identified, which included 317 patients with a single gene finding, 18 patients with two gene findings, and three patients with three gene findings. (B) Diagnostic yield of positive genetic findings within each clinical kidney disease categorization provided by physicians at enrollment. Diagnostic yield was calculated as the proportion of patients within each category with a positive genetic finding. Note: No positive findings were identified in patients categorized with thrombotic microangiopathy; as such, this category is not represented graphically in analyses pertaining to patients with positive findings. (C) The distribution of the 362 positive genetic findings across the clinical kidney disease categories. Genes are grouped by broad kidney disease types and ordered by prevalence among the cohort: cystic/tubulointerstitial (blue), glomerular (green), tubulopathy/tubular (orange), CAKUT/structural (yellow), complement (purple).
Figure 2
Figure 2
Classification of clinical diagnosis with the application of genetic data. Diagnostic utility of the molecular findings was assessed in the context of each patient's clinical diagnosis and medical history. (A) Breakdown of diagnostic effect of genetic findings among 338 positive patients. Confirm (n=115) 34.0%; diagnose (n=104) 30.8%; diagnose, partial (n=53) 15.7%; at risk (n=58) 17.2%; reclassify (n=8) 2.4%; of cases. Patients were designated at-risk if there were insufficient data provided to support classification into a diagnose or reclassify category. APOL1 high-risk genotypes were categorized as diagnose, partial, or at risk. For patients with more than one positive finding, classification was assessed based on the presumed primary driver of disease. (B) Diagnostic utility classifications stratified by pretest clinical kidney disease categorization.
Figure 3
Figure 3
The clinical effect of genetic diagnosis on patient management. Physician responses to 1-month post-test questionnaires were used to assess the effect of genetic test findings on patient management. (A) Frequency of physician-reported changes because of genetic testing in four management categories (treatment plan changes, discussions around family planning, referrals to genetic counseling, and referrals for testing for at-risk family members) among patients with positive genetic findings (red) and negative genetic findings (blue) P < 0.001 for comparisons between positive and negative groups, for all categories. (B) Frequency of treatment plan changes among patients with positive genetic findings (red) and negative genetic findings (blue). *P < 0.05, **P < 0.001. NS, not significant.
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