Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group

Abstract

About 37 million people in the United States have chronic kidney disease, a disease that encompasses multiple causes. About 10% or more of kidney diseases in adults and as many as 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.

Keywords: Delphi; disclosing test results; genetic counselor; genetic testing; kidney disease; modality; monogenic; patient perspective; transplant.

Figure 1:. Working Group activities

All activities were conducted virtually. The Working Group’s activities began with one preliminary breakout session for each group, followed by a Plenary Session, during which presentations on the topics assigned to the Breakout Groups were presented. This session prepared the Breakout Groups for three subsequent, one-hour, breakout sessions spaced over about eight weeks. During these sessions, recommendations related to the assigned topics of the respective Breakout Groups were developed. Recommendations were subsequently presented and discussed during the Consolidation Session, after which, each group submitted recommendations to the Steering Committee. The latter group refined and converted the recommendations into statements for scoring in the Delphi process.

Figure 2:. Algorithm for decisions on genetic testing for symptomatic adult and pediatric patients

Clinical scenarios in which genetic testing is indicated in symptomatic adult and pediatric individuals and the recommended tests to perform are shown. * Abnormal electrolyte/proteinuria/blood pressure/structural abnormalities including cystic disease and CAKUT, etc. † Refers to first-degree relatives only, unless the patient and extended family member’s phenotype are congruent, which suggests a recessive or X-linked disease ‡ TIN; tubulointerstitial nephropathy (evaluate for ADTKD) § Evaluate for oxalosis, Dent disease, nephrocalcinosis, docosahexaenoic acid (DHA) disease, etc. ‖ Genetic testing may not be necessary when there is clinical certainty of a genetic diagnosis, such as in in ADPKD with a classic phenotype and family history pattern ¶ Smaller phenotype-driven panels may be appropriate ** Standard WES and WGS do not detect some pathogenic variants (e.g., MUC1 variants for ADTKD-MUC1) †† CAKUT, congenital abnormalities of kidney and urinary tract; FSGS, focal segmental glomerulosclerosis; TMA, thrombotic microangiopathy; MPGN, mesangioproliferative glomerulonephritis

Figure 3:. Algorithm for decisions on genetic testing of adult and pediatric individuals at-risk for a familial (or monogenic) kidney diseases

Clinical scenarios in which genetic testing is indicated in at-risk and pediatric individuals and the recommended tests to perform are shown. * Refers to first-degree family history only, unless the individual’s or family member’s phenotype are congruent (if individual’s phenotype present) and would suggest consideration of recessive or x-linked disease † Smaller phenotype-driven panels may be appropriate ‡ At discretion of clinician

Figure 4:. Road map for advancing genetic testing in kidney diseases

Organizations and communities (1) will educate key groups (2) or advocate for resource support and development (e.g., building disease registries). Other key stakeholders will (3) develop best practice guidelines needed to guide clinicians in using appropriate genetic testing tools and concepts. These combined activities are expected to lead to increased awareness of genetic testing in professional and patient communities and increased appropriate use of genetic testing. When successful, the benefits to patients will be shorter diagnostic paths, clarity of diagnosis, and improved clinical outcomes.