Vignette-Based Reflections to Inform Genetic Testing Policies in Living Kidney Donors

Abstract

Family history of kidney disease increases risk of end-stage kidney disease (ESKD) in donors. Pre-donation genetic testing is recommended in evaluation guidelines and regulatory policy. Collaborating across several institutions, we describe cases to illustrate the utility as well as practical issues in incorporating genetic testing in transplant protocols. Case 1 is from 2009, before pervasive genetic testing. A healthy 27-year-old Caucasian male had an uneventful donor evaluation for his mother, who had early onset ESKD of unclear cause. He participated in paired-exchange kidney donation, but developed progressive kidney disease and gout over the next 10 years. A uromodulin gene mutation (NM_003361.3(UMOD):c.377 G>A p.C126Y) was detected and kidney biopsy showed tubulointerstitial kidney disease. The patient subsequently required kidney transplantation himself. Case 2 was a 36-year-old African American female who had an uneventful kidney donor evaluation. She underwent gene panel-based testing to rule out ApolipoproteinL1 risk variants, for which was negative. Incidentally, a sickle-cell trait (NM_000518.5(HBB):c.20A>T p.Glu7Val) was noted, and she was declined for kidney donation. This led to significant patient anguish. Case 3 was a 26-year-old Caucasian female who underwent panel-based testing because the potential recipient, her cousin, carried a variant of uncertain significance in the hepatocyte nuclear factor-1-β (HNF1B) gene. While the potential donor did not harbor this variant, she was found to have a likely pathogenic variant in complement factor I (NM_000204.4(CFI):c.1311dup:p.Asp438Argfs*8), precluding kidney donation. Our cases emphasize that while genetic testing can be invaluable in donor evaluation, transplant centers should utilize detailed informed consent, develop care pathways for secondary genetic findings, and share experience to develop best practices around genetic testing in donors.

Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification

“…48 In families with genetic kidney disease, resolution of VUS is particularly important because detection of genetic kidney disease in family members can not only allow for appropriate precision management but also help avoid a situation where an asymptomatic family member with a genetic pathogenic variant donate a kidney and then later develops ESKD. 49 Similarly, an unresolved VUS could delay family member carriers from serving as potential kidney donors if the variant is later unequivocally determined benign.…”