Screening of Living Kidney Donors for Genetic Diseases Using a Comprehensive Genetic Testing Strategy

C. P. Thomas; M. A. Mansilla; R. Sompallae; S. O. Mason; C. J. Nishimura; M. J. Kimble; C. A. Campbell; A. E. Kwitek; B. W. Darbro; Z. A. Stewart; R. J. H. Smith


American Journal of Transplantation. 2017;17(2):401-410. 

In This Article

Abstract and Introduction


Related living kidney donors (LKDs) are at higher risk of end-stage renal disease (ESRD) compared with unrelated LKDs. A genetic panel was developed to screen 115 genes associated with renal diseases. We used this panel to screen six negative controls, four transplant candidates with presumed genetic renal disease and six related LKDs. After removing common variants, pathogenicity was predicted using six algorithms to score genetic variants based on conservation and function. All variants were evaluated in the context of patient phenotype and clinical data. We identified causal variants in three of the four transplant candidates. Two patients with a family history of autosomal dominant polycystic kidney disease segregated variants in PKD1. These findings excluded genetic risk in three of four relatives accepted as potential LKDs. A third patient with an atypical history for Alport syndrome had a splice site mutation in COL4A5. This pathogenic variant was excluded in a sibling accepted as an LKD. In another patient with a strong family history of ESRD, a negative genetic screen combined with negative comparative genomic hybridization in the recipient facilitated counseling of the related donor. This genetic renal disease panel will allow rapid, efficient and cost-effective evaluation of related LKDs.


Kidney transplantation is superior to long-term dialysis for the management of end-stage renal disease (ESRD) because it provides greater long-term survival and better quality of life. Nevertheless, there is an ever-increasing gap between the need for transplantation and the availability of donor kidneys, with >120 000 patients currently on the deceased donor waitlist in the United States alone. This has resulted in an increasing push to encourage living donation, and today there are almost as many living donors as deceased donors annually in the United States.[1] Living kidney donor (LKD) transplants, for those fortunate to receive one, bypass the long waiting time, reduce the likelihood of death while waiting and provide better long-term allograft and recipient survival compared with deceased donor kidneys.[2,3] In some parts of the world, LKDs are the principal or only source of transplanted organs, and where long-term dialysis is prohibitively expensive or unavailable, LKD transplants provide the only available therapy for ESRD.

Living donor nephrectomy is generally considered acceptable medical practice, even though there are real risks for the donor, including death, serious injury and failure of the remaining kidney. Recent retrospective studies examining long-term outcomes of living donation compared with matched nondonor cohorts reported an increased 15-year and lifetime risk of ESRD for LKDs.[4,5] Although the absolute risk is arguably small, the relative risk is 30 per 10 000 over 15 years and 90 per 10 000 over a lifetime compared with four per 10 000 and 14 per 10 000 in matched controls. Within subpopulations, black men have a 15-year risk of 90 per 10 000 compared with just nine per 10 000 for white women.[4] Although not statistically significant, there is a twofold increased risk of ESRD among biologically related LKDs compared with unrelated LKDs.[4] The increased risk may reflect shared inheritance of genetic variants that are deleterious or a common environmental exposure that increases susceptibility to kidney disease.

In the United States, 40% of all LKDs are biologically related to their recipients.[1] Many are siblings or adult children of patients with ESRD and are in their third and fourth decades of life, making it difficult to predict future risk of kidney disease. In addition, to guide focused genetic testing of related family members for a specific inherited disease, the transplant recipient's cause of ESRD must be known. Together, diabetes and hypertension are the two most important reported causes of ESRD and account for 60% of the waitlist.[1,6] Most patients with diabetes and/or hypertension and chronic kidney disease (CKD) do not receive a kidney biopsy to verify the diagnosis, and recent studies estimated that as many as 35% of patients with presumed diabetic or hypertensive nephropathy may actually have an alternative diagnosis.[7–9]

Traditionally, establishing and/or confirming the diagnosis of a presumed genetic disease has required Sanger sequencing of the suspected gene for pathogenic variants.[10] When candidate genes are large, like COL4A5, sequencing is costly and time consuming. When the disease is heterogeneous, like focal segmental glomerulosclerosis (FSGS), serial gene-by-gene screening approaches are inefficient and impractical. These constraints can be largely overcome by using high-throughput approaches to DNA sequencing (i.e. next-generation sequencing [NGS] or massively parallel sequencing [MPS]) to sequence a large number of genes simultaneously. Targeted NGS panels have been developed to evaluate patients with a single phenotype, such as steroid-resistant nephrotic syndrome, FSGS and some ciliopathies.[11–14]

We developed a targeted renal panel that includes 115 genes implicated in a variety of kidney diseases to facilitate a diagnosis in patients with suspected genetic renal disease. We validated this panel for the evaluation of selected LKDs in whom the related transplant recipient's phenotype raised suspicion of or clearly indicated an inherited renal disease. We reported our findings from a pilot study of six controls, four transplant candidates and their six related donors.