Research Viewpoints Genetic Testing in Live Donor Transplantation

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Tantisattamo E., Reddy U.G., Ichii H.d,Ferrey A.J., Dafoe D.C., Ioannou N., Xie J., Pitman T.R., Hendricks E., Eguchi N., Kalantar-Zadeh K.: Is It Time to Utilize Genetic Testing for Living Kidney Donor Evaluation? Nephron DOI 10.1159/000520150

Living related or unrelated (altruistic) donor kidney transplantation is practically universally applied as an option for therapy of kidney failure, often as a preemptive procedure to avoid the need for dialysis. Such living donor transplantation may be the only option in countries where access to deceased donor transplants is severely limited. The Hippocratic principle of Primum non Nocere (“first do no harm”) applies to such situations and rigorous pre-donation evaluation is required to ensure that the potential donor is fully healthy and does not possess any factor that might increase the short- or long-term risks of elective removal of one healthy kidney. Pre-transplant kidney biopsy and/or genetic testing of the donor is not commonly part of this donor evaluation process, except in limited circumstances.

Tantisattamo and colleagues raise the issue of pre-donation genetic testing in a single case of autosomal dominant Alport syndrome discovered in a live donor by whole exome sequencing. The patient was an adopted white woman, without any knowledge of birth weight, who wished to altruistically donate her kidney to an unrelated friend. The donor evaluation was normal except for history of gestational diabetes and pre-eclampsia in one pregnancy. She was not obese. In addition, the endogenous 24-hour urinary creatinine clearance (Ccr) was 156 mL/min/1.73 m² and the urine albumin excretion rate (AER) was 65 mg/day, both abnormal. Repeat values were 110 mL/min/1.73 m² and 24 mg/day for Ccr and AER, respectively, 3.5 months after instruction to decrease dietary protein intake from a high value of 1.4 g/kg/day. Interestingly, dietary protein intake did not appreciably change during this interval. Hematuria was not observed during the evaluation, and blood pressure was normal. A creatinine-cystatin C eGFR was not performed. There were no hearing or ocular abnormalities found and the children were apparently normal.

She was approved for donation and underwent a uni-nephrectomy without complications. Three weeks after donation, she was found to have albuminuria (100 mg/dL) by qualitative testing and non-visible hematuria. Further follow-up over 12–18 months showed fluctuating albuminuria (UACR = 318–507 mg/g), a serum creatinine of about 0.8–0.9 mg/dL, and a Ccr of 76 mL/min/1.73 m². Hematuria was intermittent. The recipient had stable kidney function and low-grade albuminuria.

A whole exome sequencing panel investigation (RenaSight; Natera) revealed a heterozygous, likely pathogenic, mutation in the COL4A3 gene (c.2083G>A; pGly695Arg) compatible with an autosomal dominant Alport syndrome.

While quite uncommon, this case suggests that a heightened awareness of possible genetic kidney disease is appropriate when family history data is inaccessible (such as in adopted donors) and when clues to a possible underlying kidney disease are present (hyperfiltration-induced albuminuria), as in this case. As the cost of genetic screening falls, such testing might be incorporated into the routine evaluation of donors, with the Primum non Nocere doctrine in mind. We already recognize the importance of screening for APOL-1 risk alleles in donors of West African ancestry, especially when a history of low birth weight is present. A very thought-provoking case presentation.