Clinical genetic testing

Genetic testing for patients with kidney disease can have a remarkable impact on their care. The availability of “broad-panel genetic testing” for kidney patients ushers in a new era of nephrology and patient care. Tests that used to cost thousands of dollars and took months for results can now be done for a fraction of the cost in just a few weeks. New commercially available genetic tests utilize next-generation sequencing to identify multiple gene variants simultaneously. These tests can help in the management of kidney disease in multiple ways. In this blog, we will focus on the clinical utility of genetic testing for kidney transplant evaluation.

Genetic Testing for Kidney Transplant Evaluation

During the evaluation of a patient for a kidney transplant (the recipient), the assessment usually focuses on answering these questions: 

  1. Can the recipient survive elective transplant surgery? 
  2. Can the recipient tolerate immunosuppression after the transplant? 
  3. Can the recipient have a good outcome? 

In addition, evaluation of living donors try to answer questions about their suitability for donation and their risk of developing kidney failure in the future. 

Living Donor Evaluation

One of the most pressing questions when evaluating a living donor is: Will this donor develop kidney disease in the future if s/he donates a kidney now? Several studies have shown an increased risk of the donor developing kidney disease after donation. This risk is higher if the donor and the recipient are related. This may indicate that genetic factors play a role in this risk. 
In 2017, the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines suggested that “transplant programs should have a strategy for evaluating for inherited kidney disease in donor candidates when there is a family history of kidney failure and the recipient’s cause of kidney failure is uncertain.” 
These guidelines suggested genetic testing of living related donors with specific diseases such as focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome, Alport disease, sickle cell trait, and autosomal dominant tubulointerstitial kidney disease. 
Genetic testing of a living relative donor can be especially important if the recipient has polycystic kidney disease. If this mutation is identified in the recipient, the donor can then be tested and excluded if s/he has the mutation. This can give greater assurance to both the donor and recipient. 
Other genetic variants are associated with increased risk of chronic kidney disease (CKD) such as APOL1 gene variants that are associated with increased risk for nephropathy in patients of African ancestry. Incorporating testing for these genetic risk variants in the evaluation of the donor may help replace race for calculation of the so-called Kidney Donor Risk Index that is used to predict the longevity of the transplant graft. 
While it is still too early to incorporate the genetic risk variants for diabetic kidney disease and IgA nephropathy in transplant evaluation, getting more clarity on the utility of the risk variants can have a tremendous impact on the care of current patients.

Recipient Evaluation

Kidney disease is silent in its progression and symptoms do not develop until the advanced stages of CKD. One in 10 patients with advanced kidney diseases presents with end-stage kidney disease (ESKD). In many of these cases, the laboratory workup is inconclusive, and their kidneys are often too atrophic to biopsy. Unlike kidney biopsies, genetic data can be informative even after ESKD has developed.
Genetic evaluation of the recipient is, therefore, helpful in identifying the causative mutation that could have led to the disease. Using targeted gene testing, researchers were able to identify pathogenic mutations in 19% of waitlisted transplant patients under the age of 40. Broad panel genetic testing can likely have an even higher yield. Indeed, broad panel genetic testing has been shown to identify the cause of CKD in up to one-third of the patients with an unknown cause.
Genetic testing of the recipient can also help in providing individualized post-transplant care. Finding a specific mutation that leads to a localized disease in the kidneys can decrease concerns about the recurrence of the disease after transplantation.
Also, a genetic diagnosis can often point to the likelihood of disease in another organ and can prompt referral and evaluation.
Currently, researchers are collecting phenotypic and genetic information on patients receiving transplants in the iGeneTRAiN consortium. Analyzing this data in the future may have a significant impact on our understanding of transplant graft outcome.


Wouldn’t it be a relief to be able to predict in advance how someone might respond to a medication? This would save time, eliminate guesswork, and improve patient outcomes. Thanks to advances in a field of genetics called pharmacogenomics (PGx), clinicians have begun to use genetic information to personalize drug therapy.
Accurate pharmacogenomics data are now available on two transplant medications: tacrolimus and azathioprine. Although the latter is not commonly used, the former is used often. Tacrolimus is metabolized by the enzyme encoded in the gene CYP3A5. Variants in this gene can classify the patient into one of three phenotypes: extensive metabolizer, intermediate metabolizer, and poor metabolizer. Indeed, pharmacogenomic data can now be used to optimize the initial dose of tacrolimus.
Many other medications commonly used by patients have pharmacogenomic data which can also be used to optimize their dosing. Medications such as clopidogrel, voriconazole, and allopurinol are a few of these. We discussed these medications in-depth in our previous blog about pharmacogenomics.

The Bottom Line

Genetic testing is gradually becoming a significant part of the transplant evaluation of the donor and the recipient. It is particularly useful in the evaluation of living donors with a family history of kidney disease. This data has the potential to transform the care of kidney transplant patients and improve their outcomes.