Chronic kidney disease (CKD), a condition characterized by the gradual loss of kidney function, represents a massive health burden—one that affects an estimated 37 million Americans.1 The last decade has witnessed stunning advances in our understanding of the genetic causes of this multifaceted disease, opening the door for improved management and more targeted treatments.
A recent publication resulting from the KDIGO Controversies Conference on Genetics in CKD reviewed the current state of genetic knowledge and what it means for doctors seeing patients with CKD. “Given the important contribution of genetic variants to CKD,” the publication states, “practitioners with CKD patients are advised to ‘think genetic’.”2
To “think genetic,” clinicians can obtain family histories, collect information about when symptoms began and CKD was first diagnosed, and perform clinical examinations for symptoms affecting other parts of the body. These inquiries help inform the decision to pursue genetic testing.
The publication goes on to discuss the current clinical implications of our genetic knowledge. It describes how providers can integrate or further expand the use of genetic testing in their daily practice. Below we summarize some of its key points.
How Genetic Testing Can Improve Clinical Care
One of the most important benefits of genetic testing is the identification of monogenic kidney disease—CKD driven by a single, high impact genetic variant.
To date, researchers have discovered genetic variants in more than 600 genes that can cause monogenic kidney disease.3 Many of these genetic variants are rare. But monogenic disease as a whole is not rare: it accounts for as much as half of all nondiabetic CKD cases in children, and nearly a third of nondiabetic CKD cases in adults.2
Identification of these genetic variants can have important care implications, including:
Identify the genetic contributions to kidney disease
Genetic testing can identify the genetic cause or causes of disease. The chance of someone receiving a genetic diagnosis depends heavily on their clinical diagnosis, when their symptoms began, and whether their disease is affecting other parts of their body, not just the kidneys.
In a recent study of adult patients with CKD, roughly 1 in 10 patients received a genetic diagnosis, and 89% of those diagnoses had implications for clinical care.4 In adult patients with CKD of unknown cause, the rate of diagnosis is higher: studies have found that 17-56% of these patients receive a genetic diagnosis.4,5
Help guide treatment and inform screening for extrarenal symptoms
Genetic testing is already transforming how clinicians choose the appropriate therapy for CKD. For several monogenic disorders, early, accurate genetic diagnosis and treatment can help guide treatment decisions and potentially preserve kidney function:
- Fabry disease: Fabry disease is an X-linked genetic disorder that generally leads to kidney failure in male carriers in their 30s, 40s, and 50s. It has a variable presentation in female carriers.6 Early diagnosis of Fabry disease can lead to testing of at-risk relatives, referrals to specialists, and treatment with enzyme-replacement or chaperone therapy depending on the specific genetic variant involved.
- Alport syndrome: This syndrome results from disease-causing genetic variants in type IV collagen genes. For carriers of these variants, early treatment with angiotensin-converting enzyme (ACE) inhibitors have been shown to delay the onset of kidney failure by several decades.7
- Nephrotic syndrome due to coenzyme Q10 (CoQ10) deficiency: These patients frequently benefit from CoQ10 supplementation.8
- Steroid-resistant nephrotic syndrome: In 10–30% of cases, this syndrome is caused by known genetic mutations.9 For these patients, prolonged immunosuppression is often not only futile but potentially harmful.10 Appropriate genetic testing can spare them unnecessary treatment.
Several additional treatments for monogenic kidney disease are being tested in clinical trials. As these treatments become available, the clinical value of genetic testing will continue to grow.
Help determine a patient’s prognosis
For some types of CKD, such as autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome, genetic testing can help inform a patient’s prognosis and likely age of kidney failure. For example, ADPKD may be caused by genetic mutations in the PKD1 or PKD2 genes. However, patients with a mutation in the PKD2 gene generally have less severe ADPKD, experience clinical onset at a later age, and progress more slowly than patients with a PKD1 gene mutation.11
Inform monitoring for disease recurrence after kidney transplantation
Patients with certain monogenic kidney diseases, such as atypical hemolytic uremic syndrome (aHUS) and primary hyperoxaluria, face a high risk of disease recurrence after kidney transplantation. Appropriate genetic testing can guide therapy selection to help protect the transplanted kidney.
Inform counseling for at-risk relatives
Genetic testing can inform counseling for relatives, who may want testing for themselves or for their children. People who learn they carry a genetic mutation may wish to consider preimplantation genetic testing prior to pregnancy.9,12
When is Genetic Testing Warranted?
Considering the important and growing benefits of genetic testing, the recent KDIGO publication makes several recommendations. First, a thorough medical history and examination can inform the decision whether to offer genetic testing. A family history of CKD, an early age of onset, or non-kidney symptoms should raise suspicion of a genetic cause. Likewise, certain clinical diagnoses, such as polycystic kidney disease or a glomerular or tubulointerstitial disorder, imply a higher chance of genetic disease.2
When testing reveals that someone’s kidney disease has a genetic cause, their at-risk family members may wish to pursue testing for themselves or their children. Testing is especially critical for relatives wishing to be considered as kidney donors. Donation could place them at elevated risk for kidney disease.13
Finally, because of the large number of genetic variants implicated in CKD, using a gene panel or exome sequencing is generally preferable to single-gene testing.
“In general, because of the genetic heterogeneity of most forms of nephropathy, genetic testing with phenotype-driven gene panels, or exome or genome sequencing, is more efficient than sequential single-gene analyses.” - KDIGO executive conclusions
The Renasight™ Gene Panel
For providers considering genetic testing for monogenic kidney disease, Natera’s Renasight™ gene panel provides an excellent option. Using next-generation sequencing and other advanced molecular techniques, Renasight™ analyzes more than 380 genes associated with monogenic kidney disease.
Renasight™ has several benefits. Its broad gene panel misses fewer genetic diagnoses than more targeted panels.4 It also comes with Natera’s unparalleled access to board-certified genetic counselors and patient and provider support services. In addition, patients can schedule a complimentary genetic information session with a genetic counselor before or after their Renasight™ test. Click here to learn more about the Renasight™ gene panel and to order test kits.
1Kidney disease statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases. Published December 8, 2021. Accessed June 13, 2022. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease
2KDIGO Conference Participants. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2022;101(6):1126-1141. doi:10.1016/j.kint.2022.03.019
3Rasouly HM, Groopman EE, Heyman-Kantor R, et al. The Burden of Candidate Pathogenic Variants for Kidney and Genitourinary Disorders Emerging From Exome Sequencing. Ann Intern Med. 2019;170(1):11-21. doi:10.7326/M18-1241
4Groopman EE, Marasa M, Cameron-Christie S, et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med. 2019;380(2):142-151. doi:10.1056/NEJMoa1806891
5Lata S, Marasa M, Li Y, et al. Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study. Ann Intern Med. 2018;168(2):100-109. doi:10.7326/M17-1319
6Disease management. Accessed June 9, 2022. https://www.fabry-institute.com/disease-management
7Quinlan C, Rheault MN. Genetic Basis of Type IV Collagen Disorders of the Kidney. Clin J Am Soc Nephrol. 2021;16(7):1101-1109. doi:10.2215/CJN.19171220
8Kleiner G, Barca E, Ziosi M, et al. CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway. Biochim Biophys Acta Mol Basis Dis. 2018;1864(11):3708-3722. doi:10.1016/j.bbadis.2018.09.002
9Lipska-Ziętkiewicz BS. Genetic Steroid-Resistant Nephrotic Syndrome Overview. In: GeneReviews® [Internet]. University of Washington, Seattle; 2021. Accessed June 22, 2022. https://www.ncbi.nlm.nih.gov/books/NBK573219/
10Hildebrandt F. Genetic kidney diseases. Lancet. 2010;375(9722):1287-1295. doi:10.1016/S0140-6736(10)60236-X
11Igarashi P, Somlo S. Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol. 2002;13(9):2384-2398. doi:10.1097/01.asn.0000028643.17901.42
12Chaperon JL, Wemmer NM, McKanna TA, et al. Preimplantation Genetic Testing for Kidney Disease-Related Genes: A Laboratory’s Experience. Am J Nephrol. 2021;52(8):684. doi:10.1159/000518253
13Lentine KL, Kasiske BL, Levey AS, et al. KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. Transplantation. 2017;101(8S):S7-S105. doi:10.1097/tp.0000000000001769