Chronic kidney disease (CKD) affects over 37 million people in the United States.1,2 Many cases are caused by changes in a single gene, known as monogenic kidney disease. Improved early targeting for nephrology therapies could help improve patient experiences and long term outcomes. Broad panel renal genetic testing has the potential to help clinicians make better informed treatment recommendations for patients with an underlying genetic cause for their renal disease.
Recent results from a study of patients receiving Natera’s Renasight™ Kidney Gene Panel demonstrate the utility for broad panel genetic testing in clinical practice.1 Actionable genetic findings can help clinicians tailor care management plans, predict disease progression, qualify patients for clinical trials, and understand a patient’s familial risk.
Monogenic Kidney Disease
CKD represents a major public health burden in the United States. The causes of CKD are often complex, involving a combination of genetic and environmental factors. However, with the advent of widely available genetic testing and sequencing, researchers and clinicians have identified many cases of CKD driven by single, high impact genetic variants (monogenic kidney disease).
To date, researchers have identified more than 600 genes that can lead to monogenic kidney disease.3 Although many of these genetic variants are individually rare, monogenic kidney disease underlies approximately 10% of adult and 20% of pediatric CKD cases4,5, or roughly 50% of all nondiabetic pediatric CKD cases, and more than 30% of nondiabetic cases in adults.6
The Benefits of Genetic Testing for Monogenic Kidney Disease
Genetic testing for monogenic kidney disease has a number of benefits, for patients and their family members. Testing can help clinicians identify the underlying cause of someone’s kidney disease. This can often be a challenge as many symptoms can overlap or be non-specific. A genetic diagnosis can improve treatment decisions, provide prognostic insight, and facilitate referrals to specialists for extrarenal symptoms. Genetic testing can also inform testing for at-risk family members and reproductive counseling.
Genetic testing also plays an important role in kidney donation, where it can provide information about a patient’s risk of recurrence, guide post-transplant treatment, and help family members considering donation gauge their personal risk of kidney disease. Current KDIGO guidelines recommend offering genetic testing to at-risk relatives considering kidney donation.6
The Renasight™ panel
Natera designed Renasight™ to help clinicians identify patients carrying one or more of 385 genetic variants associated with CKD. These genes are associated with multiple types of kidney diseases, including cystic, tubulointerstitial, glomerular, tubular, and structural disorders. The Renasight panel was designed to cover a broad range of known genetic variants, encompassing diseases that primarily affect the kidneys and those involved in multisystem diseases, as well as both common and rare diseases.
The Renasight™ 1000 study
Natera is committed to advancing molecular diagnostics through scientific rigor and peer review. A recent paper in the American Journal of Nephrology presents the results of the Renasight™ 1000 study, an analysis of the first 1,007 Renasight™ tests performed in clinical practice. The study provides a unique window into the clinical utility of a broad gene panel and underscores the advantages of broad panel testing over targeted testing.1
A representative patient population
The Renasight™ 1000 patient population came from a diverse sample of nephrology patients. Ages ranged from 5 to 91, with a median age of 46 years old. Patient sex was evenly split, with 52.7% female patients (531/1007) and 47.3% male patients (476/1007). Of the 73.2% of patients who reported ethnicity (737/1007), 52.7% identified as White, 23.2% identified as Black, and 23.2% identified as Hispanic.
Positive results for a pathogenic or high-risk genetic variant were found in 25.1% of patients. Among patients with a genetic diagnosis, the median age was 44, and proportions of ethnicities reflected that of the overall patient population.
In the study population, 21.1% of patients tested positive for a monogenic kidney disorder (either autosomal dominant, homozygous autosomal recessive, or sex-linked) and an additional 3.9% tested positive for high-risk variants (APOL1 dual risk, meaning the individuals have the variant on both inherited chromosomes). Nearly half (45.3%) of participants were carriers of a recessive variant that could be passed on to their offspring. Sixteen (16) patients tested positive for two different monogenic kidney disorders.1
Overall, 220 variants were identified across 48 genes. The most common genes with findings were:
- PKD1 (34.1%) - Autosomal Dominant Polycystic Kidney Disease
- COL4A5 (10.9%) - Alport syndrome
- PKD2 (10.0%) - Autosomal Dominant Polycystic Kidney Disease
- COL4A4 (6.4%) - Alport syndrome and Benign familial hematuria
- COL4A3 (5.9%) - Alport syndrome, and Benign familial hematuria
Rare variants (occuring in only one person) accounted for 28% of findings, emphasizing the importance of broad panel testing.1
APOL1 Risk Allele
Most of the genetic variants Renasight™ tests for have a known mechanism for causing CKD. Only one is associated with a high risk for CKD, without a known causative mechanism: Apolipoprotein L1 (APOL1). APOL1 is involved in innate immune system responses to disease and its connection to kidney function is not fully understood. However, individuals who have two high risk for certain APOL1 variants are more likely to develop CKD.7
Patients with Black ancestry carry a 1 in 5 lifetime risk of developing CKD, with a higher risk for end-stage kidney diseases. Black patients are also more likely to carry high risk variants of APOL1. In the Renasight™ 1000 study population, 34.5% of Black participants had a positive genetic finding, and 75% of those findings involved APOL1. Of the 57 patients with APOL1 findings, 77.2% were Black, 7% were Latino, and 1.8% were White (the remaining 14% did not report ethnicity).1 Though APOL1 is more likely to be a factor for Black CKD patients, it is not the only potential genetic cause of disease and may still be found in patients with other ethnic identities.
Renasight™ results for potential kidney donors
In the Renasight™ 1000 study population, 24 patients were tested as potential kidney donors. In this small sample size, 29% (7 patients) had a positive genetic result, despite being currently asymptomatic.1 These findings emphasize the importance of genetic testing for potential donors, to identify situations where donors may have CKD in the future.
Renasight™ delivers actionable results for kidney patients
The Renasight™ 1000 study uncovered genetic factors in the chronic kidney disease of 1 in 4 patients. Nearly 1 in 2 patients were carriers of a monogenic kidney disease that could potentially be passed to their children. While many patients had findings in common genes, 28% had rare variants that would not have been detected without broad panel testing.1 In many cases, these findings enabled clinicians to better tailor treatment plans for each patient.
The Renasight™ panel offers an economical solution for broad panel genetic testing to help clinicians identify genetic causes of disease and help patients understand if and why CKD may run in their family. Natera supports the patient experience with options for mobile phlebotomy, educational resources, and complimentary genetic information sessions with Natera’s board certified genetic counselors. We support clinicians with straightforward ordering, logistical support, and easy access to experts when you have questions about our tests or services.
Click here to learn more about Renasight™, including the 385 genetic variants it tests for.
1Bleyer AJ, et al. Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel. AJNR Am J Neuroradiol. 2022;53(4):297-306. doi:10.1159/000522226
2Chronic Kidney Disease in the United States, 2021. Published August 2, 2022. Accessed August 2, 2022. https://www.cdc.gov/kidneydisease/publications-resources/ckd-national-facts.html
3Rasouly HM, 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
4Vivante A, et al. Introducing routine genetic testing for patients with CKD. Nat Rev Nephrol. 2019;15(6):321-322. doi:10.1038/s41581-019-0140-9
5Groopman EE, et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med. 2019;380(2):142-151. doi:10.1056/NEJMoa1806891
6KDIGO 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
7APOL 1 Gene. AAKP. Published August 20, 2020. Accessed August 2, 2022. https://aakp.org/center-for-patient-research-and-education/causes-of-kidney-disease/apol