Authors:

Trudy McKanna, MS, CGC, Director of Medical Education, Natera and

Paul R. Billings, MD Ph.D., Chief Medical Officer, Natera

A 28-year old man, CJ, presented to his nephrologist with a history of proteinuria since childhood which had progressed into the nephrotic range. A diagnosis of focal segmental glomerulosclerosis (FSGS) was made following renal biopsy, and CJ began typical treatment with immunosuppressants. Despite multiple drug treatment approaches, he still experienced progressive renal dysfunction, which can be observed in FSGS of genetic etiology. At this time, knowing that this history could be consistent with a non-immune (i.e. genetic) etiology, the physician ordered a comprehensive renal genetics panel, Renasight ™ in an effort to determine next steps. Natera’s Renasight™ test provides analysis on 380+ genes associated with adult-onset kidney disease, covering all major clinical categories: cystic, tubular, glomerular, complement-related, congenital disorders, and nephrolithiasis.
Chronic kidney disease (CKD) is a common and growing public health concern. The CDC estimates that one in seven American adults (roughly 37 million people) have CKD, and many are not aware they have it.¹ Patients with CKD have a higher risk of early death, heart disease, stroke, and diabetes. CKD may progress to end-stage renal disease (ESRD), which affects close to 1 million American adults, and is treated with dialysis or kidney transplant. CKD and ESRD present significant burdens to patients and the healthcare system, which will continue to grow with the increasing rate of CKD diagnosis. New tools are necessary for clinicians to accurately diagnose and manage kidney disease.

Genetic technologies have continued to advance, resulting in broader testing capabilities at lower cost. Next-generation sequencing (NGS) has led the way for laboratories to provide quicker, cheaper, and more expansive genetic analysis for patient care than ever before. It is now possible for diagnostic laboratories to conduct whole exome sequencing (WES) or broad disease panel testing as an integrated part of personalized medical care. While the technology exists to analyze an entire human genome, this may be more information than necessary to address the genetic evaluation for adult CKD. A number of recent publications have investigated the application and utility of renal genetic testing and how to best incorporate this into routine management.

A landmark paper published in the New England Journal of Medicine in 2019 demonstrated the diagnostic yield for renal genetic testing in the adult population. Overall, 9.3% of adult patients with CKD were found to have a genetic cause for their condition, with rates the highest in those presenting with cystic kidney disease (23.9%) and kidney disease of unknown etiology (17.1%). Most strikingly, the genetic diagnosis provided information that altered clinical management in 89% of patients.² This, and other studies, have demonstrated not only that genetic testing in the adult CKD population produces a high rate of diagnoses, but more importantly, that these diagnoses impact ongoing care for that patient, and often also for their relatives. The clinical utility of renal genetic testing can fall into four broad categories:

1. Classify/reclassify/diagnose disease

Up to one-third of adult-onset CKD cases have an undiagnosed cause. Broad genetic testing panels performed on these patients provided a diagnosis in 17-56% of cases.^2-4 Genetic testing can provide additional information in cases with atypical presentation, inconclusive biopsy results, or those with a diagnosis of hypertensive nephropathy, which may more accurately describe the symptoms rather than the cause. Genetic testing can also provide value in cases where a diagnosis has already been made based on clinical information. Genetic confirmation provides the patient and family with a definitive cause and mutation, may detect dual diagnoses, or could reclassify a clinical diagnosis based on the molecular findings. Up to a quarter of clinical diagnoses may be reclassified by genetic test results.^2-4

2. Provide information for family planning and counseling

Positive genetic test results not only have implications for the patient but may also identify other at-risk relatives who haven’t yet developed symptoms or may have a more mild presentation. Knowing the genetic cause is also important for living related donor workup prior to kidney transplant. For patients and relatives of reproductive age, a genetic diagnosis may also enable prenatal diagnostic testing for at-risk pregnancies, or pre-implantation genetic testing (PGT) to prevent passing on a genetic disease.

3. Target therapies, treatment, and extrarenal referrals

A genetic diagnosis may allow for targeted treatment of affected pathways, such as in Fabry disease, atypical hemolytic uremic syndrome, and primary hyperoxaluria. In the instance of steroid resistant nephrotic syndrome (SRNS), immunosuppression is less likely to be successful, but the recurrence risk after transplant is lower if a genetic cause is found. In this sense, a negative genetic test can also provide useful information by ruling out a number of possible etiologies. Some genetic conditions may present with renal findings, but also confer risks for extrarenal complications, such as hereditary transthyretin amyloidosis, which can cause progressive cardiomyopathy. Prompt referrals to other specialists may provide long-term health benefits.

4. Enroll in clinical trials and expand on current knowledge

There is still much to learn about the genetic contributions to kidney disease: variant curation, genotype/phenotype correlations, predisposition risk alleles and pharmacogenomics will all factor into the evolving integration of genetic testing into routine nephrology care. Genetic testing can confirm eligibility into specific clinical trials or provide additional information on the underpinnings of specific genetic factors in clinical presentation.

Renasight genetic testing results on CJ revealed a disease-causing mutation in the COL4A4 gene, consistent with a diagnosis of Alport syndrome. COL4A4-related Alport syndrome causes abnormalities in the collagen leading to progressive renal disease, and is associated with sensorineural hearing loss and ocular abnormalities. This diagnosis provided the physician with additional information to optimize the care of this patient: 1. Identifying the underlying structural defect leading to FSGS; 2. Reducing exposure to immunosuppressant therapies which are less effective in Alport syndrome; 3. More precise prognostication of inexorable disease progression, but low risk for recurrence post-renal transplant; 4. Targeted therapy with angiotensin inhibitors; 5. Family risk counseling and assessment.

As recent literature and CJ’s story both demonstrate, the advances in genetic technology and genetic variant classification have opened new doors for the evaluation and management of adults with chronic kidney disease. Renasight™ can help providers deliver earlier and more personalized diagnoses and insight into optimal nephrology management. With the new Renasight™ tool, Natera is committed to working with providers to further renal genetic research to improve management of CKD.

¹ https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html

²Groopman et al. N Engl J Med (2019) 380;2

³Connaughton et al. Kidney international (2019) 95, 914-928

⁴Lata et al. Ann Intern Med. 168; 2 (2019)