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Background

Chronic kidney disease (CKD) is a growing public health concern, affecting approximately 1 in 7 U.S. adults, and accounting for more than 20 percent of the Medicare budget. Diagnosing CKD early, and managing the underlying causes is critical to slowing down the progression to end-stage renal disease (ESRD), thereby reducing the burden to patients as well as the healthcare system.

However, CKD has a complex etiology, and until recently, the role of genetics in adult-onset CKD was greatly underappreciated. A seminal paper published in the New England Journal of Medicine in 2019 found that approximately one in 10 adult-onset CKD patients have a genetic etiology — a diagnostic yield comparable to that found with genetic testing in other specialties, such as oncology (Figure1, left panel). Pathogenic variants were detected across all clinical diagnoses, including CKD of unknown etiology, which represents 36 percent of adult-onset CKD cases. Further, the genetic diagnosis had implications for the clinical management of 89 percent of the study cohort (Figure 1, right panel).

Fig 1: Diagnostic yield (left) of genetic testing in CKD broken down by clinical diagnoses, and its implications for management of kidney disease patients (right)

The Current Landscape of Genetic Testing for Kidney Disease

The growing awareness of the importance of genetics in adult-onset CKD has led to the development of renal disease-specific gene panels, comprising a small number of genes that are selected based on known associations with a particular disease or phenotype. The utility of such targeted panels is highly dependent on an accurate clinical diagnosis. However, kidney diseases are complex and are often misdiagnosed based on a patient’s clinical presentation.

Kidney Disease Diagnostics Enters the Genomics Era

In this context, a broad renal genetic panel such as Renasight, may have tremendous clinical utility. Developed by Natera, it leverages next-generation sequencing to analyze over 380 genes associated with monogenic disorders linked to CKD, including those related to cystic, tubular and glomerular diseases; nephrolithiasis and electrolyte disorders, as well as congenital anomalies of the kidney and urinary tract and other structural diseases. The following case studies — presented at the 2021 National Kidney Foundation’s Annual Spring Meeting (April 6-11) — highlight several clinical scenarios where Renasight provided actionable insights that changed the patient’s management.

Reclassification of Kidney Disease
A deeper understanding of the genetic underpinnings of kidney disease has enabled the refinement and reclassification of clinical diagnoses based on genetic test results by as much as 25 percent.

An example is the case of a 46-year-old white female who was diagnosed with kidney disease secondary to hypertensive nephrosclerosis and analgesic nephropathy prior to genetic testing. Renasight test results identified a pathogenic, autosomal dominant variant in UMOD (uromodulin), resulting in the reclassification of her disease to autosomal dominant tubulointerstitial kidney disease caused by pathogenic UMOD mutation, which led to her being treated with the xanthine oxidase inhibitor, allopurinol.

This case highlights how an accurate genetic diagnosis by Renasight can influence treatment decisions for the patient, as well as future genetic testing for family members.

Dual Diagnosis
Another surprising finding from recent large-scale studies on the genetics of kidney disease is that approximately two percent of patients have more than one genetic disorder, which often results in atypical clinical presentation and earlier onset of symptoms. 

For instance, a 31-year-old African-American male with a history of uncontrolled hypertension and progressive CKD was diagnosed with collapsing focal segmental glomerulosclerosis (FSGS) upon kidney biopsy. Renasight results yielded a heterozygous COL4A4 (Collagen Type IV Alpha 4 Chain) variant and homozygous APOL1 (apolipoprotein L1) risk alleles. While mutations in the COL4A4 gene promote FSGS associated with Alport syndrome (AS), the implications of such variants combined with homozygous high-risk APOL1 variants have not been previously reported. However, another COL4A4 variant at the same amino acid has been previously reported in patients with AS. Since heterozygous COL4A4 mutations in AS is implicated in thin basement membrane nephropathy associated with FSGS, it is possible that, in this case, abnormal COL4A4 and APOL1 alleles may have a synergistic effect in promoting a progressive form of kidney injury.

Here, testing with a broad renal genetic panel uncovered a previously unreported variant combination that may further our current understanding of the genetic underpinnings of FSGS.

CKD of Unknown Etiology
More than a third of adult-onset CKD cases have an unknown etiology, and genetic testing has been shown to be especially informative in this population.

For example, in a case study of a 22-year-old asymptomatic male initially diagnosed with secondary FSGS after kidney biopsy, subsequent testing with Renasight identified two pathogenic variants in the NPHP1 (nephrocystin-1) gene, resulting in a diagnosis of Nephronophthisis (NPH), the leading genetic cause of pediatric-onset ESRD. Recent studies have shown that NPH also plays a role in adult-onset ESRD, although it often remains underdiagnosed because of a lack of awareness of its potential role in adults.

The NPH diagnosis has important implications for the patient and their family due to a 25 percent risk of inheriting NPH in each sibling. Additionally, NPHP1 variants are associated with Joubert syndrome and Senior-Løken syndrome, for which the patient is undergoing screening. The availability of a broad kidney genetic panel, capable of detecting point mutations and whole gene deletions, can lead to an enhanced understanding of the role of NPH in adult-onset ESRD, as well as other kidney conditions of unknown etiology.

Conclusion

While the genetic architecture of kidney disease has been increasingly explored in recent years, our current knowledge of this complex landscape is far from complete. Consequently, broad-based genetic tests, such as Renasight, should help expand on our understanding, as well as arm patients and providers with actionable information that can potentially improve their clinical outcomes. Finally, resources such as board-certified genetic counselors and remote testing services (including virtual ordering for providers and at home sample collection for patients) provided by Natera with Renasight at no additional cost, can drive the integration of genetic testing into routine kidney care and bring much needed innovation to nephrology diagnostics.