We’ve all had that patient walk into our clinic or emergency room with chronic kidney disease (CKD) that seemingly came out of nowhere. They may be too far along for a safe kidney biopsy or it is contraindicated for some other reason. These patients often carry a vague diagnosis such as glomerulopathy or hypertensive nephropathy or chronic kidney disease of unknown origin. I approach these patients as mysteries to be solved.
“Tell me about the health of every great uncle and cousin you’ve ever heard of.”
“Did anyone in your family wear hearing aids?”
“Do you know of anyone in the family with a cyst in their kidney?”
Unfortunately, despite my best Sherlock Holmes, most patients remain undiagnosed and ride off into the sunset (that is, kidney transplantation) without a precise diagnosis of what caused their kidney disease. This may be changing thanks to a recent New England Journal of Medicine paper from Ali Gharavi and colleagues at Columbia University. In the report, researchers performed exome sequencing from over 3,000 patients with CKD or end stage kidney disease (ESKD) with both (presumably) known and unknown etiologies and found a genetic cause of kidney disease in 9.3% of the cohort. Fascinatingly, the clinical diagnosis did not always predict the genetic diagnosis. For example, some patients found to have type IV collagen mutations consistent with Alport syndrome had a clinical diagnosis of congenital or cystic disease, hypertensive kidney disease, or CKD of unknown etiology. Of the 91 patients with a mutation in COL4A3, COL4A4, or COL4A5, only 35 previously carried a diagnosis of Alport syndrome or even thin basement membrane disease. Does having a genetic diagnosis matter? Who cares if you know the gene that caused your CKD if it’s leading to the same end result? I can think of a number of reasons why a genetic diagnosis is vitally important.
1. Every patient deserves to have a name for their kidney disease.
In my work with the Alport Syndrome Foundation I participate and facilitate patient meetings and get to hear a lot of “how I was diagnosed” stories. It’s so common to hear that a patient knew some people in the family had kidney disease but their doctors had never made a specific diagnosis. The uncertainty and confusion was hard to deal with. Am I at risk? What about my children? Once Alport Syndrome was named as the diagnosis, a weight was lifted from their shoulders. Now they know what it is. They can talk about it and find support from others similarly affected. Finally, knowing what this “thing” is, that has affected their family for generations is life-changing. While still scary, it’s easier to steel yourself against the known compared to the unknown.
2. A genetic diagnosis allows for early identification and treatment of potentially affected family members.
To use Alport syndrome as an example again (I know, I’m like a broken record), making a genetic diagnosis is only the tip of the iceberg for diagnosis. You potentially need to screen parents, children, aunts, uncles, etc. to identify other affected individuals. For boys with X-linked Alport syndrome it means convincing the mothers to take care of their own kidney health and to make sure they are properly educated about their own risk of disease. But can an early diagnosis of a genetic condition affect outcomes? They’re born with it, after all. The young boy with X-linked Alport syndrome identified during family screening with only microscopic hematuria and minimal proteinuria can start an ACE inhibitor early and potentially delay the onset of ESKD by 13-18 years.
3. A genetic diagnosis allows extrarenal manifestations to be identified and treated
The latest genetic diagnosis that seems to be popping up in my clinic with increasing frequency (maybe because I’m looking for it more and more) is cystic kidney disease due to HNF-1β mutations. Mutation in HNF-1β was found in 1 patient from the NEJM cohort. Patients with these mutations have a wildly variable renal phenotype and are additionally at risk for diabetes, gout, developmental delay or autism, and hypomagnesemia. If I make this diagnosis early, appropriate referral for developmental assessments and therapy can be made to improve outcomes in this realm. We can also add screening for hypomagnesemia and diabetes to their routine checkups.
4. A genetic diagnosis allows targeted treatment for the underlying disease pathogenesis.
Surprisingly, several patients in the NEJM cohort had PKD1 mutations without a clinical diagnosis of cystic kidney disease. Would these patients potentially benefit from tolvaptan therapy? As clinical trials of disease specific therapies are progressing in the rare kidney disease space, there may be specific drugs available for the treatment of Alport syndrome, ADPKD, and other genetic disorders in the near future. Almost as important, a genetic diagnosis can help prevent treatment with medications that may be harmful or would not be expected to work for their underlying pathophysiology. For example, the 15 patients in the NEJM cohort clinically diagnosed as “FSGS” but found to have type IV collagen mutations, could be spared exposure to immunosuppressive agents that do not have a clear benefit in Alport syndrome.
We clearly still have a lot to learn. Is genetic testing for all with chronic kidney disease the way to go? Should we be targeting specific groups that may be higher yield? For example, if only patients with a family history of kidney disease were included in the NEJM cohort, then the diagnostic yield increased to 15.2%. Are there genes out there that we haven’t identified yet as causative for kidney disease? Almost certainly. The NEJM paper by Groopman, et al. is an important glimpse into the challenge of diagnosis (and mis-diagnosis) of the patients in our care. We can do better, and that may start with genetic testing.
Commentary by Michelle Rheault
Pediatric Nephrologist, Minneapolis