Hypertensive Kidney Disease: Perfect Target for Precision Medicine

Jun 25, 2018

H-CKD may soon be more than a "phenotype of convenience with little clinical utility." How will precision medicine hone diagnosis and treatment?

It has been said of hypertensive kidney disease (H-CKD), “H-CKD is a phenotype of convenience with little clinical utility.”1 So, what exactly is this phenotype? Often an African American patient with hypertension, milder proteinuria (non-glomerular; <2 grams), and progressive chronic kidney disease (CKD).  Although clinicians typically know H-CKD when they see it, the diagnostic reality is far from straightforward. The clinical criteria for H-CKD are not standardized, the pathology is non-specific, and some patients with the diagnosis are misclassified.1 These are good reasons to study the disease; H-CKD warrants serious study because it1:

• is the second most common cause of ESRD (25% of cases)

frequently occurs in younger African Americans (this ethnic group has a 4-times greater risk of ESRD)

• is more likely to be progressive

An evolving concept

Shifting back to the common phenotype for a moment, why are not only H-CKD, but also focal glomerulosclerosis and HIV-nephropathy, more common in African Americans? The “non-specific pathology and misclassification” of H-CKD noted above may be coming to an end. Between 12% to 15% of African Americans carry two high risk APOL1 alleles (the gene coding for apolipoprotein-1).2 The gene product is a protein that lyses trypanosomes (analogous to the antimalarial hemoglobin mutation that causes sickle cell disease).2 What was once a survival gene in Africa is now an allele that predisposes persons of African ancestry to renal disease and dialysis. Some studies (ie, the Jackson Heart Study and Women’s Health Initiative) also associate APOL1 with cardiovascular disease in blacks, but others do not (SPRINT).3


Next step

Now that an at-risk gene is identified, how do we use the information to better manage disease? We have evidence that strict blood pressure control decreases mortality in individuals with high risk APOL1 genotypes.4 But that is only a beginning. The Precision Medicine Initiative (NIH, 2017) will lead to molecular phenotyping of kidney biopsy specimens using multi-omic platforms to more specifically identify biomarkers and therapeutic targets. From such refinements will follow more finely honed diagnostic tools and treatments, and better outcomes.1 Knowing exactly how APOL1 predisposes individuals to serious renal disease (it may afflict podocytes),2 will lead to better treatment choices-giving new meaning to targeted therapy.


1. Sedor JR. 2017-2018 Cleveland Clinic Update in Nephrology, May 19, 2018.

2. O’Toole JF, Bruggeman LA, Sedor JR. APOL-1 and proteinuria in the AASK: unraveling the pathobiology of APOL 1. Clin J Am Soc Nephrol. 2017; 12:1723-1725.
3. McLean NO, Robinson TW, Freedman BI. APOL-1 gene kidney risk variants and cardiovascular disease: getting to the heart of the matter. Am J Kidney Dis. 2017; 70:281-289. https://www.ncbi.nlm.nih.gov/pubmed/28143671

4. Ku E, Lipkowitz MS, Appel L, et al. Strict blood pressure control associates with decreased mortality risk by APOL-1 genotype. Kidney Int. 2017; 91:443-450. https://www.kidney-international.org/article/S0085-2538(16)30566-X/fulltext