Beyond Hypertensive Nephrosclerosis: A Closer Look at APOL1-Mediated Kidney Disease

For decades, a significant proportion of kidney disease in Black patients has been attributed to hypertension. This mislabeling may have obscured a distinct and underrecognized genetic driver, variants in the APOL1 gene.

APOL1-mediated kidney disease (AMKD) affects an estimated 6 million African Americans who carry a high-risk genotype,¹ with approximately 13% of the self-identified African American population carrying two risk alleles that confer substantially elevated kidney disease risk.² Yet AMKD remains largely absent from routine clinical practice.

In recognition of the third annual AMKD Awareness Day, HCPLive spoke with Pranav Garimella, MD, Chief Medical Officer of the American Kidney Fund, about the scope of the misclassification problem embedded in the "hypertensive nephrosclerosis" diagnosis, the systemic and patient-level barriers slowing genetic testing uptake, and what nephrologists outside major academic centers should be doing differently — right now — for patients who carry two high-risk APOL1 variants.

The American Kidney Fund has described APOL1-mediated kidney disease as historically underdiagnosed, with many cases likely labeled as hypertension-associated kidney disease. How significant is that misclassification problem in practice, and how should nephrologists be rethinking patients currently labeled with 'hypertensive nephrosclerosis'?

The misclassification problem is real and clinically important. Hypertensive nephrosclerosis is often a diagnosis of exclusion, so some patients labeled that way actually have APOL1-associated kidney disease, FSGS, glomerulonephritis, or another primary kidney disorder. One biopsy-based study found that current clinical criteria for nephrosclerosis had very low sensitivity, 0.13, and even an optimized algorithm only rose to 0.19, while 40% of test-positive cases had other treatable diagnoses such as glomerulonephritis or interstitial nephritis.

In practice, that means nephrologists should be more skeptical of the label, especially in younger patients, those with proteinuria, hematuria, rapid eGFR decline, or an atypical course. Rather than accepting hypertension as the full explanation, we should rethink those cases as 'kidney disease with hypertension' and consider whether biopsy, genetic testing, or a broader workup is warranted.

Genetic testing for APOL1 is becoming more available, but uptake in clinical practice remains limited. What are the biggest barriers—clinical, systemic, or patient-level—to broader testing in high-risk populations, and where does responsibility for closing that gap ultimately fall?

Despite increasing availability of genetic testing, several barriers continue to limit its broader uptake in clinical practice. At the clinical level, many health care professionals remain uncertain about how to act on results, particularly if the downstream implications for treatment and monitoring are not clearly defined in guidelines. In addition, genetic testing is still not well integrated into routine clinical workflows.

At the patient level, awareness of APOL1 variants remains relatively low, even among high-risk populations. Concerns about genetic privacy, potential discrimination and mistrust of the healthcare system can further reduce uptake, particularly in communities that have historically been underserved or marginalized.

Addressing these gaps will require shared responsibility across stakeholders. Professional societies and researchers must develop consensus guidelines on monitoring, including incorporating genetic counseling services. To make meaningful progress, there needs to be equitable access, coverage for genetic counseling services, and an infrastructure. At the same time, community engagement and patient education are essential to building trust and awareness, requiring coordinated efforts across the care continuum.

The third annual APOL1-mediated kidney disease Awareness Day just passed. When you talk about 'awareness,' who is the primary target—patients, clinicians, or both? And what does meaningful awareness look like in practice versus awareness that doesn't change clinical care?

Both patients and clinicians. The American Kidney Fund is working to reach all of these audiences. Given how relatively recent the link between APOL1 and kidney disease was identified, we know that awareness among patients is low, and it's fair to say that health care professionals outside of nephrology likely have not received specialized education about AMKD.

For patients, awareness means understanding that APOL1 can be relevant to kidney disease risk and knowing when to ask questions or seek testing. For clinicians, especially outside nephrology, it means recognizing when APOL1 or AMKD should be part of the differential and when a "hypertensive nephrosclerosis" label deserves a second look. The new ICD code for AMKD is a big step forward as it gives clinicians a formal way to name APOL1-mediated kidney disease instead of forcing patients into nonspecific labels like hypertensive nephrosclerosis. In practice, that should improve recognition, data capture, family counseling, and trial referral.

Awareness only matters if it changes decisions such as diagnosis, counseling, testing, referral, or follow-up — not if it just increases familiarity with the term. Actionable awareness is the goal with the American Kidney Fund's efforts surrounding AMKD awareness.

With APOL1-targeted therapies in clinical trials, what should nephrologists outside of major academic centers be doing right now for a patient with two high-risk APOL1 variants—if anything differently today compared to standard chronic kidney disease management?

Nephrologists should treat the CKD phenotype, not just the genotype, using standard measures that slow progression: RAAS blockade when indicated, SGLT2 inhibitors when appropriate, BP control, statins when indicated, nephrotoxin avoidance, and sick-day counseling.

They should monitor closely if the patient is high risk. A two-risk-variant APOL1 genotype raises concern for progressive disease, so you should be more alert to rising albuminuria, falling eGFR, and faster-than-expected progression, but the treatment backbone remains standard CKD care.

Nephrologists should also discuss family member testing to identify other high-risk carriers who may need close monitoring as well, and refer to a clinical trial if eligible and if access exists.

Lastly, use shared decision-making. If discussing APOL1 results, explain that many people with two risk variants never develop kidney disease, so genotype is risk information, not an outcome. Partner with a clinical genetic counselor for better patient understanding.

Editor’s Note; Garimella reported no relevant financial disclosures.

References

1. Srinivasan V, So PN, Kwakyi EPK, Lerma EV, Wiegley N. APOL1 mediated kidney disease: a review and look toward the future. Kidney Med. 2025;PMID:40837248. PMC12361766.

2. Pollak MR, Friedman DJ. APOL1 and APOL1-associated kidney disease: a common disease, an unusual disease gene — proceedings of the Henry Shavelle Professorship. Kidney Dis (Basel). 2023. doi:10.1159/000529227