Katalin Susztak, MD, PhD, is a Professor of Medicine and Genetics at the University of PennsylvaniaKatalin Susztak, MD, PhD, is a Professor of Medicine and Genetics at the University of Pennsylvania

Katalin Susztak, MD, PhD

9-Protein Plasma Score Predicts Kidney Failure Risk in APOL1 High-Risk Individuals Before Visible CKD

A plasma proteomic risk score built from 9 circulating proteins can identify individuals with high-risk APOL1 genotypes who are most likely to progress to kidney failure, years before standard clinical markers such as estimated glomerular filtration rate (eGFR) or albuminuria become abnormal.

The findings, derived from the Penn Medicine BioBank (PMBB) and validated in 2 independent cohorts, offer a potential precision medicine framework to address predicting which APOL1 carriers will actually develop kidney disease, one of the most persistent gaps in nephrology.

Score: APOL1 Proteomic Risk Score (APRS), 9 proteins

Population: APOL1 high-risk, eGFR ≥60, African ancestry

Status: Research tool; prospective validation needed

"APOL1 variants are common — present in about one third of African Americans — and while they confer substantial risk, only a minority of individuals develop kidney disease. So the challenge is not identifying risk, but distinguishing who will get sick from who will remain healthy," said Katalin Susztak, MD, PhD, Professor of Medicine in the Renal-Electrolyte and Hypertension Division at the University of Pennsylvania Perelman School of Medicine.

What the APOL1 Proteomic Risk Score Study Found

Researchers profiled plasma proteomes using the SomaScan platform, quantifying approximately 7549 proteoforms, in 851 PMBB participants of African ancestry who carried high-risk APOL1 genotypes (G1/G1, G2/G2, or G1/G2) and had preserved kidney function, defined as ≥ eGFR of 60 ml/min/1.73m2. Using elastic net Cox regression adjusted for age, sex, eGFR, and urine albumin-creatinine ratio (UACR), the team derived a 9-protein APOL1 Proteomic Risk Score (APRS) comprising SPON1, SUMO2, EPHA10, REG3A, WFDC2, LYZ, MMP7, NPPB, and CILP2.

The composite primary outcome of a ≥ 40% eGFR decline, kidney failure, or death occurred in 18.0% of participants, with preserved eGFR in 10 years of follow-up, underscoring the event burden in this population even before CKD is clinically apparent. APRS achieved a time-dependent area under the receiver operating characteristic curve (tAUC) of 86.5% for the composite outcome, substantially outperforming the Kidney Failure Risk Equation (KFRE; tAUC 66.1%) and polygenic risk scores (tAUC 58.5%) in this group. Risk stratification by quintile showed 10-year cumulative event rates of 62.5% in the highest APRS quintile versus 3.3% in the lowest (

 = 4.73 × 10−23). At 5 years, APRS demonstrated a sensitivity of 76.3% and specificity of 86.7%.

How APRS Performs Compared to Existing Kidney Failure Prediction Tools

The KFRE, the most widely validated clinical equation for kidney outcomes, is known to perform poorly when eGFR is preserved, precisely the population where early intervention would have the greatest benefit. Polygenic risk scores, which aggregate inherited susceptibility variants across the genome, similarly showed limited discrimination in the APOL1 high-risk group, consistent with prior observations that static genetic measures provide modest predictive value in diverse populations.

The APRS was also benchmarked against the Chronic Renal Insufficiency Cohort (CRIC) proteomic score, a 65-protein model developed in patients with established CKD. Although the CRIC score was derived from a more advanced disease population, APRS outperformed it in the preserved-eGFR group (tAUC 86.5% versus 79.0%) while performing comparably in participants with eGFR below 60 ml/min/1.73 m

Decision curve analysis confirmed greater net clinical benefit from APRS than either a treat-all or treat-none strategy across a range of decision thresholds. Assuming a treatment that reduces composite endpoint risk by 27%, the reduction reported for the investigational APOL1 inhibitor inaxaplin in prior trials, APRS at or above the 95th percentile, yielded a number needed to treat of 4.9, compared with 8.4 for KFRE and 23.9 for a CKD polygenic risk score.

External Validation of the 9-Protein Score Across Independent Cohorts

To assess generalizability, APRS was validated in 2 external population-based cohorts. In the Atherosclerosis Risk in Communities (ARIC) study, 314 APOL1 high-risk African American participants with preserved kidney function at baseline (mean eGFR 96.2 ml/min/1.73 m

) were evaluated; APRS achieved a tAUC of 82.2% over 10 years. In the UK Biobank, 204 APOL1 high-risk participants of African ancestry (mean eGFR 87.1 ml per minute per 1.73 m

) showed similarly strong discrimination, with a tAUC of 84.7%. Despite differences in recruitment era, geographic setting, and healthcare systems, performance remained consistent across both cohorts, supporting reproducibility beyond the academic medical center setting where the score was developed. 

Among the 9 component proteins, 4 were significantly associated with interstitial fibrosis in independent human kidney tissue samples at both the mRNA and protein levels, suggesting biological plausibility. Susztak noted that some proteins are linked to fibrosis and tissue injury, others to inflammatory pathways, and some to endothelial dysfunction. MMP7 has been reported as a marker of tubular injury and fibrosis; WFDC2 correlates with interstitial fibrosis and rapid eGFR decline; and LYZ is associated with fibroblast proliferation and tubular cell senescence.

The investigators acknowledge that these associations are correlative and that whether these proteins actively drive disease progression or reflect altered renal clearance remains to be established through experimental validation.

"APRS is currently a research tool," Susztak said. "While we have validated it in independent cohorts, including studies in the United Kingdom and NIH-funded populations, clinical implementation requires further work. The challenge is demonstrating that acting on this information improves outcomes, particularly in populations that have historically experienced a disproportionate burden of disease."

The investigators outline several translational steps, including independent prospective validation, assay standardization across platforms, and incorporation of APRS into clinical trials of APOL1-targeted therapies to determine whether score-guided enrollment and treatment decisions improve patient outcomes. As APOL1-directed agents such as inaxaplin advance through development, APRS may also serve as a pharmacodynamic readout of treatment effect and a subject enrichment tool to improve trial efficiency.

Editor’s Note: Susztak reports relevant disclosures with Ilead, Novo Nordisk, Novartis, and others. 

Susztak K, et al. Plasma proteomic risk score predicts kidney failure in APOL1 high-risk individuals. Nature Medicine. 2025.

Inker LA, Tangri N, Greene T, et al. Kidney Failure Risk Equation performance across eGFR strata. J Am Soc Nephrol. 2019;30(9):1731-1742.

Olabisi OA, Zhang JY, VerPlank L, et al. APOL1 nephropathy risk variants induce cytotoxicity by disrupting cellular electrolyte homeostasis. Proc Natl Acad Sci USA. 2016;113(4):830-837.

Gharavi AG, Ahmad T, Roberts JD, et al. Genome-wide association analysis improves polygenic risk prediction for CKD. J Am Soc Nephrol. 2023. [Note: Verify full citation details; PRS reference sourced from study methods.]

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Susztak, MD, PhD, offers insight into a new score that predicts which APOL1 carriers will actually develop kidney disease.

APOL1-Mediated Kidney Disease: From Genetic Discovery to the Edge of Precision Medicine


A decade and a half after APOL1 was linked to kidney disease, clinicians are still grappling with misdiagnosis, unpredictable progression, and uneven access to genetic insight, just as targeted therapies begin to emerge.

Kirk Campbell, MD, Professor of Medicine and Chief of the Renal Division at the University of Pennsylvania Perelman School of Medicine.

Pranav Garimella, MD, Chief Medical Officer of the American Kidney Fund,

Kristin Meliambro, MD, is an Associate Professor in the Department of Medicine, Division of Nephrology at the Icahn School of Medicine at Mount Sinai.

Katalin Susztak, MD, PhD, is a Professor of Medicine and Genetics at the University of Pennsylvania

John Cijan He, MD, PhD, Professor of Medicine and Pharmacological Sciences and Chief of the Division of Nephrology at the Icahn School of Medicine at Mount Sinai

A Genetic Discovery That Reshaped Kidney Disease Risk

In the span of roughly 16 years, APOL1 has moved from evolutionary curiosity to one of the most important genetic risk factors in nephrology.

The G1 and G2 variants, enriched in populations with West and Central African ancestry, rose in frequency because they confer protection against 

 infection. Today, they are recognized as among the strongest common genetic risk factors for kidney disease.

Approximately one-third of African Americans carry at least one high-risk APOL1 variant, and about 14% carry the high-risk genotype—two risk alleles in combinations such as G1/G1, G2/G2, or G1/G2. Globally, more than 100 million people in sub-Saharan Africa are estimated to carry two risk variants, with frequencies reaching 37% in parts of Ghana and 50% in southeastern Nigeria.

“It is a long time,” said Campbell. “But the fact that it took 13 years from the discovery of APOL1 kidney disease genetic association to the first proof-of-concept APOL1 inhibitor efficacy report should be celebrated.”

At the same time, Campbell emphasized ongoing uncertainty:

“There are still no approved APOL1-specific therapies, no consensus on population screening, limited ability to predict who among carriers will progress, and unresolved questions about ‘second hits,’” he said.

Rethinking a Default Diagnosis: Hypertension as Explanation — or Misclassification

Before APOL1 can be treated, it must be recognized—and that remains a persistent challenge.

Hypertensive nephrosclerosis has long served as a default diagnosis for chronic kidney disease in patients with hypertension, particularly Black patients. But emerging evidence suggests this label often obscures more specific and potentially treatable disease.

One biopsy-based study found that clinical criteria for nephrosclerosis had a sensitivity of just 0.13. Even optimized algorithms only reached 0.19, and roughly 40% of clinically diagnosed cases were found to have alternative diagnoses such as glomerulonephritis or interstitial nephritis.

Clinicians increasingly caution against treating hypertension as the primary explanation by default. “Hypertensive nephrosclerosis is often a diagnosis of exclusion,” Garimella noted. “Some patients labeled that way actually have APOL1-associated kidney disease, FSGS, or another primary kidney disorder.”

The reframing has clinical and psychological implications. Elevated blood pressure may in some cases be a consequence rather than a cause of kidney disease.

“Sometimes patients feel that explanation doesn’t fully make sense, especially if their hypertension hasn’t seemed severe,” Meliambro observed. “Recognizing that there may have been more going on can be validating rather than implying they did something wrong.”

The data on blood pressure management remain nuanced. Some studies show intensive blood pressure control does not necessarily slow progression in high-risk APOL1 carriers, while other data suggest a survival benefit with more intensive control compared with standard targets.

The introduction of a dedicated ICD code for APOL1-mediated kidney disease represents an important structural shift, enabling more precise diagnosis, counseling, and trial referral.

The Core Problem: Risk Without Prediction

While identifying APOL1 risk variants is now straightforward, predicting outcomes remains the central clinical challenge.

Carriers of two high-risk alleles face an estimated 15%–20% lifetime risk of kidney disease—meaning roughly 80% will never develop kidney failure.

“This represents a major knowledge gap,” Susztak explained. “If you receive a genotype result, you start asking: should I be doing something specific to prevent disease?”

Traditional risk models have not resolved this. Polygenic risk scores have failed to improve prediction in APOL1 high-risk individuals. Clinical risk scores based on eGFR, proteinuria, age, and sex perform well in established disease but are not clinically meaningful in preserved kidney function, she said.

“Some work has suggested that the G1/G1 genotype might be associated with a higher risk of decline in GFR and also a younger age of developing kidney disease,” Meliambro noted, adding that this requires further validation. High-risk genotype is still defined as any two risk alleles.

To address this gap, researchers turned to proteomics.

In a study of approximately 1,400 African American individuals from the Penn Medicine Biobank—many with preserved kidney function and no proteinuria at baseline—researchers analyzed roughly 7,700 circulating proteins.

Using machine learning, they identified nine proteins that, combined with clinical variables, formed the APOL1 Proteomic Risk Score (APRS), achieving a time-dependent AUC of 86.5%.

Individuals in the highest-risk quintile had approximately a 60% probability of progressing to dialysis or transplant over 10 years, while those in the lowest-risk quintile had less than a 1% risk. The score outperformed both the Kidney Failure Risk Equation and polygenic risk scores.

“Some of these proteins are related to tissue damage in the kidney that is not reflected in creatinine levels or urinary protein,” Susztak said. “For example, markers like MMP7 and matrix proteins may reflect fibrosis or injury that isn’t detected with standard tests.”

Others reflect inflammatory and endothelial pathways.

The score has been validated in external cohorts, including UK Biobank and NIH-supported data, but remains a research tool.

“We need to incorporate this biomarker into clinical trials and demonstrate that it is actionable,” she said. “Currently, we can treat the disease but not cure it.”

What APOL1 Biology Is Revealing About Early Kidney Injury

Beyond prediction, APOL1 research is reshaping understanding of early disease biology.

“In African American patients, we know the APOL1 gene is a high-risk gene for what we call APOL1-mediated glomerular disease, which is essentially like FSGS,” said He. “When this gene is highly expressed, it can cause podocyte injury through specific cellular pathways.”

“Some of these proteins are related to tissue damage in the kidney that is not reflected in creatinine levels or urinary proteins,” Susztak said.

“Other proteins are linked to inflammation. APOL1 is strongly regulated by inflammation, so individuals with higher inflammatory states may be at greater risk.”

“And there are a few proteins related to endothelial injury that we are still working to understand.”

Together, these findings suggest injury may precede traditional clinical markers such as proteinuria or eGFR decline.

From Biology to Therapy: Precision Medicine Takes Shape

Mechanistic insight has enabled targeted drug development.

“Based on that mechanism, therapies have been developed to block the pathways activated by APOL1,” He said. “These inhibitors have shown promising results in reducing proteinuria in phase 2 studies, with ongoing phase 3 trials.”

Inaxaplin directly targets APOL1 pore formation in podocytes.

“This is a very specific, targeted therapy that inhibits the pore-forming function of the APOL1 protein,” Meliambro said. “It represents a true example of precision medicine in nephrology.”

Other approaches include antisense oligonucleotides and anti-inflammatory strategies.

Despite therapeutic advances, management remains standard CKD care.

“A two-risk-variant APOL1 genotype raises concern for progressive disease,” Garimella explained. “But the treatment backbone remains standard CKD care.”

That includes RAAS blockade, SGLT2 inhibitors when appropriate, blood pressure control, statins, and avoidance of nephrotoxins.

“APOL1 testing is worth considering when the result can change follow-up, trial eligibility, transplant donor counseling, or future targeted-treatment decisions,” Campbell said. “But it should come with counseling, and it should never replace a full kidney-disease workup.”

“Awareness only matters if it changes decisions such as diagnosis, counseling, testing, referral, or follow-up,” Garimella said.

The ICD code for APOL1-mediated kidney disease may help translate awareness into action.

Barriers to Integration and Uneven Adoption

Despite availability of testing, adoption remains inconsistent.

“It’s not necessarily ordering the test—it’s interpreting and explaining the results,” Meliambro said.

Barriers include lack of guidelines, limited genetic counseling infrastructure, and patient concerns about privacy and discrimination.

Equity Will Define the Impact of Precision Medicine

“Equitable access would require more than drug approval,” Campbell said. “It would require payer coverage for testing, counseling, nephrology referral, and medication.”

“Otherwise, we risk repeating the same inequities,” he said. “Patients with better access get tested and treated, while underserved populations remain underdiagnosed.”

The decision to hold a major consensus meeting in Accra reflects the field’s shifting center of gravity.

“This is a rapidly evolving field,” Meliambro said. “There has been substantial research progress. But there are still many unresolved questions—especially around predicting disease progression and translating this knowledge into improved patient outcomes.”

“There is significant investment and enthusiasm,” she added. “Hopefully that will lead to meaningful breakthroughs in the near future.”

Campbell reports relevant disclosures with NIH, National Kidney Foundation. Garimella reports relevant disclosures with NIH. Meliambro reports no relevant disclosures identified. Susztak reports relevant disclosures with NIH. He reports no relevant disclosures identified.

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Vertex Pharmaceuticals Incorporated. Vertex advances inaxaplin (VX-147) into phase 3 portion of adaptive phase 2/3 clinical trial for the treatment of APOL1-mediated kidney disease. Press release. April 1, 2024. Accessed May 1, 2026. https://news.vrtx.com/news-releases/news-release-details/vertex-advances-inaxaplin-vx-147-phase-3-portion-adaptive-phase

Vertex Pharmaceuticals Incorporated. Vertex announces key advancements across kidney portfolio. Press release. September 25, 2025. Accessed May 1, 2026. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-key-advancements-across-kidney-portfolio

Maze Therapeutics. Maze Therapeutics doses first patient in phase 2 HORIZON clinical trial evaluating MZE829 as a potential treatment for APOL1 kidney disease. Press release. February 7, 2025. Accessed May 1, 2026. https://ir.mazetx.com/news-releases/news-release-details/maze-therapeutics-doses-first-patient-phase-2-horizon-clinical

Maze Therapeutics. Maze Therapeutics announces positive topline data from phase 2 HORIZON trial of MZE829. Press release. March 25, 2026. Accessed May 1, 2026. https://ir.mazetx.com/news-releases/news-release-details/maze-therapeutics-announces-positive-topline-data-phase-2

Articles

APOL1 G1/G2 variants, selected for trypanosome resistance, are prevalent in people with West/Central African ancestry and drive substantial CKD and FSGS risk, yet progression remains poorly predictable. Hypertensive nephrosclerosis frequently misclassifies underlying glomerular or interstitial disease, prompting calls for more precise workups and use of the new APOL1-mediated kidney disease ICD code. A nine-protein APOL1 Proteomic Risk Score stratifies 10-year kidney failure risk far better than existing models. Targeted APOL1 inhibitors (eg, inaxaplin) and other modalities are advancing, while equitable access to testing, counseling, and therapy lags.

APOL1 research is driving precision nephrology, but prediction gaps and equity challenges still limit clinical impact.