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

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.

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How to Educate Dermatology Patients on Colorism Issues, With Seemal Desai, MD, and Pearl Grimes, MD

 in partnership with the Skin of Color Society (SOCS), dermatologists Seemal R. Desai, MD, and Pearl Grimes, MD, expanded their discussion on colorism and pigmentary disorders by focusing on patient education, dangerous skin-lightening practices, and the broader advocacy efforts needed to address the global harms associated with skin bleaching.

Desai emphasized that open and detailed communication with patients is critical when evaluating pigmentary concerns in clinical practice. He explained that dermatologists must go beyond simply asking whether patients are using treatments for pigmentation and instead ask specifically about moisturizers, serums, brightening creams, and products purchased online or abroad. According to Desai, many harmful products marketed as beauty or fairness creams may contain potent topical steroids, high-dose hydroquinone, arsenic, or mercury without patients fully understanding the risks involved.

He noted that unsafe skin-lightening practices remain widespread in several parts of the world, particularly in Southeast Asia and West Africa. Desai referenced reports of severe systemic toxicity and even deaths related to chronic exposure to mercury- and arsenic-containing bleaching products, highlighting recent research he coauthored in the Journal of the American Academy of Dermatology examining these concerns.

Grimes agreed that careful product review has become an essential part of patient care. She described routinely asking patients to bring products into the office or pull ingredient lists up on their phones during visits to better understand what they are using. According to Grimes, this level of investigation is often necessary because many patients may unknowingly apply harmful agents as part of daily skin care routines influenced by societal pressures surrounding skin tone.

The discussion also turned to the growing popularity of glutathione-based skin-lightening therapies, particularly intravenous glutathione infusions marketed by clinics in the US and abroad. Grimes warned that these treatments are far from benign, citing reports in the medical literature linking IV glutathione “cocktails” to severe adverse events including anaphylaxis and Stevens-Johnson syndrome. She additionally described a recent patient case in which prolonged use of high-dose oral glutathione was suspected of contributing to severe, widespread vitiligo.

Both physicians stressed that combating colorism requires coordinated advocacy efforts involving clinicians, regulatory agencies, and professional organizations. Desai pointed to collaborations involving groups such as the American Academy of Dermatology, the Global Vitiligo Foundation, and the International League of Dermatological Societies aimed at increasing awareness of the medical and psychological harms tied to skin bleaching practices.

Grimes concluded by emphasizing the importance of helping patients appreciate their natural skin tone and identity while working to dismantle the longstanding societal stigmas that continue to fuel colorism worldwide.

Editor’s note: This description was summarized with the help of AI tools.

Desai S, Grimes P. Skin of Color Savvy: Tackling Colorism in Dermatology, With Seemal Desai, MD, and Pearl Grimes, MD. HCPLive. March 24, 2026. Accessed May 13, 2026. 

https://www.hcplive.com/view/skin-of-color-savvy-tackling-colorism-dermatology-seemal-desai-md-pearl-grimes-md

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They discuss the importance of setting clear expectations with patients, particularly the goal of achieving and maintaining complete skin clearance. The faculty emphasize that patients typically seek the most effective therapy available and expect sustained results, reinforcing the need to align treatment strategies with these expectations. They also highlighted practical tools, such as routine assessment of body surface area (BSA) and Investigator’s Global Assessment (IGA), are efficient ways to monitor progress and prompt treatment reassessment when targets are not met. These measures can also streamline clinical workflows and support performance metrics. The panelists conclude by encouraging clinicians to become familiar with a core set of biologic therapies and to confidently communicate their benefits to patients with psoriasis.

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Experts explain managing psoriasis biologic failures: reassess response, use topicals, and switch smarter to reach near‑clear skin.

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Patient-Level Treatment Drivers — Route of Administration, Psoriatic Arthritis, and Comorbidity Considerations 

Strober examines how patient preference for oral versus injectable therapy and the presence and pattern of psoriatic arthritis.

Effective psoriasis management increasingly depends on a treatment selection framework that extends beyond skin severity scores to encompass the full clinical and contextual profile of the individual patient. Route of administration is among the most practically influential of these factors. Many patients express an instinctive preference for oral medications, but that preference is rarely absolute and often shifts when the clinical conversation addresses the full picture of treatment burden — including how often injections actually occur at maintenance and how that compares with the commitment of daily oral dosing. For patients who prioritize the fewest possible interactions with a therapy once disease is controlled, the every-12-weeks maintenance schedule of an IL-23 biologic may ultimately be more acceptable than a once-daily oral pill. The clinician's role is to surface these preferences explicitly rather than assume them, and to provide the comparative context patients need to make an informed choice.

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In this segment of the video discussion on psoriasis treatment selection, Bruce Strober, MD, PhD, Clinical Professor of Dermatology at Yale University School of Medicine, describes the practical algorithm he applies at the point of prescribing. IL-23 inhibitors occupy a favored default position in his treatment approach for most patients with skin-predominant disease: they offer infrequent maintenance dosing, an essentially unrestricted comorbidity profile outside of active infection, and long-term durability data that compare favorably with other biologic classes. IL-17 inhibitors are reserved primarily for patients with significant psoriatic arthritis — particularly those with axial involvement — where the evidence for superior joint outcomes justifies accepting the more restrictive contraindication profile. Icotrokinra and other oral agents are positioned for patients who prioritize the oral route and can accept a somewhat lower efficacy ceiling than the most potent injectable biologics. This mechanism-first framework, calibrated by comorbidity and arthritis pattern before patient preference is layered on top, reflects the current complexity of psoriasis care and the degree to which therapeutic selection has evolved from a simple stepwise escalation into a nuanced, multidimensional clinical decision.

Oral therapies offer convenience, but biologics deliver faster, stronger results; experts weigh psoriatic arthritis, dosing schedules, safety profiles, and IL-17 vs IL-23 choices.

Managing Treatment Failure in Psoriasis

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They discuss the value of maintaining open communication with patients, particularly when evaluating treatment success. Even when clinical improvement is observed, patient perception of disease control remains critical in guiding next steps. The panelists highlight that some patients may be satisfied with partial improvement, while others may seek more complete clearance, reinforcing the need for shared decision-making.

The panelists explore strategies for managing suboptimal response include optimizing current therapy with adjunctive treatments, switching within the same biologic class, or transitioning to a different mechanism of action. They also introduce the concept of multi-biologic failure, where patients experience diminishing responses across multiple therapies. They raise the question of whether initiating treatment with the most effective therapy upfront may improve long-term outcomes and reduce the risk of treatment resistance. The faculty emphasize a proactive and flexible approach to treatment optimization, with the goal of achieving sustained disease control.

The next episode in this series, ‘Implementing Remission Goals in Psoriasis Practice,’ features the panelists highlighting practical approaches to implementing remission-focused care in psoriasis, emphasizing that achieving and maintaining clear skin is an attainable goal. It reinforces the importance of setting expectations, using simple assessment tools, and confidently selecting effective therapies to optimize patient outcomes.

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