Kidney Week

Abstract: SA-PO0290

Genome-Wide Association Study of Sepsis-Associated AKI

Session Information

• AKI: Epidemiology and Risk Factors
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 101 AKI: Epidemiology, Risk Factors, and Prevention

Authors

• Rajagopal, Madhumitha, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Madhumitha Rajagopal, MD, PhD

• Oh, Wonsuk, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Wonsuk Oh, PhD

• Jayaraman, Pushkala, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Pushkala Jayaraman, MS

• Fennessy, Brian, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Brian Fennessy, MSc

• Chan, Lili, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Lili Chan, MD, MS

• Nadkarni, Girish N., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Girish N. Nadkarni, MD, MPH

Background

Acute kidney injury, a complication in up to 50% of sepsis hospitalization, is associated with adverse clinical outcomes. Here, we performed a genome-wide association study (GWAS) to identify genetic variants predisposing individuals to sepsis-AKI (sAKI).

Methods

We analyzed whole genome sequences (WGS) available in the Mount Sinai Million (MSM) cohort from adult patients with sepsis hospitalizations in the Mount Sinai Health System (MSHS) between 2000 and 2023. Sepsis patients were defined by SOFA score > 2 and clinical suspicion of infection. AKI cases were defined by KDIGO criteria for serum creatinine increase. We compared AKI cases to non-AKI controls. Genetic predisposition to sAKI was assessed using three nested Firth regression models: Model 1 (age, sex, sequencing batch, top 10 PCs); Model 2 (Model 1 + comorbidity score); and Model 3 (Model 2 + baseline eGFR, SOFA score, BUN, albumin, and WBC). GWAS were conducted within ancestry classes and meta-analyzed using METAL software.

In WGS from 3,541 patients (mean age 66±15 years; 51% female; 31% White, 23% Black, 31% Hispanic), 3223 (1,742 cases, 1481 controls) passed genomic quality control. Compared to controls, cases were older with higher Elixhauser Comorbidity Index (ECI), higher admission BUN, and lower baseline eGFR.

Results

No variants reached genome-wide significance (P<5x10^-8), though several exceeded the suggestive threshold (P < 5 x 10^-6). Notably, STK32C variants (rs547893031, rs186386582) were enriched across all three models. Inclusion of admission covariates in Model 3 strengthened associations, yielding more implicated loci, primarily: MTNR1A (melatonin receptor 1A), COL14A1 (Collagen XIV alpha 1 chain) and KCNJ6(Potassium Inwardly Rectifying Channel in the Kir family)

Conclusion

STK32C, an upstream regulator of AKT1/mTOR pathway, plays a role in both protection during ischemia reperfusion injury and renal fibrosis. Melatonin acts via MTNR1A to preserve renal function during injury. Col14A1 is upregulated in myofibroblasts during kidney injury. While KCNJ6 is not directly tied to AKI, other Kir family potassium channels play a role in exacerbating tubular injury. Our study did not replicate results from prior studies. This likely reflects the complex polygenic architecture and gene-environment interactions that are prevalent in sAKI. Validation in larger cohorts will be required to confirm these findings and elucidate genetic basis of sAKI.

Funding

• NIDDK Support