Kidney Week

Abstract: FR-OR060

The Issue Is Tissue: KPMP Research Biopsies Detect Severe Tubular Injury in Stable CKD

Session Information

• Pathology: Novel Mechanisms and Modalities
  November 07, 2025 | Location: Room 371A, Convention Center
  Abstract Time: 05:20 PM - 05:30 PM

Category: Pathology and Lab Medicine

• 1800 Pathology and Lab Medicine

Authors

• Schmidt, Insa Marie, Boston University, Boston, Massachusetts, United States

Insa Marie Schmidt, MD, MPH

• Schaub, Jennifer A., University of Michigan, Ann Arbor, Michigan, United States

Jennifer A. Schaub, MD

• Limonte, Christine P., University of Washington, Seattle, Washington, United States

Christine P. Limonte, MD

• Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States

Rajasree Menon, PhD

• Fallegger, Robin Demian, Universitat Heidelberg, Heidelberg, BW, Germany

Robin Demian Fallegger

• Parikh, Chirag R., Johns Hopkins University, Baltimore, Maryland, United States

Chirag R. Parikh, MD, PhD, FASN

• Alpers, Charles E., University of Washington, Seattle, Washington, United States

Charles E. Alpers, MD

• Barisoni, Laura, Duke University, Durham, North Carolina, United States

Laura Barisoni, MD

• Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States

Jeffrey B. Hodgin, MD, PhD

• Himmelfarb, Jonathan, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Jonathan Himmelfarb, MD, FASN

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

Group or Team Name

• For the Kidney Precision Medicine Project (KPMP).

Background

Tubular injury (TI) is a key histopathologic feature in kidney disease and may contribute to the progression of both acute kidney injury and chronic kidney disease (CKD). A comprehensive understanding of the clinical, histopathologic and molecular profiles of TI could improve risk assessment and guide the development of targeted therapies.

Methods

Leveraging histopathologic evaluation, RNA-sequencing, and plasma and urine biomarker data from the Kidney Precision Medicine Project (KPMP), we characterized the structural and molecular profiles in CKD patients with (n=132) and without TI (n=101). Differences in tubulointerstitial descriptors and molecular signatures were assessed using chi-squared tests and differential gene expression analysis, respectively. Linear regression models adjusted for age, sex, and eGFR evaluated associations between TI and 19 urine and 26 plasma biomarkers. Logistic regression was used to assess the incremental predictive value of individual biomarkers for assessing TI beyond clinical characteristics and kidney function.

Results

Among individuals with CKD, 42% had TI on biopsy. Tubulointerstitial descriptors that differed significantly between patients with and without TI included tubular simplification (p<0.001), vacuolization (p=0.007), tubulitis (p=0.020), and tubular dilatation (p<0.001). Single-cell RNA sequencing revealed enrichment of endoplasmic reticulum stress signaling in patients with TI, along with upregulation of gene signatures associated with CD8+ cytotoxic T cells and T helper cells. After multivariable adjustment, patients with TI had significantly higher levels of urine KIM-1 and MCP-1, as well as plasma KIM-1, sTNFR1 and 2, and VEGF-D (all p<0.05) (Figure 1A). ROC analysis demonstrated improved discrimination for TI with the addition of plasma or urine KIM-1 to the model (Figure 1B). Urine and plasma KIM-1 levels were also significantly higher in patients with tubular simplification, vacuolization, and tubulitis (all p<0.05) (Figure 1C).

Conclusion

These findings provide insights into the molecular landscape of TI in CKD, identifying potential biomarkers and pathobiological pathways that may enhance risk stratification and inform targeted therapies.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025dbggdn5n