Kidney Week

Abstract: TH-OR118

Kidney Allografts with High Risk APOL1 Genotypes Have Worse Outcomes: Association with Decreased Podocyte Density

Session Information

• Transplantation: Top 10 Basic and Experimental Abstracts
  November 02, 2017 | Location: Room 295, Morial Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Transplantation

• 1701 Transplantation: Basic and Experimental

Authors

• Chen, Dhruti P., Case Western Reserve University, Cleveland, Ohio, United States

Dhruti P. Chen, MD



• Zaky, Ziad S., Cleveland Clinic, Cleveland, Ohio, United States

Ziad S. Zaky,

• Schold, Jesse D., Cleveland Clinic, Cleveland, Ohio, United States

Jesse D. Schold,

• Herlitz, Leal C., Cleveland Clinic, Cleveland, Ohio, United States

Leal C. Herlitz,

• El-Rifai, Rasha, None, Cleveland, Ohio, United States

Rasha El-Rifai,

• Drawz, Paul E., University of Minnesota, Minneapolis, Minnesota, United States

Paul E. Drawz,

• Bruggeman, Leslie A., None, Cleveland, Ohio, United States

Leslie A. Bruggeman,

• Sedor, John R., MetroHealth Medical Center, Cleveland, Ohio, United States

John R. Sedor,

• Poggio, Emilio D., Cleveland Clinic, Cleveland, Ohio, United States

Emilio D. Poggio,

• O'Toole, John F., Case Western Reserve University, Cleveland, Ohio, United States

John F. O'Toole,

Background

Variants in APOL1 gene (G1 or G2), which encodes apolipoprotein L1(APOL1), associate with non-diabetic kidney diseases in African Americans (AA) but the mechanisms driving this association remain unclear. Kidney diseases only develop in a subset of individuals with high risk APOL1 genotypes, consistent with a need for a “second hit” or stress to initiate disease. Mice transgenic for G2 have a podocyte depletion phenotype compared to wild-type mice or mice expressing the reference allele (G0). We hypothesized that variant APOL1 generates subclinical, prodromal podocyte injury that is a “first hit.”

Methods

A cohort of 107 AA kidney donors, living (LD) and deceased (DD), with available implant biopsy tissue and DNA were genotyped for APOL1 risk variants and evaluated for baseline kidney phenotypes, histology, and podocyte density in implant biopsies. Recipients were genotyped for APOL1 and outcomes collected, including graft loss and rate of eGFR decline.

Results

Donor demographic data and clinical phenotypes at graft implant were similar between high risk (HR, 2 risk variants, n=16) and low risk groups (LR, <2 risk variants, n=91). Glomerular volume was lower in HR group (2.58 um³X10⁶ vs. 3.13 um³X10⁶, p=0.03) of implant biopsies. Podocyte density was significantly less in HR compared to LR (108 ± 26 vs 127±40 podocytes/10⁶um³, p=0.03). Similarly, podocyte coverage of glomerular area was reduced in HR vs. LR donors (30% vs. 39%, p=0.05).

Recipients were 64% AA and 36% White or not specified;38% of AA recipients had HR APOL1. Recipients were followed for 48 months, and increased graft loss of HR donor was noted using a multivariate model (Hazard Ratio = 2.7; 95% CI, 0.9-7.8) and Kaplan Meier graft survival (HR 61% vs. LR 91%, log rank p-value=0.049). eGFR decline was also greater in recipients of HR APOL1 allografts with slope of overall decline statistically significant (p<0.001), eGFR(mL/min) at 60 months was 27 in HR vs. 51 in LR.

Conclusion

In living and deceased donors, outcomes of APOL1 HR allografts were significantly worse. Importantly, variant APOL1 generates subclinical, prodromal podocyte depletion, which only becomes clinically evident when subsequent stress supervenes and initiates progressive CKD in African Americans with APOL1 HR.

Funding

• Other NIH Support