The growth hormone/IGF-1 axis is a risk factor for long-term kidney allograft failure
Matthew Cusick, Viji Nair, Damian Fermin, John Hartman, Jeffrey A. Beamish, Zeguo Sun, Zhongyang Zhang, Edgar Otto, Rajasree Menon, Sudha Nadimidla, Nicholas Demchuk, Kelly Shaffer, Peter Heeger, Weija Zhang, Madhav C. Menon, Matthias Kretzler, Roger C. Wiggins, Abhijit S. Naik
Matthew Cusick, Viji Nair, Damian Fermin, John Hartman, Jeffrey A. Beamish, Zeguo Sun, Zhongyang Zhang, Edgar Otto, Rajasree Menon, Sudha Nadimidla, Nicholas Demchuk, Kelly Shaffer, Peter Heeger, Weija Zhang, Madhav C. Menon, Matthias Kretzler, Roger C. Wiggins, Abhijit S. Naik
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Clinical Research and Public Health Nephrology Therapeutics

The growth hormone/IGF-1 axis is a risk factor for long-term kidney allograft failure

Abstract

INTRODUCTION Maladaptive hypertrophy, podocyte stress, and depletion contribute to kidney function decline. Although insulin-like growth factor 1 (IGF-1) plays a key role in early hypertrophic responses in the single kidney state, its impact on kidney transplant (KTx) outcomes remains uncertain. This report tests the hypothesis that early IGF-1 exposure reduces KTx survival. METHODS Population datasets compared incident death-censored graft failure (DCGF) rates by age at KTx (n = 366,404) with IGF-1 levels by age (n = 15,014). A clinical study of 216 KTx recipients evaluated the association of IGF-1 exposure with DCGF and secondary outcomes of proteinuria and biopsy-proven acute rejection. IGF-1 exposure was modeled using pre-KTx IGF-1 levels and donor kidney dose estimated from the donor/recipient body surface area ratio reflecting allograft hyperfiltration. The association of DCGF with an IGF1 SNP linked to high IGF-1 levels was assessed in 724 genotyped allograft recipients. Single-cell transcriptomic data from first-year post-KTx patients and binephric donors were compared to assess intrarenal cellular expression of IGF1, IGF1R, and growth hormone receptor (GHR) transcripts. RESULTS DCGF risk by age at KTx paralleled IGF-1 levels by age. Higher IGF-1 exposure was associated with significantly increased risks of DCGF, proteinuria, and T cell–mediated rejection. Genotypic analysis showed a 50% increase in DCGF risk per risk allele at IGF1 expression quantitative trait locus rs35767. First-year biopsy results revealed no increase in intrarenal IGF1 transcripts, while GHR and IGF1R transcripts were suppressed, consistent with circulating IGF-1 (vs. graft-derived IGF-1) being the primary source of IGF-1 exposure. CONCLUSION We identify a role for the growth hormone/IGF-1 axis in reducing KTx survival.

Authors

Matthew Cusick, Viji Nair, Damian Fermin, John Hartman, Jeffrey A. Beamish, Zeguo Sun, Zhongyang Zhang, Edgar Otto, Rajasree Menon, Sudha Nadimidla, Nicholas Demchuk, Kelly Shaffer, Peter Heeger, Weija Zhang, Madhav C. Menon, Matthias Kretzler, Roger C. Wiggins, Abhijit S. Naik

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Figure 6

Relationship between IGF-1 levels and outcomes of interest in relation to the estimated kidney dose (eKD) delivered to the recipient at transplantation (n = 216).

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Relationship between IGF-1 levels and outcomes of interest in relation t...
The survival curves to help visualize adjusted outcomes from the multivariable Cox regression model are generated for different IGF-1 values (90th, 50th, and 10th percentiles of the distribution in the clinical cohort) and eKD values (1st, 10th, 25th, 50th, 75th, 90th, and 99th percentiles corresponding to 0.25, 0.37, 0.42, 0.50, 0.56, 0.67, and 1.83 transplanted kidney equivalents). Mean centering was performed for the eKD variable to allow for interpretation of the direct effect of IGF-1 at the mean of eKD in our clinical cohort. For DCGF and proteinuria, the Cox regression models were adjusted for donor age, donor race, donor sex, donor type (living or deceased), donor body surface area, recipient age, recipient race, recipient sex, and cold ischemia time. For the TCMR (and separately for BPAR), adjustments were made for pretransplant calculated panel reactive antibodies class 1 or 2 and the number of previous transplants in addition to the above variables.