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 1

Approaches used to assess the relationship between IGF-1 levels at KTx and long-term allograft survival.

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Approaches used to assess the relationship between IGF-1 levels at KTx a...
Cohort 1: Population-level study. Population-level analysis compared death-censored graft failure (DCGF) rates and time to 50% graft loss among kidney transplant (KTx) recipients 0–60 years of age with IGF-1 levels by age derived from a reference study. Cohort 2: Clinical study. This analysis involved 216 consecutive KTx recipients 0–80 years of age. Pretransplant IGF-1 levels were measured and related to long-term outcomes using survival models. These models were adjusted for donor, recipient, and transplant characteristics, including an estimated kidney dose (eKD) derived from the donor-recipient body surface area ratio (see Results). Adjustments in the Cox survival model included primary outcomes (DCGF), secondary outcomes (proteinuria > 1 g/g), and a composite of alloimmune responses (acute rejection or de novo donor-specific antibody development). Cohort 3: Genotype study. For genetic level analysis, 2 NIH-sponsored studies linking genotype to outcomes in KTx recipients were employed to test the hypothesis that an IGF1 gene variant associated with high circulating IGF-1 levels correlates with long-term allograft survival. Cohort 4: Transcriptomic study. Our previously published cohort was utilized for transcriptome-level analysis to map IGF system transcript expression in single kidney cells derived from normal kidney allografts with no histologic abnormality in the first year after transplantation, compared to normal kidneys biopsied at the time of transplantation (46).