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.