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 8

Single-cell transcriptomic analysis of IGF pathway transcripts in kidney cells derived from normal kidney biopsies obtained before transplantation.

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Single-cell transcriptomic analysis of IGF pathway transcripts in kidney...
Data are sourced from a previously reported dataset, wherein the criteria for cell identification are detailed (46). The number of cells available for analysis for each cell type is displayed to the right of each panel. The cell types are listed alphabetically from top to bottom (definitions below). For each transcript, the dot size represents the proportion of cells within the cell type that expressed detectable transcripts, while the dot color’s intensity reflects the average amount of transcript detected across all cells. The dot size and intensity calibration are shown at the lower right of each panel. The panels display transcripts for insulin-like growth factor 1 (IGF1), IGF-1 receptor (IGF1R), growth hormone receptor (GHR), insulin-like growth factor-2 (IGF2), insulin receptor (INSR), and IGF binding proteins 1–6 (IGFBP1–6). Cell designations are as follows: ATL, ascending thin limb; BCells, B cells; CNT, connecting tubule; DC, dendritic cells; DCT, distal convoluted tubule; DTL, descending thin limb; EC1, arteriolar endothelial cells; EC2, glomerular endothelial cells; EC3, peritubular capillaries; FIB, fibroblasts; IC1/2, intercalated cells 1 and 2; MAC, macrophages; MC, mesangial cells; MON, monocytes; NKC, natural killer cells; NKT, natural killer T cells; PC1/2, principal cells cluster 1 and 2; POD, podocytes; PT/DTL, proximal tubule/descending thin limb; PT1/2/3, proximal tubule subclusters 1, 2, and 3; T-ACT, activated T cells; TAL1/2, thick ascending limb subcluster 1 or 2; TCells, T cells; tDCT_CNT, transitional cells of DCT with CNT; tPC_IC, transitional principal and intercalated cells; tDAL_DCT, transitional cells between TAL and DCT; vSMC, vascular smooth muscle cells.