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 10

Diagrammatic illustration of the allograft IGF-1 exposure hypothesis for shorter KTx survival.

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Diagrammatic illustration of the allograft IGF-1 exposure hypothesis for...
The single kidney state sets the allograft up for increased IGF-1 exposure dependent on the donor kidney dose and, thereby, the extent of hyperfiltration. A higher IGF-1 exposure, with its potential diverse downstream consequences, is shown in yellow boxes. We hypothesize that in addition to its role in early glomerular hypertrophy and podocyte stress (11–13, 16), IGF-1 is likely to amplify the glomerular filtration rate by a nitric oxide–mediated vasodilatory response (3), with higher IGF-1 levels leading to a higher vasodilatory response. These data are also supported by the observations that an IGF-1R and nitric oxide inhibitor (3, 92, 93) can mitigate hyperfiltration. Furthermore, IGF-1 could promote fibroblast activation in KTx as it does in other model systems (94, 95), leading to the development of CAN purported to be a final common pathway of graft loss (96). In addition, IGF-1 is known to enhance immune activation, which was also supported in our analysis, where an increased risk of TCMR was observed. The insulin–insulin-like growth factor system (IIS) drives shorter lifespans in worms, flies, and mice. We speculate that similar IGF-1 signaling via IGF-1R may also accelerate senescence, which is reported in kidney allografts. As noted by our analysis, larger kidney doses reduce kidney exposure to hyperfiltered IGF-1, thereby relatively protecting the normal 2-kidney state from the downstream effects of high circulating IGF-1 levels under different conditions (e.g., during puberty and diseases associated with high IGF-1 levels, including acromegaly, pregnancy, and exogenous GH and IGF-1 treatments).