Introduction: Maladaptive hypertrophy and podocyte stress and depletion contribute to kidney function decline. Although IGF-1 plays a key role in early hypertrophic responses in the single kidney state, its impact on 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 (n=14) and binephric donors (n=18) were compared to assess intrarenal cellular expression of IGF1, IGF1R, and 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 eQTL rs35767. First-year biopsy results revealed no increase in intrarenal IGF1 transcript, while GHR and IGF- 1R 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 novel role for the GH-IGF-1 axis in reducing KTx survival.

ASN and RCW disclose a filed patent application for strategies to extend kidney lifespan by reducing kidney exposure to GH/IGF-1 signaling.

JAB: JAB acknowledges support from the NIH (grants K08 DK125776).PH: PH acknowledges support from the NIH (U01 AI 063594).MCM: MCM acknowledges support from the NIH (grants R01DK122164, R01DK132274 and R21AI178705) and the Department of Defense Awards (Awarding Office: USAMRAA under HT94252310454, HT94252310441). MK: MK is partially supported for this work through the George M. OBrien Michigan Kidney National Resource Center, which is funded by NIH/NIDDK grant U54DK137314 and the previous grant, the University of Michigan O'Brien Kidney Translational Core Center P30 DK081943. RCW: RCW acknowledges prior support from NIH grants R01 DK46073 and R01 DK102643 and the University of Michigan OBrien Kidney Translational Core Center P30 DK081943. ASN: ASN acknowledges support of Intramural grants from the University of Michigan O'Brien Kidney Translational Core Center P30 DK081943, First Pathway Award, Michigan Institute of Clinical Health Research UL1TR002240, Startup funds from the Department of Internal Medicine; Taubman Institute and an extramural grant from the National Institute of Health K23 DK 12552925

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