1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

2Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

2Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

Find articles by Wolf, M. in: JCI | PubMed | Google Scholar |

Published in Volume 135, Issue 8 on April 15, 2025
J Clin Invest. 2025;135(8):e191585. https://doi.org/10.1172/JCI191585.
© 2025 Fuchs et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

The authors reply: Prior to the development of contemporary tools to modify gene expression at specific times and in specific organs, kidney cross-transplantation was used to isolate the effects of the kidneys versus other organs on the regulation of complex physiological systems (1, 2). In this technique, kidneys from mice with global deletion of a target gene would be transplanted into wild-type hosts, and wild-type kidneys would be transplanted into mice with global deletion of the target gene. Mechanistic inferences rested on determining whether the phenotype of interest followed the kidney or stayed with the host.

In their Letter to the Editor, Lemoine et al. report on a patient with longstanding, parathyroid hormone-independent hypercalcemia who received a kidney transplant from his healthy brother for treatment of end-stage kidney disease (ESKD) due to nephrocalcinosis of undiagnosed cause (3). Development of de novo posttransplant nephrolithiasis in the allograft suggested that the underlying disease was caused by systemic factors in the recipient rather than an intrinsic disease in the transplanted kidney. Subsequent genetic testing uncovered a homozygous inactivating mutation in CYP24A1 in the patient, but no mutation in the kidney donor.

Acknowledging the inability to control for potential confounding factors, this “real world kidney cross-transplant experiment” in which a CYP24A1+/+ kidney was transplanted into a CYP24A1–/– host broadly supports our finding that extrarenal Cyp24a1 exerts systemic effects independent of renal Cyp24a1 (4). The case report also raises important new questions. For example, the patient’s relatively elevated levels of 1,25-dihydroxy vitamin D during the posttransplant period contrast with our findings in mice with intestine-specific deletion of Cyp24a1, in which vitamin D levels remained normal. Since the patient lacked functional CYP24A1 in all his native cells other than his kidney allograft, this finding raises the possibility that other nonrenal, nonintestinal sources of CYP24A1 might contribute to circulating 1,25-dihydroxyvitamin D. Based on the welcome and important contribution by Lemoine et al., further studies are needed to understand other potential tissue-specific effects of Cyp24a1, including in the bone, parathyroid glands, and perhaps other organs.

Footnotes

Conflict of interest: MW has equity interests in Akebia, Unicycive, and Walden and has received income in the past year from Alexion, Enyo, Japan Torii Tobacco, Kissei, and Pharmacosmos.

Address correspondence to: Myles Wolf, MMSc, 525 East 68th Street, Room M-528, New York, New York 10065, USA. Phone: 212.746.4720; Email: myleswo@med.cornell.edu.

Reference information: J Clin Invest. 2025;135(8):e191585. https://doi.org/10.1172/JCI191585.

See the related letter at Clinical evidence for independent regulation of vitamin D by intestinal CYP24A1.

See the related article at Intestinal Cyp24a1 regulates vitamin D locally independent of systemic regulation by renal Cyp24a1 in mice.

ReferencesCrowley SD, et al. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci U S A. 2006;103(47):17985–17990. Nesbitt T, et al. Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest. 1992;89(5):1453–1459. Lemoine S, et al. Clinical evidence for independent regulation of vitamin D by intestinal CYP24A1. J Clin Invest. 2025;135(8):e190972. Fuchs MAA, et al. Intestinal Cyp24a1 regulates vitamin D locally independent of systemic regulation by renal Cyp24a1 in mice. J Clin Invest. 2024;135(4):e179882.