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Prophylactic renal denervation for the prevention of tacrolimus nephrotoxicity

Award Number: K08DK143336
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Prophylactic renal denervation for the prevention of tacrolimus nephrotoxicity - Project Summary This project is designed to train Alex Dayton, MD, PhD and to help him transition into an independent career as a physician-scientist studying kidney disease. Tacrolimus (tac) is the most widely used immunosuppressive medication after solid organ transplantation. Tac usage is complicated by the development of chronic kidney disease (CKD), which develops in over 50% of non-renal solid organ transplant patients. This CKD can cause devastating consequences in these patients, leading to shortened lifespans, increased hospitalization, and even the need for dialysis or kidney transplantation. Previous studies have shown that tacrolimus can activate the renal nerves, but no study has evaluated the effect of the removal of the renal nerves (renal denervation, RDN) on the development of tac nephrotoxicity. This is particularly of interest at this time because RDN has recently been approved for clinical practice. The central hypothesis of this proposal is that prophylactic RDN is protective against the development of tac nephrotoxicity. Our laboratory has generated compelling preliminary data that suggests that RDN is protective against the development of tac nephrotoxicity in rats. We show that rats who receive RDN prior to tacrolimus treatment have increased GFR relative to sham controls and also have decreased kidney fibrosis relative to shams. Furthermore, even when only one kidney undergoes RDN within a rat, that RDN kidney demonstrates improved GFR, indicating that the protective mechanism underlying RDN is at least partially kidney-specific and not a consequence of circulating hormones or cardiovascular parameters. This grant will evaluate the mechanisms responsible for RDN’s protective effects against tac nephrotoxicity in two specific aims. In specific aim 1, we will evaluate a whole-animal model of tac nephrotoxicity and will perform a thorough investigation of renal physiology, renal cortical transcriptome, including single-cell transcriptome, and cardiovascular parameters in rats subjected to either RDN or sham and treated with tac or vehicle. In specific aim 2 we will take advantage of the powerful ability to perform RDN on only one kidney in the rat, while leaving the nerves to the other kidney intact. By using this method, we will take a detailed look at the intrinsic renal pathways underlying RDN’s protective effect on tac nephrotoxicity, including assessments of GFR, renal transcriptome and renal metabolome. The impact of this grant is rapidly translatable to patients. RDN is an FDA-approved technology and the detailed physiological insights gained in this grant will pave the way for a new treatment paradigm in solid- organ transplant recipients: by RDN at the time of transplant we may prevent the development of the devastating disease of tac nephrotoxicity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $176,028 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/13/2026	NEW	$176,028
														Subtotal = $176,028

Grand Total All Awards = $176,028

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Prophylactic renal denervation for the prevention of tacrolimus nephrotoxicity

Award Number: K08DK143336

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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