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Effect of Alkali Therapy on Vascular and Graft Function in Kidney Transplant Recipients

Award Number: R01DK130255
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Effect of Alkali Therapy on Vascular and Graft Function in Kidney Transplant Recipients - PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients (KTRs) and death from CVD is the leading cause of graft loss. KTRs demonstrate abnormal endothelium-dependent dilation (EDD) and large artery stiffness, key pathophysiological antecedents to the development of CVD. Acid retention is a common feature of patients who have received a kidney transplant. KTRs have a single kidney and a decreased number of nephrons leading to an inability to excrete the daily dietary acid load. Additionally, KTRs receive several medications that can result in acid retention including calcineurin inhibitors. Acid retention results in increased ammoniagenesis leading to activation of the alternative complement pathway. Activation of the alternative complement pathway increases inflammatory factors, collagen deposition and endothelial inflammation contributing to tubulointerstitial damage and vascular dysfunction. We show that complement activation fragments are increased in KTRs compared to healthy controls and are inversely correlated with eGFR and EDD. Lower serum bicarbonate levels, even within the normal laboratory range, in KTRs are associated with an increased risk of graft loss, cardiovascular events and mortality. Small interventional trials have shown that treatment with alkali therapy slows progression of kidney disease, even in patients with normal serum bicarbonate levels. In our preliminary data, alkali therapy improved vascular endothelial function in 20 patients with chronic kidney disease stage 3-4. Because acid retention is common in KTRs, it is plausible that alkali therapy in KTRs may also result in improved vascular and graft function. In our preliminary data, we show in a randomized, double-blind, placebo-controlled crossover safety and feasibility study that sodium bicarbonate therapy is safe and feasible in KTRs and there is a trend towards improved EDD. We are proposing a randomized, double-blinded, placebo-controlled, 12 month study in 120 KTRs to examine the effect of sodium bicarbonate therapy on surrogate markers of CVD and graft function. Our overall hypothesis is that treatment with bicarbonate will improve indicators of vascular and graft function in KTRs by decreasing complement activation. In Aim 1, we will compare changes over time in brachial artery flow- mediated dilation and arterial stiffness, measured by aortic pulse wave velocity, before and after 12 months of sodium bicarbonate therapy or placebo. In Aim 2, we will compare changes over time in tubular atrophy and interstitial fibrosis in kidney biopsies before and after 12 months of sodium bicarbonate therapy or placebo. In Aim 3, we will examine changes in plasma and urine complement activation fragments (Ba and sC5b-9) and complement deposition in kidney tissue before and after 12 months of sodium bicarbonate therapy or placebo. The results of this novel study have the potential to inform clinical practice by providing the necessary evidence to establish sodium bicarbonate therapy as an inexpensive and easy to administer option for the treatment of vascular dysfunction and graft function in KTRs.


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: 2024 ( Subtotal = $511,651 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/17/2024	NON-COMPETING CONTINUATION	$511,651
														Subtotal = $511,651

Issue Date FY: 2023 ( Subtotal = $532,971 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/7/2023	NON-COMPETING CONTINUATION	$532,971
														Subtotal = $532,971

Issue Date FY: 2022 ( Subtotal = $569,623 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	8/15/2022	SUPPLEMENT FOR EXPANSION	-$78,000
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/23/2022	SUPPLEMENT FOR EXPANSION	$114,653
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/10/2022	NON-COMPETING CONTINUATION	$532,970
														Subtotal = $569,623

Issue Date FY: 2021 ( Subtotal = $532,560 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/18/2021	NEW	$532,560
														Subtotal = $532,560

Grand Total All Awards = $2,146,805

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Effect of Alkali Therapy on Vascular and Graft Function in Kidney Transplant Recipients

Award Number: R01DK130255

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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