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Kidney Tubular Damage and Dysfunction Identify a Novel Axis of Chronic Kidney Disease

Award Number: R01DK098234
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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PROJECT SUMMARY For over 50 years, clinicians have relied upon serum creatinine and albuminuria as the sole biomarkers to measure and monitor kidney health. These measures primarily mark the glomerular filtration rate (GFR) and glomerular damage, yet the kidney tubules are responsible for a myriad of functions critical to life, including toxin secretion, nutrient reabsorption, acid/base control, and immune defense. Currently, clinicians cannot evaluate tubule health except in rare instances when kidney biopsies are obtained. In our parent grant, R01DK098234, an ancillary study in the landmark Systolic Blood Pressure Intervention Trial (SPRINT), we found that non-invasive biomarkers that characterize health of the kidney tubules predict CKD progression and cardiovascular disease events, independent of creatinine, albuminuria, and other risk factors. We also made an important additional discovery that could challenge current paradigms, and will be a major focus of this renewal application. SPRINT found that while intensive blood pressure lowering reduced cardiovascular events and mortality, it also worsened serum creatinine. Yet, we found that participants in the intensive blood pressure lowering arm appeared to have reduced tubule injury. These findings indicate that rising serum creatinine levels in this setting typically reflect hemodynamic accommodation rather than intrinsic kidney injury; yet the concern for kidney damage in clinical care prevents many individuals from receiving life-extending, optimal hypertension treatment. Building on our successes in unlocking the prognostic potential of the kidney tubules in the parent grant, this renewal has the objective of building a Kidney Tubule Health Panel (KTHP) that can be applied to individual patients for eventual translation to clinical care. Our three major goals are: a) prediction of progressive CKD; b) prediction of cardiovascular disease; and c) differentiation of intrinsic tubule damage from benign hemodynamic accommodation within individuals who develop rising creatinine levels. To accomplish these prediction goals, we must explore several additional critical functions of the kidney tubules, including toxin secretion and ammonia production; and, we must explore more sensitive measures of kidney tubule injury, including biomarkers measured in blood as well as urine. We will evaluate, compare, and combine these new measures with existing measures from the parent award to identify a parsimonious set of measures that maximally achieves each of the afore-mentioned prediction goals, utilizing latent variable approaches to develop distinct and physiologically relevant axes of kidney tubule health that will comprise the KTHP. The KTHP will then be measured, evaluated and validated in the community-based Nord-TrØndelag Health (HUNT) Study and the Norwegian Kidney Biopsy Registry. This comprehensive work will allow us to advance the KTHP as a novel and useful clinical tool to improve prediction in CKD and to maximize adherence to life-saving therapies, moving beyond kidney measures that are exclusively glomerular focused.


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: 2023 ( Subtotal = $591,938 )
2023	2023	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/28/2023	NON-COMPETING CONTINUATION	$591,938
2023	2023	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	8/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $591,938

Issue Date FY: 2022 ( Subtotal = $576,792 )
2022	2022	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	8/12/2022	NON-COMPETING CONTINUATION	$576,792
														Subtotal = $576,792

Issue Date FY: 2021 ( Subtotal = $650,208 )
2021	2021	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/14/2021	NON-COMPETING CONTINUATION	$650,208
														Subtotal = $650,208

Issue Date FY: 2020 ( Subtotal = $664,281 )
2020	2020	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	6	8/7/2020	NON-COMPETING CONTINUATION	$664,281
2020	2019	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/23/2020	COMPETING CONTINUATION	$0
2020	2019	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	2/6/2020	COMPETING CONTINUATION	$327,864
2020	2017	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/6/2020	NON-COMPETING CONTINUATION	-$327,864
														Subtotal = $664,281

Issue Date FY: 2019 ( Subtotal = $644,112 )
2019	2019	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	9/19/2019	COMPETING CONTINUATION	$644,112
2019	2017	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/11/2018	NON-COMPETING CONTINUATION	$0
2019	2017	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	9/18/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $644,112

Issue Date FY: 2017 ( Subtotal = $570,855 )
2017	2017	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/15/2017	NON-COMPETING CONTINUATION	$57,085
2017	2017	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/25/2017	NON-COMPETING CONTINUATION	$513,770
														Subtotal = $570,855

Issue Date FY: 2016 ( Subtotal = $607,359 )
2016	2016	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/4/2016	NON-COMPETING CONTINUATION	$607,359
														Subtotal = $607,359

Issue Date FY: 2015 ( Subtotal = $608,653 )
2015	2015	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/11/2015	NON-COMPETING CONTINUATION	$608,653
														Subtotal = $608,653

Issue Date FY: 2014 ( Subtotal = $653,166 )
2014	2014	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/13/2013	NEW	$653,166
														Subtotal = $653,166

Grand Total All Awards = $5,567,364

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Kidney Tubular Damage and Dysfunction Identify a Novel Axis of Chronic Kidney Disease

Award Number: R01DK098234

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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