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The Relation of Soluble Klotho with Cardiovascular Disease, Chronic Kidney Disease Progression, and Blood Pressure in the Systolic Blood Pressure Intervention Trial

Award Number: R01DK128208
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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The Relation of Soluble Klotho with Cardiovascular Disease, Chronic Kidney Disease Progression, and Blood Pressure in the Systolic Blood Pressure Intervention Trial - ABSTRACT Soluble α-klotho (“Klotho”) has systemic effects in maintenance of cell health including reduction of oxidative stress and fibrosis in the heart and kidney. Kidney tubules are the primary source of circulating (soluble) klotho and therefore the development of chronic kidney disease (CKD) results in klotho deficiency. Klotho deficiency may also paradoxically contribute to CKD progression. Rodent models of klotho deficiency display vulnerability to kidney injury and progression of kidney disease, while administration of exogenous klotho attenuates kidney damage and disease progression. Klotho deficiency may also contribute to excess cardiovascular disease (CVD) risk in CKD as klotho knockout mice display vascular calcification and pathological cardiac remodeling with cardiac hypertrophy and fibrosis. Further, blood pressure (BP) may influence klotho levels as preclinical data show that multiple models of hypertension all result in klotho deficiency. Thus far, the majority of clinical studies examining soluble klotho have relied primarily on a single commercial source of ELISA. There are concerns about the performance and reproducibility of this assay as the clinical data have been inconsistent. Some studies have reported no relationship or higher levels of soluble klotho with reduced kidney function, while others have shown a parallel decline in klotho and kidney function. This discrepancy has hindered widespread measurement of klotho in large-scale human studies and has led to a paucity of quality data examining the role of klotho in human CKD. Similarly, there are no longitudinal data on changes in klotho over time in CKD. In a pilot project using samples from the Systolic Blood Pressure Intervention Trial (SPRINT) we compared the most widely used commercial ELISA with an immunoprecipitation-immunoblot (IP-IB) assay, and found that the IP-IB assay exhibited superior performance. Subsequently, we hope to address the current lack of high quality human studies examining soluble klotho as a risk factor for CVD and CKD progression. SPRINT is the ideal cohort to answer these questions as the trial enrolled 2646 participants with CKD and has detailed CVD and kidney outcomes. This cohort is also well-suited to examine the patient-specific and disease-specific clinical factors that may impact longitudinal changes in soluble klotho including: the intensive vs. standard blood pressure control intervention, measures of mineral metabolism including FGF-23, and measures of kidney tubular injury/health. We propose to measure baseline serum and urine klotho concentrations in 2646 SPRINT participants with CKD at baseline as well as in a pre-specified subset of 1000 persons at year 1 and year 4 to: 1) compare the IP-IB assay with the commercial klotho ELISA; 2) determine the association of klotho with CVD events, death, and CKD progression; and 3) identify the clinical factors that influence longitudinal changes in klotho including intensive vs. standard BP control, markers of mineral metabolism and/or kidney tubular health. Such data can collectively set the stage for future klotho interventional trials, inform clinical risk- stratification models and provide a foundation for translational research in klotho biology and therapeutics.


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 = $289,468 )
2024	2024	TUFTS MEDICAL CENTER PARENT, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/21/2024	NON-COMPETING CONTINUATION	$289,468
														Subtotal = $289,468

Issue Date FY: 2023 ( Subtotal = $277,902 )
2023	2023	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/16/2023	NON-COMPETING CONTINUATION	$277,902
														Subtotal = $277,902

Issue Date FY: 2022 ( Subtotal = $298,859 )
2022	2022	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/6/2022	NON-COMPETING CONTINUATION	$298,859
2022	2021	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/26/2022	NEW	$0
														Subtotal = $298,859

Issue Date FY: 2021 ( Subtotal = $427,742 )
2021	2021	TUFTS MEDICAL CENTER, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/15/2021	NEW	$427,742
														Subtotal = $427,742

Grand Total All Awards = $1,293,971

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The Relation of Soluble Klotho with Cardiovascular Disease, Chronic Kidney Disease Progression, and Blood Pressure in the Systolic Blood Pressure Intervention Trial

Award Number: R01DK128208

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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