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

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2024 · $289,468

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10869872
- **Project number:** 5R01DK128208-04
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** David Alan Drew
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $289,468
- **Award type:** 5
- **Project period:** 2021-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869872

## Citation

> US National Institutes of Health, RePORTER application 10869872, The Relation of Soluble Klotho with Cardiovascular Disease, Chronic Kidney Disease Progression, and Blood Pressure in the Systolic Blood Pressure Intervention Trial (5R01DK128208-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10869872. Licensed CC0.

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