Cardiorenal Risk Stratification Pilot Study

The CDC reports that approximately 5.7 million adults in the U.S. have heart failure (HF),
and NHANES reports that 26% of individuals 60 years-of-age and older have Chronic Kidney
Disease. NHANES also reports that End-Stage Kidney Disease (ESKD) accounts for $40 billion in
Medicare and Non-Medicare costs in 2009; 37% of those patients had a prior episode of HF.
These figures demonstrate that the treatment of patients with HF and ESKD costs Americans
almost $15 billion annually. A meta-analysis of 16 studies estimates that 63% of HF patients
have some kidney impairment; a serum creatinine (Cr)>1.0mg/dL or Glomerular Filtration Rate
(GFR)<90 ml/min. Among HF patients with even mildly decreased GFR, mortality increases
significantly; those with none, any, and at least moderate CKD experienced a 24%, 38% and 51%
1-year mortality, respectively. In 2015, 66,713 patients were seen at our hospital. About 3%
of those patients had a new diagnosis of CHF and at least 30% of those patients diagnosed
with CHF had a dual diagnosis of CKD. This population alone accounted for 79,835 of visits in
the same year. It is evident that there are both fiscal and ethical incentives, both locally
and nationally, to understand how to mitigate disease progression in this population.

Current classification schemes for patients with HF and chronic kidney disease (CKD),
cardiorenal syndrome, do not significantly alter management other than managing HF or CKD
independently with respect to their individual severity. In CKD, worsening renal function
often leads to poor phosphate (PO4) regulation where hyperphosphatemia is significantly
associated as a predictor of mortality. Further characterizations of the factors that
contribute to hyperphosphatemia implicates Fibroblast Growth Factor 23 (FGF-23) as a major
hormone regulator of PO4 levels in the body. FGF-23 has repeatedly demonstrated its use as an
independent predictor of mortality in ESKD as well as an independent predictor of worsening
renal function in non-diabetic patients with mild CKD. FGF-23 achieves PO4 level control by
downregulating PO4 reabsorption via transporters in kidney's proximal tubules as well as the
small intestines through an incompletely understood mechanism. This action allows the
increased filtration of PO4 without proximal tubule reabsorption as well as indirectly
decreased uptake of dietary PO4. In ESKD, the PO4-lowering effects of FGF-23 diminish despite
rising FGF-23 levels; this indicates that pathologic hyperphosphatemia represents a
decompensated state of PO4 regulation. There are studies that suggest FGF-23 is not only
implicated in the worsening of CKD, but the pleiotropic effects of FGF-23 remain to be
understood as a factor in cardiovascular disease. Increased FGF-23 levels have been
associated with left ventricular dysfunction and atrial fibrillation as well as worsening
CKD. In one study, not a single patient with Group 5 CKD had an FGF-23 level lower than
40.2ρg/dL, and more than 70% of those patients had and FGF-23 level greater than 66.1ρg/dL.14
Despite this information, it is not currently known how FGF-23 may be used as a predictor of
mortality or progression of CKD in patients with cardiorenal syndrome prior to end-stage
renal disease. Significant results from this study may provide a predictable classification
scheme based on FGF-23 levels that may be employed in future studies to guide treatment
evaluation. The prospect of treatment to reduce morbidity and mortality is supported by
studies demonstrating that PO4 binders lower FGF-23 levels, even in healthy volunteers. The
study proposed here is an early step in evaluating options to reduce the number of patients
that progress to ESRD with a parallel step towards a reduction in significant healthcare
costs. Participants in this study will only be observed after they have granted their
informed consent. There are no significant potential risks posed by this study as blood
collected would be from routine lab vials for the participant population. If the study has
significant findings, there are immediate benefits to the population studied and the greater
society.

Participants after this study will be equipped with more knowledge to help them understand
their risk factors and help them make better decisions about their own healthcare. The
investigators hope to achieve a better understanding of what levels of FGF-23 are
significantly associated with morbidity and mortality in patients with CHF and CKD. This
information can help us answer how current clinicians may better stratify the risks of CHF
and CKD; translating theoretical disease predictions into a preventative medicine model. The
answer to this question may lay the foundation for treatment and prevention option studies
based on FGF-23 levels in patients that are not currently on hemodialysis.

We hypothesize (1) that in participants with congestive heart failure and chronic kidney
disease who are not on hemodialysis, worsening heart disease or worsening kidney disease is
associated with a significantly elevated FGF-23 serum level AND (2) participants with
congestive heart failure and chronic kidney disease who are not on hemodialysis, decreased
survival is associated with a significantly elevated FGF-23 serum level.

Inclusion Criteria:

- Patients must have a diagnosis of congestive heart failure

Exclusion Criteria:

- Patients cannot be on hemodialysis at the study onset.

- Patients cannot have hyperphosphatemia defined as persistent serum phosphorus
level>4.5mg/dL at study onset.

- Patients cannot be part of another study for the investigational treatment of heart
failure or chronic kidney disease.