Plasmatic Klotho and FGF23 Levels as Biomarkers of CKD-Associated Cardiac Disease in Type 2 Diabetic Patients

Abstract

Background: Research over the past decade has focused on the role of Klotho as a cardio protective agent that prevents the effects of aging on the heart and reduces the burden of cardiovascular disease CVD. The role of the interaction between fibroblast growth factor 23-(FGF-23)/Klotho in Klotho-mediated actions is still under debate. The main objective was to ascertain the potential use of plasmatic Klotho and FGF23 as markers for CKD-associated cardiac disease and mortality. Methods: This was a prospective analysis conducted in an outpatient diabetic nephropathy clinic, enrolling 107 diabetic patients with stage 2–3 CKD. Patients were divided into three groups according to their left ventricular mass index and relative wall thickness. Results: Multinomial regression analysis demonstrated that low Klotho and higher FGF-23 levels were linked to a greater risk of concentric hypertrophy. In the generalized linear model (GLM), Klotho, FGF-23 and cardiac geometry groups were statistically significant as independent variables of cardiovascular hospitalization (p = 0.007). According to the Cox regression model, fatal cardiovascular events were associated with the following cardiac geometric classifications; eccentric hypertrophy (p = 0.050); concentric hypertrophy (p = 0.041), and serum phosphate ≥ 3.6 mg/dL (p = 0.025), FGF-23 ≥ 168 (p = 0.0149), α-klotho < 313 (p = 0.044). Conclusions: In our population, Klotho and FGF23 are associated with cardiovascular risk in the early stages of CKD.

Gla-Rich Protein (GRP) as an Early and Novel Marker of Vascular Calcification and Kidney Dysfunction in Diabetic Patients with CKD: A Pilot Cross-Sectional Study

“…Diabetes classification was based on the guidelines from the American Diabetes Association [25]. The exclusion criteria were: Age > 65 years; previous CVD as described [26]; changes in the GFR >30% (last 3 months); changes in antihypertensive therapy (last 2 weeks), uncontrolled hypertension (BP ≥ 140/90 mmHg); albumin/creatinine ratio (ACR) ≥ 500 mg/g (assessed twice in 3 months); eGFR ≤ 15 mL/min/1.73 m 2 or ≥ 90 mL/min/1.73 m 2 ; parathyroid hormone (PTH) ≥ 350 pg/mL; phosphate (P) > 5.5 mg/dL; patients on anticoagulant therapies; type 1 diabetes; non-diabetic renal disease; neoplastic or infectious diseases. Demographic, clinical, laboratory results and medication data were collected from the clinical records.…”

“…Fasting blood samples were drawn from all subjects and plasma/serum was frozen at -80 ºC in order to measure eGFR, P, calcium (Ca), PTH, glycated hemoglobin (HbA1c), interleukin 6 (IL-6), fibroblast growth factor 23 (FGF-23) and soluble α-Klotho, as described [26,27]. Serum levels of GRP were determined using a recently developed sandwich ELISA assay for the quantification of total GRP protein forms [24].…”

“…Blinded measurements of GRP levels were performed at GenoGla Diagnostics, University of Algarve, Faro, Portugal. ACR was determined as described [26].…”

New Potential Biomarkers for Chronic Kidney Disease Management—A Review of the Literature

“…In CKD patients, decreased klotho levels were also associated with increased albumin excretion [33], higher risk of CVD [34], mortality [35], and CKD related inflammation [36]. Moreover, klotho has a pathophysiological role in ion disorders, and might be used as a marker of abnormal phosphate and bone metabolism in these patients.…”

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

“…Most of the studies investigating the association of FGF23 and mortality in CKD patients analyzed the presence of cardiac hypertrophy, known to be very common in CKD, and activation of the renin-angiotensin-aldosterone (RAAS) system. In patients with diabetic nephropathy and early CKD (stages 2 and 3), lower plasmatic Klotho and higher FGF23 levels were associated with a higher risk of concentric hypertrophy, and, thus, higher cardiovascular hospitalization [97]. It was shown that FGF23 stimulates the renin-angiotensin system by suppressing the expression of angiotensin-converting enzyme-2 (ACE2) in the kidney [98].…”