Klotho Is Associated with Collagen Synthesis but Not Cardiovascular Functional Capacity in Patients on Hemodialysis

Background: Cardiac fibrosis is a major complication in advanced CKD patients on dialysis. Fibrogenesis of the heart wall contributes to impaired cardiac function and cardiovascular functional capacity (CVC). Experimental data suggests that the anti-aging protein, Klotho, can exert anti-fibrotic effects at the heart. However, the relationship between circulating Klotho with CV structure and function is still not well understood. Herein, we investigated the role of circulating Klotho with biomarkers of fibrogenesis and CV exercise-derived ventilatory endpoints in HD patients. Methods: We performed a cross-sectional study of n=35 participants (n=15 patients on thrice-weekly HD and n=20 healthy controls (CON)). All patients underwent cardiopulmonary exercise testing (CPET). Plasma procollagen type 1 C-terminal peptide (P1CP, Cloud-Clone Corp) and galectin-3 (Gal3, Quantikine), surrogate biomarkers of cardiac fibrosis, and Klotho (IBL-America) were measured via ELISAs. Group comparisons were conducted using t-tests or Mann–Whitney U tests, and inferential analysis by multiple regression. Results: HD and CON groups were age- (P=0.32) and sex-matched (P=0.21). HD patients had a higher proportion of Black participants, BMI, resting heart rate (HR, 77.2 ± 10.4 vs 63.5 ± 8.7 BPM), and mean arterial pressure (MAP, 106.0 ± 14.6 vs 96.7 ± 10.0 mmHg) compared to CON (all P<0.003). Klotho (355.0 [313.0; 483.0] vs 734.0 [623.0, 951.0] pg/mL) and P1CP (21.5 [20.7, 22.2] vs 24.7 [23.6, 25.8] ng/mL) were lower in HD than CON (all P<0.001). Conversely, Gal3 was elevated in HD versus CON (10.4 [10.3, 10.4] vs 9.2 [8.5, 9.8] pg/mL, P<0.001). HD group exhibited impaired VO2Peak (11.9 [10.7, 15.1] vs 29.4 [26.9, 36.4] mL/min/kg) and circulatory power (1707 [1513, 2222] vs 6350 [4881, 7469] mmHg*min/mL/kg, all P<0.001). Klotho was significantly associated with P1CP even after adjusting for age, sex, race, MAP, and HR (β(SE)=244.9(100.5), P=0.02) on multiple regression. However, Klotho was not associated with Gal3 (P=0.49), circulatory power (P=0.54), or CVC (P>0.2). Conclusion: Circulating Klotho may be a regulator of total myocardial collagen volume (as suggested by P1CP). Further studies are needed to define its therapeutic role in regulating CV function in HD patients. Funding: Private Foundation Support