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Background and Aims Neprilysin inhibition (NEPi) combined with a renin-angiotensin system (RAS) blocker has been shown to play an important role among patients with heart failure (HF), whose main cause of inpatient admission is congestion, reducing effectively HF hospitalization and cardiovascular death. These benefits stem from NEPi being a natriuresis and diuresis factor while RAS, which activates subsequently, staying blocked. Thanks to this, sacubitril/valsartan is a promising tool targeting patients with chronic kidney disease (CKD) and HF, which frequently coexist and lead one to the other, challenging their management. There is evidence NEPi-RASb may be beneficial in this population but long-term outcome still lacks. The primary aim is to analyse potential improvement in HF and advanced CKD. Secondary, to evaluate the tolerability and safety profile in this population. Method A prospective observational study, conducted from October 2016 to December 2020. Twenty-five patients were included meeting the following criteria: diagnosis of HF plus reduced left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class of II-IV with indication of sacubitril/valsartan, and CKD stages 3-4. All of them were followed periodically by a Nephrologist at our Department. Results The male:women ratio was 4:21, with a mean age of 73.2 ± 5.9 years. All patients had diagnosed hypertension, 32% type 2 diabetes, and 92% dyslipidemia. By December 2020, seven patients had completed three-year follow-up, whereas 17 were followed successfully through one year of treatment. Six patients died during the study (50% due to cardiovascular event, none due to renal malfunction), another discontinued treatment due to hypotension, and no patient started renal replacement therapy. The median of the studied time of treatment was 31 months (IQR 23.5 - 35). Cardiac and renal characteristics are listed in Table 1. At first year a significant improvement in LVEF was found (p=0.018). Although it is observed a tendency to this enhancement at second and third years, statistical analysis was not significative, arguably because a limited sample. Nonetheless, the number of visits to the Emergency Department (ED) regarding congestion symptoms were significantly reduced at these periods. More interesting, kidney function improved at first year when comparing serum creatinine (p=0.043) and eGFR (p=0.008), and this improvement stays in the long term at second and third years (p=0.019, p=0.046 respectively). There were no significant changes in potassium nor in blood pressure, still urine protein excretion was significantly higher at third year (p=0.043), understandable possibly due to hyperfiltration mechanisms and diabetic nephropathy progression. Conclusion Sacubitril/valsartan showed a long-term improvement in cardiac and kidney function, explaining a reduction in the number of visits to ED due to congestion and eventually a better quality of life. Besides, the improvement in kidney function cannot be totally understood in the context of enhanced LVEF at first year as this effect fades with time. Future research should explore this line.

BACKGROUND AND AIMS Klotho is a transmembrane protein expressed mainly in distal tubular epithelial cells of the kidneys. Its gene expression and soluble form levels play a crucial role in the interaction of the aging-inflammation binomial and act as a co-receptor for the phosphaturic fibroblast growth factor 23 (FGF-23). Klotho deficiency, which is the norm in chronic kidney disease (CKD), has been reported as an independent risk factor for cardiovascular disease and subclinical atherosclerosis [1, 2]. This study investigates the evolution of Klotho and FGF-23 levels during the first 2 years after kidney transplantation and their variability depending on the glomerular filtration rate (GFR). METHOD Serum levels of Klotho and FGF-23 were determined in 42 patients right before kidney transplantation (KT) and at 3rd, 12th and 24th month after KT. The measurements were made by ELISA. The GFR of the kidney graft was performed by indirect methods (formula: MDRa and CKD-EPI) at each study visit. Variables were reported as mean ± SD, and a value of P < .05 was considered to be statistically significant for each test. RESULTS KT recipients were divided into two groups arbitrary: the first group with a GFR > 40 mL/min (n = 26) and the other one with a GFR ≤ 40 mL/min (n = 16). At the starting point, there was not found any statistical difference in Klotho and FGF-23 levels between groups (GFR > 40 mL/min: 462.65 ± 264.99 pg/mL and 786.84 ± 521.67 pg/mL, respectively; versus GFR ≤ 40 mL/min: 436.5 ± 189.33 and 779.02 ± 589.86). Those with better kidney function after KT significantly increased Klotho levels on 12th and 24th month of follow-up (baseline 462.65 ± 264.99 versus 12th month 561.96 ± 314.68 and 24th month 581.15 ± 350.10; P = .001), whereas KT recipients with a GFR ≤ 40 mL/min only proved an increase in Klotho levels at 12th month after a non-significant initial decrease at 3rd month (462 ± 204.91 versus 356.96 ± 177.07, respectively; P = .028). This trend was not confirmed at the 24th month (397.12 ± 182.05). Klotho levels were found significantly different at the 24th month between groups (P = .031). See Fig. 1. Figure 2 shows the changes in FGF-23 levels. There are significant differences in both groups from baseline to month 24. (P < .001 group GFR > 40 mL/min and P < .001 group GFR ≤ 40 mL/min). FGF-23 dropped significantly in both groups at the 3rd month (P = .018) and 12th months (P = .003). CONCLUSION Vascular disease and mineral metabolism malfunction are relevant abnormalities in patients with CKD as well as in KT recipients. This study shows that Klotho is increasingly produced after KT in those patients whose allografts achieve a better function. We failed to prove the same effect on those with a GFR < 40 mL/min. Nonetheless, FGF-23 production declines satisfactorily independently of GRF. These results suggest the promotion of cardiovascular health after KT, particularly in those with higher GFR. The clinical and prognostic value of these changes are yet to be determined.