Abstract
Introduction: Kallistatin, a serine protease inhibitor, has been implicated in cardiovascular and renal protection. This study investigates its association with clinical characteristics and outcomes in long-term kidney transplant recipients (KTRs). Methods: In this longitudinal observational cohort study, we enrolled 101 KTRs between September 2016 and October 2017. The median (IQR) time post-transplant was 52 (36-97) months, and the follow-up time was 83 (41-85) months. All patients had documented graft function of ≥24 months and no record of acute rejection or active or chronic infection at presentation. Serum kallistatin and high-sensitivity interleukin-6 (hsIL-6) were measured at baseline using commercially available enzyme-linked immunosorbent assays. A control group of 32 healthy volunteers was also recruited. Results: Higher serum kallistatin levels were observed in KTRs compared to healthy controls (15.9 vs. 13.8 µg/ml; P=0.007). Concentrations were lower in diabetic versus non-diabetic KTR (14.8 vs. 16.4 µg/ml; P=0.021). A significant interaction between diabetic status and BMI indicated a positive association with kallistatin levels only in diabetic KTRs (P=0.046). Linear mixed models assessing eGFR change over time showed improved fit after kallistatin was included in a base model with age, sex and baseline eGFR (χ²=5.089, P=0.020). Cox regression showed that higher kallistatin levels were associated with an increased risk of graft loss in diabetic patients (HR 1.120; P=0.049), but also independent of time after transplantation (HR 1.147; P=0.030). No association was observed for all-cause mortality. The best performance was estimated for kallistatin models adjusting for time post-transplant (c-index 0.779) and diabetic status (c-index 0.707). Conclusions: This study highlights the complex interactions between kallistatin, renal function and cardiometabolic status in stable, long-term KTRs. Higher kallistatin levels are associated with an increased risk of graft loss in non-diabetic patients, while showing a protective effect in diabetic patients. These findings support integrated management of cardio-reno-metabolic health in KTRs.
