Marinobufagenin, Left Ventricular Hypertrophy and Residual Renal Function in Kidney Transplant Recipients

Abstract

Background: Left ventricular hypertrophy (LVH), which is a pervasive complication of end-stage kidney disease (ESKD), persists in some uremic individuals even after kidney transplantation (Ktx), contributing to worsening CV outcomes. Marinobufagenin (MBG), an endogenous steroid cardiotonic hormone endowed with natriuretic and vasoconstrictive properties, is an acknowledged trigger of uremic cardiomyopathy. However, its clinical significance in the setting of Ktx remains undefined. Methods: In a cohort of chronic Ktx recipients (n = 40), we assessed circulating MBG together with a thorough clinical and echocardiographic examination. Forty matched haemodialysis (HD) patients and thirty healthy subjects served as controls for MBG measurements. Patients were then prospectively followed up to 12 months and the occurrence of an established cardio-renal endpoint (death, CV events, renal events, graft rejection) was recorded. Results: Median MBG plasma levels were lower in Ktx as compared with HD patients (p = 0.02), but higher as compared with healthy controls (p = 0.0005). Urinary sodium (β = 0.423; p = 0.01) and eGFR (β = −0.324; p = 0.02) were the sole independent predictors of MBG in this cohort, while a strong correlation with left ventricular mass index (LVMi), found in univariate analyses (R = 0.543; p = 0.0007), gained significance only in multivariate models not including eGFR. Logistic regression analyses indicated MBG as a significant predictor of the combined endpoint (OR 2.38 [1.10–5.12] per each 1 nmoL/L increase; p = 0.01), as well as eGFR, LVMi, serum phosphate and proteinuria. Conclusions: Ktx recipients display altered MBG levels which are influenced by sodium balance, renal impairment and the severity of LVH. Thus, MBG might represent an important missing link between reduced graft function and pathological cardiac remodelling and may hold important prognostic value for improving cardio-renal risk assessment.

Urinary Marinobufagenin in Patients with Non-Advanced Chronic Kidney Disease: A Cross-Sectional Study

“…MBG is freely filtered into urine, but the excretion mechanism, overall clearance and peripheral metabolism could be largely affected by the presence of a kidney impairment. Increased blood MBG levels have already been reported in anuric individuals undergoing chronic dialysis treatment [ 6 , 7 , 16 ], while in kidney transplant recipients with partially impaired renal function, higher blood MBG levels were inversely related to residual eGFR and predicted adverse renal outcomes [ 9 ]. By the same token, the blood MBG levels were increased in another small CKD cohort [ 17 ], while in hypertensive individuals with conserved renal function, higher MBG levels were associated with a more rapid eGFR decline over time [ 18 ].…”

“…The kidney plays a key role in maintaining systemic MBG balance by regulating urinary excretion [ 3 ]. Hence, not surprisingly, MBG accumulates in the blood of anuric individuals necessitating chronic dialysis [ 6 , 7 , 8 ], while in kidney transplant recipients, higher circulating MBG levels be associated with the severity of the graft function impairment [ 9 ].…”

Chronic kidney disease associated cardiomyopathy: recent advances and future perspectives

“…Other promising biomarkers for CKD-associated cardiomyopathy include the pro-fibrotic TGF-β family member, growth differentiation factor-15 (GDF-15), FGF-23 and soluble klotho [66,72], and osteoprotegerin [73]. Recent reports in dialysis [74] and transplant [75] patients show a correlation between the cardiotonic steroid, marinobufagenin and echocardiographic findings that reflect uremic cardiomyopathy. Several miRNAs have also been implicated in the pathophysiology of CKD-associated cardiomyopathy [76–78].…”

New Insights on the Role of Marinobufagenin from Bench to Bedside in Cardiovascular and Kidney Diseases

“…In a recent study, kidney transplant recipients displayed altered MBG levels, which were influenced by sodium balance, renal impairment and the severity of LVH. Thus, MBG might also represent an important missing link between reduced graft function and pathological cardiac remodeling and may hold important prognostic value for improving cardio-renal risk assessment [ 100 ].…”

“…Increased concentrations of circulating MBG (as a result of sodium loading or via infusion pump) caused several effects: vascular [ 24 , 59 ] and microcirculation [ 103 ] alterations, pressor changes [ 4 , 46 , 104 , 105 ] and cardiac and renal [ 8 , 9 , 58 , 61 , 91 ] fibrosis. Investigations in humans have shown elevated MBG plasma levels in many pathological conditions: heart failure [ 8 ], acute myocardial infarction (elevated urinary MBG levels) [ 106 ], primary aldosteronism [ 107 ], renal ischemia [ 108 ] and CKD [ 100 , 109 ].…”