Acute Kidney Injury Induced by Bothrops Venom: Insights into the Pathogenic Mechanisms

Abstract

Acute kidney injury (AKI) following snakebite is common in developing countries and Bothrops genus is the main group of snakes in Latin America. To evaluate the pathogenic mechanisms associated with Bothrops venom nephrotoxicity, we assessed urinary and blood samples of patients after hospital admission resulting from Bothrops snakebite in a prospective cohort study in Northeast Brazil. Urinary and blood samples were evaluated during hospital stay in 63 consenting patients, divided into AKI and No-AKI groups according to the KDIGO criteria. The AKI group showed higher levels of urinary MCP-1 (Urinary monocyte chemotactic protein-1) (median 547.5 vs. 274.1 pg/mgCr; p = 0.02) and urinary NGAL (Neutrophil gelatinase-associated lipocalin) (median 21.28 vs. 12.73 ng/mgCr; p = 0.03). Risk factors for AKI included lower serum sodium and hemoglobin levels, proteinuria and aPTT (Activated Partial Thromboplastin Time) on admission and disclosed lower serum sodium (p = 0.01, OR = 0.73, 95% CI: 0.57–0.94) and aPTT (p = 0.031, OR = 26.27, 95% CI: 1.34–512.11) levels as independent factors associated with AKI. Proteinuria showed a positive correlation with uMCP-1 (r = 0.70, p < 0.0001) and uNGAL (r = 0.47, p = 0.001). FENa (Fractional Excretion of sodium) correlated with uMCP-1 (r = 0.47, P = 0.001) and uNGAL (r = 0.56, p < 0.0001). sCr (serum Creatinine) showed a better performance to predict AKI (AUC = 0.85) in comparison with new biomarkers. FEK showed fair accuracy in predicting AKI (AUC = 0.92). Coagulation abnormality was strongly associated with Bothrops venom-related AKI. Urinary NGAL and MCP-1 were good biomarkers in predicting AKI; however, sCr remained the best biomarker. FEK (Fractional Excretion of potassium) emerged as another diagnostic tool to predict early AKI. Positive correlations between uNGAL and uMCP-1 with proteinuria and FENa may signal glomerular and tubular injury. Defects in urinary concentrations highlighted asymptomatic abnormalities, which deserve further study.

Clinical assessment and pathophysiology of Bothrops venom-related acute kidney injury: a scoping review

“…Studies reported slight increase of creatine phosphokinase level in Bothrops envenoming [14,66]. The local muscle injury caused by Bothrops venom could contribute to AKI.…”

“…There are several epidemiological studies that describe AKI. However, only a few applied the AKI definition according to KDIGO, AKIN or RIFLE criteria [5,8,11,14,56,[67][68][69][70][71][72][73][74]. Data from retrospective series described a great variable in AKI incidence, 1.4 to 44.4% [5,8,11,56,[66][67][68][69][70][71][72][73][74].…”

“…The most important pathway in Bothrops venom-related acute kidney injury is probably coagulopathy. However, almost all included studies were cross-sectional and just three presented clear definition of acute kidney injury according to stages of KDIGO, AKIN or RIFLE [5,14,66]. These studies reported the abnormal activated partial thromboplastin time (aPTT), bleeding symptoms and abnormal LDH level which are factors associated with AKI development [5,14,66].…”

“…However, almost all included studies were cross-sectional and just three presented clear definition of acute kidney injury according to stages of KDIGO, AKIN or RIFLE [5,14,66]. These studies reported the abnormal activated partial thromboplastin time (aPTT), bleeding symptoms and abnormal LDH level which are factors associated with AKI development [5,14,66]. The increase of LDH levels was observed in recent case reports about thrombotic microangiopathy in Bothrops envenoming and expressed the high cellular turnover and necrosis following the increase of creatinine levels [90,91].…”

“…Hence, this review focuses on the pathogenesis of Bothrops venom-related AKI, highlighting current studies under a perspective of clinical application. According to the literature, the main pathogenic mechanism of Bothrops venom-induced AKI is attributed to coagulation abnormalities [14]. However, direct action of venom on kidney and its hemodynamic effects, myoglobinuria, hemoglobinuria and immunologic mechanisms may play a minor role as reported in experimental studies [15][16][17][18][19][20][21].…”