Snakebite associated thrombotic microangiopathy: a systematic review of clinical features, outcomes, and evidence for interventions including plasmapheresis

Abstract

Snakebite is a neglected tropical disease with significant morbidity and mortality. Thrombotic microangiopathy (TMA) is an important but poorly understood complication of snakebite associated with acute kidney injury (AKI). Numerous treatments have been attempted based on limited evidence. We conducted a systematic review of TMA following snakebite using a pre-determined case definition of blood film red cell schistocytes or histologically diagnosed TMA. The search strategy included major electronic databases and grey literature. We present a descriptive synthesis for the outcomes of AKI, dialysis free survival (DFS), other end-organ damage, overall survival, and interventions with antivenom and therapeutic plasmapheresis (TPE). This study was prospectively registered with PROSPERO (CRD42019121436). Seventy-two studies reporting 351 cases were included, predominantly small observational studies. Heterogeneity for study selection, design, reporting and outcomes were observed. The commonest envenoming species were hump-nosed vipers (Hypnale spp.), Russell's viper (Daboia russelii) and Australian brown snakes (Pseudechis spp.). The prevalence of TMA was at least 5.4% in proven and probable Hypnale bites, and 10-15% of Australian elapid envenomings, AKI occurred in 94% (293/312) of TMA cases, excluding case reports. The majority of cases with AKI required dialysis. Included prospective and retrospective cohort studies reporting interventions and renal outcomes showed no evidence for benefit from antivenom or TPE with respect to DFS in dialysis dependant AKI. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment for quality of accumulated evidence for interventions was low. The major complication of TMA following snakebite is AKI. AKI improves in most cases. We found no evidence to support benefit from antivenom in snakebite associated TMA, but antivenom remains the standard of care for snake envenoming. There was no evidence for benefit of TPE in snakebite associated TMA, so TPE cannot be recommended. The quality of accumulated evidence was low, highlighting a need for high quality larger studies.

Fig 1. Study selection PRISMA study flow diagram derived from Moher D et al [29].

Fig 2. Risk of bias of included studies.

Reviewer judgements about each risk of bias item presented as percentages across all included studies using the Murad et al risk of bias tool [33]. AKI: acute kidney injury; DFS: dialysis free survival.

Fig 3

Study data for (A) dialysis dependant AKI (D-AKI) versus non-dialysis dependant AKI (non-D AKI); (B) dialysis free survival (DFS) for cases with dialysis dependant AKI; and (C) overall survival for all TMA cases for studies with low risk of selection bias. ESKD: End stage kidney disease.

Fig 4

Dialysis free survival for plasmapheresis (TPE) versus non-TPE treated cases for studies with low risk of selection bias: (A) total number of cases; and (B) odds ratio of dialysis free survival (DFS) for TPE vs non-TPE. p>0.05 for all calculated odds ratios. ESKD: End stage kidney disease.