Understanding the role of cell-free heme causing acute kidney injury following snakebite in India

Thesis

Snakebite is a neglected tropical disease and is estimated to cause 58 000 deaths/ year in India alone. Envenoming from Viperidae in India is characterized by venom induced consumption coagulopathy (VICC) and complications include rhabdomyolysis, microangiopathic haemolytic anaemia (MAHA) and acute kidney injury (AKI). The primary objective of this study was to determine whether protein porphyrin X-linked heme, a product of ferric-ferryl heme cycling in the kidney resulting in lipid peroxidation, was present in urine from patients with systemic haemotoxic snakebite envenoming.  

A prospective observational study of 24 participants with systemic haemotoxic envenoming and three healthy control participants was performed. Urine was analyzed using reverse phase High Performance Liquid Chromatography (HPLC) to separate organic compounds. Clinical outcomes and serum biomarkers of participants were recorded for one week. Ten participants developed AKI, of which six required renal replacement therapy. Severe rhabdomyolysis was observed in five participants and MAHA was observed in four. Sixteen participants (16/22, 72.7%) had urine chromatograms consistent with X-linked heme compared to none of the control participants. Quantitative measurement of X-linked heme using logarithmic transformation of area under curve (AUC) correlated with creatinine phosphokinase (CPK) (a biomarker of myotoxicity) and schistocyte count (a marker of MAHA) with a Spearman’s coefficients of 0.39, p= 0.07 and 0.37, p=0.07 respectively. The logarithmic AUC of X-linked heme was associated with a maximum serum creatinine with a Spearman’s coefficient of 0.66, p<0.01. 

The findings of X-linked heme in urine of patients with snakebite envenoming and clinical markers of haemolysis and or rhabdomyolysis support a hypothesis of oxidative heme-protein modification within the kidney. The correlation of X-linked heme with maximum serum creatinine may represent lipid peroxidation and oxidative nephropathy. Demonstration of this pathophysiological process in Viperidae envenoming in India raises opportunities to consider therapeutic interventions, such as haptoglobin, desferrioxamine or paracetamol, that inhibit ferric-ferryl heme redox cycling reaction in-vitro.

Authors: Lamb, T

• DOI: 10.5287/ora-wvnevzb7k
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: haemolysis; snakebite; oxidative nephropathy; AKI; rhabdomyolysis; heme-protein
• Subjects: Hemolysis and hemolysins; Snakebites; Tropical medicine