Mechanisms Underlying Early Rapid Increases in Creatinine in Paraquat Poisoning

Abstract

BackgroundAcute kidney injury (AKI) is common after severe paraquat poisoning and usually heralds a fatal outcome. The rapid large increases in serum creatinine (Cr) exceed that which can be explained by creatinine kinetics based on loss of glomerular filtration rate (GFR).Methods and FindingsThis prospective multi-centre study compared the kinetics of two surrogate markers of GFR, serum creatinine and serum cystatin C (CysC), following paraquat poisoning to understand and assess renal functional loss after paraquat poisoning. Sixty-six acute paraquat poisoning patients admitted to medical units of five hospitals were included. Relative changes in creatinine and CysC were monitored in serial blood and urine samples, and influences of non-renal factors were also studied.ResultsForty-eight of 66 patients developed AKI (AKIN criteria), with 37 (56%) developing moderate to severe AKI (AKIN stage 2 or 3). The 37 patients showed rapid increases in creatinine of >100% within 24 hours, >200% within 48 hours and >300% by 72 hours and 17 of the 37 died. CysC concentration increased by 50% at 24 hours in the same 37 patients and then remained constant. The creatinine/CysC ratio increased 8 fold over 72 hours. There was a modest fall in urinary creatinine and serum/urine creatinine ratios and a moderate increase in urinary paraquat during first three days.ConclusionLoss of renal function contributes modestly to the large increases in creatinine following paraquat poisoning. The rapid rise in serum creatinine most probably represents increased production of creatine and creatinine to meet the energy demand following severe oxidative stress. Minor contributions include increased cyclisation of creatine to creatinine because of acidosis and competitive or non-competitive inhibition of creatinine secretion. Creatinine is not a good marker of renal functional loss after paraquat poisoning and renal injury should be evaluated using more specific biomarkers of renal injury.

Serum creatinine and cystatin C provide conflicting evidence of acute kidney injury following acute ingestion of potassium permanganate and oxalic acid

“…Creatine, creatol and methylguanidine act as a homeostatic antioxidant to reduce circulating free radicals [49]. Generation of free radicals leads to extra production of sCr [50,51] to meet the higher energy demand under oxidative stress as noted following several paraquat poisoning [3]. Therefore we propose that the observed rapid and large rise of sCr is contributed by increased production and conversion of creatine to creatinine.…”

“…Increased conversion of creatine to creatinine with acidosis may also make a minor contribution to the sCr rise [3,52].…”

“…All specimens were stored briefly at -20°C after immediate processing and then at -80°C. Urine creatinine and sCr (Jaffe method) were measured according to Biolabo S. hospital admission and three months post discharge was used as the baseline as used previously in similar cohort [3].…”

“…A similar phenomenon occurs independently of AKI in paraquat poisoning [3]. We explored the extent to which a rise in sCr in oxalic acid/KMnO4 poisoning should be attributed to AKI or other mechanisms.…”

Nephrotoxicity-induced proteinuria increases biomarker diagnostic thresholds in acute kidney injury

“…Furthermore, plasma creatinine concentrations usually respond only slowly to kidney damage and may be altered by non-renal mechanisms [11, 12]. Alternative strategies for defining AKI with kidney-specific structural (injury) biomarkers have been proposed which may diagnose AKI earlier and with greater specificity and sensitivity than creatinine [13–17].…”