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

Abstract

BackgroundParaquat ingestion is frequently fatal. While biomarkers of kidney damage increase during paraquat-induced acute kidney injury (AKI), significant concurrent proteinuria may alter diagnostic thresholds for diagnosis and prognosis to an unknown extent. This study evaluated the effect of albuminuria on biomarker cutoffs for diagnosis and outcome prediction.MethodsThis was a multi-centre prospective clinical study of patients following acute paraquat self-poisoning in 5 Sri Lankan hospitals. Biomarker concentrations were quantified using ELISA and microbead assays and correlated with urinary albumin. Functional-AKI was defined by the Acute Kidney Injury Network serum creatinine definition and alternatively by a ≥50% increase in serum cystatin C. Albuminuria was defined as albumin-creatinine ratio >30 mg/g. The study outcomes were compared with a retrospective analysis of a pre-clinical study of paraquat-induced nephrotoxicity with appropriate controls.ResultsAlbuminuria was detected in 34 of 50 patients, and increased with functional-AKI severity. The concentrations of uNGAL, uCysC, uClusterin, uβ2M, and uKIM-1 were higher in albuminuric compared to non-albuminuric patients (p < 0.001). Albuminuria correlated with biomarker concentration (r > 0.6, p < 0.01) and was associated with death (p = 0.006). Optimal biomarker cutoffs for prediction of death were higher in the albuminuric group. Similar outcomes with more detailed analysis were obtained in experimental paraquat nephrotoxicity.ConclusionAlbuminuria was associated with paraquat-induced nephrotoxicity and increased excretion of low-molecular weight protein biomarkers. AKI biomarker cutoffs for diagnosis, outcome prediction and AKI stratification increased in the presence of albuminuria. This may lead to over-diagnosis of AKI in conditions independently associated with proteinuria.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-017-0532-7) contains supplementary material, which is available to authorized users.

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“…However, paraquat has been shown to exert significant toxic effects on several organs including kidneys [68]. Particularly, renal damage mediated by paraquat exposure has been observed in diverse farming communities and the renal damage is reflected through urinary excretion of renal injury biomarkers [69][70][71].…”

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“…Urine CLU is increased in acute kidney injury in both human patients of different ages [55,56] and rats [57] in experimental models, where it performs best in the acute injury phase. More importantly, in these studies urine CLU outperformed urinary albumin as a marker of kidney injury.…”

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“…These were significantly higher in albuminuric patients as compared to non-albuminuric patients. 40 These injury biomarkers were elevated within 24 hours after ingestion of PQ as compared to patients without AKI and healthy controls. This could be applied to guide early intervention for rescuing renal damage within 16-24 hours.…”

“…Albuminuria was used to evaluate the kidney function and effects on biomarker cutoffs for diagnosis and outcome prediction in PQ-intoxicated patients. 40 Albuminuria was indicated in 34 out of 50 patients and urinary neutrophil gelatinaseassociated lipocalin (uNGAL), urinary cystatin C (uCysC), uClusterin, Urine β-2 microglobulin (Uβ2M), and urinary kidney injury molecule-1 (uKIM-1) levels, as markers to diagnose functional AKI. These were significantly higher in albuminuric patients as compared to non-albuminuric patients.…”

“…41 Albuminuria was correlated to PQ-induced nephrotoxicity and causes death. 40 Nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome activation regulated by pro-inflammatory cytokine NF-κB and deathassociated protein kinase (DAPK) were molecular mechanisms that have been associated with PQ-induced AKI. 23 Therefore, proteinuria could be used in the prediction of PQ-induced nephrotoxicity.…”