Serial Quantification of Urinary Protein Biomarkers to Predict Drug-induced Acute Kidney Injury

Abstract

Background: : Drug-induced Acute Kidney Injury (AKI) develops in 10-15% of patients who receive nephrotoxic medications. Urinary biomarkers of renal tubular dysfunction may detect nephrotoxicity early and predict AKI. Methods:: We prospectively studied patients who received aminoglycosides, vancomycin, amphotericin, or calcineurin inhibitors, and collected their serial urine while on therapy. Patients who developed drug-induced AKI (fulfilling KDIGO criteria) were matched with non-AKI controls in a 1:2 ratio. Their urine samples were batch-analyzed at time-intervals leading up to AKI onset; the latter benchmarked against the final day of nephrotoxic therapy in non- AKI controls. Biomarkers examined include clusterin, beta-2-microglobulin, KIM1, MCP1, cystatin-C, trefoil-factor- 3, NGAL, interleukin-18, GST-Pi, calbindin, and osteopontin; biomarkers were normalized with corresponding urine creatinine. Results:: Nine of 84 (11%) patients developed drug-induced AKI. Biomarkers from 7 AKI cases with pre-AKI samples were compared with those from 14 non-AKI controls. Corresponding mean ages were 55(±17) and 52(±16) years; baseline eGFR were 99(±21) and 101(±24) mL/min/1.73m2 (all p=NS). Most biomarker levels peaked before the onset of AKI. Median levels of 5 biomarkers were significantly higher in AKI cases than controls at 1-3 days before AKI onset (all µg/mmol): clusterin [58(8-411) versus 7(3-17)], beta-2-microglobulin [1632(913-3823) versus 253(61-791)], KIM1 [0.16(0.13-0.76) versus 0.07(0.05-0.15)], MCP1 [0.40(0.16-1.90) versus 0.07(0.04-0.17)], and cystatin-C [33(27-2990) versus 11(7-19)], all p<0.05; their AUROC for AKI prediction were >0.80 (confidence intervals >0.50), with average accuracy highest for clusterin (86%), followed by beta-2-microglobulin, cystatin-C, MCP1, and KIM1 (57%) after cross-validation. Conclusion: : Serial surveillance of these biomarkers could improve the lead time for nephrotoxicity detection by days.

Acute kidney injury following the concurrent administration of antipseudomonal β-lactams and vancomycin: a network meta-analysis

“…However, the renal safety of combining the above treatments with vancomycin is unknown to date, and remain to be elucidated. Finally, future research should focus on the predictive ability of novel serum and urinary biomarkers of renal toxicity, such as cystatin-c, neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, aiming to achieve detection of subclinical AKI and offer timely measures to prevent antibiotic-induced nephrotoxicity in high-risk patients [105,106].…”

Clusterin as a New Marker of Kidney Injury in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation—A Pilot Study

“…Such presumption would provide the explanation for increasing levels in both serum and urine as a response to systemic and kidney stress conditions. Moreover, clusterin has turned out the most accurate marker predicting drug-induced AKI in adults, better than cystatin C or KIM-1 [ 25 ]. Interestingly, all three markers became higher compared to non-AKI controls already 1–3 days before the onset of AKI.…”

Nephrotoxicity Biomarkers: Role and Significance in the Diagnosis of Drug-Induced Kidney Injury

“…Кластерин был использован в качестве биомаркера при диагностике ЛПП в исследовании по сравнению профиля безопасности ванкомицина и комбинации ванкомицина с препаратом пиперацилин+тазобактам у крыс [66]. В проспективном клиническом исследовании с участием пациентов, получавших терапию препаратами с известным нефротоксическим действием (ванкомицин, ингибитомы кальциневрина, аминогликозиды), наибольшую прогностическую ценность при диагностике ОПП показал кластерин, затем -β2-микроглобулин, цистатин С, MCP-1 и KIM-1 [67].…”