41 2 CISPLATIN-INDUCED ACUTE KIDNEY INJURY | PART ONE Discussion The present retrospective cohort study shows that 69% of patients with LA-SCCHN developed AKI stage 1 or higher during treatment with high-dose cisplatin-based CRT, according to the KDIGO definition and staging criteria. Almost 30% of patients experienced 2 of more AKI episodes. The majority of AKI episodes (83%) was stage 1 according to KDIGO criteria; only 6% was AKI stage 3. Predictive risk factors for cisplatin-induced AKI included hypertension and uncontrolled CINV. Long-term impairment of renal function was observed in both AKI and non-AKI patients. However, renal function was significantly worse at three and twelve months in patients with AKI during CRT. DFS and DSM were comparable between AKI and non-AKI patients. Cisplatin-induced AKI has been reported to occur in 1% to 46% of patients treated with high-dose cisplatin, depending on the described grade of nephrotoxicity, and the used AKI definition and staging system [5,8,10,16]. Previous studies often used the adverse events criteria for chemotherapy, Common Toxicity Criteria for Adverse Events (CTCAE). In early versions of CTCAE (version 2.0 and 3.0), grading of renal insufficiency was based solely on the x-fold increase of the sCr level with respect to the Upper Limits of Normal (ULN). CTCAE v2.0 and 3.0 have different cutoff values for renal insufficiency than KDIGO, and no provision of a time course, which complicate direct comparisons of AKI incidence and outcome. CTCAE version 4.0 (v4.0) was the first to define AKI as sCr exceeding 26.5 µmol/l. Cutoff values for AKI grade 1 to 3 in CTCAE v4.0 resemble those according to KDIGO. However, in contrast to KDIGO, there is no provision of a time course in CTCAE v4.0. In previous trials using CTCAE criteria, AKI grade 1 and 2 were seldomly reported; only AKI grade 3 (sCr >3 x baseline or 354 µmol/l; hospitalization indicated) and grade 4 (life-threatening consequences; dialysis indicated) were reported. Consequently, the high incidence rate of AKI in the present study compared to previous studies is explained by the identification of low stage AKI by using the KDIGO system. KDIGO builds upon two earlier AKI classification systems: the Acute Kidney Injury Network (AKIN) and the Risk, Injury, Failure, Loss, End-Stage (RIFLE) criteria. Compared against AKIN and RIFLE, the incidence of AKI according to KDIGO is the highest due to the addition of an absolute increase criterion (≥0.3 mg/dl over 48 hours) to the RIFLE definition and expansion of the time limit for percentage increase (≥ 50%) in the AKIN definition from 48 hours to 7 days [17]. Therefore, AKI will be more frequently diagnosed at an early stage, if KDIGO is applied. Standard approach to prevent cisplatin-induced nephrotoxicity is the administration of intravenous (iv) isotonic saline (≥3 L/day) to induced diuresis during cisplatin administration. However, the optimal hydration solution and regimen to prevent nephrotoxicity associatedwith cisplatin administration is unclear. There are no randomized trials that have compared different regimens and/or types of iv fluids. In this study, all patients received 5 L/day of iv isotonic saline according to protocol. Forced diuresis with mannitol is frequently used, although there is no evidence that this is required. There is also concern that mannitol may over-diurese some patients, resulting in dehydration [18]. Therefore, mannitol was not used in this study. There is insufficient evidence to support using furosemide for forced diuresis, unless there is evidence of fluid overload,
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