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Background: Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI., Methods: A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function, and nephrotoxic exposure., Results: Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL) 2 /1000 predicted AKI with a sensitivity of 79% and specificity of 60%., Conclusion: Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: To determine if contrast-enhanced CT imaging performed in patients during their episode of AKI contributes to major adverse kidney events (MAKE)., Methods: A propensity score-matched analysis of 1127 patients with AKI defined by KDIGO criteria was done. Their mean age was 63 ± 16 years with 56% males. A total of 419 cases exposed to CT contrast peri-AKI were matched with 798 non-exposed controls for 14 covariates including comorbidities, acute illnesses, and initial AKI severity; outcomes including MAKE and renal recovery in hospital were compared using bivariate analysis and logistic regression. MAKE was a composite of mortality, renal replacement therapy, and doubling of serum creatinine on discharge over baseline; renal recovery was classified as early versus late based on a 7-day timeline from AKI onset to nadir creatinine or cessation of renal replacement therapy in survivors., Results: Sixty-two patients received cumulatively > 100 mL of CT contrast, 143 patients had > 50-100 mL, and 214 patients had 50 mL or less; MAKE occurred in 34%, 17%, and 21%, respectively, as compared with 20% in non-exposed controls (p = 0.008 for patients with > 100 mL contrast versus none). More contrast-exposed patients experienced late renal recovery (27% versus 20%) and longer hospital days (median 10 versus 8) than non-exposed patients (all p < 0.01). On multivariate analysis, cumulative CT contrast > 100 mL was independently associated with MAKE (odds ratio 2.39 versus non-contrast, adjusted for all confounders, p = 0.005); cumulative CT contrast under 100 mL was not associated with MAKE., Conclusions: High cumulative volume of CT contrast administered to patients with AKI is associated with worse short-term renal outcomes and delayed renal recovery., Key Points: • Cumulative intravenous iodinated contrast for CT imaging of more than 100 mL, during an episode of acute kidney injury, was independently associated with worse renal outcomes and less renal recovery. • These adverse outcomes including renal replacement therapy were not more frequent in similar patients who received cumulatively 100 mL or less of CT contrast, compared with non-exposed patients. • More patients with CT contrast exposure during acute kidney injury experienced delayed renal recovery.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major health problems. Urinary biomarkers have both diagnostic and prognostic utility in AKI and CKD. However, how biomarker excretion rates should be reported, especially whether they should be normalised to urinary creatinine concentration (uCr), is controversial. Some studies suggest that normalisation to uCr may be inappropriate at times, as urinary creatinine excretion rate may vary greatly, depending on the situation. Notably, recent studies suggest that while normalisation of values to UCr may be valid for the evaluation of CKD and prediction of AKI sequelae and occurrences, it could be inappropriate for the diagnosis of AKI, or in the presence of certain acute kidney disease states.

Objectives: The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD)., Patients and Methods: In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis., Results: The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI., Conclusions: In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury.

Background: Hypophosphatemia is common in critically ill patients and has been associated with generalized muscle weakness, ventilatory failure and myocardial dysfunction. Continuous renal replacement therapy causes phosphate depletion, particularly with prolonged and intensive therapy. In a prospective observational cohort of critically ill patients with acute kidney injury (AKI), we examined the incidence of hypophosphatemia during dialysis, associated risk factors and its relationship with prolonged respiratory failure and 28-day mortality., Methods: This is a single-center prospective observational study. Included in the study were 321 patients with AKI on continuous dialysis as initial treatment modality., Results: Four per cent of the patients had a phosphate level <2 mg/dL at initiation and 27% during dialysis. Low baseline phosphate was associated with older age, female gender, parenteral nutrition, vasopressor support, low calcium, and high urea, bilirubin and creatinine, whereas hypophosphatemia during dialysis correlated with the ischemic acute tubular necrosis etiology of renal failure, intensive dose and longer therapy. Serum phosphate decline during dialysis was associated with higher incidence of prolonged respiratory failure requiring tracheostomy [odds ratio (OR) = 1.81; 95% confidence interval (CI) = 1.07-3.08], but not 28-day mortality (OR = 1.16; 95% CI = 0.76-1.77) in multivariable analysis., Conclusions: Hypophosphatemia occurs frequently during dialysis, particularly with long and intensive treatment. Decline in serum phosphate levels during dialysis is associated with higher incidence of prolonged respiratory failure requiring tracheostomy, but not 28-day mortality.

Objective: Acid-base disorders are common in critically ill patients. Once continuous renal replacement therapy (CRRT) is initiated, it becomes a major determinant of acid-base status. We hypothesized that therapy-induced alkalemia and alkalosis is associated with increased mortality., Patients: The CCF-ARF Registry (1995-01) was used to identify 405 patients supported with bicarbonate based continuous hemodialysis. Proportion of days with an elevated pH to the number of days with normal pH was used to assess the association of alkalemia and the number of days with alkalemia, and mortality. Multivariable analyses were used to adjust for days with acidosis, and other relevant covariates., Main Results: Serum bicarbonate and pH levels plateau after 48 hrs of CRRT. Study subjects had on average 1.5 +/- 2.9 days where pH was greater than 7.45, and .4 days where serum bicarbonate level was greater than 28 mmol/L, during a median of 9 days of CRRT. Daily dialysis dose was inversely associated with the number of days with a low serum bicarbonate level, but was not associated with increased frequency of an elevated pH or serum bicarbonate level. Increasing proportion of days with elevated pH or serum bicarbonate was not associated with increased mortality in multivariable analysis., Conclusions: Alkalemia and alkalosis occur frequently during CRRT, but they are not associated with increased mortality. Persistent acidosis and acidemia while on CRRT was a strong predictor of poor outcome.

Background: In 1995, we described the technique of adapting a haemodialysis (HD) machine to produce a composition-adjustable, bicarbonate-based fluid (as our primary source for dialysate) for continuous HD in intensive care unit (ICU) patients with acute renal failure (ARF). The following studies the clinical effects, biochemical changes and economic costs of this practice in a large cohort of patients at a single centre over the last 10 years., Methods: The CCF-ARF Support Registry (1995-2001) was used to identify 405 patients initially supported with bicarbonate continuous HD. The registry is a prospective, observational cohort database that captures demographic, dialysis therapy, laboratory and outcome data. All supported ARF patients were recorded from 1995-98, and then one in five patients from 1999 to 2001. We also reviewed records of the individual dialysis procedures, dialysate disposal, dialysate monitoring tests and specific costs., Results: Continuous HD was performed for 1292 +/- 587 days from 1994 to 2004. Demographics [age 59.57 +/- 14.41 years, weight 84.2 +/- 24 kg, male 65%, chronic kidney disease (CKD) 34%] and ICU mortality (60.5%) were comparable to other reported series. Day 4 solute [BUN 52.3 mg/dl (95% CI 49.6-54.9), creatinine 2.79 mg/dl (95% CI 2.64-2.95)], electrolyte and acid-base balance [bicarbonate 24.12 mmol/l (95% CI 23.7-24.6)] were well controlled. Dialysate monitoring revealed no positive cultures or elevated endotoxin levels. Variable-composition dialysate was achieved and delivered to all patients without adverse consequences. The cost of dialysate actually declined over time (1995 = $0.91/l, 2005 = $0.67/l)., Conclusion: We have demonstrated that ICU ARF patients can be safely, effectively and economically supported with continuous HD using this source.