Stretching a Penny: Completing a Rapid Needs Assessment for a Nonprofit Community-Based Hospice Wellness Center in Ontario, Canada.

The literature pertaining to community-based hospice wellness centres, especially concerning program evaluation, is sparse. This article describes the development and implementation of a mixed-method, rapid needs assessment for a nonprofit community-based hospice wellness centre in Ontario, Canada. As part of the needs assessment, a survey and focus groups were performed to elicit responses from service users. Individuals registered for services and wellness centre attendees were asked about their needs, opinions, and preferences to help guide future program and service options. Findings and recommendations are presented for programming and service options, and implications for future program evaluation projects are discussed. The methodology of this time and cost-efficient evaluation provides insights that can be utilized by other hospice wellness centres facing similar challenges of time, money, and program evaluation expertise constraints. The findings and recommendations may inform program and service offerings at other Canadian hospice wellness centres.

Association of serum uromodulin with mortality and cardiovascular disease in the elderly-the Cardiovascular Health Study.

BACKGROUND: Uromodulin (UMOD) is released by renal tubular cells into the serum (sUMOD) and urine. Lower urine UMOD has been linked to mortality and cardiovascular disease but much less is known about sUMOD. We evaluated the association of sUMOD with these outcomes in community-dwelling older adults. METHODS: We measured sUMOD in a random subcohort of 933 participants enrolled in the Cardiovascular Health Study. The associations of sUMOD with all-cause mortality, incident heart failure (HF) and incident cardiovascular disease (CVD; myocardial infarction, stroke and mortality due to coronary disease or stroke) were evaluated using multivariable Cox regression, adjusting for study participants' demographics, estimated glomerular filtration rate (eGFR), albuminuria and CVD risk factors. Generalized additive models with splines were used to address the functional form of sUMOD with outcomes. Due to nonlinear associations of sUMOD with all outcomes, 2.5% of the values on either end of the sUMOD distribution were excluded from the analyses, limiting the range of sUMOD to 34.3-267.1 ng/mL. RESULTS: The mean age was 78 ± 5 years, 40% were male, sUMOD level was 127 ± 64 ng/mL, eGFR was 63 mL/min/1.73 m2 and 42% had CKD defined as eGFR <60 mL/min/1.73 m2. Patients in the lower sUMOD quartiles had lower eGFR and higher albuminuria (P < 0.01, respectively). During a median follow-up of 9.9 years, 805 patients died, 283 developed HF and 274 developed CVD. In multivariable analysis, higher sUMOD was significantly associated with a lower hazard for mortality {hazard ratio [HR] 0.89 [95% confidence interval (CI) 0.80-0.99] per 1 standard deviation (SD) higher sUMOD}, CVD [HR 0.80 (95% CI 0.67-0.96)] and the composite endpoint [HR 0.88 (95% CI 0.78-0.99)]; the association with HF was not statistically significant [HR 0.84 (95% CI 0.70-1.01)]. CONCLUSION: Higher sUMOD is independently associated with a lower risk for mortality and CVD in older adults.

Association of serum and urinary uromodulin and their correlates in older adults-The Cardiovascular Health Study.

Uromodulin is released into serum (sUMOD) and urine (uUMOD) exclusively by renal tubular cells. Both sUMOD and uUMOD are correlated with estimated glomerular filtration rate (eGFR), and associated with mortality and cardiovascular disease (CVD). However, no study to our knowledge has measured both sUMOD and uUMOD in the same population, thus the relationship of sUMOD with uUMOD with one another, and their respective correlates have not been evaluated simultaneously. We evaluated the correlations of sUMOD, uUMOD with eGFR in a random sub-cohort (n = 933) of the Cardiovascular Health Study and their associations with demographic and laboratory parameters and CVD risk factors using multi-variable linear regression analysis. The mean age of the cohort was 78 years, 40% were male and 15% were Black. The mean sUMOD level was 127 ng/mL, uUMOD was 30 500 ng/mL and eGFR was 63 mL/min/1.73 m2 . Correlation between sUMOD and uUMOD, adjusted for eGFR was moderate (r = 0.27 [95% confidence interval = 0.21-0.33]). The correlation of eGFR with sUMOD (r = 0.44 [0.39-0.49]) was stronger than with uUMOD (r = 0.21 [0.15-0.27]). In multi-variable analysis adjusting sUMOD for uUMOD and vice versa, sUMOD was independently associated with eGFR (ß = 1.3 [1.1-1.6]), log2 C-reactive protein (ß = -4.2 [-6.8 to -1.6]) and male sex (ß = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (ß = 3700 [400-7000]), while diabetes (ß = -6400 [-10 600 to -2100]) and hypertension (-4300 [-7500 to -1100]) were associated with lower uUMOD levels. We conclude that sUMOD is more strongly associated with eGFR compared with uUMOD. Correlates of sUMOD and uUMOD differ substantially, suggesting that apical and basolateral secretion may be differentially regulated.

Association of Serum Uromodulin With ESKD and Kidney Function Decline in the Elderly: The Cardiovascular Health Study.

RATIONALE & OBJECTIVE: Uromodulin is released by tubular epithelial cells into the serum and lower levels are associated with more severe interstitial fibrosis and tubular atrophy. Low serum uromodulin (sUMOD) levels are associated with mortality and cardiovascular disease. However, little is known about the association of sUMOD levels with long-term kidney outcomes in older adults, a population with a high prevalence of interstitial fibrosis and tubular atrophy. STUDY DESIGN: Case-cohort study and case-control study. SETTING & PARTICIPANTS: Random subcohort (n=933) and additional cases of end-stage kidney disease (ESKD) and kidney function decline (≥30% decline in estimated glomerular filtration rate [eGFR]) during follow-up of the Cardiovascular Health Study (CHS). PREDICTOR: sUMOD level. OUTCOMES: ESKD (n=14) from the random subcohort and all additional ESKD cases from outside the random subcohort (n=39) during follow-up (10 years, case-cohort study); kidney function decline of≥30% eGFR at 9 years of follow-up in individuals with repeated eGFR assessments from the random subcohort (n=56) and additional cases (n=123). 224 participants from the random subcohort served as controls (case-control study). ANALYTICAL APPROACH: Modified multivariable Cox regression for ESKD and multivariable logistic regression for kidney function decline. Both analyses adjusted for demographics, eGFR, urinary albumin-creatinine ratio, and other kidney disease progression risk factors. RESULTS: Mean age of the random subcohort was 78 years, 40% were men, 15% were black. Mean sUMOD level was 127±64ng/mL and eGFR was 63±19mL/min/1.73m2. In multivariable analysis, each 1-SD higher sUMOD level was associated with 63% lower risk for ESKD (HR, 0.37; 95% CI, 0.14-0.95). In demographic-adjusted analyses of kidney function decline, each 1-SD higher sUMOD level was associated with 25% lower odds of kidney function decline (OR, 0.75; 95% CI, 0.60-0.95); after multivariable adjustment, the association was attenuated and no longer significant (OR, 0.88; 95% CI, 0.68-1.14). LIMITATIONS: Possibility of survival bias in the kidney function decline analysis. CONCLUSIONS: Higher sUMOD levels may identify elderly persons at reduced risk for ESKD.

Associations of Urine Biomarkers with Kidney Function Decline in HIV-Infected and Uninfected Men.

BACKGROUND: HIV-infected (HIV+) persons are at increased risk of chronic kidney disease, but serum creatinine does not detect early losses in kidney function. We hypothesized that urine biomarkers of kidney damage would be associated with subsequent changes in kidney function in a contemporary cohort of HIV+ and HIV-uninfected (HIV-) men. METHODS: In the Multicenter AIDS Cohort Study, we measured baseline urine concentrations of 5 biomarkers from 2009 to 2011 in 860 HIV+ and 337 HIV- men: albumin, alpha-1-microglobulin (α1m), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and procollagen type III N-terminal propeptide (PIIINP). We evaluated associations of urine biomarker concentrations with annual changes in estimated glomerular filtration rate (eGFR) using multivariable linear mixed models adjusted for demographics, traditional kidney disease risk factors, HIV-related risk factors, and baseline eGFR. RESULTS: Over a median follow-up of 4.8 years, the average annual eGFR decline was 1.42 mL/min/1.73 m2/year in HIV+ men and 1.22 mL/min/1.73 m2/year in HIV- men. Among HIV+ men, the highest vs. lowest tertiles of albumin (-1.78 mL/min/1.73 m2/year, 95% CI -3.47 to -0.09) and α1m (-2.43 mL/min/1.73 m2/year, 95% CI -4.14 to -0.73) were each associated with faster annual eGFR declines after multivariable adjustment. Among HIV- men, the highest vs. lowest tertile of α1m (-2.49 mL/min/1.73 m2/year, 95% CI -4.48 to -0.50) was independently associated with faster annual eGFR decline. Urine IL-18, KIM-1, and PIIINP showed no independent associations with eGFR decline, regardless of HIV serostatus. CONCLUSIONS: Among HIV+ men, higher urine albumin and α1m are associated with subsequent declines in kidney function, independent of eGFR.

Haptoglobin degradation product as a novel serum biomarker for hematopoietic stem cell transplant-associated thrombotic microangiopathy.

BACKGROUND: Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a well-known complication of HSCT and carries high risk of morbidity and mortality. A lack of consistent non-invasive diagnostic criteria can delay diagnosis and lead to irreversible organ damage. METHODS: Serum samples of 100 patients that underwent HSCT at Cincinnati Children's Hospital were serially collected. Unbiased proteomic profiling by SELDI-TOF-MS was performed on serum from TA-TMA patients at baseline (pre-HSCT), 2 weeks before TMA diagnosis (pre-TMA), and at clinical TMA diagnosis. Two proteins with mass to charge ratios of 12-13 kDa were consistently elevated at the 2 week pre-TMA time point by SELDI-TOF, compared to control samples. Potential peptides were isolated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the Linear Trap Quadropole (LTQ). A MASCOT search identified haptoglobin fragments in the 12-17-kDa range. Western blot was performed to validate haptoglobin fragments as a potential biomarker. RESULTS: Western blot of TA-TMA patients showed haptoglobin fragments at 12, 14, and 17 kDa that varied between baseline, pre-TMA, and TMA time points for each patient. By densitometric analysis, the 17-kDa fragment in the pre-TMA samples differed significantly from TMA diagnosis (p < 0.0001). There was no significant difference in the concentrations of the 12-kDa and 14-kDa fragments. CONCLUSION: The 17-kDa haptoglobin degradation product may represent a novel early serum biomarker for TA-TMA that could potentially allow for earlier diagnosis and intervention.

Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus.

OBJECTIVES: To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN). METHODS: In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy. RESULTS: Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP. CONCLUSION: In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline. KEY MESSAGES: • Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.

PLISSIT Interventions and Sexual Functioning: Useful Tools for Social Work in Palliative Care?

Discussing sexual health with healthcare patients and their partners is difficult and often avoided. The PLISSIT model is a framework to effectively initiate the conversation about sexual concerns. This rapid review and small meta-analysis explores and clarifies knowledge about the effectiveness of PLISSIT in resolving sexual dysfunction and glean insight into its utility as a social work intervention in a palliative care setting. Evidence from 15 interventional studies was synthesized. Cohen's d-index served as the meta-analytic effect size statistic for each individual study. Significant ds were converted to Cohen's U3 statistic to aid in practical interpretations. Between-study heterogeneity was evaluated with Cochran's Q statistic to examine possible relationships between effect sizes and moderator variables. Statistically and practically significant evidence revealed that PLISSIT is effective in treating sexual dysfunction (d = 1.00, U3 = 84%, 95% CI = 1.06, 1.08): 84% of participants who received PLISSIT interventions scored lower on sexual dysfunction measures than did the typical participant in the comparison condition. Study design and frequency of intervention delivery moderated the overall effect. The findings and inferences may be best thought of as developed hypotheses for future research testing.

Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants After Cardiac Surgery.

BACKGROUND: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery. METHODS: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed. RESULTS: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine-defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21-7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2*IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06-7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI. CONCLUSIONS: In this pilot study, urine TIMP-2*IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice.

Preoperative levels of urinary uromodulin predict acute kidney injury after pediatric cardiopulmonary bypass surgery.

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiopulmonary bypass surgery (CPB) in children. Several promising postoperative AKI biomarkers have been identified, but no preoperative biomarkers are available. We evaluated the association of urinary uromodulin (uUMOD) with postoperative AKI. METHODS: One hundred and one children undergoing CPB were enrolled. Urine was collected prior to CPB, and AKI was defined as ≧50% increase in serum creatinine from preoperative baseline within 48 h of surgery. RESULTS: Forty-seven patients (47%) developed AKI, and 92% of participants in the lowest quartile of preoperative uUMOD concentrations developed AKI compared with 8% in the highest quartile. Patients with preoperative uUMOD levels in the lowest quartile had 132.3× increased risk of postoperative AKI versus the highest quartile. Raw uUMOD levels were significantly lower in patients with AKI vs. no AKI. Significance was unchanged after correcting uUMOD levels for urinary creatinine. Receiver operating characteristic analysis showed preoperative uUMOD strongly predicted postoperative AKI, with area under the curve (AUC) 0.90. Stepwise logistic regression analysis revealed a model combining uUMOD, and bypass time predicted AKI at p<0.001. Neither Risk Adjustment for Congenital Heart Surgery 1 (RACHS) score nor age improved the model's ability to predict AKI. Independent analysis demonstrated that while bypass time was associated with AKI, the predictive ability of bypass time (AUC 0.77) was less than that of preoperative uUMOD levels (AUC 0.9). CONCLUSIONS: Children with lowest preoperative levels of uUMOD have greatly increased risk of AKI post-CPB. If uUMOD were used to risk-stratify patients undergoing CPB, clinical measures could be taken to minimize AKI development.

Pre-operative level of FGF23 predicts severe acute kidney injury after heart surgery in children.

BACKGROUND: Early detection of acute kidney injury (AKI) after cardiac surgery has improved recently with the discovery and validation of novel urinary biomarkers. However, objective tools to predict the risk of AKI before the insult are still missing. We tested the hypothesis that pre-operative serum fibroblast growth factor 23 (FGF23) concentrations would be elevated in children who develop AKI after heart surgery with cardiopulmonary bypass (CPB). We also compared post-operative FGF23 concentrations to other biomarkers for early detection of AKI. METHODS: Blood and urine samples were collected in a prospective observational study from 83 children with congenital heart disease. Severe AKI (sAKI) development (KDIGO stages II-III) in the first seven days after surgery was the primary outcome. RESULTS: Thirty of 76 (39.5%) and 11/76 (14.5%) of patients developed AKI and sAKI, respectively. Pre-operative serum creatinine, cystatin C, and urine biomarker concentrations did not differ between sAKI patients and controls. Pre-operative serum FGF23 levels were higher in patients who developed sAKI (median [IQR] value of 819 RU/ml [397.7, 1196.8] vs. 324.3 RU/ml [124.6, 679.8] (p = 0.02). FGF23 12-24 h after the termination of CPB was also associated with sAKI in the first week after surgery (498 RU/ml [226, 928] vs. 1435 RU/ml [831, 12,996]). CONCLUSIONS: Pre- and post-operative FGF23 levels are higher in children who develop sAKI after cardiac surgery. We suggest FGF23 may be able to detect sub-clinical kidney injury and can be used with demographic AKI risk factors to enhance post-operative sAKI risk prediction.

Early postoperative measurement of fibroblast growth factor 23 predicts severe acute kidney injury in infants after cardiac surgery
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AIMS: Acute kidney injury (AKI) occurs in 30 - 40% of children after cardiac surgery (CS) and is associated with poor prognosis. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone with a pivotal role in phosphorus and vitamin D metabolism. We assessed FGF23 as an early marker for severe AKI (sAKI) in infants after CS. MATERIALS AND METHODS: Samples were previously collected in a multicenter observational study from children after CS. Serum FGF23 (n = 41) and urine AKI biomarker levels (n = 35) were assessed 4 - 8 hours after bypass. sAKI was defined as ≥ 100% rise in serum creatinine over baseline. Non-parametric and ROC analyses were used to evaluate the association between FGF23, urine AKI markers, and sAKI in the week after CS. RESULTS: Serum FGF23, urine NGAL, and urine KIM1 were higher in sAKI patients. The AUC-ROC for urine NGAL (0.74, [0.49 - 0.99]), urine KIM1 (0.79, [0.68 - 0.98]), and serum FGF23 (0.74, [0.5 - 0.9]) showed fair prediction of sAKI. CONCLUSION: Early measurement of FGF23 has predictive ability in infants who develop sAKI after CS with cardiopulmonary bypass.
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Urinary kidney injury biomarkers and tobramycin clearance among children and young adults with cystic fibrosis: a population pharmacokinetic analysis.

BACKGROUND: Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF). Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing. OBJECTIVES: We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1). METHODS: This was a prospective, observational cohort study of children/young adults with CF receiving once-daily intravenous tobramycin from October 2012 to May 2014 at Cincinnati Children's Hospital Medical Center. Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were performed using non-linear mixed-effects modelling. RESULTS: Thirty-seven patients (median age 15.3 years, IQR 12.7-19.5) received 62 tobramycin courses. A one-compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best described the data. Urinary NGAL was associated with tobramycin CL (P < 0.001), as was urinary RBP (P < 0.001). SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharmacokinetic parameter estimates were CL = 8.60 L/h/70 kg (relative standard error 4.3%) and V = 31.3 L/70 kg (relative standard error 4.7%). CONCLUSIONS: We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individualize tobramycin therapy in patients with CF.

Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study.

BACKGROUND: Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies evaluating this relationship in humans are lacking. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 953 participants enrolled in the Cardiovascular Health Study. PREDICTOR: Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples. OUTCOMES: Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision (ICD-9) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion. RESULTS: Median uromodulin level was 25.9 (IQR, 17.3-38.9) µg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93µg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26µg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58). LIMITATIONS: Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations. CONCLUSIONS: High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.

Urine biomarkers of acute kidney injury in noncritically ill, hospitalized children treated with chemotherapy.

BACKGROUND: Cisplatin (Cis), carboplatin (Carb), and ifosfamide (Ifos) are common nephrotoxic chemotherapies. Biomarkers of tubular injury may allow for early acute kidney injury (AKI) diagnosis. PROCEDURE: We performed a two-center (Canada, United States) pilot study to prospectively measure serum creatinine (SCr), urine neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) in children receiving Cis/Carb (27 episodes), Ifos (30 episodes), and in 15 hospitalized, nonchemotherapy patients. We defined AKI using the Kidney Disease Improving Global Outcomes (KDIGO) definition. We compared postchemotherapy infusion NGAL and IL-18 concentrations (immediate postdose to 3 days later) to pre-infusion concentrations. We calculated area under the receiver operating characteristic curve (AUC) for postinfusion biomarkers to discriminate for AKI. RESULTS: Prechemotherapy infusion NGAL and IL-18 concentrations were not higher than nonchemotherapy control concentrations. Increasing chemotherapy dose was associated with increasing postinfusion (0-4 hr after infusion) NGAL (P < 0.05). Post-Ifos, immediate postdose, and daily postdose NGAL and IL-18 were significantly higher than pre-infusion biomarker concentrations (P < 0.05), during AKI episodes. NGAL and IL-18 did not rise significantly after Cis-Carb infusion, relative to predose concentrations (P > 0.05). NGAL and IL-18 measured immediately after Ifos infusion discriminated for AKI with AUCs is 0.80 (standard error = 0.13) and 0.73 (standard error = 0.16), respectively. NGAL and IL-18 were not diagnostic of Cis-Carb-associated AKI. When AUCs were adjusted for age, all biomarker AUCs (Cis-Carb and Ifos) improved. CONCLUSION: Urine NGAL and IL-18 show promise as early AKI diagnostic tests in children treated with ifosfamide and may have a potential role in drug toxicity monitoring.

Serum cystatin C for acute kidney injury evaluation in children treated with aminoglycosides.

BACKGROUND: Serum cystatin C (CysC) is a more accurate glomerular filtration rate marker than serum creatinine (SCr) and may rise more quickly with acute kidney injury (AKI). METHODS: We performed a prospective cohort study of 81 non-critically ill children during 110 aminoglycoside (AG) treatments. We calculated area under the curve (AUC) for CysC to diagnose SCr-defined AKI and predict persistent AKI. SCr-AKI definition was based on the Kidney Disease: Improving Global Outcomes (≥stage 1: ≥50 % or 26.5 µmol/l SCr rise from baseline; stage 2: SCr doubling); CysC-AKI was based on a modified version using CysC rise. RESULTS: SCr-AKI and CysC-AKI developed in 45 and 48 % treatments, respectively. CysC rise predicted stage 1 (AUC = 0.75, 95 % CI 0.60-0.90) and 2 (AUC = 0.85, 95 % CI 0.75-0.95) SCr-AKI 2 days before SCr-AKI attainment. The best combined sensitivity/specificity for percent CysC rise to predict stage 1 SCr-AKI was with a 44 % CysC rise (sensitivity = 65 %, specificity = 83 %). CysC rise on day of SCr-AKI development was associated with SCr-AKI ≥48 h (AUC = 0.73, 95 % CI 0.56-0.90) and ≥50 % persistent SCr rise at treatment end (AUC = 0.76, 95 % CI 0.61-0.90). CONCLUSIONS: CysC is as an early AKI biomarker and predictive of persistent AKI on aminoglycoside treatment.

Association of urinary uromodulin with kidney function decline and mortality: the health ABC study
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BACKGROUND: Urine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes. METHODS: Using a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥ 30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression. RESULTS: The median value of uUMOD was 25.8 µg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with > 30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment. CONCLUSION: Higher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.
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Urinary biomarker incorporation into the renal angina index early in intensive care unit admission optimizes acute kidney injury prediction in critically ill children: a prospective cohort study.

BACKGROUND: The inconsistent ability of novel biomarkers to predict acute kidney injury (AKI) across heterogeneous patients and illnesses limits integration into routine practice. We previously retrospectively validated the ability of the renal angina index (RAI) to risk-stratify patients and provide context for confirmatory serum biomarker testing for the prediction of severe AKI. METHODS: We conducted this first prospective study of renal angina to determine whether the RAI on the day of admission (Day0) risk-stratified critically ill children for 'persistent, severe AKI' on Day 3 (Day3-AKI: KDIGO Stage 2-3) and whether incorporation of urinary biomarkers in the RAI model optimized AKI prediction. RESULTS: A total of 184 consecutive patients (52.7% male) were included. Day0 renal angina was present (RAI ≥8) in 60 (32.6%) patients and was associated with longer duration of mechanical ventilation (P = 0.04), higher number of organ failure days (P = 0.003) and increased mortality (P < 0.001) than in patients with absence of renal angina. Day3-AKI was present in 15/156 (9.6%) patients; 12/15 (80%) fulfilled Day0 renal angina. Incorporation of urinary biomarkers into the RAI model increased the specificity and positive likelihood, and demonstrated net reclassification improvement (P < 0.001) for the prediction of Day3-AKI. Inclusion of urinary neutrophil gelatinase-associated lipocalin increased the area under the curve receiver-operating characteristic of RAI for Day3-AKI from 0.80 [95% confidence interval (CI): 0.58, 1.00] to 0.97 (95% CI: 0.93, 1.00). CONCLUSIONS: We have now prospectively validated the RAI as a functional risk stratification methodology in a heterogeneous group of critically ill patients, providing context to direct measurement of novel urinary biomarkers and improving the prediction of severe persistent AKI.

Novel urinary tubular injury markers reveal an evidence of underlying kidney injury in children with reduced left ventricular systolic function: a pilot study.

BACKGROUND: Evolving data suggest tubular injury markers (TIM) to be diagnostic and prognostic biomarkers of kidney injury in adults with chronic cardiac dysfunction. Such data are not well delineated in asymptomatic children with cardiomyopathy. This study sought to evaluate kidney involvement in children with left ventricular (LV) systolic dysfunction. METHODS: We conducted a cross-sectional case-control study in 61 asymptomatic children (aged 1.7-21.9 years) with dilated cardiomyopathy (DCM) and LV ejection fraction (LVEF) < 55 %. Routine conventional kidney function markers and the following urinary TIM were measured: KIM-1, IL-18, neutrophil gelatinase-associated lipocalin (NGAL), and L-FABP. Characteristics and TIM data of cases were compared with those of 61 age- and gender-matched healthy controls. RESULTS: Children with DCM had higher TIM concentrations compared with controls for IL-18 (28.2 pg/mg, IQR [15.9-42.5] vs19.0 [12.6-28.6], p < 0.001), NGAL (13.2 ng/mg [6.5-44.3] vs 8.3 [3.1-17.5], p = 0.01), and KIM-1 (386 pg/mg (248-597) vs 307 [182-432], p = 0.02). All conventional kidney function markers were within normal limits in the DCM cohort. A combined model using cut-off values of KIM-1 ≥ 235, IL-18 ≥ 17.5, and (BNP) > 15 pg/ml resulted in distinction between patients with mildly depressed LV (55 > LVEF ≥ 45) and those with LVEF < 45 %. The sensitivity of this model was ≥80 % when any of the cut-off values was met and specificity 83 % when all cut-off values were met. CONCLUSIONS: Our data suggest that asymptomatic children with LVEF < 55 % might have subclinical kidney injury that cannot be detected with conventional kidney function markers. TIM in conjunction with other cardiac function markers may be utilized to distinguish asymptomatic children with DCM and moderate or worse LV dysfunction (LFEV < 45 %) from those with mild LV dysfunction (55 > LVEF ≥ 45 %).

Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity.

Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.