Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.

BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS). METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022. RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis. CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.

COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark.

Background: Although the persistence of physical symptoms after SARS-CoV-2 infection is a major public health concern, evidence from large observational studies beyond one year post diagnosis remain scarce. We aimed to assess the prevalence of physical symptoms in relation to acute illness severity up to more than 2-years after diagnosis of COVID-19. Methods: This multinational study included 64,880 adult participants from Iceland, Sweden, Denmark, and Norway with self-reported data on COVID-19 and physical symptoms from April 2020 to August 2022. We compared the prevalence of 15 physical symptoms, measured by the Patient Health Questionnaire (PHQ-15), among individuals with or without a confirmed COVID-19 diagnosis, by acute illness severity, and by time since diagnosis. We additionally assessed the change in symptoms in a subset of Swedish adults with repeated measures, before and after COVID-19 diagnosis. Findings: During up to 27 months of follow-up, 34.5% participants (22,382/64,880) were diagnosed with COVID-19. Individuals who were diagnosed with COVID-19, compared to those not diagnosed, had an overall 37% higher prevalence of severe physical symptom burden (PHQ-15 score ≥15, adjusted prevalence ratio [PR] 1.37 [95% confidence interval [CI] 1.23-1.52]). The prevalence was associated with acute COVID-19 severity: individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25 [1.85-2.74]), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92 [0.68-1.24]). The prevalence was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms: shortness of breath, chest pain, dizziness, heart racing, headaches, low energy/fatigue, trouble sleeping, and back pain. The analysis of repeated measurements rendered similar results as the main analysis. Interpretation: These data suggest an elevated prevalence of some, but not all, physical symptoms during up to more than 2 years after diagnosis of COVID-19, particularly among individuals suffering a severe acute illness, highlighting the importance of continued monitoring and alleviation of these targeted core symptoms. Funding: This work was mainly supported by grants from NordForsk (COVIDMENT, grant number 105668 and 138929) and Horizon 2020 (CoMorMent, 847776). See Acknowledgements for further details on funding.

Elevated symptoms of depression and anxiety among family members and friends of critically ill COVID-19 patients - an observational study of five cohorts across four countries.

Background: Little is known regarding the mental health impact of having a significant person (family member and/or close friend) with COVID-19 of different severity. Methods: The study included five prospective cohorts from four countries (Iceland, Norway, Sweden, and the UK) with self-reported data on COVID-19 and symptoms of depression and anxiety during March 2020-March 2022. We calculated prevalence ratios (PR) of depression and anxiety in relation to having a significant person with COVID-19 and performed a longitudinal analysis in the Swedish cohort to describe temporal patterns. Findings: 162,237 and 168,783 individuals were included in the analysis of depression and anxiety, respectively, of whom 24,718 and 27,003 reported a significant person with COVID-19. Overall, the PR was 1.07 (95% CI: 1.05-1.10) for depression and 1.08 (95% CI: 1.03-1.13) for anxiety in relation to having a significant person with COVID-19. The respective PRs for depression and anxiety were 1.15 (95% CI: 1.08-1.23) and 1.24 (95% CI: 1.14-1.34) if the patient was hospitalized, 1.42 (95% CI: 1.27-1.57) and 1.45 (95% CI: 1.31-1.60) if the patient was ICU-admitted, and 1.34 (95% CI: 1.22-1.46) and 1.36 (95% CI: 1.22-1.51) if the patient died. Individuals with a significant person with hospitalized, ICU-admitted, or fatal COVID-19 showed elevated prevalence of depression and anxiety during the entire year after the COVID-19 diagnosis. Interpretation: Family members and close friends of critically ill COVID-19 patients show persistently elevated prevalence of depressive and anxiety symptoms. Funding: This study was primarily supported by NordForsk (COVIDMENT, 105668) and Horizon 2020 (CoMorMent, 847776).

Prenatal exposure to pesticide residues in the diet in association with child autism-related traits: Results from the EARLI study.

Prior work has suggested associations between prenatal exposure to several classes of pesticides and child autism spectrum disorder (ASD). We examined a previously developed pesticide residue burden score (PRBS) and intake of high pesticide residue foods in association with ASD-related traits. Participants were drawn from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 256), a cohort following mothers who previously had a child with ASD through a subsequent pregnancy and that child's development. ASD-related traits were captured according to total Social Responsiveness Scale (SRS) scores at age 3 (mean raw total SRS score = 35.8). Dietary intake was assessed through a food frequency questionnaire collected during pregnancy. We also incorporated organic intake and fatty foods in modified versions of the PRBS. Associations between high-residue fruit and vegetable intake, the overall PRBS and modified versions of it, and SRS scores were assessed using multivariable linear regression. Overall, we did not observe associations between pesticide residues in foods and ASD-related outcomes, and modified versions of the PRBS yielded similar findings. However, reductions in ASD-related traits were observed with higher overall fruit and vegetable intake (adjusted estimates for Q4 vs. Q1: ß -12.76, 95%CI -27.8, 2.3). Thus, findings from this high familial probability cohort did not suggest relationships between pesticide residues in the diet according to the PRBS and ASD-related traits. Beneficial effects of fruit and vegetable intake may influence these relationships. Future work should consider fruit and vegetable intake in association with ASD-related outcomes. LAY SUMMARY: Diet is the main source of exposure to most pesticides in use today. In this study, we examined the relationship between pesticide exposure from residues in the diet during pregnancy and child autism-related traits. We found that these pesticide residues from the diet were not related to child autism-related outcomes at age three. However, higher prenatal fruit and vegetable intake was associated with reductions in child autism-related traits.

Association of early hyponatremia and the development of acute kidney injury in critically ill children.

BACKGROUND: Hyponatremia is an independent prognostic factor for mortality; however, the reason for this remains unclear. An observed relationship between hyponatremia and the development of acute kidney injury (AKI) has been reported in certain disease states, but hyponatremia has not been evaluated as a predictor of AKI in critically ill patients or children. METHODS: This is a single-center retrospective cohort study of critically ill children admitted to a tertiary care center. We performed regression analysis to assess the association between hyponatremia at ICU admission and the development of new or worsening stage 2 or 3 (severe) AKI on days 2-3 following ICU admission. RESULTS: Among the 5057 children included in the study, early hyponatremia was present in 13.3% of children. Severe AKI occurred in 9.2% of children with hyponatremia compared to 4.5% of children with normonatremia. Following covariate adjustment, hyponatremia at ICU admission was associated with a 75% increase in the odds of developing severe AKI when compared to critically ill children with normonatremia (aOR 1.75, 95% CI 1.28-2.39). Evaluating sodium levels continuously, for every 1 mEq/L decrease in serum sodium level, there was a 0.05% increase in the odds of developing severe AKI (aOR 1.05, 95% CI 1.02-1.08). Hyponatremic children who developed severe AKI had a higher frequency of kidney replacement therapy, AKI or acute kidney disease at hospital discharge, and hospital mortality when compared to those without. CONCLUSIONS: Hyponatremia at ICU admission is associated with the development of new or worsening AKI in critically ill children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Acute kidney disease predicts chronic kidney disease in pediatric non-kidney solid organ transplant patients.

BACKGROUND: Acute kidney disease (AKD) is defined as impaired kidney function present for <90 days with or without an acute kidney injury (AKI) event. Adults with AKD have an increased risk for progression to chronic kidney disease (CKD) and mortality. There are no data on the epidemiology of AKD in children after transplant. The aim of this study was to evaluate the incidence and risk factors for AKI, AKD, and CKD in children after transplantation. METHODS: This is a retrospective cohort study of all children undergoing non-kidney solid organ transplant between 2011 and 2019 at UPMC Children's Hospital of Pittsburgh. AKI and AKD were defined using the Kidney Disease Improving Global Outcomes criteria. Patients with a new estimated glomerular filtration rate <60 ml/min/1.73m2 persisting for >3 months met criteria for new CKD. Variables associated with AKI, AKD, and CKD were analyzed. RESULTS: Among 338 patients, 37.9% met criteria for severe AKI, 13% for AKD, and 8% for a new diagnosis of CKD. Stage 3 AKI was independently associated with AKD (OR: 5.35; 95% CI: 2.23-12.86). Severe AKI was not associated with new-onset CKD, whereas AKD was associated with new-onset CKD (OR: 29.74; CI: 11.22-78.82). CONCLUSION: AKD may be superior to AKI in predicting risk of CKD in children after non-kidney solid organ transplantation.

Beyond the Ångström Exponent: Probing Additional Information in Spectral Curvature and Variability of In Situ Aerosol Hyperspectral (0.3-0.7 µm) Optical Properties.

Ångström exponents (α) allow reconstruction of aerosol optical spectra over a broad range of wavelengths from measurements at two or more wavelengths. Hyperspectral measurements of atmospheric aerosols provide opportunities to probe measured spectra for information inaccessible from only a few wavelengths. Four sets of hyperspectral in situ aerosol optical coefficients (aerosol-phase total extinction, σ ext, and absorption, σ abs; liquid-phase soluble absorption from methanol, σ MeOH-abs, and water, σ DI-abs, extracts) were measured from biomass burning aerosols (BBAs). Hyperspectral single scattering albedo (ω), calculated from σ ext and σ abs, provide spectral resolution over a wide spectral range rare for this optical parameter. Observed spectral shifts between σ abs and σ MeOH-abs/σ DI-abs argue in favor of measuring σ abs rather than reconstructing it from liquid extracts. Logarithmically transformed spectra exhibited curvature better fit by second-order polynomials than linear α. Mapping second order fit coefficients (a 1, a 2) revealed samples from a given fire tended to cluster together, that is, aerosol spectra from a given fire were similar to each other and somewhat distinct from others. Separation in (a 1, a 2) space for spectra with the same α suggest additional information in second-order parameterization absent from the linear fit. Spectral features found in the fit residuals indicate more information in the measured spectra than captured by the fits. Above-detection σ MeOH-abs at 0.7 µm suggests assuming all absorption at long visible wavelengths is BC to partition absorption between BC and brown carbon (BrC) overestimates BC and underestimates BrC across the spectral range. Hyperspectral measurements may eventually discriminate BBA among fires in different ecosystems under variable conditions.

The Marine Neurotoxin Brevetoxin (PbTx-2) Inhibits Karenia brevis and Mammalian Thioredoxin Reductases by Targeting Different Residues.

The brevetoxins, neurotoxins produced by Karenia brevis, the Florida red tide dinoflagellate, effect fish and wildlife mortalities and adverse public health and economic impacts during recurrent blooms. Knowledge of the biochemical consequences of toxin production for K. brevis could provide insights into an endogenous role of the toxins, yet this aspect has not been thoroughly explored. In addition to neurotoxicity, the most abundant of the brevetoxins, PbTx-2, inhibits mammalian thioredoxin reductase (TrxR). The thioredoxin system, composed of the enzymes TrxR and thioredoxin (Trx), is present in all living organisms and is responsible in part for maintaining cellular redox homeostasis. Herein, we describe the cloning, expression, and semisynthesis of the selenoprotein TrxR from K. brevis (KbTrxR) and reductase activity toward a variety of substrates. Unlike mammalian TrxR, KbTrxR reduces oxidized glutathione (GSSG). We further demonstrate that PbTx-2 is an inhibitor of KbTrxR. Covalent adducts between KbTrxR and rat TrxR were detected by mass spectrometry. While both enzymes are adducted at or near the catalytic centers, the specific residues are distinct. Biochemical differences reported for high and low toxin producing strains of K. brevis are consistent with the inhibition of KbTrxR and suggest that PbTx-2 is an endogenous regulator of this critical enzyme.

Bladder Agenesis and Bilateral Ectopic Ureters in an Infant Male With Cystic Renal Dysplasia, Imperforate Anus, and Penoscrotal Transposition.

Bladder agenesis is a rare congenital anomaly infrequently reported in the literature, with an incidence of 1/600,000 patients.1 Commonly associated with other fatal malformations, the condition is often incompatible with life.2 Prior reports estimate that over 90% of living children born with this malformation are female, owing to renal preservation resulting from low pressure drainage of urine into the vagina, uterus, and vestibule.3,4 Herein we report a rare case of an infant male born with penoscrotal transposition and end stage renal disease secondary to bilateral cystic renal dysplasia found to have concurrent bladder agenesis and bilateral ureteral ectopia.

Prokinetic actions of luminally acting 5-HT4 receptor agonists.

BACKGROUND: 5-HT4 receptor (5-HT4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT4 Rs have limited their use. Since 5-HT4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4 R agonists promote intestinal motility. METHODS: Non-absorbed 5-HT4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4 R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. KEY RESULTS: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4 R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4 R antagonist and were not detected in 5-HT4 R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4 R is present in the epithelial layer of the human small and large intestines. CONCLUSIONS AND INFERENCES: These findings demonstrated that stimulation of epithelial 5-HT4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.

Association of Acute Kidney Injury With Subsequent Sepsis in Critically Ill Children.

OBJECTIVES: Acute kidney injury is a major cause of morbidity and mortality in critically ill children. A growing body of evidence has shown that acute kidney injury affects immune function, yet little is known about the association between acute kidney injury and subsequent infection in pediatric patients. Our objective was to examine the association of non-septic acute kidney injury with the development of subsequent sepsis in critically ill children. DESIGN: A single-center retrospective cohort study. SETTING: The pediatric and cardiac ICUs at a tertiary pediatric care center. PATIENTS: All patients 0-18 years old without a history of chronic kidney disease, who did not have sepsis prior to or within the initial 48 hours of ICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data for 5,538 children (median age, 5.3 yr; 58.2% male), and identified 255 (4.6%) with stage 2 or 3 acute kidney injury. Suspected sepsis occurred in 46 children (18%) with stage 2 or 3 acute kidney injury compared to 286 children (5.4%) with stage 1 or no acute kidney injury. On adjusted analysis, children with stage 2 or 3 acute kidney injury had 2.05 times greater odds of developing sepsis compared to those with stage 1 or no acute kidney injury (95% CI, 1.39-3.03; p < 0.001). Looking at acute kidney injury severity, children with stage 2 and 3 acute kidney injury had a 1.79-fold (95% CI, 1.15-2.79; p = 0.01) and 3.24-fold (95% CI, 1.55-6.80; p = 0.002) increased odds of developing suspected sepsis, respectively. CONCLUSIONS: Acute kidney injury is associated with an increased risk for subsequent infection in critically ill children. These results further support the concept of acute kidney injury as a clinically relevant immunocompromised state.

Outcomes of adults with congenital heart disease that experience acute kidney injury in the intensive care unit.

BACKGROUND: Young adults with congenital heart disease (CHD) are increasing in number with an increased risk for acute kidney injury. Little is known concerning the impact of non-recovery of kidney function for these patients. Therefore, we sought to explore the rates of acute kidney disease, persistent renal dysfunction, and their associations with adverse outcomes in young adults with CHD. METHODS: This is a single-centre retrospective study including all patients at the ages of 18-40 with CHD who were admitted to an intensive care unit between 2010 and 2014. Patients with a creatinine ≥ 1.5 times the baseline at the time of hospital discharge were deemed to have persistent renal dysfunction, while acute kidney disease was defined as a creatinine ≥ 1.5 times the baseline 7-28 days after a diagnosis of acute kidney injury. Outcomes of death at 5 years and length of hospital stay were examined using multivariable logistic regression and negative binomial regression, respectively. RESULTS: Of the (89/195) 45.6% of patients with acute kidney injury, 33.7% had persistent renal dysfunction and 23.6% met the criteria for acute kidney disease. Persistent renal dysfunction [odds ratio (OR), 3.27; 95% confidence interval (CI): 1.15-9.29] and acute kidney disease (OR: 11.79; 95% CI: 3.75-39.09) were independently associated with mortality at 5 years. Persistent renal dysfunction was associated with a longer duration of hospital stay (Incidence Rate Ratio: 1.96; 95% CI: 1.53-2.51). CONCLUSIONS: In young adults with CHD, acute kidney injury was common and persistent renal dysfunction, as well as acute kidney disease, were associated with increased mortality and length of hospitalisation.

Validation of an Electronic Pediatric Index of Mortality 2 Score in a Mixed Quaternary PICU.

OBJECTIVE: To assess the validity of an electronic version of the Pediatric Index of Mortality 2 score. DESIGN: Retrospective observational study. SETTING: Pediatric and cardiac ICUs at a quaternary medical center. PATIENTS: Patients more than 60 days old admitted to the PICU or cardiac ICU between January 1, 2010, and December 31, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After adapting the Pediatric Index of Mortality 2 score into a version applicable to retrospective electronic health record data, it was validated in a mixed-ICU cohort. A manually ascertained Pediatric Index of Mortality 2 score was directly compared with the electronically derived electronic version of the Pediatric Index of Mortality 2 score in 100 randomly selected patients with good agreement between score components with nine out of 11 components having an intraclass correlation coefficient or Cohen κ greater than or equal to 0.6. In assessing the electronic version of the Pediatric Index of Mortality 2 score in the entire cohort of 12,582 patient encounters, it had good discrimination with area under the receiver operating curve of 0.89, appropriate calibration with no significant difference between observed and expected deaths, and excellent predictive ability with a Brier score of 0.0135. CONCLUSIONS: The Pediatric Index of Mortality 2 score can be adapted to utilize retrospective electronic health record data with acceptable discrimination, calibration and accuracy a large mixed-ICU cohort.

The use of urinary biomarkers to predict acute kidney injury in children after liver transplant.

BACKGROUND: AKI after pediatric liver transplantation is associated with increased morbidity and mortality. The role of urinary biomarkers for the prediction of AKI in pediatric patients after liver transplantation has not been previously reported. The primary objective of this prospective pilot study was to determine the predictive capabilities of urinary KIM-1, NGAL, TIMP-2, and IGFBP7 for diagnosing AKI. METHODS: Sixteen children undergoing liver transplantation were enrolled in the study over a 19-month time period. The Kidney Disease Improving Outcomes criteria for urine output and serum creatinine were used to define AKI. Predictive ability was evaluated using the area under the curve obtained by ROC analysis. RESULTS: AKI occurred in 6 (37.5%) of the patients between 2 and 4 days after transplant. There were no differences in any of the biomarkers prior to transplant. When obtained within 6 hours after transplant, the area under the ROC curve for predicting AKI was 0.758 (95% CI: 0.458-1.00) for KIM-1, 0.900 (95% CI: 0.724-1.00) for NGAL, and 0.933 (95% CI: 0.812-1.00) for the product of TIMP-2 and IGFBP7 ([TIMP-2]·[IGFBP7]). CONCLUSIONS: Our results show that both NGAL and [TIMP-2]·[IGFBP7] provide significant discrimination for AKI risk following liver transplant in children. Larger studies are needed to determine the optimal time point for measuring these biomarkers and to validate our findings.

Piperacillin/Tazobactam and Antibiotic-Associated Acute Kidney Injury in Critically Ill Children.

BACKGROUND: There continues to be uncertainty about whether piperacillin/tazobactam (TZP) increases the risk of AKI in critically ill pediatric patients. We sought to compare rates of AKI among critically ill children treated with TZP or cefepime, an alternative frequently used in intensive care units, with and without vancomycin. METHODS: We conducted a retrospective cohort study assessing the risk of AKI in pediatric intensive care unit patients after exposure to vancomycin, TZP, and cefepime, alone or in combination, within 48 hours of admission. The primary outcome was development of stage 2 or 3 AKI or an increase in AKI stage from 2 to 3 within the 6 days after the 48-hour exposure window. Secondary outcomes included lengths of stay, need for RRT, and mortality. RESULTS: Of 5686 patients included, 494 (8.7%) developed stage 2 or 3 AKI. The adjusted odds of developing AKI after medication exposure were 1.56 for TZP (95% confidence interval [95% CI], 1.23 to 1.99), 1.13 for cefepime (95% CI, 0.79 to 1.64), and 0.86 for vancomycin (95% CI, 0.69 to 1.07). The adjusted odds of developing AKI for vancomycin plus TZP versus vancomycin plus cefepime was 1.38 (95% CI, 0.85 to 2.24). CONCLUSIONS: Observational data in critically ill children show that TZP use is associated with increased odds of AKI. A weaker, nonsignificant association between vancomycin plus TZP and AKI compared with vancomycin plus cefepime, creates some uncertainty about the nature of the association between TZP and AKI. However, cefepime is an alternative not associated with AKI.

Evaluating Renal Stress Using Pharmacokinetic Urinary Biomarker Data in Critically Ill Patients Receiving Vancomycin and/or Piperacillin-Tazobactam: A Secondary Analysis of the Multicenter Sapphire Study.

INTRODUCTION: A drug combination that has gained recent attention for an additive risk of nephrotoxicity is vancomycin plus piperacillin-tazobactam. Clinicians need to better understand whether tubular cell stress occurs with piperacillin-tazobactam administration to establish whether renal injury associated with this combination is a valid clinical concern. OBJECTIVE: An evaluation of the pharmacokinetics of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding-protein 7 (IGFBP7) for patients receiving vancomycin alone, piperacillin-tazobactam alone, and vancomycin plus piperacillin-tazobactam in combination was conducted to understand the impact on acute kidney cell stress and compare the rates of dialysis or death at 9 months among these three drug exposure types. METHODS: A secondary analysis of the prospective, multicenter Sapphire study (ClinicalTrials.gov identifier NCT01209169) including 35 intensive care units (ICUs) in North America and Europe was performed. Critically ill adult patients at risk for acute kidney injury (AKI) were included. Urinary [TIMP-2]∙[IGFBP7] was measured serially. Patients who received vancomycin alone, piperacillin-tazobactam alone, or vancomycin plus piperacillin-tazobactam were grouped according to their maximum AKI stage within 3 days of the first drug dose. RESULTS: Of 723 critically ill adults admitted to the ICU, 46% received either piperacillin-tazobactam (n = 110), vancomycin (n = 156), or both (n = 67). The urinary [TIMP-2]∙[IGFBP7] was highest on day 1 for the combination group. AKI stage 2/3 occurred more frequently in patients receiving the drug combination than in those receiving piperacillin-tazobactam alone (p = 0.03) but not vancomycin alone (p = 0.29). Risk of death or dialysis at 9 months was greatest for vancomycin plus piperacillin-tazobactam (48%) and similar for patients receiving vancomycin alone (29%) or piperacillin-tazobactam alone (35%) (p = 0.03 for unadjusted and p = 0.048 after adjusting for covariates). CONCLUSION: After exposure to piperacillin-tazobactam and vancomycin in combination, there was a greater release of AKI biomarkers in patients who develop AKI than with piperacillin-tazobactam or vancomycin monotherapy and the combination is associated with possible increased long-term adverse outcomes.

eResearch in acute kidney injury: a primer for electronic health record research.

Acute kidney injury (AKI) has a significant impact on patient morbidity and mortality as well as overall health care costs. eResearch, which integrates information technology and information management to optimize research strategies, provides a perfect platform for necessary ongoing AKI research. With the recent adoption of a widely accepted definition of AKI and near-universal use of electronic health records, eResearch is becoming an important tool in AKI research. Conducting eResearch in AKI should ideally be based on a relatively uniform methodology. This article is the first of its kind to describe a methodology for pursuing eResearch specific to AKI and includes an illustrative database example for critically ill patients. We discuss strategies for using serum creatinine and urine output in large databases to identify and stage AKI and ways to interpolate missing values and validate data. Issues specific to the pediatric population include variation in serum creatinine with growth, varied severity of illness scoring systems and medication dosage based on weight. Many of these same strategies used to optimize AKI eResearch can be applicable to real-time AKI alerts with potential integration of additional clinical variables.

Value of Renal Biopsy in Diagnosing Infantile Nephropathic Cystinosis Associated With Secondary Nephrogenic Diabetes Insipidus.

Cystinosis is the most common cause of inherited renal Fanconi syndrome in young children, and typically presents with laboratory findings of a proximal tubulopathy and corneal crystals by one year of age. We describe here renal biopsy findings in a 20-month-old patient with an atypical presentation of distal renal tubular acidosis, diabetes insipidus, and the absence of corneal crystals. Although renal biopsy is usually not necessary to establish the diagnosis of cystinosis, when the patient presents with atypical signs and symptoms, a renal biopsy may be extremely valuable. A 20-month-old boy presented with failure to thrive, polyuria, polydipsia, and rickets. He initially showed evidence of a renal tubular acidosis, mild renal insufficiency, and nephrogenic diabetes insipidus. His initial ophthalmologic examination did not demonstrate corneal crystals. His subsequent workup revealed phosphaturia, suggesting a partial proximal tubulopathy. Concomitantly, a renal biopsy revealed prominent podocytes with an immature glomerular appearance, and electron microscopy analysis showed numerous intracellular crystals within tubular epithelial cells. Subsequent laboratory and genetic testing confirmed a diagnosis of infantile nephropathic cystinosis. This case highlights the variability in the clinical presentation of cystinosis, resulting in an uncommon clinical picture of a rare disease. Given that treatment is available to prolong renal function and minimize the extra-renal manifestations of this disorder, early diagnosis is essential. It is important to raise the index of suspicion of cystinosis by recognizing its subtle morphological changes in young patients, and that nephrogenic diabetes insipidus can be secondary to this disorder.

Drug-associated acute kidney injury: who's at risk?

The contribution of nephrotoxic medications to the development of acute kidney injury (AKI) is becoming better understood concomitant with the increased incidence of AKI in children. Treatment of AKI is not yet available, so prevention continues to be the most effective approach. There is an opportunity to mitigate severity and prevent the occurrence of AKI if children at increased risk are identified early and nephrotoxins are used judiciously. Early detection of AKI is limited by the dependence of nephrologists on serum creatinine as an indicator. Promising new biomarkers may offer early detection of AKI prior to the rise in serum creatinine. Early detection of evolving AKI is improving and offers opportunities for better management of nephrotoxins. However, the identification of patients at increased risk will remain an important first step, with a focus on the use of biomarker testing and interpretation of the results.