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AbstractObjectiveTo determine whether electronic health record alerts for acute kidney injury would improve patient outcomes of mortality, dialysis, and progression of acute kidney injury.DesignDouble blinded, multicenter, parallel, randomized controlled trial.SettingSix hospitals (four teaching and two non-teaching) in the Yale New Haven Health System in Connecticut and Rhode Island, US, ranging from small community hospitals to large tertiary care centers.Participants6030 adult inpatients with acute kidney injury, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria.InterventionsAn electronic health record based “pop-up” alert for acute kidney injury with an associated acute kidney injury order set upon provider opening of the patient’s medical record.Main outcome measuresA composite of progression of acute kidney injury, receipt of dialysis, or death within 14 days of randomization. Prespecified secondary outcomes included outcomes at each hospital and frequency of various care practices for acute kidney injury.Results6030 patients were randomized over 22 months. The primary outcome occurred in 653 (21.3%) of 3059 patients with an alert and in 622 (20.9%) of 2971 patients receiving usual care (relative risk 1.02, 95% confidence interval 0.93 to 1.13, P=0.67). Analysis by each hospital showed worse outcomes in the two non-teaching hospitals (n=765, 13%), where alerts were associated with a higher risk of the primary outcome (relative risk 1.49, 95% confidence interval 1.12 to 1.98, P=0.006). More deaths occurred at these centers (15.6% in the alert group v 8.6% in the usual care group, P=0.003). Certain acute kidney injury care practices were increased in the alert group but did not appear to mediate these outcomes.ConclusionsAlerts did not reduce the risk of our primary outcome among patients in hospital with acute kidney injury. The heterogeneity of effect across clinical centers should lead to a re-evaluation of existing alerting systems for acute kidney injury.Trial registrationClinicalTrials.gov NCT02753751.

Acute kidney injury is common among hospitalized individuals, particularly those exposed to certain medications, and is associated with substantial morbidity and mortality. In a pragmatic, open-label, National Institutes of Health-funded, parallel group randomized controlled trial (clinicaltrials.gov NCT02771977), we investigate whether an automated clinical decision support system affects discontinuation rates of potentially nephrotoxic medications and improves outcomes in patients with AKI. Participants included 5060 hospitalized adults with AKI and an active order for any of three classes of medications of interest: non-steroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, or proton pump inhibitors. Within 24 hours of randomization, a medication of interest was discontinued in 61.1% of the alert group versus 55.9% of the usual care group (relative risk 1.08, 1.04 – 1.14, p = 0.0003). The primary outcome – a composite of progression of acute kidney injury, dialysis, or death within 14 days - occurred in 585 (23.1%) of individuals in the alert group and 639 (25.3%) of patients in the usual care group (RR 0.92, 0.83 – 1.01, p = 0.09). Trial Registration Clinicaltrials.gov NCT02771977. In a multicenter randomized trial, researchers found that electronic alerts increased the rate of discontinuation of potential nephrotoxins. This did not translate into improved clinical outcomes, except among those exposed to proton-pump inhibitors.

Background Acute kidney injury (AKI) is associated with significant short-term morbidity and mortality in children. However, the risk for long-term outcomes after AKI is largely unknown. Methods We performed a systematic review and meta-analysis to determine the cumulative incidence rate of proteinuria, hypertension, decline in glomerular filtration rate (GFR), and mortality after an episode of AKI. After screening 1934 published articles from 1985–2013, we included 10 cohort studies that reported long-term outcomes after AKI in children. Results A total of 346 patients were included in these studies with a mean follow-up of 6.5 years (range 2–16) after AKI. The studies were of variable quality and had differing definitions of AKI with five studies only including patients who required dialysis during an AKI episode. There was a substantial discrepancy in the outcomes across these studies, most likely due to study size, disparate outcome definitions, and methodological differences. In addition, there was no non-AKI comparator group in any of the published studies. The cumulative incidence rates for proteinuria, hypertension, abnormal GFR (<90 ml/min/1.73 m 2 ), GFR < 60 ml/min/1.73 m 2 , end stage renal disease, and mortality per 100 patient-years were 3.1 (95% CI 2.1-4.1), 1.4 (0.9-2.1), 6.3 (5.1-7.5), 0.8 (0.4 -1.4), 0.9 (0.6-1.4), and 3.7 (2.8-4.5) respectively. Conclusions AKI appears to be associated with a high risk of long-term renal outcomes in children. These findings may have implications for care after an episode of AKI in children. Future prospective studies with appropriate non-AKI comparator groups will be required to confirm these results.

Chronic kidney disease (CKD) has become a significant public health concern, as it is associated with substantial morbidity. Prior research has evaluated multiple novel CKD biomarkers to supplement serum creatinine and proteinuria. The ultimate goal of this research is to find biomarkers that can be used to accurately predict CKD progression and to better time outpatient follow-up, and referral for transplant. Also, an optimal panel of biomarkers can augment the predictive value of proteinuria and serum creatinine by enriching patient enrollment in clinical trials. In this review, we discuss salient findings on 12 candidate plasma and urine biomarkers and their reported association with CKD. We explore the common pathways of CKD progression and the pathophysiologic processes of tubulointerstitial injury, inflammation, repair, and fibrosis that are potentially classified by specific biomarkers. We describe both pediatric and adult findings and highlight the paucity of pediatric research in CKD progression. It will be important for cohorts with longitudinal follow-up to evaluate these CKD biomarkers for potential use in pediatric clinical trials and routine CKD management.

False negative SARS-CoV-2 tests can lead to spread of infection in the inpatient setting to other patients and healthcare workers. However, the population of patients with COVID who are admitted with false negative testing is unstudied. To characterize and develop a model to predict true SARS-CoV-2 infection among patients who initially test negative for COVID by PCR. Retrospective cohort study. Five hospitals within the Yale New Haven Health System between 3/10/2020 and 9/1/2020. Adult patients who received diagnostic testing for SARS-CoV-2 virus within the first 96 hours of hospitalization. We developed a logistic regression model from readily available electronic health record data to predict SARS-CoV-2 positivity in patients who were positive for COVID and those who were negative and never retested. This model was applied to patients testing negative for SARS-CoV-2 who were retested within the first 96 hours of hospitalization. We evaluated the ability of the model to discriminate between patients who would subsequently retest negative and those who would subsequently retest positive. We included 31,459 hospitalized adult patients; 2,666 of these patients tested positive for COVID and 3,511 initially tested negative for COVID and were retested. Of the patients who were retested, 61 (1.7%) had a subsequent positive COVID test. The model showed that higher age, vital sign abnormalities, and lower white blood cell count served as strong predictors for COVID positivity in these patients. The model had moderate performance to predict which patients would retest positive with a test set area under the receiver-operator characteristic (ROC) of 0.76 (95% CI 0.70-0.83). Using a cutpoint for our risk prediction model at the 90th percentile for probability, we were able to capture 35/61 (57%) of the patients who would retest positive. This cutpoint amounts to a number-needed-to-retest range between 15 and 77 patients. We show that a pragmatic model can predict which patients should be retested for COVID. Further research is required to determine if this risk model can be applied prospectively in hospitalized patients to prevent the spread of SARS-CoV-2 infections.

Abstract BackgroundPaxlovid (nirmatrelvir/ritonavir) is a novel drug available under emergency use authorization by the Food and Drug Administration for the treatment of COVID-19 infection. Tacrolimus, a calcineurin inhibitor, is commonly used as an immunosuppressant medication in children with kidney transplants. While tacrolimus is metabolized by the cytochrome P450 system (CYP3A4), ritonavir is a potent CYP3A4 inhibitor. There is a paucity of data regarding the drug-drug interaction between nirmatrelvir/ritonavir and tacrolimus in children with kidney transplants.Case-Diagnosis/TreatmentThis is a case report of a 14-year-old female with a history of a kidney transplant, maintained on tacrolimus and prednisone, who starts nirmatrelvir/ritonavir for a COVID-19 infection. She subsequently develops supratherapeutic tacrolimus levels and an increase in serum creatinine. Her tacrolimus was held, and the nirmatrelvir/ritonavir was stopped. Over time, her kidney function returned to baseline, her tacrolimus levels returned to the therapeutic goal, and her tacrolimus was resumed.ConclusionsOur case report highlights the strong interaction with concomitant use of tacrolimus and nirmatrelvir/ritonavir in a pediatric kidney transplant recipient and the development of supratherapeutic tacrolimus levels. Providers should therefore be cautious when prescribing nirmatrelvir/ritonavir to a pediatric patient currently on tacrolimus.

Acute kidney injury (AKI) in deceased donors is not associated with graft failure (GF). We hypothesize that hemodynamic AKI (hAKI) comprises the majority of donor AKI and may explain this lack of association. In this ancillary analysis of the Deceased Donor Study, 428 donors with available charts were selected to identify those with and without AKI. AKI cases were classified as hAKI, intrinsic (iAKI), or mixed (mAKI) based on majority adjudication by three nephrologists. We evaluated the associations between AKI phenotypes and delayed graft function (DGF), 1-year eGFR and GF. We also evaluated differences in urine biomarkers among AKI phenotypes. Of the 291 (68%) donors with AKI, 106 (36%) were adjudicated as hAKI, 84 (29%) as iAKI and 101 (35%) as mAKI. Of the 856 potential kidneys, 669 were transplanted with 32% developing DGF and 5% experiencing GF. Median 1-year eGFR was 53 (IQR: 41-70) ml/min/1.73m2. Compared to non-AKI, donors with iAKI had higher odds DGF [aOR (95%CI); 4.83 (2.29, 10.22)] and had lower 1-year eGFR [adjusted B coefficient (95% CI): -11 (-19, -3) mL/min/1.73 m2]. hAKI and mAKI were not associated with DGF or 1-year eGFR. Rates of GF were not different among AKI phenotypes and non-AKI. Urine biomarkers such as NGAL, LFABP, MCP-1, YKL-40, cystatin-C and albumin were higher in iAKI. iAKI was associated with higher DGF and lower 1-year eGFR but not with GF. Clinically phenotyped donor AKI is biologically different based on biomarkers and may help inform decisions regarding organ utilization.

BACKGROUNDWhile urinary biomarkers show promise in predicting diabetic kidney disease (DKD) progression, distal tubular markers remain understudied. We investigated the association of distal tubule markers, epidermal growth factor (EGF) and uromodulin (UMOD), with DKD progression in the Veterans Affairs Diabetes in Nephropathy (VA NEPHRON-D) clinical trial. We used Cox regression models to evaluate the association between each biomarker and DKD progression and the relationship between change over time in biomarker and DKD progression. We used mixed models to investigate biomarker levels at baseline, 12 months, and over time and their relationships with longitudinal eGFR change. Participants (n = 1,116) had type 2 diabetes, urine albumin-to-creatinine ratio (UACR) ≥ 300 mg/g, and eGFR 30-89.9 mL/min/1.73 m2. Mean age was 65 years, mean eGFR was 56 (SD 19) mL/min/1.73 m2, and median UACR was 840 (IQR 424-1,780) mg/g. One hundred forty-four participants (13%) had DKD progression over a median follow-up of 2.2 (1.3-3.1) years. Higher baseline EGF and UMOD were independently associated with a lower risk of DKD progression (adjusted HR 0.68, 95% CI 0.47, 0.99 and 0.85, [0.75, 0.98] per 2-fold higher concentration of EGF and UMOD, respectively). Serial biomarker measurements were performed at baseline and 12 months, and a slower decline in biomarkers was associated with a lower risk of DKD progression when adjusted for baseline biomarker levels. Urinary EGF and UMOD may serve as valuable prognostic biomarkers in DKD. gov NCT00555217. NIH U01DK102730, U01DK103225, K23 DK118198, R01DK137087, U01DK103225, R37DK039773, U01DK114866, U01DK106962, U01DK129984, and R01DK093770; National Institute of Diabetes and Digestive and Kidney Diseases contract U01DK106965.

Prenatal exposure to arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) may be nephrotoxic, yet limited studies have examined subclinical kidney injury biomarkers in children. We assessed whether metal exposure in the second trimester (2T), a crucial time of kidney development, is associated with altered urine kidney injury and function biomarkers in preadolescent children. Analyses included 494 children participating in a birth cohort study in Mexico City. Concentrations of As, Cd, and Pb were measured from pregnant women in 2T blood and urine, and Hg in urine only. Kidney biomarkers were measured from children in urine at age 8–12 years. We assessed the associations between individual metals and (1) kidney biomarkers using linear regression and (2) a multi-protein kidney mixture using weighted quantile sum (WQS) regression. Associations of separate urine and blood metal mixtures with individual kidney biomarkers were assessed via WQS. Within the multi-protein mixture, the association with increased urinary As was predominated by urine alpha-1-microglobulin (A1M), interferon gamma-induced protein 10 (IP10), and fatty acid binding protein 1; the association with increased urinary Cd was predominated by A1M, clusterin, and albumin. The urine metal mixture was associated with increased albumin (0.23 ng/mL; 95% confidence interval (CI): 0.10, 0.37), IP10 (0.15 ng/mL; 95% CI: 0.02, 0.28), and cystatin C (0.17 ng/mL; 95% CI: 0.04, 0.31); these associations were mainly driven by urinary As and Cd. We observed null associations between prenatal blood or urine metal mixtures and estimated glomerular filtration rate. Higher prenatal urinary metals, individually and as a mixture were associated with altered kidney injury biomarkers in children. Further research and longer participant follow-up are required to ascertain the risk of kidney disease later in life.

Children with chronic kidney disease (CKD) can have an inherent vulnerability to dehydration. Younger children are unable to freely access water, and CKD aetiology and stage can associate with reduced kidney concentrating capacity, which can also impact risk. This article aims to review the risk factors and consequences of mild dehydration and underhydration in CKD, with a particular focus on evidence for risk of CKD progression. We discuss that assessment of dehydration in the CKD population is more challenging than in the healthy population, thus complicating the definition of adequate hydration and clinical research in this field. We review pathophysiologic studies that suggest mild dehydration and underhydration may cause hyperfiltration injury and impact renal function, with arginine vasopressin as a key mediator. Randomised controlled trials in adults have not shown an impact of improved hydration in CKD outcomes, but more vulnerable populations with baseline low fluid intake or poor kidney concentrating capacity need to be studied. There is little published data on the frequency of dehydration, and risk of complications, acute or chronic, in children with CKD. Despite conflicting evidence and the need for more research, we propose that paediatric CKD management should routinely include an assessment of individual dehydration risk along with a treatment plan, and we provide a framework that could be used in outpatient settings. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information