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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel oral anti-hyperglycemic drugs that demonstrate cardiovascular and metabolic benefits for patients with type 2 diabetes (T2D), heart failure (HF), and chronic kidney disease (CKD). There is limited knowledge of real-world data to predict adherence to SGLT-2i in an ambulatory setting. The study aims to predict SGLT-2i adherence in patients with T2D and/or HF and/or CKD by building a prediction model using electronic prescription claims data presented within EPIC datasets. This is a retrospective study of 174 adult patients prescribed SGLT-2i at UC San Diego Health ambulatory pharmacies between 1 January 2020 to 30 April 2021. Adherence was measured by the proportion of days covered (PDC). R packages were used to identify regression and non-linear regression predictive models to predict adherence. Age, gender, race/ethnicity, hemoglobin A1c, and insurance plan were included in the model. Diabetes control based on hemoglobin A1c (HbA1c) and the glomerular filtration rate (GFR) was also evaluated using Welch t-test with a p-value of 0.05. The best predictive model for measuring adherence was the simple decision tree. It had the highest area under the curve (AUC) of 74% and accuracy of 82%. The model accounted for 21 variables with the main node predictors, including glycated hemoglobin, age, gender, and insurance plan payment amount. The adherence rate was inversely proportional to HbA1c and directly proportional to the plan payment amount. As for secondary outcomes, HbA1c values from baseline till 90 days post-treatment duration were consistently higher in the non-compliant group: 7.4% vs. 9.6%, p < 0.001 for the PDC ≥ 0.80 and PDC < 0.80, respectively. Baseline eGFR was 55.18 mL/min/1.73m2 vs. 54.23 mL/min/m2 at 90 days. The mean eGFR at the end of the study (minimum of 90 days of treatment) was statistically different between the groups: 53.1 vs. 59.6 mL/min/1.73 m2, p < 0.001 for the PDC ≥ 0.80 and PDC < 0.80, respectively. Adherence predictive models will help clinicians to tailor regimens based on non-adherence risk scores.

BackgroundAcute Kidney Injury (AKI) incidence has continued to rise and is recognized as a major risk factor for kidney disease progression and cardiovascular complications. Early recognition of factors associated with post-AKI complications is fundamental to stratifying patients that could benefit from closer follow-up and management after an episode of AKI. Recent studies have shown that proteinuria is a prevalent sequela after AKI and a strong predictor of complications post-AKI. This study aims to evaluate the frequency and timing of the development of de-novo proteinuria after an AKI episode in patients with known kidney function and no prior history of proteinuria.MethodsWe retrospectively analyzed data from adult AKI patients with pre- and post-kidney function information between Jan 2014 and March 2019. The presence of proteinuria determined before and after index AKI encounter was based on ICD-10 code and/or urine dipstick and UPCR during the follow-up period.ResultsOf 9697 admissions with AKI diagnoses between Jan 2014 and March 2019, 2120 eligible patients with at least one assessment of Scr and proteinuria before AKI index admission were included in the analysis. The median age was 64 (IQR 54-75) years, and 57% were male. 58% (n-1712) patients had stage 1 AKI, 19% (n = 567) stage 2 AKI, and 22% (n = 650) developed stage 3 AKI. De novo proteinúria was found in 62% (n = 472) of patients and was already present by 90 days post-AKI in 59% (209/354). After adjusting for age and comorbidities, severe AKI (stage 2/3 AKI) and diabetes, were independently associated with increased risk for De novo proteinuria.ConclusionSevere AKI is an independent risk factor for subsequent de novo proteinuria post-hospitalization. Further prospective studies are needed to determine whether strategies to detect AKI patients at risk of proteinuria and early therapeutics to modify proteinuria can delay the progression of kidney disease.

In recent decades, clinical research on early biomarkers of renal injury has been frequent and intensive, with proenkephalin (PENK) being indicated as a promising filtration biomarker (BM). From a cohort of 57 patients, blood samples were collected preoperatively and 48 h after liver transplantation (LT). The following BMs were analyzed: PENK, cystatin-C (CYS-C), and serum creatinine (Scr). Diagnosis of AKI was based on the KDIGO criteria. Of the 57 patients undergoing LT, 50 (88%) developed acute kidney injury (AKI) and were categorized as follows: no-AKI/mild-AKI - 21 (36.8%) and severe-AKI 36 (63.2%). During the preoperative period, only PENK was significantly higher in patients with severe AKI, with an AUC of 0.69 (CI 0.54-0.83), a cutoff of 55.30 pmol/l, a sensitivity of 0.86, a specificity of 0.52, and an accuracy of 0.75. In addition, subclinical AKI was determined preoperatively in 32 patients. Forty-eight hours after LT, PENK maintained its performance in determining severe AKI, with an AUC of 0.83 (CI 0.72-0.94), a cutoff of 119.05 pmol/l, a sensitivity of 0.81, a specificity of 0.90, and an accuracy of 0.84. PENK detected AKI 48 h earlier than serum creatinine. In a multivariate linear regression analysis, PENK was an independent predictor of severe AKI. This small study suggests that the filtration biomarker PENK shows promise for detecting AKI in patients undergoing LT, revealing greater accuracy and an earlier rise in patients with severe AKI. The combination of kidney functional and filtration BMs may aid in the management and prevention of AKI progression.

Compare ICU outcomes and respiratory system mechanics in patients with and without acute kidney injury during invasive mechanical ventilation.DesignsRetrospective cohort study.SettingsICUs of the University of California, San Diego, from January 1, 2014, to November 30, 2016.PatientsFive groups of patients were compared based on the need for invasive mechanical ventilation, presence or absence of acute kidney injury per the Kidney Disease: Improving Global Outcomes criteria, and the temporal relationship between the development of acute kidney injury and initiation of invasive mechanical ventilation.InterventionsNone.Measurements and main resultsA total of 9,704 patients were included and 4,484 (46%) required invasive mechanical ventilation; 2,009 patients (45%) had acute kidney injury while being treated with invasive mechanical ventilation, and the mortality rate for these patients was 22.4% compared with 5% in those treated with invasive mechanical ventilation without acute kidney injury (p < 0.01). Adjusted hazard of mortality accounting for baseline disease severity was 1.58 (95% CI, 1.22-2.03; p < 0.001]. Patients with acute kidney injury during invasive mechanical ventilation had a significant increase in total ventilator days and length of ICU stay with the same comparison (both p < 0.01). Acute kidney injury during mechanical ventilation was also associated with significantly higher plateau pressures, lower respiratory system compliance, and higher driving pressures (all p < 0.01). These differences remained significant in patients with net negative cumulative fluid balance.ConclusionsAcute kidney injury during invasive mechanical ventilation is associated with increased ICU mortality, increased ventilator days, increased length of ICU stay, and impaired respiratory system mechanics. These results emphasize the need for investigations of ventilatory strategies in the setting of acute kidney injury, as well as mechanistic studies of crosstalk between the lung and kidney in the critically ill.

The use of mobile devices by healthcare providers has transformed many aspects of clinical practice. Mobile devices and medical applications provide many benefits, perhaps most significantly increased access to point-of-care (POC) tools, which has been shown to support better clinical decision making and improved patient outcomes. In LMICs, where computer-based technology is limited, the use of mobile technology has the potential to immensely increase access to point of care tools. In this study, we conducted an interventional, pre-post study to determine whether the use of a medical application could help healthcare providers accurately recognize and diagnose AKI. After preparing 20 clinical vignettes based on AKI cases from our center Global Snapshot study report, we asked 50 last year medical students to identify the presence and stage of AKI first without and then with the use of the IRA SLANH App (IRA SLANH app, Island of the Moon® V.1, 2014; Cochabamba-Bolivia), which was designed specifically for this study. Before the IRA SLANH app was introduced, the mean number of correctly identified cases of AKI was 14.7 ± 4.7 with a minimum of 3 and a maximum of 20. The stage of AKI was correctly identified in only 6.7 ± 4.4 of the cases. After the app was introduced, the number of correctly identified and staged cases of AKI was 20. Medical applications are useful point-of-care tools in the practice of evidence-based medicine. Their use has the potential to play a very important role in early identification and classification of AKI, particularly in LMICs potentially allowing for earlier intervention with preventive and treatment strategies to reverse kidney injury and improve recovery.

BackgroundIntradialytic hypotension (IDH) is a frequent complication of intermittent hemodialysis (IHD), occurring from 15 to 50% of ambulatory sessions, and is more frequent among hospitalized patients with hypoalbuminemia. IDH limits adequate fluid removal and increases the risk for vascular access thrombosis, early hemodialysis (HD) termination, and mortality. Albumin infusion before and during therapy has been used for treating IDH with the varying results. We evaluated the efficacy of albumin infusion in preventing IDH during IHD in hypoalbuminemic inpatients.MethodsA randomized, crossover trial was performed in 65 AKI or ESKD patients with hypoalbuminemia (albumin

ObjectiveRegional citrate anticoagulation (RCA) is the preferred anticoagulation method for continuous kidney replacement therapy (CKRT) recommended by KDIGO. Limited availability of calcium-free solutions often imposes challenges to the implementation of RCA for CKRT (RCA-CKRT). The principal purpose of this study was to characterize the outcomes of RCA-CKRT using calcium-containing solutions.Study designRetrospective cohort study.Setting & participantsWe evaluated the safety and efficacy of RCA-CKRT with calcium-containing dialysate and replacement fluid used for 128 patients. A total of 571 filters and 1,227 days of CKRT were analyzed.ExposuresLiver disease, sepsis in the absence of liver disease, and sepsis with liver disease.OutcomesFilter life and metabolic complications per 100 CKRT days.Analytical approachLinear mixed-effects model and generalized linear mixed-effects models.ResultsThe majority of patients were male (91; 71.1%), 32 (25%) had liver disease, and 29 (22.7%) had sepsis without liver disease. Median filter life was 50.0 (interquartile range, 22.0-118.0) hours, with a maximum of 322 hours, and was significantly lower (33.5 [interquartile range, 17.5-60.5] h) in patients with liver disease. Calcium-containing replacement solutions were used in 41.6% of all CKRT hours and reduced intravenous calcium requirements by 31.7%. Hypocalcemia (ionized calcium10.6mg/dL) were observed in 6.0 and 6.7 per 100 CKRT days, respectively. Citrate accumulation was observed in 13.3% of all patients and was associated with metabolic acidosis in 3.9%, which was not significantly different in patients with liver disease (9.3%; P = 0.2).LimitationsLack of control groups that used calcium-free dialysate and replacement solutions with RCA-CKRT. Possible overestimation of filter life from incomplete data on cause of filter failure.ConclusionsOur study suggests that RCA-CKRT with calcium-containing solutions is feasible and safe in critically ill patients, including those with sepsis and liver disease.

BackgroundVancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant Staphylococcusaureus. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis. In this study, we investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses.MethodsUrine samples from patients with V-AKI who were enrolled in the DIRECT study and matched healthy controls from the UAB-UCSD O'Brien Center Biorepository were included in the analysis. Exosomes were extracted using solvent exclusion principle and polyethylene glycol induced precipitation. Protein identity and quantification was determined by label-free liquid chromatography mass spectrometry (LC/MS). The mean peak serum creatinine was 3.7 ± 1.4 mg/dL and time to kidney injury was 4.0 ± 3.0 days. At discharge, 90% of patients demonstrated partial recovery; 33% experienced full recovery by day 28. Proteomic analyses on five V-AKI and 7 control samples revealed 2009 proteins in all samples and 251 proteins significantly associated with V-AKI (Pi-score > 1). The top discriminatory proteins were complement C3, complement C4, galectin-3-binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin.ConclusionUrinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers.

Background"Dynamic" baseline serum creatinine (sCr), based on a rolling 48-h window, and a static baseline sCr (previous outpatient sCr) were used to define acute kidney injury (AKI).MethodsRetrospective cohort study of adult admissions to the University of Alabama (UAB) Health System hospitals for years 2016-2018. Included admissions had >1- and 2 inpatient sCr measurements, and an averaged estimated glomerular filtration rate >15 mL/min/1.73 m2. The final cohort of 62,380 patients included 100,570 admissions, 3,509 inpatient deaths, and 1,916 admissions with inpatient dialysis. AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria and a static or dynamic baseline sCr. Discrimination was evaluated with area under receiver operator curves (AUC), logistic regression, and net reclassification improvement (NRI).ResultsPreadmission outpatient "static" sCr values were available for 43,433 admissions. The lowest sCr value during a rolling 48-h window before each inpatient sCr defined a "dynamic" baseline sCr. Using point-wise comparisons, the dynamic baseline sCr performed better than static baseline sCr for inpatient mortality (AUC [0.819 vs. 0.741; p < 0.001] and NRI ≥0.306 [p < 0.001]) and inpatient dialysis (AUC [0.903 vs. 0.864; p < 0.001] and NRI ≥0.317 [p < 0.001]).ConclusionsThe dynamic baseline sCr is available without reference to preadmission sCr values and avoids confounding associated with missing outpatient sCr values. AKI defined with the dynamic baseline sCr significantly improved discrimination of risk for inpatient mortality and dialysis compared to static baseline sCr.

BackgroundAcute kidney injury (AKI) is increasingly encountered in community settings and contributes to morbidity, mortality, and increased resource utilization worldwide. In low-resource settings, lack of awareness of and limited access to diagnostic and therapeutic interventions likely influence patient management. We evaluated the feasibility of the use of point-of-care (POC) serum creatinine and urine dipstick testing with an education and training program to optimize the identification and management of AKI in the community in 3 low-resource countries.Methods and findingsPatients presenting to healthcare centers (HCCs) from 1 October 2016 to 29 September 2017 in the cities Cochabamba, Bolivia; Dharan, Nepal; and Blantyre, Malawi, were assessed utilizing a symptom-based risk score to identify patients at moderate to high AKI risk. POC testing for serum creatinine and urine dipstick at enrollment were utilized to classify these patients as having chronic kidney disease (CKD), acute kidney disease (AKD), or no kidney disease (NKD). Patients were followed for a maximum of 6 months with repeat POC testing. AKI development was assessed at 7 days, kidney recovery at 1 month, and progression to CKD and mortality at 3 and 6 months. Following an observation phase to establish baseline data, care providers and physicians in the HCCs were trained with a standardized protocol utilizing POC tests to evaluate and manage patients, guided by physicians in referral hospitals connected via mobile digital technology. We evaluated 3,577 patients, and 2,101 were enrolled: 978 in the observation phase and 1,123 in the intervention phase. Due to the high number of patients attending the centers daily, it was not feasible to screen all patients to assess the actual incidence of AKI. Of enrolled patients, 1,825/2,101 (87%) were adults, 1,117/2,101 (53%) were females, 399/2,101 (19%) were from Bolivia, 813/2,101 (39%) were from Malawi, and 889/2,101 (42%) were from Nepal. The age of enrolled patients ranged from 1 month to 96 years, with a mean of 43 years (SD 21) and a median of 43 years (IQR 27-62). Hypertension was the most common comorbidity (418/2,101; 20%). At enrollment, 197/2,101 (9.4%) had CKD, and 1,199/2,101 (57%) had AKD. AKI developed in 30% within 7 days. By 1 month, 268/978 (27%) patients in the observation phase and 203/1,123 (18%) in the intervention phase were lost to follow-up. In the intervention phase, more patients received fluids (observation 714/978 [73%] versus intervention 874/1,123 [78%]; 95% CI 0.63, 0.94; p = 0.012), hospitalization was reduced (observation 578/978 [59%] versus intervention 548/1,123 [49%]; 95% CI 0.55, 0.79; p < 0.001), and admitted patients with severe AKI did not show a significantly lower mortality during follow-up (observation 27/135 [20%] versus intervention 21/178 [11.8%]; 95% CI 0.98, 3.52; p = 0.057). Of 504 patients with kidney function assessed during the 6-month follow-up, de novo CKD arose in 79/484 (16.3%), with no difference between the observation and intervention phase (95% CI 0.91, 2.47; p = 0.101). Overall mortality was 273/2,101 (13%) and was highest in those who had CKD (24/106; 23%), followed by those with AKD (128/760; 17%), AKI (85/628; 14%), and NKD (36/607; 6%). The main limitation of our study was the inability to determine the actual incidence of kidney dysfunction in the health centers as it was not feasible to screen all the patients due to the high numbers seen daily.ConclusionsThis multicenter, non-randomized feasibility study in low-resource settings demonstrates that it is feasible to implement a comprehensive program utilizing POC testing and protocol-based management to improve the recognition and management of AKI and AKD in high-risk patients in primary care.

BackgroundHypothyroidism is highly prevalent in patients with chronic kidney disease (CKD) and has been associated with poorer clinical outcomes, including faster decline of kidney function. However, there is no consensus whether low free thyroxin (LFT) affects the rate of estimated glomerular filtration rate (eGFR) decline and how the presence of proteinuria influences the progression of renal dysfunction in hypothyroidism.MethodsWe assessed thyroid status, proteinuria, and progression of eGFR by Modification of Diet in Renal Disease equation and CKD-EPI equation in a cohort of CKD patients followed in general nephrology clinics. We estimated the association of LFT levels, and the degree of proteinuria on progression of eGFR. We adjusted for other covariables: age, gender, body mass index, diabetes, hypertension, HbA1c, uric acid, cholesterol, and triglycerides levels..ResultsOne thousand six hundred ten patients (64 ± 15 years, 46.8% men, 25.3% diabetic) were included. At beggnining of follow up eGFR was between 45 and 60, 30-45 and 15-30 ml/min/1.73m2 in 479 (29.8%), 551(34.2%), and 580(36.0%) patients, respectively. LFT levels were available at initial evaluation in 288(17.9%) patients and 735(48.5%) had assessment of proteinuria (19.6% with LFT vs. 15.4% without LFT, p = 0.032). Median follow-up time was of 21 months, and 1223(76%) had at least 1 year of follow up. Overall, eGFR decline per month was - 0.05(- 0.26, 0.23) ml/min/1.73m2, reaching 1.7(1.3, 2.4) ml/min/1.73m2 by the end of study period. Similar results were obtained using CKD-EPI. Multivariable mixed linear analysis showed that proteinuria and age were independently associated with eGFR decline, with no effect of LFT, and no interaction between proteinuria and LFT. In patients without proteinuria, there was an improvement of eGFR despite the presence of LFT.ConclusionsWe confirmed a faster rate of eGFR declined in patients with proteinuria. However, despite the pathophysiological rational that hypothyroidism can lead to increased rate of CKD progression, we failed to demonstrate an association between LFT and rate of CKD progression. We conclude that the benefit of hypothyroidism treatment in CKD patients needs to be evaluate in prospective studies.

BackgroundInterstitial fibrosis (IF) on kidney biopsy is one of the most potent risk factors for kidney disease progression. The furosemide stress test (FST) is a validated tool that predicts the severity of acute kidney injury (especially at 2 h) in critically ill patients. Since furosemide is secreted through the kidney tubules, the response to FST represents the tubular secretory capacity. To our knowledge there is no data on the correlation between functional tubular capacity assessed by the FST with IF on kidney biopsies from patients with chronic kidney disease (CKD). The aim of this study was to determine the association between urine output (UO), Furosemide Excreted Mass (FEM) and IF on kidney biopsies after a FST.MethodsThis study included 84 patients who underwent kidney biopsy for clinical indications and a FST. The percentage of fibrosis was determined by morphometry technique and reviewed by a nephropathologist. All patients underwent a FST prior to the biopsy. Urine volume and urinary sodium were measured in addition to urine concentrations of furosemide at different times (2, 4 and 6 h). We used an established equation to determine the FEM. Values were expressed as mean, standard deviation or percentage and Pearson Correlation.ResultsThe mean age of the participants was 38 years and 44% were male. The prevalence of diabetes mellitus, hypertension and diuretic use was significantly higher with more advanced degree of fibrosis. Nephrotic syndrome and acute kidney graft dysfunction were the most frequent indications for biopsy. eGFR was inversely related to the degree of fibrosis. Subjects with the highest degree of fibrosis (grade 3) showed a significant lower UO at first hour of the FST when compared to lower degrees of fibrosis (p = 0.015). Likewise, the total UO and the FEM was progressively lower with higher degrees of fibrosis. An inversely linear correlation between FEM and the degree of fibrosis (r = - 0.245, p = 0.02) was observed.ConclusionsOur findings indicate that interstitial fibrosis correlates with total urine output and FEM. Further studies are needed to determine if UO and FST could be a non-invasive tool to evaluate interstitial fibrosis.Trial registrationClinicalTrials.gov NCT02417883.

BackgroundAcute kidney injury (AKI) is independently associated with increased morbidity and mortality. Quality improvement has been identified as an important goal in the care of patients with AKI. Different settings can be targeted to improve AKI care, broadly classified these include the inpatient and outpatient environments. In this paper, we will emphasize quality indicators associated with the management and secondary prevention of AKI in hospitalized patients to limit the severity, duration, and complications.MethodsDuring the 22nd Acute Disease Quality Initiative (ADQI) consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations for AKI-related quality indicators (QIs) and care processes to improve patient outcomes. The management and secondary prevention of AKI in hospitalized patients were discussed, and recommendations were summarized.ResultsThe first step in optimizing the quality of AKI management is the determination of baseline performance. Data regarding each institution's/center's performance can provide a reference point from which to benchmark quality efforts. Quality program initiatives should prioritize achievable goals likely to have the highest impact according to the setting and context. Key AKI quality metrics should include improvement in timely recognition, appropriate diagnostic workup, and implementation of known interventions that limit progression and severity, facilitating recovery, and mitigating AKI-associated complications. We propose the Recognition-Action-Results framework to plan, measure, and report the progress toward improving AKI management quality.ConclusionsThese recommendations identified and outlined an approach to define and evaluate the quality of AKI management in hospitalized patients.

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address.

Kidney disease is prevalent in low-resource settings worldwide, but tests for its diagnosis are often unavailable. The saliva urea nitrogen (SUN) dipstick is a laboratory and electricity independent tool, which may be used for the detection of kidney disease. We investigated the feasibility and performance of its use in diagnosing kidney disease in community settings in Africa. Adult patients at increased risk of kidney disease presenting to three community health centres, a rural district hospital and a central hospital in Malawi were recruited between October 2016 and September 2017. Patients underwent concurrent SUN and creatinine testing at enrolment, and at 1 week, 1 month, 3 months and 6 months thereafter. Of 710 patients who presented at increased risk of kidney disease, 655 (92.3%) underwent SUN testing at enrolment, and were included (aged 38 (29-52) years, 367 (56%) female and 333 (50.8%) with HIV). Kidney disease was present in 482 (73.6%) patients and 1479 SUN measurements were made overall. Estimated glomerular filtration rate (eGFR) correlated with SUN (r=-0.39; ptest pad #1) compared with patients with non-elevated SUN (p

BACKGROUND: Chromogranin A (CHGA) is an index granin protein critical for biogenesis and exocytotic release of catecholamine storage granules. It is elevated in plasma of patients with sympathetic over-activity and kidney dysfunction. Several CHGA polymorphisms are associated with hypertensive kidney disease. Previously, we unraveled the molecular mechanism by which CHGA expression is regulated in African Americans carrying a genetic variation associated with hypertensive chronic kidney disease (CKD). METHOD: Experimental CKD mouse model were created by 5/6th nephrectomy (Npx) using wild-type and Chga-/- knockout mouse strains to delineate the role of CHGA in CKD. RESULT: Wild-type-Npx mice expressing Chga developed exacerbated azotemia and fibrosis as compared with their knockout-Npx counterparts. Gene expression profiling revealed downregulation of mitochondrial respiratory complexes genes consistent with maladaptive mitochondria in wild-type-Npx mice, contrasted to knockout-Npx. In healthy individuals, an inverse relationship between circulating CHGA levels and glomerular function was observed. In vitro, mesangial cells treated with CHGA-triggered nitric oxide release by a signaling mechanism involving scavenger receptor SR-A. The CHGA-treated and untreated mesangial cells displayed differential expression of cytokine, chemokine, complement, acute phase inflammatory and apoptotic pathway genes. Thus, build-up of plasma CHGA because of kidney injury served as an insult to the mesangial cells resulting in expression of genes promoting inflammation, fibrosis, and progression of CKD. CONCLUSION: These findings improve understanding of the role of elevated CHGA in the progression of CKD and reveal novel pathways that could be exploited for therapeutic strategies in hypertensive kidney disease.

OBJECTIVES:Although the majority of the global population lives in developing countries, most of the epidemiological data related to intensive care unit (ICU) acute kidney injury (AKI) comes from developed countries. This systematic review aims to ascertain the methodology of studies on ICU AKI patients in developing and developed countries, to determine whether epidemiological comparisons between these two settings are possible, and to present a summary estimate of AKI incidence. METHODS:A systematic review of published studies reporting AKI in intensive care units (2005-2015) identified in PubMed, LILACS, and IBECs databases was conducted. We compared developed and developing countries by evaluating study methodology, AKI reference serum creatinine definitions, population characteristics, AKI incidence and mortality. AKI incidence was calculated with a random-effects model. RESULTS:Ninety-two studies were included, one of which reported data from both country categories: 60 from developed countries (1,057,332 patients) and 33 from developing countries (34,539 patients). In 78% of the studies, AKI was defined by the RIFLE, AKIN or KDIGO criteria. Oliguria had 11 different definitions and reference creatinine 23 different values. For the meta-analysis, 38 studies from developed and 18 from developing countries were selected, with similar AKI incidence: 39.3% and 35.1%, respectively. The need for dialysis, length of ICU stay and mortality were higher in developing countries. CONCLUSION:Although patient characteristics and AKI incidence were similar in developed and developing countries, main outcomes were worse in developing country studies. There are significant caveats when comparing AKI epidemiology in developed and developing countries, including lack of standardization of reference serum creatinine, oliguria and the timeframe for AKI assessment. Larger, prospective, multicenter studies from developing countries are urgently needed to capture AKI data from the overall population without ICU access.

BACKGROUND:Acute kidney injury (AKI) is a common complication in patients undergoing liver transplant (LT) and is associated with high morbidity and mortality. We aim to evaluate the pattern of urine and plasma neutrophil gelatinase-associated lipocalin (NGAL) elevation during the perioperative period of LT and to assess it as a prognostic marker for AKI progression, need for dialysis and mortality. METHODS:We assessed NGAL levels before induction of anesthesia, after portal reperfusion and at 6, 18, 24, and 48 h after surgery. Patients were monitored daily during the first week after LT. RESULTS:Of 100 enrolled patients undergoing liver transplant, 59 developed severe AKI based on the KDIGO serum creatinine (sCr) criterion; 34 were dialysed, and 21 died within 60 days after LT. Applying a cut-off value of 136 ng/ml, UNGAL values 6 h after surgery was a good predictor of AKI development within 7 days after surgery, having a positive predictive value (PPV) of 80% with an AUC of 0.76 (95% CI 0.67-0.86). PNGAL at 18 h after LT was also a good predictor of AKI in the first week, having a PPV of 81% and AUC of 0.74 (95% CI 0.60-0.88). Based on PNGAL and UNGAL cut-off criteria levels, time to AKI diagnosis was 28 and 23 h earlier than by sCr, respectively. The best times to assess the need for dialysis were 18 h after LT by PNGAL and 06 h after LT by UNGAL. CONCLUSION:In conclusion, the plasma and urine NGAL elevation pattern in the perioperative period of the liver transplant can predict AKI diagnosis earlier. UNGAL was an early independent predictor of AKI development and need for dialysis. Further studies are needed to assess whether the clinical use of biomarkers can improve patient outcomes. TRIAL REGISTRATION:Registered at Clinical Trials ( clinicaltrials.gov ) in March 24th, 2014 by title "Acute Kidney Injury Biomarkers: Diagnosis and Application in Pre-operative Period of Liver Transplantation (AKIB)" and identifier NCT02095431, retrospectively registered.

BackgroundIntradialytic hypotension, a complication of intermittent hemodialysis, decreases the efficacy of dialysis and increases long-term mortality. This study was aimed to determine whether different predialysis ultrasound cardiopulmonary profiles could predict intradialytic hypotension.MethodsThis prospective observational single-center study was performed in 248 critically ill patients with acute kidney injury undergoing intermittent hemodialysis. Immediately before hemodialysis, vena cava collapsibility was measured by vena cava ultrasound and pulmonary congestion by lung ultrasound. Factors predicting intradialytic hypotension were identified by multiple logistic regression analysis.ResultsIntradialytic hypotension was observed in 31.9% (n = 79) of the patients, interruption of dialysis because of intradialytic hypotension occurred in 6.8% (n = 31) of the sessions, and overall 28-day mortality was 20.1% (n = 50). Patients were classified in four ultrasound profiles: (A) 108 with B lines > 14 and vena cava collapsibility > 11.5 mm m-2, (B) 38 with B lines  14 and vena cava collapsibility Di ≤ 11.5 mm m-2, and (D) 66 with B lines  11.5 mm m-2. There was an increased risk of intradialytic hypotension in patients receiving norepinephrine (odds ratios = 15, p = 0.001) and with profiles B (odds ratios = 12, p = 0.001) and C (odds ratios = 17, p = 0.001).ConclusionIn critically ill patients on intermittent hemodialysis, the absence of hypervolemia as assessed by lung and vena cava ultrasound predisposes to intradialytic hypotension and suggests alternative techniques of hemodialysis to provide better hemodynamic stability.

High serum concentrations of kidney-derived protein uromodulin [Tamm-Horsfall protein (THP)] have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with postsurgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity, and our findings might help explain how circulating THP deficiency is linked with poor outcomes and increased mortality.

Acute kidney injury (AKI) is a frequent event in hospitalized patients, with an incidence that continues to rise, reaching as high as 70-80% in intensive care settings. The need for dialysis and progression to end-stage kidney disease (ESKD) after an episode of AKI is relatively low, from 5 to 20%. However, it is now recognized that patients with AKI may have very different kidney outcomes, varying from complete recovery, incipient chronic kidney disease (CKD), to progression to ESKD. Recent studies have shown that even mild AKI episodes can be associated with a 90% increased risk of developing CKD during long-term follow-up. There is a significant need to focus our efforts on factors that could mitigate the progression of kidney dysfunction and ultimately improve outcomes from AKI. The first step toward this goal encompasses a better understanding of tubular and glomerular alterations during and following an AKI episode. Our current approach, based solely on glomerular filtration rate (GFR), is flawed, since the loss of kidney function does not correspond to the degree of decline in estimated GFR (eGFR), and eGFR does not reflect tubular function. Changes in tubular concentration, reabsorptive and secretory capacity are recognized in AKI; however, they have not been incorporated in clinical assessments of overall kidney function. Here we review a few candidates to assess glomerular filtration/permeability, tubular dysfunction, and injury and how we expect these markers to alter during the development and recovery phase of AKI.

BackgroundIn evidence-based medicine, multicenter, prospective, randomized controlled trials (RCTs) are the gold standard for evaluating treatment benefits and ensuring the effectiveness of interventions. Patient-centered outcomes, such as mortality, are most often the preferred evaluated outcomes. While there is currently agreement on how to classify renal dysfunction in critically ill patients , the application frequency of this new classification system in RCTs has not previously been evaluated. In this study, we aim to assess the definition of renal dysfunction in multicenter RCTs involving critically ill patients that included mortality as a primary endpoint.MethodsA comprehensive search was conducted for publications reporting multicenter randomized controlled trials (RCTs) involving adult patients in intensive care units (ICUs) that included mortality as a primary outcome. MEDLINE and PUBMED were queried for relevant articles in core clinical journals published between May 2004 and December 2017.ResultsOf 418 articles reviewed, 46 multicenter RCTs with a primary endpoint related to mortality were included. Thirty-six (78.3%) of the trial reports provided information on renal function in the participants. Only seven articles (15.2%) included mean or median serum creatinine levels, mean creatinine clearance or estimated glomerular filtration rates. Sequential organ failure assessment (SOFA) score was the most commonly used definition of renal dysfunction (20 studies; 43.5%). Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) criteria were used in five (10.9%) trials. In thirteen trials (28.3%), no renal dysfunction criteria were reported. Only one trial excluded patients with renal dysfunction, and it used urinary output or need for renal replacement therapy (RRT) as criteria for this diagnosis.ConclusionThe presence of renal dysfunction was included as a baseline patient characteristic in most RCTs. The RIFLE, AKIN and KDIGO classification systems were infrequently used; renal dysfunction was generally defined using the SOFA score.

Acute kidney injury (AKI) can potentially lead to the accumulation of antimicrobial drugs with significant renal clearance. Drug dosing adjustments are commonly made using the Cockcroft-Gault estimate of creatinine clearance (CLcr). The Modified Jelliffe equation is significantly better at estimating kidney function than the Cockcroft-Gault equation in the setting of AKI. The objective of this study is to assess the degree of antimicrobial dosing discordance using different glomerular filtration rate (GFR) estimating equations. This is a retrospective evaluation of antimicrobial dosing using different estimating equations for kidney function in AKI and comparison to Cockcroft-Gault estimation as a reference. Considering the Cockcroft-Gault estimate as the criterion standard, antimicrobials were appropriately adjusted at most 80.7% of the time. On average, kidney function changed by 30 mL/min over the course of an AKI episode. The median clearance at the peak serum creatinine was 27.4 (9.3⁻66.3) mL/min for Cockcroft Gault, 19.8 (9.8⁻47.0) mL/min/1.73 m² for MDRD and 20.5 (4.9⁻49.6) mL/min for the Modified Jelliffe equations. The discordance rate for antimicrobial dosing ranged from a minimum of 8.6% to a maximum of 16.4%. In the event of discordance, the dose administered was supra-therapeutic 100% of the time using the Modified Jelliffe equation. Use of estimating equations other than the Cockcroft Gault equation may significantly alter dosing of antimicrobials in AKI.

Acute kidney injury (AKI) is a common complication, impacting short- and long-term patient outcomes. Although the application of the classification systems for AKI has improved diagnosis, early clinical recognition of AKI is still challenging, as increments in serum creatinine may be late and low urine output is not always present. The role of urinary biochemistry has remained unclear, especially in critically ill patients. Differentiating between a transient and persistent acute kidney injury is of great need in clinical practice, and despite studies questioning their application in clinical practice, biochemistry indices continue to be used while we wait for a novel early injury biomarker. An ideal marker would provide more detailed information about the type, intensity, and location of the injury. In this review, we will discuss factors affecting the fractional excretion of sodium (FeNa) and fractional excretion of urea (FeU). We believe that the frequent assessment of urinary biochemistry and microscopy can be useful in evaluating the likelihood of AKI reversibility. The availability of early injury biomarkers could help guide clinical interventions.

BackgroundIn low and middle-income countries, reliable data on the epidemiology of childhood acute kidney injury (AKI) is lacking. The Global Snapshot, conducted by the ISN "0by25" AKI initiative, was a world-wide cross-sectional, observational study to evaluate AKI in hospitalized patients. Here we report the pediatric results of this study.Patients and methodsWe prospectively collected data on children who met the Kidney Disease Improving Global Outcomes AKI criteria during a 10-week window in late 2014. AKI risk factors, etiological factors, management and outcomes were recorded using standardized forms and protocols. Countries were classified according to their 2014 gross national income (GNI) per person into high-income countries (HIC), upper-middle income countries (UMIC) and low and low-middle income countries (LLMIC). Need for renal replacement therapy, mortality, and renal recovery were assessed 7 days after AKI diagnosis or at hospital discharge, whichever came first.Results92 centers from 41 countries collected data on 354 pediatric AKI patients; 53% of the children developed AKI while hospitalized and 47% in the community. The most common etiological factors for AKI differed across GNI categories as well as between patients with community-acquired vs. hospital-acquired AKI. Children from HIC were younger, and larger proportion of AKI in this group were due to post-surgical complications vs. other etiologies when compared to other income categories. In patients with hypotension as the cause of AKI, the adjusted risk of death was almost 10-fold higher compared to patients without hypotension as an etiological factor for AKI development. Mortality was similar within AKI stages in HIC and UMIC. In LLMIC, patients with the highest AKI level of severity had higher mortality than patients in higher income categories. Patients from LLMIC and UMIC had a 57-fold and 11 fold higher adjusted risk of death, respectively, compared to patients from HIC.ConclusionIn resource-limited countries, pediatric AKI-associated mortality is disproportionately higher when compared to high-resource areas, especially among patients with more severe AKI.

BackgroundThis study aimed to identify predictors of early (7-day) mortality in patients with septic acute kidney injury (AKI) who required continuous renal replacement therapy (CRRT).MethodsProspective cohort of 186 septic AKI patients undergoing CRRT at a tertiary hospital, from October 2005 to November 2010.ResultsAfter multivariate adjustment, five variables were associated to early mortality: norepinephrine utilization, liver failure, medical condition, lactate level, and pre-dialysis creatinine level. These variables were combined in a score, which demonstrated good discrimination, with a C-statistic of 0.82 (95% CI = 0.76-0.88), and good calibration (χ 2 = 4.3; p = 0.83). SAPS 3, APACHE II and SOFA scores demonstrated poor performance in this population.ConclusionsThe HEpatic failure, LactatE, NorepInephrine, medical Condition, and Creatinine (HELENICC) score outperformed tested generic models. Future studies should further validate this score in different cohorts.

The incidence of acute kidney injury (AKI) among acutely ill patients is reportedly very high and has vexing consequences on patient outcomes and health care systems. The risks and impact of AKI differ between developed and developing countries. Among developing countries, AKI occurs in young individuals with no or limited comorbidities, and is usually due to environmental causes, including infectious diseases. Although several risk factors have been identified for AKI in different settings, there is limited information on how risk assessment can be used at population and patient levels to improve care in patients with AKI, particularly in developing countries where significant health disparities may exist. The Acute Disease Quality Initiative consensus conference work group addressed the issue of identifying risk factors for AKI and provided recommendations for developing individualized risk stratification strategies to improve care. We proposed a 5-dimension, evidence-based categorization of AKI risk that allows clinicians and investigators to study, define, and implement individualized risk assessment tools for the region or country where they practice. These dimensions include environmental, socioeconomic and cultural factors, processes of care, exposures, and the inherent risks of AKI. We provide examples of these risks and describe approaches for risk assessments in the developing world. We anticipate that these recommendations will be useful for health care providers to plan and execute interventions to limit the impact of AKI on society and each individual patient. Using a modified Delphi process, this group reached consensus regarding several aspects of AKI risk stratification.

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.

IntroductionNephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD.MethodsA total of 800 patients will be enrolled worldwide and blood samples for DNA collected. Data on the patient risk factors, vital signs, laboratory parameters, drug exposure, and DIKD course will be recorded. A panel of nephrologists will adjudicate all cases. Genome-wide association studies will be conducted using population controls matched on biogeographic ancestry to determine whether there is a genetic predisposition to DIKD. The primary endpoint is the identification of specific drug-related polymorphisms associated with DIKD. Secondary endpoints include the following: frequency of DIKD by causal drug and drug combinations; DIKD genetic variability; exploration of causality assessment tools; risk factor identification; description of the course of DIKD, including mortality and dialysis dependency at hospital discharge and 28 and 90 days post-event.ResultsData are currently being analyzed. Results are pending.DiscussionThe Genetic Contribution to Drug Induced Renal Injury (DIRECT) study will be the first observational cohort study to investigate the genetic determinants of DIKD. If the trial is positive, its findings will potentially translate into safer patient outcomes, by genotypic individualization of therapy and minimization of harm.

Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition.

Abstract Introduction Serum creatinine concentration (sCr) is the marker used for diagnosing and staging acute kidney injury (AKI) in the RIFLE and AKIN classification systems, but is influenced by several factors including its volume of distribution. We evaluated the effect of fluid accumulation on sCr to estimate severity of AKI. Methods In 253 patients recruited from a prospective observational study of critically-ill patients with AKI, we calculated cumulative fluid balance and computed a fluid-adjusted sCr concentration reflecting the effect of volume of distribution during the development phase of AKI. The time to reach a relative 50% increase from the reference sCr using the crude and adjusted sCr was compared. We defined late recognition to estimate severity of AKI when this time interval to reach 50% relative increase between the crude and adjusted sCr exceeded 24 hours. Results The median cumulative fluid balance increased from 2.7 liters on day 2 to 6.5 liters on day 7. The difference between adjusted and crude sCr was significantly higher at each time point and progressively increased from a median difference of 0.09 mg/dL to 0.65 mg/dL after six days. Sixty-four (25%) patients met criteria for a late recognition to estimate severity progression of AKI. This group of patients had a lower urine output and a higher daily and cumulative fluid balance during the development phase of AKI. They were more likely to need dialysis but showed no difference in mortality compared to patients who did not meet the criteria for late recognition of severity progression. Conclusions In critically-ill patients, the dilution of sCr by fluid accumulation may lead to underestimation of the severity of AKI and increases the time required to identify a 50% relative increase in sCr. A simple formula to correct sCr for fluid balance can improve staging of AKI and provide a better parameter for earlier recognition of severity progression.