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Background: Acute changes in glomerular filtration rate (GFR) can occur following initiation of interventions for chronic kidney disease (CKD) progression. These complicate the interpretation of treatment effects on long term progression of (CKD). We sought to assess the magnitude and consistency of acute effects in randomized clinical trials (RCT) and explore factors that might impact them. Methods: We performed a meta-analysis of 53 RCTs for CKD progression enrolling 56,413 participants that had at least one estimated GFR measurement by six months following randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable meta-regression to assess the impact of intervention type, disease state, baseline GFR and albuminuria on the magnitude of acute effects. Results: The mean acute effect across all studies was -0.21 mL/min/1.73m2 (95% CI -0.63 to 0.22) over three months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 mL/min/1.73m2). Negative average acute effects were observed in renin angiotensin system blockade, blood pressure lowering and sodium-glucose cotransporter 2 inhibitor trials while positive acute effects were observed in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with higher mean baseline GFR. Conclusion: The magnitude and consistency of acute GFR effects varies across different interventions, and is larger at higher baseline GFR. Understanding the nature and magnitude of the acute effects can help inform the optimal design of RCTs in CKD evaluating kidney disease progression.

Background The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (Findings We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pinteraction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group. Interpretation Pharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines. Funding British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School.

Hypertension is frequently both a cause and complication of CKD. The optimal blood pressure target in CKD has been of hot debate over the decades with little data to inform the goals. Here, we review the data from the Systolic Blood Pressure Intervention Trial (SPRINT), Modification of Diet in Renal Disease (MDRD), African American Study of Kidney Disease and Hypertension (AASK), Ramipril Efficacy in Nephropathy-2 (REIN-2), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials to use the available evidence to better inform what blood pressure goal should be recommended in patients with CKD and to answer the question "How low should we go?".

In the original publication of the article, the majority of changes stem from misclassification of “medium adherence” when using the Morisky Medication Adherence Scale (MMAS-8) and not using the correct scoring algorithm for one of the responses when calculating MMAS-8 total scores.

Background The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from

The concept of multinephron segment diuretic therapy (MSDT) has been recommended in severe diuretic resistance with only expert opinion and case-level evidence. The purpose of this study was to investigate the safety and efficacy of MSDT, combining 4 diuretic classes, in acute heart failure (AHF) complicated by diuretic resistance.A retrospective analysis was conducted in patients hospitalized with AHF at a single medical center who received MSDT, including concomitant carbonic anhydrase inhibitor, loop, thiazide, and mineralocorticoid receptor antagonist diuretics. Subjects served as their own controls with efficacy evaluated as urine output and weight change before and after MSDT. Serum chemistries, renal replacement therapies, and in-hospital mortality were evaluated for safety. Patients with severe diuretic resistance before MSDT were analyzed as a subcohort. A total of 167 patients with AHF and diuretic resistance received MSDT. MSDT was associated with increased median 24-hour urine output in the first day of therapy compared with the previous day (2.16 L [0.95-4.14 L] to 3.08 L [1.74-4.86 L], P = .003) in the total cohort and in the Severe diuretic resistance cohort (0.91 L [0.43-1.43 L] to 2.08 L [1.13-3.96 L], P.001). The median cumulative weight loss at day 7 or discharge was -7.4 kg (-15.3 to -3.4 kg) (P = .02). Neither serum sodium, chloride, potassium, bicarbonate, or creatinine changed significantly relative to baseline (P.05 for all).In an AHF cohort with diuretic resistance, MSDT was associated with increased diuresis without changes in serum chemistries or kidney function. Prospective studies of MSDT in AHF and diuretic resistance are warranted.

BACKGROUND: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%.OBJECTIVE: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial.DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934).SETTING: 306 sites in 32 countries.PARTICIPANTS: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure.INTERVENTION: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo.MEASUREMENTS: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models.RESULTS: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days).LIMITATION: Other than heart failure, the primary reason for each hospitalization was unspecified.CONCLUSION: Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life.PRIMARY FUNDING SOURCE: Sanofi at initiation and Lexicon Pharmaceuticals at completion.

Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials.Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1.73 m(2), or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria.Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3.4 years (IQR 2.3-4.2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0.89 (95% Bayesian credible interval [BCI] 0.13-1.70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R-2 0.47, 95% BCI 0.02-0.96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3.4 mg/mmol; R-2 0.72, 0.05-0.99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0.7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0.68, and 95% of sufficiently large studies would have HRs between 0.47 and 0.95.Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes., Graphical abstract

Background and objectives Incidence of ESKD is three times higher in black Americans than in whites, and CKD prevalence continues to rise among black Americans. Community-based kidney disease screening may increase early identification and awareness of black Americans at risk, but it is challenging to implement. This study aimed to identify participants’ perspectives of community kidney disease screening. The Health Belief Model provides a theoretic framework for conceptualization of these perspectives and optimization of community kidney disease screening activities. Design, setting, participants, & measurements Researchers in collaboration with the Tennessee Kidney Foundation conducted three focus groups of adults in black American churches in Nashville, Tennessee. Questions examined views on CKD information, access to care, and priorities of kidney disease health. Content analysis was used. Guided by the Health Belief Model, a priori themes were generated, and additional themes were derived from the data using an inductive approach. Results Thirty-two black Americans completed the study in 2014. Participants were mostly women (79%) with a mean age of 56 years old (range, 24–78). Two major categories of barriers to kidney disease screening were identified: ( 1 ) participant factors, including limited kidney disease knowledge, spiritual/religious beliefs, emotions, and culture of the individual; and ( 2 ) logistic factors, including lack of convenience and incentives and poor advertisement. Potential facilitators of CKD screening included provision of CKD education, convenience of screening activities, and use of culturally sensitive and enhanced communication strategies. Program recommendations included partnering with trusted community members, selecting convenient locations, tailored advertising, and provision of compensation. Conclusions Findings of this study suggest that provider-delivered culturally sensitive education and stakeholder engagement are critical to increase trust, decrease fear, and maximize participation and early identification of kidney disease among black Americans considering community screening.

Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations 34% are safe and provide maximal efficacy. .

In March of 2018, the National Kidney Foundation, in collaboration with the US Food and Drug Administration and the European Medicines Agency, sponsored a workshop in which surrogate endpoints other than currently established event-time endpoints for clinical trials in chronic kidney disease (CKD) were presented and discussed. One such endpoint is a slope-based parameter describing the rate of decline in the estimated glomerular filtration rate (eGFR) over time. There are a number of challenges that can complicate such slope-based analyses in CKD trials. These include the possibility of an early but short-term acute treatment effect on the slope, both within-subject and between-subject heteroscedasticity, and informative censoring resulting from patient dropout due to death or onset of end-stage kidney disease. To address these issues, we first consider a class of mixed-effects models for eGFR that are linear in the parameters describing the mean eGFR trajectory but which are intrinsically nonlinear when a power-of-mean variance structure is used to model within-subject heteroscedasticity. We then combine the model for eGFR with a model for time to dropout to form a class of shared parameter models which, under the right specification of shared random effects, can minimize bias due to informative censoring. The models and methods of analysis are described and illustrated using data from two CKD studies one of which was one of 56 studies made available to the workshop analytical team. Lastly, methodology and accompanying software for prospectively determining sample size/power estimates are presented.

Item does not contain fulltext BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0.83 (95% CI 0.74-0.94), decreasing to 0.78 (0.66-0.92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction

TGF-β has been implicated as a major pathogenic factor in diabetic nephropathy. This randomized, double-blind, phase 2 study assessed whether modulating TGF-β1 activity with a TGF-β1–specific, humanized, neutralizing monoclonal antibody (TGF-β1 mAb) is safe and more effective than placebo in slowing renal function loss in patients with diabetic nephropathy on chronic stable renin-angiotensin system inhibitor treatment. We randomized 416 patients aged ≥25 years with type 1 or type 2 diabetes, a serum creatinine (SCr) level of 1.3–3.3 mg/dl for women and 1.5–3.5 mg/dl for men (or eGFR of 20–60 ml/min per 1.73 m2), and a 24-hour urine protein-to-creatinine ratio ≥800 mg/g to TGF-β1 mAb (2-, 10-, or 50-mg monthly subcutaneous dosing for 12 months) or placebo. We assessed a change in SCr from baseline to 12 months as the primary efficacy variable. Although the Data Monitoring Committee did not identify safety issues, we terminated the trial 4 months early for futility on the basis of their recommendation. The placebo group had a mean±SD change in SCr from baseline to end of treatment of 0.33±0.67 mg/dl. Least squares mean percentage change in SCr from baseline to end of treatment did not differ between placebo (14%; 95% confidence interval [95% CI], 9.7% to 18.2%) and TGF-β1 mAb treatments (20% [95% CI, 15.3% to 24.3%], 19% [95% CI, 14.2% to 23.0%], and 19% [95% CI, 14.0% to 23.3%] for 2-, 10-, and 50-mg doses, respectively). Thus, TGF-β1 mAb added to renin-angiotensin system inhibitors did not slow progression of diabetic nephropathy.

Introduction: Oral phosphate binders are the main stay of treatment of hyperphosphatemia. Adherence rates to ferric citrate, a recently approved phosphate binder, are unknown. Methods: We conducted a post-hoc analysis to evaluate whether adherence rates were different for ferric citrate vs. active control in 412 subjects with end stage kidney disease (ESKD) who were randomized to ferric citrate vs. active control (sevelamer carbonate and/or calcium acetate). Adherence was defined as percent of actual number of pills taken to total number of pills prescribed. Findings: There were no significant differences in baseline characteristics including gender, race/ethnicity, and age between the ferric citrate and active control groups. Baseline phosphorus, calcium, and parathyroid hormone levels were similar. Mean (SD) adherence was 81.4% (17.4) and 81.7% (15.9) in the ferric citrate and active control groups, respectively (P = 0.88). Adherence remained similar between both groups after adjusting for gender, race/ethnicity, age, cardiovascular disease (CVD), and diabetic nephropathy (mean [95% CI]: 81.4% [78.2, 84.6] and 81.5% [77.7, 85.2] for ferric citrate and active control, respectively). Gender, race/ethnicity, age, and diagnosis of diabetic nephropathy did not influence adherence to the prescribed phosphate binder. Subjects with CVD had lower adherence rates to phosphate binder; this was significant only in the active control group. Discussion: Adherence rates to the phosphate binder, ferric citrate, were similar to adherence rates to active control. Similar adherence rates to ferric citrate are notable since tolerance to active control was an entry criteria and the study was open label. Gender, race/ethnicity, nor age influenced adherence.

In this manuscript, nephrologist-investigators from one of five Clinical Center Networks of the Systolic Blood Pressure Intervention Trial (SPRINT) provide background information and context on the intensity of anti-hypertensive therapy in conjunction with the release of detailed results from SPRINT's primary analysis. The authors highlight published evidence on the safety and efficacy of differing intensities of anti-hypertensive therapy in mild to moderate CKD, where SPRINT will help to inform practice, as well as where gaps in evidence will remain. The authors also challenge the nephrology community to renew its attention and efforts on hypertension clinical care and research.

Background: Accurate identification of Clostridioides difficile infections (CDIs) from electronic data sources is important for surveillance. We evaluated how frequently laboratory findings were supported by diagnostic coding and treatment data in the electronic health record. Methods: We analyzed a retrospective cohort of patients in the Veterans’ Affairs Health System from 2006 through 2016. A CDI event was defined as a positive laboratory test for C. difficile toxin or toxin genes in the inpatient, outpatient, or long-term care setting with no prior positive test in the preceding 14 days. Events were classified as incident (no CDI in the prior 56 days), or recurrent (CDI in the prior 56 days) and were evaluated for evidence of clinical diagnosis based on International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM codes and at least 1 dose of an anti-CDI agent (intravenous or oral metronidazole, fidaxomicin, or oral vancomycin). We further assessed the possibility of treatment without testing by quantifying positive laboratory tests and diagnostic codes among inpatients receiving an anti-CDI agent. A course of anti-CDI therapy was defined as continuous treatment with the same drug. Results: Among 119,063 incident and recurrent CDI events, 70,114 (58.9%) had a diagnosis code and 15,850 (13.3%) had no accompanying treatment. The proportion of patients with ICD codes was highest among patients treated with fidaxomicin (82.6% of 906) or oral vancomycin (74.3% of 30,777) and was lower among patients receiving metronidazole (63.3% of 103,231) and those without treatment (29.9% of 15,850). The proportion of events with ICD codes and treatment was similar between incident and recurrent episodes. During the study period, there were ~470,000 inpatient courses of metronidazole, fidaxomicin, and oral vancomycin. Table 1 shows the presence of ICD codes and positive laboratory tests by anti-CDI agents. Among 51,100 courses of oral vancomycin, 51% had an ICD code and 44% had a positive test for C. difficile within 7 days of treatment initiation. Among 1,013 courses of fidaxomicin, 79% had an ICD code and 56% had a positive laboratory test. Conclusions: In this large cohort, there was evidence of substantial CDI treatment without confirmatory C. difficile testing and, to a lesser extent, some positive tests without accompanying treatment or coding. A combination of data sources may be needed to more accurately identify CDI from electronic health records for surveillance purposes.Funding: NoneDisclosures: None

Recurrent Clostridioides difficile infection (rCDI) may be mediated in part by secondary bile acids. Here we report salvage therapy with ursodeoxycholic acid (UDCA) to prevent rCDI in 16 high-risk patients. Patients on UDCA had a low observed recurrence rate (12.5%). Controlled trials are needed to confirm these observations.

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P

Background: Low serum bicarbonate level has been reported to be an independent predictor of kidney function decline and mortality in patients with chronic kidney disease. Mechanisms underlying low serum bicarbonate levels may differ in patients with and without diabetes. We aimed to specifically investigate the association of serum bicarbonate level with kidney disease progression and cardiovascular outcome in a cohort of patients with type 2 diabetes and nephropathy.Study Design: Post hoc analysis of 2 multicenter randomized controlled trials.Setting & Participants: 2,628 adults with type 2 diabetes and nephropathy.Factor: Serum bicarbonate level.Outcomes: Incidence of: (1) end-stage renal disease (ESRD), (2) ESRD or doubling of serum creatinine level, (3) all-cause mortality, (4) cardiovascular events (fatal/nonfatal stroke/myocardial infarction), and (5) heart failure.Measurements: Serum bicarbonate was measured at baseline as total carbon dioxide. Associations of baseline serum bicarbonate level with end points were investigated using Cox regression models. Serum bicarbonate levels were studied as a continuous variable and stratified in quartiles. Follow-up was 2.8 +/- 1.0 (SD) years.Results: Cox regression analyses showed that serum bicarbonate level had inverse associations with incident ESRD (HR, 0.91; 95% CI, 0.89-0.93; P 0.05). Analysis of bicarbonate quartiles showed similar results for the quartile with the lowest bicarbonate (Limitations: Post hoc analysis and single measurement of serum bicarbonate.Conclusions: In this cohort of patients with type 2 diabetes with nephropathy, serum bicarbonate level associations with kidney disease end points were not retained after adjustment for estimated glomerular filtration rate, which is in contrast to results of earlier studies in nondiabetic populations. (C) 2015 by the National Kidney Foundation, Inc.

A technical expert panel (TEP) was convened to evaluate all available literature in the area of bone and mineral metabolism and advise the Centers for Medicare and Medicaid services on the creation and collection of quality measures. The proposed quality measures were evaluated for importance, usability, feasibility, and scientific acceptability. All are important parameters to avoid unintended harmful consequences of a quality measure causing harm to patients or to the delivery of their health care.

Ferric citrate is a novel phosphate binder that allows the simultaneous treatment of hyperphosphatemia and iron deficiency in patients being treated for end-stage renal disease with hemodialysis (HD). Multiple clinical trials in HD patients have uniformly and consistently demonstrated the efficacy of the drug in controlling hyperphosphatemia with a good safety profile, leading the US Food and Drug Administration in 2014 to approve its use for that indication. A concurrent beneficial effect, while using ferric citrate as a phosphate binder, is its salutary effect in HD patients with iron deficiency being treated with an erythropoietin-stimulating agent (ESA) in restoring iron that becomes available for reversing chronic kidney disease (CKD)-related anemia. Ferric citrate has also been shown in several studies to diminish the need for intravenous iron treatment and to reduce the requirement for ESA. Ferric citrate is thus a preferred phosphate binder that helps resolve CKD-related mineral bone disease and iron-deficiency anemia.

Albuminuria is a risk factor for progression of kidney disease. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers slow the progression to ESRD, an effect that is correlated with reduction in albuminuria. This has led to the hypothesis that albuminuria should be a target for therapy. This work argues that there are issues with this hypothesis. The previously reported studies were not designed to test the hypothesis that achieving a specific albuminuria target would be beneficial in and of itself irrespective the mechanism used to achieve that goal. One cannot assume that the beneficial effect observed was causally related to the effect on albuminuria or that it would extend to other interventions. Most importantly, it is not known if the approach of maximizing therapy to reduce proteinuria is safe. Recent studies have shown that combining renin-angiotensin system therapies decreases albuminuria without significant clinical benefit but with increased risk of adverse events. More studies are needed, but at this time, albuminuria has not jumped the hurdle needed to be accepted as a surrogate end point or target for treatment. Primum non nocere, first do no harm.

BACKGROUND: Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events. STUDY DESIGN: Data on AKI resulting in or during hospitalization or emergency department visits were collected as part of the serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: 9361 participants aged 50 or older with one or more risk factors for cardiovascular disease. INTERVENTIONS: Participants were randomly assigned to a systolic BP target of

A 22-year-old male without significant prior medical history presented to the hospital with headache and double vision of 1 month's duration. He reported a trip to the island of Hawaii 1.5 months prior, where he spent time on the beach, including in the ocean, and ate various types of seafood

Diabetic kidney disease and diabetic nephropathy are the leading cause of end-stage kidney disease in the United States and most developed countries. Diabetes accounts for 30% to 50% of the incident cases of end-stage kidney disease in the United States. Although this represents a significant public health concern, it is important to note that only 30% to 40% of patients with diabetes develop diabetic nephropathy. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin-angiotensin system (RAS). Recommendations for therapy include targeting a hemoglobin A1c concentration

Bilirubin, a potent endogenous antioxidant, was found to protect against the development of diabetic nephropathy (DN) in rodents. In humans, cross-sectional studies found an inverse relation between bilirubin and DN. We prospectively investigated whether bilirubin is associated with progression of DN toward end-stage renal disease (ESRD). To this end, we performed a post hoc analysis in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial with independent replication in the Irbesartan Diabetic Nephropathy Trial (IDNT). Subjects with type 2 diabetes and nephropathy with alanine aminotransferase, aspartate aminotransferase (AST), and bilirubin levels

Background Inappropriate or unnecessary use of antibiotics exacerbates antimicrobial resistance and can lead to adverse clinical outcomes. To address this issue, NHSN created the Antimicrobial Use (AU) Option to report antimicrobial use within acute care facilities. A pilot program was started to implement AU reporting in VA in 2013. Methods With support from VA Antimicrobial Stewardship Task Force and NHSN, we deployed one team to focus on implementation and another on technical aspects. We used an iterative recruitment approach with four cohorts to date (Tiers), starting with highly engaged facilities with strong stewardship infrastructure. Our implementation approach (Figure 1) was based on the Promoting Action on Research Implementation (PARiHS) framework for successful implementation of evidence into clinical practice. We evaluated our implementation with focus groups conducted using Skype chat to collect feedback from participants about the implementation process. Group 1 contained six participants from Tiers 1 and 2. Group 2 had three participants from Tiers 3 and 4. Questions were constructed using the PARiHS framework (Table 1). An implementation team member conducted interviews, monitored the discussion, then coded major themes of responses. Results To date, there are over 90 facilities reporting AU to NHSN. Major themes to responses are summarized in Table 1. Overall, focus group participants were supportive of the program, but there were differences between early and later adopters. Conclusion A coordinated, centralized approach to facilitating implementation of NHSN AU reporting has been successful so far. Major themes from focus group responses did differ in some categories depending on tier in a way that appears concordant with the theory diffusion of innovation, e.g., early tiers were enthusiastic despite a lack of institutional support while later tiers reported being motivated by regulatory requirements and had solid institutional support. More research would further inform how to efficiently implement complex programs in large systems. Disclosures All authors: No reported disclosures.

Background Antimicrobial inappropriateness is highly contextual and dynamic, depending not only on the patient’s disease condition but also the information available at the time. To estimate the extent to which antimicrobials could theoretically be decreased with antimicrobial stewardship, we sought to capture unnecessary inpatient antimicrobial use in context over time as manifested in the electronic health record in Veterans Affairs (VA). Methods We extracted antimicrobial use, administrative, admission, and laboratory data from all acute care VA medical centers between 2010 and 2016. Information present during Choice (hospital day [HD] 1–3), Change (HD 4–5), Completion (HD 6–7), and Post-completion (thereafter) was used to determine context. All antimicrobial use without any documented infection was considered unnecessary (admission, discharge, or otherwise). Choice Anti-MRSA agents were considered unnecessary in cellulitis without history of or current positive culture for MRSA. Choice HOMDR agents were unnecessary in cellulitis without history of positive culture for ceftriaxone-resistant Gram-negative rods. Also unnecessary were broad-spectrum antimicrobials (anti-methicillin-resistant Staphylococcus aureus [MRSA] and hospital-onset multidrug-resistant [HOMDR] organisms antimicrobials as defined by the National Healthcare Safety Network) administered without evidence of multidrug-resistant organisms existed during Change and Completion time frames. Results Figure 1 demonstrates the distribution of facility proportions of unnecessary antimicrobials of different classes over time. Table 1 illustrates the percentage of unnecessary antimicrobials administered during choice, change, completion, and post-completion time-frames. Conclusion By this measure, unnecessary anti-MRSA and HOMDR use has been decreasing in VA over time. The bulk of unnecessary use is empiric but there is a substantial proportion that is used for longer stays, during which time more information was likely present. More research is necessary to determine how well these simple rules correlate with clinical determinations of appropriateness. Also ICD-10-CM was implemented in October 2015, which may have introduced an ascertainment bias. Disclosures V. Stevens, Pfizer, Inc.: Grant Investigator, Research grant.

Summary Background and objectives The impact of AKI on adverse drug events and therapeutic failures and the medication errors leading to these events have not been well described. Design, setting, participants, & measurements A single-center observational study of 396 hospitalized patients with a minimum 0.5 mg/dl change in serum creatinine who were prescribed a nephrotoxic or renally eliminated medication was conducted. The population was stratified into two groups by the direction of their initial serum creatinine change: AKI and AKI recovery. Adverse drug events, potential adverse drug events, therapeutic failures, and potential therapeutic failures for 148 drugs and 46 outcomes were retrospectively measured. Events were classified for preventability and severity by expert adjudication. Multivariable analysis identified medication classes predisposing AKI patients to adverse drug events. Results Forty-three percent of patients experienced a potential adverse drug event, adverse drug event, therapeutic failure, or potential therapeutic failure; 66% of study events were preventable. Failure to adjust for kidney function (63%) and use of nephrotoxic medications during AKI (28%) were the most common potential adverse drug events. Worsening AKI and hypotension were the most common preventable adverse drug events. Most adverse drug events were considered serious (63%) or life-threatening (31%), with one fatal adverse drug event. Among AKI patients, administration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antibiotics, and antithrombotics was most strongly associated with the development of an adverse drug event or potential adverse drug event. Conclusions Adverse drug events and potential therapeutic failures are common and frequently severe in patients with AKI exposed to nephrotoxic or renally eliminated medications.

Aim Proteinuria and estimated glomerular filtration rate (eGFR) predict progression of renal impairment in type 2 diabetic nephropathy (DN) but are they still predictive when these patients are treated with angiotensin receptor blockers (ARB)? We investigated whether residual (after ≥3 months of ARB treatment) urinary protein/creatinine ratio (rPCR) or urinary albumin/creatinine ratio (rACR) and residual eGFR (reGFR), predict subsequent progression. Methods One thousand, two hundred and forty-five patients with type 2 DN from two international multi-center studies were analysed. Cross classification of rPCR, rACR with reGFR (rPCR

Most dialysis patients require phosphate binders to control hyperphosphatemia. Ferric citrate has been tested in phase 2 trials as a phosphate binder. This trial was designed as a dose-response and efficacy trial.Prospective, phase 3, multicenter, open-label, randomized clinical trial.151 participants with hyperphosphatemia on maintenance hemodialysis therapy.Fixed dose of ferric citrate taken orally as a phosphate binder for up to 28 days (1, 6, or 8 g/d in 51, 52, and 48 participants, respectively).Primary outcome is dose-response of ferric citrate on serum phosphorus level; secondary outcomes are safety and tolerability.Serum chemistry tests including phosphorus, safety data.151 participants received at least one dose of ferric citrate. Mean baseline phosphorus levels were 7.3 ± 1.7 (SD) mg/dL in the 1-g/d group, 7.6 ± 1.7 mg/dL in the 6-g/d group, and 7.5 ± 1.6 mg/dL in the 8-g/d group. Phosphorus levels decreased in a dose-dependent manner (mean change at end of treatment, -0.1 ± 1.3 mg/dL in the 1-g/d group, -1.9 ± 1.7 mg/dL in the 6-g/d group, and -2.1 ± 2.0 mg/dL in the 8-g/d group). The mean difference in reduction in phosphorus levels between the 6- and 1-g/d groups was 1.3 mg/dL (95% CI, 0.69 to 1.9; P0.001), between the 8- and 1-g/d groups was 1.5 mg/dL (95% CI, 0.86 to 2.1; P0.001), and between the 8- and 6-g/d groups was 0.21 mg/dL (95% CI, -0.39 to 0.81; P = 0.5). The most common adverse event was stool discoloration.Sample size and duration confirm efficacy, but limit our ability to confirm safety.Ferric citrate is efficacious as a phosphate binder in a dose-dependent manner. A phase 3 trial is ongoing to confirm safety and efficacy.

Diabetic nephropathy (DN) refers to the structural and functional changes in the kidneys of patients with diabetes mellitus (type 1 or 2). A subset of patients with presumed DN may not have overt proteinuria as a prerequisite to renal failure, contrary to the classical paradigm. No animal model fully recapitulates the human subset. All studies on this subject are observational and most lack biopsy data. Many mechanisms have been postulated, including use of renin-angiotensin system agents, recurrent bouts of acute kidney injury, genetic predisposition, and renal lesions other than DN. A well-designed biopsy study and a series of intervention trials are needed to fully understand this entity.

This letter describes the nonsexual transmission of Zika virus with no mosquito vector from a patient who had fatal ZIKV infection with a high viral load.

Oral phosphate binders are the main stay of treatment of hyperphosphatemia. Adherence rates to ferric citrate, a recently approved phosphate binder, are unknown.We conducted a post-hoc analysis to evaluate whether adherence rates were different for ferric citrate vs. active control in 412 subjects with end stage kidney disease (ESKD) who were randomized to ferric citrate vs. active control (sevelamer carbonate and/or calcium acetate). Adherence was defined as percent of actual number of pills taken to total number of pills prescribed.There were no significant differences in baseline characteristics including gender, race/ethnicity, and age between the ferric citrate and active control groups. Baseline phosphorus, calcium, and parathyroid hormone levels were similar. Mean (SD) adherence was 81.4% (17.4) and 81.7% (15.9) in the ferric citrate and active control groups, respectively (P = 0.88). Adherence remained similar between both groups after adjusting for gender, race/ethnicity, age, cardiovascular disease (CVD), and diabetic nephropathy (mean [95% CI]: 81.4% [78.2, 84.6] and 81.5% [77.7, 85.2] for ferric citrate and active control, respectively). Gender, race/ethnicity, age, and diagnosis of diabetic nephropathy did not influence adherence to the prescribed phosphate binder. Subjects with CVD had lower adherence rates to phosphate binder; this was significant only in the active control group.Adherence rates to the phosphate binder, ferric citrate, were similar to adherence rates to active control. Similar adherence rates to ferric citrate are notable since tolerance to active control was an entry criteria and the study was open label. Gender, race/ethnicity, nor age influenced adherence.

Background: A phase II open-label study was conducted in hemodialysis patients evaluating the short-term safety, tolerability, and iron absorption with ferric citrate when used as a phosphate binder. Methods: Enrollment occurred in two periods. Period 1 recruited patients taking 6–15 pills/day of binder with phosphorus of ≥2.5 mg/dl. Period 2 recruited patients taking ≥12 pills/day of binder with phosphorus of ≥3.5 mg/dl. Participants with ferritin ≥1,000 µg/l or transferrin iron saturation (TSAT) ≥50% at screening were excluded. Subjects discontinued their previous binders and started 4.5 g/day of ferric citrate (period 1) or 6 g/day (period 2) and were titrated for 4 weeks to maintain a phosphorus of 3.5–5.5 mg/dl. Chemistries and complete blood count were obtained weekly and a gastrointestinal questionnaire was administered at drug initiation and final visit. Iron therapy was permitted if the ferritin was Results: Fifty-five subjects were enrolled. Four serious adverse events were reported; none were related to the study drug. Findings from the gastrointestinal questionnaire included stool discoloration (69%), constipation (15%), and bloating (7%). Mean iron parameters at the beginning of the study were ferritin 554 ± 296 µg/l, iron 68 ± 21 µg/dl, and iron saturation 30 ± 7.8%. At the end of study, mean ferritin was 609 ± 340 µg/l (p = 0.02), iron 75 ± 27 µg/dl (p = 0.04), and TSAT was 35 ± 13% (p = 0.001). Mean phosphorus and calcium levels were unchanged from baseline at the end of study. Conclusion: Ferric citrate was well tolerated by patients after 4 weeks with no significant clinical or biochemical adverse events related to exposure.

Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy. Kidney International (2012) 82, 330-337; doi:10.1038/ki.2012.74; published online 21 March 2012

Background Change in glomerular filtration rate (GFR) is important for clinical decision making. GFR estimates from serum creatinine level provide an unbiased but imprecise estimate of GFR at single time points. However, the accuracy of estimated GFR over time is not well known. Study Design Longitudinal study of diagnostic test accuracy. Settings & Participants 4 clinical trials with longitudinal measurements of GFR and serum creatinine on the same day, including individuals with and without kidney disease with a wide range of kidney function, diverse racial backgrounds, and varied clinical characteristics. Index Test GFR estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Reference Test GFR measured using urinary clearance of 125 I-iothalamate. Results Data included 19,735 GFR measurements in 3,531 participants during a mean follow-up of 2.6 years. Mean values at baseline for measured and estimated GFR and error (measured GFR – estimated GFR) were 73.1 (95% CI, 71.6 to 74.5), 72.7 (95% CI, 71.5 to 74.0), and 0.14 (95% CI, −0.35 to 0.63) mL/min/1.73 m 2 , respectively. Mean rates of change in measured and estimated GFR and error were −2.3 (95% CI, −2.4 to −2.1), −2.2 (95% CI, −2.4 to −2.1), and −0.09 (95% CI, −0.24 to 0.05) mL/min/1.73 m 2 per year ( P P P = 0.2, respectively). Variability (ie, standard deviation) among participants in rate of change in measured GFR, estimated GFR, and error was 4.3, 3.4, and 3.3 mL/min/1.73 m 2 per year, respectively. Only 15% of participants had a rate of change in error >3 mL/min/1.73 m 2 per year, and only 2% had a rate of change in error >5% per year. Limitations Participants' characteristics were not available over time. Conclusion The accuracy of GFR estimates did not change over time. Clinicians should interpret changes in estimated GFR over time as reflecting changes in measured GFR rather than changes in errors in the GFR estimates in most individuals.

Chronic kidney disease associated mineral and bone disorders arise as a result of aberrant bone mineral metabolism in patients with advancing levels of renal dysfunction and end-stage renal disease. One of the cornerstones of treatment is the use of phosphate-binding agents. We describe the rationale and study design for a clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder. This trial is a three-period, international, multicenter, randomized, controlled clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder, consisting of a 2-week washout period, a 52-week safety assessment period in which subjects are randomized to ferric citrate or active control, and a 4-week efficacy assessment period in which subjects randomized to ferric citrate in the safety assessment period are randomized to ferric citrate or placebo. Eligible subjects include end-stage renal disease patients who have been treated with thrice-weekly hemodialysis or peritoneal dialysis for at least 3 months in dialysis clinics in the United States and Israel. Primary outcome measure will be the effect of ferric citrate vs. placebo on the change in serum phosphorus. Safety assessments will be performed by monitoring adverse events, concomitant medication use, and sequential blood chemistries (including iron parameters, phosphorus, and calcium). This three-period trial will assess the efficacy of ferric citrate as a phosphate binder. If proven safe and efficacious, ferric citrate will likely provide an additional phosphate binder to treat chronic kidney disease associated mineral and bone disorders.

Objective Alerting systems, a type of clinical decision support, are increasingly prevalent in healthcare, yet few studies have concurrently measured the appropriateness of alerts with provider responses to alerts. Recent reports of suboptimal alert system design and implementation highlight the need for better evaluation to inform future designs. The authors present a comprehensive framework for evaluating the clinical appropriateness of synchronous, interruptive medication safety alerts. Methods Through literature review and iterative testing, metrics were developed that describe successes, justifiable overrides, provider non-adherence, and unintended adverse consequences of clinical decision support alerts. The framework was validated by applying it to a medication alerting system for patients with acute kidney injury (AKI). Results Through expert review, the framework assesses each alert episode for appropriateness of the alert display and the necessity and urgency of a clinical response. Primary outcomes of the framework include the false positive alert rate, alert override rate, provider non-adherence rate, and rate of provider response appropriateness. Application of the framework to evaluate an existing AKI medication alerting system provided a more complete understanding of the process outcomes measured in the AKI medication alerting system. The authors confirmed that previous alerts and provider responses were most often appropriate. Conclusion The new evaluation model offers a potentially effective method for assessing the clinical appropriateness of synchronous interruptive medication alerts prior to evaluating patient outcomes in a comparative trial. More work can determine the generalizability of the framework for use in other settings and other alert types.

Background: Previous studies have shown that patients with chronic kidney disease, including those with diabetic nephropathy, are more likely to die of cardiovascular disease than reach end-stage renal disease (ESRD). This analysis was conducted to determine whether ESRD is a more common outcome than cardiovascular death in patients with type 2 diabetic nephropathy, significant proteinuria, and decreased kidney function who were selected for participation in a clinical trial.Study Design: Retrospective analysis of the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database derived from 2 prospective randomized controlled clinical trials (IDNT [Irbesartan Diabetic Nephropathy Trial] and RENAAL [Reduction of Endpoints in Non-Insulin-dependent Diabetes With the Angiotensin II Antagonist Losartan]).Setting & Participants: 3,228 adult patients with type 2 diabetic nephropathy from IDNT and RENAAL were combined to establish the DIAMETRIC database. This is the largest global source of clinical information for patients with type 2 diabetic nephropathy who have decreased kidney function and significant proteinuria.Intervention: Angiotensin receptor blocker versus non-angiotensin receptor blocker therapy to slow the progression of type 2 diabetic nephropathy (in the prospective trials).Outcomes & Measurements: Incidence rates of ESRD, cardiovascular death, and all-cause mortality.Results: Mean follow-up was 2.8 years; 19.5% of patients developed ESRD, approximately 2.5 times the incidence of cardiovascular death and 1.5 times the incidence of all-cause mortality. ESRD was more common than cardiovascular death in all subgroups analyzed with the exception of participants with low levels of albuminuria (albumin excretion 45 mL/min/1.73 m(2)) at baseline.Limitations: All participants were included in a prospective clinical trial.Conclusions: Patients with type 2 diabetic nephropathy, characterized by decreased kidney function and significant proteinuria, are more likely to reach ESRD than die during 3 years' mean follow-up. Given the rapidly increasing number of cases of type 2 diabetes worldwide, this has implications for predicting future renal replacement therapy requirements. Am J Kidney Dis. 59(1): 75-83. (C) 2011 by the National Kidney Foundation, Inc.

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin 11 receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine >= 6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.