Evaluating a low anion gap: A practical approach.

In teaching and in practice, little attention is given to a low anion gap. This oversight can result in a missed opportunity to diagnose acute or chronic disorders requiring treatment. In this article, we review the constituents of the anion gap, build a differential diagnosis for a low anion gap using case examples, and provide a stepwise approach to diagnostic testing to evaluate this abnormal finding.

Incidence and Risk Factors for Dialysis Reinitiation among Patients with a History of Dialysis Dependency.

BACKGROUND AND OBJECTIVES: Recovery of kidney function after the start of maintenance dialysis can occur, but data on the incidence and risk factors for restarting dialysis after recovery of kidney function in this population are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective study of adult Medicare beneficiaries who started dialysis between 2005 and 2015 according to the United States Renal Data System but who had recovery of kidney function (defined as a ≥90-day dialysis-free interval). We identified risk factors that were associated with the risk for the reinitiation of dialysis within a 3-year time frame following the recovery of kidney function and at any time during follow-up using Cox proportional hazards models. RESULTS: Of the 34,530 individuals previously on dialysis who had recovery of kidney function, 7217 (21%) restarted dialysis (absolute rate of 11.5 per 100 person-years) within 3 years of recovery of kidney function, and 9120 (26%) restarted dialysis during the entire follow-up period (absolute rate of 8.8 per 100 person-years). Among those with CKD stage 1 or 2 after recovery of kidney function, 10% of individuals restarted dialysis within 3 years of their recovery of kidney function, whereas among those with CKD stage 3, 4, or 5, 13%, 27%, and 36% of individuals restarted dialysis within 3 years of recovery of kidney function, respectively. Age at first dialysis, cause of kidney disease, history of CKD or nephrology care prior to starting dialysis, presence of heart failure, CKD stage following recovery of kidney function, and location of first dialysis initiation (inpatient versus outpatient) were some of the risk factors that were strongly associated with the risk of restarting dialysis after the recovery of kidney function. CONCLUSIONS: Over one in five patients with recovery of kidney function after kidney failure restarted dialysis within 3 years.

Electronic Decision Support for Management of CKD in Primary Care: A Pragmatic Randomized Trial.

RATIONALE & OBJECTIVE: Most adults with chronic kidney disease (CKD) in the United States are cared for by primary care providers (PCPs). We evaluated the feasibility and preliminary effectiveness of an electronic clinical decision support system (eCDSS) within the electronic health record with or without pharmacist follow-up to improve the management of CKD in primary care. STUDY DESIGN: Pragmatic cluster-randomized trial. SETTING & PARTICIPANTS: 524 adults with confirmed creatinine-based estimated glomerular filtration rates of 30 to 59mL/min/1.73m2 cared for by 80 PCPs at the University of California San Francisco. Electronic health record data were used for patient identification, intervention deployment, and outcomes ascertainment. INTERVENTIONS: Each PCP's eligible patients were randomly assigned as a group into 1 of 3 treatment arms: (1) usual care; (2) eCDSS: testing of creatinine, cystatin C, and urinary albumin-creatinine ratio with individually tailored guidance for PCPs on blood pressure, potassium, and proteinuria management, cardiovascular risk reduction, and patient education; or (3) eCDSS plus pharmacist counseling (eCDSS-PLUS). OUTCOMES: The primary clinical outcome was change in blood pressure over 12 months. Secondary outcomes were PCP awareness of CKD and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and statin therapy. RESULTS: All 80 eligible PCPs participated. Mean patient age was 70 years, 47% were nonwhite, and mean estimated glomerular filtration rate was 56±0.6mL/min/1.73m2. Among patients receiving eCDSS with or without pharmacist counseling (n=336), 178 (53%) completed laboratory measurements and 138 (41%) had laboratory measurements followed by a PCP visit with eCDSS deployment. eCDSS was opened by the PCP for 102 (74%) patients, with at least 1 suggested order signed for 83 of these 102 (81%). Changes in systolic blood pressure were-2.1±1.5mm Hg with usual care, -2.8±1.8mm Hg with eCDSS, and -1.1±1.1 with eCDSS-PLUS (P=0.7). PCP awareness of CKD was 16% with usual care, 26% with eCDSS, and 32% for eCDSS-PLUS (P=0.09). In as-treated analyses, PCP awareness of CKD was significantly greater with eCDSS and eCDSS-PLUS (73% and 69%) versus usual care (47%; P=0.002). LIMITATIONS: Recruitment of smaller than intended sample size and limited uptake of the testing component of the intervention. CONCLUSIONS: Although we were unable to demonstrate the effectiveness of eCDSS to lower blood pressure and uptake of the eCDSS was limited by low testing rates, eCDSS use was high when laboratory measurements were available and was associated with higher PCP awareness of CKD. FUNDING: Grants from government (National Institutes of Health) and not-for-profit (American Heart Association) entities. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02925962.

Screening for CKD To Improve Processes of Care among Nondiabetic Veterans with Hypertension: A Pragmatic Cluster-Randomized Trial.

BACKGROUND AND OBJECTIVES: We conducted a pilot, pragmatic, cluster-randomized trial to evaluate feasibility and preliminary effectiveness of screening for CKD using a triple-marker approach (creatinine, cystatin C, and albumin/creatinine ratio), followed by education and guidance, to improve care of hypertensive veterans in primary care. We used the electronic health record for identification, enrollment, intervention delivery, and outcome ascertainment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We randomized 1819 veterans without diabetes but with hypertension (41 clusters) into three arms: (1) CKD screening followed by patient and provider education; (2) screening, education, plus pharmacist comanagement; or (3) usual care. The primary clinical outcome was BP change over 1 year. Implementation and process measures included proportion screened; CKD detection rate; and total and new use of renin-angiotensin system inhibitors, nonsteroidal anti-inflammatory drugs, and diuretics. RESULTS: Median age was 68 years, 55% were white, 1658 (91%) had a prior creatinine measure, but only 172 (9%) had prior urine albumin/creatinine ratio, and 83 (5%) had a prior cystatin C measure. Among those in the intervention, 527 of 1215 (43%) were identified with upcoming appointments to have CKD screening. Of these, 367 (69%) completed testing. Among those tested, 77 (21%) persons had newly diagnosed CKD. After 1 year, change in systolic BP was -1 mm Hg (interquartile range, -11 to 11) in usual care, -2 mm Hg (-11 to 11) in the screen-educate arm, and -2 mm Hg (-13 to 10) in the screen-educate plus pharmacist arm; P=0.49. There were no significant differences in secondary outcomes in intention-to-treat analyses. In as-treated analyses, higher proportions of participants in the intervention arms initiated a renin-angiotensin system inhibitor (15% and 12% versus 7% in usual care, P=0.01) or diuretic (9% and 12% versus 4%, P=0.03). CONCLUSIONS: The pragmatic design made identification, enrollment, and intervention delivery highly efficient. The limited ability to identify appointments resulted in inadequate between-arm differences in CKD testing rates to determine whether screening improves clinical outcomes.

A Pragmatic Cluster Randomized Trial of an Electronic Clinical Decision Support System to Improve Chronic Kidney Disease Management in Primary Care: Design, Rationale, and Implementation Experience.

BACKGROUND: The diagnosis of chronic kidney disease (CKD) is based on laboratory results easily extracted from electronic health records; therefore, CKD identification and management is an ideal area for targeted electronic decision support efforts. Early CKD management frequently occurs in primary care settings where primary care providers (PCPs) may not implement all the best practices to prevent CKD-related complications. Few previous studies have employed randomized trials to assess a CKD electronic clinical decision support system (eCDSS) that provided recommendations to PCPs tailored to each patient based on laboratory results. OBJECTIVE: The aim of this study was to report the trial design and implementation experience of a CKD eCDSS in primary care. METHODS: This was a 3-arm pragmatic cluster-randomized trial at an academic general internal medicine practice. Eligible patients had 2 previous estimated-glomerular-filtration-rates by serum creatinine (eGFRCr) <60 mL/min/1.73m2 at least 90 days apart. Randomization occurred at the PCP level. For patients of PCPs in either of the 2 intervention arms, the research team ordered triple-marker testing (serum creatinine, serum cystatin-c, and urine albumin-creatinine-ratio) at the beginning of the study period, to be completed when acquiring labs for regular clinical care. The eCDSS launched for PCPs and patients in the intervention arms during a regular PCP visit subsequent to completing the triple-marker testing. The eCDSS delivered individualized guidance on cardiovascular risk-reduction, potassium and proteinuria management, and patient education. Patients in the eCDSS+ arm also received a pharmacist phone call to reinforce CKD-related education. The primary clinical outcome is blood pressure change from baseline at 6 months after the end of the trial, and the main secondary outcome is provider awareness of CKD diagnosis. We also collected process, patient-centered, and implementation outcomes. RESULTS: A multidisciplinary team (primary care internist, nephrologists, pharmacist, and informaticist) designed the eCDSS to integrate into the current clinical workflow. All 81 PCPs contacted agreed to participate and were randomized. Of 995 patients initially eligible by eGFRCr, 413 were excluded per protocol and 58 opted out or withdrew, resulting in 524 patient participants (188 usual care; 165 eCDSS; and 171 eCDSS+). During the 12-month intervention period, 53.0% (178/336) of intervention patient participants completed triple-marker labs. Among these, 138/178 (77.5%) had a PCP appointment after the triple-marker labs resulted; the eCDSS was opened for 73.9% (102/138), with orders or education signed for 81.4% (83/102). CONCLUSIONS: Successful integration of an eCDSS into primary care workflows and high eCDSS utilization rates at eligible visits suggest this tailored electronic approach is feasible and has the potential to improve guideline-concordant CKD care. TRIAL REGISTRATION: ClinicalTrials.gov NCT02925962; https://clinicaltrials.gov/ct2/show/NCT02925962 (Archived by WebCite at http://www.webcitation.org/78qpx1mjR). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14022.

Implementation of a pragmatic randomized trial of screening for chronic kidney disease to improve care among non-diabetic hypertensive veterans.

BACKGROUND: Whether screening for chronic kidney disease (CKD) can improve the care of persons at high risk for complications remains uncertain. We describe the design and early implementation experience of a pilot, cluster-randomized pragmatic trial to evaluate the feasibility, implementation, and effectiveness of a "triple marker" CKD screening program (creatinine, cystatin C and albumin to creatinine ratio) for improving care among hypertensive veterans seen in primary care at one Veterans Administration Hospital. METHODS/DESIGN: Non-diabetic hypertensive veterans age 18-80 without known CKD were randomized in clusters determined by primary care provider (unit of randomization) into three arms. Usual care will be compared with two incrementally intensified treatment strategies: (1) screen for CKD followed by patient and provider education or (2) screen-educate plus a clinical pharmacist-led CKD and BP management program. The primary clinical outcome is systolic blood pressure (BP) change from baseline. Secondary clinical outcome is BP control. The primary process outcomes is triple marker screening (across three arms), and secondary process outcomes include use of inhibitors of the renin-angiotensin system (ACE/ARB) overall and in persons with albuminuria, CKD recognition by PCP, use of non-steroidal anti-inflammatory drugs (NSAIDs) and NSAID education by PCP. The design uses the Veterans Health Administration electronic health record (EHR) to identify participants, deliver the interventions and ascertain study outcomes. Assessment of the program implementation will use the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Study duration is 12 months. RESULTS: A total of 1,819 patients have been randomized within 41 provider clusters. The median age (interquartile range) is 68 years (61-72), and 99% of participants are male. Approximately 16% are Black, and 5% Hispanic. In the first 6 months of the trial, 434 triple marker screening tests have been ordered, and 217(50%) have been tested. A total of 48 new CKD cases have been identified among those tested, for a preliminary yield of 22%. CONCLUSION: We have successfully implemented a pragmatic protocol that uses the EHR to identify and characterize eligible participants, deliver the intervention, and ascertain study outcomes with high rates of participation by providers and patients. Results from this study can guide design of pragmatic trials in the field of CKD. TRIAL REGISTRATION: NCT01978951 ; Date or Registration: 1/17/2014.

Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2002.

BACKGROUND: Chronic kidney disease (CKD) and hyperuricemia often coexist, and both conditions are increasing in prevalence in the United States. However, their shared role in cardiovascular risk remains highly debated. STUDY DESIGN: Cross-sectional and longitudinal. SETTING & PARTICIPANTS: Participants in the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2002 (n = 10,956); data were linked to mortality data from the National Death Index through December 31, 2006. PREDICTORS: Serum uric acid concentration, categorized as the sex-specific lowest (< 25th), middle (25th- < 75th), and highest (≥ 75th) percentiles; and kidney function assessed by estimated glomerular filtration rate (eGFR) based on the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation and urinary albumin-creatinine ratio (ACR). OUTCOMES: Cardiovascular death and all-cause mortality. RESULTS: Uric acid levels were correlated with eGFR(cr-cys) (r = -0.29; P < 0.001) and were correlated only slightly with ACR (r = 0.04; P < 0.001). There were 2,203 deaths up until December 31, 2006, of which 981 were due to cardiovascular causes. Overall, there was a U-shaped association between uric acid levels and cardiovascular mortality in both women and men, although the lowest risk of cardiovascular mortality occurred at a lower level of uric acid for women compared with men. There was an association between the highest quartile of uric acid level and cardiovascular mortality even after adjustment for potential confounders (HR, 1.48; 95% CI, 1.13-1.96), although this association was attenuated after adjustment for ACR and eGFR(cr-cys) (HR, 1.25; 95% CI, 0.89-1.75). The pattern of association between uric acid levels and all-cause mortality was similar. LIMITATIONS: GFR not measured; mediating events were not observed. CONCLUSIONS: High uric acid level is associated with cardiovascular and all-cause mortality, although this relationship was no longer statistically significant after accounting for kidney function.

Temporal changes in incidence of dialysis-requiring AKI.

The population epidemiology of AKI is not well described. Here, we analyzed data from the Nationwide Inpatient Sample, a nationally representative dataset, to identify cases of dialysis-requiring AKI using validated International Classification of Diseases, Ninth Revision (ICD-9) codes. From 2000 to 2009, the incidence of dialysis-requiring AKI increased from 222 to 533 cases per million person-years, averaging a 10% increase per year (incidence rate ratio=1.10, 95% CI=1.10-1.11 per year). Older age, male sex, and black race associated with higher incidence of dialysis-requiring AKI. The rapid increase in incidence was evident in all age, sex, and race subgroups examined. Temporal changes in the population distribution of age, race, and sex as well as trends of sepsis, acute heart failure, and receipt of cardiac catheterization and mechanical ventilation accounted for about one third of the observed increase in dialysis-requiring AKI among hospitalized patients. The total number of deaths associated with dialysis-requiring AKI rose from 18,000 in 2000 to nearly 39,000 in 2009. In conclusion, the incidence of dialysis-requiring AKI increased rapidly in all patient subgroups in the past decade in the United States, and the number of deaths associated with dialysis-requiring AKI more than doubled.

Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.

To determine whether acute renal failure (ARF) increases the long-term risk of progressive chronic kidney disease (CKD), we studied the outcome of patients whose initial kidney function was normal or near normal but who had an episode of dialysis-requiring ARF and did not develop end-stage renal disease within 30 days following hospital discharge. The study encompassed 556,090 adult members of Kaiser Permanente of Northern California hospitalized over an 8 year period, who had pre-admission estimated glomerular filtration rates (eGFR) equivalent to or greater than 45 ml/min/1.73 m(2) and who survived hospitalization. After controlling for potential confounders such as baseline level of eGFR and diabetes status, dialysis-requiring ARF was independently associated with a 28-fold increase in the risk of developing stage 4 or 5 CKD and more than a twofold increased risk of death. Our study shows that in a large, community-based cohort of patients with pre-existing normal or near normal kidney function, an episode of dialysis-requiring ARF was a strong independent risk factor for a long-term risk of progressive CKD and mortality.

Some methodological issues in studying the long-term renal sequelae of acute kidney injury.

There has been great interest recently in better understanding how an episode of acute kidney injury (AKI) affects risk of development or acceleration of chronic kidney disease. This area of epidemiology research presents several methodological challenges that have not been sufficiently discussed in the literature. These are related to the current consensus definitions of AKI; the determination of 'baseline' renal function before the AKI episode; and the possibility that observed associations between AKI and future adverse events are confounded by differences in the severity of baseline chronic kidney disease. In this study, we discuss several potential solutions to these problems. Concerted efforts to address these methodological issues will propel research in this field to a higher level.