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

Rationale & objectiveMost 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 designPragmatic cluster-randomized trial.Setting & participants524 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.InterventionsEach 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).OutcomesThe 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.ResultsAll 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).LimitationsRecruitment of smaller than intended sample size and limited uptake of the testing component of the intervention.ConclusionsAlthough 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.FundingGrants from government (National Institutes of Health) and not-for-profit (American Heart Association) entities.Trial registrationRegistered at ClinicalTrials.gov with study number NCT02925962

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.

BackgroundThe 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.ObjectiveThe aim of this study was to report the trial design and implementation experience of a CKD eCDSS in primary care.MethodsThis 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.ResultsA 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).ConclusionsSuccessful 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 registrationClinicalTrials.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

Fibroblast-derived ECM decreases Lung Cancer Cell Growth.

<p>(A) A549, H358 and HPL1D cells were grown on fibroblast derived matrices and every day one well of cells was trypsinized and manually counted in triplicate using trypan blue. (B) A549, H358 and HPL1D cells were grown on fibroblast derived matrices and every day Alamar Blue was added to wells of cells in triplicate and relative conversion of Alamar Blue was determined. n = 3. *, p-value ≤ 0.05.</p

Characterization of fibroblasts and their ECM.

<p>A. Microscopic analysis of fibroblasts and de-cellularized matrix. Left colum- 5X phase contrast imaging of confluent fibroblasts just prior to de-cellularazation. Middle colum- 40X phase contrast microscopy of ECM following decellularization. Right column- Immunofluorescent confocal microscopy of fibroblast-derived ECM using an NHS-ester probe conjugated to Alexa Fluor 488. (B) Protein content of ECM was quantitated after scraping of the ECM from decellularized plates. Protein amount is indicated a μg/cm², N = 3. (C) SDS-PAGE and colloidal blue stain of fibroblast-derived ECM. n = 3.</p

Fibroblast-derived ECM alters Protein Levels of A549 Cells.

<p>(A) A549 cells were cultured on the indicated substrate for 48 hours and then cells were harvested and western blots were performed with the indicated antibodies. (B) Cells were treated as in panel A and westerns were performed with indicated antibodies. (C) A549 cells were seeded on either fibronectin (FN) or WI38-derived ECM and then plates were incubated under hypoxic or normoxic conditions. Cells were harvested and westerns were performed with the indicated antibodies.</p

Fibroblast-Derived Extracellular Matrices: An Alternative Cell Culture System That Increases Metastatic Cellular Properties - Table 1

<p>Fibroblast-Derived Extracellular Matrices: An Alternative Cell Culture System That Increases Metastatic Cellular Properties - Table 1 </p

Fibroblast-derived ECM alters mRNA profile of A549 and H358 Cells.

<p>Heat map significantly changed genes from microarray (fold-change >1.5 and p-value ≤ 0.05). Columns represent individual gene probes; rows are the different samples and each row represents one of the biological triplicates ran on the microarray. (B) Validation of microarray data. Representative genes were chosen for quantitative real-time qRT-PCR analysis. New biological triplicates were prepared, RNA extracted and converted to cDNA, and real-time qRT-PCR was performed. All samples tested were validated and all genes were changed in the same direction as the microarray, however some amplitudes of change were slightly different.</p

Fibroblast-derived ECM alter Lung Cancer Cell Line Morphology.

<p>(A) Phase contrast microscopy photos of A549, H358, and HPL1D cells on FN, WI38 ECM, IMR90, and HDF ECM. (B) Immunofluorescent confocal microscopy of A549 cells on WI38-derived ECM stained with Phallodin and DAPI. (C) The circularity of A549 on FN and 3 different fibroblast-derived ECM was calculated. n = 10. *, p ≤ 0.05.</p

Fibroblast-derived ECM Protects Lung Cancer Cell Lines from Serum Deprivation.

<p>(A) A549, H358, and HPL1D cells were grown on fibronectin (FN) or on WI38 ECM in serum-free media for 48 hours and then photographed. (B) Relative cell numbers were quantified for A549 cells (B), H358 cells (C) and HPL1D cells (D) using Alamar Blue every 24 hours after cells were put into serum free media. By the fourth day in serum free media, basically all cells were dead.</p