Baclofen and the risk of fall and fracture in older adults: A real-world cohort study.

BACKGROUND: The growth of oral muscle relaxant prescriptions among older adults in the United States is concerning due to the drugs' adverse sedative effects. Baclofen is a gamma-aminobutyric acid agonist muscle relaxant that is associated with encephalopathy. We characterized the risk of fall and fracture associated with oral baclofen against other muscle relaxants (tizanidine or cyclobenzaprine) in older adults. METHODS: We designed a new-user, active-comparator study using tertiary health system data from Geisinger Health, Pennsylvania (January 2005 through December 2018). Older adults (aged ≥65 years) newly treated with baclofen, tizanidine, or cyclobenzaprine were included. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance the treatment groups on 58 baseline characteristics. Fine-Gray competing risk regression was used to estimate the risk of fall and fracture. RESULTS: The study cohort comprised of 2205 new baclofen users, 1103 new tizanidine users, and 9708 new cyclobenzaprine users. During a median follow-up of 100 days, baclofen was associated with a higher risk of fall compared to tizanidine (IPTW incidence rate, 108.4 vs. 61.9 per 1000 person-years; subdistribution hazard ratio [SHR], 1.68 [95% CI, 1.20-2.36]). The risk of fall associated with baclofen was comparable to cyclobenzaprine (SHR, 1.17 [95% CI, 0.93-1.47]) with a median follow-up of 106 days. The risk of fracture was similar among patients treated with baclofen versus tizanidine (SHR, 0.85 [95% CI, 0.63-1.14]) or cyclobenzaprine (SHR, 0.85 [95% CI, 0.67-1.07]). CONCLUSIONS: The risk of fall associated with baclofen was greater than tizanidine, but not compared to cyclobenzaprine in older adults. The risk of fracture was comparable among the older users of baclofen, tizanidine, and cyclobenzaprine. Our findings may inform risk-benefit considerations in the increasingly common clinical encounters where oral muscle relaxants are prescribed.

Association of eGFR and Albuminuria with Venous Thromboembolism.

BACKGROUND: CKD has been implicated as a risk factor of venous thromboembolism, but the evidence is limited to relatively healthy populations. The objective of this study was to discern whether parameters of kidney function and damage are associated with the occurrence of venous thromboembolism after hospitalization. METHODS: We conducted a retrospective study including 23,899 and 11,552 adult individuals hospitalized within Geisinger Health System and New York University (NYU) Langone Health from 2004 to 2019 and 2012 to 2022, respectively. A Poisson model was used to evaluate adjusted incidence rates of venous thromboembolism according to eGFR and albuminuria categories in each cohort. Cox proportional hazards models were used to analyze associations of eGFR and urinary albumin-to-creatinine ratio (UACR) with venous thromboembolism, and hazard ratios (HRs) were meta-analyzed across cohorts. RESULTS: Both lower eGFR and higher UACR were associated with higher risks of venous thromboembolism. In the Geisinger cohort, the incidence of venous thromboembolism after hospital discharge ranged from 10.7 (95% confidence interval [CI], 9.2 to 12.6) events per 1000 person-years in individuals in G1A1 (eGFR >90 ml/min per 1.73 m 2 and UACR <30 mg/g) to 27.7 (95% CI, 20.6 to 37.2) events per 1000 person-years in individuals with G4-5A3 (eGFR <30 ml/min per 1.73 m 2 and UACR >300 mg/g). A similar pattern was observed in the NYU cohort. Meta-analyses of the two cohorts showed that every 10 ml/min per 1.73 m 2 reduction in eGFR below 60 ml/min per 1.73 m 2 was associated with a 6% higher risk of venous thromboembolism (HR 1.06 [95% CI, 1.02 to 1.11], P = 0.01), and each two-fold higher UACR was associated with a 5% higher risk of venous thromboembolism (HR 1.05 [95% CI, 1.03 to 1.07], P < 0.001). CONCLUSIONS: Both eGFR and UACR were independently associated with higher risk of venous thromboembolism after hospitalization. The incidence rate was higher with greater severity of CKD. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_12_14_CJN0000000000000352.mp3.

Baclofen and the Risk of Encephalopathy: A Real-World, Active-Comparator Cohort Study.

OBJECTIVE: To quantify the risk of encephalopathy associated with oral baclofen compared with other muscle relaxants-tizanidine or cyclobenzaprine. PATIENTS AND METHODS: We conducted a new-user, active-comparator study of 2 pairwise cohorts using tertiary health system data from Geisinger Health in Pennsylvania (January 1, 2005, through December 31, 2018). Adults (aged ≥18 years) newly treated with baclofen or tizanidine were included in cohort 1. Adults newly treated with baclofen or cyclobenzaprine were included in cohort 2. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance the respective cohorts on 45 patient characteristics. Fine-Gray competing risk regression was used to estimate the risk of encephalopathy. RESULTS: Cohort 1 included 16,192 new baclofen users and 9782 new tizanidine users. The 30-day risk of encephalopathy was higher in patients treated with baclofen vs tizanidine (IPTW incidence rate, 64.7 vs 28.3 per 1000 person-years) with an IPTW subdistribution hazard ratio (SHR) of 2.29 (95% CI, 1.43 to 3.67). This risk persisted through 1 year (SHR, 1.32 [95% CI, 1.07 to 1.64]). Similarly in cohort 2, baclofen vs cyclobenzaprine was associated with a greater risk of encephalopathy at 30 days (SHR, 2.35 [95% CI, 1.59 to 3.48]) that persisted through the first year of treatment (SHR, 1.94 [95% CI, 1.56 to 2.40]). CONCLUSION: The risk of encephalopathy was greater with baclofen vs tizanidine or cyclobenzaprine use. The elevated risk was apparent as early as 30 days and persisted through the first year of treatment. Our findings from routine care settings may inform shared treatment decisions between patients and prescribers.

Are Digital Health Technologies and Models of Nutrition Care the Future of Chronic Kidney Disease Management?

People living with chronic kidney disease (CKD) require long-term support at varying levels of individualization, intensity, and frequency. Mobile and digital models of nutrition care can facilitate long-term behavior change, address nutrition issues proactively, reduce travel burden, and reach people without access to health care more easily. However, while traditional health delivery continues to be digitally disrupted, there are many barriers to address before mobile and digitally supported models of nutrition care can become business as usual in nephrology and nutrition care practice. This paper overviews the current evidence base concerning the past and present mobile and digital health programs to improve nutrition in CKD and highlights the novel future trends in this field. The way nutrition and dietetic care can be feasible, safe, and potentially effective when delivered using various digital and virtual technologies, including consultations, assessments, establishment of diagnoses, formulation of plans, and monitoring/reviewing clinical progress is discussed. Of the available evidence to date, these modalities appear to improve dietary sodium intake and diet quality, self-efficacy, interdialytic weight gain, and body weight. Many barriers exist to sustaining the continued and widespread adoption of digital and mobile health-supported nutrition care in CKD. These include patient-, clinician-, and health system-specific and are discussed in detail. Mobile and digital-supported models of nutrition care present an exciting opportunity to assist kidney dietitians deliver patient-centred nutrition care in CKD.

Effects of the Dietary Approaches to Stop Hypertension Diet on Change in Cardiac Biomarkers Over Time: Results From the DASH-Sodium Trial.

Background The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to reduce biomarkers of cardiovascular disease. We aimed to characterize the time course of change in biomarkers of cardiac injury (high-sensitivity cardiac troponin I), cardiac strain (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and inflammation (hs-CRP [high-sensitivity C-reactive protein]) while consuming the DASH diet. Methods and Results The DASH-Sodium trial was a randomized controlled trial of 412 adults with elevated blood pressure or hypertension. Participants were randomly assigned to 12 weeks of the DASH diet or a typical American diet. Energy intake was adjusted to maintain body weight. Measurements of high-sensitivity cardiac troponin I, NT-proBNP, and hs-CRP were performed in stored serum specimens, collected at baseline and ≈4, 8, and 12 weeks after randomization. In both the control diet and DASH diet, levels of NT-proBNP decreased; however, there was no difference between diets (P-trend compared with control=0.22). On the DASH diet versus control, levels of high-sensitivity cardiac troponin I decreased progressively during follow-up (P-trend compared with control=0.025), but a statistically significant between-diet difference in change from baseline levels was not observed until week 12 (% difference, 17.78% [95% CI, -29.51% to -4.09%]). A similar pattern was evident for hs-CRP (P-trend compared with control=0.01; % difference at week 12, 19.97% [95% CI, -31.94% to -5.89%]). Conclusions In comparison with a typical American diet, the DASH diet reduced high-sensitivity cardiac troponin I and hs-CRP progressively over 12 weeks. These results suggest that the DASH diet has cumulative benefits over time on biomarkers of subclinical cardiac injury and inflammation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000608.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Including measures of chronic kidney disease to improve cardiovascular risk prediction by SCORE2 and SCORE2-OP.

AIMS: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach. METHODS: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. RESULTS: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. CONCLUSION: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

Glucose-Lowering Agents and the Risk of Hypoglycemia: a Real-world Study.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) are increasingly recommended in type 2 diabetes. Hypoglycemia is a serious adverse effect of glucose-lowering agents. Real-world comparison of hypoglycemic risks among SGLT2i, GLP1RA, dipeptidyl peptidase-4 inhibitor (DPP4i), and sulfonylureas is limited. OBJECTIVE: Quantify the risk of hypoglycemia associated with SGLT2i, GLP1RA, DPP4i, and sulfonylureas (the primary reference group). DESIGN: Retrospective cohort study conducted using electronic health records from Geisinger Health, Pennsylvania (2015-2019). PARTICIPANTS: A total of 10,713 patients with type 2 diabetes who newly received SGLT2i (n=1487), GLP1RA (n=1241), DPP4i (n=2938), or sulfonylureas (n=5047). Propensity score-based inverse probability of treatment weighting was used to balance patient characteristics across four treatment groups simultaneously. MAIN MEASURES: Hypoglycemia was defined as capillary blood glucose <70 mg/dL; severe hypoglycemia was defined as capillary blood glucose <54 mg/dL. A weighted Cox proportional hazards regression model was used to estimate the risk of outcomes for pairwise comparisons of SGTL2i, GLP1RA, DPP4i, and sulfonylureas. KEY RESULTS: Median follow-up was 21.3 months. Compared with sulfonylureas, the risk of hypoglycemia was lower with SGLT2i (hazard ratio 0.60 [95% confidence interval 0.48-0.75]), GLP1RA (0.49 [0.34-0.69]), and DPP4i (0.60 [0.48-0.78]). The risk of severe hypoglycemia was also lower with SGLT2i (0.43 [0.35-0.74]), GLP1RA (0.50 [0.28-0.87]), and DPP4i (0.64 [0.46-0.90]) compared to sulfonylureas. The risks of hypoglycemia and severe hypoglycemia were similar across the SGLT2i, GLP1RA, and DPP4i groups (SGLT2i vs. DPP4i: 0.95 [0.67-1.34]; GLP1RA vs. DPP4i: 0.81 [0.55-1.19]; SGLT2i vs. GLP1RA: 1.17 [0.76-1.82] for hypoglycemia). CONCLUSION: SGLT2i and GLP1RA confer a lower risk of hypoglycemia compared with sulfonylureas and similar risk compared with DPP4i. Given the known cardiovascular benefits associated with SGLT2i and GL1PRA, our results suggesting the safety of SGLT2i and GL1PRA further support their use.

Pharmacologic Treatment of Type 2 Diabetes in the U.S., Sweden, and Israel.

OBJECTIVE: To characterize and compare glucose-lowering medication use in type 2 diabetes in the U.S., Sweden, and Israel, including adoption of newer medications and prescribing patterns. RESEARCH DESIGN AND METHODS: We used data from the National Health and Nutrition Examination Survey (NHANES) from the U.S., the Stockholm CREAtinine Measurements (SCREAM) project from Sweden, and Maccabi Healthcare Services (Maccabi) from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 was examined. RESULTS: Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in NHANES and SCREAM than in Maccabi (66.0% in NHANES, 68.4% in SCREAM, and 88.1% in Maccabi in 2017-2018). Among patients who took at least one glucose-lowering medication in 2017-2018, metformin use was also lower in NHANES and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in NHANES (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was slower in NHANES and SCREAM than in Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, or albuminuria was not consistently associated with greater use of SGLT2i or glucagon-like peptide 1 receptor agonists (GLP1RA) across the three countries. CONCLUSIONS: There were substantial differences in real-world use of glucose-lowering medications across the U.S., Sweden, and Israel, with more optimal pharmacologic management in Israel. Variation in access to care and medication cost across countries may have contributed to these differences. SGLT2i and GLP1RA use in patients at high risk was limited in all three countries during this time period.

Weight changes following antidiabetic mediation use: Real-world evidence from health system data.

Objective: Newer antidiabetic medications such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) result in weight loss in clinical trials. However, the real-world effectiveness remains unclear. The magnitude of weight change associated with antidiabetic medication using real-world data was examined. Methods: Patients with diabetes who initiated SGLT2i (n = 906), GLP1RA (n = 782), dipeptidyl peptidase-4 inhibitors (DPP4i, n = 1881), or sulfonylureas (n = 3255) in Geisinger Health System were identified. Outcomes were percent weight change per year and time to 5% weight loss. Propensity scores were used to account for differences across groups. Results: The mean ± SD age of patients was 57.5 ± 14.1 years, 3381 (49.5%) were female, and 6450 (94.5%) had body mass index ≥25 kg/m2. Compared with sulfonylureas, newer antidiabetic medications were associated with significant weight loss (-3.2% [95% confidence interval: -3.8%, -2.6%] per year for SGLT2i; -2.9% [-3.6%, -2.3%] per year for GLP1RA; and -1.7% [-2.1%, -1.3%] per year for DPP4i). SGLT2i and GLP1RA were also associated with significant weight loss compared with DPP4i. Among patients with overweight or obesity, SGLT2i and GLP1RA users were more likely to achieve 5% weight loss compared with sulfonylureas and DPP4i. Conclusions: In real-world practice, SGLT2i and GLP1RA were associated with significant weight loss compared with sulfonylureas and DPP4i. These results may further motivate uptake of SGLT2i and GLP1RA, especially among patients who were overweight or had obesity.

A Simpler Machine Learning Model for Acute Kidney Injury Risk Stratification in Hospitalized Patients.

Background: Hospitalization-associated acute kidney injury (AKI), affecting one-in-five inpatients, is associated with increased mortality and major adverse cardiac/kidney endpoints. Early AKI risk stratification may enable closer monitoring and prevention. Given the complexity and resource utilization of existing machine learning models, we aimed to develop a simpler prediction model. Methods: Models were trained and validated to predict risk of AKI using electronic health record (EHR) data available at 24 h of inpatient admission. Input variables included demographics, laboratory values, medications, and comorbidities. Missing values were imputed using multiple imputation by chained equations. Results: 26,410 of 209,300 (12.6%) inpatients developed AKI during admission between 13 July 2012 and 11 July 2018. The area under the receiver operating characteristic curve (AUROC) was 0.86 for Random Forest and 0.85 for LASSO. Based on Youden's Index, a probability cutoff of >0.15 provided sensitivity and specificity of 0.80 and 0.79, respectively. AKI risk could be successfully predicted in 91% patients who required dialysis. The model predicted AKI an average of 2.3 days before it developed. Conclusions: The proposed simpler machine learning model utilizing data available at 24 h of admission is promising for early AKI risk stratification. It requires external validation and evaluation of effects of risk prediction on clinician behavior and patient outcomes.

Effect of age and rural residency on perceptions about SARS-CoV-2 pandemic and vaccination in kidney transplant recipients.

BACKGROUND: Transplant patients have poor outcomes in coronavirus-disease 2019 (COVID-19). The pandemic's effects on rural patients' overall care experience, attitudes to telemedicine, and vaccination are poorly understood. METHODS: We administered a cross-sectional survey to adult kidney transplant recipients in central Pennsylvania across four clinical sites between March 29, 2021 and June 2, 2021. We assessed the pandemic's impact on care access, telemedicine experience, attitudes toward preventive measures, vaccination, and variation by sociodemographic variables. RESULTS: Survey completion rate was 51% (303/594). Of these, 52.8% were rural residents. The most common impact was use of telemedicine (79.2%). Predominant barriers to telemedicine were lack of video devices (10.9%), perceived complexity (5.6%), and technical issues (5.3%). On a 0-10 Likert scale, the mean positive impression for telemedicine was 7.7; lower for patients with telephone-only versus video visits (7.0 vs. 8.2; p < .001), and age ≥60 years (7.4 vs. 8.1; p = .01) on univariate analyses. Time/travel savings were commonly identified (115/241, 47.7%) best parts of telemedicine and lack of personal connection (70/166, 42.2%) the worst. Only 68.9% had received any dose of COVID vaccination. The vaccinated group members were older (58.4 vs. 53.5 years; p = .007), and less likely rural (47.8% vs. 65.2%; p = .005). Common themes associated with vaccine hesitancy included concerns about safety (27/59, 46%), perceived lack of data (19/59, 32%), and distrust (17/59, 29%). At least one misconception about the vaccines or COVID-19 was quoted by 29% of vaccine-hesitant patients. CONCLUSIONS: Among respondents, the pandemic significantly impacted healthcare experience, especially in older patients in underserved communities. COVID-19 vaccination rate was relatively low, driven by misconceptions and lack of trust.

Socioeconomic status and use of obesogenic and anti-obesity medications in the United States: A population-based study.

Background: The Endocrine Society Clinical Practice Guidelines recommend the avoidance of medications that may cause weight gain (i.e., obesogenic medications) in individuals with overweight or obesity. Obesity disproportionately affects people with lower socioeconomic status (SES); however, it is unknown whether the use of obesogenic medications differs by SES. Methods: We included adults with overweight or obesity and used prescription medications from 2009-2018 of the US National Health and Nutrition Examination Survey. We examined the associations between a composite measure of SES and use of obesogenic medications and anti-obesity medications. The composite SES included

Association of Rosuvastatin Use with Risk of Hematuria and Proteinuria.

BACKGROUND: Despite reports of hematuria and proteinuria with rosuvastatin use at the time of its approval by the US Food and Drug Association (FDA), little postmarketing surveillance exists to assess real-world risk. Current labeling suggests dose reduction (maximum daily dose of 10 mg) for patients with severe CKD. METHODS: Using deidentified electronic health record data, we analyzed 152,101 and 795,799 new users of rosuvastatin and atorvastatin, respectively, from 2011 to 2019. We estimated inverse probability of treatment-weighted hazard ratios (HRs) of hematuria, proteinuria, and kidney failure with replacement therapy (KFRT) associated with rosuvastatin. We reported the initial rosuvastatin dose across eGFR categories and evaluated for a dose effect on hematuria and proteinuria. RESULTS: Overall, we identified 2.9% of patients with hematuria and 1.0% with proteinuria during a median follow-up of 3.1 years. Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria (HR, 1.08; 95% confidence interval [95% CI], 1.04 to 1.11), proteinuria (HR, 1.17; 95% CI, 1.10 to 1.25), and KFRT (HR, 1.15; 95% CI, 1.02 to 1.30). A substantial share (44%) of patients with eGFR <30 ml/min per 1.73 m2 was prescribed high-dose rosuvastatin (20 or 40 mg daily). Risk was higher with higher rosuvastatin dose. CONCLUSIONS: Compared with atorvastatin, rosuvastatin was associated with increased risk of hematuria, proteinuria, and KFRT. Among patients with eGFR <30 ml/min per 1.73 m2, 44% were prescribed a rosuvastatin daily dose exceeding the FDA's recommended 10 mg daily dose. Our findings suggest the need for greater care in prescribing and monitoring rosuvastatin, particularly in patients who receive high doses or who have severe CKD.

Concomitant Use of Diltiazem With Direct Oral Anticoagulants and Bleeding Risk in Atrial Fibrillation.

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m2. At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m2) (P for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.

Modifiable Lifestyle Behaviors and CKD Progression: A Narrative Review.

Living a healthy lifestyle is one of the safest and most cost-effective ways to improve one's quality of life and prevent and/or manage chronic disease. As such, current CKD management guidelines recommend that patients adhere to a healthy diet, perform ≥150 minutes per week of physical activity, manage their body weight, abstain from tobacco use, and limit alcohol. However, there are limited studies that investigate the relationship between these lifestyle factors and the progression of CKD among people with established CKD. In this narrative review, we examine the reported frequencies of health lifestyle behavior engagement among individuals with non-dialysis-dependent CKD and the existing literature that examines the influences of diet, physical activity, weight management, alcohol consumption, and tobacco use on the progression of CKD, as measured by decline in GFR, incident ESKD, or elevated proteinuria or albuminuria in individuals with CKD. Many of the available studies are limited by length of follow-up and small sample sizes, and meta-analyses were limited because the studies were sparse and had heterogeneous classifications of behaviors and/or referent groups and of CKD progression. Further research should be done to determine optimal methods to assess behaviors to better understand the levels at which healthy lifestyle behaviors are needed to slow CKD progression, to investigate the effect of combining multiple lifestyle behaviors on important clinical outcomes in CKD, and to develop effective techniques for behavior change. Despite the lack of evidence of efficacy from large trials on the ability of lifestyle behaviors to slow CKD progression, maintaining a healthy lifestyle remains a cornerstone of CKD management given the undisputed benefits of healthy lifestyle behaviors on cardiovascular health, BP control, and survival.

Vignette-Based Reflections to Inform Genetic Testing Policies in Living Kidney Donors.

Family history of kidney disease increases risk of end-stage kidney disease (ESKD) in donors. Pre-donation genetic testing is recommended in evaluation guidelines and regulatory policy. Collaborating across several institutions, we describe cases to illustrate the utility as well as practical issues in incorporating genetic testing in transplant protocols. Case 1 is from 2009, before pervasive genetic testing. A healthy 27-year-old Caucasian male had an uneventful donor evaluation for his mother, who had early onset ESKD of unclear cause. He participated in paired-exchange kidney donation, but developed progressive kidney disease and gout over the next 10 years. A uromodulin gene mutation (NM_003361.3(UMOD):c.377 G>A p.C126Y) was detected and kidney biopsy showed tubulointerstitial kidney disease. The patient subsequently required kidney transplantation himself. Case 2 was a 36-year-old African American female who had an uneventful kidney donor evaluation. She underwent gene panel-based testing to rule out ApolipoproteinL1 risk variants, for which was negative. Incidentally, a sickle-cell trait (NM_000518.5(HBB):c.20A>T p.Glu7Val) was noted, and she was declined for kidney donation. This led to significant patient anguish. Case 3 was a 26-year-old Caucasian female who underwent panel-based testing because the potential recipient, her cousin, carried a variant of uncertain significance in the hepatocyte nuclear factor-1-ß (HNF1B) gene. While the potential donor did not harbor this variant, she was found to have a likely pathogenic variant in complement factor I (NM_000204.4(CFI):c.1311dup:p.Asp438Argfs*8), precluding kidney donation. Our cases emphasize that while genetic testing can be invaluable in donor evaluation, transplant centers should utilize detailed informed consent, develop care pathways for secondary genetic findings, and share experience to develop best practices around genetic testing in donors.

Use of nephrotoxic medications in adults with chronic kidney disease in Swedish and US routine care.

Background: To characterize the use of nephrotoxic medications in patients with chronic kidney disease (CKD) Stages G3-5 in routine care. Methods: We studied cohorts of adults with confirmed CKD G3-5 undergoing routine care from 1 January 2016 through 31 December 2018 in two health systems [Stockholm CREAtinine Measurements (SCREAM), Stockholm, Sweden (N = 57 880) and Geisinger, PA, USA (N = 16 255)]. We evaluated the proportion of patients receiving nephrotoxic medications within 1 year overall and by baseline kidney function, ranked main contributors and examined the association between receipt of nephrotoxic medication and age, sex, CKD G-stages comorbidities and provider awareness of the patient's CKD using multivariable logistic regression. Results: During a 1-year period, 20% (SCREAM) and 17% (Geisinger) of patients with CKD received at least one nephrotoxic medication. Among the top nephrotoxic medications identified in both cohorts were non-steroidal anti-inflammatory drugs (given to 11% and 9% of patients in SCREAM and Geisinger, respectively), antivirals (2.5% and 2.0%) and immunosuppressants (2.7% and 1.5%). Bisphosphonate use was common in SCREAM (3.3%) and fenofibrates in Geisinger (3.6%). Patients <65 years of age, women and those with CKD G3 were at higher risk of receiving nephrotoxic medications in both cohorts. Notably, provider awareness of a patient's CKD was associated with lower odds of nephrotoxic medication use {odds ratios [OR] 0.85[95% confidence interval (CI) 0.80-0.90] in SCREAM and OR 0.80 [95% CI 0.72-0.89] in Geisinger}. Conclusions: One in five patients with CKD received nephrotoxic medications in two distinct health systems. Strategies to increase physician's awareness of patients' CKD and knowledge of drug nephrotoxicity may reduce prescribing nephrotoxic medications and prevent iatrogenic kidney injury.