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Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin.
Vaduganathan, M, Sattar, N, Xu, J, Butler, J, Mahaffey, KW, Neal, B, Shaw, W, Rosenthal, N, Pfeifer, M, Hansen, MK, et al
Journal of the American College of Cardiology. 2022;(5):432-444
Abstract
BACKGROUND Circulating biomarkers reflecting different mechanistic pathways may identify at-risk individuals with diabetes who may benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitors. OBJECTIVES The purpose of this study was to determine if high-sensitivity cardiac troponin T (hs-cTnT), soluble suppression of tumorigenesis-2 (sST2), and insulin-like growth factor binding protein 7 (IGFBP7) levels, either alone or in combination, may modify the treatment benefits of canagliflozin. METHODS In the CANVAS (CANagliflozin cardioVascular Assessment Study) biomarker substudy, we evaluated the prognostic significance of baseline biomarker measurements, the long-term trajectory of each, and response to canagliflozin on key cardiovascular and kidney outcomes. RESULTS Among the 4,330 study participants, baseline hs-cTnT, sST2, and IGFBP7 were available in 3,503 (81%), 3,084 (71%), and 3,577 (83%). In total, 39% had elevated hs-cTnT ≥14 pg/mL, 6% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5 ng/mL. Canagliflozin significantly slowed increases of hs-cTnT (P = 0.027) and sST2 (P = 0.033) through 6 years. Each biomarker was significantly associated with cardiovascular and kidney outcomes, independent of clinical covariates. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Patients with hs-cTnT ≥14 ng/L and those with sST2 >35 ng/mL derived greater relative benefit for major adverse cardiovascular events (MACE) (both Pinteraction ≤0.05). A panel of all 3 biomarkers predicted each cardiac and kidney outcome evaluated; participants with an increasing number of abnormal circulating biomarkers appeared to have greater relative reductions in MACE from canagliflozin treatment (Pinteraction trend = 0.005). CONCLUSIONS Canagliflozin delays longitudinal rise in hs-cTnT and sST2 compared with placebo out to 6 years. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Elevated cardiovascular biomarkers, either alone or in combination, may identify individuals who may derive greater MACE benefit from SGLT2 inhibition. CANVAS (CANagliflozin cardioVascular Assessment Study; NCT01032629).
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Effect of an Intensive Weight-Loss Lifestyle Intervention on Kidney Function: A Randomized Controlled Trial.
Díaz-López, A, Becerra-Tomás, N, Ruiz, V, Toledo, E, Babio, N, Corella, D, Fitó, M, Romaguera, D, Vioque, J, Alonso-Gómez, ÁM, et al
American journal of nephrology. 2021;(1):45-58
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Abstract
INTRODUCTION Large randomized trials testing the effect of a multifactorial weight-loss lifestyle intervention including Mediterranean diet (MedDiet) on renal function are lacking. Here, we evaluated the 1-year efficacy of an intensive weight-loss intervention with an energy-reduced MedDiet (erMedDiet) plus increased physical activity (PA) on renal function. METHODS Randomized controlled "PREvención con DIeta MEDiterránea-Plus" (PREDIMED-Plus) trial is conducted in 23 Spanish centers comprising 208 primary care clinics. Overweight/obese (n = 6,719) adults aged 55-75 years with metabolic syndrome were randomly assigned (1:1) to an intensive weight-loss lifestyle intervention with an erMedDiet, PA promotion, and behavioral support (intervention) or usual-care advice to adhere to an energy-unrestricted MedDiet (control) between September 2013 and December 2016. The primary outcome was 1-year change in estimated glomerular filtration rate (eGFR). Secondary outcomes were changes in urine albumin-to-creatinine ratio (UACR), incidence of moderately/severely impaired eGFR (<60 mL/min/1.73 m2) and micro- to macroalbuminuria (UACR ≥30 mg/g), and reversion of moderately (45 to <60 mL/min/1.73 m2) to mildly impaired GFR (60 to <90 mL/min/1.73 m2) or micro- to macroalbuminuria. RESULTS After 1 year, eGFR declined by 0.66 and 1.25 mL/min/1.73 m2 in the intervention and control groups, respectively (mean difference, 0.58 mL/min/1.73 m2; 95% CI: 0.15-1.02). There were no between-group differences in mean UACR or micro- to macroalbuminuria changes. Moderately/severely impaired eGFR incidence and reversion of moderately to mildly impaired GFR were 40% lower (HR 0.60; 0.44-0.82) and 92% higher (HR 1.92; 1.35-2.73), respectively, in the intervention group. CONCLUSIONS The PREDIMED-Plus lifestyle intervention approach may preserve renal function and delay CKD progression in overweight/obese adults.
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The effects of 0.9% saline versus Plasma-Lyte 148 on renal function as assessed by creatinine concentration in patients undergoing major surgery: A single-centre double-blinded cluster crossover trial.
Weinberg, L, Li, MH, Churilov, L, Macgregor, C, Garrett, K, Eyles, J, Bellomo, R
PloS one. 2021;(5):e0251718
Abstract
OBJECTIVES Saline and Plasma-Lyte have different physiochemical contents; consequently, they may differently affect patients' renal function. We compared the effects of fluid therapy with 0.9% saline and with Plasma-Lyte 148 on renal function as assessed by creatinine concentration among patients undergoing major surgery. METHODS We conducted a prospective, double-blinded cluster crossover trial comparing the effects of the two fluids on major surgery patients. The primary aim was to establish the pilot feasibility, safety and preliminary efficacy evidence base for a large interventional trial to establish whether saline or Plasma-Lyte is the preferred crystalloid fluid for managing major surgery patients. The primary efficacy outcome was the proportion of patients with changes in renal function as assessed by creatinine concentration during their index hospital admission. We used changes in creatinine to define acute kidney injury (AKI) according to the RIFLE criteria. RESULTS The study was feasible with 100% patient and clinician acceptance. There were no deviations from the trial protocol. After screening, we allocated 602 patients to saline and 458 to Plasma-Lyte. The median (IQR) volume of intraoperative fluid received was 2000 mL (1000:2000) in both groups. Forty-nine saline patients (8.1%) and 49 Plasma-Lyte patients (10.7%) developed a postoperative AKI (adjusted incidence rate ratio [aIRR]: 1.34; 95% CI: 0.93-1.95; p = 0.120). No differences were observed in the development of postoperative complications (aIRR: 0.98; 95% CI: 0.89-1.08) or the severity of the worst complication (aIRR: 1.00; 95% CI: 0.78-1.30). The median (IQR) length of hospital stay was six days (3:11) for the saline group and five days (3:10) for the Plasma-Lyte group (aIRR: 0.85; 95% CI: 0.73-0.98). There were no serious adverse events relating to the trial fluids, nor were there fluid crossover or contamination events. CONCLUSIONS The study design was feasible to support a future follow-up larger clinical trial. Patients treated with saline did not demonstrate an increased incidence of postoperative AKI (defined as changes in creatinine) compared to those treated with Plasma-Lyte. Our findings imply that clinicians can reasonably use either solution intraoperatively for adult patients undergoing major surgery. TRIAL REGISTRATION Registry: Australian New Zealand Clinical Trials Registry; ACTRN12613001042730; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364988.
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Cardio/Kidney Composite End Points: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.
Ferreira, JP, Kraus, BJ, Zwiener, I, Lauer, S, Zinman, B, Fitchett, DH, Koitka-Weber, A, George, JT, Ofstad, AP, Wanner, C, et al
Journal of the American Heart Association. 2021;(7):e020053
Abstract
Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.
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Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.
Heerspink, HJL, Jongs, N, Chertow, GM, Langkilde, AM, McMurray, JJV, Correa-Rotter, R, Rossing, P, Sjöström, CD, Stefansson, BV, Toto, RD, et al
The lancet. Diabetes & endocrinology. 2021;(11):743-754
Abstract
BACKGROUND Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease with and without type 2 diabetes in the DAPA-CKD trial. In this pre-specified analysis, we assessed the effect of dapagliflozin on the rate of change in estimated glomerular filtration rate (eGFR)-ie, the eGFR slope. METHODS DAPA-CKD was a randomised controlled trial that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73m2. Participants were randomly assigned (1:1) to oral dapagliflozin 10 mg once daily or placebo, added to standard care. In this pre-specified analysis, we analysed eGFR slope using mixed-effect models with different slopes from baseline to week 2 (acute eGFR decline), week 2 to end of treatment (chronic eGFR slope), and baseline to end of treatment (total eGFR slope). DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150, and is now complete. FINDINGS Between Feb 2, 2017, and April 3, 2020, 4304 participants were recruited, of whom 2152 (50%) were assigned to dapagliflozin and 2152 (50%) were assigned to placebo. At baseline, the mean age was 62 years (SD 12), 1425 (33·1%) participants were women, 2906 (67·5%) participants had type 2 diabetes. The median on-treatment follow-up was 2·3 years (IQR 1·8-2·6). From baseline to the end of treatment, dapagliflozin compared with placebo slowed eGFR decline by 0·95 mL/min per 1·73 m2 per year (95% CI 0·63 to 1·27) in the overall cohort. Between baseline and week 2, dapagliflozin compared with placebo resulted in an acute eGFR decline of 2·61 mL/min per 1·73 m2 (2·16 to 3·06) in patients with type 2 diabetes and 2·01 mL/min per 1·73 m2 (1·36 to 2·66) in those without type 2 diabetes. Between week 2 and end of treatment, dapagliflozin compared with placebo reduced the mean rate of eGFR decline by a greater amount in patients with type 2 diabetes (mean difference in chronic eGFR slope 2·26 mL/min per 1·73 m2 per year [1·88 to 2·64]) than in those without type 2 diabetes (1·29 mL/min per 1·73 m2 per year [0·73 to 1·85]; pinteraction=0·0049). Between baseline and end of treatment, the effect of dapagliflozin compared with placebo on the decline of total eGFR slope in patients with type 2 diabetes was 1·18 mL/min per 1·73 m2 per year (0·79 to 1·56) and without type 2 diabetes was 0·46 mL/min per 1·73 m2 per year (-0·10 to 1·03; pinteraction=0·040). The total eGFR slope was steeper in patients with higher baseline HbA1c and UACR; the effect of dapagliflozin on eGFR slope was also more pronounced in patients with higher baseline HbA1c and UACR. INTERPRETATION Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with type 2 diabetes, higher HbA1c, and higher UACR. FUNDING AstraZeneca.
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Effect of a Moderate Carbohydrate-Restricted Diet on DPP-4 Inhibitor Action among Individuals with Type 2 Diabetes Mellitus: A 6-Month Intervention Study.
Kobayashi, M, Miura, T, Miura, K, Hiroyama, N, Akashi, K
Journal of nutritional science and vitaminology. 2020;(2):114-118
Abstract
To decrease body weight and insulin resistance, a calorie-restricted diet-with minimal caloric intake required for daily activities-is the primary treatment strategy for patients with type 2 diabetes (T2D) in Japan. However, many patients cannot continue with this diet for long, because calorie restriction is difficult and nutritional balance is hard to understand. Carbohydrate-restricted diets are easier for patients than conventional calorie-restricted diet. In this study we aimed to elucidate the effects of a moderate carbohydrate-restricted diet on glucose metabolism and renal function in patients with T2D on dipeptidyl peptidase-4 (DPP-4) inhibitors. Nineteen outpatients with T2D continued on a moderate carbohydrate-restricted diet (targeting 50% of calories) for 6 mo. Meanwhile, 10 other outpatients with T2D on DPP-4 inhibitors had the conventional calorie-restricted diet using the food exchange table. No change in prescription drugs occurred for both groups during the study period. After the intervention, the carbohydrate content in dietary intake was lowered significantly from 56.8±8.3 to 46.8±10.1%, while the lipid concentration, primarily n-6 polyunsaturated fatty acids, was significantly increased. There was no significant change in protein intake. Hemoglobin A1c (HbA1c) fell from 7.22±0.74% to 6.95±0.72% (mean±SD). Furthermore, salt intake decreased significantly from 6.8±2.5 g prior to the intervention, to 5.7±1.9 g after the intervention. The estimated glomerular filtration rates (eGFR) decreased slightly, while serum creatinine levels did not change. These findings suggest that a moderate carbohydrate-restricted diet (50%) is effective in patients with T2D, without affecting kidney function.
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Evaluation of Renal Function at 24, 48, and 72 Hours and 3 Months After Transplant: Comparison of 3 Anesthetic Techniques.
Calixto-Flores, A, Román-Sánchez, M, Jiménez-Sánchez, E, Cruz-Santiago, J, Meza-Jiménez, G, Bernáldez-Gómez, G
Transplantation proceedings. 2020;(4):1094-1101
Abstract
BACKGROUND General anesthesia is the conventional management of renal transplant, and its evolution has revolved around the development of new drugs; however, a group of patients meet conditions for neuraxial anesthesia, because of their comorbidities, who are at greater risk of complications with general anesthesia and are not favorable to grafting. METHODS We conducted a controlled clinical trial of 109 renal transplant recipients where renal function was evaluated at 24, 48, and 72 hours and 3 months after transplant, and we compared regional, general anesthesia with inhaled anesthetic and total intravenous anesthesia. It was performed for 1 year, and serum creatinine, urea nitrogen, and electrolytes were evaluated. During the intraoperative period central venous pressure, mean arterial pressure, vasopressors, fluid therapy, diuretics, surgical time, anesthesia, hot and cold ischemia, immunosuppressants, and antihypertensives were evaluated. They were analyzed with χ2 independence and 1-way and 2-way repeated measures. RESULTS The type of anesthesia was associated with hemodynamic stability (P = .018), the use of vasopressor (P = .005), and fluid therapy (P = .011). A value of P = .005 was found for central venous pressure at discharge from the operating room, and preincisional mean arterial pressure (P = .015) was among the types of anesthesia. Creatinine, blood urea nitrogen, sodium, and potassium were statistically significant over time (P < .001) but showed no difference between types of anesthesia. CONCLUSION There is no difference between anesthetic techniques and clinical results over time. The personalized anesthetic technique will improve the neuroendocrine response and surgical stress, decrease the need for vasopressors and analgesics, and reduce complications.
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Impact of Serum Bicarbonate Levels on Muscle Mass and Kidney Function in Pre-Dialysis Chronic Kidney Disease Patients.
Kittiskulnam, P, Srijaruneruang, S, Chulakadabba, A, Thokanit, NS, Praditpornsilpa, K, Tungsanga, K, Eiam-Ong, S
American journal of nephrology. 2020;(1):24-34
Abstract
BACKGROUND Treatment of metabolic acidosis to target the higher serum bicarbonate level than guideline recommendation may downregulate muscle protein degradation and improve renal function among chronic kidney disease (CKD) patients. We conducted a study to test the effects of increased serum bicarbonate level on muscle parameters, nutrition, and renal function in pre-dialysis CKD patients. METHODS This was a randomized, controlled study. CKD stage 3-4 patients with serum HCO3- <22 mEq/L were randomized to either receive oral sodium bicarbonate with high target bicarbonate level of 25 ± 1 or standard level of 22 ± 1 mEq/L as control group using protocol-based titration of dosage adjustment. The changes of muscle mass measured by bioelectrical impedance analysis (BIA), muscle strength by hand grip dynamometer, estimated glomerular filtration rate (eGFR) using CKD-Epidemiology Collaboration equation, nutritional markers, and muscle-related biomarkers were determined. Data at baseline and after 4 months of sodium bicarbonate supplementation were compared between groups using Student t test or chi-square test as appropriate. RESULTS Forty-two patients completed the study (n = 21 per group). The mean age and eGFR were 61.2 ± 9.8 years and 32.4 ± 14.1 mL/min respectively. Serum bicarbonate levels at baseline were 21.0 ± 2.1 mEq/L. Baseline data including sex, diabetes, serum bicarbonate level, creatinine, and blood pressure were similar. After 4 months of treatment, the average serum bicarbonate levels in both groups were 24.0 ± 1.4 and 20.7 ± 2.3 mEq/L (p < 0.001). Both BIA-derived total-body muscle mass and appendicular lean balance were increased at 4 months in the higher bicarbonate group (26.0 ± 5.3 to 26.7 ± 5.5 kg, p = 0.04 and 19.8 ± 4.1 to 20.7 ± 4.4 kg, p = 0.06, respectively) despite comparable body weight and protein intake. Patients in the high bicarbonate group had a significant reduction of plasma myostatin levels, a surrogate of muscle degradation, at the study exit after adjusting for baseline values (-3,137.8; 95% CI -6,235.3 to -40.4 pg/mL, p= 0.04), but unaltered insulin-like growth factor-1 level, as the mediator of muscle cell growth, (141 [106-156] to 110 [87-144] ng/mL, p = 0.13) compared to the control group. Muscle strength, eGFR as well as serum prealbumin were not significantly different between 2 groups (p > 0.05). Neither worsening hypertension nor congestive heart failure was found throughout the study. CONCLUSION Bicarbonate supplementation to achieve the serum level ∼24 mEq/L demonstrates better muscle mass preservation in patients with pre-dialysis CKD. The impact of alkaline therapy on renal function may require a longer period of study.
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Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial.
Perkovic, V, Toto, R, Cooper, ME, Mann, JFE, Rosenstock, J, McGuire, DK, Kahn, SE, Marx, N, Alexander, JH, Zinman, B, et al
Diabetes care. 2020;(8):1803-1812
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Abstract
OBJECTIVE Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m2) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532). RESEARCH DESIGN AND METHODS Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia. RESULTS A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories. CONCLUSIONS Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c and no difference in AEs were observed.
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Felodipine and renal function in lung transplantation: A randomized placebo-controlled trial.
Hornum, M, Iversen, M, Oturai, P, Andersen, MJ, Zemtsovski, M, Bredahl, P, Bjarnason, NH, Christensen, KB, Carlsen, J, Møller, CH, et al
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2020;(6):541-550
Abstract
BACKGROUND Calcium channel blockers may ameliorate the decline in renal function caused by calcineurin inhibitors in lung transplantation (LTX) recipients. We hypothesized that pre-operative and 12-week post-operative treatment with the calcium channel blocker felodipine would reduce the decline in glomerular filtration rate (GFR). METHODS In this prospective, randomized, double-blind trial, 39 LTX recipients were transplanted and received placebo (n = 19; GFR, 102 ml/min/1.73 m2 [range, 91-113 ml/min/1.73 m2]) or felodipine (n = 20, GFR, 96 ml/min/1.73 m2 [range, 88-104 ml/min/1.73 m2]). Pre-operative treatment was titrated post-operatively to 10 mg or the maximum tolerable dose. The primary end-point was the change in GFR using Cr-51-labeled EDTA from LTX to 12 weeks thereafter, and follow-up was 52 weeks. RESULTS The treatment group showed an absolute mean decline in GFR of 31 ml/min/1.73 m2 (95% CI: -40 to 22 ml/min/1.73 m2), whereas that of the placebo group was 48 ml/min/1.73 m2 (95% confidence interval [CI]: -56 to 40 ml/min/1.73 m2). Thus, the difference between groups at 12 weeks was 17 ml/min/1.73 m2 (95% CI: 4-29 ml/min/1.73 m2; p = 0.01). Half of the patients were unable to complete the 3-month primary follow-up, and the analysis includes these patients by intention-to-treat. After 52 weeks (40 weeks after termination of treatment), the treatment effect was maintained at 12 ml/min/1.73 m2 (95% CI: 0-24 ml/min/1.73 m2, p = 0.05). The number of days with registered hypotension was significantly higher in the felodipine group than in the placebo group (39 days vs 13 days, rate ratio: 2.9 [95% CI: 1.5-5.3]). CONCLUSIONS Use of felodipine in select patients was associated with greater preservation in renal function early (90 days) after LTX. The observed benefits were attenuated by 1 year, although trends in better renal function were noted.