Levetiracetam pharmacokinetics in critically ill patients undergoing renal replacement therapy.

PURPOSE: To determine clearance of levetiracetam in patients requiring continuous renal replacement therapy (CRRT) or sustained low efficiency dialysis (SLED). MATERIALS AND METHODS: Adult patients with acute kidney injury or end stage renal disease requiring either CRRT or SLED and levetiracetam were eligible for inclusion. Simultaneous arterial, venous, and effluent samples for analysis of levetiracetam concentrations were collected every two hours for up to 6-8 h. Levetiracetam clearance (CL) and half-life (t1/2) were calculated for each modality. RESULTS: Eight CRRT patients and 4 SLED patients completed the study: 67% male, mean age 50 ± 13 years, and 83% had AKI. Seven CRRT patients received continuous venovenous hemodiafiltration (CVVHDF) [median pre-replacement rate 700 mL/h (range 500-1000), post-replacement rate 500 mL/h (range 200-1000), effluent rate 2500 mL/h (range 1700-3650) and delivered CRRT dose 27 mL/kg/h (range 19-54)] and one patient received CVV hemofiltration (CVVH). The mm mean levetiracetam CL during CVVHDF was 31.2 ± 8.5 mL/min, and the and the mean t1/2 was 10.4 ± 2.2 h. For the patient requiring CVVH, clearance and t1/2 were 22.5 mL/min and 9.5 h, respectively. Mean levetiracetam CL during SLED performed at a blood flow rate of 250 mL/min and a dialysate flow rate of 100 mL/min was 74.0 ± 25.3 mL/min and t1/2 was 4.8 ± 2.3 h. CONCLUSIONS: Levetiracetam clearance was substantial with both modalities under the operating conditions reported. There is the potential for subtherapeutic concentrations with current recommended dosing strategies that account only for kidney function and not these extracorporeal routes of elimination.

Factors Associated With Increased Hospital Length of Stay in Peritoneal Dialysis Patients With Peritonitis: A Need for Antimicrobial Stewardship?

Background: Peritonitis remains a complication of peritoneal dialysis (PD) and contributes to morbidity. Adherence to evidence-based recommendations should resolve peritonitis within 5 days; however, hospital length of stay (LOS) for patients with PD-associated peritonitis (PDAP) varies. Factors contributing to increased LOS and vigilance with antimicrobial stewardship (ASP) in this population are not well described. Methods: This was a system-wide, retrospective cohort of adult patients presenting with PDAP from August 2012 to August 2017. Patients were divided into 2 groups based on LOS: <7 days (reduced LOS) versus ≥7 days (prolonged LOS). Patient demographics, resolution of peritonitis by day 5, intensive care unit (ICU) admission, infectious diseases (ID) consultation, changes in dialysis modality, blood glucose, and pathogen/antimicrobial characteristics were compared. In-hospital mortality and 30-day readmissions were also evaluated. Results: Of the 401 patients screened, 90 were included: 53% women, 88% African American, age 52 ± 2 years (reduced LOS: 46 patients; prolonged LOS: 44 patients). Increased LOS was associated with ICU admission (P = .014), ID consultation (P = .015), PD catheter removal (P = .001), hemodialysis conversion (P < .001), antifungal therapy (P = .021), and days with blood glucose >180 mg/dL (P = .028). Opportunities for antimicrobial de-escalation were identified in 24 (52%) and 22 (50%) patients in the reduced and prolonged LOS groups, respectively; however, de-escalation occurred in only 5 (21%) and 6 (27%) of these patients. There were no differences in mortality or 30-day readmissions. Conclusions: Longer LOS was influenced by acuity of illness and possibly lack of enforced ASP. Improvement of ASP within the PDAP population is necessary.

Predialysis coronary revascularization and postdialysis mortality.

Objectives: Coronary artery bypass grafting (CABG) is associated with better survival than percutaneous coronary intervention (PCI) in patients with mild-to-moderate chronic kidney disease (CKD) and End-Stage Renal Disease (ESRD). However, the optimal strategy for coronary artery revascularization in advanced CKD patients who transition to ESRD is unclear. Methods: We examined a contemporary national cohort of 971 US veterans with incident ESRD, who underwent first CABG or PCI up to 5 years prior to dialysis initiation. We examined the association of a history of CABG versus PCI with all-cause mortality following transition to dialysis, using Cox proportional hazards models adjusted for time between procedure and dialysis initiation, socio-demographics, comorbidities and medications. Results: 582 patients underwent CABG and 389 patients underwent PCI. The mean age was 66±8 years, 99% of patients were male, 79% were white, 19% were African Americans, and 84% were diabetics. The all-cause post-dialysis mortality rates after CABG and PCI were 229/1000 patient-years (PY) [95% CI: 205-256] and 311/1000PY [95% CI: 272-356], respectively. Compared to PCI, patients who underwent CABG had 34% lower risk of death [multivariable adjusted Hazard Ratio (95% CI) 0.66 (0.51-0.86), p=0.002] after initiation of dialysis. Results were similar in all subgroups of patients stratified by age, race, type of intervention, presence/absence of myocardial infarction, congestive heart failure and diabetes. Conclusion: CABG in advanced CKD patients was associated lower risk of death after initiation of dialysis compared to PCI.

Acute kidney injury following coronary revascularization procedures in patients with advanced CKD.

BACKGROUND: Previous studies reported that compared with percutaneous coronary interventions (PCIs), coronary artery bypass grafting (CABG) is associated with a reduced risk of mortality and repeat revascularization in patients with mild to moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). Information about outcomes associated with CABG versus PCI in patients with advanced stages of CKD is limited. We evaluated the incidence and relative risk of acute kidney injury (AKI) associated with CABG versus PCI in patients with advanced CKD. METHODS: We examined 730 US veterans with incident ESRD who underwent a first CABG or PCI up to 5 years prior to dialysis initiation. The association of CABG versus PCI with AKI was examined in multivariable adjusted logistic regression analyses. RESULTS: A total of 466 patients underwent CABG and 264 patients underwent PCI. The mean age was 64 ± 8 years, 99% were male, 20% were African American and 84% were diabetic. The incidence of AKI in the CABG versus PCI group was 67% versus 31%, respectively (P < 0.001). The incidence of all stages of AKI were higher after CABG compared with PCI. CABG was associated with a 4.5-fold higher crude risk of AKI {odds ratio [OR] 4.53 [95% confidence interval (CI) 3.28-6.27]; P < 0.001}, which remained significant after multivariable adjustments [OR 3.50 (95% CI 2.03-6.02); P < 0.001]. CONCLUSION: CABG was associated with a 4.5-fold higher risk of AKI compared with PCI in patients with advanced CKD. Despite other benefits of CABG over PCI, the extremely high risk of AKI associated with CABG should be considered in this vulnerable population when deciding on the optimal revascularization strategy.

Age and Outcomes Associated with BP in Patients with Incident CKD.

BACKGROUND AND OBJECTIVES: Hypertension is the most important treatable risk factor for cardiovascular outcomes. Many patients with CKD are elderly, but the ideal BP in these individuals is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From among 339,887 patients with incident eGFR<60 ml/min per 1.73 m(2), we examined associations of systolic BP (SBP) and diastolic BP (DBP) with all-cause mortality, incident coronary heart disease (CHD), ischemic strokes, and ESRD from the time of developing CKD until the end of follow-up (July 26, 2013, for mortality, CHD, and stroke, and December 31, 2011, for ESRD) in multivariable-adjusted survival models categorized by patients' age. RESULTS: Of the total cohort, 300,424 (88%) had complete data for multivariable analysis. Both SBP and DBP showed a U-shaped association with mortality. SBP displayed a linear association with CHD, stroke, and ESRD, whereas DBP showed no consistent association with either. SBP>140 mmHg was associated with higher incidence of all examined outcomes, but with an incremental attenuation of the observed risk in older compared with younger patients (P<0.05 for interaction) The adjusted hazard ratios and 95% confidence intervals associated with SBP≥170 mmHg (compared with 130-139 mmHg) in patients <50, 50-59, 60-69, 70-79, and ≥80 years were 1.95 (1.34 to 2.84), 2.01 (1.75 to 2.30), 1.68 (1.49 to 1.89), 1.39 (1.25 to 1.54), and 1.30 (1.17 to 1.44), respectively. The risk of incident CHD, stroke, and ESRD was incrementally higher with higher SBP in patients aged <80 years but showed no consistent association in those aged ≥80 years (P<0.05 for interaction for all outcomes). CONCLUSIONS: In veterans with incident CKD, SBP showed different associations in older versus younger patients. The association of higher SBP with adverse outcomes was present but markedly reduced in older individuals, especially in those aged ≥80 years. Elevated DBP showed no consistent association with vascular outcomes in patients with incident CKD.

Discontinuation of tenofovir disoproxil fumarate for presumed renal adverse events in treatment-naïve HIV-1 patients: meta-analysis of randomized clinical studies.

BACKGROUND: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naïve, HIV-infected patients. METHODS: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naïve adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. RESULTS: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01%-0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). CONCLUSIONS: In clinical studies using TDF-containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators.

Observational modeling of strict vs conventional blood pressure control in patients with chronic kidney disease.

IMPORTANCE: The effect of strict blood pressure control on clinical outcomes in patients with chronic kidney disease (CKD) is unclear. OBJECTIVE: To compare the outcomes associated with a treated systolic blood pressure (SBP) of less than 120 mm Hg vs those associated with the currently recommended SBP of less than 140 mm Hg in a national CKD database of US veterans. DESIGN, SETTING, AND PARTICIPANTS: Historical cohort study using a nationwide cohort of US veterans with prevalent CKD, estimated glomerular filtration rate less than 60 mL/min/1.73 m(2), and uncontrolled hypertension, who then received 1 or more additional blood pressure medications with evidence of a decrease in SBP. Propensity scores were calculated to reflect each individual's probability for future SBP less than 120 vs 120 to 139 mm Hg. MAIN OUTCOMES AND MEASURES: The effect of SBP on all-cause mortality was evaluated by the log-rank test, and in Cox models adjusted for propensity scores. RESULTS: Using a database of 651,749 patients with CKD, we identified 77,765 individuals meeting the inclusion criteria. A total of 5760 patients experienced follow-up treated SBP of less than 120 mm Hg and 72,005 patients had SBP of 120 to 139 mm Hg. During a median follow-up of 6.0 years, 19,517 patients died, with 2380 deaths in the SBP less than 120 mm Hg group (death rate, 80.9/1000 patient-years [95% CI, 77.7-84.2/1000 patient-years]) and 17,137 deaths in the SBP 120 to 139 mm Hg group (death rate, 41.8/1000 patient-years [95% CI, 41.2-42.4/1000 patient-years]; P < .001). The mortality hazard ratio (95% CI) associated with follow-up SBP less than 120 vs 120 to 139 mm Hg was 1.70 (1.63-1.78) after adjustment for propensity scores. CONCLUSIONS AND RELEVANCE: Our results suggest that stricter SBP control is associated with higher all-cause mortality in patients with CKD. Confirmation of these findings by ongoing clinical trials would suggest that modeling of therapeutic interventions in observational cohorts may offer useful guidance for the treatment of conditions that lack clinical trial data.

Different antidiabetic regimens and the development of renal dysfunction in US Veterans with type 2 diabetes mellitus.

AIM: The aim of this study was to evaluate the development of renal dysfunction in veterans with type 2 diabetes mellitus (T2DM) treated with different antidiabetic regimens. METHODS: A retrospective cohort study involving 1715 patients with T2DM and baseline serum creatinine (SCr) of 1.5 mg/dL or lesser. The development of renal dysfunction, defined as 0.5 mg/dL or greater increase from baseline SCr during 4.8 years of follow-up with monotherapy metformin (M), 2 combination therapy groups: metformin + insulin (MI) and metformin + sulfonylurea (MS) users were compared with changes observed in sulfonylurea monotherapy users (S). RESULTS: Both MI and MS groups had higher mean baseline hemoglobin A1C (HbA1C) (9.0 and 8.6%, respectively) and higher rates of baseline macroalbuminuria (17.3 and 12.1%, respectively) as compared with M and S groups (mean HbA1C7.7% in both groups, and proteinuria M-5.1% and S-7.4%). In unadjusted analysis, the development of renal dysfunction was more frequent in MI and MS but not in M group as compared with sulfonylurea monotherapy (unadjusted HRs and [95% confidence interval (CI), 2.1[1.4-3.0], 1.4[1.1-1.9], and 1.0[0.6-1.7], respectively). However, differences in the development of renal dysfunction were not significant between the 4 groups after adjusting for baseline variables. Baseline macroalbuminuria was a strong predictor of Scr elevation of 0.5 mg/dL or greater during follow-up (adjusted HR, 3.1[1.9-4.7]). Unexpectedly, baseline use of renin-angiotensin-aldosterone system blockers was also associated with the development of renal dysfunction (adjusted HR, 1.9[1.3-2.8]). CONCLUSIONS: In this retrospective cohort study involving US predominantly male veterans with T2DM, baseline macroalbuminuria and use of RAAS blockers were associated with increased risk of development of renal dysfunction, whereas different antidiabetic regimens were not.

Evaluation of vancomycin and gentamicin dialysis clearance using in vivo and in vitro systems.

Advances in hemodialysis (HD) techniques have increased the potential for drug removal. Quantifying drug clearance in clinical studies for all possible dialysis conditions is impractical, given the variability in dialysis conditions. The purpose of this study was to determine the dialysis clearance (CL(D)) of vancomycin and gentamicin using in vitro and in vivo methods and evaluate the applicability of in vitro data. In vitro dialysis was used to determine the CL(D) of vancomycin and gentamicin under conditions of intermittent HD (IHD) and sustained low-efficiency dialysis (SLED). Two Fresenius polysulfone dialyzers were studied: F180NR for IHD and F50 for SLED. Data were compared with in vivo CL(D) determined in patients with end-stage renal disease receiving IHD and from the literature for SLED. Under IHD conditions, in vitro CL(D) of vancomycin and gentamicin was 131 ± 3 and 154 ± 3 mL/min, respectively, and under SLED condition it was 72 ± 9 and 84 ± 11 mL/min, respectively. These values were 11-27% higher than in vivo CL(D) for IHD (103 ± 15 mL/min for vancomycin and 132 ± 25 mL/min for gentamicin) and SLED (63 mL/min for vancomycin and 76 ± 38 mL/min for gentamicin). There was a statistically significant difference in vancomycin clearance by IHD for the in vitro study compared with in vivo data (p = 0.012), but not for gentamicin (p = 0.18). In vitro methods overestimated in vivo CL(D), but are reasonable to assist with drug regimen design if one considers the limitations.

Age and cystatin C in healthy adults: a collaborative study.

BACKGROUND: Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum. METHODS: The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. RESULTS: Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction). CONCLUSIONS: There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.

Hypercalcemia associated with tertiary hyperparathyroidism managed conservatively with pamidronate in a hemodialysis patient.

Secondary hyperparathyroidism and the associated metabolic abnormalities are common complications of chronic kidney disease. When these disorders cannot be managed by conventional measures, including phosphate restriction, phosphate binders, vitamin D therapy, and calcimimetics, tertiary hyperparathyroidism and the associated metabolic abnormalities may develop. In such cases parathyroidectomy is required. We report a case in which a patient with tertiary hyperparathyroidism and refractory hypercalcemia who was not a surgical candidate was managed with the bisphosphonate pamidronate. This patient had failed conventional measures to manage hypercalcemia and presented with mental status changes. Pamidronate therapy was associated with a sustained decrease in serum calcium concentration and improvement in clinical symptoms. This is the first case, to our knowledge, in which pamidronate was used in a patient refractory to all other reasonable medical management, including calcimimetics.

Effect of metformin-containing antidiabetic regimens on all-cause mortality in veterans with type 2 diabetes mellitus.

OBJECTIVE: There are conflicting reports concerning metformin use and mortality rates in patients with type 2 diabetes (T2DM). The aim of this study was to examine the relationship between metformin use and all-cause mortality in veterans with T2DM. RESEARCH DESIGN AND METHODS: An observational cohort study involving 2206 patients with T2DM was performed using computerized database from the Veterans Affairs Medical Center, Memphis, TN. All-cause mortality was compared among cohorts of metformin and nonmetformin users. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HR) for all-cause mortality after adjusting for age, race, baseline estimated glomerular filtration rate, glycosylated hemoglobin, use of insulin, use of ACE inhibitors or angiotensin II receptor blockers or statins. RESULTS: The average length of follow-up in metformin and nonmetformin users was 62 +/- 17 and 61 +/- 18 months, respectively. The mean age was 63 +/- 11 years. Crude mortality rates were similar in both groups: 266 (22%) metformin users and 253 (25.3%) nonmetformin users died. There was a trend for improved survival with metformin use (unadjusted HR 0.85, P = 0.07). After multivariate adjustment, metformin users had significantly decreased HR for time to all-cause mortality compared with nonmetformin users (adjusted HR 0.77, P < 0.01). Insulin use was an independent predictor of worsened survival in both univariate and multivariate analyses. In subgroup analysis of patients exposed to insulin, all-cause mortality remained decreased in metformin users (adjusted HR 0.62, P < 0.04). CONCLUSION: Treatment of T2DM with regimens containing metformin alone or in combination with other hypoglycemic agents was associated with reduced all-cause mortality compared with regimens without metformin.