INTRODUCTION:Patients often receive propofol for sedation and clevidipine for hypertension in the intensive care unit. Both agents are formulated as a lipid emulsion, which may increase the risk of hypertriglyceridemia and acute pancreatitis with their coadministration. We aimed to determine the incidence of hypertriglyceridemia and acute pancreatitis with concurrent administration of propofol and clevidipine and identify patient risk factors for hypertriglyceridemia. METHODS:This was a multicenter retrospective study of adult patients (≥ 18 years old) receiving concurrent propofol and clevidipine infusions for ≥ 6 h. The primary outcome was the frequency of triglyceride levels greater than 400 mg/dL and acute pancreatitis. The secondary outcome was risk factors associated with hypertriglyceridemia during concurrent propofol and clevidipine infusions until both infusions had been discontinued. Univariable and multivariable logistic regression analyses were used to assess risk factors of hypertriglyceridemia in patients receiving concurrent propofol and clevidipine infusions. RESULTS:Across 1,226 patients, the median duration of infusion overlap was 12.4 [interquartile range (IQR) 8.3, 22.7] hours. The mean age of the cohort was 59.6 [standard deviation (SD) 14.9] years, and 59.4% were male. Assuming those without a triglyceride level drawn did not have hypertriglyceridemia, hypertriglyceridemia after initiation of propofol and clevidipine infusion was found in 7.7% [95% confidence interval (CI) 6.3% to 9.3%] of the entire cohort. Twenty-six patients (2.1%) had a diagnosis of pancreatitis after initiation of lipid infusions, of which 12 cases were possibly infusion-related, and one case was likely infusion-related. After calculating the Naranjo Scale, all 13 cases of pancreatitis were possibly related to propofol or clevidipine infusions. Based on a multivariable logistic regression of those with a triglyceride level available, risk factors for hypertriglyceridemia included pancreatitis within the past 5 years [adjusted odds ratio (aOR) 2.77, 95% CI, 1.23 to 6.23] and statin use (aOR 1.94, 95% CI, 1.13 to 3.34). CONCLUSIONS:In our cohort of patients receiving concurrent propofol and clevidipine, the frequency of hypertriglyceridemia and acute pancreatitis was low. Further comparative studies are warranted to assess the risk of pancreatitis with the addition of clevidipine to propofol.
In 2023, international consensus recommendations suggested the use of prolonged-infusion beta-lactam antibiotics over short-infusion dosing in severely ill adult patients to improve mortality or clinical cure, although the certainty of evidence was very low. With the availability of several new randomized controlled trials (RCTs), this focused update re-evaluates the efficacy of prolonged versus short infusion among severely ill adult patients. The original Population, Intervention, Comparator, and Outcome (PICO) question VII was separated into two questions addressing mortality (VIIa) and clinical cure (VIIb). Methods used for study identification, screening, and evidence grading were consistent with the original guideline, with the addition of Bayesian meta-analyses. A total of 28 RCTs evaluating mortality in severely ill adults were analyzed, with pooled estimates favoring prolonged infusion (RR 0.91; 95% confidence interval 0.85 to 0.97), supported by Bayesian analyses demonstrating a 98.76% posterior probability of benefit. Across 21 RCTs evaluating clinical cure, prolonged infusion improved outcomes compared with short infusion (RR 1.11; 95% confidence interval 1.06 to 1.17), supported by Bayesian analyses demonstrating a 99.97% posterior probability of benefit. Certainty of evidence was strengthened to moderate for mortality and low for clinical cure. Consistent with the original recommendation (PICO X), subgroup analyses evaluating loading doses suggested improved outcomes when a loading dose is used before continuous infusion. Overall, the cumulative evidence reinforces and strengthens the recommendation for use of prolonged-infusion beta-lactam therapy in severely ill adult patients to improve survival and clinical cure. Continued use of loading doses when initiating continuous-infusion therapy is suggested. Future research should identify subpopulations most likely to benefit, clarify optimal prolonged-infusion strategies, and define the role of therapeutic drug monitoring.
BACKGROUND:Current consensus guidelines recommend therapeutic drug monitoring of vancomycin to target a 24-h area under the curve (AUC24) of 400-600 mg*hr/L. Recommended methods for estimation of AUC24 include the use of first-order (linear) pharmacokinetic equations or Bayesian software. Limited data exist to compare these methods in pediatric patients. This study aimed to compare calculated AUC24 using first-order equations with two drug concentrations at steady state to Bayesian one- and two-concentration estimations. METHODS:This was a single center retrospective review of hospitalized pediatric patients receiving intravenous vancomycin. Patients with two concentrations collected at steady-state within 96 h of vancomycin initiation were screened. Pharmacokinetic parameters and AUC24 were estimated using first-order equations and InsightRx Bayesian software. Pearson's correlation and clinical agreement were used to compare methods. Bland-Altman plots were used to assess mean difference (MD) and 95% limits of agreement (LOA) to assess variability. RESULTS:Overall, 196 patients (22 neonates, 17 infants, 114 children, and 43 adolescents) were included in the final analysis. Reasonable agreement was observed between linear and Bayesian two-concentration methods (84.2%; R2 = 0.723) and between Bayesian two- and one-concentration methods (82.7%, R2 = 0.839). Some variability was noted with 95% LOA of -123 to 178 (MD = 27 mg*hr/L) and -88 to 110 (MD = 11 mg*hr/L), for the respective comparisons. Lower agreement was noted between linear and Bayesian one-concentration methods (73.9%, R2 = 0.544), and the greatest amount of variability was demonstrated with 95% LOA of -179 to 211 (MD = 16 mg*hr/L). In subgroup analysis, neonates demonstrated significantly lower clinical agreement (54.5%) and correlation (R2 = 0.2986) between linear and Bayesian one-concentration methods. CONCLUSIONS:Linear and Bayesian two-concentration methods demonstrated reasonable agreement with acceptable variability and may be considered comparable for estimating vancomycin AUC24 in pediatric patients. Similarly, Bayesian two-concentration and one-concentration methods demonstrated reasonable agreement with acceptable variability, supporting the comparability of these methods to estimate AUC24. As poor agreement was demonstrated between linear and Bayesian one-concentration methods in neonatal sub-analysis, additional investigation is warranted to determine the comparability of these methods in neonates.
INTRODUCTION:Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxicities. Oxidative hepatic metabolism of zongertinib in vitro is principally driven by cytochrome P450 (CYP) 3A. It is necessary, therefore, to assess the effect of a strong CYP3A inhibitor on the pharmacokinetics of zongertinib in humans. OBJECTIVE:This study investigated the effect of multiple oral doses of the strong CYP3A inhibitor and regulatory-recommended probe inhibitor of P-glycoprotein (P-gp), itraconazole, on the pharmacokinetics of a single dose of zongertinib in healthy male participants. METHODS:This open-label, two-period, fixed-sequence, clinical drug-drug interaction study assessed the pharmacokinetics of a 15 mg oral dose of zongertinib in the absence and presence of multiple oral doses of itraconazole. The extent of drug-drug interaction was estimated using the adjusted geometric mean (gMean) ratios (90% confidence intervals [CIs]) for the test (T) treatment (zongertinib and itraconazole) vs. the reference (R) treatment (zongertinib alone). Primary endpoints were the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and the maximum measured plasma concentration (Cmax) of zongertinib. The secondary pharmacokinetic endpoint was AUC for zongertinib from time 0 to the last quantifiable time point (AUC0-tz). RESULTS:Sixteen participants received zongertinib alone (Period 1, R), followed by co-administration with itraconazole (Period 2, T). In terms of zongertinib exposure, the gMean ratio of T to R was 141.2% (90% CI: 126.3-157.7%) for AUC0-∞, 142.8% (90% CI: 126.0-161.9%) for AUC0-tz, and 126.9% (90% CI: 106.6-151.0%) for Cmax. CONCLUSION:Co-administration with itraconazole resulted in a mild increase in total exposure to zongertinib that was not considered clinically relevant given its wide therapeutic window. These data indicate that the approved 120 mg dose of zongertinib can be administered without dose adjustment in combination with CYP3A/P-gp inhibitors.
Menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor and genitourinary symptoms of menopause; however, its use declined sharply following the publication of the Women's Health Initiative (WHI). Misinterpretation and limitations of WHI findings have led to persistent misconceptions and underutilization of MHT. This expert opinion aims to clarify evidence-based approaches to MHT selection, safety, and individualized management. This article was informed by a structured narrative review of the literature with the aim to contextualize evolving pharmacotherapeutic evidence and inform clinical decision-making. PubMed/MEDLINE, Embase, and the Cochrane Library were searched for studies published from 2002 to 2025. Key opinion statements were developed through expert consensus and paired with a synthesis of contemporary evidence to form recommendations. A critical appraisal of the WHI and subsequent analyses demonstrates that age at initiation, timing since menopause, and hormone formulation utilized significantly influence outcomes. Contemporary data support the preferential use of transdermal estradiol due to its lower risk of venous thromboembolism and favor oral micronized progesterone (MP) over synthetic progestogens when endometrial protection is required. Individualization of therapy-including formulation, route, and dosing-is emphasized as central to optimizing the benefit-risk profile. Current evidence supports the safety of low-dose vaginal estrogen for genitourinary syndrome of menopause including in cancer survivors. Further evidence highlights potential cardiovascular and cognitive benefits when MHT is initiated within 10 years of menopause. Clinicians caring for menopausal women should promote individualized, evidence-based MHT through education, therapeutic selection, shared decision making, and ongoing monitoring. Continued research is needed to refine dosing targets, evaluate long-term preventive outcomes, and expand evidence for modern formulations beyond WHI-era therapies. Ultimately, MHT should be viewed not as a one-size-fits-all therapy, but as a personalized, evidence-informed strategy that supports the health and quality of life of menopausal women.
Optimal cephalexin and cefadroxil dosing for skin and soft tissue infections (SSTIs) is unclear. We summarize clinical and pharmacokinetic/pharmacodynamic (PK/PD) data that compare dosing strategies for SSTIs. Additionally, we conduct population PK target attainment simulations for varying doses of cephalexin and cefadroxil for Staphylococcus aureus and Group A Streptococcus. Although some clinical data support lower doses in mild SSTIs, higher doses optimize PK/PD parameters in moderate-severe SSTIs, especially due to Staphylococcus aureus. Further prospective clinical and PK/PD studies, especially in obese adults, would be beneficial.
BACKGROUND:Voriconazole is a triazole antifungal, primarily metabolized by the liver, and poses a dosing challenge in patients with liver impairment. Although the manufacturer recommends a maintenance dose reduction for mild-to-moderate hepatic dysfunction, no standardized recommendations exist for severe liver impairment. Prior evidence suggests a need for significant dose reduction in the setting of severe liver failure; however, there is limited data on empirical dosing in patients undergoing orthotopic liver transplant (OLT) evaluation and surgery. METHODS:This is a single-center, retrospective cohort study assessing voriconazole dosing and therapeutic drug monitoring (TDM) in patients with advanced cirrhosis who received voriconazole during urgent OLT evaluation and/or surgery. Patients were included if voriconazole trough concentrations were collected at least 7 days after therapy initiation pre-OLT or at least 5 days post-OLT. The target therapeutic range was defined as 1-4 mcg/mL. The primary outcome was the distribution of voriconazole trough concentrations in the pre- and post-transplant cohorts. RESULTS:The pre-OLT cohort comprised 76 patients with 124 concentrations, and the post-OLT cohort comprised 36 patients with 71 concentrations. As anticipated, the pre-OLT group exhibited more abnormal liver enzymes and a high median Model for End-Stage Liver Disease (MELD) score of 35 (Interquartile Range (IQR) 29.5-40). In the pre-OLT setting, doses less than 2 mg/kg/dose were more likely associated with therapeutic voriconazole concentrations. Supratherapeutic concentrations were observed in 41 patients (average dose of 2.4 mg/kg/dose), of which five patients required therapy interruption. In the post-OLT group, only 23 of 71 concentrations fell within the therapeutic range, with an average dose of 2.8 mg/kg/dose. CONCLUSION:We found that empiric voriconazole dosing in patients with advanced cirrhosis undergoing OLT evaluation should not exceed 2 mg/kg/dose initially to mitigate the risk of drug accumulation and potential toxicity. In post-OLT patients, it is reasonable to consider reverting to standard manufacturer-recommended dosing. Given the pharmacokinetic variability observed, TDM is essential for effective and safe management in this high-risk patient population.
INTRODUCTION:Patients supported with extracorporeal membrane oxygenation (ECMO) frequently require prolonged, high-intensity analgosedation because of neuromuscular blockade, pain related to procedures, and pharmacokinetic alterations. These exposures increase the risk of iatrogenic medication toxicity and withdrawal. OBJECTIVES:We evaluated whether buprenorphine (BUP) use during ECMO reduced full agonist opioid exposure and improved sedation compared with matched comparators. METHODS:Using a retrospective matched case-control cohort design among ECMO patients in a cardiovascular intensive care unit, we contrasted 30 patients treated with BUP versus 30 comparator patients not treated with BUP (NO-BUP) matched using an a priori deterministic hierarchy. Comparisons were anchored to two matched time points: (i) the day before BUP exposure and (ii) the day after attaining the full therapeutic BUP dose; NO-BUP comparators were assessed on the analogous ECMO days. The primary outcome was the between-group difference in change in daily intravenous morphine milligram equivalents (MME) across this time period. RESULTS:Each cohort included 27 venovenous and three venoarterial ECMO patients. Demographics and illness severity did not differ between groups. Groups significantly differed in MME change scores (p < 0.001) with the BUP cohort decreasing significantly (p < 0.001) from 184.1 (interquartile range [IQR] 70.2-367.2) to 0.0 (IQR 0.0-11.6) median MME whereas NO-BUP comparators nonsignificantly decreased (p = 0.517) from 230.8 (IQR 153.3-567.0) to 177.2 (IQR 85.3-663.1). Groups also differed (p = 0.031) in time in target RASS range (-2 to 0); the BUP cohort significantly improved from 53.9% to 91.2% (p < 0.001) whereas NO-BUP comparators nominally improved from 37.8% to 46.1% (p = 0.275). In the BUP cohort, there was no precipitated withdrawal, opioid-induced constipation, or respiratory depression. Rates of tracheostomy, mortality, and extubation before decannulation did not differ significantly. CONCLUSION:BUP initiation among ECMO patients was feasible and associated with a marked reduction in full agonist opioid exposure and improved light-sedation target attainment. These findings are hypothesis-generating given the retrospective design and potential residual confounding.
BACKGROUND AND OBJECTIVE:Intravenous magnesium is commonly used in critically ill patients; however, data on the serum level response following its administration are limited. This study aimed to evaluate serum magnesium changes after administration of intravenous magnesium sulfate (IV-MgSO4) and identify predictors of a greater response among critically ill patients. METHODOLOGY:This retrospective multicenter study included adult critically ill patients from the Medical Information Mart for Intensive Care IV and eICU databases. Patients were included if they received IV-MgSO4 and had serum magnesium measured within 36 h before and after administration. Patients receiving renal replacement therapy, total parenteral nutrition, magnesium-containing intravenous fluids, or oral magnesium supplementation were excluded. Linear regression analyses were performed to identify predictors of greater magnesium response. RESULTS:The study included 25,637 patients who received 54,556 doses of IV-MgSO4. The mean age was 62.8 ± 16.5 Standard deviation years, and 13,180 (51.4%) were females. The most common intensive care unit admission diagnoses were cardiovascular (n = 7399; 28.9%) and respiratory (n = 4245; 16.6%). Baseline magnesium levels were normal in 39,149 (71.8%) episodes, mild-to-moderate hypomagnesemia in 13,588 (24.9%), and severe hypomagnesemia in 1819 (3.3%). Median serum magnesium increased by 0.15 mg/dL (interquartile range (IQR) 0.05-0.25) per 1 g of IV-MgSO4 administered, and the greatest increase was observed in patients with severe hypomagnesemia (median [IQR]: 0.25 mg/dL [0.10-0.50]), followed by mild-to-moderate hypomagnesemia (median [IQR]: 0.22 mg/dL [0.10-0.40]). Predictors of greater response to IV-MgSO4 were lower initial magnesium (β = 0.2035; 95% confidence interval (CI): 0.193 to 0.214; p < 0.001) and reduced renal function (β = 0.2557; 95% CI: 0.212 to 0.300; p < 0.001). CONCLUSION:Among a large cohort of critically ill patients, 1 g of IV-MgSO4 was associated with a median serum magnesium increase of 0.15 mg/dL. Lower initial magnesium and reduced renal function were predictors of greater serum magnesium increase with intravenous replacement.
BACKGROUND:Patient self-management (PSM) is a warfarin management strategy that allows patients to independently adjust their doses. PSM significantly reduces thrombosis events and has been widely implemented internationally. However, adoption of PSM is limited in the United States. This study estimated the cost-effectiveness of PSM compared with available strategies, including anticoagulation management services (AMS) and usual care (UC) for patients with non-valvular atrial fibrillation (NVAF) aged 70 years and older in the United States. METHODS:A cost-effectiveness analysis was performed to estimate lifetime costs and outcomes of PSM compared with AMS and UC employing a Markov model. The model simulated a 70-year-old with NVAF over the patient's lifetime from modified societal and payer perspectives. Transition probabilities were derived from annual event rates reported in the ARISTOTLE trial. Comparative efficacy and safety among the interventions were obtained from a network meta-analysis. Costs, presented in 2024 US dollars (USD), and utility data were obtained from data sources in the United States. A discount rate of 3% was applied for future costs and outcomes. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the findings. RESULTS:The lifetime costs from the modified societal perspective were $137,509 USD for UC, $129,216 USD for AMS, and $76,515 USD for PSM. Discounted quality-adjusted life years (QALYs) were estimated to be 8.27 for UC, 8.30 for AMS, and 8.47 for PSM. Additionally, PSM substantially reduced stroke incidence compared with AMS and UC, contributing to lower costs and greater QALYs. Probabilistic sensitivity analysis showed that PSM appeared to be the most cost-effective at any willingness-to-pay threshold. CONCLUSIONS:PSM is the most cost-effective strategy for managing warfarin in the target population at any willingness-to-pay threshold. Implementation of PSM in the US health care setting should be considered.
BACKGROUND:Meropenem is widely used to treat hospital-acquired pneumonia in critically ill patients, with efficacy dependent on the time that free concentrations exceed the minimum inhibitory concentration (fT > MIC). In practice, single-sample therapeutic drug monitoring (TDM) may not ensure target attainment, particularly in patients requiring continuous renal replacement (CRRT). Model-informed precision dosing (MIPD) enables individualized, real-time adjustments, but implementation is limited. Herein, we developed a Shiny application for Bayesian meropenem dose optimization. METHODS:A previously published nonparametric model was translated into a parametric Bayesian framework with maximum a posteriori (MAP) updating implemented through a Shiny interface. Plasma pharmacokinetic (PK) data from critically ill patients served for external validation. Posterior predictions were benchmarked against population and individual (MAP) outputs from Pmetrics 3.09 and population median profiles from 1000 Monte Carlo simulations per patient. Predictive performance was assessed using relative median prediction error (rMPE) and relative median absolute prediction error (rMAPE), for the combined cohort overall and stratified by CRRT status. Sparse sampling scenarios (one, two, and three observations per patient) were also evaluated. RESULTS:Eighteen patients were evaluated (non-CRRT n = 13; CRRT n = 5). In Pmetrics, rMPE ranged from -7.7% to 9.4% and rMAPE from 18.5% to 25.5% across renal replacement strata and prediction types. Simulation-based population predictions yielded greater error, with rMPE/rMAPE of -25%/34% in CRRT patients and -21%/30% in non-CRRT patients. Across Bayesian Dosing Simulator (BDS) sampling scenarios, prediction error remained within prespecified limits (rMPE ±20%, rMAPE ≤ 30%), with F20 ranging from 80% to 94% and F30 from 87% to 94%. CONCLUSION:A validated nonparametric meropenem model was successfully implemented within an open-source Bayesian framework yielding predictive accuracy comparable to the reference model with robust performance under sparse sampling, supporting its feasibility for individualized meropenem dosing. Prospective evaluation of its clinical safety and effectiveness is needed.
INTRODUCTION:Treatment for pediatric acute lymphoblastic leukemia includes asparaginase as an integral component of therapy. Hypersensitivity reactions or silent inactivation to Escherichia coli (E. coli) formulations may necessitate switching to Erwinia-based asparaginase (asparaginase Erwinia chrysanthemi [E-ASP] or recombinant asparaginase Erwinia chrysanthemi [R-ASP]). However, pharmacokinetic data for R-ASP in pediatrics remain limited, and recommended dosing schedules present logistical challenges. We investigated if adherence to approved dosing regimens for R-ASP is necessary to achieve optimal pharmacokinetic exposure in pediatric patients with leukemia or lymphoma. METHODS:We performed a single institution, retrospective review of pharmacokinetic data in patients who received R-ASP between October 1, 2021 and September 30, 2024. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to evaluate asparaginase pharmacokinetic activity. The pharmacokinetic model was used to determine if the labeled dosing window for R-ASP is required to achieve effective asparagine depletion. RESULTS:Twenty-six patients with 115 measurements of serum asparaginase activity (SAA) were included in the analysis. Based on model simulations from our pediatric patient data, maintaining SAA ≥ 0.1 IU/mL in 90% of patients throughout the dosing interval with R-ASP 25/25/50 mg/m2 administered intramuscularly on Monday, Wednesday, and Friday requires precise timing. Specifically, the Friday 50 mg/m2 dose must be administered within 58 h of the Wednesday morning dose to sustain therapeutic activity. Additionally, only 62.5% of patients maintained SAA ≥ 0.1 IU/mL at 72 h after the last dose with R-ASP 25 mg/m2 administered intramuscularly on a Monday, Wednesday, and Friday dosing schedule. CONCLUSION:Overall, our findings support the importance of adhering closely to the United States Food and Drug Administration approved dosing schedule for R-ASP to ensure adequate asparaginase activity in pediatric patients with leukemia or lymphoma.
BACKGROUND:Antistaphylococcal penicillins (ASPs) are highly effective against infections caused by methicillin-susceptible Staphylococcus aureus (MSSA). Nafcillin and oxacillin are ASPs with similar spectra of activity, rates of efficacy, pharmacokinetic profiles, and cost. However, there is a growing body of evidence suggesting key distinctions between the safety profiles of nafcillin and oxacillin, including a higher rate of acute kidney injury (AKI) with nafcillin. This retrospective study aims to compare the rate of AKI with nafcillin versus oxacillin at a large academic medical center. METHODS:A retrospective cohort study was conducted including adult inpatients who were treated with at least six doses of oxacillin or nafcillin. The primary outcome was the incidence of AKI during treatment. Secondary outcomes included change in serum creatinine from baseline, AKI stage, duration of therapy, duration of hospitalization, and in-hospital mortality. Exploratory outcomes included the incidence of moderate hypokalemia, severe hypokalemia, and hepatotoxicity. RESULTS:Among 638 patients (171 on nafcillin, 467 on oxacillin), AKI occurred in 33.3% of patients in the nafcillin group compared to 19.5% in the oxacillin group (adjusted risk ratio 1.55, 95% confidence interval 1.16-2.06; p < 0.01). Nafcillin was associated with a greater incidence of AKI at each stage, longer duration of hospitalization, higher in-hospital mortality rate, and increased rates of moderate and severe hypokalemia compared to oxacillin. CONCLUSION:In this study, nafcillin was associated with a significantly higher incidence of AKI than oxacillin.
BACKGROUND:Simultaneous heart-kidney transplantation (SHKT) has become increasingly common over the past decade, accompanied by evolving recipient characteristics and outcomes introduced by the 2018 United Network for Organ Sharing (UNOS) heart allocation policy change. However, contemporary data on immunosuppression practices in SHKT recipients remain limited. To address these knowledge gaps, this study characterizes contemporary immunosuppression practices in SHKT recipients and evaluates their association with post-transplant outcomes. METHODS AND RESULTS:This UNOS registry analysis included adult SHKT recipients from January 2013 to June 2025. We evaluated induction and maintenance immunosuppression strategies and 1-year outcomes including treated rejection, graft failure, infection, and mortality. Among 2634 recipients, T-cell depleting agents remained the most used induction strategy (41.3%), followed by basiliximab (36.8%) and no induction (21.9%). Basiliximab use increased post-2018, while anti-thymocyte globulin use declined. mTOR inhibitor use at 1 year was highest among patients receiving T-cell depleting agents. Despite these shifts, adjusted analyses showed no significant differences in 1-year rejection, graft failure, or mortality across induction groups. CONCLUSION:Contemporary SHKT recipients experience similar 1-year outcomes across induction strategies. Basiliximab may be sufficient for standard-risk SHKT recipients.
INTRODUCTION:Tacrolimus (Tac or FK-506) is an immunosuppressive agent that inhibits T-cell activation and proliferation. It has a narrow therapeutic index and shows inter-patient variabilities in its plasma concentration. Human Leucocyte Antigen (HLA) plays a major role in immune regulation and function. Tac inhibits the T-cells, and HLA antigens are expressed in T-cells. The objective of this study was to determine the role of the HLA Class I (HLA-A, HLA-B, and HLA-C) and Class II (HLA-DRB1, HLA-DQB1, and HLA-DQA1) in influencing Tac PK among renal transplant patients. MATERIAL AND METHODS:This study included HLA genotyping data of 462 renal transplant patients. Tacrolimus blood trough concentration/dose (Co/D) was calculated on day 7 and months 1, 3, 6, and 12 post-transplantation, and the association with HLA alleles was studied. Furthermore, biopsy-proven toxicity, rejection, and pathological events were evaluated for their association with HLA alleles. RESULT:One-way ANOVA analysis showed that HLA-B*51:01 and HLA-C*16:02 were significantly associated with Tac Co/D at multiple time points, with a significance level of p < 0.05. In addition, HLA-DRB1*04:03 was associated with post-renal transplant toxicity [Hazard Ratio (HR) = 8.500, 95% Confidential Interval (CI) (1.517-47.619)] and pathological events [HR = 2.310, 95% CI (1.149-4.642)]. HLA-A*02:11 [HR = 3.530, 95% CI (1.074-11.601)], and HLA-DQB*03:01 [HR = 5.055, 95% CI (1.544-16.551)] were associated with high risk of transplant rejection. CONCLUSION:Our data suggest that HLA alleles influence the PK of Tac and affect graft survival in renal transplant patients.
Sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are nephroprotective and their use is recommended for adults with chronic kidney disease (CKD). The role of SGLT2i and GLP-1 RAs in patients with acute kidney injury (AKI) is unknown. This systematic review aimed to estimate the effect of SGLT2i or GLP-1 RAs on clinical outcomes in AKI. We systematically searched Embase, MEDLINE, Scopus, Web of Science Core Collection, and clinical trials registries for observational studies and clinical trials from database inception to July 3, 2025. Included studies evaluated adults (≥ 18 years) with AKI during a hospitalization and compared patients subsequently exposed to either SGLT2i or GLP-1 RAs to a non-exposed control group. Random effects meta-analyses were performed. Six studies related to SGLT2i (five observational, one randomized trial) and one related to GLP-1 RAs (one observational) met eligibility criteria (N = 432,048 patients). SGLT2i/GLP-1 RA exposure was associated with lower odds of major adverse kidney events (MAKE) (OR 0.63, 95% CI 0.46-0.86) and all-cause mortality [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.21-0.62] compared to controls. The odds for kidney replacement therapy were lower with SGLT2i therapy in the three studies where it was evaluated (OR 0.61, 95% CI 0.40-0.93). Sensitivity analyses restricted to SGLT2i data were consistent with the overall findings [MAKE OR 0.63 (95% CI 0.42-0.95); Mortality OR 0.34 (95% CI 0.18, 0.65)]. Exposure to SGLT2i or GLP-1 RAs after AKI, examined primarily in observational studies, was associated with improved clinical outcomes. These findings are promising and warrant evaluation in randomized clinical trials.
Diabetic kidney disease (DKD) is a leading cause of chronic and end-stage renal diseases. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) confer renoprotection; however, emerging evidence suggests that combination therapy has synergistic benefits. This meta-analysis evaluated dual versus monotherapy, focusing on the urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. PubMed, Scopus, Embase, CINAHL, Medline, and Web of Science were searched until August 2025 for RCTs comparing GLP-1RA plus SGLT2i versus monotherapy or placebo in adults with T2D. The primary outcome was the change in UACR, and the secondary outcome was eGFR. Pooled standardized mean differences (SMD) were estimated using random-effects models, including subgroup and sensitivity analyses. Eight RCTs (n = 1974; sample size, 41-4000; follow-up, 16 weeks-3.4 years) were included. Combination therapy was well tolerated and significantly reduced UACR compared with monotherapy (SMD -0.25, 95% confidence interval (CI) -0.38, -0.13; I2 = 0%). The benefits remained significant against SGLT2i alone (SMD, -0.28) but not for GLP-1RA alone. For eGFR, dual therapy provided a modest benefit versus SGLT2i (SMD 0.12, 95% CI 0.00-0.23) but not for GLP-1RA. The effects were consistent in patients with DKD and in larger trials. Early SGLT2is and GLP-1RA combination therapy is safe and provides superior renoprotection compared to monotherapy in patients with type 2 diabetes, albuminuria, and high cardiorenal risk. Broader adoption of combination therapy could improve outcomes, although cost and access barriers remain an issue.
