Vancomycin-associated nephrotoxicity is prevalent among internal medicine patients, with 5.36-fold higher odds if piperacillin-tazobactam is concomitantly administered.

Objective To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia. Design A systematic review and meta-analysis of phase II and III clinical trial data was completed. Patients or Participants Eight studies (2 phase II and 4 phase III trials with 2 subgroup analyses) were included in the qualitative analysis whereas six studies (2 phase II and 4 phase III trials) were included in the meta-analysis. Measurements and Results There was significant heterogeneity in the meta-analysis with an I2 value ranging from 80.6–99.6%. A random-effects meta-analysis was applied for all endpoints. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, there was a significant −0.70mEq/L (95% confidence interval [CI] −0.48 to −0.91mEq/L) change in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was −0.36mEq/L (range of standard deviation: 0.07 to 0.30). The primary endpoint for ZS-9-- change in potassium at 48 hours-- was −0.67mEq/L (95% CI −0.45 to −0.89mEq/L). By 1 hour after ZS-9 administration, change in potassium was −0.17mEq/L (95% CI −0.05 to −0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with adverse effects of urinary tract infections (1.1%) and edema (0.9%). Conclusion Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary endpoint of this meta-analysis. Given the adverse effect profile and the observed time dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia.

Background and Objectives No evaluation of sex and race influences on MPA pharmacokinetics and adverse effects (AE) during enteric coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. MPA and MPA glucuronide(MPAG) pharmacokinetics with gastrointestinal AE were investigated in 67 stable renal transplant recipients: 22 African American males(AAM); 13 AA females(AAF); 16 Caucasian males(CM) and 16 Caucasian females(CF) receiving ECMPS and tacrolimus. Methods Validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting and acid suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under concentration time curve 0-12 (AUC0-12) and dose normalized AUC 0-12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. Results Males had more rapid apparent MPA clearance (CM: 13.8 ± 6.27 L/h vs. AAM: 10.2 ± 3.73 L/h) compared to females (CF: 8.70 ± 3.33 L/h and AAF: 9.71 ± 3.94 L/hr; P=0.014) with a race-sex interaction (P=0.043). Sex differences were observed in MPA clearance/BMI (P=0.033) and AUC* (P=0.033). MPA AUC0-12 was greater than 60 mg•h/L in 57% of RTR with 71% of patients demonstrating gastrointestinal AE and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared to males (P=0.024). Race (P=0.044) and sex (P=0.005) differences were evident with greater MPAG AUC0-12 in AAF and CF. Conclusion Sex and race differences were evident with females having slower MPA clearance, higher MPAG AUC0-12 and more severe gastrointestinal AE. These findings suggest consideration of sex and race during MPA immunosuppression.

IntroductionHyperkalemia is a serious medical condition that often manifests in patients with chronic kidney disease and heart failure. Renin–angiotensin–aldosterone system inhibitors are known to improve outcomes in these disease states but can also cause drug-induced hyperkalemia. New therapeutic options exist for managing hyperkalemia in these patients which warrant evidence-based evaluation.AimThe objective of this article was to review the efficacy and safety evidence for patiromer, sodium zirconium cyclosilicate (ZS9), and sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia.Evidence reviewCurrent treatment options to enhance potassium excretion are SPS and loop diuretics, which are complicated by ambiguous efficacy and known toxicities. Patiromer and ZS9 are new agents designed to address this treatment gap. Both unabsorbable compounds bind potassium in the gastrointestinal (GI) tract to facilitate fecal excretion. The capacity to bind other medications in the GI tract infers high drug–drug interaction potential, which has been demonstrated with patiromer but not yet investigated with ZS9 or SPS. Phase II and III clinical trials of patiromer and ZS9 demonstrated clear evidence of a dose-dependent potassium-lowering effect and the ability to initiate, maintain, or titrate renin–angiotensin–aldosterone system inhibitors. There is limited evidence base for SPS: two small clinical trials indicated potassium reduction in chronic hyperkalemia. All agents may cause adverse GI effects, although they are less frequent with ZS9. Concerns remain for SPS to cause rare GI damage. Electrolyte abnormalities occurred with patiromer and SPS, whereas urinary tract infections, edema, and corrected QT-interval prolongations were reported with ZS9.ConclusionPatiromer and ZS9 have improved upon the age-old standard SPS for the treatment of hyperkalemia. Additional research should focus on drug–drug interactions in patients on multiple medications, incidence of rare adverse events, and use in high-risk populations.

Extrarenal adverse effects (AEs) associated with calcineurin inhibitor (CNI) and mycophenolic acid (MPA) occur frequently but are unpredictable posttransplant complications. AEs may result from intracellular CNI accumulation and low activity of P-glycoprotein, encoded by the ABCB1 gene. Since ABCB1 single nucleotide polymorphisms (SNPs) and sex influence P-glycoprotein, we investigated haplotypes and extrarenal AEs.A prospective, cross-sectional study evaluated 149 patients receiving tacrolimus and enteric coated mycophenolate sodium or cyclosporine and mycophenolate mofetil. Immunosuppressive AE assessment determined individual and composite gastrointestinal, neurologic, aesthetic, and cumulative AEs. Lipids were quantitated after 12-hour fast. ABCB1 SNPs: c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642) were determined with haplotype associations computed using the THESIAS program, and evaluated by immunosuppression, sex and race using multivariate general linear models.Tacrolimus patients exhibited more frequent and higher gastrointestinal AE scores compared with cyclosporine with association to CTT (P = 0.018) and sex (P = 0.01). Aesthetic AE score was 3 times greater for cyclosporine with TTC haplotype (P = 0.005). Females had higher gastrointestinal (P = 0.022), aesthetic (P < 0.001), neurologic (P = 0.022), and cumulative AE ratios (P < 0.001). Total cholesterol (TCHOL), low-density lipoproteins (LDL), and triglycerides were higher with cyclosporine. The TTC haplotype had higher TCHOL (P < 0.001) and LDL (P = 0.005). Higher triglyceride (P = 0.034) and lower high-density lipoproteins (P = 0.057) were associated with TTT with sex-adjusted analysis.ABCB1 haplotypes and sex were associated with extrarenal AEs. Using haplotypes, certain female patients manifested more AEs regardless of CNI. Haplotype testing may identify patients with greater susceptibility to AEs and facilitate CNI individualization.