Search

Background: To date, the evidence for proteasome‐inhibitor (PI) based antibody mediated rejection (AMR) therapy has been with the first‐generation PI bortezomib. Results have demonstrated encouraging efficacy for early AMR with lesser efficacy for late AMR. Unfortunately, bortezomib is associated with dose‐limiting adverse effects in some patients. We report use of the second generation proteosome inhibitor carfilzomib for AMR treatment in two pediatric patients with a kidney transplant. Methods: The clinical data on two patients who experienced dose limiting toxicities from bortezomib were collected along with their short‐ and long‐term outcomes. Results: A two‐year‐old female with simultaneous AMR, multiple de novo DSAs (DR53 MFI 3900, DQ9 MFI 6600, DR15 2200, DR51 MFI 1900) and T‐cell mediated rejection (TCMR) completed three carfilzomib cycles and experienced stage 1 acute kidney injury after the first two cycles. At 1 year follow up, all DSAs resolved, and her kidney function returned to baseline without recurrence. A 17‐year‐old female also developed AMR with multiple de novo DSAs (DQ5 MFI 9900, DQ6 MFI 9800, DQA*01 MFI 9900). She completed two carfilzomib cycles, which were associated with acute kidney injury. She had resolution of rejection on biopsy and decreased but persistent DSAs on follow‐up. Conclusions: Carfilzomib treatment for bortezomib‐refractory rejection and/or bortezomib toxicity may provide DSA elimination or reduction, but also appears to be associated with nephrotoxicity. Clinical development of carfilzomib for AMR will require a better understanding of efficacy and development of approaches to mitigate nephrotoxicity. [ABSTRACT FROM AUTHOR]

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10–15 ng/mL in the first 4 weeks and 7–10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03–8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre‐transplant CYP3A5 testing at our institution. [ABSTRACT FROM AUTHOR]

Background: Nonadherence to immunosuppression is common among pediatric, adolescent, and young adult kidney transplant recipients and a leading cause of graft loss. Assessing barriers to medication adherence in clinical practice may identify patients at risk for rejection and provide therapeutic targets. Methods: Kidney transplant patients and/or their caregivers were assessed for 14 barriers to medication adherence using the barriers assessment tool. We compared rejection rates between patients with at least one reported adherence barrier to those without reported adherence barriers using a Kaplan-Meier estimator and Cox proportional hazard models to adjust for other mediators of acute rejection at 2 years following barriers assessment. Results: Ninety-eight patients were assessed for barriers to adherence. Over the 2-year observation period, 22 patients developed biopsy-proven acute rejection (BPAR). Kaplan-Meier estimates show that patients with an identified barrier to adherence were more likely to have BPAR (p = 0.02) than patients without an identified barrier in the 24 months following barriers assessment. The median time to rejection for patients who experienced acute rejection was 175.5 days (IQR 63–276 days) from the time of barriers assessment. An identified barrier to adherence remained the only statistically significant predictor of BPAR with Cox modeling (HR 2.6, p = 0.04), after accounting for age, sex, and race. Conclusions: Pediatric and adolescent kidney transplant recipients with identified adherence barriers are at increased risk for acute rejection. Barriers to adherence provide a potentially modifiable therapeutic target that can be assessed in clinic to guide targeted interventions. [ABSTRACT FROM AUTHOR]

MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia ( P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant. [ABSTRACT FROM AUTHOR]

Patient-identified barriers to immunosuppressive medications are associated with poor adherence and negative clinical outcomes in transplant patients. Assessment of adherence barriers is not part of routine post-transplant care, and studies regarding implementing such a process in a reliable way are lacking. Using the Model for Improvement and PDSA cycles, we implemented a system to identify adherence barriers, including patient-centered design of a barriers assessment tool, identification of eligible patients, clear roles for clinic staff, and creating a culture of non-judgmental discussion around adherence. We performed time-series analysis of our process measure. Secondary analyses examined the endorsement and concordance of adherence barriers between patient-caregiver dyads. After three methods of testing, the most reliable delivery system was an EHR-integrated tablet that alerted staff of patient eligibility for assessment. Barriers were endorsed by 35% of caregivers (n=85) and 43% of patients (n=60). The most frequently patient-endorsed barriers were forgetting, poor taste, and side effects. Caregivers endorsed forgetting and side effects. Concordance between patient-caregiver dyads was fair (k=0.299). Standardized adherence barriers assessment is feasible in the clinical care of pediatric kidney transplant patients. Features necessary for success included automation, redundant systems with designated staff to identify and mitigate failures, aligned reporting structures, and reliable measurement approaches. Future studies will examine whether barriers predict clinical outcomes (eg, organ rejection, graft loss). [ABSTRACT FROM AUTHOR]

Pri-mary cilia sense environmental conditions, including osmolality, butwhether cilia participate in the osmotic response in renal epithelialcells is not known. The transient receptor potential (TRP) channelsTRPV4 and TRPM3 are osmoresponsive. TRPV4 localizes to cilia incertain cell types, while renal subcellular localization of TRPM3 is notknown. We hypothesized that primary cilia are required for maximalactivation of the osmotic response of renal epithelial cells and thatciliary TRPM3 and TRPV4 mediate that response. Ciliated [murineepithelial cells from the renal inner medullary collecting duct(mIMCD-3) and 176-5] and nonciliated (176-5Δ) renal cells ex-pressedTrpv4andTrpm3. Ciliary expression of TRPM3 was observedin mIMCD-3 and 176-5 cells and in wild-type mouse kidney tissue.TRPV4 was identified in cilia and apical membrane of mIMCD-3cells by electrophysiology and in the cell body by immunofluores-cence. Hyperosmolal stress at 500 mOsm/kg (via NaCl addition)induced the osmotic response genes betaine/GABA transporter (Bgt1)and aldose reductase (Akr1b3) in all ciliated cell lines. This inductionwas attenuated in nonciliated cells. A TRPV4 agonist abrogatedBgt1andAkr1b3induction in ciliated and nonciliated cells. A TRPM3agonist attenuatedBgt1andAkr1b3induction in ciliated cells only.TRPM3 knockout attenuatedAkr1b3induction. Viability under os-motic stress was greater in ciliated than nonciliated cells.Akr1b3induction was also less in nonciliated than ciliated cells when man-nitol was used to induce hyperosmolal stress. These findings suggestthat primary cilia are required for the maximal osmotic response inrenal epithelial cells and that TRPM3 is involved in this mechanism.TRPV4 appears to modulate the osmotic response independent ofcilia. [ABSTRACT FROM AUTHOR]