Visualization of intracellular ATP dynamics in different nephron segments under pathophysiological conditions using the kidney slice culture system.

ATP depletion plays a central role in the pathogenesis of kidney diseases. Recently, we reported spatiotemporal intracellular ATP dynamics during ischemia reperfusion (IR) using GO-ATeam2 mice systemically expressing an ATP biosensor. However, observation from the kidney surface did not allow visualization of deeper nephrons or accurate evaluation of ATP synthesis pathways. Here, we established a novel ATP imaging system using slice culture of GO-ATeam2 mouse kidneys, evaluated the ATP synthesis pathway, and analyzed intracellular ATP dynamics using an ex vivo IR-mimicking model and a cisplatin nephropathy model. Proximal tubules (PTs) were found to be strongly dependent on oxidative phosphorylation (OXPHOS) using the inhibitor oligomycin A, whereas podocytes relied on both OXPHOS and glycolysis using phloretin an active transport inhibitor of glucose. We also confirmed that an ex vivo IR-mimicking model could recapitulate ATP dynamics in vivo; ATP recovery in PTs after reoxygenation varied depending on anoxic time length, whereas ATP in distal tubules (DTs) recovered well even after long-term anoxia. After cisplatin administration, ATP levels in PTs decreased first, followed by a decrease in DTs. An organic cation transporter 2 inhibitor, cimetidine, suppressed cisplatin uptake in kidney slices, leading to better ATP recovery in PTs, but not in DTs. Finally, we confirmed that a mitochondria protection reagent (Mitochonic Acid 5) delayed the cisplatin-induced ATP decrease in PTs. Thus, our novel system may provide new insights into the energy dynamics and pathogenesis of kidney disease.

Comparison of cisplatin-based versus standard preoperative chemotherapy in patients with operable triple-negative breast cancer: propensity score matching and inverse probability of treatment weighting analysis.

PURPOSE: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. METHODS: This retrospective study consecutively included previously untreated patients with stage I-III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. RESULTS: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). CONCLUSION: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment.

Model-Informed Dosing Optimization of Tacrolimus for Concomitant Administration with Itraconazole to Japanese Lung Transplant Recipients.

BACKGROUND: Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients. METHODS: This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed. RESULTS: A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug-drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation. CONCLUSIONS: This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.

Investigation of severe acute respiratory syndrome coronavirus 2 infection status in solid organ transplant recipients treated with tixagevimab/cilgavimab.

INTRODUCTION: Tixagevimab and cilgavimab (T/C) are neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be used to prevent SARS-CoV-2 infection in solid organ transplant (SOT) recipients. However, their neutralizing activity against recent variants was reduced, raising concerns regarding the emergence of breakthrough coronavirus diseases 2019 (COVID-19). This study aimed to investigate the status of the COVID-19 breakthrough after T/C administration. METHODS: We retrospectively investigated breakthrough COVID-19 in SOT recipients administered T/C at Kyoto University Hospital, Japan, from November 2022 to March 2023. Patients were monitored for 6 months after T/C administration. SARS-CoV-2 infection was diagnosed using polymerase chain reaction or antigen tests. The monthly incidence rates of SARS-CoV-2 infection were calculated using the person-time method. RESULTS: T/C were administered to 67 SOT recipients (liver, 16; lung, 36; and kidney, 15), of whom five were infected with SARS-CoV-2. All five cases were classified as mild, and none of these patients required admission to the intensive care unit (ICU) or died. All infected individuals tested positive for SARS-CoV-2 after March 2023, when T/C-resistant subvariant strains became predominant. The monthly incidence rate of SARS-CoV-2 infection, calculated using the person-time method, suggested an increasing trend. CONCLUSIONS: During the T/C-resistant variant epidemic, SARS-CoV-2 infections were identified even after T/C administration, suggesting that the prophylactic effects of T/C were invalid. Therefore, emerging variants must be carefully monitored and characterized to determine appropriate antiviral strategies, such as the use of suitable neutralizing antibodies.

Comparison of the safety and cost-effectiveness of nebulized liposomal amphotericin B and amphotericin B deoxycholate for antifungal prophylaxis after lung transplantation.

INTRODUCTION: Fungal infection after lung transplantation can lead to poor clinical outcome, for which lung transplant recipients require prophylaxis. One of the antifungal agents used after lung transplantation is nebulized amphotericin B (AMB). Nebulized AMB causes adverse events such as dyspnea and airway irritation, and long-term use leads to high economic costs. So far, prophylactic regimens employing AMB deoxycholate (AMB-d) and liposomal AMB (L-AMB) have been developed. This study compared the efficacy, safety, and cost of AMB-d and L-AMB. PATIENTS AND METHODS: Patients who underwent lung transplantation at Kyoto University Hospital from January 2021 to May 2023 were included in this study. Thirty-three patients received nebulized AMB-d, whereas 29 received nebulized L-AMB. RESULTS: Both regimens maintained comparable prophylactic efficacy regarding the development of fungal infection in the AMB-d and L-AMB groups (3.0% vs. 3.4%, P = 0.877). Patients treated with nebulized L-AMB experienced fewer respiratory-related adverse reactions than those treated with nebulized AMB-d (6.9% vs. 30.3%, P < 0.05), leading to a longer treatment duration with L-AMB than with AMB-d. Additionally, the daily cost of administering L-AMB was lower than that of administering AMB-d (3609 Japanese yen vs. 1792.3 Japanese yen, P < 0.05). DISCUSSION: These results suggest that nebulized L-AMB is safer and more cost-effective than nebulized AMB-d, with comparable efficacy.

Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort.

OBJECTIVES: Biosimilars are anticipated to be widely used in the treatment of rheumatoid arthritis (RA), owing to their cost efficiency; LBEC0101 was the first etanercept (ETN) biosimilar approved in Japan. However, there are limited real-world data comparing its safety and effectiveness with those of a reference product. METHODS: This study used data from the Kyoto University Rheumatoid Arthritis Management Alliance cohort, including patients with RA who received ETN therapy-ETN reference product (ETN-RP) or LBEC0101-between 2015 and 2021. Serum ETN levels were measured using liquid chromatography-tandem mass spectrometry. RESULTS: The 1-year continuation rates of ETN-RP and LBEC0101 were 58.7% and 74.4%, respectively. Effectiveness of treatment was evaluated in 18 patients; both products significantly reduced the 28-joint RA disease activity score and erythrocyte sedimentation rate (DAS28-ESR). Moreover, to determine equivalence, we analysed 11 patients who switched from ETN-RP to LBEC0101; the DAS28-ESR and serum ETN levels before and after switching were not significantly different. CONCLUSIONS: This real-world cohort study confirmed that the biosimilar of ETN, LBEC0101, was comparable to the reference product in terms of continuation rate, effectiveness at initiation of introduction, and effect persistence before and after switching in clinical practice.

Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series.

PURPOSE: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients. METHODS: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry. RESULTS: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase. CONCLUSION: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

A case of successful contribution of therapeutic drug monitoring of valganciclovir as the prophylaxis against cytomegalovirus infection in a lung transplant recipient.

BACKGROUND: Ganciclovir and its prodrug, valganciclovir, are first-line agents for cytomegalovirus infection prophylaxis after lung transplantation. Although valganciclovir prophylaxis is known to result in severe leukopenia as an adverse effect, dosage adjustment based on therapeutic drug monitoring (TDM) of ganciclovir concentration is not generally implemented in clinical practice. CASE PRESENTATION: In this report, we describe the case of a female in her fifties after lung transplantation who successfully maintained valganciclovir prophylaxis under TDM with a minimal occurrence of severe leukopenia. Valganciclovir administration was initiated at a conventional dose of 450 mg/day on postoperative day 43 but was reduced to 450 mg/2 days on postoperative day 69 because of a decrease in white blood cell count and an increase in trough ganciclovir concentration. Subsequently, the valganciclovir dose adjustment was switched from label-indicated renal function-guided dosing to TDM-based dosing, targeting a trough level of 300-800 ng/mL. This target range was determined through deliberations with infectious disease specialists and pharmacists based on previously reported data. The TDM-based dose adjustment successfully prevented cytomegalovirus reactivation without causing significant adverse effects. Valganciclovir prophylaxis was completed on postoperative day 256, and the patient was transferred to another hospital for rehabilitation. CONCLUSIONS: The findings of the present case suggest that TDM-based dosing could be helpful for clinicians in optimizing the prophylactic administration of valganciclovir in patients undergoing lung transplantation.

Association between Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Acute Kidney Injury: A Nested Case-Control Study.

BACKGROUND: An association between proton pump inhibitor (PPI) use and an increased risk of acute kidney injury (AKI) has been confirmed. This study aimed to evaluate the effects of PPI use on the risk of AKI in patients with cancer who were administered immune checkpoint inhibitors (ICIs), a class of drugs used in cancer treatment, and in those who were not. METHODS: We used a database provided by the Health, Clinic, and Education Information Evaluation Institute, which included demographic data, diagnoses, prescriptions, and laboratory results. We conducted a nested case-control study of 38,930 patients with cancer who were new PPI or ICI users and had no history of AKI before cohort entry. The odds ratio (OR) for AKI was estimated using conditional logistic regression models. RESULTS: During a mean follow-up of 8.3 months, 5,870 cases of AKI were identified (incidence rate, 21.9/100 person-years). Compared to never or past PPI use without ICI use, the adjusted ORs of AKI for current PPI use without ICI use, past or never PPI use with prior ICI use, current PPI use with prior ICI use were 1.82 (95% CI, 1.67 to 2.00), 1.47 (95% CI, 1.17 to 1.86), or 2.13 (95% CI, 1.42 to 3.20), respectively. The risk of AKI in patients treated with both PPIs and ICIs was not higher than the additional or multiplication of the risks in those who were treated with PPIs or ICIs alone. CONCLUSIONS: This study reinforces the association between PPIs and ICIs use and the increased risk of AKI. Although the interaction between the two drug classes was not detected, these findings highlight the need for careful monitoring and evaluation of kidney function in patients treated with PPIs and ICIs.

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series.

BACKGROUND: Among the oral antivirals used for treating patients with mild-to-moderate novel coronavirus disease 2019 (COVID-19), nirmatrelvir/ritonavir (NMV/RTV) and ensitrelvir (ESV) are inhibitors of cytochrome P450 (CYP) 3A, and therefore, can cause drug-drug interactions with concomitant medications. Tacrolimus (TAC), a substrate of CYP3A4/5, is administered for a long period to prevent rejection after kidney transplantation. TAC should be discontinued while using NMV/RTV because blood TAC levels significantly increase when these drugs are concomitantly administered. However, the influence of ESV on blood TAC levels has not yet been reported, and the management of TAC doses during the use of ESV remains unclear. CASE PRESENTATION: We experienced three kidney transplant recipients with COVID-19, whose blood trough levels of TAC increased by the concomitant use of NMV/RTV or ESV. In two patients administering NMV/RTV, blood trough levels of TAC increased more than tenfold after combination therapy, whereas in one patient administering ESV, TAC level increased approximately threefold. CONCLUSIONS: These cases suggest that TAC administration should be discontinued during NMV/RTV treatment to maintain blood TAC levels within the therapeutic range, and a reduced TAC dose is sufficient during ESV treatment.