The use of once-daily LCP-Tacrolimus with adolescent and young adult solid organ transplant recipients.

BACKGROUND: Adolescent and young adult (AYA) solid organ transplant (SOT) recipients experience increased rates of rejection and graft loss surrounding the time of health care transition, in part due to poor medication adherence. This study aims to examine the impact of a once-daily formulation of tacrolimus, LCP-tacrolimus (LCPT), on medication adherence for AYA SOT patients. METHODS: A retrospective descriptive analysis was performed for all patients who underwent SOT and were prescribed LCPT after the age of 12 at our single-center pediatric hospital. Medication adherence was assessed via provider documentation and the medication level variability index (MLVI). RESULTS: Twenty-nine patients were prescribed LCPT as part of their immunosuppression regimen. Twenty patients were converted to LCPT from immediate-acting (IR) tacrolimus; six patients were initiated immediately following transplant, and three patients were unable to receive LCPT due to insurance denial. There was a numeric improvement in medication adherence for converted patients when measured by provider assessment (45.0% vs. 68.4%, p = .140) and MLVI (40.0% vs. 71.4%, p = .276), though these did not reach statistical significance. There were no differences in episodes of rejection or adverse effects. LCPT prescription was not associated with decreased medication burden, and two patients transitioned back to IR tacrolimus due to increased cost. CONCLUSIONS: LCPT use did not significantly improve patient adherence; however, it resulted in numerically higher perceived and measured adherence rates. LCPT appears to be safe and effective in the management of SOT recipients; however, it may not affect pill burden and may result in a higher financial burden. Use may be considered for a select group of AYA SOT recipients.

Topical Tacrolimus Ointment Alone versus in Combination with Microneedling for Refractory Stable Vitiligo.

OBJECTIVE: To assess the efficacy of microneedling in combination with topical tacrolimus ointment 0.1% versus topical tacrolimus ointment 0.1% for treatment of refractory stable vitiligo. STUDY DESIGN: Comparative cross-sectional study. Place and Duration of the Study: Department of Dermatology, PNS Shifa, Karachi, Pakistan, from December 2022 to May 2023. METHODOLOGY: The study included 30 clinically diagnosed individuals of either gender who had refractory symptoms and aged between 20 and 60 years. For every patient, two comparable lesions on two comparable limb regions were selected. Group A (right side) received treatment with both topical tacrolimus ointment 0.1% twice daily in addition to microneedling every two weeks, whereas, Group B (left side) was treated with topical tacrolimus ointment 0.1% only. Every lesion was investigated as a separate entity. Both groups were subsequently observed for a further six months. RESULTS: When topical tacrolimus ointment 0.1% was combined with microneedling, the total re-pigmentation rate was substantially higher than the usage of tacrolimus ointment 0.1% alone. Fifty-three percent of lesions treated with topical tacrolimus ointment 0.1% alone and 76.7% of lesions treated with microneedling in conjunction with it showed a good-to-excellent response. No adverse negative effects were noted. During the follow-up period, no problems or recurrences were noted. CONCLUSION: Tacrolimus ointment combined with microneedling is a successful treatment for refractory stable vitiligo. KEY WORDS: Dermapen, Depigmentation, Microneedling, Tacrolimus ointment, Vitiligo.

Association of systemic lupus erythematosus standard of care immunosuppressants with glucocorticoid use and disease outcomes: a multicentre cohort study.

BACKGROUND: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.

A novel reverse perilesional home phototherapy can promote the repigmentation of vitiligo patches with complete leukotrichia: A 12-week, open-label, double-arm, multicenter, randomized clinical trial.

BACKGROUND/PURPOSE: Existing phototherapies are ineffective for treating patients with vitiligo with complete leukotrichia. We compared the efficacy of reverse perilesional irradiation, during which only the lesional areas are covered, with conventional narrowband ultraviolet B (NB-UVB) home phototherapy for repigmentation of non-segmental vitiligo in patients with complete leukotrichia. METHODS: This was a 12-week, open-label, double-arm, multicenter clinical trial, with a total of 121 patients with non-segmental vitiligo who were randomly divided into two groups (both received topical tacrolimus): the conventional NB-UVB irradiation (CI) and reverse perilesional NB-UVB irradiation (RI) groups. RESULTS: A statistically significant difference in improvement from baseline was observed in the RI group compared with the findings in the CI group (-30.8% ± 11.8% vs. -25.5% ± 11.05%, respectively [p = .010]; pair-wise comparison p = .900 at week 4, p = .104 at week 8, and p = .010 at week 12). At week 12, the average percentage change from baseline of leukotrichia in the irradiation area significantly decreased from 100% to 82.2% ± 13.65% in the RI group, and from 100% to 88.7% ± 9.64% in the CI group (p = .027). Adverse events were minor, including desquamation, dryness, erythema, and blisters. No severe or lasting side effects were observed during the study. CONCLUSION: RI mediated better repigmentation of vitiligo with complete leukotrichia than CI.

Linagliptin ameliorates tacrolimus-induced renal injury: role of Nrf2/HO-1 and HIF-1α/CTGF/PAI-1.

BACKGROUND: Tacrolimus (TAC) is a frequently used immunosuppressive medication in organ transplantation. However, its nephrotoxic impact limits its long-term usage. This study aims to investigate the effect of linagliptin (Lina) on TAC-induced renal injury and its underlying mechanisms. METHODS AND RESULTS: Thirty-two Sprague Dawley rats were treated with TAC (1.5 mg/kg/day, subcutaneously) and/or Lina (5 mg/kg/day, orally) for 4 weeks. Histological examination was conducted, and serum and urinary biomarkers were measured to assess kidney function and integrity. Furthermore, ELISA, Western blot analysis and immunohistochemical assay were employed to determine signaling molecules of oxidative stress, profibrogenic, hypoxic, and apoptotic proteins. Tacrolimus caused renal dysfunction and histological deterioration evidenced by increased serum creatinine, blood urea nitrogen (BUN), urinary cystatin C, and decreased serum albumin as well as elevated tubular injury and interstitial fibrosis scores. Additionally, TAC significantly increased the expression of collagen type-1, alpha-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-beta1 (TGF-ß1) renal content. Moreover, TAC decreased the expression of nuclear factor erythroid-2-related factor2 (Nrf2), heme oxygenase 1 (HO-1), and mitochondrial superoxide dismutase (SOD2). In addition, TAC increased protein expression of hypoxia-inducible factor1-alpha (HIF-1α), connective tissue growth factor (CTGF), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), as well as nitric oxide (NO), 4-hydroxynonenal, caspase-3 and Bax renal contents. Furthermore, TAC decreased Bcl-2 renal contents. The Lina administration markedly attenuated these alterations. CONCLUSION: Lina ameliorated TAC-induced kidney injury through modulation of oxidative stress, hypoxia, and apoptosis related proteins.

Nirmatrelvir/ritonavir treatment of patients with COVID-19 taking tacrolimus: case series describing the results of drug-drug interactions.

Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.

Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data.

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.

Effects of Antithymocyte Globulin, Basiliximab, and Induction-Free Treatment in Living Donor Kidney Transplant Recipients on Tacrolimus-Based Immunosuppression.

OBJECTIVES: Induction treatment in renal transplant is associated with better graft survival. However, intensified immunosuppression is known to cause unwanted side effects such as infection and malignancy. Furthermore, the effects of the routine use of immunosuppressants in low-risk kidney transplant recipients are still not clear. In this study, we assessed the first-year safety and efficacy of induction treatment. MATERIALS AND METHODS: We examined first living donor kidney transplant patients who were on tacrolimus based immunosuppression therapy. We formed 3 groups according to the induction status: antithymocyte globulin induction, basiliximab induction, and no induction. We collected outcome data on delayed graft function, graft loss, creatinine levels, estimated glomerular filtration rates, acute rejection episodes, hospitalization episodes, and infection episodes, including cytomegalovirus infection and bacterial infections. RESULTS: We examined a total of 126 patients (age 35 ± 12 years; 65% male). Of them, 25 received antithymocyte globulin, 52 received basiliximab, and 49 did notreceive any induction treatment. We did not observe any statistically significant difference among the 3 groups in terms of acute rejection episodes, delayed graft function, and first-year graft loss. The estimated glomerular filtration rates were similar among the groups. Overall bacterial infectious complications and cytomegalovirus infection showed similar prevalence among all groups. Hospitalization was less common in the induction-free group. CONCLUSIONS: In low-risk patients, induction-free regimens could be associated with a better safety profile without compromising graft survival. Therefore, induction treatment may be disregarded in first living donor transplant patients who receive tacrolimusbased triple immunosuppression treatment.

Alzheimer-like behavior and synaptic dysfunction in 3 × Tg-AD mice are reversed with calcineurin inhibition.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Current treatments are unable to achieve satisfactory therapeutic effects or reverse the progression of the disease. Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and neuronal calcineurin may be hyperactivated in AD. To investigate the effects and underlying mechanisms of FK506, a calcineurin inhibitor, on Alzheimer-like behavior and synaptic dysfunction in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease, we investigated the effect of FK506 on cognitive function and synaptic plasticity in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease. The results showed that FK506 treatment ameliorated cognitive deficits, as indicated by the decreased latency in the water maze, and attenuated tau hyperphosphorylation in 3 × Tg-AD mice. Treatment with FK506 also reduced the levels of certain markers of postsynaptic deficits, including PSD-95 and NR2B, and reversed the long-term potentiation deficiency and dendritic spine impairments in 3 × Tg-AD mice. These findings suggest that treatment with calcineurin inhibitors such as FK506 can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial Alzheimer's disease and related tauopathies.

Identification and characterization of critical values in therapeutic drug monitoring: a retrospective analysis.

Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely reporting and intervention of critical values during TDM are essential for patient safety. In this study, we retrospectively analyzed the laboratory data to provide an overview of the incidence, distribution pattern and biochemical correlates of critical values during TDM. A total of 19,110 samples were tested for nine drug concentrations between January 1, 2019, and December 31, 2020. Of these, 241 critical values were identified in 165 patients. The most common critical values were vancomycin trough (63.4%), followed by tacrolimus trough (16.9%) and digoxin (15.2%). The primary sources of drug critical values were the department of general intensive care unit (ICU), cardiology, and surgery ICU. At baseline or the time of critical value, significant differences were found between the vancomycin, digoxin, and tacrolimus groups in terms of blood urea nitrogen (BUN), creatinine, N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and lymphocyte percentage, P < 0.05. Therefore, it is important to prioritize and closely monitor drug concentrations to reduce laboratory critical values during TDM.

Induction of diabetes by Tacrolimus in a phenotypic model of obesity and metabolic syndrome.

Introduction: The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome. Methods: Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas. Results: Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon. Discussion: This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.

Mycophenolate mofetil vs. cyclophosphamide-based induction regimens for lupus nephritis: Outcomes at a tertiary care centre in Lahore, Pakistan.

Objectives: To compare the efficacy of mycophenolate mofetil with intravenous cyclophosphamideas induction therapy in lupus nephritis. METHODS: The observational, prospecrive, cohort study was conducted at the Rheumatology Department of Fatima Memorial Hospital, Lahore, Pakistan, from July 2016 to June 2019, and comprised lupus nephritis patients. For induction therapy, the patients were assigned at the discretion of the treating rheumatologist to mycophenolate mofetil group MMF, and intravenous cyclophosphamide group CYC. The latter group was further divided into NIH subgroup that received the therapy as per the protocol of the National Institutes of Health, and ELNT subgroup which recived the therapy as per the Euro Lupus Nephritis Trial protocol. Maintenance therapy in all groups was mycophenolate mofetil. Tacrolimus was added in case of non-response. The outcome was the achievement of complete renal response at 6, 12 and 24 months. Data was analysed using SPSS 26. RESULTS: Of the 131 patients, 126(96.2%) were females. The overall mean age was 27±7.7 years. There were 58(44.2%) patients in group MMF and 73(55.7%) in group CYC, which had subgroup NIH 46(63%) and subgrpup ELNT 27(37%). The complete renal response rates at 6, 12, and 24 months were 22 (43.1%), 35 (71.4%), and 40(83.3%) for group MMF; 5(12.5%), 9(22%) and 24 (58.5%) for subgroup NIH, and 6(26.1%), 8(36.4%) and 14(63.6%) for subgroup ELNT. Group MMF outcomes were significantly better than the rest (p<0.05). CONCLUSIONS: Mycophenolate mofetil induction therapy was more effective than intraveenous cyclophosphamide in terms of achieving remission at 6, 12 and 24 months.

Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study.

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C0/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C0/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C0/D ratio crossed over the threshold of 1.05 ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C0/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Tacrolimus's Time Below Therapeutic Range Is Associated With Acute Pancreatic Graft Rejection and the Development of De Novo Donor-specific Antibodies.

Tacrolimus is pivotal in pancreas transplants but poses challenges in maintaining optimal levels due to recipient differences. This study aimed to explore the utility of time spent below the therapeutic range and intrapatient variability in predicting rejection and de novo donor-specific antibody (dnDSA) development in pancreas graft recipients. This retrospective unicentric study included adult pancreas transplant recipients between January 2006 and July 2020. Recorded variables included demographics, immunosuppression details, HLA matching, biopsy results, dnDSA development, and clinical parameters. Statistical analysis included ROC curves, sensitivity, specificity, and predictive values. A total of 131 patients were included. Those with biopsy-proven acute rejection (BPAR, 12.2%) had more time (39.9% ± 24% vs. 25.72% ± 21.57%, p = 0.016) and tests (41.95% ± 13.57% vs. 29.96% ± 17.33%, p = 0.009) below therapeutic range. Specific cutoffs of 31.5% for time and 34% for tests below the therapeutic range showed a high negative predictive value for BPAR (93.98% and 93.1%, respectively). Similarly, patients with more than 34% of tests below the therapeutic range were associated with dnDSA appearance (38.9% vs. 9.4%, p = 0.012; OR 6.135, 1.346-27.78). In pancreas transplantation, maintaining optimal tacrolimus levels is crucial. Suboptimal test percentages below the therapeutic range prove valuable in identifying acute graft rejection risk.

Case report: Successful treatment of acute generalized pustular psoriasis with multiple comorbidities with oral tacrolimus.

Acute generalized pustular psoriasis (GPP) is a serious illness. Despite various treatment methods, there is still lack of effective treatment plans for refractory cases with multiple comorbidities. This case report presents a 67-year-old woman with acute GPP, stage 4 chronic kidney disease (CKD), type 2 diabetes, and cardiovascular disease, in whom skin symptom disappearance and kidney function improvement were observed after the use of oral tacrolimus as the sole therapy. This is the first report on the application of tacrolimus in the treatment of acute GPP, especially refractory acute GPP. The successful treatment indicates that there are shared immune pathways between acute GPP and CKD, and the pathways can be interdicted by tacrolimus. Further studies are needed to optimize the therapy to maximize efficacy and minimize toxicity.

Coadministration of fluconazole to boost subtherapeutic sirolimus concentrations: A case report.

Individual sirolimus whole blood concentrations are highly variable, critically influenced by the concomitant use of cytochrome P450 (CYP) 3A inducers or inhibitors, and also modulated by food. Therapeutic drug monitoring is therefore recommended, especially at treatment start or in circumstances that can influence sirolimus exposure. In this case report, we highlight the challenge of achieving therapeutic sirolimus concentrations and present pragmatic solutions with regimen adaptions, pharmacokinetic enhancement (use of a drug-drug interaction), concentration monitoring, and subsequent modeling of population pharmacokinetics to support treatment decisions. In a 69-year-old female patient with allogeneic hematopoietic stem cell transplantation, tacrolimus concentrations were stable until she developed cerebral toxoplasmosis with tonic-clonic seizures. During treatment of this acute infection, tacrolimus concentrations dropped to subtherapeutic levels and remained largely unaffected by dose increases. Only the simultaneous administration of the CYP3A4 inhibitor fluconazole and a shortening of the sirolimus dosing intervals to a (non-approved) twice-daily administration led to successful control of the concentrations, which ultimately even made a dose reduction possible. This intervention resulted in an increase of sirolimus mean trough concentration to 5.85 ng/mL, i.e., into the desired target range. Additionally, a higher ratio of sirolimus trough levels/daily dose from 26.9 to 109 ng/mL/mg/kg/day was achieved with the initiation of fluconazole. Thus, this case report describes the use of clinical pharmacological concepts and pharmacokinetic modeling to optimize treatment strategies in an individual patient. This strategy could be generalized to other CYP inhibitors and other treatment regimens.

Comparison of different genetic testing modalities applied in paediatric patients with steroid-resistant nephrotic syndrome.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) are monogenic in some cases, however, there are still no clear guidelines on genetic testing in the clinical practice of SRNS in children. METHODS: Three hundred thirty-two children were diagnosed with SRNS, and all children underwent genetic testing, including gene panels and/or whole-exome/genome sequencing (WES/WGS), during treatment. We analysed the relationship between clinical manifestation and genotype, and compared different genetic testing methods' detection rates and prices. RESULTS: In this study, 30.12% (100/332) of children diagnosed with SRNS had monogenic causes of the disease. With 33.7% (122/332) of children achieving complete remission, 88.5% (108/122) received steroids combined with tacrolimus (TAC). In detectability, WES increased by 8.69% (4/46) on gene panel testing, while WGS increased by 4.27% (5/117) on WES, and WES was approximately 1/7 of the price of WGS for every further 1% increase in pathogenicity. CONCLUSIONS: We verified that steroids combined with TAC were the most effective option in paediatric SRNS. In detection efficiency, we found that WGS was the highest, followed by WES. The panel was the lowest, but the most cost-effective method when considering the economic-benefit ratio, and thus it should be recommended first in SRNS.

In Vitro Profiling of Commonly Used Post-transplant Immunosuppressants Reveals Distinct Impact on Antiviral T-cell Immunity Towards CMV.

Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an in vitro infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease.

Introduction: Defective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present. Aim: We examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model. Methods: Using a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect. Results: Treatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced. Conclusion: Addition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.