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Introduction: The early diagnosis of histological kidney damage after lung transplantation (LT) is of paramount importance given the negative prognostic implications of kidney disease. Methods: Three pathologists analyzed all kidney biopsies (KBs) (N = 100) performed from 2010 to 2021 on lung transplant patients in 4 Paris transplantation centers. Results: The main indication for biopsy was chronic renal dysfunction (72% of patients). Biopsies were performed at a median of 26.3 months after transplantation and 15 months after a decline in estimated glomerular filtration rate (eGFR) or the onset of proteinuria. Biopsies revealed a wide spectrum of chronic lesions involving the glomerular, vascular, and tubulointerstitial compartments. The 4 most frequent final diagnoses, observed in 18% to 49% of biopsies, were arteriosclerosis, acute calcineurin inhibitor (CNI) toxicity, thrombotic microangiopathy (TMA) and acute tubular necrosis (ATN). TMA was significantly associated with a combination of mTOR inhibitors (mTORi) or CNIs with biological signs present in only 50% of patients. The eGFR was poorly correlated with most lesions, particularly percent glomerulosclerosis, and with the risk of end-stage renal disease (ESRD). Thirty-four patients progressed to ESRD at an average of 20.1 months after biopsy. Three factors were independently associated with the risk of ESRD: postoperative dialysis, proteinuria >3 g/g and percent glomerulosclerosis >4%. Conclusion: Given the great diversity of renal lesions observed in lung transplant recipients, early referral to nephrologists for KB should be considered for these patients when they present with signs of kidney disease.

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OBJECTIVE: Eczema is the most burdensome skin condition worldwide and topical anti-inflammatory treatments are commonly used to control symptoms. The relative effectiveness and safety of different topical anti-inflammatory treatments is uncertain. DESIGN: Network meta-analysis performed within a Cochrane systematic review to compare and statistically rank efficacy and safety of topical anti-inflammatory eczema treatments. DATA SOURCES: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to June 2023. ELIGIBILITY CRITERIA FOR SELECTED TRIALS: Included trials were within-participant or between-participant randomised controlled trials. Participants had eczema that was not clinically infected and was not contact dermatitis, seborrheic eczema or hand eczema. Interventions were topical anti-inflammatory treatments but not complementary treatments, antibiotics alone, wet wraps, phototherapy or systemic treatments. Comparators were no treatment/vehicle or another topical anti-inflammatory. RESULTS: We identified 291 trials (45,846 participants), mainly in high-income countries. Most were industry-funded with median 3 weeks treatment duration. Risk of bias assessed using the Cochrane Risk of Bias 2.0 tool was high in 89% of trials, mainly due to risk of selective reporting. Network meta-analysis of binary outcomes ranked potent and/or very potent topical steroids, tacrolimus 0.1% and ruxolitinib 1.5% among the most effective treatments for improving patient-reported symptoms (40 trials, all low confidence) and clinician-reported signs (32 trials, all moderate confidence). For investigator global assessment, the Janus kinas inhibitors ruxolitinib 1.5%, delgocitinib 0.5% or 0.25%, very potent/potent topical steroids and tacrolimus 0.1% were ranked as most effective (140 trials, all moderate confidence). Continuous outcome data were mixed. Local application site reactions were most common with tacrolimus 0.1% (moderate confidence) and crisaborole 2% (high confidence) and least common with topical steroids (moderate confidence). Skin thinning was not increased with short-term use of any topical steroid potency (low confidence) but skin thinning was reported in 6/2044 (0.3%) participants treated with longer-term (6-60 months) topical steroids. CONCLUSION: Potent topical steroids, Janus kinase inhibitors and tacrolimus 0.1% were consistently ranked as among the most effective topical anti-inflammatory treatments for eczema.

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Background: Kidney transplantation is followed by immunosuppressive therapy involving calcineurin inhibitors (CNIs) such as cyclosporin A. However, long-term high CNIs doses can lead to vitamin D deficiency, and genetic variations influencing vitamin D levels can indirectly impact the necessary CNIs dosage. This study investigates the impact of genetic variations of vitamin D binding protein (DBP) rs2282679 and CYP2R1 hydroxylase rs10741657 polymorphisms on the cyclosporin A dosage in kidney transplant recipients. Additional polymorphisims of genes that are predicted to influence the pharmacogenetic profile were included. Methods: Gene polymorphisms in 177 kidney transplant recipients were analyzed using data mining techniques, including the Random Forest algorithm and Classification and Regression Trees (C&RT). The relationship between the concentration/dose (C/D) ratio of cyclosporin A and genetic profiles was assessed to determine the predictive value of DBP rs2282679 and CYP2R1 rs10741657 polymorphisms. Results: Polymorphic variants of the DBP (rs2282679) demonstrated a strong predictive value for the cyclosporin A C/D ratio in post-kidney transplantation patients. By contrast, the CYP2R1 polymorphism (rs10741657) did not show predictive significance. Additionally, the immune response genes rs231775 CTLA4 and rs1800896 IL10 were identified as predictors of cyclosporin A response, though these did not result in statistically significant differences. Conclusions:DBP rs2282679 polymorphisms can significantly predict the cyclosporin A C/D ratio, potentially enhancing the accuracy of CNI dosing. This can help identify patient groups at risk of vitamin D deficiency, ultimately improving the management of kidney transplant recipients. Understanding these genetic influences allows for more personalized and effective treatment strategies, contributing to better long-term outcomes for patients.

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Immunosuppressive medications play a pivotal role in kidney transplantation, and the calcineurin inhibitors (CNIs), including cyclosporine A (CsA) and tacrolimus (TAC), are considered as the backbone of maintenance immunosuppressive regimens. Since the introduction of CNIs in kidney transplantation, the incidence of acute rejection has decreased, and allograft survival has improved significantly. However, CNI nephrotoxicity has been a major concern, believed to heavily impact long-term allograft survival and function. To address this concern, several CNI-sparing regimens were developed and studied in randomized, controlled, clinical trials, aiming to reduce CNI exposure and preserve long-term allograft function. However, more recent information has revealed that CNI nephrotoxicity is not the primary cause of late allograft failure, and its histopathology is neither specific nor pathognomonic. In this review, we discuss the historical development of maintenance immunosuppressive regimens in kidney transplantation, covering the early era of transplantation, the CNI-sparing era, and the current era where the alloimmune response, rather than CNI nephrotoxicity, appears to be the major contributor to late allograft failure. Our goal is to provide a chronological overview of the development of maintenance immunosuppressive regimens and summarize the most recent information for clinicians caring for kidney transplant recipients (KTRs).

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Calcineurin inhibitor-induced pain syndrome is a rare but debilitating complication of organ transplantation. This case report describes a man in his forties who developed bilateral hip pain, an atypical presentation of calcineurin inhibitor-induced pain syndrome, after undergoing renal transplantation. Initially, avascular necrosis was suspected as a potential cause of pain. The initial radiographs revealed no abnormalities. However, high trough levels of calcineurins and subsequent magnetic resonance imaging of the hip revealed bilateral symmetric bone marrow edema, which was consistent with calcineurin inhibitor-induced pain syndrome. Adjustments made to the immunosuppressive regimen and multidisciplinary management resulted in an improvement in the patient's symptoms. This case report emphasizes the importance of adopting a comprehensive approach to post-transplantation pain management. Moreover, this report emphasizes the importance of considering the diagnosis of calcineurin inhibitor-induced pain syndrome while investigating and managing post-transplantation patients presenting with hip pain. Clinicians need a high index of suspicion for calcineurin inhibitor-induced pain syndrome, thereby contributing to enhanced post-transplantation care and outcomes while improving the quality of life of transplant recipients experiencing musculoskeletal pain.

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Atopic dermatitis (AD) is a prevalent inflammatory skin condition impacting both children and adults globally, with a prevalence of 15-30%. It ranks as the most prevalent skin disorder based on disability-adjusted life-years by the World Health Organization. It presents with symptoms like skin irritation, redness, dryness, itchiness, and vesicular blisters and commonly coexists with other atopic symptoms like allergic rhinitis, asthma, and food allergies. The pathophysiology involves a complex interplay of genetic predispositions, immunological dysfunctions, and environmental factors leading to tissue inflammation and disrupted skin barrier integrity. Alopecia areata is characterized by nonscarring hair loss and shares correlations with AD including a higher prevalence of atopic diseases, shared intracellular mechanisms involving the JAK-STAT pathway, and potential treatment overlap such as dupilumab. These correlations could direct new areas of research and increased insight for both diseases. Treatment of AD requires a personalized approach due to its complex, multifactorial nature integrating nonpharmacological interventions like skin hydration and trigger avoidance as well as topical and systemic approaches, if necessary, with topical corticosteroids being the first line for flares; long term corticosteroid use poses risk for adverse effects like skin atrophy. Severe cases may require systemic treatments or phototherapy. Future treatment prospects include targeting the dysbiotic microbiome and identifying biomarkers for tailored therapeutic strategies, emphasizing the importance of personalized medicine in optimizing AD management.

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Cyclosporin A (CsA), an immunosuppressive drug used in transplant recipients, inhibits graft rejection by binding to cyclophilins and competitively inhibiting calcineurin. While concerns about respiratory infections in immunosuppressed patients exist, contradictory data emerged during the COVID-19 pandemic, prompting investigations into CsA's impact on viral infections. This study explores CsA's antiviral effects on SARS-CoV-2 Omicron BA.1, Delta variants, and human parainfluenza virus 3 (HPIV3) using an ex vivo model of human airway epithelium (HAE). CsA exhibited a dose-dependent antiviral effect against the SARS-CoV-2 Delta variant, reducing viral load over 10 days. However, no significant impact was observed against SARS-CoV-2 Omicron or HPIV3, indicating a virus-specific effect. At high concentrations, CsA was associated with an increase of IL-8 and a decrease of IFNλ expression in infected and noninfected HAE. This study highlights the complexity of CsA's antiviral mechanisms, more likely involving intricate inflammatory pathways and interactions with specific viral proteins. The research provides novel insights into CsA's effects on respiratory viruses, emphasizing the need for understanding drug-virus interactions in optimizing therapeutic approaches for transplant recipients and advancing knowledge on immunosuppressive treatments' implications on respiratory viral infections. Limitations include the model's inability to assess T lymphocyte activation, suggesting the necessity for further comprehensive studies to decipher the intricate dynamics of immunosuppressive treatments on respiratory viral infections.

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BACKGROUND: Early substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. METHODS: In the SCHEDULE trial, 115 de novo HTx recipients were randomized to (1) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or (2) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12-year long-term follow-up of the study. RESULTS: A total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8% (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73 m2 and 61.0 (52.3-69.7) ml/min/1.73 m2 in the everolimus and CNI group, respectively (p < 0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p = 0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p = 0.99). CONCLUSIONS: De novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.

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Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a critical complication of hematopoietic stem cell transplantation. Awareness about TA-TMA has increased in recent years, resulting in the implementation of TA-TMA screening in most centers. Methods: Retrospective analysis of children who underwent autologous or allogeneic hematopoietic stem cell transplantation at our center between January 2018 and December 2022 was conducted to evaluate the incidence, clinical features, and outcomes of TA-TMA following the administration of different therapeutic options. Results: A total of 45 patients comprised the study cohort, of whom 10 developed TA-TMA with a cumulative incidence of 22% by 100 days after transplantation. Patients with and without TA-TMA in our cohort displayed an overall survival of 80% and 88%, respectively (p = 0.48), and a non-relapse mortality of 0% and 5.7%, respectively (p = 0.12), at 1 year after transplantation. Risk factors for TA-TMA development included allogeneic transplantation and total body irradiation-based conditioning regime. Among the 10 patients with TA-TMA, 7 did not meet the high-risk criteria described by Jodele and colleagues. Of these seven patients, two responded to calcineurin-inhibitor withdrawal without further therapy and five developed multiorgan dysfunction syndrome and were treated with anti-inflammatory steroids (prednisone), and all responded to therapy. The three patients with high-risk TA-TMA were treated with complement blockade or prednisone, and all responded to therapy. Conclusion: TA-TMA is a multifactorial complication with high morbidity rates. Patients with high-risk TA-TMA may benefit from complement blockade using eculizumab. No consensus has been reached regarding therapy for patients who do not meet high-risk criteria. Our analysis showed that these patients may respond to anti-inflammatory treatment with prednisone.

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INTRODUCTION: BV is an antibody-drug conjugate directed against CD30 and is safe and effective in relapsed/refractory (R/R) Hodgkin lymphoma (HL). Most patients with r/r cHL respond well to BV monotherapy; however, the large of majority of them eventually progress on this drug, and BV-resistant HL remains an unmet need. Preclinical data suggest that BV resistance is mediated at least in part by increased drug efflux associated with increased expression of multidrug resistance pump 1 (MDR1) while CD30 expression appears to be preserved in BV resistant cell lines and patient samples. We conducted a phase 1 study evaluating BV + cyclosporine (CsA) in BV-refractory HL and previous reported results in the dose finding cohort. Here we report the final results from the phase 1 study. METHODS: This was a phase I trial of BV + CsA in patients with r/r HL with dose-finding and dose escalation cohorts. Eligibility criteria included age ≥ 18 years with r/r HL after at least 1 prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously on day 1 and CsA 5 to 7.5 mg/kg PO twice daily on days 1 to 5; cycles were 21 days long. Patients in the expansion cohort had to have cHL refractory to BV. The primary objectives were to evaluate safety and tolerability and to determine MTD of BV + CsA; the secondary objective was to determine efficacy of this combination. RESULTS: 29 patients were enrolled onto the study, 14 in the dose finding cohort and 15 in the dose expansion BV refractory cohort. Study accrual was terminated before target accrual due to unacceptable toxicity. 62% of patients were male, and the median age was 36 years (range: 20-69). The median number of prior therapies was 5 (range: 3-12); all patients had prior BV, and 93% had PD-1 directed therapy, and 93% were BV-refractory. Of 22 evaluable patients, CR rate was 27% and ORR 64%; median DOR 4.9 months. Treatment-related deaths occurred in 3 patients, and another patient died during cycle 1 due to cardiac arrest deemed unlikely related to be protocol therapy. All grade GI toxicity was seen in 90% of patients (G3+ in 24%); other common adverse events were nausea (90%), hypertension (90%), nausea (90%), hypertension (90%), anemia (86%), fatigue (76%), neutropenia (76%), leukopenia (76%), hypomagnesemia (76%), anorexia (66%), and hyponatremia (66%). DISCUSSION: BV + CsA demonstrated modest activity in BV-refractory r/r HL; however, toxicity is substantial.

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The calcineurin inhibitor tacrolimus, which is available as an immediate- or extended-release formulation, is the standard-of-care immunosuppression after kidney transplantation with low rejection rates, especially in the first year after transplantation. However, its highly variable metabolism rate, narrow therapeutic window, and nephrotoxic side effects require close drug monitoring and individual dosing. Here, we describe first the application of extended-release tacrolimus (ER-Tac) twice daily with beneficial effects in a kidney transplant recipient under extensive therapeutic drug monitoring. A 47-year-old female kidney transplant recipient, who was identified as a fast metabolizer for tacrolimus, presented with declining allograft function and low tacrolimus through levels over time and 8 years after a second kidney transplantation despite the administration of high doses of ER-Tac once daily. Therefore, the area under the concentration-time curve (AUC) showed exceedingly high blood levels of ER-Tac. The latest biopsy of the kidney transplant showed arteriolar hyalinosis with pole vessel stenosis as a sign of chronic transplant vasculopathy and transplant glomerulopathy as a sign of chronic humoral rejection. After the exclusion of other options for immunosuppressive therapy due to the patient's high immunological risk, the patient was switched from ER-Tac once daily to ER-Tac twice daily. After switching to ER-Tac twice daily, the AUC for oral tacrolimus decreased and the transplant function improved despite higher tacrolimus trough levels and a lower total dose administered. This case highlights the importance of careful therapeutic drug monitoring with the performance of an AUC in the follow-up management of kidney transplant recipients.

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We present a case of a 23-year-old male who developed thrombotic microangiopathy associated with the induction dose of tacrolimus. Get an early diagnosis and give timely treatment of thrombotic microangiopathy is essential to improve the prognosis of the kidney transplant.

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AIM: Calcineurin inhibitors (CNIs) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects contribute to allograft injury. Renal parenchymal lesions occur for cyclosporine A (CsA) as well as for the currently favored tacrolimus (Tac). We aimed to study whether chronic CsA and Tac exposures, before reaching irreversible nephrotoxic damage, affect renal compartments differentially and whether related pathogenic mechanisms can be identified. METHODS: CsA and Tac were administered chronically in wild type Wistar rats using osmotic minipumps over 4 weeks. Functional parameters were controlled. Electron microscopy, confocal, and 3D-structured illumination microscopy were used for histopathology. Clinical translatability was tested in human renal biopsies. Standard biochemical, RNA-seq, and proteomic technologies were applied to identify implicated molecular pathways. RESULTS: Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction, enhanced apoptosis, impaired proteostasis and oxidative stress. Lesion characteristics were confirmed in human renal biopsies. CONCLUSION: We conclude that pathogenetic alterations in the renal compartments are specific for either treatment. Considering translation to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share protein signatures identified from multiomics with potential pathognomonic relevance.

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Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life-threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well-controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid-resistant LM with fulminant relapse.

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OBJECTIVES: To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). METHODS: Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. RESULTS: A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767 µg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). CONCLUSIONS: The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure.

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We report a successful, albeit complicated pregnancy with a live-born healthy baby at 28 weeks' gestation, after 10 pregnancy failures, in a 39-year-old patient with a history of liver transplantation and chronic kidney disease with hypertension and proteinuria. Multidisciplinary management (obstetrician, nephrologist and hepatology transplant specialist) allowed close monitoring, adaptation of immunosuppressive treatments and strict control of fetal growth. The onset of preeclampsia at 28 weeks' gestation led to a cesarean section, resulting in the birth of a healthy 830 g boy, with subsequent normal development. Following pregnancy, the patient experienced liver transplant rejection, which resolved after adapting immunosuppressive drugs. No deterioration in kidney function was observed in the year following delivery.

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Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, with more than half of the patients developing lupus nephritis (LN), which significantly contributes to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The treatment of lupus nephritis has always been challenging. Tacrolimus (TAC), an effective immunosuppressant, has been increasingly used in the treatment of LN in recent years. This review aims to explore the mechanisms of action of tacrolimus in treating LN. Firstly, we briefly introduce the pharmacological properties of tacrolimus, including its role as a calcineurin (CaN) inhibitor, exerting immunosuppressive effects by inhibiting T cell activation and cytokine production. Subsequently, we focus on various other immunomodulatory mechanisms of tacrolimus in LN therapy, including its effects on T cells, B cells, and immune cells in kidney. Particularly, we emphasize tacrolimus' regulatory effect on inflammatory mediators and its importance in modulating the Th1/Th2 and Th17/Treg balance. Additionally, we review its effects on actin cytoskeleton, angiotensin II (Ang II)-specific vascular contraction, and P-glycoprotein activity, summarizing its impacts on non-immune mechanisms. Finally, we summarize the efficacy and safety of tacrolimus in clinical studies and trials. Although some studies have shown significant efficacy of tacrolimus in treating LN, its safety remains a challenge. We outline the potential adverse reactions of long-term tacrolimus use and provide suggestions on effectively monitoring and managing these adverse reactions in clinical practice. In general, tacrolimus, as a novel immunosuppressant, holds promising prospects for treating LN. Of course, further research is needed to better understand its therapeutic mechanisms and ensure its safety and efficacy in clinical practice.