Adaptative Strategy of Immunosuppressive Drugs Dosage Adjustments When Combined With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients With COVID-19.

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery.

Monogenic Kidney Diseases in Kidney Transplantation.

Monogenic kidney diseases are involved in up to 15% of end-stage kidney diseases (ESKDs) in adults, and in 70 % of pediatric patients. When these disorders lead to kidney failure (KF), kidney transplantation (KT) is the preferred mode of replacement therapy. KT requires specific considerations depending on the nature of the genetic disorder, the potential oncological risk, the risk of recurrence in the graft, the possibility of specific complications of immunosuppression, and the issue of living donation. The availability of genetic testing should play an increasing role in the evaluation of patients or related living donor candidates before transplantation, relevant for the pretransplantation and posttransplantation management.

Donor- and isolation-related predictive factors of in vitro secretory function of cultured human islets.

Background and aims: Human islet preparations designated for research exhibit diverse insulin-secretory profiles. This study aims to assess the impact of donor- and isolation-related factors on in vitro islet secretory function. Methods: A retrospective analysis of 46 isolations from 23 pancreata discarded for clinical transplantation was conducted. In vitro islet secretory function tests were performed on Day 1 and Day 7 of culture. Linear mixed-effects models (LMMs) were employed to investigate the relationships between various predictors characterizing the patient and donor characteristics as well as the isolation effectiveness and two functional outcomes including the islet stimulation index (SI) and area under the insulin curve (AUC). Fixed effects were introduced to represent the main effects of each predictor, and backward elimination was utilized to select the most significant fixed effects for the final model. Interaction effects between the timepoint (Day 7 vs. Day 1) and the predictors were also evaluated to assess whether predictors were associated with the temporal evolution of SI and AUC. Fold-change (Fc) values associated with each predictor were obtained by exponentiating the corresponding coefficients of the models, which were built on log-transformed outcomes. Results: Analysis using LMMs revealed that donor body mass index (BMI) (Fc = 0.961, 95% CI = 0.927-0.996, p = 0.05), donor gender (female vs. male, Fc = 0.702, 95% CI = 0.524-0.942, p = 0.04), and donor hypertension (Fc = 0.623, 95% CI = 0.466-0.832, p= <0.01) were significantly and independently associated with SI. Moreover, donor gender (Fc = 0.512, 95% CI = 0.302-0.864, p = 0.02), donor cause of death (cerebrovascular accident vs. cardiac arrest, Fc = 2.129, 95% CI = 0.915-4.946, p = 0.09; trauma vs. cardiac arrest, Fc = 2.129, 95% CI = 1.112-7.106, p = 0.04), pancreas weight (Fc = 1.01, 95% CI = 1.001-1.019, p = 0.03), and islet equivalent (IEQ)/mg (Fc = 1.277, 95% CI = 1.088-1.510, p ≤ 0.01) were significantly and independently associated with AUC. There was no predictor significantly associated with the temporal evolution between Day 1 and Day 7 for both SI and AUC outcomes. Conclusion: This study identified donor- and isolation-related factors influencing in vitro islet secretory function. Further investigations are essential to validate the applicability of these results in clinical practice.

In situ management of late thrombosis of a renal graft vein in a patient with Cockett syndrome / Prise en charge in situ d'une thrombose tardive de la veine d'un greffon rénal chez une patiente avec un syndrome de Cockett

Late thrombosis of the renal graft vein is a rare complication that results in graft loss in the majority of cases. We describe the case of a 57-year-old female patient who had a kidney transplant 32 years ago and developed a late thrombosis of the graft vein, accompanied by extensive thrombosis in the common femoral and iliac veins. Risk factors included severe malnutrition, chronic inflammation due to an anal fistula, and Cockett syndrome. The treatment consisted of mechanical thrombectomy of the iliac vein, placement of a stent in the common iliac vein, partial thromboaspiration of the renal vein thrombus with local thrombolysis, followed by systemic anticoagulation. With this approach, renal function fully recovered without major complications.

La thrombose tardive de la veine du greffon rénal est une complication rare qui conduit à la perte du greffon dans la majorité des cas. Nous présentons le cas d'une femme de 57 ans, transplantée depuis 32 ans, qui a développé une thrombose de la veine du greffon, se manifestant par une insuffisance rénale aiguë anurique. Cette thrombose compliquait une thrombose extensive débutant dans la veine fémorale superficielle et s'étendant dans les veines fémorale commune et iliaque. La patiente présentait plusieurs facteurs de risque de thrombose veineuse, tels qu'un état de malnutrition sévère, une inflammation chronique due à une fistule anale chronique et un syndrome de Cockett. La patiente a été traitée en plusieurs étapes successives : une thrombectomie mécanique de toute la veine iliaque a d'abord été réalisée, suivie de la mise en place d'un stent dans la veine iliaque commune gauche en raison du syndrome de Cockett, puis d'une thrombo-aspiration partielle du thrombus de la veine rénale combinée à une thrombolyse locale (par urokinase) de la veine rénale via un cathéter, et enfin d'une anticoagulation systémique. Cette approche a permis une récupération complète de la fonction rénale sans complication notable. Nous rapportons cette prise en charge in situ d'une thrombose tardive de la veine d'un greffon rénal chez une patiente avec un syndrome de Cockett, ayant permis une issue favorable.

Impact of thrice-weekly cotrimoxazole prophylaxis on creatinine and potassium plasma levels in kidney transplant recipients.

INTRODUCTION: Cotrimoxazole (CTX) 800/160 mg daily or thrice-weekly is recommended as prophylaxis of Pneumocystis jirovecii pneumonia in kidney transplant recipients. Cotrimoxazole 800/160 daily elevates plasma creatinine and potassium levels but whether the thrice-weekly regimen does so is unknown. METHODS: Medical records of 225 kidney transplant recipients at Cliniques Universitaires Saint-Luc were analyzed retrospectively. All received thrice-weekly CTX 800/160 for 6 months after transplantation. Monthly laboratory results, co-medications, and tacrolimus trough levels were compared. Standard statistical tests were used. RESULTS: One month after CTX stop, creatinine level decreased by 0.11 mg/dl (8%, p = 0.029). This contrasts with its stability in previous and subsequent months. No co-medication change accounted for this decrease. The decrease averaged 0.17 mg/dl (p < 0.01) in the highest initial creatinine tertile. The higher the initial creatinine level, the greater the decrease after CTX stop (p < 0.001), and urea levels remained stable after CTX stop. Potassium levels decreased by 0.09 mmol/L (p = 0.021) one month after CTX stop, and decreased by 0.23 mmol/L (p < 0.01) in the highest initial potassium level tertile. CONCLUSIONS: Our study pinpoints the impact of CTX 800/160 thrice-weekly on creatinine and potassium levels in kidney transplant recipients. This should be considered when interpreting the evolution of plasma creatinine over time, especially in patients with graft dysfunction. Thus, creatinine levels of cohorts with 6 months versus lifelong CTX require different interpretations.

Continuous vs. discontinuous purification of isolated human islets: functional and morphological comparison.

Background: The COBE 2991 cell processor, commonly used for pancreatic islet isolation, is no longer distributed in Europe, leading to a search for alternative purification procedures with equivalent efficacy. The aim of this study was to evaluate the efficacy of an alternative method based on the discontinuous purification of islets. Methods: The conventional isolation procedure using a standard continuous islet purification with COBE 2991 of n = 4 human pancreas was compared to n = 8 procedures using a discontinuous purification with a "bottle" method from donors of similar characteristics. Islet equivalents, purity, and dynamic glucose-stimulated insulin secretion were evaluated. Results: A similar islet yield was obtained using continuous vs. discontinuous purification methods (76,292.5 ± 40,550.44 vs. 79,625 ± 41,484.46 islet equivalents, p = 0.89). Islets from both groups had similar purity (78.75% ± 19.73% vs. 55% ± 18.16%, p = 0.08) and functionality both in terms of stimulation index (3.31 ± 0.83 vs. 5.58 ± 3.38, p = 0.22) and insulin secretion (1.26 ± 0.83 vs. 1.53 ± 1.40 mean AUC, p = 0.73). Moreover, the size of the islets was significantly larger in the discontinuous vs. continuous purification group (19.2% ± 10.3% vs. 45.4% ± 18.8% of islets less than 100 µm, p = 0.0097 and 23.7% ± 5.3% vs. 15.6% ± 5.8% of 200-250 µm islet size, p = 0.03). Conclusion: Compared to the conventional purification procedure, discontinuous purification with a bottle method shows similar results with regard to isolation yield and islet secretory function. Furthermore, this alternative technique allows for obtaining larger islets.

Clinical and Prognostic Factors in Patients with IgG4-Related Kidney Disease.

BACKGROUND: IgG4-related kidney disease is a major manifestation of IgG4-related disease, a systemic fibroinflammatory disorder. However, the clinical and prognostic kidney-related factors in patients with IgG4-related kidney disease are insufficiently defined. METHODS: We conducted an observational cohort study using data from 35 sites in two European countries. Clinical, biologic, imaging, and histopathologic data; treatment modalities; and outcomes were collected from medical records. Logistic regression was performed to identify the possible factors related to an eGFR ≤30 ml/min per 1.73 m 2 at the last follow-up. Cox proportional hazards model was performed to assess the factors associated with the risk of relapse. RESULTS: We studied 101 adult patients with IgG4-related disease with a median follow-up of 24 (11-58) months. Of these, 87 (86%) patients were male, and the median age was 68 (57-76) years. Eighty-three (82%) patients had IgG4-related kidney disease confirmed by kidney biopsy, with all biopsies showing tubulointerstitial involvement and 16 showing glomerular lesions. Ninety (89%) patients were treated with corticosteroids, and 18 (18%) patients received rituximab as first-line therapy. At the last follow-up, the eGFR was below 30 ml/min per 1.73 m 2 in 32% of patients; 34 (34%) patients experienced a relapse, while 12 (13%) patients had died. By Cox survival analysis, the number of organs involved (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.55) and low C3 and C4 concentrations (HR, 2.31; 95% CI, 1.10 to 4.85) were independently associated with a higher risk of relapse, whereas first-line therapy with rituximab was protective (HR, 0.22; 95% CI, 0.06 to 0.78). At their last follow-up, 19 (19%) patients had an eGFR ≤30 ml/min per 1.73 m 2 . Age (odd ratio [OR], 1.11; 95% CI, 1.03 to 1.20), peak serum creatinine (OR, 2.74; 95% CI, 1.71 to 5.47), and serum IgG4 level ≥5 g/L (OR, 4.46; 95% CI, 1.23 to 19.40) were independently predictive for severe CKD. CONCLUSIONS: IgG4-related kidney disease predominantly affected middle-aged men and manifested as tubulointerstitial nephritis with potential glomerular involvement. Complement consumption and the number of organs involved were associated with a higher relapse rate, whereas first-line therapy with rituximab was associated with lower relapse rate. Patients with high serum IgG4 concentrations (≥5 g/L) had more severe kidney disease.

Evaluation of a commercial interferon-γ release assay for the detection of SARS-CoV-2 T-cell response after vaccination.

Objective: Evidence regarding the role of cellular immunity in protecting against COVID-19 is emerging. To better assess immune status, simple and robust assays measuring specific T-cell responses associated with humoral responses are needed. We aimed to evaluate the Quan-T-Cell SARS-CoV-2 test for measuring cellular immune responses in vaccinated healthy and immunosuppressed subjects. Methods: T-cell responses were assessed in healthy vaccinated and unvaccinated and unexposed healthcare workers to determine the sensitivity and specificity of the EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test performed on vaccinated kidney transplant recipients (KTRs). Results: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity (87.2%) and specificity (92.3%) at the calculated 147 mIU/mL cutoff, with an 88.33% accuracy. In KTRs, specific cellular immunity was lower than the antibody response; however, those with a positive IGRA result produced as much IFN-γ as healthy individuals. Conclusions: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity and specificity for the detection of specific T-cell responses against the SARS-CoV-2 spike protein. These results present an additional tool for better management of COVID-19, especially in vulnerable populations.

Intermittent Surface Oxygenation Results in Similar Mitochondrial Protection and Maintenance of Aerobic Metabolism as Compared to Continuous Oxygenation during Hypothermic Machine Kidney Machine Perfusion.

Short bubble and subsequent surface oxygenation is an innovative oxygenation technique and alternative for membrane oxygenation during hypothermic machine perfusion (HMP). The metabolic effect of the interruption of surface oxygenation for 4 h (mimicking organ transport) during HMP was compared to continuous surface and membrane oxygenation in a pig kidney ex situ preservation model. After 30 min of warm ischemia by vascular clamping, a kidney of a ±40 kg pig was procured and subsequently preserved according to one of the following groups: (1) 22-h HMP + intermittent surface oxygenation (n = 12); (2) 22-h HMP + continuous membrane oxygenation (n = 6); and (3) 22-h HMP + continuous surface oxygenation (n = 7). Brief perfusate O2 uploading before kidney perfusion was either obtained by direct bubble (groups 1, 3) or by membrane (group 2) oxygenation. Bubble oxygenation during minimum 15 min was as efficient as membrane oxygenation in achieving supraphysiological perfusate pO2 levels before kidney perfusion. Metabolic tissue analysis (i.e., lactate, succinate, ATP, NADH, and FMN) during and at the end of the preservation period demonstrated similar mitochondrial protection between all study groups. Short bubble and subsequent intermittent surface oxygenation of the perfusate of an HMP-kidney might be an effective and cheap preservation strategy to protect mitochondria, eliminating the need/costs of a membrane oxygenator and oxygen source during transport.

Current Evidence and Future Perspectives to Implement Continuous and End-Ischemic Use of Normothermic and Oxygenated Hypothermic Machine Perfusion in Clinical Practice.

The use of high-risk renal grafts for transplantation requires the optimization of pretransplant assessment and preservation reconditioning strategies to decrease the organ discard rate and to improve short- and long-term clinical outcomes. Active oxygenation is increasingly recognized to play a central role in dynamic preservation strategies, independent of preservation temperature, to recondition mitochondria and to restore the cellular energy profile. The oxygen-related decrease in mitochondrial succinate accumulation ameliorates the harmful effects of ischemia-reperfusion injury. The differences between normothermic and hypothermic machine perfusion with regard to organ assessment, preservation, and reconditioning, as well as the logistic and economic implications, are factors to take into consideration for implementation at a local level. Therefore, these different techniques should be considered complementary to the perfusion strategy selected depending on functional intention and resource availability. This review provides an overview of the current clinical evidence of normothermic and oxygenated hypothermic machine perfusion, either as a continuous or end-ischemic preservation strategy, and future perspectives.

Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

Peripheral embolism as first and only clinical symptom of a true aneurysmal degeneration of the radial artery after ligation of a radiocephalic fistula.

True aneurysmal degeneration of the inflow artery after arteriovenous fistula ligation is extremely rare. Pain is the most common symptom and surgical treatment by an autologous venous bypass is considered as the treatment of choice with good long-term results. We present a patient with peripheral embolism as first and only symptom leading to the diagnosis of a true aneurysmal degeneration of the entire left radial artery. It was discovered 5 years after the ligation of his radiocephalic fistula. As illustrated by this case, a conservative treatment by antiplatelet and anticoagulation therapy should be considered a satisfying alternative to the standard bypass surgery in patients with anatomical variations (e.g. an incomplete arterial palmar arch) since the latter include a higher risk of postoperative ischemic complications.

First clinical kidney transplantation series using brief bubble and direct surface oxygenation as alternative for membrane oxygenation during hypothermic machine perfusion.

BACKGROUND: Active oxygen during hypothermic machine perfusion has the potential to improve mitochondrial preservation and subsequently decrease the harmful effects of ischemia reperfusion injury. Brief bubble, and subsequent surface oxygenation are an alternative oxygenation technique for membrane-oxygenated kidneys during hypothermic machine perfusion (HMP). METHODS: Between March 20, 2022, and June 13, 2022, 5 kidney grafts originating from 3 donors after circulatory death were oxygenated by bubble and surface oxygenation during HMP. RESULTS: No adverse events related to this new oxygenation technique were observed. All five recipients experienced no dialysis-dependency after transplantation with excellent initial graft function at 3 months after transplantation. CONCLUSIONS: For the first time in human, this new oxygenation technique was successfully applied to 5 HMP-kidneys, originating from donation after circulatory death. If confirmed on larger scale cohorts, this innovative oxygenation technique, as alternative oxygenation technique for membrane-oxygenated kidneys, has the potential to be widely implemented because its simplicity and efficacy, and reducing economic and ecological costs by eliminating the need for a membrane oxygenator and oxygen source during transport.

Safety, Efficacy, and Relapse of Nirmatrelvir-Ritonavir in Kidney Transplant Recipients Infected With SARS-CoV-2.

Introduction: The efficacy of nirmatrelvir-ritonavir (NR; Paxlovid, Pfizer, New York, NY) to decrease the risk of progression to severe COVID-19 in high-risk patients has been demonstrated. However, evidence in infected kidney transplant recipients (KTRs) is lacking. Moreover, NR has significant and potentially harmful interactions with calcineurin inhibitors (CNIs). Methods: In this single-center retrospective study, we included all KTRs treated with NR from April 28 to June 3, 2022. A standard management strategy of CNI dose adaptation (discontinuation of tacrolimus 12 hours before the start of NR and administration of 20% of the cyclosporine dose) and laboratory follow-up was applied. Results: A total of 14 patients were included. Compared with day-0 (day before NR initiation), day-7 plasma creatinine concentrations and SARS-CoV-2 viral loads were similar (P = 0.866) and decreased (P = 0.002), respectively. CNI trough concentrations at the end of the treatment were satisfactory, nonetheless, with high individual variability. After a median follow-up time of 34 days, no death or viral pneumonia were observed. Nevertheless, 2 patients experienced early SARS-CoV-2 infection relapses (at day-10 and day-21) associated with an increase in SARS-CoV-2 viral loads. Conclusion: NR can be used in KTRs but requires a strict protocol of drug adaptation. We observed 2 cases of early relapse after NR treatment that need further investigations.