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.

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.

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.

Adherence to antihypertensive drug treatment in kidney transplant recipients.

PURPOSE: Hypertension is a common cardiovascular co-morbidity after kidney transplantation and contributes to shortened graft and patient survival outcomes. However, by contrast with adherence to immunosuppressive drugs, adherence to antihypertensive treatment in kidney transplant recipients has been seldom explored. The aim of the current study was to assess adherence to antihypertensive drugs in kidney transplant recipients from the Cliniques Universitaires Saint-Luc and to look for demographic and clinical characteristics associated with drug adherence. METHODS: Demographic and clinical data were collected from medical files in a standardised case report form. Blood pressure was measured in the sitting position after 5 min rest, using validated oscillometric devices. Drug adherence was assessed by drug dosage in urine using liquid chromatography coupled with tandem mass spectrometry. RESULTS: Our analysis included 53 kidney transplants recipients (75% of men, mean age: 57.2 ± 12.6 years, time since kidney transplantation: 9.5 ± 7.3 years, blood pressure: 130 ± 16/78 ± 11 mmHg on 2.1 ± 1.1 antihypertensive drugs). The proportion of patients showing full drug adherence, partial drug adherence, and total non-adherence to antihypertensive drugs was 79% (N = 42), 15% (N = 8), and 6% (N = 3), respectively. Adherent patients did not differ from less or non- adherers in any of the analysed characteristics. CONCLUSION: The proportion of patients adhering to antihypertensive drug treatment among kidney transplant recipients appears similar to that reported for immunosuppressive drugs in renal transplanted patients (∼70%), but much higher than that observed in patients with drug-resistant hypertension (30-40%). Our results need further confirmation in a large, multicenter, prospective cohort.

Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection.

The urinary chemokines CXCL9 and CXCL10 are promising noninvasive diagnostic markers of acute rejection (AR) in kidney recipients, but their levels might be confounded by urinary tract infection (UTI) and BK virus (BKV) reactivation. Multiparametric model development and validation addressed these confounding factors in a training set of 391 samples, optimizing the diagnostic performance of urinary chemokines. CXCL9/creatinine increased in UTI and BKV viremia with or without nephropathy (BKVN) (no UTI/leukocyturia/UTI: -0.10/1.61/2.09, P = .0001 and no BKV/viremia/BKVN: -0.10/1.90/2.29, P < .001) as well as CXCL10/creatinine (1.17/2.09/1.98, P < .0001 and 1.13/2.21/2.51, P < .001, respectively). An optimized 8-parameter model (recipient age, sex, estimated glomerular filtration rate, donor specific antibodies, UTI, BKV blood viral load, CXCL9, and CXCL10) diagnosed AR with high accuracy (area under the curve [AUC]: 0.85, 95% confidence interval [CI]: 0.80-0.89) and remained highly accurate at the time of screening (AUC: 0.81, 95% CI: 0.48-1) or indication biopsies (AUC: 0.85, 95% CI: 0.81-0.90) and within the first year (AUC: 0.86, 95% CI: 0.80-0.91) or later (AUC: 0.90, 95% CI: 0.84-0.96), achieving AR diagnosis with an AUC of 0.85 and 0.92 (P < .0001) in 2 external validation cohorts. Decision curve analyses demonstrated the clinical utility of the model. Considering confounding factors rather than excluding them, we optimized a noninvasive multiparametric diagnostic model for AR of kidney allografts with unprecedented accuracy.

Coinfection of Mycobacterium malmoense and Mycobacterium chimaera in a kidney transplant recipient: A case report and review of the literature.

Nontuberculous mycobacteria (NTM) are ubiquitous organisms found in soil and water. Solid organ recipients are at increased risk of NTM infections due to impaired immunity. Although the NTM infections rate is low, it increases morbidity and the risk of mortality. Diagnosis is often delayed because of the lack of specific clinical symptoms and requires a high index of suspicion. Management may be challenging: long-term treatment with risks of side effects and interactions with immunosuppressive regimen; reduction of immunosuppression; and risk of allograft rejection. Prognosis is widely variable. We report the first case of Mycobacterium malmoense chest infection with concomitant Mycobacterium chimaera urinary tract infection in a kidney transplant recipient. The evolution was marked by poor tolerance of the treatment with severe adverse events and disabled functional status.

Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go?

PURPOSE OF REVIEW: Checkpoint inhibitors (CPIs) provide impressive response rates among immunocompetent patients with various solid tumors. So far, organ transplant recipients have been excluded from clinical studies due to the putative risk of allograft rejection however 48 cases of liver and renal transplant patients treated with CPI were already described in literature. RECENT FINDINGS: Here we discuss 19 cases of liver and 29 cases of renal transplant patients who received CPI for advanced cancer. Disease control rate [stable disease, complete response (CR) and partial response (PR) together] was 35% (21% for liver and 45% for kidney transplant patients). Graft rejection was seen in 37% of liver and 45% and kidney transplant patients. Significantly, our analysis shows that an 'ideal' response occurs in 21% of all patients (antitumor response accompanied with durable graft tolerance). SUMMARY: We believe that transplant patients can be treated with CPI in a controlled setting and for well informed patients. To obtain a durable antitumor immune response while avoiding rejection, to be able to adjust immunosuppression and to have the opportunity to develop biomarkers for tumor response and transplant rejection, these patients should be treated according to a clinical care path or a prospective clinical trial.

Baseline graft status is a critical predictor of kidney graft failure after diarrhoea.

BACKGROUND: Diarrhoea is one of the most frequent complications after kidney transplantation (KT). Non-infectious diarrhoea has been associated with reduced graft survival in kidney transplant recipients. However, the risk factors for renal allograft loss following diarrhoea remain largely unknown. METHODS: Between January 2010 and August 2011, 195 consecutive KT recipients who underwent standardized microbiological workups for diarrhoea at a single centre were enrolled in this retrospective study. RESULTS: An enteric pathogen was readily identified in 91 patients (47%), while extensive microbiological investigations failed to find any pathogen in the other 104. Norovirus was the leading cause of diarrhoea in these patients, accounting for 30% of the total diarrhoea episodes. The baseline characteristics were remarkably similar between non-infectious and infectious diarrhoea patients, with the exception that the non-infectious group had significantly lower graft function before diarrhoea (P = 0.039). Infectious diarrhoea was associated with a longer duration of symptoms (P = 0.001) and higher rates of acute kidney injury (P = 0.029) and hospitalization (P < 0.001) than non-infectious diarrhoea. However, the non-infectious group had lower death-censored graft survival than the infectious group (Gehan-Wilcoxon test, P = 0.038). Multivariate analysis retained three independent predictors of graft failure after diarrhoea: diarrhoea occurring ≥5 years after KT [hazard ratio (HR) 4.82; P < 0.001], re-transplantation (HR 2.38; P = 0.001) and baseline estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR 11.02; P < 0.001). CONCLUSION: Our study shows that pre-existing conditions (re-transplantation, chronic graft dysfunction and late occurrence) determine the primary functional long-term consequences of post-transplant diarrhoea.

No clinical benefit of rapid versus gradual tapering of immunosuppression to treat sustained BK virus viremia after kidney transplantation: a single-center experience.

Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T0 ) were similar among patient groups. However, following onset, the dose of MPA at 1 month (P = 0.002) and 3 months (P = 0.005) and Tac T0 at 1 month (P = 0.030) and 3 months (P = 0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P < 0.001) and resulted in a better protection of graft function in patients with confirmed BKV-associated nephropathy (P = 0.033) without impacting 5-year graft survival. Survival without rejection was similar (P = 0.571), but the RT group had increased the development of de novo donor-specific antibodies (dnDSAs; P < 0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin® induction [hazard ratio (HR), 3.090; P = 0.001] and the RT strategy (HR, 6.021; P = 0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium-term clinical outcome but increases the risk of developing dnDSAs.

Reduction in late onset cytomegalovirus primary disease after discontinuation of antiviral prophylaxis in kidney transplant recipients treated with de novo everolimus.

BACKGROUND: Donor (D)+/recipient (R)- serostatus is closely associated with a higher risk of cytomegalovirus (CMV) infection and disease. Antiviral prophylaxis is conventionally used in such patients, but late onset CMV infection/disease still occurs after the discontinuation of prophylaxis. METHODS: We retrospectively analyzed the data of 215 low immunological risk patients who received kidney transplantation in our center between 2011 and 2016. RESULTS: Ninety-seven patients received a combination of everolimus (EVL)/reduced doses of calcineurin inhibitors (CNI) (EVL group) de novo, and 118 received a combination of mycophenolic acid (MPA)/standard doses of CNI (MPA group) de novo. All patients received induction by basiliximab, steroids, and standardized antiviral prophylaxis depending on their CMV D/R serostatus. D+/R- recipients comprised 17% (n = 16) of the EVL group and 19% (n = 22) of the MPA group (P = .722). In the D+/R- subgroup, the 1-year incidence of late onset CMV primary disease after the withdrawal of prophylaxis was lower in the EVL group than in the MPA group (6% vs 41%, P = .025) while the rate of CMV disease in the D+/R+ group (8% vs 6%, P = 1) and the D-/R+ group (12% vs 9%, P = 1) were similar. Kaplan-Meier analysis of 1-year CMV primary disease-free survival in seronegative patients was significantly better in the EVL group (P = .029, log-rank test). CONCLUSIONS: Our data suggest that de novo use of EVL may reduce late onset CMV primary disease after the withdrawal of antiviral prophylaxis in kidney transplantation patients.