ABO-incompatible (ABOi) living donor kidney transplantation (LDKTx) has become an established strategy for overcoming blood group barriers and expanding access to transplantation. However, its implementation remains limited in many developing countries because of the complexity and cost associated with desensitization protocols. We report the first ABO-incompatible LDKTx performed in Morocco. A 23-year-old woman with end-stage kidney disease secondary to congenital uropathy underwent kidney transplantation from her mother despite ABO incompatibility (donor B+, recipient O+). Pre-transplant immunological assessment revealed the absence of anti-HLA antibodies and a negative complement-dependent cytotoxicity crossmatch. Baseline anti-B isoagglutinin titers were 1:64 for IgG and 1:32 for IgM. The desensitization protocol consisted of rituximab administration (500 mg) on day -30, followed by the initiation of tacrolimus, mycophenolate mofetil, and corticosteroids on day-15. Three plasma exchange and one immunoadsorption sessions were subsequently performed before transplantation. No intravenous immunoglobulins were administered. Prior to transplantation, IgM titers became undetectable, while IgG titers decreased to 1:4. There was immediate graft function and no perioperative complications. During one year of follow-up, no episodes of rejection, infectious complications, or graft dysfunction were observed. At one year, i) serum creatinine remained stable at approximately 100 µmol/L, and ii) anti-B isoagglutinin titers remained low (IgG titers of 1:2; undetectable IgM titers). This first Moroccan experience demonstrates that ABO-incompatible LDKTx is both feasible and safe in our setting, using a simplified desensitization protocol without intravenous immunoglobulins. We have recently performed a successful second ABOi case with the same protocol.

Highly sensitized kidney transplant candidates face limited access to compatible organs due to persistent anti-human leukocyte antigen (HLA) antibodies (Abs) and memory B cell (mBc) responses, which are generally not concomitantly targeted by current desensitization therapies. In this single-arm phase 1b/2 trial (NCT05145296), 5 highly sensitized kidney transplant candidates (calculated panel-reactive Ab >99%) were treated with belatacept and daratumumab to evaluate safety and mechanistic efficacy. Serum anti-HLA Ab levels, HLA-specific mBc, and bone marrow (BM)-residing long-lived plasma cells (PCs) were analyzed using single antigen beads, functional B cell assays, and spectral flow cytometry. The regimen was well-tolerated, with no serious adverse events attributable to study drugs. Three of 4 evaluable patients showed substantial serologic response by means of elimination and reductions in mean fluorescence intensity Abs and titers, mainly anti-HLA class I. HLA-specific mBc and CD38+ PC were significantly depleted in responders in peripheral blood and BM. Multidimensional profiling revealed depletion of CD38+ natural killer, T follicular helper, and PC in both peripheral blood and BM, which was accompanied by a reduction in calculated panel-reactive Ab levels, primarily in class I Abs. Dual targeting of T/B cell costimulation and PC using belatacept and daratumumab is a safe and mechanistically effective approach for desensitization in highly sensitized kidney transplant candidates. These findings support further investigation in larger trials.

Complement dysregulation is frequently implicated in the thrombotic microangiopathy (TMA) known as atypical hemolytic uremic syndrome (aHUS). Diacylglycerol kinase epsilon (DGKE) mutations encode a non-complement regulatory protein, and pathogenic variants in DGKE define a distinct form of aHUS. Indeed, the DGKEgene encodes a key enzyme involved in intracellular signaling. While eculizumab and other anti-C5 monoclonal antibodies are widely used in complement-related aHUS, their relevance in DGKE-associated forms remains controversial. We report a case of a patient followed from the age of eight months for suspected aHUS. Genetic testing, performed only at the age of 13 years, revealed a homozygous DGKE mutation (c.412T>C; p.C138R), despite a typical presentation, including hemolytic anemia, thrombocytopenia, and acute kidney injury. Due to severe disease progression and a fatal family history, empirical eculizumab therapy was initiated. Although the treatment resulted in a stable overall clinical status, relapses manifested as isolated nephrotic-range proteinuria (without hemolysis) on two occasions during treatment interruptions. Complement C3 levels remained consistently within the normal range. In this case, eculizumab did not prevent disease relapses, which occurred in the absence of complement activation. The persistence of proteinuria despite C5 blockade further highlights this distinction. The lack of genetic testing options has led to overtreatment in this patient with that type of mutation, with additional costs associated with the drug (eculizumab) and an increased risk of life-threatening infectious complications for the patient.

Chronic hemodialysis is a well-established supportive therapy for patients with end-stage kidney disease. However, this therapy is rarely implemented in low-income countries because of its high cost. We herein report a single-center experience in one of the poorest countries in the world, i.e., Niger, involving patients in whom hemodialysis was initiated. This cross-sectional study included all incident patients presenting with serum creatinine levels greater than 1000 µmol/L between January 2018 and December 2022. All patients agreed to undergo self-funded chronic hemodialysis. Survival was assessed as of December 2024. A total of 544 patients initiated hemodialysis therapy. Among them, 423 (77.8

Coronavirus disease 2019 (COVID-19) has been associated with an increased long-term cardiovascular risk, potentially mediated by magnitude of the acute inflammatory response inflammation. Interleukin-6 (IL-6) and serum amyloid A (SAA) are key components of the inflammatory cascade and may serve as biomarkers of post-COVID cardiovascular vulnerability. This longitudinal observational study investigated the association between post- COVID-19 infection IL-6 and SAA levels and major cardiovascular events over a six-year follow-up period. A total of 97 individuals with documented prior SARS-CoV-2 infection were included. Circulating IL-6 and SAA concentrations were measured in the acute phase. The composite endpoint included incident arrhythmia, myocardial infarction, and all-cause mortality. Biomarker distributions were right-skewed and were therefore analyzed using non-parametric methods and penalized logistic regression models. During follow-up, 14.4% of participants experienced the composite endpoint. Individuals with adverse outcomes had significantly higher IL-6 and SAA levels compared with event-free participants. IL-6 demonstrated the strongest association with mortality, whereas SAA showed particularly robust associations with the composite endpoint, and with myocardial infarction. Both biomarkers independently predicted long-term adverse events. Circulating IL-6 and SAA concentrations measured during the acute phase of SARS-CoV-2 infection were analyzed in relation to long-term cardiovascular outcomes. These findings support the hypothesis that the magnitude of the acute inflammatory response during SARS-CoV-2 infection may be associated with long-term cardiovascular outcomes and suggest that combined assessment of IL-6 and SAA may have potential utility for hypothesis-generating prognostic signal requiring validation, pending validation in larger studies.

We report 2 cases of donor-derived West Nile virus infection in kidney transplant recipients in France. Both recipients had mild disease develop and recovered without sequelae. A more proactive screening strategy in France, particularly during periods of highest risk for West Nile virus circulation, would help reduce risk for donor-derived infections.

KEY POINTS:Pretransplant early acute rejection risk stratification offers a novel approach to personalized immunosuppression management in patients who received a kidney transplant. Stratifying immunologic risk independent of donor characteristics may help guide immunosuppression management in patients who received a kidney transplant. The pretransplant risk assessment gene set reflects metabolic and immune pathways involved in T-cell- and antibody-mediated mechanisms of transplant rejection. BACKGROUND:Although donor and recipient characteristics are used to estimate graft failure risk, they remain limited in predicting early acute rejection (EAR). We developed and validated a next-generation sequencing assay targeting the pretransplant immunologic profile to predict EAR following kidney transplantation. METHODS:This prospective, international study enrolled 321 kidney transplant participants across 13 sites, forming discovery and validation cohorts. Peripheral blood was collected before transplant and at 1, 3, 6, 12, and 24 months post-transplant, with protocol biopsies performed at 3 and 12 months, as well as any indication biopsies. Biopsies were assessed by a blinded central pathologist according to the 2019 Banff criteria. The pretransplant risk assessment (PTRA) test to evaluate RNA expression of a 29-gene signature algorithm designed to predict EAR risk was clinically validated using 122 deceased donor kidney transplant recipients. RESULTS:PTRA classified 31 of 122 participants (25%) as high risk and 91 (75%) as low risk. There were nine EAR events in the first 60 days post-transplant: 6/31 (19%) in the high-risk group and 3/91 (3%) in the low-risk group. PTRA discrimination for EAR at 60 days post-transplant yielded an area under the curve of 0.78 (95% confidence interval [CI], 64.4 to 91.5), P < 0.001. A cutoff of ≤45 was defined as low risk and >45 as high risk for EAR within 60 days post-transplant. Sensitivity was 0.67 (95% CI, 0.36 to 0.97), specificity 0.78 (95% CI, 0.70 to 0.86), positive predictive value 0.19 (95% CI, 0.05 to 0.33), and negative predictive value 0.97 (95% CI, 0.93 to 1.00). The odds ratio comparing patients identified as high versus low risk by PTRA was 7.04 (95% CI, 1.64 to 30.2), P = 0.009. CONCLUSIONS:This study validates the ability of PTRA to stratify kidney transplant recipients as high or low risk for EAR using a pretransplant transcriptomic profile, with implications for graft health and personalized treatment management.

Pakistan, a resource-limited country, faces a growing number of patients with end-stage kidney disease, many of whom could benefit from living-related kidney transplantation. To expand the living donor pool, we implemented the largest ABO-incompatible kidney transplantation program in the country. The program started in February 2023, and 21 transplants have been performed to date. Pretransplant desensitization consisted of rituximab (375 mg/m²) at day (D) -30, tacrolimus, mycophenolic acid, and steroids starting at D -15, along with apheresis sessions to achieve isoagglutinin titers below 1:4 on the day of transplantation. Among the recipients, 16 were males and 5 females. Eighteen patients had been on hemodialysis for more than 6 months, and 3 underwent pre-emptive transplantation. The median recipient age was 39 years (range, 18-66). After a median follow-up of 12 months (range, 2-32), 3 patients (14.3%) had died with functioning grafts, while no graft loss occurred. The median serum creatinine at last follow-up was 1.1 mg/dL (range, 0.8-1.4). One patient experienced delayed graft function. Three patients developed acute rejection (2 cellular, 1 antibody-mediated), all successfully treated. Infectious complications occurred in ten patients (47.6%), resulting in 2 deaths. In conclusion, ABO-incompatible living donor kidney transplantation is feasible and effective in our setting, achieving excellent short-term graft outcomes. However, infectious and cardiac complications remain significant causes of morbidity and mortality.

OBJECTIVES:Chronic hypotension is uncommon among kidney transplant recipients, and may adversely affect graft outcomes. PATIENTS AND METHODS:Single-center retrospective cohort study including adult recipients who underwent living-donor kidney transplantation, between 2009 and 2024. Of the 1678 recipients screened, 187 met the inclusion criteria. Hypotension was defined as persistent systolic blood pressure (SBP) <100 mm Hg or mean arterial pressure (MAP) <70 mm Hg throughout follow-up; normotensive had SBP ranging from 100 to 130 mm Hg. Early outcomes included primary non-function (PNF), delayed-graft function (DGF), acute rejection, and thrombotic events, whereas late outcomes included graft survival, renal function, proteinuria, and chronic rejection. RESULTS:A total of 187 recipients were included (57 hypotensive and 130 normotensive). Hypotensive recipients experienced significantly higher rates of early adverse outcomes, including DGF, PNF, graft vein thrombosis, and acute cellular rejection. Late outcomes were also inferior, with higher rates of chronic rejection and graft failure, as well as poorer graft function and increased proteinuria. Kaplan-Meier analysis demonstrated significantly reduced graft survival among hypotensive recipients (P = .001). On multivariable analysis, persistent hypotension independently predicted both rejection and graft failure. CONCLUSION:Baseline hypotension is an underrecognized risk factor in kidney transplantation, associated with an increased risk of early and late graft complications.

BACKGROUND:Tacrolimus (TAC) is metabolized primarily by the CYP3A-encoded enzyme family (CYP3A4, CYP3A5, and CYP3A7). Individuals expressing the CYP3A51 allele are considered fast metabolizers and generally require higher TAC doses to reach therapeutic levels. AIM:To evaluate the predictive value of the TAC concentration-to-dose (C0/D) ratio for identifying CYP3A5 polymorphisms in renal transplant recipients. METHODS:Eighty-six de novo kidney transplant recipients with TAC-based immunosuppression from the Department of Nephrology and Dialysis at Military Hospital 103 (Hanoi, Vietnam) were included in this retrospective study. Blood samples were collected within the first week post-transplantation to monitor TAC levels and to perform genotyping for CYP3A5 genetic polymorphisms. RESULTS:The CYP3A53/3 genotype was identified in 37 patients (43%), CYP3A51/3 in 40 patients (46.5%), and CYP3A51/1 in 9 patients (10.5%). Patients carrying the CYP3A51/3 or CYP3A51/1 genotype, classified as fast metabolizers (CYP3A5 expressers), had significantly lower TAC C0 concentrations and C0/D ratios compared to slow metabolizers (CYP3A53/3 genotype) at multiple time points during follow-up (all P < 0.001). Notably, the TAC C0/D ratio obtained on day 1 (0.91) was shown to predict CYP3A5 polymorphism with a sensitivity of 84.6% and a specificity of 84.6%. CONCLUSION:This study demonstrates that the TAC C0/D ratio provides a reliable predictive value for CYP3A5 polymorphisms, which can be used to individualize TAC dosing in renal transplant recipients in Vietnam and other low-income countries.

BACKGROUND:In France, nitazoxanide is available through compassionate use authorization, as there is no summary of product characteristics for this medication. However, it has been marketed in the United States for several years, with evidence supporting its use in the treatment of chronic norovirus infections in immunocompromised individuals. Due to its limited use, data on the efficacy and safety of this drug remain sparse. CASE SUMMARY:We report the case of a 79-year-old immunocompromised patient, a renal transplant recipient undergoing treatment with mycophenolate mofetil and tacrolimus, who developed toxic agranulocytosis, as absolute neutrophil count dropped from 2.93 G/L to 0.09 G/L within 17 days following the introduction of nitazoxanide for the treatment of chronic diarrhea caused by norovirus infection. Clinical and laboratory findings suggest a toxic mechanism, most likely attributable to nitazoxanide. CONCLUSION:This case highlights the potential of nitazoxanide to induce dose-dependent toxic agranulocytosis. While this adverse effect does not necessarily contraindicate reintroduction of the drug, it underscores the necessity for close hematological monitoring in such cases.

A 35-year-old patient was diagnosed with biopsy-confirmed, steroid-and rituximab-resistant primary focal-segmental-glomerulosclerosis. While on hemodialysis, diuresis was maintained; proteinuria persisted at 9 g/g creatinine. He underwent kidney transplantation; 2-months post-transplantation, persistent proteinuria (3 g/g creatinine; albuminuria exceeding 50%) was observed. The serum creatinine level was 2.2 mg/dL. The kidney-transplant biopsy was normal. Technetium-99m-dimercaptosuccinic-acid (DMSA) renal scan revealed that native kidneys contributed to 30% of renal function. Irbesartan 150 mg/d/dapagliflozin 10 mg/d was started. Six months post-transplantation, proteinuria progressively increased to 7 to 8 g/g. We therefore decided to implement daily immunoadsorption sessions (11 sessions) followed by rituximab (1 infusion of 350 mg/m²). This allowed partial remission.

Although maintenance immunosuppression with calcineurin inhibitors (CNIs) has greatly reduced rejection rates in renal transplant recipients, long-term use can contribute to eventual nephrotoxicity, potentially leading to allograft injury and loss. Several clinical trials have shown that, compared with CNIs, belatacept-based maintenance immunosuppression can improve renal function, reduce the incidence of de novo donor-specific antibodies, and improve long-term patient/graft survival. However, the US Food and Drug Administration-approved belatacept-based regimen is also associated with higher acute rejection (AR) rates than CNI-based immunosuppression. Recent data from clinical trials and real-world studies suggest that initial posttransplant treatment with CNI-based immunosuppression followed by conversion to a belatacept-based regimen can lower the AR risk while preserving patient and renal health. This review article summarizes the available data pertaining to belatacept treatment protocols, with a focus on conversion to belatacept. Also discussed are studies of protocol modifications intended to further mitigate AR risks and belatacept-related outcomes in special populations, such as patients receiving marginal kidneys and those at risk of new-onset diabetes. Overall, the available data suggest that conversion from CNI- to belatacept-based immunosuppression ≥6 mo posttransplant appears to be effective in lowering the AR risk compared with belatacept use in the de novo setting or conversion <6 mo posttransplant. The addition of an extended transient or low-dose CNI treatment to de novo belatacept or a prolonged CNI taper in the conversion setting may also help lower the AR risk. However, additional studies will be needed to optimize the many variables applicable to belatacept treatment, particularly for different patient subgroups.

Background: Chronic kidney diseases (CKD) represent a significant public health issue worldwide, particularly in developing countries. Often with a silent onset, kidney diseases are frequently diagnosed late, necessitating hemodialysis treatment. Hence, prevention through screening remains the primary approach to addressing this issue. Objective: To screen for CKD patients hospitalized at the National Hospital of Zinder, Niger (HNZ) and scheduled for surgery. Methods: This cross-sectional study was conducted within 8 surgical departments of the National Hospital of Zinder (HNZ) in Niger over six months. The study included patients scheduled for surgery across various departments of HNZ. Results: During this period, 497 patients were screened leading to the identification of 91 cases of CKD (stage 3 and below), representing a prevalence of 18.3%. Among the children tested, 33 out of 47 (70.2%) had CKD stage 3 and above, without proteinuria. The mean age of all patients was 31 +/- 8 years, with a gender ratio of 2.6. Medical histories revealed high blood pressure (n=24;4.8%), diabetes (1 patient), urinary tract infections (n=13;2.6%), and obstructive syndrome of the lower urinary tract (n=30;7.8%). Overweight was observed in 4.8% of cases. De novo high blood pressure was identified in 98 patients (24.7%). Dipstick screening yielded positive results in 17 patients (3.4% of cases). Renal ultrasound examination was performed in 75(15.1%) patients, with hydronephrosis being the most frequent finding (n=22, i.e., 29.3% of tested patients). Regarding the absolute number of patients, among the different departments of surgery, CKD prevalence was higher in general surgery, urology, and pediatric surgery. Conclusion: Our findings demonstrate that childhood, hypertension, and urological pathologies are risk factors for CKD. Subclinical renal abnormalities can be detected through screening via urine dipstick urinalysis, biological examinations, and renal ultrasound.

Background:Kidney transplant (KT) candidates with very high calculated panel reactive alloantibody (cPRA >95%) have limited chances to receive an HLA-matched transplant unless they undergo pretransplant desensitization. Objective:To assess the efficacy of immunoadsorption (IA) in desensitizing pretransplant KT candidates with high cPRA and positive crossmatch. Materials and methods:This was a single-center retrospective cohort study involving highly HLA-sensitized patients (cPRA >85%). Forty-nine patients underwent HLA-incompatible (HLAi) KT, of whom 25 (51%) received kidneys from deceased donors. Of these 49 patients, 23 had either a positive complement-dependent cytotoxic cross-match (CDC) and/or a positive flow cytometry cross-match (FCM). The remaining 26 patients had donor-specific anti-HLA (DSAs) detectable only by Luminex (CDC and FCM cross-matches were negative). Only CDC-positive and FCM-positive patients were desensitized. These 49 patients were compared with 160 patients who had cPRA >85% but underwent HLA-compatible (HLAc) KT, i.e., without pretransplant DSAs.Pretransplant desensitization included IA sessions, rituximab, tacrolimus, steroids, and mycophenolate mofetil. Induction therapy consisted of antithymocyte globulins. Results:The mean follow-up duration was 7.4 ± 4 years. At 1-year and at last follow-up, 43 patient and death-censored graft survival rates were similar between HLAc and HLAi patients. However, HLAi patients experienced significantly more biopsy-proven rejections compared to HLAc patients. These rejections were predominantly antibody-mediated. Finally, the rate of infectious complications was similar between HLAc and HLAi patients. Conclusion:IA in addition to immunosuppression is an effective option for desensitizing HLAi patients, yielding favorable long-term outcomes.

BACKGROUND:Kidney marginality criteria consider the impact of donor characteristics on graft failure risk. To evaluate graft quality according to both the donor and recipient, we identified recipient characteristics that may modify the predictive capacity of a donor marginality score. METHODS:From the French DIVAT (Données Informatisées et VAlidées en Transplantation) cohort, we included 8299 patients who received a single deceased donor kidney graft between 2000 and 2022. From the learning sample (n = 5533), we constructed a Cox model with death or return to dialysis as the outcome. The model was both internally (n = 2766) and externally (n = 3178) validated. A recipient-relative marginality score was defined by screening the interactions between recipient characteristics and a donor-only graft marginality score. The scores' performances were compared using time-dependent receiver operating characteristic curves. RESULTS:Five donor characteristics (age, cerebrovascular death, cytomegalovirus serology, and histories of diabetes and hypertension) defined the donor marginality score. This score had a nonlinear interaction with recipient age. Thus, the level of risk related to marginal kidneys depended on recipient's age. Marginal grafts induced a higher graft failure risk for old recipients (hazard ratio [HR], 1.79 [for a 0.5-unit increase in marginality for a 70-y-old recipient]; 95% confidence interval [CI], 1.40-2.15) compared with middle-age recipients (HR, 1.47 [for a 55-y-old recipient]; 95% CI, 1.34-1.70; HR, 1.36 [for a 40-y-old recipient]; 95% CI, 1.14-1.64). The donor score provided good discrimination on the whole sample but not after stratifying by recipient age. However, the recipient-relative score retained acceptable discrimination in recipients older than 60 y. CONCLUSIONS:Our results suggest that the consideration of candidate profiles may improve graft quality assessments.

Calcineurin inhibitors (CNIs) are a cornerstone of post-transplant immunosuppressive regimens. However, their use is associated with adverse effects, most notably chronic nephrotoxicity, which remains a leading cause of long-term allograft dysfunction. Belatacept, a selective costimulation blocker, offers a promising alternative to CNIs by aiming to reduce nephrotoxicity while maintaining efficacy in preventing acute rejection. While its use in de novo transplantation has been associated with improved graft and patient survival, it has also been linked to a higher incidence of acute rejection. Early post-transplantation conversion to belatacept has demonstrated significant improvements in renal function (eGFR gains ranging from +8.8 to +38.2 mL/min/1.73 m2 at 1 year post-conversion) but carries a higher risk of opportunistic infections. Late conversion protocols, typically initiated beyond 6 months post-transplantation, have shown sustained—although less pronounced—eGFR improvements and better long-term graft survival compared to CNI-based regimens. Additionally, belatacept appears to reduce the incidence of donor-specific antibodies. Future directions for the use of belatacept need further exploration, including its role in rescuing poor renal function, its combination with low-dose CNIs, mTOR inhibitors, or tocilizumab, and its application in desensitization protocols. By potentially striking a balance between efficacy and safety, belatacept may redefine the future landscape of transplant immunosuppression.

Antibody-mediated rejection (AMR) has been recognized as a significant cause of acute and chronic lung allograft dysfunction after lung transplantation. Some treatments, eculizumab, an anti-complement (C)5 component monoclonal antibody (Mab), seem to have a promising effect in the management of some patients with AMR. We present two patients with acute AMR after lung transplantation who received the anti-C5 Mab therapy. In both cases, we identified the presence of C4d deposition in the peritubular capillaries on trans-alveolar biopsies, which suggested activation of complement in AMR. Prior to eculizumab therapy, both patients had also received immunoadsorption, courses of intravenous immunoglobulins (IVIG) and rituximab. For the first patient, we have shown that eculizumab can serve as an effective bridge to re-transplantation. For the second patient, we observed the absence of clinical and biological efficacy, and without a clear therapeutic efficacy the therapy with eculizumab had been discontinued after two months.