Nuria Montero

Online haemodiafiltration improves inflammatory state in dialysis patients: A longitudinal study

Background Patients undergoing conventional hemodialysis (C-HD) present a greater immuno-inflammatory state probably related to uremia, sympathetic nervous system (SNS) activation and /or membrane bioincompatibility, which could improve with a technique-switching to online hemodiafiltration (OL-HD). The antigen-independent pathway activation of this modified immunologic state turns dendritic cells (DC) into an accurate cell model to study these patients. The aim of this study is to further evaluate the immune-inflammatory state of patients in C-HD assessed by DC maturation. Methods 31 patients were submitted to C-HD and after 4 months switched to the OL-HD technique. Monocytes-derived DCs from HD patients were cultured in the presence of IL-4/GM-CSF. DC-maturation was evaluated by assessing the maturation phenotype by flow cytometry (FACs). DCs-functional capacity to elicit T-cell alloresponse was studied by mixed leucocyte reaction. Cytokine release was assessed by FACs and SNS was evaluated measuring renalase levels by ELISA. Results An up-regulation of maturation markers was observed in C-HD DCs which induced two fold more T cells proliferation than OL-HD DCs. Also, C-HD-mDCs presented with over-production of pro-inflammatory cytokines (IL-6, IL-1β, IL-8, IL-10 and TNF-α) compared with OL-HD-mDC (P<0·05). Results were correlated with clinical data. When SNS was evaluated, hypotension events and blood pressure were significantly lower and renalase levels were significantly higher after conversion to OL-HD. Diabetes mellitus type 2 patients also found beneficial reduction of mDC when converted to OL-HD compared to non-diabetics. Conclusions OL-HD could interfere with immuno-inflammatory state in HD patients with an improvement of renalase levels as potential key mediators in the mechanistic pathway of down-regulation of DC maturation.

Combining sensitive cross-match assays with donor/recipient HLA Eplet matching predicts Living-donor Kidney Transplant outcome

Introduction Despite the different assays available for immune-risk stratification before living-donor kidney transplantation (LDKT), the precise type and number of tests to perform remain uncertain. Methods In a cohort of 330 consecutive LDKT patients, all of which were complement-dependent cytotoxicity (CDC)−crossmatch negative, we retrospectively analyzed the impact on main clinical outcomes of most sensitive immunoassays (complement-dependent cytotoxicity−panel-reactive antibody [CDC-PRA], flow cytometry crossmatch [FC-XM], donor-specific antibodies [DSAs], and their complement-binding capacity DSA-C3d]), together with donor/recipient HLA eplet matching. Mean follow-up was 67 months (range 24−190 months). Results Of 330 patients, 35 (11%) showed a CDC-PRA >20%; 17 (5%) FC-XM+; 30 (9%) DSA+, 18(5%) DSA-C3d+, with low overlapping results (10 patients positive in all donor-specific tests). Unlike HLA allele compatibility, the mean number of HLA class II eplet mismatches was higher in LDKT patients with positive baseline test results. DSA-C3d+ showed higher mean fluorescence intensity (MFI) DSA, with a cut-off MFI of 6192 accurately predicting complement fixation (area under the curve = 0.85, P = 0.008). Although all assays were associated with acute rejection (AR), only DSA-C3d+ (odds ratio [OR] = 6.64, P = 0.038) or high MFI-DSA (OR = 7.54, P = 0.038) independently predicted AR. Likewise, poorly HLA class II eplet−matched patients were at higher risk for AR, particularly patients with negative baseline test results (OR = 1.14, P = 0.019). Finally, previous AR and FC-XM+/DSA+, regardless of C3d positivity, independently predicted graft loss. Conclusion Combining FC-XM and solid-phase assays with the evaluation of donor/recipient HLA eplet mismatches, are most accurate tools for immune-risk stratification prior LDKT.

Impact of immunosuppressive therapy on arterial stiffness in kidney transplantation: are all treatments the same?

ABSTRACT Arterial stiffness is a biologic process related to ageing and its relationship with cardiovascular risk is well established. Several methods are currently available for non-invasive measurement of arterial stiffness that provide valuable information to further assess patients’ vascular status in real time. In kidney transplantation recipients, several factors could accelerate the stiffness process, such as the use of calcineurin inhibitors (CNIs), the presence of chronic kidney disease and other classical cardiovascular factors, which would explain, at least in part, the high cardiovascular mortality and morbidity. Despite the importance of arterial stiffness as a biomarker of cardiovascular risk, and unlike other cardiovascular risk factors (e.g. left ventricular hypertrophy), only a few clinical trials or retrospective studies of kidney recipients have evaluated its impact. In this review we describe the clinical impact of arterial stiffness as a prognostic marker of cardiovascular disease and the effects of different immunosuppressive regimens on its progression, focusing on the potential benefits of CNI-sparing protocols and supporting the rationale for individualization of immunosuppression in patients with lower arterial elasticity. Among the immunosuppressive drugs, a belatacept-based regimen seems to offer better vascular protection compared with CNIs, although further studies are needed to confirm the preliminary positive results.

Value of monitoring circulating donor-reactive memory B cells to characterize antibody-mediated rejection after kidney transplantation

Antibody‐mediated rejection (ABMR) is defined by specific histopathological lesions and evidence of circulating donor‐specific antibodies (DSA). Although DSA are not always detectable, monitoring donor‐reactive memory B cells (mBC) could identify patients at risk of developing ABMR. Peripheral donor‐reactive mBC using a novel HLA B cell ELISpot assay, serum DSA, and numbers of different B cell subsets were assessed in 175 consecutive kidney transplants undergoing either for‐cause or 6‐ and 24‐month surveillance biopsies for their association with main histological lesions of ABMR and impact on allograft outcome. In 85 incident for‐cause biopsies, high frequencies of donor‐reactive mBC were detected in all 16 (100%) acute ABMR/DSA+ and most chronic ABMR, with or without DSA (24/30[80%] and 21/29[72.4%], respectively). In a longitudinal cohort of 90 nonsensitized patients, a progressively higher expansion of donor‐reactive mBC than de novo DSA was observed at 6 and 24 months (8.8% vs 7.7% and 15.5% vs 11.1%, respectively) and accurately identified patients with ongoing subclinical ABMR (area under the curve = 0.917 and area under the curve = 0.809, respectively). An unsupervised hierarchical cluster analysis revealed a strong association between donor‐reactive mBC with main fundamental allograft lesions associated with ABMR and conferred a significant deleterious impact on graft outcome. Monitoring donor‐reactive mBC may be useful to further characterize humoral rejection after kidney transplantation.