Six‐year outcomes in broadly HLA‐sensitized living donor transplant recipients desensitized with intravenous immunoglobulin and rituximab

Desensitization with intravenous immunoglobulin (IVIG) and rituximab can improve transplantation rates in broadly sensitized kidney transplant recipients. However, long‐term outcomes are lacking. Here we analyze long‐term outcomes in living donor kidney transplant recipients desensitized with this regimen and compare them to low‐risk recipients. Living donor kidney transplants that took place between July 2006 and December 2010 were considered retrospectively. The primary end point of the study was death‐censored allograft survival at last follow‐up. Secondary end points included patient survival, incidence of rejection, glomerular filtration rate (GFR), and proteinuria. There were 66 sensitized and 111 low‐risk patients included. Average follow‐up was 68 months. There was no difference in long‐term patient or graft survival. The rate of rejection was similar in the groups with more early rejection in the sensitized group and more late rejection in the low‐risk group. There was more antibody‐mediated rejection in the sensitized group. Estimated GFR was similar during the follow‐up period. Risk factors for rejection included a positive cross‐match (HR: 2.4 CI: 1.35–4.40) and age (HR: 0.97 CI: 0.95–0.99). Desensitization with IVIG and rituximab has good long‐term results with graft outcomes similar to non‐HLA‐sensitized patients despite higher immunologic risk.     

Impact of de novo donor‐specific HLA antibodies detected by Luminex solid‐phase assay after transplantation in a group of 88 consecutive living‐donor renal transplantations

De novo donor‐specific HLA antibodies (DSA) after renal transplantation are known to be correlated with poor graft outcome and the development of acute and chronic rejection. Currently, data for the influence of de novo DSA in patient cohorts including only living‐donor renal transplantations (LDRT) are limited. A consecutive cohort of 88 LDRT was tested for the occurrence of de novo DSA by utilizing the highly sensitive Luminex solid‐phase assay for antibody detection. Data were analyzed for risk factors for de novo DSA development and correlated with acute rejection (AR) and graft function. Patients with de novo DSA [31 (35%)] showed a trend for inferior graft function [mean creatinine change (mg/dL/year) after the first year: 0.15 DSA (+) vs. 0.02 DSA (?) (P = 0.10)] and a higher rate of AR episodes, especially in case of de novo DSA of both class I and II [6 (55%), (P = 0.05)]. Antibody‐mediated rejection (AMR) appeared in five patients and was significantly correlated with de novo DSA (P = 0.05). Monitoring for de novo DSA after LDRT may help to identify patients at risk of declining renal function. Especially patients with simultaneous presence of de novo DSA class I and class II are at a high risk to suffer AR episodes.     

The use of NGAL and IP‐10 in the prediction of early acute rejection in highly sensitized patients following HLA‐incompatible renal transplantation

Acute rejection is a significant problem for patients undergoing HLA‐incompatible renal transplantation, affecting between 12 and 53% of patients. Any mechanism of detecting rejection in advance of current methods would offer significant benefit. This study aimed to evaluate whether serum biomarkers could predict rejection in HLAi transplants recipients. Sera from 94 HLAi transplant recipients from a single centre were analysed for a panel of biomarkers including: NGAL, KIM‐1, IP‐10, cystatin C, cathepsin L and VEGF. Biomarker levels pre‐operatively, day 1 and at day 30 post‐transplant were correlated with the development of early rejection. Significantly higher levels of IP‐10 and NGAL were seen on day 1 following transplant in those patients who developed acute rejection (P < 0.001 and 0.005) and generated AUC of 0.73 and 0.67, respectively. No differences were seen for the other biomarkers or at the other time points. In this study cohort, IP‐10 and NGAL have demonstrated good predictive ability for the development of acute rejection at a very early time point. They may have a role in identifying patients at higher risk for rejection and stratifying immunosuppression or surveillance.     

Increased gene expression of TGF‐β in peripheral blood mononuclear cells from renal transplant patients with polyomavirus BK viremia

We aimed to investigate the roles of cytokines during polyomavirus BK (BKV) reactivation in renal transplant patients. Forty‐eight renal allograft recipients were enrolled, and their sera BKV viral load and mRNA expression levels of cytokines in peripheral blood mononuclear cells were measured by real‐time polymerase chain reaction. Patient's age and gene expression levels of interleukin (IL)‐2 (10.04 ± 2.63 vs. 8.70 ± 2.40, p = 0.049) and transforming growth factor (TGF)‐β (12.58 ± 2.59 vs. 10.89 ± 1.91, p = 0.015) were significantly higher in BKV viremia (+) renal transplant patients. Multivariate logistic regression analysis revealed that age and mRNA expression levels of TGF‐β, but not IL‐2, significantly correlated with the presence of BKV viremia. Sera BKV viral loads showed a positive correlation with patient age and the levels of TGF‐β and IL‐6 mRNA. After adjusting for age and sex in the regression model, both age and TGF‐β mRNA levels maintained a significant positive association with sera BKV viral loads. Serum TGF‐β concentration tended to be higher in BKV viremia (+) patients (p = 0.079). In conclusion, expression levels of TGF‐β were found to correlate with both BKV viremia positivity and sera BKV viral loads in renal transplant patients.     

Role of BK virus infection in end‐stage renal disease patients waiting for kidney transplantation – viral replication dynamics from pre‐ to post‐transplant

We report the prevalence of BK virus (BKV) infection before renal transplantation and the dynamics of BKV viremia from pre‐ to post‐transplantation. We assessed 60 kidney transplanted patients from a single cohort in Italy, treated with identical immunosuppressive therapy, for BK viremia at pre‐transplantation, 12 h, and three and six months post‐transplantation. Polymerase chain reaction showed that the prevalence of plasma BKV replication – considered a marker of infection – was 20% in pre‐transplant patients. All pre‐transplant‐positive patients remained positive post‐transplant, whereas the majority of pre‐transplant‐negative patients remained negative. Viremia dynamics classification revealed three clusters of patients: Cluster A++, pre‐transplant‐positive patients (20%) who tested positive at least once post‐transplant; Cluster B?+, pre‐transplant‐negative patients (28%) who tested positive at least once post‐transplant; and Cluster C– –, pre‐transplant‐negative patients (52%) who remained negative throughout. These clusters presented significant differences related to the prevalence of substantially positive patients with high plasma viral load (>10³ copies/mL) in cluster A, but not in donors’ or grafts’ characteristics. We suggest that pre‐transplant viral status should be considered as an additional risk factor for post‐transplant BKV replication. Therefore, pre‐transplant BKV infection screening in kidney transplant patients should be performed for improving planning of personalized immunosuppressant schemes and specific post‐transplant surveillance.     

Interleukin‐1β induces angiogenesis and innervation in human intervertebral disc degeneration

Degenerative disorders of the intervertebral discs (IVDs) are generally characterized by enhanced matrix degradation, angiogenesis, innervation, and increased expression of catabolic cytokines. In this study, we investigated the effects of inflammatory cytokines, IL‐1β, and TNF‐α, on the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and neurotrophic factors, nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF), in human IVD degeneration. IL‐1β and TNF‐α stimulated the gene expression of VEGF, NGF, and BDNF in nucleus pulposus (NP) cells isolated from patient tissues. Immunohistochemical results demonstrated a positive correlation between IL‐1β and VEGF/NGF/BDNF expression in human IVD tissues. RNA expression analysis of patient tissues also identified positive correlations between VEGF and platelet endothelial cell adhesion molecule‐1 (PECAM‐1) and between NGF/BDNF and protein gene product 9.5 (PGP9.5). Our findings suggest that IL‐1β is generated during IVD degeneration, which stimulates the expression of VEGF, NGF, and BDNF, resulting in angiogenesis and innervation. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:265–269, 2011