Antigen-Specific versus Non-Antigen-Specific Immunoadsorption in ABO-Incompatible Renal Transplantation

Introduction: ABO-incompatible (ABOi) renal transplantation (RTx) from living donors is an established procedure to expand the donor pool for patients with end stage renal disease. Immunoadsorption (IA) is a standard procedure for the removal of preformed antibodies against the allograft. In this study, antigen-specific and non-antigen-specific IA in ABOi RTx were compared. Patients and Methods: 10 patients underwent antigen-specific IA (Glycosorb group) and 13 patients non-antigen-specific IA (Immunosorba group). The effects of both procedures regarding antibody reduction, number of treatments, complications, costs, as well as the allograft function and patient survival were compared between both groups. Results: Although the IgG levels were reduced equally by both procedures (p=0.82), the reduction of the IgM level was more effective in the Glycosorb group (p=0.0172). Patients in both groups required a median number of 6 IA before ABOi RTx. Allograft function at one year after AB0i RTx was similar in both groups (estimated glomerular filtration rate: 66 vs. 64 ml/min/1.73m² respectively), with a death-censored graft survival of 90.0% and 92.3% respectively. Complication rates did not differ between procedures. Due to the reuse of non-antigen-specific Immunosorba columns, costs were considerably lower in this group; however, the use of the Immunosorba-based IA was less time-efficient. Conclusion: Considering upcoming alternatives as simultaneous performance of dialysis and IA or a possible reuse of Glycosorb columns, this might become less relevant in the future

The Tacrolimus Metabolism Rate Influences Renal Function after Kidney Transplantation

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient’s risk management strategies.</p

Does the Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? – A systematic review

BACKGROUND: Pharmacogenetic testing to individualize ACE inhibitor therapy remains controversial. We conducted a systematic review to assess the effect modification of the insertion/deletion (I/D) polymorphism of the ACE gene on any outcome in patients treated with ACE inhibitors for cardiovascular and/or renal disease. METHODS: Our systematic review involved searching six electronic databases, then contacting the investigators (and pharmaceutical industry representatives) responsible for the creation of these databases. Two reviewers independently selected relevant randomized, placebo-controlled trials and abstracted from each study details on characteristics and quality. RESULTS: Eleven studies met our inclusion criteria. Despite repeated efforts to contact authors, only four of the eleven studies provided sufficient data to quantify the effect modification by genotypes. We observed a trend towards better response to ACE inhibitors in Caucasian DD carriers compared to II carriers, in terms of blood pressure, proteinuria, glomerular filtration rate, ACE activity and progression to end-stage renal failure. Pooling of the results was inappropriate, due to heterogeneity in ethnicity, clinical domains and outcomes. CONCLUSION: Lack of sufficient genetic data from the reviewed studies precluded drawing any convincing conclusions. Better reporting of genetic data are needed to confirm our preliminary observations concerning better response to ACE inhibitors among Caucasian DD carriers as compared to II carriers

Serum osteoprotegerin is associated with pulse pressure in kidney transplant recipients

Pulse pressure (PP) reflects increased large artery stiffness, which is caused, in part, by arterial calcification in patients with chronic kidney disease. PP has been shown to predict both cardiovascular and cerebrovascular events in various patient populations, including kidney transplant (KTX) recipients. Osteoprotegerin (OPG) is a marker and regulator of arterial calcification, and it is related to cardiovascular survival in hemodialysis patients. Here we tested the hypothesis that OPG is associated with increased pulse pressure. We cross-sectionally analyzed the association between serum OPG and PP in a prevalent cohort of 969 KTX patients (mean age: 51 +/- 13 years, 57% male, 21% diabetics, mean eGFR 51 +/- 20 ml/min/1.73 m2). Independent associations were tested in a linear regression model adjusted for multiple covariables. PP was positively correlated with serum OPG (rho = 0.284, p < 0.001). Additionally, a positive correlation was seen between PP versus age (r = 0.358, p < 0.001), the Charlson Comorbidity Index (r = 0.232, p < 0.001), serum glucose (r = 0.172, p < 0.001), BMI (r = 0.133, p = 0.001) and serum cholesterol (r = 0.094, p = 0.003). PP was negatively correlated with serum Ca, albumin and eGFR. The association between PP and OPG remained significant after adjusting for multiple potentially relevant covariables (beta = 0.143, p < 0.001). We conclude that serum OPG is independently associated with pulse pressure in kidney transplant recipients

Immunological Monitoring of Renal Transplant Recipients to Predict Acute Allograft Rejection Following the Discontinuation of Tacrolimus

Contains fulltext : 69863.pdf (publisher's version ) (Open Access)BACKGROUND: Transplant patients would benefit from reduction of immunosuppression providing that graft rejection is prevented. We have evaluated a number of immunological markers in blood of patients in whom tacrolimus was withdrawn after renal transplantation. The alloreactive precursor frequency of CD4+ and CD8+ T cells, the frequency of T cell subsets and the functional capacity of CD4+CD25+FoxP3+ regulatory T cells (Treg) were analyzed before transplantation and before tacrolimus reduction. In a case-control design, the results were compared between patients with (n = 15) and without (n = 28) acute rejection after tacrolimus withdrawal. PRINCIPAL FINDINGS: Prior to tacrolimus reduction, the ratio between memory CD8+ T cells and Treg was higher in rejectors compared to non-rejectors. Rejectors also had a higher ratio between memory CD4+ T cells and Treg, and ratios <20 were only observed in non-rejectors. Between the time of transplantation and the start of tacrolimus withdrawal, an increase in naive T cell frequencies and a reciprocal decrease of effector T cell percentages was observed in rejectors. The proportion of Treg within the CD4+ T cells decreased after transplantation, but anti-donor regulatory capacity of Treg remained unaltered in rejectors and non-rejectors. CONCLUSIONS: Immunological monitoring revealed an association between acute rejection following the withdrawal of tacrolimus and 1) the ratio of memory T cells and Treg prior to the start of tacrolimus reduction, and 2) changes in the distribution of naive, effector and memory T cells over time. Combination of these two biomarkers allowed highly specific identification of patients in whom immunosuppression could be safely reduced

The neurogenic effects of exogenous neuropeptide Y: early molecular events and long-lasting effects in the hippocampus of trimethyltin-treated rats.

Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 \ub5g/2 \ub5l, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-induced neurodegeneration involves early Shh pathway activation and results in a functional integration of newly-generated neurons into the local circuit