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Immune monitoring after pediatric liver transplantation - the prospective ChilSFree cohort study.
Goldschmidt, I, Karch, A, Mikolajczyk, R, Mutschler, F, Junge, N, Pfister, ED, Möhring, T, d'Antiga, L, McKiernan, P, Kelly, D, et al
BMC gastroenterology. 2018;(1):63
Abstract
BACKGROUND Although trough levels of immunosuppressive drugs are largely used to monitor immunosuppressive therapy after solid organ transplantation, there is still no established tool that allows for a validated assessment of functional degree of immunosuppression or the identification of clinically relevant over- or under-immunosuppression, depending on graft homeostasis. Reliable non-invasive markers to predict biopsy proven acute rejection (BPAR) do not exist. Literature data suggest that longitudinal measurements of immune markers might be predictive of BPAR, but data in children are scarce. We therefore propose an observational prospective cohort study focusing on immune monitoring in children after liver transplantation. We aim to describe immune function in a cohort of children before and during the first year after liver transplantation and plan to investigate how the immune function profile is associated with clinical and laboratory findings. METHODS In an international multicenter prospective approach, children with end-stage liver disease who undergo liver transplantation are enrolled to the study and receive extensive immune monitoring before and at 1, 2, 3, 4 weeks and 3, 6, 12 months after transplantation, and whenever a clinically indicated liver biopsy is scheduled. Blood samples are analyzed for immune cell numbers and circulating levels of cytokines, chemokines and factors of angiogenesis reflecting immune cell activation. Statistical analysis will focus on the identification of trajectorial patterns of immune reactivity predictive for systemic non-inflammatory states, infectious complications or BPAR using joint modelling approaches. DISCUSSION The ChilSFree study will help to understand the immune response after pLTx in different states of infection or rejection. It may provide insight into response mechanisms eventually facilitating immune tolerance towards the graft. Our analysis may yield an applicable immune panel for non-invasive early detection of acute cellular rejection, with the prospect of individually tailoring immunosuppressive therapy. The international collaborative set-up of this study allows for an appropriate sample size which is otherwise difficult to achieve in the field of pediatric liver transplantation.
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Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation.
Ettenger, R, Chin, H, Kesler, K, Bridges, N, Grimm, P, Reed, EF, Sarwal, M, Sibley, R, Tsai, E, Warshaw, B, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017;(6):1549-1562
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Abstract
The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (-2.1) (p = 0.028) and BMI (-1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.
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Con: Nutritional vitamin D replacement in chronic kidney disease and end-stage renal disease.
Agarwal, R, Georgianos, PI
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2016;(5):706-13
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Insufficiency of 25-hydroxyvitamin D [25(OH)D] is highly prevalent among patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) and is a critical component in the pathogenesis of secondary hyperparathyroidism. Accordingly, current National Kidney Foundation-Kidney Disease Outcomes Quality Initiative and Kidney Disease: Improving Global Outcomes guidelines recommend the correction of hypovitaminosis D through nutritional vitamin D replacement as a first-step therapeutic approach targeting secondary hyperparathyroidism. In this Polar Views debate, we summarize the existing evidence, aiming to defend the position that nutritional vitamin D replacement is not evidence-based and should not be applied to patients with CKD. This position is supported by the following: (i) our meta-analysis of randomized controlled trials shows that whereas nutritional vitamin D significantly increases serum 25(OH)D levels relative to placebo, there is no evidence either in predialysis CKD or in ESRD that parathyroid hormone (PTH) is lowered; (ii) on the other hand, in randomized head-to-head comparisons, nutritional vitamin D is shown to be inferior to activated vitamin D analogs in reducing PTH levels; (iii) nutritional vitamin D is reported to exert minimal to no beneficial actions in a series of surrogate risk factors, including aortic stiffness, left ventricular mass index (LVMI), epoetin utilization and immune function among others; and (iv) there is no evidence to support a benefit of nutritional vitamin D on survival and other 'hard' clinical outcomes. Whereas nutritional vitamin D replacement may restore 25(OH)D concentration to near normal, the real target of treating vitamin D insufficiency is to treat secondary hyperparathyroidism, which is untouched by nutritional vitamin D. Furthermore, the pleotropic benefits of nutritional vitamin D remain to be proven. Thus, there is little, if any, benefit of nutritional vitamin D replacement in CKD.
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Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.
Dugast, E, Soulillou, JP, Foucher, Y, Papuchon, E, Guerif, P, Paul, C, Riochet, D, Chesneau, M, Cesbron, A, Renaudin, K, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016;(11):3255-3261
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Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.
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Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis.
Moustafa, M, Aronoff, GR, Chandran, C, Hartzel, JS, Smugar, SS, Galphin, CM, Mailloux, LU, Brown, E, Dinubile, MJ, Kartsonis, NA, et al
Clinical and vaccine immunology : CVI. 2012;(9):1509-16
Abstract
Bacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses against Staphylococcus aureus in patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conserved S. aureus surface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 μg V710 (with or without adjuvant), 90 μg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a ≥2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a ≥2.5 GMFR in anti-IsdB antibodies compared to the baseline (P values of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis.
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Update on vitamin D and its newer analogues: actions and rationale for treatment in chronic renal failure.
Malluche, HH, Mawad, H, Koszewski, NJ
Kidney international. 2002;(2):367-74
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Vitamin D is an important hormone for mineral homeostasis and the proper formation and maintenance of bone. In addition, vitamin D has broader functions in the body that expand its traditionally known role in mineral balance. In chronic renal failure, calcitriol deficiency contributes to the development and progression of secondary hyperparathyroidism, bone disorders, and altered mineral metabolism. Recent revelations of the broader role of vitamin D also suggest calcitriol deficiency may contribute to decreased cardiac and immune function in chronic renal failure patients. Research on vitamin D has led to a more complete understanding of the actions of vitamin D at the transcriptional level and with respect to the clinical use of vitamin D and its analogs to control parathyroid hormone overactivity and to replace the other D hormone-dependent actions in patients with renal failure. Limitations of vitamin D and its metabolites include hypercalcemia, hyperphosphatemia and suppression of bone turnover with the risk of adynamic bone disease. Vitamin D analogs may offer greater selectivity and potentially greater safety as compared to calcitriol because of their altered relative potency on calcium and phosphorus metabolism. This review focuses on the current understanding of the biological actions of vitamin D and its analogs and the rationale for treating patients with chronic renal failure.
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Effect of vitamin E-bonded membrane on the 8-hydroxy 2'-deoxyguanosine level in leukocyte DNA of hemodialysis patients.
Tarng, DC, Huang, TP, Liu, TY, Chen, HW, Sung, YJ, Wei, YH
Kidney international. 2000;(2):790-9
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Abstract
BACKGROUND 8-Hydroxy 2'-deoxyguanosine (8-OHdG) of leukocyte DNA has been identified as a surrogate marker of oxidative stress in chronic hemodialysis (HD) patients. In this study, we focused on the determinants of the 8-OHdG level in leukocyte DNA of HD patients. We further investigated the influence of vitamin E-modified, regenerated cellulose (CL-E) membrane on the oxidative DNA damage, intracellular reactive oxygen species (ROS) production of granulocytes, and plasma alpha-tocopherol concentration. METHODS 8-OHdG content in cellular DNA of leukocytes was measured by a high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method. Intracellular production of ROS, H2O2 and O2-. were analyzed by flow cytometry in leukocytes with and without phorbol-12-myristate-13-acetate (PMA) stimulation before dialysis, as well as at 15 and 30 minutes of dialysis. Plasma alpha-tocopherol concentration was measured by a HPLC method, and the value of alpha-tocopherol was corrected by total blood lipid concentration. RESULTS In the prospective cross sectional study, the mean 8-OHdG level in leukocyte DNA was equally lower in the patients of the CL-E, polymethylmethacrylate (PMMA), and polysulfone (PS) groups as compared with the cellulosic group (ANOVA, P < 0.001). The leukocyte 8-OHdG level correlated negatively with plasma alpha-tocopherol and blood lipid-adjusted plasma alpha-tocopherol, but correlated positively with serum iron and percentage of transferrin saturation. Forward stepwise multiple regression showed that dialysis membrane type, serum iron, and blood lipid-adjusted plasma alpha-tocopherol were the independent determinants of the leukocyte 8-OHdG level in HD patients. Like synthetic membranes, granulocyte ROS production was less augmented during dialysis with the CL-E membrane as compared with the cellulose membrane. Exposure to cellulose membrane impaired intracellular ROS production of granulocytes in response to PMA challenge, whereas the CL-E and synthetic membranes improved the granulocyte responsiveness to PMA. In the longitudinal cross-over study, the 8-OHdG level significantly decreased, and blood lipid-adjusted plasma alpha-tocopherol increased after switching the cellulose membrane to CL-E or synthetic membrane for eight weeks. In contrast, the 8-OHdG level dramatically rose, and blood lipid-adjusted plasma alpha-tocopherol declined after shift of CL-E or synthetic membrane to the cellulose membrane. CONCLUSIONS CL-E membrane exhibited biocompatible and bioactive characteristics. Like synthetic membranes, treatment with a CL-E dialyzer effectively reduced the 8-OHdG content in leukocyte DNA, suppressed intracellular ROS production of granulocytes, and preserved the plasma level of vitamin E. It could further improve granulocyte responsiveness to a PMA challenge. Reduced DNA damage and improved immune function of leukocytes may reduce the cancer and infection risks in chronic HD patients.