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Bakkaloğlu Introduction Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are associated with significant alterations in immune function On the one hand, CKD is associated with a state of chronic inflammation, which in turn has been associated with increased muscle catabolism, vascular calcification, insulin resistance, and malnutrition [1] However, patients with CKD and ESKD also have immunodeficiency, as manifested by an increased risk for infection and sepsis and impaired response to vaccinations [1] Infection is a leading reported cause of death in children with ESKD [2, 3] Peritoneal dialysis (PD) continues to be plagued with the infectious complication of peritonitis, and hemodialysis (HD) is complicated by the development of catheter- related bacteremia Excluding transplantation, infection is reported to be the most common reason for dialysis modality termination in children [2] The treatment and the prevention of infections are therefore important A N Chua Department of Pediatrics, Duke Children’s Hospital, Durham, NC, USA S A Bakkaloğlu (*) Department of Pediatric Nephrology, Gazi University School of Medicine, Ankara, Turkey e-mail: sevcan@gazi.edu.tr elements in the care of pediatric dialysis patients, both for reduction of mortality and morbidity, and in the setting of PD, for preservation of the peritoneal membrane function This chapter will provide a brief review of currently available information regarding the immune dysfunction associated with CKD and ESKD. In addition, because delivery of routine childhood and supplemental vaccinations remains a cornerstone of infection prevention, data regarding response to immunizations in children with CKD and alterations to the routine immunization schedule for healthy children required for children with CKD will be presented Immune Dysfunction Information regarding immune function in children with CKD or ESKD is sparse The incidence of peritonitis and catheter-related infections in children is higher than that found in adults, and infants and children up to 6 years of age develop peritonitis more frequently than older children Immaturity of the immune system also contributes to the immune system dysfunction in children with CKD and ESKD. Therefore, the results obtained from adults cannot be directly extrapolated to children A complete review of innate and acquired immunity in CKD is beyond the scope of this chapter; however, the following provides a brief overview of this complex topic © Springer Nature Switzerland AG 2021 B A Warady et al (eds.), Pediatric Dialysis, https://doi.org/10.1007/978-3-030-66861-7_33 633 634 hite Blood Cell Differentiation W and Function Lymphopenia has been noted in adult dialysis patients; however, the percentages of B-cells, T-cells, and T-cell subsets are usually normal [4–11] Several studies evaluating lymphocyte number and the percentages of B-cells, T-cells, T-cell subsets, and NK cells in the peripheral blood of children with CKD or ESKD have produced conflicting results [12–18] Children with pre-dialytic CKD have been reported to have alterations in memory T-cell subsets, and reduced numbers of memory B-cells have been reported in children on dialysis [19, 20] Possible explanations for the reduced numbers of memory B-cells are a general suppression, suboptimal T helper activity, or disturbances in the B-cell migration process caused by uremia or dialysis treatment Irrespective of the mechanism of memory B-cell reduction, the consequence might be a lower capacity to mount a secondary immune response, resulting in a decreased response to vaccination and predisposition to increased infection rates [20, 21] In addition to alterations in the number or percentage of T-cells, abnormalities of T-cell- mediated immune responses have been demonstrated in CKD [7, 22–25] T-cells from dialysis-treated patients show a combination of reduced proliferation and signs of activation [26– 28] The abnormal T-cell proliferation of uremic patients might be due to a defect within the T-cell population itself, to circulating inhibiting factors in uremic serum, or to the function of accessory cells such as monocytes [25, 29–39] In children, data on this subject are scarce and conflicting Two studies could not establish a difference in lymphocyte proliferation between children with CKD, dialyzed or not, and healthy children [12, 13] George et al performed an analysis of T-cell populations in children with CKD and demonstrated significant skewing toward advanced differentiation phenotypes in both the CD8 and CD4 subsets, which may represent features of advanced immune exhaustion and senescence [40] Various alterations in cytokine production, particularly IFN-γ (gamma), have been reported A N Chua and S A Bakkaloğlu in children with CKD, with one study demonstrating normalization of these abnormalities with HD [17, 41, 42] Phagocytic Cells and Receptors Reduced chemotaxis, adhesion, migration, and phagocytosis characterize the dysfunction of neutrophils and monocytes demonstrated in patients on dialysis [27, 43–46] Data on the characteristics and function of phagocytes in children with CKD are limited [47, 48] Interestingly, one study demonstrated that treatment with recombinant human growth hormone enhanced the oxidative burst activity of neutrophils in uremic children [47] Wasik and colleagues concluded that PD improves phagocytosis and intracellular killing of bacteria by peritoneal macrophages but not by peripheral blood neutrophils in ESKD patients [48] In another study of pediatric patients with ESKD, marked dysregulation in inflammatory cell chemokine receptor expression and responsiveness was noted and was more pronounced in the subgroup of patients who had multiple serious bacterial infections in the preceding year [49] Limited information is available on the impact of CKD on IgG receptor (Fcγ(gamma)R) and complement receptor (CR) expression or function [50–54] These receptors are important components in the interaction between humoral and cellular immunity and facilitate the phagocytic process Some authors described an increased CD16 (Fcγ(gamma)RIII)-positive monocyte population in adult PD and HD patients when compared to healthy controls, a phenotype that has been linked to tissue macrophages in the context of the state of maturation [50, 51] In children with pre-dialytic CKD and ESKD, studies have demonstrated a lower expression of Fcγ(gamma)RII (CD32) on peripheral blood monocytes and neutrophils compared to healthy children [41, 55–58] Furthermore, reduced CR type (CR1) expression, which is important for inducing phagocytosis of complement-coated bacteria, on lymphocytes and increased expression of Fcγ(gamma)R and CR on peritoneal 33 Immune Function and Immunizations in Dialyzed Children acrophages and neutrophils have been shown in m pediatric CKD patients [41, 55–58] Immunoglobulins Low levels of IgG and/or subclasses have been described in patients on PD, attributed to peritoneal loss in most of the studies [59–70] However, two studies in children reported that the immunoglobulin deficiency was already present before dialysis started, which suggests inhibition of synthesis by the uremic state [63, 64] In one study, a deficiency of one or more IgG subclasses was present in 40% of children with CKD, with IgG2 being the major subclass affected [64] Children receiving PD had the lowest serum Ig levels [64] The role of serum IgG or subclass deficiency in the pathogenesis of PD-associated peritonitis is unclear Studies in adults could not establish a relationship between the peritonitis incidence and IgG or subclass deficiency [65, 70] In children, a study by Kuizon et al found a significant relationship between IgG and the incidence of peritonitis [71] In another study, although not all children with IgG deficiency had a high incidence of peritonitis, all of the children with a high number of peritonitis episodes were in the IgG-deficient group [64] On the contrary, a study by Lalan et al found that while hypogammaglobulinemia is a frequent complication of peritoneal dialysis during infancy, it was not associated with an increased risk of peritonitis, and some infants developed peritonitis even after therapeutic IVIG administration [72] In summary, numerous abnormalities in immune function have been described in CKD; however, these deficiencies are not consistently seen in pediatric patients In addition, although the uremic state is likely a major contributor to this immune dysfunction, it seems plausible that a variety of uremic toxins may impact the individual components of the immune reaction in disparate ways For the dialysis patient, it follows that a dialysis prescription measured only in terms of small solute clearance cannot be expected to optimize all of the factors that influence immune function In addition, the impact of 635 the dialysis procedure itself on immune function and activation must be considered Thus, specific CKD-related treatment strategies to improve immune function, beyond the obvious goals of optimizing nutrition and correcting mineral bone disorder, metabolic imbalance, and anemia, remain elusive It bears mentioning that despite data demonstrating low IgG levels in children receiving PD, there are no data at this time to support the routine use of intravenous immunoglobulin infusions for peritonitis treatment or prevention One treatment strategy that is available specifically to minimize risk for infection in pediatric dialysis patients is the timely delivery of routine and supplemental immunizations, and the remainder of the chapter focuses on this topic Immunizations Children with CKD and dialysis may have reduced response to and/or reduced duration of antibody after immunization and therefore may be at increased risk for infection from vaccine- preventable diseases In order to minimize this risk, they require all the recommended childhood immunizations according to the standard schedule and additional vaccines and booster doses [73–77] The completion of the vaccination schedule before renal transplantation (RTx) is of particular importance Due to the complexity of clinical care of these children, immunizations can be delayed, overlooked, or not properly recorded In fact, in a recent retrospective case series, only 22 out of 254 dialysis patients (9%) presented complete vaccination coverage prior to RTx In particular, vaccination coverage against hepatitis B and MMR was more reasonable compared to varicella and pneumococci (89%, 83%, 59%, and 42%, respectively) [78] The United States Renal Data System (USRDS) 2013 report revealed that among prevalent pediatric dialysis patients, approximately 40% received seasonal influenza vaccine between 2008 and 2011, and only 16% received vaccination against Streptococcus pneumoniae [79] Although immunization recommendations for dialysis patients slightly vary among countries ... of innate and acquired immunity in CKD is beyond the scope of this chapter; however, the following provides a brief overview of this complex topic © Springer Nature Switzerland AG 2021 B A Warady... defect within the T-cell population itself, to circulating inhibiting factors in uremic serum, or to the function of accessory cells such as monocytes [25, 29–39] In children, data on this subject... mortality and morbidity, and in the setting of PD, for preservation of the peritoneal membrane function This chapter will provide a brief review of currently available information regarding the immune