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In this review, we describe the multidisciplinary, multidimensional care required to optimize outcomes for pediatric transplant recipients with rare genetic kidney diseases. Transplant success, recipient survival, and improvement in quality of life depend on collaboration between patients, families, and a team of specialists with medical, as well as nonmedical expertise. A multidisciplinary transplant team composed of experts from medicine, surgery, nursing, nutrition, social services, transplant coordination, psychology, and pharmacology, is now standard in most transplant centers and is critical to the success of a transplant. In addition to these professionals, other specialists, such as cardiologists, urologists, geneticists, metabolic disease specialists, occupational therapists, case management, child life, chaplain, and palliative care services, have a crucial role to play in the preparation, surgery, and follow-up care, especially when a pediatric patient has a rare genetic disorder leading to renal involvement, and the need for transplantation. In order to describe this multidisciplinary care, we divide the genetic renal diseases into five subgroups-metabolic and tubular disorders, glomerular diseases, congenital anomalies of the kidney and urinary tract, ciliopathies including cystic diseases, and miscellaneous renal conditions; and describe for each, the need for care beyond that provided by the standard transplant team members., (© 2023 Wiley Periodicals LLC.)

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD). Arginine, the endogenous precursor for nitric oxide synthesis, is produced in the kidneys. Arginine bioavailability contributes to endothelial and myocardial dysfunction in CKD. Plasma from 129X1/SvJ mice with and without CKD (5/6th nephrectomy), and banked plasma from children with and without CKD were analyzed for amino acids involved in arginine metabolism, ADMA, and arginase activity. Echocardiographic measures of myocardial function were compared with plasma analytes. In a separate experiment, a non-specific arginase inhibitor was administered to mice with and without CKD. Plasma citrulline and glutamine concentrations correlated with multiple measures of myocardial dysfunction. Plasma arginase activity was significantly increased in CKD mice at 16 weeks vs. 8 weeks ( p = 0.002) and ventricular strain improved after arginase inhibition in mice with CKD ( p = 0.03). In children on dialysis, arginase activity was significantly increased vs. healthy controls ( p = 0.04). Increasing ADMA correlated with increasing RWT in children with CKD (r = 0.54; p = 0.003). In a mouse model, and children, with CKD, arginine dysregulation correlates with myocardial dysfunction.

Transplantation is the only curative treatment for patients with kidney failure but it poses unique immunological challenges that must be overcome to prevent allograft rejection and ensure long-term graft survival. Alloreactive T cells are important contributors to graft rejection, and a clearer understanding of the mechanisms by which these cells recognize donor antigens - through direct, indirect or semi-direct pathways - will facilitate their therapeutic targeting. Post-T cell priming rejection responses can also be modified by targeting pathways that regulate T cell trafficking, survival cytokines or innate immune activation. Moreover, the quantity and quality of donor-reactive memory T cells crucially shape alloimmune responses. Of note, many fundamental concepts in transplant immunology have been derived from models of infection. However, the programmed differentiation of allograft-specific T cell responses is probably distinct from that of pathogen-elicited responses, owing to the dearth of pathogen-derived innate immune activation in the transplantation setting. Understanding the fundamental (and potentially unique) immunological pathways that lead to allograft rejection is therefore a prerequisite for the rational development of therapeutics that promote transplantation tolerance., (© 2022. Springer Nature Limited.)

Background and Objectives: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients., Methods: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions., Results: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits., Conclusions: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Renal vascular thrombosis (RVT) is a major cause of early allograft loss in the first year following pediatric kidney transplantation. We examined recent trends in allograft loss due to RVT and identified associated risk factors., Methods: We identified 14,640 kidney-only transplants performed between 1995 and 2014 with follow-up until June 30, 2016, in 13,758 pediatric patients aged < 19 years from the US Renal Data System. We examined the 1-year incidence of allograft loss due to RVT by year of transplant, and plotted the trend over time. Cox proportional hazards models were used to investigate the relationship between year of transplant as well as recipient, donor, and transplant characteristics with allograft loss due to RVT., Results: The incidence of allograft loss due to RVT consistently declined among pediatric kidney transplant performed between 1995 and 2014. Among transplants performed between 1995 and 2004, 128/7542 (1.7%) allografts were lost due to RVT compared to 53/7098 (0.8%) among transplants performed between 2005 and 2014; average 1-year cumulative incidence was 1.5% (95% CI, 1.3-1.9%) and 0.6% (95% CI, 0.5-0.8%), respectively. Increased risk for allograft loss due to RVT was associated with en bloc kidney transplantation (HR, 3.42; 95% CI 1.38-8.43) and cold ischemia time ≥ 12 h (HR, 1.78; 95% CI, 1.15-2.76). Interestingly, these risk factors were more prevalent in the latter decade., Conclusions: The incidence of allograft loss due to RVT significantly and continuously declined among pediatric kidney transplants performed between 1995 and 2014. The causes for this improvement are unclear in the present analysis.

Background: Uremic cardiomyopathy, characterized by left ventricular hypertrophy, diastolic dysfunction, and impaired myocardial strain, contributes to increased cardiovascular mortality in patients with CKD. Emerging evidence suggests a pathogenic role for T cells during chronic heart failure., Methods: To determine whether T cells contribute to uremic cardiomyopathy pathogenesis, we modeled this condition by inducing CKD via 5/6th nephrectomy in mice. We used flow cytometry to assess expression of markers of T cell memory or activation by lymphocytes from CKD mice and controls, as well as lymphocyte capacity for cytokine production. Flow cytometry was also used to quantify immune cells isolated from heart tissue. To test effects of T cell depletion on cardiac function, we gave CKD mice anti-CD3 antibody injections to deplete T cells and compared heart function (assessed by echocardiography) with that of controls. Finally, we correlated T cell phenotypes with structural and functional measures on clinically acquired echocardiograms in children with CKD., Results: Mice with CKD accumulated T cells bearing markers of memory differentiation (CD44 hi ) and activation (PD-1, KLRG1, OX40), as reported previously in human CKD. In addition, mice with CKD showed T cells infiltrating the heart. T cell depletion significantly improved both diastolic function and myocardial strain in CKD mice without altering hypertension or degree of renal dysfunction. In children with CKD, increasing frequency of T cells bearing activation markers PD-1 and/or CD57 was associated with worsening diastolic function on echocardiogram., Conclusions: CKD results in an accumulation of proinflammatory T cells that appears to contribute to myocardial dysfunction., (Copyright © 2019 by the American Society of Nephrology.)

Introduction: There are limited data to guide optimal treatment strategies for acute cellular rejection (ACR) based on Banff grade for pediatric kidney transplant recipients. This report reviews a large pediatric transplant center's experience with ACR., Materials and Methods: A retrospective analysis of pediatric kidney transplant recipients at our center from 2007 to 2014 was performed. Primary outcomes were incidence of graft failure and graft function one year following ACR based on Banff grade and treatment received., Results: A total of 204 patients were reviewed, of which 65 received rejection treatment with either an oral steroid cycle (n = 16), intravenous steroid pulse (n = 28), or anti-thymocyte globulin (rATG, n = 21). Overall, patients received rATG for treatment of more severe rejection associated with impaired graft function and as a group experienced statistically significant improvements in eGFR over the year following treatment, though most did not regain baseline graft function., Discussion: Our data suggest that rATG is partially effective in treating ACR, but our study was underpowered to determine the effect of different treatments based on Banff grade. Since there is limited literature to guide clinical treatment of ACR in children, large transplant centers should collaborate to evaluate outcomes and establish evidence-based practice., (© 2018 Wiley Periodicals, Inc.)

Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD) in children and confers improved survival, skeletal growth, heath-related quality of life, and neuropsychological development compared with dialysis. Kidney transplantation in children with ESRD results in 10-year patient survival exceeding 90%. Therefore, the long-term management of these patients is focused on maintaining quality of life and minimizing long-term side effects of immunosuppression. Optimal management of pediatric kidney transplant recipients includes preventing rejection and infection, identifying and reducing the cardiovascular and metabolic effects of long-term immunosuppressive therapy, supporting normal growth and development, and managing a smooth transition into adulthood., (Copyright © 2018 Elsevier Inc. All rights reserved.)

While most human T cells express the CD28 costimulatory molecule constitutively, it is well known that age, inflammation, and viral infection can drive the generation of CD28 null T cells. In vitro studies have demonstrated that CD28 null cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28 null cells may precipitate costimulation blockade-resistant rejection. However, CD28 + cells possess more proliferative and multifunctional capacity, factors that may increase their ability to successfully mediate rejection. Here, we performed a retrospective immunophenotypic analysis of adult renal transplant recipients who experienced acute rejection on belatacept treatment as compared to those who did not. Intriguingly, our findings suggest that patients possessing higher frequency of CD28 + CD4 + T EM prior to transplant were more likely to experience acute rejection following treatment with a belatacept-based immunosuppressive regimen. Mechanistically, CD28 + CD4 + T EM contained significantly more IL-2 producers. In contrast, CD28 null CD4 + T EM isolated from stable belatacept-treated patients exhibited higher expression of the 2B4 coinhibitory molecule as compared to those isolated from patients who rejected. These data raise the possibility that pretransplant frequencies of CD28 + CD4 + T EM could be used as a biomarker to predict risk of rejection following treatment with belatacept., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

There is an increasing need to understand long-term metabolic changes and resultant comorbidities because life expectancy is increasing after pediatric kidney and liver transplants. We evaluated differences in classic and novel cardiometabolic biomarkers among obese and normal weight adolescent transplant recipients. We enrolled a total of 80 adolescent (mean±SD, 14.8 years ±3.0) transplant recipients (63 kidney, 17 liver) with mean duration from transplantation of 6.0 (±4.1) years. Among kidney transplant recipients, overweight and obese individuals had higher leptin (16.7 vs 7.5 μg/mL, P<.001), lower HDL (1.1 vs 1.3 mmol/L, P=.02), higher free fatty acid (0.6 vs 0.5 mmol/L, P=.03), higher apoB-to-apoA1 ratio (0.8 vs 0.6, P=.03), and higher glucose (5.8 vs 4.3 mmol/L, P=.03) concentrations compared to normal weight individuals. Regardless of obesity status, over half of all participants (57.5%) were considered at high cardiometabolic risk using consensus guidelines, and this was more pronounced for kidney transplant recipients (61.9%). Post-transplantation adolescents have increased cardiometabolic risk characterized by traditional risk factors of obesity and diabetes. The presence of obesity significantly worsens biomarkers of cardiometabolic risk. Future studies should explore whether treatment of obesity can improve the health and long-term outcomes for children undergoing solid organ transplant., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: Altered differentiation and activation of T-cell subsets occur in patients with chronic kidney disease (CKD), but the impact on graft rejection and protective immunity during transplantation are not fully understood., Recent Findings: Patients with CKD have decreased frequency of naïve T cells, accumulation of activated, terminally differentiated memory cells, and skewed regulatory versus T helper 17 ratio. Naïve and memory T-cell subsets do not appear to improve following kidney transplantation. Retained thymic output is associated with acute rejection, whereas naïve lymphopenia and accumulation of CD8 TEMRA cells correlate with long-term graft dysfunction. CD28 memory cells accumulate during CKD and appear to confer protection against acute rejection under standard immunosuppression and possibly costimulation blockade. T cells bearing CD57 are also increased in patients with CKD and may underlie rejection during costimulation blockade., Summary: The mechanisms by which CKD alters the differentiation and activation status of T-cell subsets is poorly understood. Further research is also needed to understand which cell populations mediate rejection under various immunosuppressive regimens. To date, there is little use of animal models of organ failure in transplant immunology research. CKD mouse models may help identify novel pathways and targets to better control alloimmunity in posttransplant.

Uremic cardiomyopathy is responsible for high morbidity and mortality rates among patients with chronic kidney disease (CKD), but the underlying mechanisms contributing to this complex phenotype are incompletely understood. Myocardial deformation analyses (ventricular strain) of patients with mild CKD have recently been reported to predict adverse clinical outcome. We aimed to determine if early myocardial dysfunction in a mouse model of CKD could be detected using ventricular strain analyses. CKD was induced in 5-week-old male 129X1/SvJ mice through partial nephrectomy (5/6Nx) with age-matched mice undergoing bilateral sham surgeries serving as controls. Serial transthoracic echocardiography was performed over 16 weeks following induction of CKD. Invasive hemodynamic measurements were performed at 8 weeks. Gene expression and histology was performed on hearts at 8 and 16 weeks. CKD mice developed decreased longitudinal strain (-25 ± 4.2% vs. -29 ± 2.3%; P = 0.01) and diastolic dysfunction (E/A ratio 1.2 ± 0.15 vs. 1.9 ± 0.18; P < 0.001) compared to controls as early as 2 weeks following 5/6Nx. In contrast, ventricular hypertrophy was not apparent until 4 weeks. Hearts from CKD mice developed progressive fibrosis at 8 and 16 weeks with gene signatures suggestive of evolving heart failure with elevated expression of natriuretic peptides. Uremic cardiomyopathy in this model is characterized by early myocardial dysfunction which preceded observable changes in ventricular geometry. The model ultimately resulted in myocardial fibrosis and increased expression of natriuretic peptides suggestive of progressive heart failure., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of α-subtypes of type I interferons (IFNαs). We found that genetic knockout of the common type I IFN receptor (IFNARI-/-) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNβ and IFNαs: IFNβ expression peaks at 4 h, earlier than IFNαs, and continues at the same level at 24 h; expression of IFNαs also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNαs relative to baseline is much greater than that of IFNβ. We show by immunohistology and study of isolated cells that IFNβ is produced by renal leukocytes and IFNαs are produced by renal tubules. IRF1, IFNαs, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNα expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNαs. Furthermore, we found that IFNα stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNα > IFNARI > CXCL2.

There has been enormous progress in the understanding of acute kidney injury (AKI) over the past 5 years. This article reviews some of the salient new findings, the challenges revealed by these findings and new insights into the pathogenesis of ischemic AKI. Clinical studies have demonstrated that even a small, transient rise in serum creatinine increases the risk of mortality in hospitalized patients and that a single event of AKI increases the risk for developing chronic kidney disease. Although the overall mortality rate from AKI has improved over the past 2 decades, it continues to be significant. Current treatment is focused on maintaining renal perfusion and avoiding volume overload. However, new therapeutic targets are emerging for the treatment of AKI as our understanding of the pathogenesis of ischemic injury and inflammation increases. Early diagnosis, however, continues to be challenging as the search continues for sensitive and specific biomarkers.

Ischemic acute kidney injury (AKI) contributes to considerable morbidity and mortality in hospitalized patients and can contribute to rejection during kidney transplantation. Maladaptive immune responses can exacerbate injury, and targeting these responses holds promise as therapy for AKI. In the last decade, a number of molecules and receptors were identified in the innate immune response to ischemia-reperfusion injury. This review primarily focuses on one pathway that leads to maladaptive inflammation: toll-like receptor 4 (TLR4) and one of its ligands, high mobility group box protein 1 (HMGB1). The temporal-spatial roles and potential therapeutics targeting this particular receptor-ligand interaction are also explored.

Although leukocytes infiltrate the kidney during ischemic acute kidney injury (AKI) and release interleukin 6 (IL6), their mechanism of activation is unknown. Here, we tested whether Toll-like receptor 4 (TLR4) on leukocytes mediated this activation by interacting with high-mobility group protein B1 (HMGB1) released by renal cells as a consequence of ischemic kidney injury. We constructed radiation-induced bone marrow chimeras using C3H/HeJ and C57BL/10ScNJ strains of TLR4 (-/-) mice and their respective TLR4 (+/+) wild-type counterparts and studied them at 4 h after an ischemic insult. Leukocytes adopted from TLR4 (+/+) mice infiltrated the kidneys of TLR4 (-/-) mice, and TLR4 (-/-) leukocytes infiltrated the kidneys of TLR4 (+/+) mice but caused little functional renal impairment in each case. Maximal ischemic AKI required both radiosensitive leukocytes and radioresistant renal parenchymal and endothelial cells from TLR4 (+/+) mice. Only TLR4 (+/+) leukocytes produced IL6 in vivo and in response to HMGB1 in vitro. Thus, following infiltration of the injured kidney, leukocytes produce IL6 when their TLR4 receptors interact with HMGB1 released by injured renal cells. This underscores the importance of TLR4 in the pathogenesis of ischemic AKI.

Ischemic acute kidney injury (AKI) triggers an inflammatory response which exacerbates injury that requires increased expression of endothelial adhesion molecules. To study this further, we used in situ hybridization, immunohistology, and isolated endothelial cells, and found increased Toll-like receptor 4 (TLR4) expression on endothelial cells of the vasa rectae of the inner stripe of the outer medulla of the kidney 4 h after reperfusion. This increase was probably due to reactive oxygen species, known to be generated early during ischemic AKI, because the addition of hydrogen peroxide increased TLR4 expression in MS1 microvascular endothelial cells in vitro. Endothelial TLR4 may regulate adhesion molecule (CD54 and CD62E) expression as they were increased on endothelia of wild-type but not TLR4 knockout mice in vivo. Further, the addition of high-mobility group protein B1, a TLR4 ligand released by injured cells, increased adhesion molecule expression on endothelia isolated from wild-type but not TLR4 knockout mice. TLR4 was localized to proximal tubules in the cortex and outer medulla after 24 h of reperfusion. Thus, at least two different cell types express TLR4, each of which contributes to renal injury by temporally different mechanisms during ischemic AKI.