Pediatric kidney transplantation.
Roach Jonathan P,Bock Margret E,Goebel Jens
Seminars in pediatric surgery
Since first performed in 1954, kidney transplantation has evolved as the preferred long-term treatment of children with end stage renal disease (ESRD). The etiology of chronic kidney disease (CKD) and ESRD in children is broad and can be quite complicated, necessitating a multidisciplinary team to adequately care for these patients and their myriad needs. Precise surgical techniques and modern protocols for immunosuppression provide excellent long-term patient and graft survival. This article reviews the many etiologies of renal failure in the pediatric population focusing on those most commonly leading to the need for kidney transplantation. The processes of evaluation, kidney transplantation, short-term and long-term complications, as well as long-term outcomes are also reviewed.
Xenotransplantation of the kidney: a pediatric perspective.
Platt J L
Pediatric nephrology (Berlin, Germany)
The major factor limiting the application of allotransplantation for the treatment of renal failure is a severe shortage of donor organs. One approach to overcoming this limitation is the use of kidneys from animals for clinical transplantation, that is xenotransplantation. Although of interest for many years, the application of xenotransplantation has been prevented because of the devastating immune responses of the recipient against the graft. Research conducted in recent years has elucidated the immune mechanisms underlying the rejection of xenografts and has led to the development of incisive therapeutic strategies, including the genetic engineering of donor animals. Success in dealing with the xenogeneic immune response has encouraged the view that xenotransplantation might be feasible in the near future. It also raises consideration of two additional hurdles, the potential limitations of xenogeneic kidneys as physiological replacement for human kidneys and the possibility that the animal organ might transfer infectious organisms to the recipient and to the wider population. This paper reviews recent progress in the field of xenotransplantation of the kidney and offers a perspective on the hurdles to clinical application that remain.
Anti-IL-2 receptor antibody vs. polyclonal anti-lymphocyte antibody as induction therapy in pediatric transplantation.
Di Filippo Sylvie
Current concerns in pediatric transplantation focus on chronic rejection which commonly leads to graft loss, and on long-term maintenance immunosuppression toxicity. Acute rejection has been associated with the subsequent development of chronic rejection. Therefore, induction therapy may provide potential benefits by preventing early acute rejection episodes and allowing delayed administration of calcineurin inhibitors or steroid avoidance. This review of the literature showed that induction therapy can reduce early and recurrent acute rejection episodes after pediatric solid organ transplantation. Whether this might result in better long-term graft survival has still to be confirmed. However, induction therapy has beneficial effects in high-risk recipients and allows steroid avoidance or calcineurin inhibitor minimization. Because they are very well tolerated, anti-IL-2 receptor antibodies are increasingly preferred to rabbit-antithymocyte globulin, but the former have not yet been proven to be more effective or to have less late toxicity than polyclonal agents. Benefits in early outcome and no increase in adverse events lead to recommend the use of IL-2 receptor antagonists as induction therapy after pediatric organ transplantation.
Liver transplantation. The pediatric challenge.
McDiarmid S V
Clinics in liver disease
Successful liver transplantation in a child is often a hard-won victory, requiring all the combined expertise of a dedicated pediatric transplant team. This article outlines the considerable challenges still facing pediatric liver transplant physicians and surgeons. In looking to the future, where should priorities lie to enhance the success already achieved? First, solutions to the donor shortage must be sought aggressively by increasing the use of from split-liver transplants, judicious application of living-donor programs, and increasing the donation rate, perhaps by innovative means. The major immunologic barriers, to successful xenotransplantation make it unlikely that this option will be tenable in the near future. Second, current immunosuppression is nonspecific, toxic, and unable to be individually adjusted to the patient's immune response. The goal of achieving donor-specific tolerance will require new consideration of induction protocols. Developing a clinically applicable method to measure the recipient's immunoreactivity is of paramount importance, for future studies of new immunosuppressive strategies and to address the immediate concern of long-term over-immunosuppression. The inclusion of pediatric patients in new protocols will require the ongoing insistence of pediatric transplant investigators. Third, the current immunosuppressive drugs have a long-term morbidity and mortality of their own. These long-term effects are particularly important in children who may well have decades of exposure to these therapies. There is now some understanding of their long-term renal toxicity and the risk of malignancy. New drugs may obviate renal toxicity, whereas the risk of malignancy is inherent in any nonspecific immunosuppressive regimen. Although progress is being made in preventing and recognizing PTLD, this entity remains an important ongoing concern. The global effect of long-term immunosuppression on the child's growth, development, and intellectual potential is unknown. Of particular concern is the potential for neurotoxicity from the calcineurin inhibitors. Fourth, recurrent disease and new diseases, perhaps potentiated by immunosuppressive drugs, must be considered. Already the recurrence of autoimmune disease and cryptogenic cirrhosis have been documented in pediatric patients. Now, a new lesion, a nonspecific hepatitis, sometimes with positive autoimmune markers, that may progress to cirrhosis has been recognized. It is not known whether this entity is an unusual form of rejection, an unrecognized viral infection, or a response to immunosuppressive drugs themselves. Finally, pediatric transplant recipients, like any other children, must be protected and nourished physically and mentally if they are to fulfill their potential. After liver transplantation the child's growth, intellectual functioning, and psychologic adaptation may all require special attention from parents, teachers, and physicians alike. There is limited understanding of how the enormous physical intervention of a liver transplantation affects a child's cognitive and psychologic function as the child progresses through life. The persons caring for these children have the difficult responsibility of providing services to evaluate these essential measures of children's health over the long term and to intervene if necessary. Part of the transplant physician's our duty to protect and advocate for children is to fight for equal access to health care. In most of the developing world, economic pressures make it impossible to consider liver transplantation a health care priority. In the United States and in other countries with the medical infrastructure to support liver transplantation, however, health care professionals must strive to be sure that the policies governing candidacy for transplantation and allocation of organs are applied justly and uniformly to all children whose lives are threatened by liver disease. In the current regulatory climate that increasingly takes medical decisions out of the hands of physicians, pediatricians must be even more prepared to protect the unique and often complicated needs of children both before and after transplantation. Only in this way can the challenges of the present and the future be met.
Anti-interleukin-2 receptor antibodies for the prevention of rejection in pediatric renal transplant patients: current status.
The anti-interleukin-2 receptor (anti-IL-2R) antibody therapy is an exciting approach to the prevention of acute rejection after renal allograft transplantation whereby immunosuppression is exerted by a selective and competitive inhibition of IL-2-induced T cell proliferation, a critical pathway of allorecognition. The anti-IL-2R antibodies specifically block the alpha-subunit of the IL-2R on activated T cells, and prevent T cell proliferation and activation of the effector arms of the immune system. The anti-IL-2R antibodies are used as induction therapy, immediately after renal transplantation, for prevention of acute cellular rejection in children and adults. During acute rejection, the IL-2Ralpha chain is no longer expressed on T cells; thus, the antibodies cannot be used to treat an existing acute rejection. Two anti-IL-2R monoclonal antibodies are currently in clinical use: daclizumab and basiliximab. In placebo-controlled phase III clinical trials in adults, daclizumab and basiliximab in combination with calcineurin inhibitor-based immunosuppression, significantly reduced the incidence of acute rejection and corticosteroid-resistant acute rejection without increasing the risk of infectious or malignant complications, and neither antibody was associated with the cytokine-release syndrome. Children who receive calcineurin inhibitors and corticosteroids for maintenance immunosuppression, as well as children who receive augmented immunosuppression to treat acute rejection, are at increased risk of growth impairment, hypertension, hyperlipidemia, lymphoproliferative disorders, diabetes mellitus, and cosmetic changes. In older children, the cosmetic adverse effects frequently reduce compliance with the treatment, and subsequently increase the risk of allograft loss. Being effective and well tolerated in children, the anti-IL-2R antibodies reduce the need for calcineurin inhibitors while maintaining the overall efficacy of the regimen; thus, the anti-IL-2R antibodies increase the safety margin (less toxicity, fewer adverse effects) of the baseline immunosuppression. Secondly, the anti-IL-2R antibodies decrease the need for corticosteroids and muromonab CD3 (OKT3) in children as a result of decreased incidence of acute rejection. The recommended pediatric dose of daclizumab is 1 mg/kg intravenously every 14 days for five doses, with the first dose administered within 24 hours pre-transplantation. This administration regimen maintains daclizumab levels necessary to completely saturate the IL-2Ralpha (5-10 microg/mL) in children for at least 12 weeks.The recommended pediatric dose of basiliximab for recipients <35 kg is 10 mg, and 20 mg for recipients > or =35 kg, intravenously on days 0 and 4 post-transplantation. This administration regimen maintains basiliximab levels necessary to completely saturate the IL-2Ralpha (>0.2 microg/mL) in children for at least 3 weeks.
Immunization guidelines for pediatric renal disease.
Fivush B A,Neu A M
Seminars in nephrology
It is imperative that pediatric nephrologists monitor the immunization status of pediatric chronic renal insufficiency, dialysis and transplantation patients closely to reduce the risk of vaccine-preventable disease. Pediatric patients with chronic renal insufficiency and those on dialysis should receive all the standard immunizations according to the schedule as deliniated by the Red Book. In addition to these standard vaccines, these patients will also benefit from influenza and pneumococcal vaccine. Pediatric renal transplant recipients should also be immunized with standard and special vaccines; however, all live viral vaccines should be avoided in this population. Because patients with renal disease may not respond optimally to all immunizations, it is important to study antibody response to MMR and varicella in patients before transplantation. If these patients are unprotected, they should be immunized before transplantation. It seems that pediatric dialysis and transplantation patients may not respond optimally to hepatitis B vaccine. Therefore, if at all possible, this vaccine should be administered before these therapies. Doubling the recommended dose of hepatitis B vaccine may improve response. Antibody levels to hepatitis B should be monitored every other year, and this vaccine should be readministered when the antibody level decreases to less than 10 mIU/mL. Hopefully the morbidity and mortality associated with vaccine-preventable disease can be reduced in this population by ensuring that pediatric patients with chronic renal disease are adequately immunized.
Transplantation tolerance. A complex scenario awaiting clinical applicability.
Sayegh Mohamed H,Perico Norberto,Remuzzi Giuseppe
Contributions to nephrology
Organ transplantation is now firmly established as the therapy of choice for end-stage organ failure. Specific immunological tolerance of transplant recipients towards their foreign organ or tissue grafts is a goal that has been sought by transplant biologists for almost 50 years following the original description of the phenomenon in experimental animals by Medawar and colleagues. Since that time, a wealth of experimental data has accumulated relating to strategies for extending allograft survival and function. Recent studies have shed new light on the molecular and cellular basis of transplant rejection and have better defined the mechanisms of allograft tolerance with particular emphasis on a role for regulatory T cells. Still, the question remains of how near we are to the day when long-term tolerance of engrafted organs or tissues will be a clinical reality. Recently, clinical trials to explore pilot tolerance protocols in humans have been initiated under the auspices of the Immune Tolerance Network (www.immunetolerance.org). In this review we will highlight the promise and challenges of making transplantation tolerance a clinical reality.
Role of the PD-1 pathway in the immune response.
Riella L V,Paterson A M,Sharpe A H,Chandraker A
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Understanding immunoregulatory mechanisms is essential for the development of novel interventions to improve long-term allograft survival. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, have emerged as critical inhibitory signaling pathways that regulate T cell response and maintain peripheral tolerance. PD-1 signaling inhibits alloreactive T cell activation, and can promote induced regulatory T cell development. Furthermore, the upregulation of PD-L1 on nonhematopoietic cells of the allograft may actively participate in the inhibition of immune responses and provide tissue-specific protection. In murine transplant models, this pathway has been shown to be critical for the induction and maintenance of graft tolerance. In this review, we discuss the current knowledge of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential in transplantation.
The evolving role of mTOR inhibition in transplantation tolerance.
McMahon Gearoid,Weir Matthew R,Li Xian C,Mandelbrot Didier A
Journal of the American Society of Nephrology : JASN
The mammalian target of rapamycin (mTOR) plays a key role in the immune response. mTOR inhibitors suppress T cell activation and proliferation and are effective immunosuppressants. Today there is growing interest in their potential role in inducing tolerance after transplantation. mTOR inhibitors induce anergy in naïve T cells, promote the expansion of regulatory T cells, and inhibit the maturation of dendritic cells, thus promoting immunologic tolerance. Here we review the mechanisms by which mTOR inhibitors promote tolerance. We discuss the clinical relevance of these mechanisms and suggest how they might be used in the design of future protocols to induce tolerance.
Tolerance: is it achievable in pediatric solid organ transplantation?
Seyfert-Margolis Vicki,Feng Sandy
Pediatric clinics of North America
In the clinical arena of transplantation, tolerance remains, for the most part, a concept rather than a reality. Although modern immunosuppression regimens have effectively handled acute rejection, nearly all organs except the liver commonly suffer chronic immunologic damage that impairs organ function, threatening patient and allograft survival. In addition to the imperfect control of the donor-directed immune response, there are additional costs. First, there is the burden of mortality from infection and malignancy that can be directly attributed to a crippled immune system. Second, there are insidious effects on renal function, cardiovascular profile (hypertension, hyperglycemia, and dyslipidemia), bone health, growth, psychological and neurocognitive development, and overall quality of life. It is likely that the full consequences of lifelong immunosuppression on our pediatric transplant recipients will not be fully appreciated until survival routinely extends beyond 1 or 2 decades after transplantation. Therefore, it can be argued that the holy grail of transplantation tolerance is of the utmost importance to children who undergo solid organ transplantation.
Clinical Relevance of HLA Antibodies in Kidney Transplantation: Recent Data from the Heidelberg Transplant Center and the Collaborative Transplant Study.
Süsal Caner,Fichtner Alexander,Tönshoff Burkhard,Mehrabi Arianeb,Zeier Martin,Morath Christian
Journal of immunology research
Herein, we summarize our recent findings from the international Collaborative Transplant Study (CTS) and Heidelberg Transplant Center regarding the role of HLA antibodies in kidney transplantation and their application into the clinical routine. Based on the antibody findings from the CTS serum study, an algorithm was developed in 2006 for the transplantation of high-risk sensitized patients at the Heidelberg Transplant Center which includes seven different pre- and posttransplant measures. Using this algorithm, the number of transplantations could be increased in high-risk presensitized patients and the previously existing impact of antibodies on graft survival could greatly be diminished but not totally eliminated. More recent findings led to the hypothesis that T cell help from a preactivated immune system supports the harmful effects of pretransplant donor-specific HLA antibodies that otherwise disappear in many cases after transplantation without any consequence.
The immunological monitoring of kidney and liver transplants in adult and pediatric recipients.
Truong Dinh Quang,Bourdeaux Christophe,Wieërs Grégoire,Saussoy Pascale,Latinne Dominique,Reding Raymond
Over the last half century, kidney and liver transplantation have been recognized as the treatment of choice for adult and children with end-stage renal or liver failure. Infants present a relative naïve immune system, but they are capable of mounting both cellular and humoral immune responses to the foreign antigens presented by the allograft. Immune monitoring is a way of measuring functional and molecular correlates of immune reactivity which may provide clinically useful information for identifying patients who have an increase risk of acute rejection prior to clinical symptoms or develop transplant tolerance. However, although numerous assays have been shown to predict rejection, to date no assays have been demonstrated to detect or predict transplantation tolerance. This is a summary of the published literature on promising antigen-specific and non-antigen-specific assays used for immunological monitoring in solid organ transplantation. This work also attempts to review their applicability to pediatric transplantation, specifically, pediatric kidney and liver recipients.
Development and function of Foxp3(+) regulatory T cells.
Wang Yuan Min,Ghali Joanna,Zhang Geoff Yu,Hu Min,Wang Ya,Sawyer Andrew,Zhou Jimmy Jianheng,Hapudeniya Dhanushka A,Wang Yiping,Cao Qi,Zheng Guoping,Harris David C,Alexander Stephen I
Nephrology (Carlton, Vic.)
Regulatory T cells (Tregs) have been recognized as having a major role in maintaining peripheral tolerance and preventing and limiting autoimmune and chronic inflammatory diseases. Tregs derive from the thymus and also develop peripherally. In this review, we discuss recent progress in our understanding of the basic mechanisms involved in Treg development and function in protecting against autoimmunity in the periphery, including thymic selection, peripheral induction and the many mechanisms of Treg suppression. Specifically in kidney disease, Tregs have been shown to play a role in limiting injury and may potentially have a therapeutic role.
Cellular alloresponses for rejection-risk assessment after pediatric transplantation.
Sindhi Rakesh,Ashokkumar Chethan,Higgs Brandon W
Current opinion in organ transplantation
PURPOSE OF REVIEW:Current immune monitoring practices detect antidonor antibodies and antibody-mediated rejection, and are less suited for the detection of acute cellular rejection (ACR), the predominant form of rejection after transplantation. We review the use of mixed lymphocyte coculture-based assays that measure cellular alloresponses, for measurement of the risk of ACR after liver, intestine, and kidney transplantation. RECENT FINDINGS:Flow cytometry enables the rapid measurement of cellular alloresponses using dilution of the intravital dye carboxyfluorescein succinimidyl ester within 72 h or of intracellular CD154 in alloantigen-specific T-cells or B-cells within 16 h. Assay output is personalized by expressing donor-induced alloresponse as a fraction of the third-party alloresponse for each patient. The resulting parameter called the immunoreactivity index indicates increased risk of rejection if donor-response exceeds third-party response. The rejection-risk threshold immunoreactivity index predicts or associates with ACR of liver, kidney, or intestine allografts with sensitivity and specificity of 75% or more. Lifelong assessment is facilitated by using 'surrogate' donor stimulators from normal human individuals in lieu of actual donor cells, without compromising rejection-risk assessment. SUMMARY:Cellular alloresponses can measure the risk of ACR accurately in the clinic, so that immunosuppression may be managed safely and more effectively in individual patients.
Paediatric renal transplantation--current perspectives.
Yap H K
The Journal of the Singapore Paediatric Society
Chronic dialysis is a viable modality for treatment of end-stage renal disease in children, however, its limitation include negative effects on growth, progressive bone disease, and a poorer quality of life. Renal transplantation, on the other hand, allows the child a virtually normal life-style, with good prospects for employment and family life as an adult. Both patient and graft survival are significantly improved in children transplanted in centres with full paediatric facilities where special problems in young children are better addressed, such as that of fluid balance during the perioperative period, the age-related heightened immune responsiveness, and the different pharmacokinetic and pharmacodynamic handling of the various immunosuppressive agents in the child. Moreover, consideration of the problems of growth and developmental is crucial for maximal psychosocial rehabilitation of the paediatric transplant recipient.
Pediatric kidney transplantation: kids are different.
Iranian journal of kidney diseases
The pediatric kidney transplant recipient differs from the adult recipient in many ways, including immune responsiveness, drug metabolism and clearance, perfusion of transplanted organs, and risk for posttransplant lymphoproliferative disease. Pediatric patients also have special quality of life issues such as cosmetic side effects of medications, stunted growth and sexual maturation, and separation from their peers. Congenital urological anomalies and glomerulosclerosis are the most common causes of pediatric end-stage renal disease. In the pediatric patients, consideration for preemptive transplantation should be first and arteriovenous fistula placement second. Pediatric patients should receive priority for kidneys from deceased donors to shorten the wait time for transplant. Fevers or changes in blood pressure may identify allograft dysfunction weeks before changes in creatinine occur. Thus, monitoring serum creatinine level is a poor indicator of allograft dysfunction in this setting. There is great concern about nonadherence to immunosuppressive therapy as children reach the stage of adolescence. This report highlights these and other important differences in the evaluation and management of the pediatric kidney transplant recipients compared with the adult and provides practical guidance to the practitioners involved in caring for such patients.
Biomarkers to detect rejection after kidney transplantation.
Dharnidharka Vikas R,Malone Andrew
Pediatric nephrology (Berlin, Germany)
Detecting acute rejection in kidney transplantation has been traditionally done using histological analysis of invasive allograft biopsies, but this method carries a risk and is not perfect. Transplant professionals have been working to develop more accurate or less invasive biomarkers that can predict acute rejection or subsequent worse allograft survival. These biomarkers can use tissue, blood or urine as a source. They can comprise individual molecules or panels, singly or in combination, across different components or pathways of the immune system. This review highlights the most recent evidence for biomarker efficacy, especially from multicenter trials.
The effect of chronic kidney disease on T cell alloimmunity.
Winterberg Pamela D,Ford Mandy L
Current opinion in organ transplantation
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.
Pediatric renal transplantation.
International journal of organ transplantation medicine
Although the number of children with end-stage renal disease (ESRD) in need for renal transplantation is small compared with adults, the problem associated with renal transplant in children are numerous, varied, and often peculiar. Pre-emptive transplantation has recently been growing in popularity as it avoids many of the associated long-term complications of ESRD and dialysis. Changes in immunosuppression to more potent agents over the years will have affected transplant outcome; there is also evidence that tacrolimus is more effective than cyclosporine. This review will discuss the short- and long-term complications such as acute and chronic rejection, hypertension, infections, and malignancies as well as factors related to long-term graft function. Chronic allograft nephropathy is the leading cause of renal allograft loss in pediatric renal transplant recipients. It is likely that it reflects a combination of both immune and nonimmune injury occurring cumulatively over time so that the ultimate solution will rely on several approaches. Transplant and patient survival have shown a steady increase over the years. The major causes of death after transplantation are cardiovascular disease, infection and malignancy. Transplantation in special circumstances such as children with abnormal urinary tracts and children with diseases that have the potential to recur after transplantation will also be discussed in this review. Non-compliance with therapeutic regimen is a difficult problem to deal with and affects patients and families at all ages, but particularly so at adolescence. Growth may be severely impaired in children with ESRD which may result in major consequences on quality of life and self-esteem; a better height attainment at transplantation is recognized as one of the most important factors in final height achievement. Although pediatric kidney transplantation is active in some parts of many developing countries, it is still inactive in many others and mostly relying on living donors. The lacking deceased programs in most of these countries is one of the main issues to be addressed to adequately respond to organ shortage. In conclusion, transplantation is currently the best option for children with ESRD. Although improvement in immunosuppression demonstrated excellent results and has led to greater 1-year graft survival rates, chronic graft loss remains relatively unchanged and opportunistic infectious complications remain a problem.
Challenges in pediatric renal transplantation.
Peruzzi Licia,Amore Alessandro,Coppo Rosanna
World journal of transplantation
Transplantation in children is the best option to treat renal failure. Over the last 25 years the improvements in therapy have dramatically reduced the risk of early acute rejection and graft loss, however the long term results in terms of graft survival and morbidity still require search for new immunosuppressive regimens. Tolerance of the graft and minimization of side effects are the challenges for improving the outcome of children with a grafted kidney. Notwithstanding the difficulties in settling in children large multicenter trials to derive statistically useful data, many important contributions in the last years brought important modifications in the immunosuppressive therapy, including minimization protocols of steroids and calcineurin inhibitors and new induction drugs. New methods for diagnosis of anti HLA antibodies and some new protocols to improve both chance and outcome of transplantation in immunized subjects represent area of ongoing research of extreme interest for children.
Antibody-mediated rejection in pediatric kidney transplantation: pathophysiology, diagnosis, and management.
Ng Yolanda W,Singh Manpreet,Sarwal Minnie M
Kidney transplant is the preferred treatment of pediatric end-stage renal disease. One of the most challenging aspects of pediatric kidney transplant is the prevention and treatment of antibody-mediated rejection (ABMR), which is one of the main causes of graft dysfunction and early graft loss. Most challenges are similar to those faced in adult kidney transplants; however, factors unique to the pediatric realm include naivety of the immune system and the small number of studies and randomized controlled trials available when considering pharmacological treatment options. Here, we present a case of ABMR in a pediatric patient and a review of the pathophysiology, diagnosis, and management of ABMR. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because (1) there still remain many unidentified potential antigens leading to ABMR, (2) children and adults are at different stages of their immune system development, and, thus, (3) the full pathophysiology of alloimmunity is still not completely understood, and (4) the efficacy and safety of treatment in adults may not be directly translated to children. As we continue to gain a better understanding towards the precise alloimmune mechanism that drives a particular ABMR, we can also improve pharmacotherapeutic choices. With continued research, they will become more precise in treating a particular mechanism versus using a broad scope of immunosuppression such as steroids. However, there is much more to be uncovered, such as identifying more non-human leukocyte antigens and their role in alloimmunity, determining the exact mechanism of adults achieving complete operational tolerance, and understanding the difference between pediatric and adult transplant recipients. Making strides towards a better understanding of these mechanisms will lead to continued efficacy and safety in treatment of pediatric ABMR.
Regulatory T cells in kidney disease and transplantation.
Hu Min,Wang Yuan Min,Wang Yiping,Zhang Geoff Y,Zheng Guoping,Yi Shounan,O'Connell Philip J,Harris David C H,Alexander Stephen I
Regulatory T cells (Tregs) have been shown to be important in maintaining immune homeostasis and preventing autoimmune disease, including autoimmune kidney disease. It is also likely that they play a role in limiting kidney transplant rejection and potentially in promoting transplant tolerance. Although other subsets of Tregs exist, the most potent and well-defined Tregs are the Foxp3 expressing CD4(+) Tregs derived from the thymus or generated peripherally. These CD4(+)Foxp3(+) Tregs limit autoimmune renal disease in animal models, especially chronic kidney disease, and kidney transplantation. Furthermore, other subsets of Tregs, including CD8 Tregs, may play a role in immunosuppression in kidney disease. The development and protective mechanisms of Tregs in kidney disease and kidney transplantation involve multiple mechanisms of suppression. Here we review the development and function of CD4(+)Foxp3(+) Tregs. We discuss the specific application of Tregs as a therapeutic strategy to prevent kidney disease and to limit kidney transplant rejection and detail clinical trials in this area of transplantation.
Biologics in renal transplantation.
Pediatric nephrology (Berlin, Germany)
The biologics used in transplantation clinical practice include several monoclonal and polyclonal antibodies aimed at specific cellular receptors. The effect of their mechanisms of action includes depleting or blocking specific cell subpopulations, complement system, or removing circulating preformed antibodies and blocking their production. They are used in induction, desensitization ABO-incompatible renal transplantation, rescue therapy of steroid-resistant acute rejection, treatment of posttransplant recurrence of primary disease such as nephrotic syndrome or atypical hemolytic-uremic syndrome, and in late humoral rejection. There are various indications for the use of biologic agents before and early or late after renal transplantation in both high- and low-risk recipients. In the latter situation, the biologics-based induction is used to further minimize immunosuppression maintenance. The targets of several biologic agents are present across a variety of cells, and manipulation of the immune system with biologics may be associated with significant risk of acute and late-onset adverse events; therefore, clinical risk-versus-benefit ratio must be carefully balanced in every case. Several trials on novel biologics are reported in adults but not in the pediatric population.
Recent developments in kidney transplantation in children.
Rusai Krisztina,Szabo Attila J
Current opinion in organ transplantation
PURPOSE OF REVIEW:Renal transplantation in childhood is a well established procedure with excellent short-term outcomes. However, waiting times for transplantation are still relatively long if living donation cannot be performed, and long-term outcomes after transplantation have not significantly improved during the last decade. RECENT FINDINGS:This review describes alternative modalities to improve donation rates such as en bloc kidney transplantation from young donors, ABO-incompatible transplantation and kidney paired donation. This review also deals with long-term post-transplant morbidities, such as follows: first, medication side-effects (metabolic syndrome, cardiovascular disease) and with the benefits of steroid and calcineurin inhibitor drug minimization; second, the deleterious impact of viral infections and their management and third, chronic antibody-mediated rejection, its therapeutic and prevention possibilities. SUMMARY:Donor shortage and long-term morbidities, after transplantation, are still relevant issues in paediatric renal transplantation medicine. Significant research and efforts have been made to advance the field and create novel approaches for improvement of transplantation rates and post-transplant graft or patient survival. These modalities are to be established in the routine setting.
Emerging therapeutic potential of group 2 innate lymphoid cells in acute kidney injury.
Cameron Guy J M,Jiang Simon H,Loering Svenja,Deshpande Aniruddh V,Hansbro Philip M,Starkey Malcolm R
The Journal of pathology
Acute kidney injury (AKI) remains a global challenge and, despite the availability of dialysis and transplantation, can be fatal. Those that survive an AKI are at increased risk of developing chronic kidney disease and end stage renal failure. Understanding the fundamental mechanisms underpinning the pathophysiology of AKI is critical for developing novel strategies for diagnosis and treatment. A growing body of evidence indicates that amplifying type 2 immunity may have therapeutic potential in kidney injury and disease. Of particular interest are the recently described subset of innate immune cells, termed group 2 innate lymphoid cells (ILCs). Group 2 ILCs are crucial tissue-resident immune cells that maintain homeostasis and regulate tissue repair at multiple organ sites, including the kidney. They are critical mediators of type 2 immune responses following infection and injury. The existing literature suggests that activation of group 2 ILCs and production of a local type 2 immune milieu is protective against renal injury and associated pathology. In this review, we describe the emerging role for group 2 ILCs in renal homeostasis and repair. We provide an in-depth discussion of the most recent literature that use preclinical models of AKI and assess the therapeutic effect of modulating group 2 ILC function. We debate the potential for targeting these cells as novel cellular therapies in AKI and discuss the implications for future studies and translation. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Innate Immune Response in Kidney Ischemia/Reperfusion Injury: Potential Target for Therapy.
Kezić Aleksandra,Stajic Natasa,Thaiss Friedrich
Journal of immunology research
Acute kidney injury caused by ischemia and subsequent reperfusion is associated with a high rate of mortality and morbidity. Ischemia/reperfusion injury in kidney transplantation causes delayed graft function and is associated with more frequent episodes of acute rejection and progression to chronic allograft nephropathy. Alloantigen-independent inflammation is an important process, participating in pathogenesis of injurious response, caused by ischemia and reperfusion. This innate immune response is characterized by the activity of classical cells belonging to the immune system, such as neutrophils, macrophages, dendritic cells, lymphocytes, and also tubular epithelial cells and endothelial cells. These immune cells not only participate in inflammation after ischemia exerting detrimental influence but also play a protective role in the healing response from ischemia/reperfusion injury. Delineating of complex mechanisms of their actions could be fruitful in future prevention and treatment of ischemia/reperfusion injury. Among numerous so far conducted experiments, observed immunomodulatory role of adenosine and adenosine receptor agonists in complex interactions of dendritic cells, natural killer T cells, and T regulatory cells is emphasized as promising in the treatment of kidney ischemia/reperfusion injury. Potential pharmacological approaches which decrease NF-B activity and antagonize mechanisms downstream of activated Toll-like receptors are discussed.
Special Considerations in Pediatric Kidney Transplantation.
Hebert Sean A,Swinford Rita D,Hall David R,Au Jason K,Bynon John S
Advances in chronic kidney disease
Universally accepted as the treatment of choice for children needing renal replacement therapy, kidney transplantation affords children the opportunity for an improved quality of life over dialysis therapy. Immunologic and surgical advances over the last 15 years have improved the pediatric patient and kidney graft survival. Unique to pediatrics, congenital genitourinary anomalies are the most common primary diseases leading to kidney failure, many with urological issues. Early urological evaluation for post-transplant bladder dysfunction and emphasis on immunization adherence are the mainstays of pediatric pretransplant and post-transplant evaluations. A child's height can be challenging, sometimes requiring an intra-abdominally placed graft, particularly if the patient is <20 kg. Maintenance immunosuppression regimens are similar to adult kidney graft recipients, although distinctive pharmacokinetics may change dosing intervals in children from twice a day to thrice a day. Viral infections and secondary malignancies are problematic for children relative to adults. Current trends to reduce/remove corticosteroid therapy from post-transplant protocols have produced improved linear growth with less steroid toxicity; although these studies are still ongoing, graft function and survival are considered acceptable. Finally, all children with a kidney transplant need a smooth transition to adult clinics. Future research in pertinent psychosocial aspects and continued technological advances will only serve to optimize the transition process. Although some aspects of kidney transplantation are similar in children and adults, for instance immunosuppression and immunosuppressive regimens, and rejection mechanisms and their diagnosis using the Banff criteria, there are important differences this review will focus on and which continue to drive innovation.
Combined liver and kidney transplantation in children.
Jalanko Hannu,Pakarinen Mikko
Pediatric nephrology (Berlin, Germany)
Simultaneous combined liver-kidney transplantation (CLKT) is a rare operation in pediatric patients so that annually only 10-30 operations are performed worldwide. The main indications for CLKT are primary hyperoxaluria type 1 and autosomal recessive polycystic kidney disease. In addition, CLKT is indicated in individual patients with metabolic or cirrhotic liver diseases and end-stage kidney disease. The surgery and immediate post-operative management of CLKT remain challenging in infants and small children. The patients should be operated on before they become severely ill or develop major systemic manifestations of their metabolic disorder. The liver allograft is immunologically protective of the kidney graft in simultaneous CLKT, often resulting in well-preserved kidney function. The long-term outcome after CLKT is nowadays comparable to that of isolated liver and kidney transplantations.
Organ allocation and utilization in pediatric transplantation.
Andrews Walter S,Kane Bartholomew J,Hendrickson Richard J
Seminars in pediatric surgery
Pediatric transplant candidates include heart, lung, liver, pancreas, small intestine, and kidney. The purpose of this article is to review the history and current methods for determining priority of the above-mentioned transplantable organs. The methods used by the authors involved the review of historical and current manuscripts and UNOS policy documents. We summarized the findings in order to create a concise review of the current policies and wait times for transplantation in pediatric transplant patients.
Pediatric kidney transplantation: a historical review.
Verghese Priya S
Successful renal transplantation is the optimal treatment for chronic kidney failure, but this was not always so for children. Beginning with the first kidney transplants in the 1950s, children experienced poorer patient and graft survival rates than adult patients. But over the last 6 decades, an improved understanding of the immune system which has steered pediatric multi-center clinical/pharmacokinetic and mechanistic studies that have sculpted our immunosuppression with markedly better patient and graft survivals. In addition, uniquely pediatric issues related to growth, development, neurocognitive maturation, increased complications from primary viral infections, and comorbid congenital/inherited disorders, are now diagnosed and effectively managed in these children. Refined pretransplant preparation (vaccinations for preventable diseases, attention to cognitive delays, effective dialysis and nutrition) improved donor selection, and more potent immunosuppression have all contributed to enhanced outcomes. Similarly, improvements in pediatric surgical techniques, postoperative care and better antiviral prophylaxis have all shortened hospitalizations and reduced morbidity. Today pediatric kidney transplant outcomes are markedly improved and younger children today experience better long-term graft survival than adults! While difficult problems remain, we have made tremendous progress and anticipate even more advances in the future of pediatric kidney transplantation.
Pediatric kidney transplantation.
Shapiro Ron,Sarwal Minnie M
Pediatric clinics of North America
Kidney transplantation in pediatric patients has become a routinely successful procedure, with 1- and 5-year patient survival rates of 98% and 94%, and 1- and 5-year graft survival rates of 93% to 95% and 77% to 85% (the range takes into account differences between living and deceased donors). These good outcomes represent the cumulative effect of improvements in pre- and posttransplant patient care, operative techniques, immunosuppression, and infection prophylaxis, diagnosis, and treatment. This article provides a brief historical overview, discusses the indications for transplantation, describes the evaluation process for the recipient and the potential donor, outlines the operative details, reviews the various causes of and risk factors for graft dysfunction, and analyzes outcomes.
Transplantation: Pediatric kidney donation after cardiac death.
Sung Randall S
Nature reviews. Nephrology
A Dutch study has evaluated the outcomes after transplantation of kidneys from pediatric patients after cardiac death. Such programs instigate ethical debate regarding the classification of donors, and raise questions about the suitability of protocols for determining when an individual can be declared dead, and thus, can donate their organs.
Chronic kidney disease: Obesity in children with end-stage renal disease.
Krmar Rafael T,Bárány Peter
Nature reviews. Nephrology
A recent publication by Bonthuis et al. shows a high prevalence of overweight or obesity in children with end-stage renal disease, particularly in renal transplant recipients. Underweight is more prevalent in infants than in other age groups. This study highlights the need to evaluate and implement interventional strategies in this patient population.
Growth in children after kidney transplantation with living related donor graft or cadaveric graft.
Pape L,Ehrich J H H,Zivicnjak M,Offner G
Lancet (London, England)
The extent to which growth after renal transplantation differs between children with a living related donor graft (LRD) and those with a cadaveric donor graft (CAD) is unclear. We retrospectively studied growth in the 5 years after transplantation in 30 boys who received LRD and 21 who received CAD. Height was similar in both groups after transplantation but was greater in LRD than in CAD recipients during follow-up. LRD recipients were taller at all ages, and had greater growth velocity in infancy and during puberty. Glomerular filtration rate (GFR) was higher immediately after transplantation in LRD than in CAD recipients, but did not differ between the groups during follow-up. GFR and other factors did not affect height 5 years after transplantation. These findings support use of LRD as the preferred option in children.
Kidney disease in children: latest advances and remaining challenges.
Bertram John F,Goldstein Stuart L,Pape Lars,Schaefer Franz,Shroff Rukshana C,Warady Bradley A
Nature reviews. Nephrology
To mark World Kidney Day 2016, Nature Reviews Nephrology invited six leading researchers to highlight the key advances and challenges within their specialist field of paediatric nephrology. Here, advances and remaining challenges in the fields of prenatal patterning, acute kidney injury, renal transplantation, genetics, cardiovascular health, and growth and nutrition, are all discussed within the context of paediatric and neonatal patients with kidney disease. Our global panel of researchers describe areas in which further studies and clinical advances are needed, and suggest ways in which research in these areas should progress to optimize renal care and long-term outcomes for affected patients.
Long-term effects of paediatric kidney transplantation.
Holmberg Christer,Jalanko Hannu
Nature reviews. Nephrology
Renal transplantation in paediatric patients usually provides excellent short-term and medium-term results. Early diagnosis of chronic kidney disease and active therapy of end-stage renal disease before and after transplantation enables the majority of children to grow and develop normally. The adverse effects of immunosuppressive medication and reduced graft function might, however, hamper long-term outcomes in these patients and can lead to metabolic complications, cardiovascular disease, reduced bone health, and malignancies. The neurocognitive development and quality of life of paediatric transplant recipients largely depend on the primary diagnosis and on graft function. Poor adherence to immunosuppression is an important risk factor for graft loss in adolescents, and controlled transition to adult care is of utmost importance to ensure a continued normal life. In this Review, we discuss the outcomes and long-term effects of renal transplantation in paediatric recipients, including consequences on growth, development, bone, metabolic, and cardiovascular disorders. We discuss the key problems in the care of paediatric renal transplant recipients and the remaining challenges that should be the focus of future research.