Richard C. Rink, MD, FAAP, FACS

• Robert A. Garrett Professor of Pediatric Urology,
• Indiana University School of Medicine
• Chief, Pediatric Urology,
• James Whitcomb Riley Hospital for Children, Indiana
• University Medical Center,
• Indianapolis, Indiana

The European Renal Association - European Dialysis and Transplant Association Registry Annual Report 2014: a summary symptoms 4dpo 25mg antivert. Papachristou F treatment 7th feb cardiff purchase antivert without a prescription, Stabouli S medicine of the wolf order antivert 25 mg line, Printza N medicine express cost of antivert, Mitsioni A treatment nail fungus purchase antivert canada, Stefanidis C symptoms night sweats best antivert 25 mg, Miserlis G, Dotis J, Kapogiannis A, Georgaki-Angelaki H, Gkogka C, Kollios K, Papanikolaou V. Long-term outcome of pediatric kidney transplantation: a single-center experience from Greece. Outcome differences between young children and adolescents undergoing kidney transplantation. Age at graft loss after pediatric kidney transplantation: exploring the highrisk age window. Loss of pediatric kidney grafts during the "high-risk age window": insights from pediatric liver and simultaneous liver-kidney recipients. The influence of low donor age, living related donation and pre-emptive transplantation on end-organ damage based on arterial hypertension after paediatric kidney transplantation. Optimizing the utilization of kidneys from small pediatric deceased donors under 15 kg by choosing pediatric recipients. Role of race in kidney transplant outcomes in children with focal segmental glomerulosclerosis. Racial and ethnic disparities in pediatric renal allograft survival in the United States. Racial and ethnic differences in pediatric access to preemptive kidney transplantation in the United States. Do six-antigen-matched cadaver donor kidneys provide better graft survival to children compared with onehaploidentical living-related donor transplants The Effect of Donor-Recipient relationship on long-term outcomes of living related donor renal transplantation. The impact of human leukocyte antigen mismatching on sensitization rates and subsequent retransplantation after first graft failure in pediatric renal transplant recipients. Identification of risk factors for vascular thrombosis may reduce early renal graft loss: a review of recent literature. Improvement in specific aspects of neurocognitive performance in children after renal transplantation. Long-term outcome of focal segmental glomerulosclerosis after pediatric renal transplantation. Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence. Recurrence of idiopathic focal segmental glomerulosclerosis after kidney transplantation: experience of a Korean tertiary center. Focal segmental glomerulosclerosis in children: multivariate analysis indicates that donor type does not alter recurrence risk. Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the united states. Loss of living donor renal allograft survival advantage in children with focal segmental glomerulosclerosis. Preemptive plasmapheresis and recurrence of focal segmental glomerulosclerosis in pediatric renal transplantation. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Patrakka J, Ruotsalainen V, Reponen P, Qvist E, Laine J, Holmberg C, Tryggvason K, Jalanko H. Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Recurrence of membranoproliferative glomerulonephritis after renal transplantation in Denys-Drash. Living donor kidney transplantation from relatives with mild urinary abnormalities in Alport syndrome: long-term risk, benefit and outcome. Late presentation of Alport posttransplantation anti-glomerular basement membrane disease. Allograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis. Membranoproliferative glomerulonephritis type I in renal transplantation patients: a single-center study of a cohort of 68 renal transplants followed up for 11 years. Recurrence of renal disease after kidney transplantation in children: 24 years of experience in a single center. Serial estimates of serum permeability activity and clinical correlates in patients with native kidney focal segmental glomerulosclerosis. Recurrent primary focal segmental glomerulosclerosis managed with intensified plasma exchange and concomitant monitoring of soluble urokinase-type plasminogen activator receptor-mediated podocyte beta3-integrin activation. Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients. Shishido S, Satou H, Muramatsu M, Hamasaki Y, Ishikura K, Hataya H, Honda M, Asanuma H, Aikawa A. Combination of pulse methylprednisolone infusions with cyclosporine-based immunosuppression is safe and effective to treat recurrent focal segmental glomerulosclerosis after pediatric kidney transplantation. High-dose oral cyclosporin therapy for recurrent focal segmental glomerulosclerosis in children. Intravenous cyclosporine therapy in recurrent nephrotic syndrome after renal transplantation in children. Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis. Hubsch H, Montane B, Abitbol C, Chandar J, Shariatmadar S, Ciancio G, Burke G, Miller J, Strauss J, Zilleruelo G. Recurrent focal glomerulosclerosis in pediatric renal allografts: the Miami experience. Chaudhuri A, Kambham N, Sutherland S, Grimm P, Alexander S, Concepcion W, Sarwal M, Wong C. Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type. Chikamoto H, Hattori M, Kuroda N, Kajiho Y, Matsumura H, Fujii H, Ishizuka K, Hisano M, Akioka Y, Nozu K, Kaito H, Shimizu M. Pretransplantation combined therapy with plasmapheresis and rituximab in a second living-related kidney transplant pediatric recipient with a very high risk for focal segmental glomerulosclerosis recurrence. Rituximab in post-transplant pediatric recurrent focal segmental glomerulosclerosis. Resolution of recurrent focal segmental glomerulosclerosis proteinuria after rituximab treatment. Successful therapy of C3Nef-positive C3 glomerulopathy with plasma therapy and immunosuppression. Recurrent membranoproliferative glomerulonephritis after second renal graft treated with plasmapheresis and rituximab. Sanchez-Moreno A, De La Cerda F, Cabrera R, Fijo J, Lopez-Trascasa M, Bedoya R, Rodriguez De Cordoba S, Ybot-Gonzalez P. Outcome of renal allograft in patients with Henoch-Schonlein nephritis: single-center experience and systematic review. Histologic recurrence of Henoch-Schonlein Purpura nephropathy after renal transplantation on routine allograft biopsy. Kanaan N, Mourad G, Thervet E, Peeters P, Hourmant M, Vanrenterghem Y, De Meyer M, Mourad M, Marechal C, Goffin E, Pirson Y. Recurrence and graft loss after kidney transplantation for henochschonlein purpura nephritis: a multicenter analysis. Long-term outcome of renal transplantation patients with Henoch-Schonlein purpura. Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. Chronic renal disease is more prevalent in patients with hemolytic uremic syndrome who had a positive history of diarrhea. Shiga toxin-associated hemolytic uremic syndrome: absence of recurrence after renal transplantation. The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Fremeaux-Bacchi V, Legendre C. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Outcome of renal transplantation in patients with nonShiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Plasma therapy for atypical haemolytic uraemic syndrome associated with heterozygous factor H mutations. Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome. Hofer J, Giner T, Cortina G, Jungraithmayr T, Masalskiene J, Dobiliene D, Mitkiene R, Pundziene B, Rudaitis S. Successful living-related renal transplantation in a patient with factor H antibody-associated atypical hemolytic uremic syndrome. Outcomes of renal transplant in patients with anti-complement factor H antibody-associated hemolytic uremic syndrome. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Eculizumab for Atypical Hemolytic Uremic Syndrome Recurrence in Renal Transplantation. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Outcome after transplantation of young patients with systemic lupus erythematosus: a report of the North American pediatric renal transplant cooperative study. Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients. Identifying patients at risk of renal allograft thrombosis and evaluating strategies for prevention. Trends in renal transplantation rates in patients with congenital urinary tract disorders. Does lower urinary tract status affect renal transplantation outcomes in children Alexopoulos S, Lightner A, Concepcion W, Rose M, Salcedo-Concepcion K, Salvatierra O. Pediatric kidney recipients with small capacity, defunctionalized urinary bladders receiving adult-sized kidney without prior bladder augmentation. Challenges facing renal transplantation in pediatric patients with lower urinary tract dysfunction. Native nephrectomy prior to pediatric kidney transplantation: biological and clinical aspects. Efficacy of nephrectomy for the treatment of nephrogenic hypertension in a pediatric population. Nephrectomy for hypertension in pediatric patients with a unilateral poorly functioning kidney: a contemporary cohort. Long-term cardiovascular effects of pre-transplant native kidney nephrectomy in children. Benefits of transperitoneal approach to bilateral pretransplant laparoscopic nephrectomies in pediatric patients. Clinical predictors of neurocognitive deficits in children with chronic kidney disease. Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1. An institutional experience of pre-emptive liver transplantation for pediatric primary hyperoxaluria type 1. Complexity of pre-emptive liver transplantation in children with primary hyperoxaluria type 1. Current treatment for primary hyperoxaluria type 1: when should liver/kidney transplantation be considered. Early cardiac dysfunction in pediatric patients on maintenance dialysis and post kidney transplant. Association between left ventricular mass index and cardiac function in pediatric dialysis patients. Congenital nephrotic syndrome: preemptive bilateral nephrectomy and dialysis before renal transplantation. An update on immunizations before and after transplantation in the pediatric solid organ transplant recipient.

Large-volume drainage of less heavily blood-stained fluid generally indicates residual peritoneal dialysate (if the peritoneum was breached) medicine bow wyoming 25mg antivert with amex, lymph symptoms uterine fibroids cheap 25 mg antivert overnight delivery, or urine treatment jaundice cheap antivert 25 mg without a prescription. Urine is excluded by biochemical analysis or absence of glucose on dipstick testing symptoms 8 days before period order antivert on line amex. The careful positioning of the kidney at time of surgery can be undone readily by a restless recipient flexing the hips because of pain medicine daughter lyrics discount antivert 25mg on line, urinary catheter intolerance medicine you can give cats order cheap antivert, and hypoxia, or an unhelpful radiographer who determines that the recipient should sit bolt upright for a mobile chest x-ray. Transplanted kidneys producing urine at the end of the surgical procedure are easier to manage, particularly if urine is being produced in volumes that could not be achieved by residual native kidney function. If no urine has been seen on the operating table or in recovery and the recipient is hemodynamically stable with a central venous pressure of at least 5 cmH2O, ultrasound examination is useful before the recipient leaves the operating suite complex, particularly if difficulty was encountered with kidney positioning during wound closure. Out of routine working hours, it helps if the transplant surgeon is adept with the use of an ultrasound machine dedicated to the transplant unit. An inadequate arterial signal and significant collections are indications for an immediate return to the operating room. However, when the patient is placed in a sitting or standing position, downward movement of abdominal contents can cause external compression of the transplanted kidney or change its position. Contributing factors include a large native polycystic kidney, heavy fat-laden small-bowel mesentery, and greater omentum in a patient with truncal obesity. A paralytic ileus or pseudoobstruction of the large bowel can be frustrating to manage in the first week after transplantation. It demonstrates a small disruption of the anastomosis (arrow) that led to catastrophic bleeding 10 days after transplant surgery. The perfusion of the kidney transplant in the right iliac fossa was compromised by gross pseudoobstruction of the large and small bowel. Surgical decompression with insertion of a mesh to relieve pressure may be required. Most hematomas are small and insignificant ultrasound findings that resolve spontaneously. Those associated with discomfort, hypotension, transplant dysfunction, and falling hemoglobin are not. Others expand progressively within the retroperitoneal space with inevitable external pressure on the transplant and adverse effect on arterial blood inflow or venous outflow. Ultrasound examination is appropriate to assess transplant perfusion but because of surrounding bowel gas is unreliable for assessment of hematoma size. Indications for surgical exploration of the transplanted kidney include symptoms, progression of size, ongoing blood loss, and transplant dysfunction. Surgical exploration in the first day or so after transplantation for hematoma evacuation might locate active bleeding from a hilar vessel, a retroperitoneal vein, or divided abdominal wall muscle. Bruising in dependent subcutaneous areas lateral to and below the transplant, such as the labia or the scrotum, is often seen several days later. The risk of hematoma formation is increased by the use of anticoagulants, particularly in patients receiving heparin by infusion for prophylaxis against vascular thrombosis. The reported risk of need for surgical intervention in patients heparinized after transplantation is 30% to 60%. They are prescribed increasingly on a long-term basis by cardiologists and nephrologists in patients with significant cardiovascular disease or in attempts to improve fistula patency. However, they do reduce the margin for surgical error and dictate the need for meticulous hemostasis at time of surgery. Compared with other forms of vascular surgery, the incidence of thrombosis is low, perhaps because of the highly vascular nature of the kidney. The low incidence may also support the traditional view that renal failure is associated with a bleeding tendency secondary to platelet and clotting factor dysfunction. Interruption of the venous drainage can be spectacular with graft rupture and bleeding. It has an equally disappointing prospect for kidney salvage because of the rapidity of the process after occlusion of the renal vein has occurred. Thrombotic complications are minimized by identification and management of risk at the time of transplantation. Thrombosis of the kidney vasculature is the end result of stasis, endothelial changes, and procoagulant factors and can be multifactorial. Causes of stasis are largely technical in nature and readily identifiable at the time of transplant exploration. They include poorly constructed anastomoses, malpositioning of the transplant, rotation of the kidney, or external compression. Recipient hypovolemia and inadequate cardiac output, for whatever reason, are contributory but not causal factors. Because this is often not the case, intrarenal causes are probably underestimated and underdiagnosed. Epidemiologic studies have attempted to identify other risk factors, particularly those amenable to preventive strategies. A large registry-based and case-matched study has shown that half of all cases of kidney transplant vascular thrombosis occur in repeat transplant recipients. Recipients dependent on peritoneal dialysis before transplantation are more likely to have thrombotic complications, likely due to intravascular hypovolemia. With higher hemoglobin values, there is an increased risk of adverse cardiac events. Thromboembolic events and symptoms of lethargy, malaise, and headache necessitate repeated venipuncture and may be necessary in up to 30% of these patients. The problem is more common in male patients, smokers, and patients with a rejection-free course. By chance, patients introduced to small doses of an angiotensin-converting enzyme inhibitor for the management of hypertension were noted to have progressive reduction of hematocrit to more normal levels. When a thrombotic event of any kind occurs in a patient older than 45 years and in the absence of a family history, these deficiencies are unlikely. It is found, however, in 15% to 20% of patients with venous thromboembolism and 60% of patients with a family history of thromboembolism. A case could therefore be made for routine genetic screening for these polymorphisms in patients awaiting a renal transplant. Although present in about 10% of patients, related clinical events are less common. They have a universal incidence of graft loss to thrombosis when prophylaxis is not employed. Equally, anticoagulation after transplantation offers protection against graft loss. The subsequent immune complex activates platelets, predisposes the patient to clotting of veins and arteries, and causes the platelets to be consumed. Anticoagulation can be provided with direct thrombin inhibitors such as lepirudin, argatroban, or bivalirudin. Rapid onset of oliguria and hematuria is accompanied by graft enlargement and rupture associated with extreme patient discomfort and life-threatening bleeding. The operative findings will match the ultrasound description along with active arterial bleeding from the ruptured cortex. Some surgeons of that era performed prophylactic division of the kidney capsule to allow the kidney to cope better with the inevitable parenchymal swelling associated with tubular necrosis. If identified in the early period after transplantation, simple reopening of the wound and making more space for the transplanted kidney may be associated with a rapid improvement in appearance of the kidney. Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura is an infrequent but well-described complication of cyclosporine use. The diagnosis, seen soon after transplantation, is based on deteriorating renal function, decreasing platelet count, and characteristic glomerular thrombi seen in core biopsy specimens. Reports also describe the same presentation with tacrolimus, which responds with conversion to cyclosporine. If thrombus is present in the renal vein of a right-sided donor kidney, removal of the kidney and reperfusion with preservation solution may be the only practical option. The donor kidney is retransplanted with consideration given to provision of greater mobilization of the iliac vein and more proximal siting of the venous anastomosis. It can be seen in a subacute situation associated with secondary causes, such as iliofemoral vein thrombosis, de novo membranous nephropathy, glomerulonephritis, and thrombophilic states. Because of the time of presentation many months after surgery, percutaneous combined mechanical and chemical thrombolysis is feasible. Hence, failure to anastomose an accessory artery, or thrombosis of an accessory artery or branch, will lead inevitably to a wedge-shaped infarct of the kidney. Inability to transplant a small upper-pole accessory artery or branch is a not uncommon event and is usually of little significance. It will be obvious at the time of transplantation as an ischemic area on the cortex of the kidney and a small perfusion defect may be apparent with ultrasound examination. Larger accessory vessel or branch vessel occlusion will have a more significant effect on the transplanted kidney. If the necrosis is full thickness, from capsule to calyceal system, urine leakage and formation of a urinoma may occur from about the fifth day after transplantation. It is not inevitable, and if not apparent by the end of the second week of transplantation, urine leakage is unlikely to occur (see Chapter 29 for management). It usually is due to technical reasons such as arterial kinking or torsion of the renal vascular pedicle. The renal arteries of kidneys that have failed because of chronic rejection often remain patent for many years. Arterial thrombosis is a terminal event that can be averted only if arterial inflow is considered as a cause of poor graft function, and immediate intervention undertaken; hence, the importance of recognition of an arterial problem before thrombosis occurs. Stasis at the time of and after transplant surgery will be minimized by optimal surgical technique and fluid management. The recognition of thrombophilic states as a major contributor to vascular thrombosis after kidney transplantation introduces the possible need for routine screening and, in turn, directed therapy to reduce the risk of thrombosis. It would therefore be reasonable to limit investigation to potential recipients with previous or family history of thrombotic events, including deep and superficial vein thromboses, pulmonary emboli, thrombosed fistulas, multiple occlusions of central venous dialysis catheters, and problematic clotting of dialysis lines. To this list could be added patients undergoing preemptive transplantation with a living donor kidney. For known thrombophilia and a history of clinical events, perioperative heparinization followed by long-term anticoagulation with warfarin has proven efficacy, including successful retransplantation. For recipients without known risk factors, a systematic review exploring the role of low-dose aspirin in kidney transplant recipients demonstrated a 43% reduction in the risk of allograft failure, 89% reduction in the risk of thrombosis and 28% reduction in cardiac events or mortality when aspirin was prescribed. The need for this is usually prompted by difficulty closing the abdominal musculature without compromising the transplant kidney vasculature. Because of its very low incidence, the diagnosis of torsion is often overlooked and possible warning signs of pain, nausea, and oliguria are missed. Imaging is likely to show absence or very limited perfusion of the kidney transplant. Vascular Access Thrombosis the arteriovenous fistula acts as a lifeline for dialysis-dependent patients, with effective vascular access surveillance being clinical examination along with longitudinal assessment of flow, pump speeds, and pressure readings. After transplantation, the fistula provides reassurance for the recipient with delayed graft function, and even after successful transplantation, recipients and clinicians are reluctant to ligate. However, with less surveillance, progressive intimal hyperplasia leads in the majority to eventual and "silent" loss of the fistula flow that is not worthy of resuscitation. In others, the size of the native vein fistula continues to grow, with the feeding artery and vein continuing to adapt to the low-resistance fistula circuit by becoming progressively more ectatic and tortuous. In turn, cardiac output increases progressively with 3, 4, and more liters of blood passing through the fistula anastomosis each minute. Tortuosity may lead to progressive kinking of the fistula vein and eventual stasis, and thrombosis that extends proximally. In the current era of good long-term transplant graft function, a case can be made for a more proactive approach to ligation of a problematic native vein fistula after transplantation, particularly in patients with ectatic feeding arteries or concerns about the effect of the fistula circuit on cardiac output. If left, the feeding artery will become progressively aneurysmal with tension in the artery wall proportional to the radius and arterial pressure. Intraluminal mural thrombus forms, from which emboli head toward the distal arteries. Deep Vein Thrombosis After any major surgery, a hypercoagulable state persists for 4 weeks. Risk of thromboembolic events after renal transplantation is reported to be eightfold higher than the general population. Risk factors include hospitalization, use of sirolimus immunosuppression, and anemia, with use of renin-angiotensin system inhibitors conferring protection. Nevertheless, it can happen, presenting with dramatic ipsilateral leg swelling followed by loss of graft function. Failure to preserve increases the risk of necrosis or stenosis of the distal end of the ureter. The problem is usually diagnosed when the recipient presents with a hydronephrosis after removal of the ureteric stent placed at the time of transplantation. Surgical correction is challenging and involves either anastomosis of the native ureter to the transplant renal pelvis or a new transplant ureteroneocystostomy to be performed after mobilization of bladder and viable transplant ureter (see Chapter 29). The study referenced earlier suggests that routine use of thromboprophylaxis is warranted, especially during periods of hospitalization. Prophylactic measures include the fitting of below-knee antithrombosis stockings before surgery and the use of intermittent calf compression during surgery. They are considered to be as effective as subcutaneous heparin, provided that the stockings are worn throughout the inpatient stay, and early ambulation and calf exercises are undertaken. However, caution must be exercised in the use of compression stockings in a population with high incidence of preexisting peripheral vascular disease. In these patients, subcutaneous heparin can be added, with unfractionated preferred to long-acting fractionated heparin because of its ability to reverse in situations such as troublesome hematuria or the need for a kidney transplant biopsy, and the risk of accumulation of low molecular weight heparin in patients with delayed graft function.

Activation of the innate immune system inevitably leads to the initiation and amplification the adaptive response that involves T cells medicine 101 discount antivert 25 mg with visa, B cells symptoms flu proven antivert 25 mg, and antibodies medications not to take before surgery discount antivert online american express. T cells require a minimum of two signals for activation symptoms 2 days after ovulation order 25mg antivert visa, antigen recognition (often referred to signal 1) and costimulation (referred to as signal 2) symptoms food poisoning purchase antivert with paypal. The majority of B cells require help from T cells to initiate antibody production symptoms 9dpiui order antivert discount. Antibodies reactive to donor antigens, including major and minor histocompatibility antigens and blood group antigens, can trigger or contribute to rejection early, and late, after transplantation. Multiple factors determine the decision as to how the immune response to a transplant will be triggered and evolve, including where the antigen is "seen" and the conditions that are present at the time-in particular, the presence or absence of inflammation associated with activation of the innate response. In general, the innate response is neither specific nor is it altered significantly with multiple antigenic challenges. In contrast, the adaptive response is specific for a particular antigen or combination of antigens and "remembers" when it encounters the same antigen again, augmenting its activity and the rapidity of the response at each encounter. When the immune system encounters an antigen, it has to decide which type of response to make. In most cases, even though one component of the immune system may dominate and lead to rejection, the process is usually multifactorial, resulting from the integration of multiple mechanisms. Understanding the molecular and cellular mechanisms that lead to allograft rejection has provided insights leading to the development of therapeutics that suppress this unwanted immune response after transplantation. A diverse collection of small-molecule and biologic immunosuppressive agents are approved and available for use in the clinic that have the potential to control or inhibit allograft rejection. Each immunosuppressive agent acts on a different aspect of the immune response to an allograft and can therefore be used effectively in combination. Unfortunately, all of these agents are globally nonspecific in their suppressive activity, and each has some deleterious side effects. These immunosuppressive drugs can be used with good success to prevent or control acute allograft rejection; however, they are less effective at controlling the long-term response to injury and activation of the immune system. They also appear to be unable to induce the development of unresponsiveness or tolerance to the donor alloantigens consistently, at least in the way they are used clinically at present. For nearly all transplant recipients, continued survival of the allograft depends on life-long administration of several immunosuppressive drugs. These mechanisms do not discriminate between effector cells that could be damaging to the transplant and immune regulatory cells that have the potential to control allograft rejection. Each immunosuppressive agent targets a specific step in the activation and proliferation of T lymphocytes. The development of immunologic tolerance or specific unresponsiveness to donor alloantigens in the short term or the long term after transplantation appears to offer the best possibility of achieving effectiveness and specificity in the control of the immune system after transplantation in either the absence or at least reduced loads of nonspecific immunosuppressive agents. This article is therefore dedicated to discussion of the mechanisms underlying tolerance induction and strategies used to induce unresponsiveness in transplanted allografts. The next section of the chapter sets the scene for discussing the different approaches to tolerance induction being explored most actively at present. This leaves the T cells with receptors that have an intermediate affinity to enter the bloodstream where they recirculate between blood and peripheral lymphoid tissue. A subpopulation of T cells that will be discussed later, so-called thymus-derived or naturally occurring regulatory T cells (Treg), are also selected in the thymus and migrate to the periphery. A mature T cell repertoire is developed through this thymic selection process that is not only diverse, but can also react to foreign antigen while still remaining tolerant to self-antigens. Second signals or costimulation is provided by additional cell surface interactions. This interaction delivers a signal to the T cell that lowers the threshold for T cell activation. The two-signal model of T cell activation is well accepted, but it is important to note that this is a simplification. These will be recruited to the allograft where they can suppress ischemia reperfusion injury. Cytokines and chemokines can modulate expression of the cell surface molecules mentioned previously in addition to the expression of cytokine and chemokine receptors themselves. Activation signals in the form of cytokines propagate the responses initiated by signals 1 and 2 and are often referred to as the third signal in T cell activation. Many experimental models have established that donor antigen must be present continuously to maintain a tolerant state, before or after transplantation, irrespective of the precise mechanisms involved. During the induction and maintenance phases of tolerance, the presence of alloantigen is the key factor driving the outcome. As is often the case with the immune system, the same element can influence the response both positively and negatively. In the case of donor antigen, presentation in the wrong context, such as in a proinflammatory environment as outlined previously, could lead to activation with the potential of destroying the tolerant state and triggering graft rejection, but once tolerance is established, persistence of antigen is critical for maintaining the tolerant state. A constant balance exists to ensure an effective but not excessive response to unwanted stimuli. Many mechanisms of tolerance are, in fact, continuously used by the body to prevent reactions against self-antigens that would ultimately lead to autoimmune pathologies. Many of these same mechanisms and regulatory cell populations can be harnessed to induce and maintain tolerance to alloantigens, at least in animal models. Although theoretically regulation could function exclusively through a single mechanism, such as deletion of donor-reactive T cells and B cells from the repertoire (as will be discussed next), at present there is little evidence to support this as the only or even the dominant mechanism for inducing and maintaining unresponsiveness to cell and organ transplants. The more likely scenario is that different mechanisms work in concert and that distinct combinations of mechanisms are brought into play depending on donor and recipient characteristics, immunosuppression, infection, and so on, as the immune response to the transplant evolves. The death or deletion of lymphocytes capable of recognizing and responding to self-antigens or, after transplantation, donor alloantigens is a very effective mechanism for eliminating lymphocytes from the immune repertoire that have the potential to damage the host or the graft, thereby creating unresponsiveness or tolerance to self or donor alloantigens. Importantly, if this is the only mechanism in operation to either induce or maintain tolerance, deletion needs to be sustained indefinitely. Central tolerance by clonal deletion of T cells in the thymus is the major mechanism by which tolerance to self-antigens is induced. Central deletion of donor alloantigen-reactive T cells has been particularly successful in the context of therapeutic strategies using donor bone marrow in combination with nonmyeloablative therapy, such as T cell depletion or costimulation blockade, for the induction of tolerance. In mixed allogeneic chimeras in the mouse, donorderived dendritic cells were shown to reside and persist in the recipient thymus,35 resulting in continuous deletion of donor-reactive thymocytes leading to the absence of donorreactive T cells in the periphery and hence tolerance to donor alloantigens. Data from some clinical studies suggest that transient rather than persistent chimerism may be sufficient in the presence of other immunosuppressive agents to achieve tolerance in some individuals,36 whereas others suggest that only the achievement of full donor chimerism is consistent with the ability to withdraw immunosuppression and maintain graft survival. The introduction of high doses of defined antigens intravenously or orally has been shown to result in deletion of mature T cells in the peripheral lymphoid organs. The mechanisms by which T cells are deleted in the thymus and the periphery is an area of active investigation. Two distinct modes of apoptosis have been implicated as the mechanism essential for T cell death in these settings. Fas-ligand expression has been shown to be an important contributor enabling these sites to maintain their immune privilege status. The Fas pathway also has been implicated in deletional tolerance after administration of allogeneic bone marrow. The elimination of B cells from the repertoire is also a mechanism that has evolved to ensure that polyreactive B cells capable of binding self-antigens are eliminated in the bone marrow before they enter the periphery. Estimates vary, but suggest that up to 70% of the immature B cells produced are self-reactive. When an immature B cell recognizes self-antigen with high avidity, it rapidly internalizes the antigen and undergoes a period of developmental arrest. Any B cell undergoing this process will die after 1 to 2 days if it fails to express a nonautoreactive receptor. Death through this pathway does not require Fas and is in part because of antigen-induced expression of the Bcl-2 interacting mediator of cell death (Bim), which inhibits B cell survival proteins from the Bcl-2 family. Receptor editing is a mechanism that could be used to delete immature B cells capable of recognizing donor alloantigens from the B cell repertoire and particularly in situations where the repertoire is reshaped after leukocyte depletion48 or the induction of mixed chimerism36 and when organs are transplanted into young infants. This mechanism of control or regulation has been studied using immunoglobulin transgenic mice and the data obtained suggest that B cells are deleted efficiently when the antigen they recognize is membrane-bound. The efficiency of this process was found to be dependent on the probability that the immature B cells encountered the relevant self-antigen and therefore its efficiency is clearly related to antigen density/frequency. Deletion of B cells capable of recognizing donor alloantigens from the immune repertoire of a transplant recipient is a mechanism that can be harnessed in transplantation. This mechanism of regulation is most efficient when the antigens recognized are present at high doses. Data from neonatal tolerance studies suggested that additional mechanisms beyond deletion of donor-reactive cells were involved. First, as mentioned previously, thymus-derived or naturally occurring (tTreg) differentiate in the thymus and are thought to function primarily to suppress responses to self-antigen and hence prevent autoimmune disease. Evidence for this comes from studies in patients with rare genetic defects and in mice with either naturally occurring or genetically engineered defects. However, under these circumstances, the balance between rejection and regulation is against regulation as the suppressive activity of any Treg present is overwhelmed by the destructive response mediated by effector T cells. The presence of preexisting donor alloantigen-reactive memory T cells in the recipient can also overwhelm immune regulation as the kinetics of activation of the memory cells is very rapid and unless very high numbers of Treg are present at the outset of the response, the balance between rejection and regulation is pushed markedly in favor of rejection. In terms of developing potential clinical approaches, it is important to clarify whether induction strategies that ultimately lead to long-term operational tolerance can drive Treg development independently of the graft itself. Moreover, data demonstrating that the presence of the allograft alone can lead to the development of T cells with regulatory properties that can protect a challenge graft from rejection,30 even when the allograft itself has been rejected,85 have been reported. Another important issue is understanding where Treg that can control allograft rejection function most effectively and where they can be found or detected in vivo. There is evidence that the location in which Treg function may change with time after transplantation. Early in the response after transplantation, Treg have been shown to be present and functionally active in the draining lymph nodes, whereas later in the posttransplant course Treg have been shown to function within the allograft itself. Arguably, a much more relevant question for clinical application of this approach is what role do Treg play in an intact immune system It has been suggested that there is a link between regulatory B cells and T cells, with Breg acting as potent generators of Treg. In experimental models, a shift in both peripheral and intragraft gene expression from IgG to IgM was observed, and IgM+, but not IgG+ B cell clusters within rat kidney allografts. Interestingly, in renal transplant recipients with a functioning graft in the absence of immunosuppression, a B cell signature was found to be associated with this state of operational tolerance to donor alloantigens. Not surprisingly, data are emerging demonstrating that different immunosuppressive drugs have a significant effect. In transplantation, macrophage activation occurs initially as a result of the tissue injury that is associated with ischemia and reperfusion and can contribute to early graft damage. Alternatively activated macrophages also play an important role in wound healing and tissue repair by producing growth factors that can stimulate epithelial cells and fibroblasts. However, later in the response, tissue repair responses may be less desirable because they have been shown to contribute to delayed allograft failure by causing occlusion of blood vessels within 342 Kidney Transplantation: Principles and Practice the allograft, a process referred to as transplant arteriosclerosis or transplant-associated vasculopathy. It has been proposed that "regulatory macrophages" may represent an additional, distinct macrophage population whose main physiologic role is to dampen inflammatory immune responses and prevent the immunopathology associated with prolonged classical macrophage activation. Some evidence suggests that they may act partly through the induction or sparing of Treg. Clearly, to be able to achieve operational tolerance would have a major benefit for the patient, reducing the morbidity and mortality associated with lifelong immunosuppression. However, operational tolerance remains a relatively rare event in the clinical setting and thus far not reliably predictable through biomarkers. A small number of bone marrow transplant recipients who subsequently required a renal transplant were transplanted with a kidney from their bone marrow donor. Clinical reports of patients exhibiting spontaneous tolerance to an allograft after withdrawal of immunosuppression in the absence of a bone marrow transplant are still infrequent but cases are accruing. The majority of patients who are able to stop immunosuppression without rejection of their allograft arrive at that point as a result of either (1) discontinuation of immunosuppression by the clinical team as a consequence of the side effects of immunosuppression, nonadherence/compliance; or (2) as a result of weaning of immunosuppression based on a clinical protocol (particularly in liver transplant recipients) designed to minimize immunosuppressive drugs without compromising the function of the allograft. There is also a smaller group of patients who have been treated with protocols designed with the deliberate aim of inducing tolerance to a kidney transplant that will be discussed in detail later. Liver allografts and skin grafts (when they are not part of a vascularized composite allograft) are at the two opposite ends of this spectrum. In experimental transplantation, liver allografts are sometimes accepted spontaneously in the absence of any immunosuppression or immunomodulation. Estimates vary, but on the order of 10% to 20% select adult and pediatric liver transplant recipients appear to have the potential to be weaned from immunosuppression without the risk of rejection. In other words, the molecular signature and the transplant biopsy can be used to provide a risk assessment of which patients are more likely to wean from immunosuppression without the risk of rejection, which is an exciting development for the future of clinical liver transplantation. In kidney transplantation, there are far fewer patients able to continue to have a functioning allograft in the absence of immunosuppression. Nevertheless, a small number of patients who are immunosuppression-free can be identified and have been studied in depth to determine whether there is a molecular signature of tolerance after kidney transplantation. The predominance of B cells in the peripheral blood in the absence of donor-specific antibody was found in the "kidney" signature as mentioned previously and was supported by gene expression data. Further work examining the prevalence of this signature in kidney transplant recipients still being treated with immunosuppression has demonstrated that different drugs in clinical use have a distinct influence on the molecular signature in a particular patient. Strategies With the Potential to Induce Immunologic Tolerance to an Allograft the strategies for tolerance induction being explored most actively at present invoke one or more of the mechanisms of tolerance outlined previously, including the continuous deletion of donor-reactive leukocytes by establishing the presence of high levels of donor cells in the recipient (mixed chimerism), short-term depletion and/or deletion of donor-reactive leukocytes combined with the establishment of immunoregulation and suppression of responses to donor alloantigens in the longer term after transplantation, and costimulation blockade leading to the induction of T cell unresponsiveness in the presence of an organ graft. Instead they attempt to use novel strategies that are relatively nonspecific in their mode of action at the time of transplantation to create an environment that promotes the development of operational tolerance to the graft in the long term in the presence of the allograft. This often means that patients are treated with immunosuppressive drugs in the short term after transplantation with weaning of immunosuppression later in the transplant course.

Serum cathelicidin level is associated with viral etiology and severity of bronchiolitis medicine during the civil war discount antivert online master card. Lactate dehydrogenase and caspase activity in nasopharyngeal secretions are predictors of bronchiolitis severity medications used for anxiety generic 25mg antivert with visa. A robust cytokine and chemokine response in nasopharyngeal secretions is associated with decreased severity in children with physician diagnosed bronchiolitis medicine journal purchase antivert overnight delivery. Nasopharyngeal bacterial burden and antibiotics: influence on inflammatory markers and disease severity in infants with respiratory syncytial virus bronchiolitis treatment diarrhea best 25mg antivert. Virus type and genomic load in acute bronchiolitis: severity and treatment response with inhaled adrenaline treatment refractory cheap antivert 25mg visa. Risk factors for requiring intensive care among children admitted to ward with bronchiolitis conventional medicine purchase 25 mg antivert. Effect of oxygen supplementation on length of stay for infants hospitalized with acute viral bronchiolitis. Hospital course and discharge criteria for children hospitalized with bronchiolitis. Inter-observer agreement between physicians, nurses, and respiratory therapists for respiratory clinical evaluation in bronchiolitis. Bronchiolitis: recommendations for diagnosis, monitoring and management of children one to 24 months of age. Is nasal suctioning warranted before measuring O2 saturation in infants with bronchiolitis Effect of oxygen desaturations on subsequent medical visits in infants discharged from the emergency department with bronchiolitis. Effect of oximetry on hospitalization in bronchiolitis: a randomized clinical trial. Predictors of airspace disease on chest x-ray in emergency department patients with clinical bronchiolitis: a systematic review and meta-analysis. Assessing the utility of urine testing in febrile infants aged 2 to 12 months with bronchiolitis. The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial. High-flow nasal cannula oxygen for bronchiolitis in a pediatric ward: a pilot study. Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics. Decreased lung function precedes severe respiratory syncytial virus infection and post-respiratory syncytial virus wheeze in term infants. Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Chickenpox (Varicella zoster virus) pneumonia may be associated with group A streptococcus since it seems to transiently affect host defenses and predispose to infection from commensal bacteria. In rare cases, it can be the result of bacteremic spread, usually when there is a predisposing factor. Radiologic findings include bronchopneumonia 427 Pneumonia is broadly defined as inflammation in the lung caused by an infectious agent that stimulates a response resulting in damage to lung tissue. Different definitions for pneumonia vary from "detection of pulmonary pathogens in lung specimens" to the "presence of pulmonary infiltrates on chest radiographs," or even clinically based criteria, such as age-specific tachypnea or lower chest retractions. Over 13 million new cases of pneumococcal pneumonia were estimated, with a global yearly incidence of 2228 cases per 100,000 children younger than 5 years of age, ranging from 462/100,000 cases in Europe to 3397/100,000 cases in Africa. The estimated global incidence of Hib pneumonia in the absence of vaccination was 1304 per 100,000 children younger than 5 years of age. Viruses are, by far, the most prevalent cause of pneumonia throughout childhood, with the highest burden observed among infants. However, pathogens are epidemiologically interconnected, and coinfections, both with two or more viruses, or with viruses and bacteria, are very common. Currently, Streptococcus pneumoniae and Mycoplasma pneumoniae are the most prevalent bacterial agents among immunized populations, especially beyond the neonatal period. Contiguous spread for viruses and microaspiration of bacteria from the upper airways are main pathogenic mechanisms. Clinical and radiological parameters are highly variable, and diagnosis remains a challenge, especially in young children. General management includes supportive measures and in the case of suspected bacterial etiology, antimicrobials are warranted. Major clinical complications are tissue necrosis, pleural effusion, empyema, and lung abscess. The prognosis for healthy children is usually good and complete recovery is the rule, although restrictive lung disease and recurrent wheezing can occur in a small subset of patients. These infiltrates may coalesce and evolve to large areas of consolidation and cavitation. Destruction of bronchial walls may lead to air trapping and pneumatocele formation in at least 30% of cases. Pleural effusion and empyema are found in as many as 60% of the cases, and pneumothorax or pyopneumothorax are common complications. An increase in white blood cell counts is usual, but is not sufficiently sensitive or specific to suggest the etiologic diagnosis. Although the appearance of staphylococcal pneumatoceles may be dramatic, usually once the infection is controlled, the pneumatoceles resolve completely in the following few months. Common clinical findings include fever, chills, tachypnea, productive cough, lower chest indrawing, abdominal pain, and chest pain, all of which suggest-but do not prove-pneumonia. For Hib, the clinical picture is similar to other typical bacteria, although a more insidious onset is the rule. However, evolving knowledge of the human microbiome, using highthroughput sequencing-based studies, has shown that the lower airways are transiently or even chronically colonized. Viruses usually reach the lower airways through contiguous spread and replication, and a similar mechanism of invasion is believed to occur with atypical bacteria. Microaspiration from the upper respiratory tract is the most common mechanism for most bacterial pneumonia. The presence of a cough, as well as a longer duration of both a fever and a cough, was more likely associated with occult pneumonia. Infants in the first 3 months of life may present with a cough and respiratory distress associated with lowgrade or no fever. In the early clinical stages of disease, patients with bacterial pneumonia may have normal chest radiographs. There is also significant variation in the interpretation of these radiographs in children, with considerable intraobserver and interobserver disagreement. Specificity ranges from 42% to 100% in different studies because of the varying definitions of pneumonia. When comparing the presence of any infiltrate (end-point or other infiltrates not matching this definition), agreement was lower. In a study by Bachur and colleagues, 26% of the patients younger than 5 years of age who presented to the emergency department with fever, leukocytosis greater than 20,000 cells/mm3, and no clinical findings suggestive of pneumonia, had a confirmed diagnosis of pneumonia on radiograph. However, evidence suggests that this last group is successfully treated with oral antibiotics. Children with danger signs (inability to drink, persistent vomiting, convulsions, lethargy, impaired level of consciousness, stridor, and severe malnutrition) are classified as having severe or very severe pneumonia. Other respiratory signs may also indicate pneumonia, but no sign by itself can be used to diagnose or to rule out pneumonia. The respiratory rate seems to provide better interobserver agreement than auscultation of the chest, especially when examining infants. Tachypnea is usually more sensitive and specific than crackles on auscultation, after the exclusion of a diagnosis of bronchiolitis or asthma. By contrast, in affluent countries, most children (especially infants) who present acutely with an increased respiratory rate have either viral bronchiolitis or asthma associated with a viral infection. Systemic toxicity is less common in viral compared to bacterial infection because respiratory viruses rarely cause viremia. On the other hand, viruses were the most frequent pathogens among those who wheezed. Bacterial cultures of the throat or nasopharynx do not correlate well with lung parenchyma and are more likely to confound than to help, with the known exception of the high correlation between upper and lower airway cultures in sick patients with cystic fibrosis. However, pleural fluid should be cultured whenever technically accessible, unless the effusion is too small or when clinical recovery is uneventful. Diagnostic methods for etiologic identification can be divided into microbiologic, immunologic, and molecular methods of detection (see Chapter 22). Blood cultures are positive in less than 10% of the samples and should be considered only in hospitalized children or those with complicated pneumonia. Repeating blood cultures to document resolution of bacteremia is not recommended for patients who are clinically improving, except for those with S. In children, pneumococcal urinary antigen has a high sensitivity, but a positive test is frequently due to nasal carriage. Diagnosis and Differential Diagnosis Pneumonia should be suspected in children with fever, cough, tachypnea, lower chest indrawing, or crackles on chest auscultation. However, no single clinical feature has sufficient accuracy to diagnose pneumonia. Abdominal pain or nausea, when associated with fever, can present as the sole clinical finding in pneumonia affecting the lower pulmonary lobes. Infants and small children presenting with fever and respiratory signs are frequently sent for a chest radiograph and often receive antimicrobial treatment for a presumptive diagnosis of bacterial pneumonia. Importantly, a chest x-ray cannot reliably differentiate between viral and bacterial etiologies, which may coexist. Although "atypical" pneumonia is often described with several different presentations, in clinical practice neither signs nor symptoms alone, or with radiologic findings have sufficient accuracy to differentiate M. Nonresolving pneumonia with persistence or recurrent radiologic findings should alert the physician to possible noninfectious primary causes or infection with bacterial agents, such as M. In this situation, the child usually should be reexamined within 48 hours after beginning treatment. Fluid intake should be carefully monitored because pneumonia can be complicated by hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion. The benefit of nasogastric tube feeding should be weighed against its potential for respiratory distress due to the obstruction of a nostril, or by inducing gastroesophageal reflux. No randomized, controlled trials have addressed the use of noninvasive ventilation for children with pneumonia. Respiratory failure, when present, should be managed appropriately and noninvasive ventilation may be used to avoid tracheal intubation. Children should be admitted to an intensive care facility with continuous cardiorespiratory monitoring capabilities when invasive ventilation is required, or pulse oximetry measurements are below 92% with the child on inspired oxygen concentrations of 50% or more. Of note were a low prevalence of positive radiographic findings (14%) and a relatively high rate (20%) of treatment failure, which suggests that there may have been a high proportion of viral pneumonia. The prevalence of penicillin resistance also varies widely throughout different countries and continents. Susceptibility breakpoints have been revised due to the cumulative evidence of clinical improvement even with conventional doses of penicillin for strains that were previously considered intermediately resistant. However, for oral penicillin, the previous breakpoints are still valid, due to lower serum levels achieved with enteral presentations. Vancomycin or teicoplanin should be reserved for severely ill patients, when coverage for highly resistant pneumococcus is desired, because overuse may lead to increased resistance from other pathogens. Antibiotic resistance is usually associated with changes in the penicillin-binding sites of the transpeptidases of the bacteria, and it may be associated with cross-resistance to other -lactams and carbapenems. However, therapeutic decisions can be difficult because most tests do not adequately differentiate viral from bacterial infection in an individual child. An additional issue is the fact that many patients harbor mixed viral and bacterial agents. Prior antibiotic therapy, daycare attendance, travel, and coexisting morbidities are risk factors for resistance. It is also important to keep in mind that, in an era of effective vaccines against Hib and S. Several randomized studies assessing different antibiotics for pneumonia have shown that children under 5 years with tachypnea or indrawing of the lower chest without danger signs can be safely treated with oral amoxicillin. In real-life situations, causative agents are rarely identified, and the choice of antibiotics is based on models that include both the age of the child and the clinical presentation. Methicillin/oxacillin may be the best choice if the clinical picture is suggestive of S. For symptomatic children between 3 weeks and 3 months of age with interstitial infiltrates visible on chest radiograph, if a viral etiology is not the most likely diagnosis, a macrolide should be used to cover for agents such as C. Of note, azithromycin has a distinct pharmacokinetic profile and it does not reach high serum levels, which is a potential disadvantage in the treatment of bacterial pneumonia.

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