Collaborative Multidisciplinary Incident Command at Seattle Children's Hospital for Rapid Preparatory Pediatric Surgery Countermeasures to the COVID-19 Pandemic.

Washington was the first US state to have a patient test positive for COVID-19. Before this, our children's hospital proactively implemented an incident command structure that allowed for collaborative creation of safety measures, policies, and procedures for patients, families, staff, and providers. Although the treatment and protective standards are continuously evolving, this commentary shares our thoughts on how an institution, and specifically, surgical services, may develop collaborative process improvement to accommodate for rapid and ongoing change. Specific changes outlined include early establishment of incident command; personal protective equipment conservation; workforce safety; surgical and ambulatory patient triage; and optimization of trainee education. Please note that the contents of this manuscript are shared in the interest of providing collaborative information and are under continuous development as our regional situation changes. We recognize the limitations of this commentary and do not suggest that our approaches represent validated best practices.

Solid tumors following kidney transplantation in children.

Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100,000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100,000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.

Donor and recipient size mismatch in adolescents undergoing living-donor renal transplantation affect long-term graft survival.

BACKGROUND: Controversies exist in the adult literature regarding the use of kidneys from small donors into larger recipients. Little is known regarding this issue in pediatric kidney transplantation. To assess the impact of donor/recipient size mismatch on long-term renal graft survival in pediatric patients undergoing living-donor renal transplantation. METHODS: We reviewed the United Network for Organ Sharing database from 1987 to 2010 for adolescent (11-18 years old) patients who underwent primary living-donor renal transplantation. According to donor/recipient body surface area (BSA) ratio, patients were stratified into two categories: BSA ratio <0.9 and ≥0.9. Graft survival rates were compared between these two groups using Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: Of the 1880 patients identified, 116 (6.2%) had a donor/recipient BSA ratio <0.9 and 1764 (93.8%) had a donor/recipient BSA ratio ≥0.9 group. BSA ratio <0.9 conferred an increased risk of graft loss (adjusted hazard ratio, 1.61; 95% confidence interval, 1.13-2.27; P=0.008). Patients with a donor/recipient BSA ratio ≥0.9 group had a significantly longer graft survival compared with those with a donor/recipient BSA ratio <0.9 after adjustment for donor age and gender, recipient age, gender, ethnicity, cause of renal failure, as well as clinical factors, such as cold and warm ischemia time and HLA mismatch. CONCLUSION: We conclude that low donor/recipient BSA ratio was associated with an increased risk of graft loss. Appropriate size matching conferred better long-term graft survival in adolescents receiving live-donor kidney transplants.

Impaired graft survival in pediatric renal transplant recipients with donor-specific antibodies detected by solid-phase assays.

SAB assays have increased the sensitivity and specificity to detect HLA alloantibodies, but there is uncertainty about the clinical relevance of SAB-positive alloantibodies when the FCXM is negative. We performed a retrospective study to evaluate the clinical significance of SAB-detected DSA in 82 pediatric recipients of a first kidney transplant between January 2000 and December 2005 who had a negative pretransplant FCXM. Pretransplant sera were evaluated by SAB for DSA. Graft loss and rejection between patients with (DSA+) and without DSA (DSA-) were compared. DSA were detected in 13.9%. Eighty percent of DSA+ subjects were DD transplant recipients vs. 56.9% in the DSA- cohort. The RR of graft loss in DSA+ vs. DSA- was 3.3 (95% CI, 1.4-7.9) and in DD was 4.3 (95% CI 1.4-13.1). By Cox regression, the HR of graft loss in DSA+ vs. DSA- was 2.8 (95% CI 0.7-10.9; p = 0.14) and in DD was 5.1 (95% CI 1-25.6; p = 0.05). Acute rejection occurred in 60% in the DSA+ vs. 44.4% in DSA- (p = 0.5). SAB-detected DSA was associated with impaired renal allograft survival in pediatric renal transplant recipients. Impaired graft survival in pediatric renal transplant recipients with DSA detected by solid-phase assays.

Subclinical viremia increases risk for chronic allograft injury in pediatric renal transplantation.

The impact of subclinical viral infection on chronic allograft injury in the pediatric renal transplant population is not well defined. We prospectively assessed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNAemia by monthly PCR in 55 pediatric renal transplant recipients for the first 2 years after transplantation. Subclinical CMV and EBV infection occurred in 22 and 36%, respectively. Multivariable linear regression analysis suggested that both subclinical CMV and EBV infection independently associate with significant declines in GFR during the first 2 years after transplantation. CMV seronegativity associated with a significantly greater decline in GFR than seropositivity (P < 0.01). Subclinical CMV infection and subclinical EBV infection each associated with approximately fourfold greater odds of histologic evidence of chronic allograft injury (odds ratio 4.61 [95% confidence interval 1.18 to 18.07] and odds ratio 4.33 [95% confidence interval 1.34 to 14.00], respectively). An increase in viral load of CMV or EBV also associated with increased risk for moderate to severe chronic allograft injury. Taken together, these results demonstrate an association between subclinical CMV and EBV infections, which occur despite standard antiviral prophylaxis, and chronic allograft injury in pediatric renal transplant recipients.

KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary.

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Current state of pediatric renal transplantation.

Renal transplantation is the goal for the pediatric patient with end stage renal disease. Recent advances in technology and immunosuppression have greatly enhanced patient and graft survival. However, the chronic immunosuppression exposes children to multiple complications and side effects. The current objective of pediatric renal transplantation is to develop management strategies which minimize or eliminate immunosuppression morbidities in order to maximize the growth and development of this unique population.

BK virus nephropathy in pediatric renal transplant recipients: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry.

BACKGROUND AND OBJECTIVES: There is limited information regarding BK virus nephropathy in pediatric kidney transplantation. The objective of this study was to evaluate cases of BK virus nephropathy in the North American Pediatric Renal Trials and Collaborative Studies database. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a questionnaire that was sent to North American Pediatric Renal Trials and Collaborative Studies centers, we assessed the incidence, risk factors, clinical features, and outcomes of BK virus nephropathy in pediatric renal transplant recipients who received a transplant between 2000 and 2004. RESULTS: BK virus nephropathy was reported in 25 (4.6%) of 542 patients at a median onset of 10.1 mo after transplantation. The median age was 11 yr. All patients who were tested reported BK viruria, and 19 (91%) of 21 who had plasma tested reported BK viremia. Treatment of BK virus nephropathy included reduction of immunosuppression (84%), cidofovir (24%), leflunomide (8%), and intravenous Ig (20%). Simultaneous rejection treatment was reported in four (16%). The median creatinine was 2.0 mg/dl at a mean follow-up of 24 mo. There were six (24%) graft failures in the patients with BK virus nephropathy at a mean of 24 mo after diagnosis. Rejection occurred in eight (32%) after diagnosis. Multivariate analysis showed that use of polyclonal induction therapy and zero HLA DR mismatch were associated with the development of BK virus nephropathy. CONCLUSIONS: This first multicenter, retrospective, cohort study of BK virus nephropathy in pediatric renal transplant recipients found a BK virus nephropathy incidence of 4.6% and identified polyclonal induction and zero HLA DR mismatch as significant risk factors for BK virus nephropathy.

Adolescents are more likely to develop posttransplant lymphoproliferative disorder after primary Epstein-Barr virus infection than younger renal transplant recipients.

BACKGROUND: Primary Epstein-Barr virus (EBV) infection is the most important risk factor for development of posttransplant lymphoproliferative disorder (PTLD). Pediatric patients are often EBV seronegative pretransplant placing them at high risk. In the immune-competent population, primary herpesvirus infection is associated with higher morbidity with increasing age. METHODS: We performed a retrospective cohort study to describe the outcome of pediatric renal transplant recipients with primary EBV infection. All patients received 3 months of ganciclovir prophylaxis. Real-time quantitative polymerase chain reaction was used to determine the EBV viral load. Primary EBV infection was categorized as PTLD, symptomatic infection, or subclinical infection. RESULTS: There were a total of 46 patients with primary EBV infection: 11 developed PTLD, 12 had symptomatic infection, and 23 had subclinical infection. Adolescents were significantly more likely to develop PTLD than younger transplant recipients (P=0.05, chi-square). Multivariate analysis using logistic regression found that older age was the only significant risk factor for PTLD (odds ratio 1.24, 95% confidence interval 1.04-1.47; P=0.03). Among the 11 cases of PTLD, there were two deaths and two graft failures which all occurred in adolescent recipients (P=0.002). CONCLUSIONS: Among pediatric renal transplant recipients with primary EBV infection, adolescents are at significantly higher risk to develop PTLD and have poorer outcomes compared to younger recipients.

Contributions of the Transplant Registry: The 2006 Annual Report of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS).

This summary of the NAPRTCS 2006 Annual Report of the Transplant Registry highlights the significant impact the registry has had in advancing knowledge in pediatric renal transplantation worldwide. This cooperative group has collected clinical information on children undergoing a renal transplantation since 1987 and now includes over 150 participating medical centers in the USA, Canada, Mexico, and Costa Rica. Currently, the NAPRTCS transplant registry includes information on 9837 renal transplants in 8990 patients (NAPRTCS 2006 Annual Report). Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in outcome after renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation.

Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co-therapy.

We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C(max)), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m(2), and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r(2) = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI.

Emerging viral infections in transplantation.

Viral infections are an important complication of transplantation. The introduction of more potent immunosuppressive agents over the past decade correlates with an increase in the rate of hospitalizations of transplant patients with infections. Specifically, viral infections have emerged as a major source of morbidity and mortality in transplantation. There are several potential intervention strategies in the face of emerging infections and it is likely that the approach will differ depending on the virus in question. These include viral surveillance and pre-emptive therapy, intervention of the transplant community, and policy change at the level of government, blood bank and organ procurement organizations. This review focuses on the emergence of the herpesviruses; HHV-6 and HHV-7. In addition, the issue of virus transmission through organ transplant is addressed with a discussion of West Nile virus and the rabies virus.

Sonic tooth brushing reduces gingival overgrowth in renal transplant recipients.

Cyclosporine (CSA) is a commonly used immunosuppressive medication in pediatric transplantation. Drug-induced gingival overgrowth (DIGO) is a frequent side effect associated with CSA use and can impair the patient's ability to achieve good oral hygiene. This study tested the hypothesis that sonic tooth brushing and oral hygiene instruction can reduce the occurrence or severity of DIGO in CSA-treated pediatric renal transplant recipients. Twenty-three pediatric renal transplant patients with DIGO were randomly allocated to treatment or control groups. The treatment group received oral hygiene instruction and use of a sonic toothbrush, while the control group continued their usual home care with manual brushes. Dental impressions and photographs of all subjects were taken at baseline and every 3 months for a year. The casts and photographs were evaluated by a dental panel to compare the DIGO levels from baseline until the end of the study. After 12 months the control group had significantly more severe DIGO than did the sonic tooth brushing and oral hygiene instruction group (OR=4.5, 95%CI=1.2-16.0, P=0.03). Of the risk factors considered, only male gender was significantly associated with worse outcome (OR=6.1, 95%CI=2.3-16.1, P=0.03). The use of a powered toothbrush, together with oral hygiene instruction, may be an important component of health maintenance for pediatric transplant patients on CSA.

Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System.

BACKGROUND: Characterization of the incidence of posttransplant lymphoma over time may help guide the timing and intensity of posttransplant monitoring. We analyzed the United States Renal Data System to describe the occurrence of lymphoma following renal transplantation. METHODS: All end-stage renal disease patients placed on the transplant waiting list between January 1, 1990 and December 31, 1999 were considered. Survival analysis was used to estimate lymphoma risk in renal transplant patients. RESULTS: Of 89,260 eligible patients, a total of 556 lymphoma cases were identified with 357 in transplant patients. The overall rate of posttransplant lymphoma was 33.3/10,000 person-years in transplant patients. There was variation in the duration and magnitude of increased lymphoma risk by age. The highest rates of lymphoma were among transplanted patients in the first 12 months, after which the rate of lymphoma decreased. Among Caucasian transplant recipients less than 25 years of age, the adjusted relative risk of lymphoma ranged from 13.82 [95% CI: (3.96, 48.15)] within 6 months posttransplant to 3.46 [95% CI: (0.69, 17.44)] within months 30-36 posttransplant. Only patients under 25 years had a notably increased risk beyond the first 2 posttransplant years. The risk of lymphoma differed by race, with Caucasian patients at nearly double the risk of African-Americans. Gender was not associated with lymphoma incidence. CONCLUSIONS: We found and quantified a time-varying relationship between renal transplant and lymphoma risk. This information can be used in combination with knowledge of established risk factors to guide the schedule of posttransplant monitoring.

Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation.

PURPOSE: To evaluate the efficacy of a low-dose chemotherapy regimen in children with Epstein-Barr virus (EBV) -positive, post-transplantation lymphoproliferative disease (PTLD) after organ transplantation who have experienced failure with front-line therapy for PTLD. PATIENTS AND METHODS: Eligible patients received cyclophosphamide (600 mg/m2 intravenous for 1 day) and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles. RESULTS: Thirty-six patients treated on study were assessable for analyses. Front-line therapies for PTLD before study entry included immune suppression reduction or withdrawal (n = 36), antiviral therapy (n = 33), surgical resection (n = 8), rituximab (n = 2), and interferon alfa (n = 1). Reasons for failure of front-line therapy included progressive disease (PD; n = 33) and persistent disease with concurrent allograft rejection (n = 3). Thirty patients (83%) had stage III to IV disease, 92% had extranodal disease, and 75% had > or = three sites of disease. The overall response rate was 83% (75% complete response + 8% partial response). The relapse rate was 19%, with only one of five relapsed patients alive and disease-free. Four patients presented with fulminant, disseminated PTLD; only one of these four patients achieved a response, and all four died of PD. Two patients died of treatment-related toxicity. Three patients (8%) experienced allograft loss, but two of the three patients are alive and disease-free after a second transplantation. The 2-year overall, relapse-free, and failure-free (without PTLD and with functioning original allograft) survival rates were 73%, 69%, and 67%, respectively. CONCLUSION: This low-dose chemotherapy regimen is effective for children with EBV-positive, nonfulminant PTLD who have experienced treatment failure with front-line therapy, and this study represents the largest series of PTLD patients treated prospectively with a uniform chemotherapy regimen.

Renal transplantation in adolescents.

Renal transplantation remains the goal for the pediatric patient with end-stage renal disease. Recent advances in technology and immunosuppression have greatly enhanced patient and graft survival, while reducing significant complications. However, transplantation of adolescents is still fraught with the potential for serious problems. The increased risk of graft loss, late acute rejection, and incomplete rejection reversal observed in the adolescent age group demands further investigation. Lack of adherence to immunosuppression regimens may be an important contributory factor. Strategies to address the unique concerns of this high-risk population, including the use of a multidisciplinary team, are essential to improving outcomes.

Pediatric transplantation, 1994-2003.

This article uses OPTN/SRTR data to review trends in pediatric transplantation over the last decade. In 2003, children younger than 18 made up 3% of the 82,885 candidates for organ transplantation and 7% of the 25,469 organ transplant recipients. Children accounted for 14% of the 6,455 deceased organ donors. Pediatric organ transplant recipients differ from their adult counterparts in several important aspects, including the underlying etiology of organ failure, the complexity of the surgical procedures, the pharmacokinetic properties of common immunosuppressants, the immune response following transplantation, the number and degree of comorbid conditions, and the susceptibility to post-transplant complications, especially infectious diseases. Specialized pediatric organ transplant programs have been developed to address these special problems. The transplant community has responded to the particular needs of children and has provided them special consideration in the allocation of deceased donor organs. As a result of these programs and protocols, children are now frequently the most successful recipients of organ transplantation; their outcomes following kidney, liver, and heart transplantation rank among the best. This article demonstrates that substantial improvement is needed in several areas: adolescent outcomes, outcomes following intestine transplants, and waiting list mortality among pediatric heart and lung candidates.

Polyomavirus nephropathy in pediatric kidney transplant recipients.

Given the limited information regarding BK virus-associated nephropathy (BKVN) in pediatric kidney transplant recipients, we assessed the incidence, risk factors, clinical and virologic features of BKVN in pediatric renal transplant recipients at a single transplant center by means of a retrospective cohort study. Histologically confirmed BKVN developed in 6 of 173 (3.5%) kidney transplant recipients at a median of 15 months post-transplant (range: 4-47 months). At a median follow-up of 28 months (range: 5-32), all patients had functioning grafts with mean creatinine and GFR of 1.9 mg/dL and 58 mL/min/1.73 m2, respectively. At the time of diagnosis, all cases had viruria (median 6.1 x 10(6) copies/mL, range: 10(5) to 3.9 x 10(8) copies/mL) and viremia (median 21,000 copies/mL, range: 10,000-40,000 copies/mL). Recipient seronegativity for BKV was significantly associated with the development of BKVN (p = 0.01). BKVN is an important cause of late allograft dysfunction and is strongly associated with recipient seronegativity in pediatric kidney transplant recipients. Further studies to confirm this finding and to define the clinical utility of routine pre-transplant BKV serologic testing are warranted.

Current immunosuppressive agents in pediatric renal transplantation: efficacy, side-effects and utilization.

Advances in immunosuppressive therapy over the past decade have led to dramatic improvements in graft survival. The immunosuppression that is used is center-dependent and is constantly evolving with the development of new medications. The goal remains to find the best combination that will optimize graft survival, while minimizing the adverse effects.