Ruth A. McDonald

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.

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease

To the Editor: We have read the letter to the editor by Jerzy Przedlacki1 and the response from the authors2 of the Kidney Disease-Improving Global Outcomes (KDIGO) clinical practice guidelines for bisphosphonate (BP) treatment in chronic kidney disease (CKD), and would like to share our concerns regarding the use of BP treatment of CKD. The kidney is the organ that excretes many drugs, and any change in renal function will affect the pharmacology of these drugs. Existing or residual renal function of the patient will have to be taken into account while prescribing drugs. This is just as important for the patient with CKD 4 or 5, including those with CKD 5 already on peritoneal dialysis or hemodialysis, who may still have residual renal function. Nephrotoxic drugs including nonsteroidal anti-inflammatory drugs can very readily destroy whatever residual renal function patients may still have. Residual renal function is important to preserve as it contributes to less patient morbidity and mortality3 in the dialysis patient. Recently, there have been adverse reports of a certain BP that works by inhibiting osteoclast-mediated bone resorption, thereby slowing the breakdown of bone to reduce the risk of fractures. As of 14 August 2009, there have been 139 post-marketing reports of renal impairment following its use as an infusion worldwide. Many of these occur in patients with pre-existing medical conditions or risk factors (elderly, renal impairment, and/or concurrent dehydration), or in those on nonsteroidal anti-inflammatory drugs or other concurrent exposure to other nephrotoxic agents. There have also been cases requiring dialysis, and occasional fatal outcomes have been reported in patients with pre-existing renal impairment and concomitant risk factors.4, 5, 6, 7

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

Abstract:  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.

Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids

Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double‐blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3‐fold higher in children aged ≤5 versus those >12 years (p = 0.0017). EBV seronegative subjects had a 4.7‐fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient– (D+/R–) subjects, the RH increased by 6.1‐fold (p = 0.0001). In a multivariate model, risk factors included recipient age ≤5 years (RH 3.2, 95% CI: 1.1–9.6, p = 0.034) and EBV D+/R– status (RH 7.7, 95% CI: 1.6–35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This ‘robust’ immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over‐immunosuppression in a high‐risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.

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 transplant outcomes in adolescents: a report of the North American Pediatric Renal Transplant Cooperative Study.

Abstract: Recipient age at transplant is an important predictor of outcome. The age most commonly associated with increased risk is infancy. An important, but less recognized, age group at high risk is the adolescent. We analyzed the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database to determine the patient and graft outcomes of adolescents (13–17 yr of age) compared with younger children. The adolescent age group had a similar percentage patient survival rate compared to that of the younger age groups, except for the infants (0–1 yr), who had a dramatic drop‐off in the early post‐transplant period. Regarding the long‐term graft survival for living donor recipients, adolescents had the poorest percentage graft survival compared to the other age groups, including the infants (p < 0.001). Among cadaver donor recipients, the adolescent group had a significantly poorer graft survival than the 2–5 yr and 6–12 yr age groups (p < 0.001). Although the infants had the poorest graft survival (p < 0.001), after the sharp drop‐off in the immediate post‐transplant period the slope of their graft‐survival curve was similar to that of the 13–17 yr age group. The percentage of late acute rejection episodes among the 6–12 yr (26.0%) and 13–17 yr (22.2%) age groups was significantly higher than in the younger age groups (p < 0.001). The adolescents had relatively poor rejection reversal outcomes compared to the other age groups, with fewer complete rejection reversals and a greater number of partial reversals (p < 0.001). The increased risk of graft loss, late acute rejection, and incomplete rejection reversal observed in the adolescent age group demands further investigation. Lack of compliance with immunosuppression regimens may be an important contributory factor. Strategies to address the unique concerns of this high‐risk population will be essential to improve outcomes.

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 × 106 copies/mL, range: 105 to 3.9 × 108 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.

Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study

Abstract:  The North American Pediatric Renal Transplant Cooperative Study has collected clinical information on children undergoing a renal transplantation since 1987. This cooperative group now includes over 150 participating medical centers in the United States, Canada, Mexico, and Costa Rica. This report covers the years from 1987 through 2001 and includes data on 7545 renal transplants in 6878 patients. This report demonstrates changing trends in many areas of pediatric transplantation including increasing numbers of African American and Hispanic children receiving transplantation, remarkable improvements in the rate of acute rejection, rejection reversal, and short‐ and long‐term allograft survival. In the most recent cohorts of patients, we now see that 1‐yr allograft survival is no different in cadaver donor compared to living donor recipients and in infants compared to all other age groups. However, this analysis also reveals areas of continued challenges including inferior outcomes in African American and adolescent populations, chronic rejection, and the adverse effects of immunosuppression.

The 1997 Annual Renal Transplantation in Children Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

Abstract: This report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), covering the years 1987–96 (January 15, 1997), analyzed data on 4898 patients who received 5362 transplants. Over the 10 yr of the study, 21.3% of the patients were under the age of 6 yr. Of the disorders that lead to end‐stage renal disease (ESRD), structural and developmental anomalies of aplasia, dysplasia, and obstructive uropathy accounted for over 1500 patients. Despite the potential therapies for focal segmental glomerulosclerosis (FSGS), there has been little change in its incidence and this lesion continues to be the most common cause of renal failure and transplantation among acquired diseases. Eighty‐nine per cent of patients with a functioning graft continue to receive cyclosporin A (CsA) 5 yr post‐transplantation, and 84% of patients continue to receive azathioprine (AZA), whereas 26% of patients receive alternate‐day steroid therapy at 4 yr post‐transplant. Thirty‐seven per cent of the living donor (LD) recipients and 47% of cadaver donor (CD) recipients were treated with the polyclonal T‐cell antibody ATG/ALG for induction, and the monoclonal T‐cell antibody, OKT3, was utilized for induction in 12% of LD patients and in 19% of CD patients. Twenty‐five per cent of the 5362 transplants (1333) have failed over the 10‐yr period. Graft survival is 90% at 1 yr and 74% at 6 yr for LD kidneys, and is 80% at 1 yr and 58% at 6 yr for CD patients. The most common cause for graft failure (30%) is chronic rejection. For recipients of LD grafts, relative risk (RR) factors for graft survival are African–American race (RR = 2.1, p<0.001) and greater than five prior transfusions (RR = 1.6, p<0.001). Prophylactic anti‐T‐cell antibody reduces the risk of graft failure (RR = 0.76, p=0.009). For recipients of cadaver kidneys, risk factors are: recipient age < 2 yr (RR = 2, p<0.001), donor age < 6 yr (RR = 1.3, p=0.005), and absence of induction T‐cell antibody (RR = 1.31, p<0.001).

Measuring Health-Related Quality of Life in Children With ESRD: Performance of the Generic and ESRD-Specific Instrument of the Pediatric Quality of Life Inventory (PedsQL)

BACKGROUND Minimal data exist to describe health-related quality of life in children with end-stage renal disease (ESRD). STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS 193 children aged 5 to 18 years with ESRD and 190 parents of children aged 2 to 18 years with ESRD at 4 pediatric nephrology centers across the United States. OUTCOMES & MEASUREMENTS Generic and disease-specific health-related quality of life. The Pediatric Quality of Life Inventory version 4.0 (PedsQL 4.0) Generic Core Scales encompass: (1) Physical Functioning (8 items), (2) Emotional Functioning (5 items), (3) Social Functioning (5 items), and (4) School Functioning (5 items). The PedsQL 3.0 ESRD Module encompasses: (1) General Fatigue (4 items), (2) About My Kidney Disease (5 items), (3) Treatment Problems (4 items), (4) Family and Peer Interaction (3 items), (5) Worry (10 items), (6) Perceived Physical Appearance (3 items), and (7) Communication (5 items). RESULTS Internal consistency reliability for the PedsQL 4.0 Generic Core Scales and the PedsQL 3.0 ESRD Module was acceptable for both parent-proxy report and child self-report, with the exception of 1 parent-proxy report and 3 child self-report scales on the ESRD Module. The PedsQL Generic Core Scales differentiated between healthy children and children with ESRD, supporting discriminant validity. Intercorrelations between the PedsQL Generic Core Scales and the ESRD Module were in the medium to large range, supporting construct validity. A confirmatory factor analysis further supported construct validity of the ESRD Module. LIMITATIONS Test-retest reliability was not conducted, limited generalizability may exist given the age distribution of the children included, and imperfect agreement between child and parent-proxy reports. CONCLUSIONS Results support the feasibility, reliability, and validity of the PedsQL 4.0 Generic Core Scales in children with ESRD and provide initial support for the PedsQL 3.0 ESRD Module, although additional validation testing is warranted.