Should pediatric patients wait for HLA-DR-matched renal transplants?

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA-DR mismatches on graft survival. Zero HLA-DR-mismatched kidneys had statistically comparable 5-year graft survival (71%), to 1-DR-mismatched kidneys (69%) and 2-DR-mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel-reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA-A, -B or -DR mismatch of the first transplant, nor was there a 'dose effect' when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA-DR-matched kidney.

Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol.

Immunosuppression with SRL may provide an opportunity to avoid long-term exposure to the nephrotoxicity of CNI. Thus, we have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients (median age 15.5 yr, IQR 8.5, range 1.3-21.7). The recipients were treated with daclizumab every 2 wk for the first 2 months, prednisone on a tapering schedule, MMF at 1200 mg/m(2)/day and SRL given b.i.d. The SRL was dosed to achieve defined target whole blood 12-h trough levels. We performed 24 SRL PK profiles in 13 stable pediatric renal transplant recipients at 1 and 3 months post-transplant. Half-life (T(1/2)) and terminal T(1/2) were 9.7 (7.1-24.6) and 10.8 (4.4-95.2) hours (median, range) respectively at month 1, and were 9.6 (5-17.8) and 12.1 (4.7-71.0) hours respectively at month 3. SRL trough levels correlated with AUC (r(2) = 0.84, p < 0.001). There was no relationship between SRL and mycophenolic acid (MPA) AUC values (r(2) = 0.04). During the first 3 months post-transplant only one patient experienced severe neutropenia and another patient had subclinical (histologic) evidence of a mild acute rejection episode with no change in renal function. We conclude that the T(1/2) of SRL in pediatric renal transplant recipients not treated with CNI is much shorter than what has been reported for adults, due to rapid metabolism. We conclude that children require SRL dosing every 12 h, higher doses and frequent drug monitoring to achieve target SRL concentrations.

Single-center analysis of early recurrence of nephrotic syndrome following renal transplantation in children.

Recurrence of nephrotic syndrome (NS) after transplantation (Tx) occurs in 20-50% of renal transplant recipients, with a median time to recurrence of 14 days and a 50% rate of graft loss. We performed a retrospective analysis of 22 pediatric patients with NS who received renal transplants at the Children's Hospital, Boston, between 1982 and 1999. During the first 14 days following Tx, 13 (59%) patients developed clinical recurrent nephrotic syndrome (RNS). RNS developed in 50% of living donor recipients and in 70% of cadaveric donor recipients (p= non-significant). Seven of the 13 patients with RNS were treated with plasmapheresis, while six received standard immunosuppressive induction therapy only. Two of the seven treated patients and one of the six untreated patients lost their grafts to RNS, yielding a total RNS graft loss rate of 23%. However, patients with RNS who achieved remission had significantly higher cumulative graft survival at 5 yr than did RNS patients who did not achieve remission (p< 0.001). Overall cumulative graft survival at 5 yr was not significantly different between the two groups: 67% in those with non-recurrent nephrotic syndrome (NRNS) vs. 64% in those with RNS, p= non-significant. We conclude that successful reversal of early RNS improves long-term graft survival in pediatric RNS. Multi-center studies are sorely needed to develop novel, less toxic therapies for native and recurrent NS.

Management of pediatric postrenal transplantation infections.

Infections are the leading cause of hospitalization and death after renal transplantation in children. Various agents are implicated in posttransplantation infections. Viral infections due to the cytomegalovirus and Epstein-Barr virus have assumed greater importance as other infections such as pneumocystis pneumonia have come under control. Multiple factors contribute to the difficulty in the prevention, diagnosis, and treatment of pediatric postrenal transplantation infections. Prevention of infections by adequate preparation before transplantation and the use of chemoprophylaxis should be made a priority. An aggressive approach to diagnosis is required when investigating fever in children. It is hoped that the use of more specific immunosuppressive agents that block only the alloactivated T cells and leave the rest of the immune response intact may result in a reduction in the number and frequency of infections.

Predictors for abnormal voiding cystourethrography in pediatric patients undergoing renal transplant evaluation.

The role of pretransplant voiding cystourethrography (VCUG) in adults has been questioned owing to the low prevalence of abnormal findings. As there are no studies evaluating the relevance of VCUG in children and because vesicoureteral reflux (VUR) occurs with higher prevalence in children, we performed a retrospective cohort study to identify any predictors for abnormal VCUG. We reviewed 271 consecutive renal transplants performed between 1980 and 1997. By logistic regression, the etiology of end-stage renal disease (ESRD) and age at transplantation (Tx) were strong predictors of abnormal pretransplant VCUG findings in children. On multi-variate analysis, children with urologic etiologies of renal disease had an odds ratio (OR) of 16.5 (p < 0.0001) for abnormal VCUG as compared to children with non-urologic or acquired causes of ESRD. Similarly, children transplanted when younger than 8 yr of age had an OR of 3.0 (p = 0.0043) for having an abnormal VCUG when compared with older children. Finally, our analysis suggests that children with abnormal pretransplant VCUG findings, whether or not pretransplant surgical correction was performed, were over three-fold more likely to require post-transplant urologic surgery when compared to children with normal pretransplant VCUG. We conclude that urologic causes of ESRD and age under 8 yr are strong independent predictors of abnormal pretransplant VCUG findings, and that these findings are of clinical relevance both in deciding whether to pursue pretransplant VCUG and in the post-transplant course of the patient.

Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date. METHODS: We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation. RESULTS: The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 843048) to a median of 190 days (range 42-944). PTLD occurred with greater frequency in white children (P=0.003) and in cadaver donor transplants (P=0.019), but there was no significant predilection for gender, younger children (0-5 years), or primary diagnosis. No significant difference was found in the use of anti-T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P<0.0001). CONCLUSIONS: There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.

Loss of living donor renal allograft survival advantage in children with focal segmental glomerulosclerosis.

BACKGROUND: Because of concerns of increased risk of graft loss with recurrent disease, living donor (LD) transplantation in children with focal segmental glomerulosclerosis (FSGS) has been controversial. METHODS: The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database from January 1987 to January 2000 was examined to determine differences in demographics, treatment, and outcomes in children with FSGS compared with other renal diseases. RESULTS: Data on 6484 children, 752 (11.6%) with FSGS, demonstrated that FSGS patients were more likely to be older and black, and were less likely to receive either pre-emptive or LD transplant (P < 0.001). No differences existed in human lymphocyte antigen (HLA) matching or immunosuppression regimens. Acute tubular necrosis occurred in more FSGS patients following LD (11.8 vs. 4.6%) or cadaveric (CD; 27.9 vs. 16.3%) transplants (P < 0.001). Graft survival was worse for LD FSGS patients (5 years 69%) compared with no FSGS (82%, P < 0.001) and was not significantly different than CD graft survival in the FSGS (60%) and No FSGS groups (67%). The LD to CD ratios of relative risk of graft failure were higher in FSGS patients (test for interaction, P = 0.01). Recurrence of original disease was the only cause of graft failure that differed between groups (P < 0.001). A greater percentage of LD FSGS graft failures was attributed to recurrence (P = 0.06). CONCLUSIONS: The impact of FSGS on graft survival in children is greatest in LD transplants, resulting in loss of expected LD graft survival advantage. The rationale for LD grafts in children with FSGS should be based on factors other than better outcomes typically associated with LD transplantation.

Renal branch artery occlusion in a 13-year-old hypertensive girl: initial treatment and treatment of recurrent stenosis by balloon angioplasty.

A 13-year-old girl who recently developed hypertension was diagnosed to have an occluded right renal branch artery and was treated successfully with percutaneous transluminal angioplasty (PTA). To our knowledge, PTA has not been reported as a treatment for totally occluded renal branch arteries, and there is no data available regarding the success rate and possible complications.

Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.

Many complications after renal transplantation can be prevented if they are detected early. Guidelines have been developed for the prevention of diseases in the general population, but there are no comprehensive guidelines for the prevention of diseases and complications after renal transplantation. Therefore, the Clinical Practice Guidelines Committee of the American Society of Transplantation developed these guidelines to help physicians and other health care workers provide optimal care for renal transplant recipients. The guidelines are also intended to indirectly help patients receive the access to care that they need to ensure long-term allograft survival, by attempting to systematically define what that care encompasses. The guidelines are applicable to all adult and pediatric renal transplant recipients, and they cover the outpatient screening for and prevention of diseases and complications that commonly occur after renal transplantation. They do not cover the diagnosis and treatment of diseases and complications after they become manifest, and they do not cover the pretransplant evaluation of renal transplant candidates. The guidelines are comprehensive, but they do not pretend to cover every aspect of care. As much as possible, the guidelines are evidence-based, and each recommendation has been given a subjective grade to indicate the strength of evidence that supports the recommendation. It is hoped that these guidelines will provide a framework for additional discussion and research that will improve the care of renal transplant recipients.

Increased nuclear factor-kappaB and angiotensinogen gene expression in posttransplant recurrent focal segmental glomerulosclerosis.

In an attempt to identify potential markers of steroid-resistance in focal segmental glomerulosclerosis (FSGS) we evaluated intra-graft gene expression of IkappaBalpha, nuclear factor-kappaB (NF-kappaB), and angiotensinogen in 60 biopsies from 27 pediatric renal transplant recipients. Intra-graft NF-kappaB expression was significantly elevated in recurrent FSGS (R-FSGS) (218.3 + 55.6 ag/fg versus NON-FSGS 121.1 + 19.9, P=0.04) but not in acute rejection. NF-kappaB:IkappaBalpha ratios were higher in cadaveric donor versus living related donor recipients (15.7 + 2.8 vs. 8.8 + 1.3, respectively, P=0.015), and in African-American versus Caucasian recipients (15.6 + 2.9 vs. 9.1 + 1.3, respectively, P=0.03). Intra-graft angiotensinogen gene expression was significantly elevated in R-FSGS (30.5 + 8.8 ag/fg R-FSGS vs. 16.0 + 4.7 NON-FSGS, P=0.009). We conclude that increased NF-kappaB and angiotensinogen gene expression are associated with R-FSGS. Increased NF-kappaB:IkappaBalpha ratios are associated with cadaveric donor recipients and African-American race.

Predictive factors for delayed graft function (DGF) and its impact on renal graft survival in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

We define delayed graft function (DGF) as the need for dialysis during the first post-transplant week. We analyzed 5272 transplants, of which 2486 were of living donor (LD) and 2786 were of cadaver donor (CD) origin. Twelve per cent (620/5272) of all patients developed DGF. Donor specific rates were 5.6% for LD and 19.1% for CD patients. Factors predictive of DGF in CD patients were: African-American race (25%), prolonged cold ischemia (24%), absence of T-cell induction antibody therapy and absence of HLA-DR matching. The relative risk (RR) for graft failure due to DGF was 6.02 (p < 0.001) in LD patients and 2.58 (p < 0.001) for CD recipients. Two-year graft survival (GS) in LD patients without DGF was 89.6%, compared to 41.6% for those with DGF (p < 0.001); in CD patients it was 80.2% and 49.5%, respectively (p < 0.001). Censoring for primary non-function, GS for LD patients with a functioning graft at 30 d post-transplant and no DGF was 91.5%, compared to 70.1% for those with DGF (p < 0.001); GS for CD patients was 83.8% and 68.7%, respectively (p < 0.001). However, when patients whose grafts had failed during the first year were censored no differences in GS were noted between patients with and without DGF for either LD or CD recipients. To determine whether DGF acts as an independent risk factor for graft failure, patients were segregated into four groups: rejection with DGF; rejection without DGF; DGF without rejection; and no DGF, no rejection. When these groups were compared DGF emerged as an independent risk factor for graft failure. This large study reviewing pediatric renal transplantation over 10 yr clearly delineates the role of DGF as a major risk factor for graft failure.

Optimal care of the pediatric end-stage renal disease patient on dialysis.

This manuscript is an effort on behalf of the American Society of Pediatric Nephrology to provide recommendations designed to optimize the clinical care of pediatric patients with end-stage renal disease (ESRD). Although many of the recommendations are evidenced-based with the supporting data being derived from a variety of sources, including patient registries, others are opinion-based and derived from the combined clinical experience of the authors. In all cases, it is recommended that the decision to initiate dialysis should be made only after an assessment of a combination of biochemical and clinical characteristics. Irrespective of the choice of dialysis modality (hemodialysis v peritoneal dialysis), dialysis efficacy should be measured regularly, and the dialysis prescription should be designed to achieve target clearances. Attention to dialysis adequacy, control of osteodystrophy, nutrition, and correction of anemia is mandatory, because all may influence patient outcome in terms of growth, cognitive development, and school performance. Finally, the availability of a multidisciplinary team of pediatric specialists is desirable to provide all facets of pediatric ESRD care, including renal transplantation, in an optimal manner. Future clinical research efforts intended to address topics such as dialysis adequacy, anemia management, and growth should be encouraged.

A new allocation plan for renal transplantation.

BACKGROUND: A novel plan of renal allograft allocation has been conducted by United Network for Organ Sharing Region 1 transplant centers since September 3, 1996, based upon HLA matching, time waiting, and population distance points. The objectives of this plan were to achieve a balance between increasing the opportunity of renal transplantation for those patients listed with long waiting times and promoting local organ donor availability. METHODS: A single list of candidates was formulated for each cadaver donor, assigning a maximum of 8 points for time waiting, a maximum of 8 points for population distance from the donor hospital, and HLA points based upon the degree of B/DR mismatch. Additional points were awarded to a cross-match-negative patient with a panel-reactive antibody of >80%, and to pediatric patients. RESULTS: The total number of kidneys transplanted to patients who had waited >3 years was 100 (46%), and to patients who had waited >2.5-3 years was 29 (13%). However, the total number of kidneys transplanted to patients with the maximum population distance points was only 72 (33%). Thus, although the plan achieved a favorable distribution of kidneys to patients with longer waiting times (nearly 60%), the other, equally important objective of promoting local donor availability was not initially accomplished. Moreover, minor HLA B/DR differences between the donor and the recipient (i.e., not phenotypically matched) were unexpectedly consequential in determining allocation. As a result of these observations, the following adjustments were made in the plan (as of December 3, 1997): a maximum of 10 points for population distance, a maximum of 8 points for time waiting (both by a linear correlation), and the retention of HLA points for 0 B/DR mismatch only. After these interval changes, the percentage of patients receiving a kidney with some population distance points increased from 85% to 96%. Conclusions. We have shown that a heterogeneous region of multiple transplant centers can devise (and modify) an innovative and balanced plan that provides an equitable system of allocation for an ever-increasing number of patients.

Steady improvement in short-term graft survival of pediatric renal transplants: the NAPRTCS experience.

This report of pediatric renal transplantation covers the years 1987-1998. Since its inception in 1987, the NAPRTCS has collected data on 6,038 transplants performed in 5,516 patients provided by 73 renal centers across the country. FSGS, together with developmental lesions of dysplasia and obstructive uropathy, account for 40% of all transplants. There has been a steady increase in the use of LD donors among children with 54% of all transplants in 1996 and 1997 being live-related. About 72% of LD transplants are performed in Caucasian children, with African-American children unfortunately receiving a disproportionate percentage of CD kidneys. There has been a steady decline in the use of CD kidneys recovered from young individuals and a gradual decline in the number of transplants performed in young recipients (< 6 years old). Graft survival for LD recipients was 91%, 84% and 79% at one, 3 and 5 years, respectively, and the comparative figures for CD recipients were 81%, 72% and 64%, respectively. Acute and chronic rejections account for most of the graft losses, with chronic rejection accounting for more than 30%. There has been a steady improvement in one-year graft survival of CD recipients with the 1997-1998 cohort exhibiting an improvement of 16% over the 1987-1988 cohort. This improvement has been brought about by eliminating the use of infant donor kidneys, reducing the number of random transfusions and increasing the maintenance dose of cyclosporine. Posttransplant growth continues to be poor, with catch-up growth being exhibited only in children under age 6.

A novel united network for organ sharing region kidney allocation plan improves transplant access for minority candidates.

BACKGROUND: We report the consequences of a novel kidney allocation system on access of non-Caucasians (NC) to kidney transplantation. This new plan has provided a balance of allocation determinants between time waiting, HLA match, and geography (population density between donor and recipient center). METHODS: Three sequential systems of regional allocation were analyzed: period I (September 1994 to September 1996), period II (September 1996 to November 1997), and period III (December 1997 to March 1 1999). Periods II and III are reflective of the new allocation plan. RESULTS: During periods II and III, the NC rate of kidney transplantation increased closer to the NC proportion on the wait list, comparatively exceeding the national UNOS data. There was no statistical difference in regional mean wait time between Caucasian and NC. Improvements in access to transplantation for NCs between period I and periods II and III appear to be related to changes in geographic allocation weight from local unit to population density points, to the inclusion of the entire region in the plan, and to the deletion of intermediate degrees of B/DR mismatching in the revised plan. Despite the increased proportion of NCs on the wait list from period I to period III, the percentage difference between the proportion of NCs waiting on the list and the proportion NCs receiving a transplant fell from 7.8% to 4.9%. CONCLUSIONS: These data demonstrate that this new allocation plan was associated with improved access of minority candidates to transplantation. The broadening of geographic allocation and the alteration of HLA points appear to permit a more favorable opportunity for renal transplantation to NC candidates. selection, compared to the UNOS formula. In this report, we analyze the consequences of the Region 1 allocation system on the access of non-Caucasian (NC) candidates to cadaver donor kidney transplantation.

Cytotoxic lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts.

BACKGROUND: We have shown previously that heightened expression of the cytotoxic lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. METHODS: We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. RESULTS: Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. CONCLUSION: Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection.