PRIOR rhGH AND RENAL TRANSPLANT FUNCTION

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. 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. 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). 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.

The risk of progressing to end-stage renal disease in children with lupus glomerulonephritis is 18% to 50%. Published reports of transplantation secondary to end-stage renal failure in adult patients with systemic lupus erythematosus (SLE) demonstrate equivalent patient and graft survival. The purpose of this analysis is to compare patient and graft outcomes of pediatric SLE renal transplant recipients with an age-, race-, and gender-matched control group. A retrospective analysis of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database identified 100 renal transplants performed in 94 young SLE patients. A control group of 470 children having received 501 renal transplants was identified. The SLE cohort was primarily female (82%), non-Caucasian (61%), adolescents and differed from the control group in being less likely to be preemptively transplanted, in receiving longer pretransplant dialysis, and in being likely to have received more than five pretransplant transfusions. After transplantation, there were no differences seen in patient survival at 3 years (89% vs. 95%, SLE vs. control) or in overall graft failure rates (31% vs. 29%, SLE vs. control). There was a trend toward poorer graft survival in non-white SLE patients receiving living donor grafts compared with white SLE patients. An increased graft failure rate was seen among those SLE cadaveric transplant recipients receiving peritoneal dialysis before transplant compared with controls and compared with SLE patients receiving hemodialysis. No differences were seen in rates of acute tubular necrosis or overall acute rejection incidence, although there was a significant increase in the percentage of living donor SLE patients who experienced greater than four rejection episodes. There were nonsignificant trends toward increased graft loss due to patient death with a functioning graft as well as increased mortality secondary to infection in the SLE patients. The results of renal transplantation in young SLE patients are comparable to those seen in an age-, race- and gender-matched control group. The similar patient and graft survival is seen despite the SLE patients having an underlying disease with multiorgan involvement and despite receiving immunosuppression for potentially prolonged periods before transplantation. No outcome differences were seen except for an unexplained increase in the incidence of recurrent rejections (> or =4) in the living donor SLE patients as well as increased graft failure rate in those patients receiving cadaveric renal transplants after a period of peritoneal dialysis. The nonsignificant trends toward increased graft failures in non-white SLE patients receiving living donor grafts, increased graft loss secondary to death with a functioning graft, as well as the increased mortality due to infection deserve recognition and further study.

834 Peritoneal Dialysis (PD) is a major form of renal replacement therapy and is employed in more than 60% of pediatric patients with end stage renal disease. However, there are no large studies on the outcome of renal transplantation (Tx) in North American children on PD. This study presents an analysis of North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) data and compares graft and patient survival rates, incidence of acute tubular necrosis (ATN), acute rejection episodes, and causes of graft failure in pediatric patients maintained on PD prior to renal Tx with those maintained on hemodialysis (HD) and those undergoing preemptive Tx (PET). There were 2495 children (59% male; 61% Caucasian) who underwent primary renal Tx between 1/1/1992 and 12/31/1996. Of these, 1090 (43.7%) were on PD, 780 (31.3%) on HD, and 625 (25.1%) were PET. The mean (±S.D) duration of follow-up post Tx was (in months): 28.6±19.5 (PET), 27.5±19.1 (PD), and 27±18.9 (HD). The overall graft survival rate was similar in PD and HD groups; however, both were decreased compared to the PET group (3 year; 82% for both PD and HD; 89% PET; overall p=0.0003; PD vs. HD, p=NS). There was no difference in the overall patient survival rates in the three groups (96% PET, 95% PD, 97% HD). The incidence of ATN in the first seven days post Tx was higher in PD and HD patients compared to PET (11% PD and 12% HD vs. 2% PET, p<0.001; HD vs. PD, p=NS). There was no significant difference in the time to first acute rejection episode in any of the three groups. Both PD and HD groups had longer initial hospital stay (>9 days) compared to PET (72% for PD or HD vs. 63% PET; p<0.001). The major single cause of graft failure in each group was: PD - vascular thrombosis (20%), HD - chronic rejection (27%), PET - acute rejection and chronic rejection (21% each). Conclusion: We confirm small European and North American studies showing comparable patient and graft survival rates for children receiving PD prior to Tx to those achieved in HD patients. However, graft survival is improved in patients receiving PET compared to both PD and HD. Graft loss due to vascular thrombosis is more common in children receiving PD compared to HD.

This report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) covers the years 1987-1997, and analyses data on 3,133 cadaver donor (CD) transplants performed in 2,736 patients. There has been a steady decline in the number of CD transplants in children since 1996. Kidneys recovered from donors under 10 years of age accounted for 35% of all transplants in 1987, whereas by 1996 they comprised less than 20%. Caucasian children received 54% of CD transplants, whereas African-American children received 21%. Children under 6 years of age received 17% of CD transplants. Approximately half (46%) of the patients were induced with a T-cell antibody, and at 7 years post-transplant triple therapy is used in 70% of those with a functioning graft. Cyclosporin A is the primary immunosuppressant, with 92% of the patients being maintained on it at 5 years post-transplant. Among patients receiving a transplant in 1997, 11% were initiated with another calcineurin inhibitor, tacrolimus. At 15 days post-transplant 20% of the patients have had a rejection episode and by day 45, 46% have had an acute rejection. The probability of developing a rejection within the first year was reduced from 71% in 1987-1988 to 47% in 1995-1996.

Growth failure associated with mild Chronic Renal Insufficiency (Glomerular Filtration Rate between 50-75 ml/min/1.73 M2): A report from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 1667

ABSTRACT. Hypertension frequently complicates the course of chronic renal insufficiency (CRI) in children. This study sought to define the role of hypertension in progression of CRI in children by using the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) CRI database. The study cohort consisted of 3834 patients aged 2 to 17 yr with an estimated GFR (eGFR) ≤75 ml/min·1.73 m² enrolled onto NAPRTCS. The time to end point was defined as the time between registry enrollment and progression to renal substitution therapy or a 10 ml/min·1.73 m² drop in GFR from baseline, whichever was first. Forty-eight percent of the study patients had hypertension at baseline. There was a significant difference in reaching end points between hypertensive and normotensive children (58% <i>versus</i> 49%, respectively, <i>P</i> &lt; 0.001). Significant difference in outcome between hypertensive and nonhypertensive patients was seen in children with eGFR 50 to 75 ml/min·1.73 m² (<i>P</i> &lt; 0.001). Multivariate Cox regression modeling demonstrated that systolic hypertension was a significant independent predictor of progression of CRI (<i>P</i> = 0.003). Other significant predictors of CRI progression in this model included older age (<i>P</i> = 0.0001), African American ethnicity (<i>P</i> = 0.03), acquired cause of renal disease (<i>P</i> = 0.0001), and baseline eGFR &lt;50 ml/min·1.73 m² (<i>P</i> = 0.0001). Hypertension is a highly significant and independent predictor for progression of CRI in children. E-mail: Mark.Mitsnefes@cchmc.org

The care and management of renal transplant recipients, and especially of pediatric renal transplant recipients, is potentially complex and exacting. Balancing the amount of immunosuppression to prevent toxicity and to avoid rejection is not always straightforward. In addition, the specific needs of pediatric patients add another layer of complexity to their care. A reasonable question is whether routine protocol kidney biopsies (by definition, in patients with stable renal function) will help to optimize the management of pediatric kidney recipients, and whether the benefits justify making them the standard of care for all pediatric kidney recipients. I would argue that they do not, and that protocol biopsies should not yet be performed routinely in all patients. There is no question that obtaining renal allograft biopsies to evaluate renal dysfunction is essentially mandatory. Without a biopsy to establish the diagnosis, any therapeutic intervention is a poorly educated guess. However, the use of invasive biopsies to evaluate all children with stable renal function is another matter. It is certainly possible, even likely, that such biopsies, preferably in combination with mechanistic studies of immunologic reactivity, represent important research tools. They can reveal whether important subclinical events are occurring that can impact on long-term patient and graft survival. Such studies should be performed in selected centers with the manpower and expertise to perform protocol biopsies safely and routinely. It is even reasonable for a given center to consider them as its standard of care. At issue is whether the results from studies that have performed protocol biopsies justify their expansion to every pediatric kidney transplant program. There is a fairly substantial literature on protocol biopsies in adult renal transplant recipients, and a smaller literature on pediatric recipients. These studies show a variable incidence of subclinical acute rejection, ranging from 2.6–100%, with many reports in the 25–30% range (1–18). There is also a literature demonstrating an incidence of subclinical chronic allograft nephropathy (CAN) (6, 8, 10, 13, 14, 17–25), and a suggestion that the presence of CAN with vasculopathy is a poor prognostic factor for long-term outcome (8). However, the important issue in protocol biopsies is whether performing them will lead to management changes that will improve long-term graft survival and function. The only randomized trial that has demonstrated a benefit to diagnosing and treating subclinical acute rejection is the adult Winnipeg experience and, while it is persuasive, it is a relatively small, single center experience (3–6). The pediatric protocol biopsy experience from Winnipeg, which was not randomized, was associated with excellent three-yr graft survival and renal function, but was associated with an incidence of CAN of 86%, despite the aggressive treatment of subclinical rejection (26). While the risks of protocol biopsies are low, they are not zero. Substantial morbidity, and even mortality, has been associated with kidney transplant biopsies; fortunately, these catastrophic complications are rare (12, 27). In patients with an indication for a biopsy, the low risk is justified by the benefit of knowing the cause of the renal dysfunction. In a protocol biopsy setting, it is a reasonable question to ask whether the risk is justified. By making protocol biopsies the standard of care in all programs, there is an increased risk of a serious biopsy-related adverse event, especially in centers without the infrastructure and expertise to perform biopsies routinely and safely. There is additionally the issue of who will pay for the increased number of biopsies. While protocol biopsies may be useful in centers where there is sufficient expertise to perform them and ideally where concomitant immunologic studies can be performed, it is not clear that there is enough benefit to expand their use to every pediatric transplantation program. It would certainly be worth considering a large, multicenter randomized trial of protocol biopsies in pediatric kidney transplant recipients, along the lines of the Winnipeg trial, to see if there would be a demonstrated benefit, in terms of graft survival and function. This would be a worthwhile project for either the International Pediatric Transplantation Association (IPTA) or North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to consider, and would provide a real answer to this question.

The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) group has analyzed its database from January 1987 to October 1998. During this time we enrolled 6,395 transplants: of these, 5,323 were primary and 1,072 were repeat transplants. Overall, 30.8% (483/1,566) of the grafts failed as a result of chronic rejection. For living donor (LD) grafts, the failure rate as a result of chronic rejection was 32% (175/553), and it was 30% (308/1,013) for cadaveric donor (CD) transplants. A proportional hazards model identified first acute rejection, multiple rejections, and a late acute rejection as risk factors for the development of chronic rejection. Additional risk factors for the development of chronic rejection were African-American race, a repeat transplant, and a cyclosporin A (CsA) dose of < 5 mg/kg/day. Our analysis found that one acute rejection episode increases the risk of chronic rejection graft failure three-fold. Patients with two or more acute rejections have a 12-fold increased relative risk (RR) of chronic rejection graft loss (CRGL). A late acute rejection (> 365 days post-transplant) increases the RR by six-fold. Two or more acute rejections, when the first is a late initial rejection, increases the RR 26-fold. Based on this information we have initiated a multicenter trial of intervention in patients with one or more acute rejections.

The main goals of renal transplantation in children with end-stage renal disease (ESRD) are to improve long-term patient and graft survival, quality of life, and optimize growth and development. Currently 52% of all children in North America undergoing renal transplantation receive a kidney from a live donor [North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)] (1), and children under five years of age are more likely to receive living donor kidneys.

Acute rejection is a frequent event in pediatric renal transplantation; it can diminish allograft function and affect long-term outcome. Recent data from the North American Pediatric Renal Transplant Cooperative Study indicates that the rate of acute rejection remains high despite current immunosuppressive regimens. In this retrospective series, we examined 37 pediatric renal transplant recipients who received induction doses of antithymocyte globulin combined with maintenance immunotherapy using tacrolimus, mycophenolate mofetil, and prednisone. The postoperative course was reviewed for initial and total hospital stay, number of rehospitalizations, evidence of posttransplant complications, graft fibrosis, and overall patient and graft survival. Three episodes of acute rejection (8.1%) were recorded in the first year posttransplant. The median initial hospital stay for patients receiving a kidney transplant was 8 days. Patient and graft survival were 100% and 91.9% at 1 year, respectively. The incidence of viral infection (cytomegalovirus, BK virus, and Epstein-Barr virus) and posttransplant lymphoproliferative disease remained low. Urinary tract infection and fluid and electrolyte complications were the main causes of posttransplant hospitalization. We conclude that induction with antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone should be considered a valuable tool in the management of children undergoing renal transplantation.

Peritonitis is the most common complication and the leading cause of death in pediatric peritoneal dialysis (PD) patients. According to the most recent data available from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), approximately 25% of pediatric PD patients who die succumb to infection. There are no reported cases of Mycobacterium tuberculosis (MTB) or Mycobacterium avium-intracellulare peritonitis in the NAPRTCS registry. With an increasing incidence of MTB worldwide and the impairment of cellular immunity in chronic renal failure patients, it is not surprising that mycobacterium peritonitis can occur in PD patients. We report two pediatric PD patients with mycobacterial peritoneal infection diagnosed over an 11-year period at our institution. One patient presented with a malfunctioning Tenckhoff catheter and again 3 years later with hyponatremia and ascites. The other presented with recurrent culture-negative peritonitis. These cases illustrate the importance of more extensive evaluation of PD complications, to include evaluation for mycobacterium with special media or peritoneal biopsy, in the above clinical settings if the routine work-up is unrevealing.

Reduction in Acute Rejections Decreases Chronic Rejection Graft Failure in Children: A Report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

Graft thrombosis is a common cause of graft failure in pediatric renal transplantation. Several previous studies, including a North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) review of pretransplant dialysis status and graft outcomes, have described a potential correlation of peritoneal dialysis (PD) and graft thrombosis. This issue is of particular concern for pediatric transplant programs as more than 65% of children with end stage renal disease are treated with PD. We reviewed 7247 pediatric renal transplants performed between 1987 and 2001. Thrombosis was the cause of graft loss in 2.7% (199) of all the transplants performed. Among failed transplants, thrombosis was the third most common cause of graft loss in both index (11.6%) and subsequent transplants (14.5%). Thrombosis becomes the most common cause of graft failure (21%, 61/294) if one looks at transplants in the later cohort, from 1996 to 2001. This change is primarily because of a decrease in the incidence of acute rejection. In the PD group, 3.4% of all grafts were lost as a result of thrombosis. This compares with 1.9% in the hemodialysis group, 2.4% in the pre-emptive transplant group, and 4.1% among patients who received both dialysis modalities. There was a statistically significant difference in thrombosis failure risk in the different dialysis groups (p = 0.005) with those who received only peritoneal dialysis having the highest risk. Additional significant risk factors for graft thrombosis included; cadaver donor source (p < 0.001), cold ischemia time >24 h (p < 0.001), history of prior transplant (p < 0.001), donor age <6 yr (p < 0.001), and >5 pretransplant blood transfusions (p = 0.02). Using stepwise proportional hazards modeling, only pretransplant peritoneal dialysis, >24 h cold ischemia time, prior transplant, and donor age <6 yr were simultaneously associated with an increased risk of thrombosis. We conclude that pretransplant PD is associated with an increased risk of graft thrombosis. Special precautions should be undertaken in pediatric renal transplant patients who have received PD, especially infants and young children.

Supplemental feedings are commonly recommended for young children on dialysis but their effect on growth parameters and mortality has not been well documented. We report the results of a North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) survey on the impact of supplemental feedings on growth and mortality in children < 6 years of age at dialysis initiation. Sixty-four nonsurvivors (NonS) were matched with 110 survivors (S) for age at dialysis initiation, primary renal disease, and year of entry into the NAPRTCS database. Questionnaires were completed by participating centers on 137 patients (51 NonS, 86 S). Supplemental feedings were given to 70% of patients and more commonly given to patients < 2 years of age compared to those 2-5 years of age at dialysis initiation (P < 0.001). Supplemental feedings were also more commonly given to patients with nonrenal disease in addition to renal disease compared to those with renal disease only (P < 0.001). In patients receiving supplemental feedings, the method of supplemental feeding was most commonly by nasogastric tube in patients < 2 years of age compared to those 2-5 years of age (P = 0.027). Supplemental feeding use was not different in S compared to NonS. There were no differences in height standard deviation score (SDS), weight SDS, or change in height or weight SDS in patients receiving supplemental feedings compared to those who did not. The height and weight SDS did not improve over time on supplemental feeds. In summary, despite the common use of supplemental feedings in young patients on dialysis, height, weight, and mortality remain unaffected. Prospective long-term evaluation of this therapy is needed to determine the effectiveness of supplemental feeding.

We examined whether height less than the 1% for age (z score <-2.5) at dialysis initiation predicts adverse clinical outcomes for children with kidney failure. National cohort study of children initiating dialysis, followed for a minimum of 1 month to a maximum of 8 years. Voluntary consortium of pediatric nephrology centers across the United States and Canada in the North American Pediatric Renal Transplant Cooperative Study. Two thousand three hundred six patients </=21 years old initiated on dialysis between 1992 and 2000. Outcome Measures. School attendance, transplant wait listing, hospitalization rates, and survival. Although there were no differences in transplant wait listings, school-aged children with short stature were less likely to be attending school full-time than were their counterparts with more normal height, even if medically capable. Short-stature patients have significantly more hospital days per month of dialysis follow-up than those patients with better growth (mean: 1.92 vs 1.58; median: 0.73 vs 0.44 hospital days per month of follow-up). Cox proportional hazards regression analyses show that children with height <1% for age have a twofold higher risk of death than those with more normal height, even after controlling for patient age, race, gender, cause of end-stage renal disease, wait list status, and dialysis modality. Poor growth during chronic renal insufficiency leading to short stature at dialysis initiation is a marker for a more complicated clinical course for children with kidney failure. Aggressive nutritional support and early referral to a nephrologist to optimize growth may improve long-term outcomes for children with chronic kidney disease.