The effects of the DASH dietary pattern on clinical outcomes and quality of life in adults with uncontrolled asthma: Design and methods of the ALOHA Trial.

BACKGROUND: Poor diet quality is an important risk factor for increased asthma prevalence and poor asthma control. To address the question of whether adults with asthma can benefit from following a healthy diet, this trial will test the efficacy and mechanisms of action of a behavioral intervention promoting the Dietary Approaches to Stop Hypertension (DASH) dietary pattern with sodium reduction among patients with uncontrolled asthma. METHODS: In this 2-arm randomized clinical trial, 320 racially/ethnically and socioeconomically diverse adults with uncontrolled asthma on standard controller therapy will be randomized to either a control or an intervention group and assessed at baseline, 3, 6 and 12 months. Control and intervention participants will receive education on lung health, asthma, and other general health topics; additionally, the intervention group will receive DASH behavioral counseling over 12 months. The primary hypothesis is that the DASH behavioral intervention, compared with the education-only control, will lead to significantly more participants with minimum clinically important improvement (responders) in asthma-specific quality of life at 12 months. Secondary hypotheses will test the intervention effects on other asthma (e.g., asthma control, lung function) and non-asthma outcomes (e.g., quality of life). Additionally, therapeutic (e.g., short chain fatty acids, cytokines) and nutritional biomarkers (e.g., dietary inflammatory index, carotenoids) will be assessed to understand the mechanisms of the intervention effect. CONCLUSION: This trial can substantially advance asthma care by providing rigorous evidence on the benefits of a behavioral dietary intervention and mechanistic insights into the role of diet quality in asthma. CLINICALTRIALS: gov #: NCT05251402.

Subclinical inflammation and chronic renal allograft injury in a randomized trial on steroid avoidance in pediatric kidney transplantation.

Steroid avoidance is safe and effective in children receiving kidney transplants in terms of graft function and survival, but the effects on allograft histology are unknown. In this multicenter trial, 130 pediatric renal transplant recipients were randomized to steroid-free (SF; n = 60) or steroid-based (SB; n = 70) immunosuppression, and underwent renal allograft biopsies at the time of graft dysfunction and per protocol at implantation and 6, 12 and 24 months after transplantation. Clinical follow-up was 3 years posttransplant. Subclinical acute rejection was present in 10.6% SF versus 11.3% SB biopsies at 6 months (p = 0.91), 0% SF versus 4.3% SB biopsies at 1 year (p = 0.21) and 0% versus 4.8% at 2 years (p = 0.20). Clinical acute rejection was present in 13.3% SF and 11.4% SB patients by 1 year (p = 0.74) and in 16.7% SF and 17.1% SB patients by 3 years (p = 0.94) after transplantation. The cumulative incidence of antibody-mediated rejection was 6.7% in SF and 2.9% in SB by 3 years after transplantation (p = 0.30). There was a significant increase in chronic histological damage over time (p < 0.001), without difference between SF and SB patients. Smaller recipient size and higher donor age were the main risk factors for chronic histological injury in posttransplant biopsies.

Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up.

To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years posttransplant. Standardized height Z-score change after 3 years follow-up was -0.99 ± 2.20 in SF versus -0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z-score at 3 years -0.43 ± 1.15 vs. -1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow-up. Over the 3 year follow-up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

A peripheral blood diagnostic test for acute rejection in renal transplantation.

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation.

In an effort to reduce rejection, extend allograft survival and minimize complications, we hypothesized that robust immunosuppression during the first 6 months after transplantation would allow for the safe withdrawal of steroids. A total of 274 pediatric subjects were enrolled and received an anti-CD25 antibody, sirolimus, calcineurin inhibitor and steroids. At 6 months after transplantation, subjects were randomized to steroid withdrawal (n=73) versus continued low-dose steroids (n=59). This study was stopped prior to target enrollment because of the incidence of post-transplant lymphoproliferative disorder. At the time of study termination, 132 subjects had been randomized and were available for analysis. At 18 months after transplantation, there was no difference in the standardized height z score; however, the standardized height velocity was greater in the steroid withdrawal group compared to the control group (p=0.033). There were no differences in acute rejection episodes between treatment groups. The 3-year allograft survival rate was 84.5% in the control group and 98.6% in the steroid withdrawal group (p=0.002). The immunosuppressive protocol utilized in this study allowed for the withdrawal of steroids without an increased risk of rejection or allograft loss. However, the complications associated with the use of this immunosuppressive protocol were too high to recommend its routine use in pediatric patients.

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 < or =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 < or =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.

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.

Cyclosporin A inhibits CD40 ligand expression in T lymphocytes.

The ligand for CD40 is expressed on activated T lymphocytes and delivers contact-dependent activation signals to B lymphocytes. The mechanisms regulating CD40 ligand gene expression are largely unknown. Optimal expression of CD40 ligand required activation of protein kinase C and a rise in intracellular calcium concentration. CD40 ligand expression was inhibited by pretreatment of T cells with cyclosporin A. Cyclosporin A analogues inhibited CD40 ligand expression with a potency mirroring the ability of each compound to inhibit calcineurin activity, indicating that calcineurin plays a key role in CD40 ligand gene expression. Cyclosporin A inhibited IL-4-driven CD40 ligand-dependent IgE isotype switching in PBMC but did not inhibit IgE synthesis induced by CD40 mAb plus IL-4. PBMC derived from transplant patients receiving cyclosporin A failed to express CD40 ligand upon stimulation. These results suggest that patients receiving cyclosporin A may be deficient in CD40 ligand-dependent T cell help.

Left ventricular mechanics and contractile state in children and young adults with end-stage renal disease: effect of dialysis and renal transplantation.

The potential existence of a specific uremia-associated myocardial depressant factor was explored by evaluating nine pediatric subjects (3 to 21 years) without evidence of coronary artery disease or long-standing hypertension 1) before entering a dialysis program, 2) while undergoing a long-term dialysis regimen, and 3) after successful renal transplantation. Myocardial contractility was quantitated with load-independent indexes using the end-systolic pressure-dimension relation (Emax) and the relation of rate-corrected velocity of shortening to end-systolic wall stress. Myocardial loading status was determined by the direct measurement of afterload (end-systolic wall stress) and the functional quantitation of preload (differences between the relation of fractional shortening and velocity of shortening to end-systolic stress). Most patients (55%) were found to have abnormal ejection phase indexes of ventricular function either before or after entry into dialysis. However, contractility was normal in all subjects at each of their evaluations, and no change in contractility was found after dialysis or transplantation. Loading status was highly variable and usually abnormal before transplantation and accounted entirely for the abnormalities of fractional shortening and velocity of shortening. Transplantation invariably resulted in normalization of loading status and ejection phase indexes of ventricular function. In these children and young adults with uremia, abnormal ejection phase indexes of ventricular function were frequent and caused by associated abnormalities in ventricular loading. Contractility, however, was normal and no evidence of a uremia-associated myocardial depressant was found.

Progressive tubulointerstitial renal disease in infancy with associated hepatic abnormalities.

Clinical, pathologic, and biochemical data are reported in two male infants who had rapidly progressive renal failure, enlarged kidneys, hepatosplenomegaly, and fat malabsorption. One infant, studied prior to the onset of significant renal insufficiency, manifested renal Fanconi syndrome, hyperparathyroidism, and marked hypocalcemia. After a brief period of dialysis, both received renal transplants. Neither has clinical evidence of reoccurrence of the renal disorder in the transplant, but both still have hepatic abnormalities. Morphologic features present in both patients include a renal lesion characterized by tubulointerstitial injury with a tubulocystic component and hepatic abnormalities with bile duct proliferation, portal fibrosis, and inflammation. These cases do not readily conform to any single published diagnostic category, including nephronophthisis-congenital hepatic fibrosis or infantile polycystic kidney disease, and appear to be unique.

Long-term patient survival in a pediatric renal transplantation program.

In adult renal transplant recipients, reports have shown continuing mortality beyond 5 years after transplantation with the majority of deaths due to myocardial infarctions, malignancies, and liver failure. Little information is available on the long-term survival of children following renal transplantation. Children with end-stage renal disease have fewer systemic complications than adults and should have better long-term survival. Furthermore, analysis of mortality in the pediatric population should be more informative of the risks of renal transplantation, separate from underlying pretransplant diseases and the inherent complications of aging. We analyzed, therefore, the long-term mortality of renal transplant recipients in a single pediatric center. A total of 299 renal transplants were performed in 251 patients from 1971 through 1990. No patient was excluded from the evaluation. Over all, actuarial survival was 91% at 1 year, 83% at 10 years, and 81% at 15 years. Patient's age at transplantation, donor source, and number of previous allografts were not correlated with patient survival. There were 35 deaths with 51% attributable to infections. The majority of deaths (71%) occurred within the first 6 months after renal transplantation during the period of greatest immunosuppression. Mortality within the first 12 months following renal transplantation was higher during the period 1971-1974 when compared to subsequent years. These data demonstrate that in a pediatric renal transplant center, long-term patient survival is excellent. Most deaths occur within the first 6 months following renal transplantation and are caused by infections. As expected, long-term survival in children is better than reports in adult renal transplant recipients and may more accurately reflect true renal-transplant-related mortality.

The effect of donor age on graft survival in pediatric cadaver renal transplant recipients--a report of the North American Pediatric Renal Transplant Cooperative Study.

Data from the North American Pediatric Renal Transplant Cooperative Study were analyzed to determine the effect of donor age on graft survival for pediatric recipients of cadaver donor renal transplants. Between January 1, 1987, and November 16, 1990, 787 cadaver donor renal transplants in children less than 18 years of age were registered in the study. The ages of the donors were less than or equal to 5 years in 203 transplants, between 6 and 9 years in 87, between 10 and 39 in 389, and greater than or equal to 40 years in 108. The risk of graft loss was related to donor age by a proportional hazards analysis. The ideal donor age was 20-25 years. The risk of graft loss was increased by both young and old donor age. The risk of graft loss from a neonate donor was 2.7-fold that of the ideal donor, and the risk from a 50-year-old donor was 1.8-fold that of the ideal donor. The relationship between donor age and graft survival was not affected by the age of the recipient. Cold storage time had an added impact on graft survival: grafts with cold storage time greater than 24 hr were 1.5 times more likely to fail than grafts with shorter cold storage time for all donor ages. Analysis of the causes of graft failure revealed that 9.9% of grafts from donors less than or equal to 5 years of age were lost due to vascular thrombosis, primary nonfunction, and other technical causes, compared with 4.6% in 6-9, 4.4% in 10-39, and 2.8% in greater than or equal to 40-year-old donors. We conclude that kidneys from both young and old donors are at increased risk for graft loss, and this increased risk is seen in all recipient age groups. Many of the losses from the young donors--but not older donors--may be due to technical causes. Knowledge of these risks can be used to develop strategies for optimal utilization of kidneys from young and old donors.

Endocrinologic evaluation of children who grow poorly following renal transplantation.

Some children do not grow well following successful renal transplantation. We reviewed 25 children with renal allografts who receive regular medical care in the renal transplant program at The Children's Hospital, were less than or equal to 18 years of age, and had stable renal function. We compared children who were growing well (n = 14) with those who were growing poorly (n = 11). The children with poor growth more frequently had elevated serum creatinine concentrations (8/11 vs. 3/14). The mean age at transplantation was the same, although the duration of follow-up was shorter for the children growing well (3.3 +/- 0.5 years) than for those growing poorly (6.2 +/- 1.0 years, P less than 0.02). Eight of the children who were growing poorly underwent endocrinologic evaluation. Plasma growth hormone (GH) concentrations were measured during sleep, after arginine and L-DOPA administration, and during a 4-hr oral glucose tolerance test. In 4 patients, the maximum GH concentration was inadequate both following pharmacologic stimulation (4.0 +/- 2.6 ng/ml, n = 4) and during sleep (4.4 +/- 0.2 ng/ml, n = 3). In 2 additional patients, maximal GH concentrations were subnormal during sleep despite adequate responses during pharmacologic stimulation. In the final two patients, GH secretion was adequate both during sleep and after stimulation. All children studied had some degree of renal insufficiency with a mean creatinine clearance of 39 +/- 4 ml/min/1.73 m2. Plasma concentrations of thyroxine, thyrotropin, and IGF-I were normal for age in all eight patients. We conclude that abnormalities in GH secretion occur frequently among patients who grow poorly following successful renal transplantation. Evaluation of GH secretion may be useful in evaluating growth failure in this group of patients, and the usefulness of GH therapy should be investigated.

Graft thrombosis in pediatric renal transplant recipients. A report of the North American Pediatric Renal Transplant Cooperative Study.

Data from the North American Pediatric Renal Transplant Cooperative Study were analyzed to determine the incidence and possible causes of graft thrombosis in pediatric renal transplant recipients. Between January 1987, and November 1989, 1045 renal transplants in recipients less than 18 years of age were registered in the study, including 484 living-related donor and 561 cadaver donor transplants. There were 213 graft failures (67 LRD, 146 CAD), and of these 27 were caused by thrombosis (8 LRD, 19 CAD). Thrombosis occurred in 2.6% of all transplants and accounted for 22.5% (27/120) of all graft failures that occurred in the first 60 days following transplantation. Among the LRD recipients, there were 24 graft failures in those less than 6 years of age, and 7 of these were due to thrombosis, compared to 1 thrombosis in 43 graft losses in recipients greater than 6 years (P less than 0.01). In recipients less than 6 years old, the thrombosis rate for those who received transplants without prior dialysis was 4/32 (12.5%) versus 3/109 (2.8%) with prior dialysis. Among the CAD recipients, age of the recipient did not influence graft thrombosis. Donor age, however, was strongly associated with the risk of thrombosis, as was cold storage time. Donor age and cold storage time were not independently distributed within the population, with longer cold storage times required for younger donors. Both factors, however, independently affected outcome. Other factors, including prior nephrectomy, prior transplant, center size, and use of cyclosporine were not associated with increased risk of thrombosis in LRD or CAD recipients. We conclude that graft thrombosis is an important cause of renal graft loss in children. In LRD transplants the risk of graft thrombosis is increased in recipients less than 6 years old, and preliminary data suggest that the lack of prior dialysis may be associated with thrombotic risk in these patients. CAD transplant recipients who receive grafts from young donors, particularly those with long cold storage time, are at increased risk for graft failure due to thrombosis.

Analysis of rejection outcomes and implications--a report of the North American Pediatric Renal Transplant Cooperative Study.

For this study, we analyzed the role of rejection in graft failure in children. Rejection results were examined after 3004 pediatric renal transplants (1367 living donor, 1637 cadaver source). A total of 3453 (1298 living donor, 2155 cadaver source) rejection episodes have occurred, for rejection ratios of .95 for living donor and 1.32 for cadaver source transplants, with a constant difference of 18% points after four months, in the percentage of patients ever experiencing a rejection. Rejection results were examined by patient age (0-1 vs. 2-5 vs. 6-12 vs. > or = 13). Rejection ratios, annualized rejection frequency, time to first rejection, and mean number of rejections for patients with rejection were not elevated in the younger patients. However, for the initial rejection episode, recipients less than six years of age had significantly (P < .001) poorer outcome from the rejection episode with an increased risk of graft failure in both donor source groups. This age effect on rejection outcome is only seen with the first rejection episode and is not observed with subsequent rejection episodes.

Alternate-day steroid dosing improves growth without adversely affecting graft survival or long-term graft function. A report of the North American Pediatric Renal Transplant Cooperative Study.

Data from the North American Pediatric Renal Transplant Cooperative Study were analyzed to determine the effects of alternate-day (QOD) steroid dosing on growth, graft survival, and graft function in children with functioning grafts 12 months after transplantation. At 12 months after transplantation, 16.8% (337/2001) of transplant recipients were receiving QOD dosing. The basis for the selection of a steroid dosing regimen cannot be determined from registry data; however, the frequency of QOD dosing differed by donor source, race, age at transplant, and the occurrence of rejection episodes in the first year. The effect of the steroid dosing pattern on growth was evaluated in children continuously on either QOD or daily (QD) steroid dosing. The mean change in the standardized height scores from 1 month to 24 months after transplantation was significantly greater in those on QOD dosing (+0.5 +/- 0.06) than in those on QD dosing (+0.1 +/- 0.03). Using multiple regression analyses, better growth was associated with QOD dosing, recipient age less than 13 years, lower total steroid dose over 48 hr, and lower serum creatinine (all P < 0.001). Graft survival did not differ on the basis of the steroid dosing pattern. In a proportional hazards model for survival of living donor grafts after 12 months, graft survival was negatively associated with the use of QD dosing, black race, rejection episodes in the first year, and a higher serum creatinine at 12 months. The survival of cadaver grafts was negatively associated with the use of QD steroid dosing, recipient age less than 2 years, rejection episodes in the first year, and a higher serum creatinine at 12 months. In addition, the decline in graft function did not differ between those on QOD steroid therapy and those on QD therapy. We conclude that selected pediatric renal transplant recipients receiving QOD dosing have better growth than those receiving QD dosing without compromising allograft survival or function.

Posttransplant deaths and factors that influence the mortality rate in North American children.

Of 2457 patients in the North American Pediatric Renal Transplant Cooperative Study registry who were followed for 5481 patient-years after the index transplantation, we observed 136 deaths, for an average annual rate of 24.8 deaths per 1000 patient-years. Death resulted primarily from infection (n = 55, 40%), cardiovascular causes (n = 28, 21%), hemorrhage (n = 16, 12%), and malignancies (n = 9, 7%). Cadaver-donor source was associated with greater mortality (6.7%) than a living-donor source (4.0%) (P < 0.005). Recipients aged 0-1, 2-5, 6-12, and 13-17 years old had mortality rates of 17.5, 8.0, 3.6, and 4.5%, respectively (P < .001). Mortality rates increased substantially when examined by recipient and cadaver donor ages (mortality rates of up to 45%), the greater the concordance between young donor and recipient ages. Interestingly, acute tubular necrosis and graft failure less than 30 days after transplantation (GH30) were each associated with markedly elevated mortality rates. (The risk ratio for ATN was 3.1 [P < 0.001] and for GF30 it was 6.4 [P < 0.001].) Mortality after transplantation was also affected by the underlying renal disease, with high mortality rates observed for oxalosis (n = 21, 33.3%), congenital nephrotic syndrome (n = 79, 15.2%), pyelo/interstitial nephritis (n = 54, 11.1%), and Drash syndrome (n = 14, 21.4%). When the joint effect of these risk factors was examined in a Cox proportional hazards model, young recipient age (0-1 years old) and GF30 were significant (P < .001) risk factors of mortality for recipients of living-donor organs. For recipients of cadaver kidneys, young recipient age--0-1 years old (P < .001) and 2-5 years old (P = .002)--ATN (P = .029), and GF30 (P < .001) were all significant risk factors. Recipient age is the major determinant of increased mortality after renal transplantation. Avoidance of acute tubular necrosis by reducing cold time and preventing early graft failure by better matching techniques in this vulnerable population may improve the mortality rate.

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.

Cell-mediated cytotoxicity: a predictor of chronic rejection in pediatric HLA haploidentical renal transplants.

BACKGROUND: Recipient antidonor cytotoxic T-cell activity has been associated with graft loss and acute rejection in renal allograft recipients. The role of immunologic mechanisms in the development of chronic graft rejection is controversial. We analyzed all living related renal transplants performed at Children's Hospital (Boston, MA) from 1983 to 1995 to assess whether cell-mediated cytotoxicity, determined in vitro and measured before transplantation, was predictive of chronic rejection. METHODS: Eighty-three patients were studied retrospectively. Fifty-seven patients with one haplotype-matched renal transplants from living related donors were studied to determine the association between cell-mediated lympholysis (CML) level, acute rejection, chronic rejection, and graft failure. Acute rejection was defined by the decision to treat. Chronic rejection was defined by histology and/or the absolute serum creatinine value using an increasing serum creatinine level >1.0 mg/dl for children less than 3, a creatinine level >1.5 mg/dl for children between 3 and 10 years of age, and a creatinine level >2.0 mg/dl for children above 10 years of age. Return to dialysis or retransplantation was considered graft failure. RESULTS: Of the 57 haploidentical patients, there were 33 males and 24 females. The mean age at transplant was 11.1 years (SD=6.7). Twelve patients developed chronic rejection, 24 patients developed acute rejection, and 7 patients had graft failure. Pretransplant cytotoxic T lymphocyte activity was associated with chronic rejection (P=0.001) and graft failure (P=0.013) but only marginally with acute rejection (P=0.058). Controlling for age and sex, Cox's proportional hazards model revealed that CML level was predictive of time to chronic rejection (P<0.01) but not acute rejection (P=0.11). It was estimated that every 1-unit increase in CML level raises the monthly risk of chronic rejection by 7%. Ten children received HLA-identical kidneys from their siblings. There were no episodes of chronic rejection after 5 years. Two patients with high CML levels had episodes of acute rejection; both patients responded to treatment. CONCLUSION: Our data demonstrate an association between pretransplant cell-mediated cytotoxicity and the occurrence of chronic rejection in living related one-haploidentical renal transplants in pediatric patients.