ABSTRACT
Post-transplant lymphoproliferative disorder (PTLD) has been associated with high mortality, but recent anecdotal survival appeared better. From 1988 to 2010, the NAPRTCS registry had 235 registered PTLD cases. We sent a special 25-point questionnaire study to the NAPRTCS centers with the most recent 150 cases to obtain additional follow-up data not collected in the master registry, our objective being to determine the recent outcomes after PTLD and determine prognostic factors. We received 92 completed responses, in which only 12 (13%) deaths were reported, 2 from nonmedical causes, 10 with a functioning graft. Kaplan-Meier-calculated patient survival was 90.6% at 1 year and 87.4% at 3, 4 and 5 years post-PTLD. Graft survival post-PTLD was 81.8% at 1 year, 68.0% at 3 years and 65.0% at 5 years. Seven patients received a retransplant after PTLD, with no PTLD recurrence reported. Using all 235 PTLD cases, the covariates associated with better patient survival were more recent year of PTLD diagnosis (adjusted hazard ratio AHR 0.86, p < 0.001), and with worse survival were late PTLD (AHR 1.98, p = 0.0176) and patient age above 13 at PTLD (AHR 3.43, p value 0.022). In children with kidney transplants, patient survival has improved with more recent PTLDs.
Subject(s)
Graft Survival , Kidney Transplantation/adverse effects , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/mortality , Postoperative Complications , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Risk Factors , Surveys and Questionnaires , Survival Rate , Treatment OutcomeABSTRACT
Short-term graft survival has improved in renal transplants without significant effect on long-term graft survival. As GFR decline precedes graft loss, an understanding of variables affecting eGFR after TX may help improve graft survival. NAPRTCS data were analyzed to assess effects of donor, recipient, and other variables on Schwartz eGFR after transplantation. For 8438 children with a functioning graft at day 30, data were censored for children dying with a functioning graft, and those with <3 yr follow-up. Multivariate linear regression and repeated measures analyses identified factors related to eGFR at day 30 after TX and during follow-up. Young, female, non-black, children without ATN and acute rejection in the first 30 days, TX after 1995, those with better eGFR at day 30, and receiving tacrolimus had better long-term eGFR. Transplant from ideal (6-35 yr) donors had best short-term eGFR, young donors (<5 yr) had lower eGFR and poor graft survival. After one yr, eGFR improved in surviving grafts of young donors and matched ideal donors. Acute rejection, BP medications, and hospitalizations in prior six months had negative association with subsequent eGFR. Regardless of variables, eGFR deteriorated with time. Slope of eGFR decline has not changed in the recent era indicating the need for innovative therapies.
Subject(s)
Glomerular Filtration Rate , Graft Survival/physiology , Kidney Diseases/surgery , Kidney Transplantation , Registries , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Kidney Diseases/physiopathology , MaleABSTRACT
Improvements in human immunodeficiency virus (HIV)-associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9-4.9). One- and 3-year liver recipients' survival was 91% and 64%, respectively; kidney recipients' survival was 94%. One- and 3-year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999-2004 transplants in the national database. CD4+ T-cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1- and 3-year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28-75%) and 70% (48-92%), respectively. Two-thirds of hepatitis C virus (HCV)-infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV-related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV-infected patients cared for at centers with adequate expertise.
Subject(s)
HIV Infections/complications , Kidney Transplantation/statistics & numerical data , Liver Transplantation/statistics & numerical data , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Cadaver , Female , Follow-Up Studies , Graft Rejection/epidemiology , HIV Infections/drug therapy , Humans , Kidney Transplantation/immunology , Liver Transplantation/immunology , Living Donors , Male , Middle Aged , Time Factors , Tissue Donors/statistics & numerical data , Treatment Outcome , Viral LoadABSTRACT
UNLABELLED: Infections now exceed rejection as a cause of hospitalization in the first 2 years post-renal transplantation. We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine risks for hospitalization for infection (HI), either bacterial (HBI) or viral (HVI). 3106 children transplanted between 1996 and 2002 with 2-year follow-up were analyzed. Univariate and multivariate logistic regression analyses identified factors for cause-specific hospitalization. RESULTS: 23.4% experienced HBI, 23.9% HVI; 8.9% were hospitalized for both. Children 0-1 years age at transplant had higher rates of HI (64.2%), HBI (40.3%) and HVI (43.3%) compared to >12 years (31%, 17.5% and 18.9%, p < 0.0001). In comparison to no induction, patients receiving monoclonal or polyclonal antibody were more likely to have HI (>42% vs. 34.0%), HBI (>24% vs. 21%) or HVI (>29% vs. 21%, all p < 0.003) but had equivalent graft survival (p = NS). Higher rates of HI, HBI and HVI were also seen with prophylactic antimicrobial use and with >5 transfusions pretransplant. Since antibody induction in recent era was not associated with better graft or patient survival but was associated with more HI and HVI, the need for routine antibody induction in children needs to be reassessed.
Subject(s)
Antibodies/adverse effects , Bacterial Infections/epidemiology , Immunosuppression Therapy/adverse effects , Kidney Transplantation , Postoperative Complications/epidemiology , Virus Diseases/epidemiology , Antibodies/administration & dosage , Bacterial Infections/prevention & control , Child , Child, Preschool , Female , Hospitalization/statistics & numerical data , Humans , Infant , Infant, Newborn , Male , Postoperative Complications/prevention & control , Risk Factors , United States/epidemiology , Virus Diseases/prevention & controlABSTRACT
BACKGROUND: The incidence of renal post transplant diabetes mellitus (PTDM) in adults varies from 3-46%. METHODS: We did a retrospective analysis of 1365 children in The North American Pediatric Renal Transplant Cooperative Study with renal transplant (Tx) reported between January 92 and July 1997. PTDM, defined as >2 weeks of insulin therapy after Tx, developed in 36 patients. A control group of 153/1329 non-PTDM patients was selected and matched for age at Tx and primary diagnosis. RESULTS: African-Americans were overrepresented (36.1 vs. 17.6%, P=0.017) and Hispanics were underrepresented (5.6 vs. 26.1%, P=0.019) among cases. Although prednisone dose 30 days post-Tx was higher among cases (0.89 mg/kg/day) versus controls (0.71 mg/kg/day), P=0.019, cyclosporine dose was similar. No differences in prednisone or cyclosporine doses were observed at 6, 12, or 24 months post-Tx. Tacrolimus use in PTDM group was high (45%). The estimated incidence of first acute rejection at 1, 3, and 12 months was higher among cases, 0.41+/-0.08, 0.52+/-0.08, 0.61+/-0.08, compared to controls, 0.23+/-0.02, 0.37+/-0.02, and 47+/-0.02 (P=0.058). Crude graft failure rates of 13.5% (5/36) and 12.4% (19/153) were similar between the two groups, so was the calculated creatinine clearance at 12 and 24 months and post-Tx hospitalization days. CONCLUSION: PTDM occurs in <3% of children. African-Americans are at higher risk and Hispanics at lower risk for PTDM. Tacrolimus is a significant risk factor for PTDM. Children with PTDM had a higher incidence of acute rejection, but graft survival, kidney function, and hospitalization rates were similar to selected controls.
Subject(s)
Diabetes Mellitus/etiology , Kidney Transplantation/adverse effects , Adolescent , Black or African American/statistics & numerical data , Child , Child, Preschool , Diabetes Complications , Diabetes Mellitus/epidemiology , Diabetes Mellitus/ethnology , Female , Graft Rejection/epidemiology , Graft Rejection/etiology , Hispanic or Latino/statistics & numerical data , Humans , Immunosuppressive Agents/adverse effects , Incidence , Male , North America , Reference Values , Retrospective Studies , Risk Factors , Tacrolimus/adverse effectsABSTRACT
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.
Subject(s)
Kidney Transplantation , Lymphoproliferative Disorders/epidemiology , Postoperative Complications/epidemiology , Black or African American , Cadaver , Child , Child, Preschool , Databases, Factual , Follow-Up Studies , Humans , Immunosuppressive Agents/therapeutic use , Incidence , Infant , Kidney Transplantation/immunology , Living Donors , Registries , Risk Factors , Time Factors , Tissue Donors , United States , White PeopleABSTRACT
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.
Subject(s)
Glomerulosclerosis, Focal Segmental/surgery , Graft Survival , Kidney Transplantation , Living Donors , Child , Child, Preschool , Female , Graft Rejection , Humans , Infant , Infant, Newborn , Male , RecurrenceABSTRACT
Historically, higher acute rejection rates, earlier first rejection, and an inability to reverse the rejection characterize pediatric renal transplantation. In recent years, short-term (1-year) graft survival of pediatric renal transplants has steadily improved. To test the hypothesis that these improvements were mediated by changes in acute rejection, we considered the rejection profile of patients who received a renal allograft between 1987 and 1989 (cohort A) and compared it with recipients transplanted between 1997 and 1999 (Cohort B). Cohort A comprised 1469 transplants and cohort B comprised 1189 transplants. Restricting the data to the first year of follow-up, rejection ratios were 1.6 and 0.7, respectively (p < 0.001). Sixty per cent of the later cohort (B) were rejection free at 1 year, compared with 29% for the earlier cohort (A) (p < 0.001). Controlling for donor source, the rejection reversal rate for the later cohort was significantly better than that of the early cohort (p < 0.001). Cumulative distribution of times to first rejection was significantly better for cohort B (p < 0.001). One-year graft survival for cohort B at 94% was significantly better than 80% for cohort A (p < 0.001). We conclude that the improved short-term graft survival is mediated by improvements in the rejection profile in more recently transplanted patients and that this may translate into a better half-life for pediatric renal transplant recipients who received an allograft in the years 1997-99.
Subject(s)
Graft Rejection/epidemiology , Graft Survival , Kidney Transplantation/physiology , Adolescent , Child , Child, Preschool , Cohort Studies , Follow-Up Studies , Graft Survival/physiology , HLA-DR Antigens/immunology , Histocompatibility Testing , Humans , Infant , Retrospective Studies , Time Factors , Treatment Outcome , United StatesABSTRACT
Antibodies generated by candidate HIV-1 vaccines in a phase I clinical trial were assessed for neutralizing activity with a panel of eight well-characterized, genetically diverse clade B primary isolates having an R5 phenotype. The vaccines consisted of one of three different recombinant canarypox vectors expressing membrane-anchored HIV-1(MN)gp120 (ALVAC vCP205, vCP1433, and vCP1452) followed by boosting with a soluble gp160 hybrid consisting of MNgp120 and the majority of gp41 from strain IIIB. Serum samples from a subset of volunteers in each arm of the trial, containing moderate to high titers of neutralizing antibodies to HIV-1 MN, were analyzed. Competition assays with peptides revealed that the majority of neutralizing activity was specific for the MN-V3 loop. Despite MN-specific neutralization titers that sometimes exceeded 1:500, no neutralization of primary isolates was detected and, in some cases, mild infection enhancement was observed. In addition, little or no neutralization of the HIV-1 IIIB heterologous T cell line-adapted strain of virus was detected. These results reinforce the notion that monovalent HIV-1 ENV is a poor immunogen for generating cross-reactive neutralizing antibodies.
Subject(s)
AIDS Vaccines/immunology , Avipoxvirus/genetics , HIV Antibodies/immunology , HIV Envelope Protein gp120/immunology , HIV Envelope Protein gp160/immunology , HIV Infections/prevention & control , HIV-1/immunology , Adult , Amino Acid Sequence , Cell Membrane/metabolism , Genetic Vectors , HIV Antibodies/biosynthesis , HIV Antibodies/blood , HIV Envelope Protein gp120/genetics , HIV Envelope Protein gp120/metabolism , HIV Envelope Protein gp160/genetics , HIV Envelope Protein gp160/metabolism , Heteroduplex Analysis , Humans , Immunization, Secondary , Male , Middle Aged , Molecular Sequence Data , Neutralization Tests , Peptides/chemistry , Peptides/immunology , Phylogeny , Vaccination , Vaccines, Synthetic/immunologyABSTRACT
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).
Subject(s)
Kidney Diseases/surgery , Kidney Transplantation/statistics & numerical data , Adolescent , Adult , Annual Reports as Topic , Child , Child, Preschool , Female , Graft Rejection , Graft Survival , Humans , Immunosuppression Therapy , Infant , Kidney Diseases/immunology , Kidney Transplantation/immunology , Living Donors , Male , North America , Time FactorsABSTRACT
An inverse relationship between mortality and center volume has been established for several surgical procedures. Given the distinctiveness of pediatric renal transplantation and the large variation in center volume, investigation for relationships between center volume and graft outcome was pursued using the North American Pediatric Transplant Cooperative Study database. Center volume groups were based on the total number of pediatric transplants reported from 1987 to 1995. Centers reporting > 100, 51-100, or < or = 50 transplants were grouped as high- (n=11), moderate- (n=28), or low-volume (n=65), respectively. Differences between groups included increasing rates of cadaver donor graft thrombosis (2.4%, 4.3%, and 5.7%, P<0.01) and acute tubular necrosis (ATN) (10.2%, 11.5%, and 14.0%, P<0.01) with decreasing center volume. Treatment differences included a higher rate of induction with an anti-T-cell antibody preparation in the larger-volume groups, 60.2%, 51.8%, and 39.2% (P<0.001). Decreasing graft survival for decreasing center size groups was noted at 3 months post transplant, 90.4%, 90.2%, and 88.4%. These differences were significant only with the exclusion of anti-T-cell induction from the proportional hazards model (relative risk=0.81 and =0.70 for the moderate- and high-volume groups, P<0.02). Superior graft survival in the high-volume centers noted at 3 months post transplant appears predominantly the result of lower rates of cadaver donor graft thrombosis and ATN. Analysis points to the need for low-volume centers to identify risk factors influencing these outcomes.
Subject(s)
Kidney Transplantation/statistics & numerical data , Cadaver , Child , Graft Survival , Humans , Kidney Transplantation/methods , Kidney Tubular Necrosis, Acute/epidemiology , North America , Postoperative Complications , Risk Factors , T-Lymphocytes/immunology , Thrombosis/epidemiologyABSTRACT
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.
Subject(s)
Graft Survival , Kidney Transplantation/physiology , Adolescent , Adult , Cadaver , Child , Child, Preschool , Ethnicity , Follow-Up Studies , Graft Rejection/epidemiology , Histocompatibility Testing , Humans , Infant , Kidney Transplantation/statistics & numerical data , Living Donors , North America , Postoperative Complications/classification , Postoperative Complications/epidemiology , Retrospective Studies , Time Factors , Tissue Donors/statistics & numerical dataABSTRACT
Using the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 1,552 pediatric renal transplant patients who had received a graft from a biological parent to determine if parental donor sex influences the development of rejection. There were 102/675 (15.1%) graft failures in paternal grafts compared to 144/877 (16.4%) graft failures in maternal grafts. Overall graft survival (p=0.48) and time to first rejection (p>0.9) were not different in patients receiving paternal versus maternal grafts. The overall frequency of graft loss to rejection was also not different. However, maternal donation was associated with a significantly longer time to first rejection in patients less than one year of age at the time of transplantation (p=0.01). Time to first rejection was not different between maternal and paternal grafts in older recipients. In summary, the present study did not demonstrate a difference in graft survival between maternal and paternal donations, but the youngest patients may experience a longer time to first rejection with maternal donation. The number of young patients is small, however, and further data are necessary to confirm this observation.
Subject(s)
Graft Rejection/etiology , Kidney Transplantation , Parents , Sex , Tissue Donors , Adolescent , Age Factors , Child , Child, Preschool , Databases, Factual , Female , Graft Rejection/epidemiology , Humans , Infant , Kidney Transplantation/adverse effects , Kidney Transplantation/immunology , Kidney Transplantation/methods , Male , North America/epidemiology , Retrospective Studies , Risk Factors , Survival Analysis , Survival Rate , Time Factors , Treatment OutcomeABSTRACT
Acute rejection is a frequent event in pediatric transplantation. In addition to graft loss, acute rejection episodes stimulate the development of chronic rejection and inhibit growth in children post-transplantation. In this study, we analyzed our data from 1987 through 1996 to identify acute rejection episodes in children. In 2,520 living donor (LD) transplants there were 2,540 rejection episodes (rejection ratio: 1.1), and in 2,579 cadaver donor (CD) transplants 3,653 episodes were observed (rejection ratio: 1.32). For LD recipients the first rejection occurred sooner when there was at least one HLA-DR mismatch (RR=1.6, p<0.001) and prophylactic T-cell antibody was not used (RR=1.4, p<0.001). For CD transplants absence of prophylactic T-cell antibody (RR=1.2, p<0.001) and donor age below five years were risk factors (RR=1.5, p<0.001). Late initial acute rejections were seen in 327 of 1,471 patients (22.2%) who were rejection free at one year. At risk for the development of late rejections were children over the age of six years at transplantation (RR=1.7, p<0.001) and children of non-white origin (RR=1.5, p <0.002). For LD transplant recipients in the age range of 0-5 years, irreversible rejection was observed in 8.7% compared to 4.1% for older children (RR=1.46, p<0.001). Similar results for CD transplants were 12.6% versus 6.6% (RR=1.5, p<0.00). The high frequency of rejection episodes in children and the greater irreversibility in younger children suggest pediatric patients may have a more robust immune response. Current ongoing studies in the molecular mechanisms of the pathogenesis of rejection in surveillance biopsies of children may help determine if this hypothesis is valid.
Subject(s)
Graft Rejection/etiology , Immunosuppression Therapy/adverse effects , Kidney Transplantation/adverse effects , Preoperative Care/adverse effects , Tissue Donors/statistics & numerical data , Acute Disease , Adolescent , Age Distribution , Child , Child, Preschool , Follow-Up Studies , Histocompatibility Testing , Humans , Immunosuppression Therapy/methods , Infant , Kidney Transplantation/immunology , Kidney Transplantation/methods , North America , Preoperative Care/methods , Racial Groups , Risk Factors , Time FactorsABSTRACT
We investigated the safety and immunogenicity of a candidate HIV-1 vaccine, Env 2-3 (Chiron Biocine Co.), in combination with an adjuvant emulsion, MF59, with or without an additional immune modulator, MTP-PE 78 healthy HIV-1-seronegative adults. Sixteen subjects participated in a dose escalation study of MTP-PE in MF59 without Env 2-3, given at 0 and 1 months; 48 subjects participated in a study of a fixed dose of 30 micrograms of Env 2-3 in MF59 with increasing doses of MTP-PE (0, 5, 10, 25, 50, and 100 micrograms), and 14 subjects participated in a study of 100 micrograms of Env 2-3 in MF59 without MTP-PE. Subjects were assigned to study groups under a randomized, double-blind allocation. Subjects received immunization at 0, 1, and 6 months, and had the option of receiving a fourth dose at 12-18 months. Env 2-3 in MTP-PE/MF59 was associated with significant reactogenicity, in that severe, although self-limited systemic and/or local reactions occurred in 15 of 30 vaccinees. In contrast, Env 2-3 in MF59 without MTP-PE was relatively well tolerated, and severe local and/or systemic reactions occurred in only 2 of 18 subjects. Env 2-3 stimulated serum antibodies to HIV-1 envelope protein (gp120) as detected by Western blot in 39 of 43 subjects and to HIV-1 virus lysate by EIA in 28 of 43 subjects after three injections. The majority of subjects also developed EIA antibodies to recombinant gp120 (SF-2), gp120 (LAI), and V3 peptide (SF-2). Neutralizing antibodies to the homologous SF-2 strain developed in 30 of 43 and 27 of 34 subjects, and fusion inhibition antibodies in 25 of 43 and 15 of 36 subjects after three and four injections, respectively. Lymphoproliferative responses to the immunogen, Env 2-3 were observed in over 80% of the vaccinees examined, and CD4+ cytotoxic T cell activity directed against HIV-1 was noted transiently in 2 of 20 vaccinees. Addition of MTP-PE to Env 2-3 or increasing the dose of Env 2-3 from 30 to 100 micrograms did not augment immunogenicity. Env 2-3 in MF59 was well tolerated and immunogenic in HIV-1-seronegative individuals. The addition of MTP-PE significantly increased reactogenicity, but had little, if any, effect on immunogenicity.
Subject(s)
AIDS Vaccines/administration & dosage , Adjuvants, Immunologic/administration & dosage , HIV Envelope Protein gp120/immunology , HIV Infections/prevention & control , HIV-1/immunology , Polysorbates/administration & dosage , Squalene/administration & dosage , AIDS Vaccines/immunology , Adolescent , Adult , Amino Acid Sequence , Cells, Cultured , Consumer Product Safety , Dose-Response Relationship, Immunologic , Double-Blind Method , Female , HIV Antibodies/blood , HIV Infections/immunology , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Male , Middle Aged , Molecular Sequence Data , Squalene/immunology , T-Lymphocytes, Cytotoxic/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunologyABSTRACT
The data base of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) was used to examine the effect of primary diagnosis on the outcome of renal transplantation in children. The relative risk of graft failure for eight diagnostic groups was determined, with patients with congenital and structural anomalies of the urinary tract serving as the reference group. Covariate analysis was used to control for the effects of age, race and transfusion history in recipients of living-related donor kidneys, and for age, donor age, antilymphocyte prophylaxis, prior transplantation, prior dialysis and cold ischemia time in recipients of cadaver kidneys. In recipients of living-related donor kidneys, the lowest graft failure rates were associated with the diagnoses of cystinosis, familial nephritis and hemolytic uremic syndrome (HUS), while the highest failure rates were observed in patients with a primary diagnosis of congenital nephrotic syndrome (CNS) or focal segmental glomerulosclerosis (FSGS). In cadaver allograft recipients, the lowest graft failure rates were associated with primary diagnoses of glomerulonephritis, congenital/structural disease and cystinosis, while patients with FSGS, HUS and CNS had the highest graft failure rates. This study suggests that patients with a primary diagnosis of cystinosis have superior outcomes, while the diagnoses of FSGS and CNS carry with them the highest risks of graft failure.
Subject(s)
Graft Survival , Kidney Diseases/surgery , Kidney Transplantation/statistics & numerical data , Canada , Child , Graft Rejection , Humans , Kidney Diseases/mortality , Kidney Transplantation/mortality , Multivariate Analysis , Risk , Tissue Donors , United StatesABSTRACT
Changes in height deficit and standard deviation score (SDS) were evaluated in 524 recipients who were growth retarded at transplantation (SDS > -2.00) and were followed for at least 2 years post transplant. At 2 years the delta SDS was 0.32 +/- 0.04 and the delta height deficit was 0.75 +/- 0.23. Therefore despite improvement in the SDS at 2 years post transplant, the change in height deficit was < 1 cm. Change in height deficit may be a better indication of "catch-up" growth following transplantation.
Subject(s)
Growth/physiology , Kidney Transplantation/physiology , Adolescent , Child , Child, Preschool , Female , Growth Disorders/complications , Humans , Kidney Diseases/complications , Kidney Diseases/therapy , Male , Regression AnalysisABSTRACT
We examined the safety and immunogenicity of a baculovirus-derived recombinant HIV-1 envelope glycoprotein vaccine candidate, rgp160 (VaxSyn; MicroGeneSys, Meriden, CT), administered at doses of 160 or 640 micrograms to 56 healthy, HIV-1-seronegative adults, in a randomized, double-blind, placebo-controlled study. Immunizations were given intramuscularly at 0, 1, 6, and 12 months. Both doses were generally well tolerated, although self-limited local reactions were frequent. No other clinical or laboratory toxicities were noted, and no effects on CD4 or CD8 lymphocyte counts or percentages were noted. Serum antibody responses to HIV proteins were detected by Western blot (WB) in 19 of 20 and in 19 of 19 recipients of four doses of 160 and 640 micrograms, respectively. Western blot responses developed more rapidly in the 640-micrograms group. High rates of EIA antibody responses to HIV-1 lysate were also present in both groups, and developed more rapidly in the 640-micrograms group. Enzyme immunoassay antibody responses to the immunogen (rgp160) were also frequent, but were infrequent to V3 to gp41 peptides. Neutralizing antibodies against the homologous HIV-1 LAI isolate were seen in 3 of 20 subjects (GMT = 11) who received four doses of 160 micrograms, and in 10 of 19 subjects who received four doses of 640 micrograms (GMT = 32). Fusion inhibiting antibody was not detected. CD4 blocking activity was seen in 3 of 19 subjects who received four doses of 640 micrograms. Complement-mediated antibody-dependent enhancement was found in sera from 11 of 19 volunteers in the 640-micrograms group. Lymphocyte proliferative responses to the immunogen were detected in 4 of 4 subjects tested, but no cytotoxic T cell activity was noted in 11 subjects. Administration of the 640-micrograms dose of this rgp160 vaccine candidate relative to the lower doses was associated with increased immunogenicity, including higher rates of homologous neutralizing antibody responses, although at low titer.
Subject(s)
AIDS Vaccines/immunology , Gene Products, env/immunology , HIV-1/immunology , Protein Precursors/immunology , AIDS Vaccines/adverse effects , Adult , Amino Acid Sequence , Antibodies, Viral/blood , Antibodies, Viral/immunology , Dose-Response Relationship, Immunologic , Double-Blind Method , Female , Follow-Up Studies , HIV Envelope Protein gp160 , HIV Seronegativity/immunology , Humans , Immunity, Active/immunology , Immunity, Cellular , Immunoenzyme Techniques , Male , Middle Aged , Molecular Sequence Data , Neutralization Tests , Recombinant Proteins/adverse effects , Recombinant Proteins/immunology , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/immunologyABSTRACT
The purpose of this randomized, double-blind study was to test the safety and immunogenicity of an HIV-1LAI recombinant gp160 (rgp160) vaccine in healthy, uninfected volunteers using accelerated dosing schedules. Thirty volunteers were randomly assigned to receive 50-micrograms doses of rgp160 in one of two immunization schedules. Group 1 received rgp160 at times 0, 1, 2 and 5 months; and group 2 received rgp160 at times 0, 1, 2, 3 and 4 months. The vaccine was safe and stimulated high levels of HIV-1 envelope-specific binding antibody and T cell memory. There was a trend (P < 0.10) suggesting neutralizing antibodies were better induced by the regimen incorporating a rest period before the final immunization in group 1 volunteers. Both accelerated immunization schedules induced immune responses at levels similar to or better than those achieved by four rgp160 vaccine injections given over 12-18 months in other studies.
Subject(s)
AIDS Vaccines/administration & dosage , Vaccines, Synthetic/administration & dosage , AIDS Vaccines/immunology , Adult , Amino Acid Sequence , Analysis of Variance , Double-Blind Method , Enzyme-Linked Immunosorbent Assay , Female , Gene Products, env/immunology , HIV Envelope Protein gp160 , Humans , Immunization Schedule , Male , Middle Aged , Molecular Sequence Data , Protein Precursors/immunology , Vaccines, Synthetic/immunologyABSTRACT
BACKGROUND AND METHODS: The safety of long-term immunosuppression with cyclosporine in renal-transplant recipients is not well understood. This drug may cause a progressive toxic nephropathy, but it also preserves renal function because it prevents rejection. To determine the effect of cyclosporine on renal function and graft rejection, we conducted a retrospective analysis of data on 1663 renal-transplant recipients at six centers. RESULTS: The rate of graft survival was 78 percent (median follow-up, 36 months). Grafts were was lost in 279 patients (17 percent), mostly because of acute rejection (68 patients) or chronic graft dysfunction that was unresponsive to a reduction in the dose of cyclosporine (125 patients); 92 patients died with functioning grafts. The median change in the serum creatinine concentration in all patients after transplantation was less than 0.001 mg per deciliter per month (< 0.09 mumol per liter per month). Patients who had episodes of rejection had decreased rates of long-term graft function and survival. Eight percent of patients with functioning grafts at one year had first episodes of rejection more than one year after transplantation. These late first rejections were associated with noncompliance with therapy (in 34 percent), blood cyclosporine concentrations that were marginally lower than those of patients who had no episodes of rejection, and a low rate of successful reversal of rejection (77 percent, vs. 97 percent in patients with rejection during the first year; P < 0.001). CONCLUSIONS: The majority of renal-transplant patients tolerate long-term cyclosporine therapy without evidence of progressive toxic nephropathy. Graft failure is most often due to rejection.