Quantifying spillover benefits in value assessment: a case study of increased graft survival on the US kidney transplant waitlist.

AIM: To quantify the wider impacts of increased graft survival on the size of the kidney transplant waitlist and health and economic outcomes. MATERIALS AND METHODS: The analysis employed known steady-state solutions to a double-queueing system as well as simulations of this system. Baseline input parameters were sourced from the Organ Procurement and Transplant Network and the United States Renal Data System. Three increased graft survival scenarios were modeled: decreases in repeat transplant candidates joining the waitlist of 25%, 50%, and 100%. RESULTS: Under the three scenarios, we estimated that the US waitlist size would decrease from 91,822 to 85,461 (6.9% decrease), 80,073 (12.8% decrease), and 69,340 (24.4% decrease), respectively. Patient outcomes improved, with lifetime quality-adjusted life years (QALYs) for a 1-year cohort of transplant recipients increasing by 10,010, 16,888, and 43,345 over the three scenarios. Discounted lifetime costs for the cohort in the new steady state were lower by $1.6 billion, $2.3 billion, and $9.0 billion for each scenario, respectively. Spillover impacts (i.e. benefits that accrued beyond the patients who directly experienced increased graft survival) accounted for 41-48% of the QALY gains and ranged from cost increases of 3.3% to decreases of 5.5%. LIMITATIONS: The model is a simplification of reality and does not account for the full degree of patient heterogeneity occurring in the real world. Health economic outcomes are extrapolated based on the assumption that the median patient is representative of the overall population. CONCLUSIONS: Increasing graft survival reduces demand from repeat transplants candidates, allowing additional candidates to receive transplants. These spillover impacts decrease waitlist size and shorten wait times, leading to improvements in graft and patient survival as well as quality-of-life. Cost-effectiveness analyses of treatments that increase kidney graft survival should incorporate spillover benefits that accrue beyond the direct recipient of an intervention.

[Influence of hypertension on renal allograft survival in pediatric patients]. / Influência da hipertensão na sobrevida do enxerto renal em pacientes pediátricos.

BACKGROUND: To evaluate the effect of 1 year systemic arterial hypertension on 3-year allograft survival in children with kidney transplantation. METHODS: A retrospective study was carried out of pediatric patients submitted to kidney transplantation at the Universidade Federal de São Paulo (UNIFESP) between January, 1998 and January, 2003. Patients were classified as normotensive or hypertensive according to presence of hypertension within the first year after transplantation. Survival analyses were performed with the Kaplan-Meier survival method, and survival curves were compared with the log-rank test. A p value of < 0.05 was considered statistically significant. RESULTS: Prior to transplantation there were 86 patients (64%) and after 1 year, 70 children (52%) were classified as hypertensive, respectively. Overall, the 3-year graft survival was of 92.5%. Survival of the normotensive group was 95.3% and 90.0% for the hypertensive group; the difference was not statistically significant. CONCLUSION: Although the difference between the two groups was not statistically significant the higher survival of the normotensive group seems to be clinically significant and allows hypothesizing that arterial hypertension could be a risk factor for pediatric graft survival. However, due to limitations of the study it is impossible to affirm that hypertension is an independent risk factor for lower graft survival.

Influência da hipertensão na sobrevida do enxerto renal em pacientes pediátricos / Influence of hypertension on renal allograft survival in pediatric patients

OBJETIVO: Avaliar a influência da hipertensão arterial sistêmica com um ano de transplante renal na sobrevida do enxerto renal três anos após o transplante em crianças. MÉTODOS: Estudo observacional e retrospectivo na série de pacientes transplantados renais pediátricos da Universidade Federal de São Paulo (UNIFESP) no período de janeiro/1998 a janeiro/2003. Ao final do primeiro ano pós-transplante, os pacientes foram classificados em dois grupos: normotensos e hipertensos. A análise estatística de sobrevida foi através do método de Kaplan-Meier. A comparação entre grupos foi realizada utilizando-se o teste do "log-rank". Para os testes adotamos o limite de 5 por cento (α < 0,05) para rejeição da hipótese de nulidade. RESULTADOS: Antes do transplante 86 pacientes (64 por cento) e após um ano 70 indivíduos (52 por cento) foram classificados como hipertensos, respectivamente. A sobrevida do enxerto renal após três anos de transplante foi de 92,5 por cento para a amostra completa do estudo. O grupo de normotensos apresentou sobrevida de 95,3 por cento e os hipertensos 90 por cento; a diferença não foi estatisticamente significante. CONCLUSÃO: Apesar do resultado estatístico não ser significante, a diferença observada entre os dois grupos após três anos de transplante, de 5 por cento maior sobrevida nos indivíduos que eram normotensos um ano após o transplante, nos parece clinicamente significativa e nos permite levantar a hipótese de que a hipertensão arterial pode ser um fator de risco para a sobrevida do enxerto pediátrico. Entretanto, não nos seria possível afirmar que a hipertensão é fator de risco independente para menor sobrevida do enxerto devido às limitações do estudo.

BACKGROUND: To evaluate the effect of 1 year systemic arterial hypertension on 3-year allograft survival in children with kidney transplantation. METHODS: A retrospective study was carried out of pediatric patients submitted to kidney transplantation at the Universidade Federal de São Paulo (UNIFESP) between January, 1998 and January, 2003. Patients were classified as normotensive or hypertensive according to presence of hypertension within the first year after transplantation. Survival analyses were performed with the Kaplan-Meier survival method, and survival curves were compared with the log-rank test. A p value of < 0.05 was considered statistically significant. RESULTS: Prior to transplantation there were 86 patients (64 percent) and after 1 year, 70 children (52 percent) were classified as hypertensive, respectively. Overall, the 3-year graft survival was of 92.5 percent. Survival of the normotensive group was 95.3 percent and 90.0 percent for the hypertensive group; the difference was not statistically significant. CONCLUSION: Although the difference between the two groups was not statistically significant the higher survival of the normotensive group seems to be clinically significant and allows hypothesizing that arterial hypertension could be a risk factor for pediatric graft survival. However, due to limitations of the study it is impossible to affirm that hypertension is an independent risk factor for lower graft survival.

Risk factors for hypertension 3 years after renal transplantation in children.

We performed a case-control study in renal transplant patients between 1998 and 2003 to identify risk factors for arterial hypertension over the medium term in pediatric patients undergoing renal transplantation. Three years after transplant, patients were classified into hypertensive or control groups. The following risk factors were analyzed: hypertension before transplant, glomerular filtration rate at sixth posttransplant month, acute rejection episodes, renal artery stenosis, accumulated prednisone and calcineurin inhibitor doses, presence of native kidneys, donor type (living or cadaver), body mass index at 1 year posttransplant, and glomerular disease as renal insufficiency etiology. Of 161 transplants, 124 fulfilled the inclusion criteria; 63 were hypertensive, and 61 were controls. Univariate analysis showed hypertension before transplant (52/63 vs. 27/61, p < 0.001), glomerulopathies (23/63 vs. 12/61, p = 0.001), glomerular filtration rate at 6 months (71 +/- 18 vs, 80 +/- 18 ml/min per 1.73 m(2), p = 0.003) as risk factors. A tendency to statistical significance was observed with regard to body mass index (SDS) in the first year (0.40 +/- 1.10 vs, 0.04 +/- 1.10, p = 0.072). Multivariate analysis showed statistical significance concerning previous hypertension and glomerular filtration rate at 6 months. Hypertension before transplant and early graft function are the major risk factors for hypertension in the medium term following renal transplant.

An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination.

BACKGROUND: The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects. METHODS: Between June 1999 and February 2000, 70 recipients of primary one-haplotype living-related donor renal allografts were randomized to receive SRL (2 mg/d) or azathioprine (AZA) (2 mg/kg/d) combined with cyclosporine and prednisone. The primary end-point was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 3 months after transplantation. RESULTS: From week 4 to month 12, SRL patients received lower cyclosporine (week 4: 364 mg/d vs. 455 mg/d, p = 0.004; month 12: 195 mg/d vs. 255 mg/d, p = 0.038) doses and showed lower cyclosporine concentrations (week 4: 247 ng/mL vs. 309 ng/mL, p = 0.04; month 12: 143 ng/mL vs. 188 ng/mL, p = 0.045). Compared with AZA, SRL patients showed reduced 3-month primary end point (0% vs. 17.1%, p = 0.025), and reduced incidence of biopsy-confirmed acute rejection at 3 months (0% vs. 14.3%, p = 0.01) but not at 12 months (11.4% vs. 14.3%, NS). Mean creatinine at 12 months were not different (1.8 +/- 0.6 vs. 1.6 +/- 0.6, p = 0.23). Hyperlipidemia was the only adverse event more frequent among SRL patients (49% vs. 17%, p = 0.01). There were no differences in infections and no malignancies in both groups. CONCLUSIONS: The combination of 2 mg fixed doses of SRL, reduced cyclosporine exposure and prednisone was associated with a low incidence of acute rejection and did not result in significantly impaired graft function compared with patients receiving AZA, standard doses of cyclosporine and prednisone.

The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring.

UNLABELLED: The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. We sought to determine the influence of ethnic miscegenation on tacrolimus pharmacokinetics and trough concentrations during the first 6 months after transplantation. METHODS: Tacrolimus concentrations were measured in blood samples obtained from 22 transplant recipients during the first week of transplant, within pharmacokinetic profiles, and throughout the first 6 months post-transplant, using the Pro Tac II ELISA method. Pharmacokinetic parameters and between- and within-subject blood concentration variability were compared stratifying the total population in two distinct ethnic groups of white (W) and non-white (NW) patients, according to a stringent criterion. RESULTS: Between-subject variability in dose-adjusted concentrations during dosing interval varied from 38.8 to 69.5%. Compared with W patients, NW patients showed higher variability in blood tacrolimus concentrations during dosing interval (37.40 +/- 5.64 vs. 56.95 +/- 11.49, p < 0.001) and lower drug exposures (AUC: 229.4 +/- 55.5 vs. 66.9 +/- 67.1 ng x h/mL, p=0.036). The correlation coefficients (r2) between C0, C12 or Cmax and AUC were 0.83, 0.91 and 0.5, respectively. An equation derived from early time concentrations (C0, C1.5 and C4) accounted for 94% of the variability observed in AUC. Compared with W patients, a higher proportion of tacrolimus blood determinations during the first week were below 10 nug/mL in NW patients (24% vs. 62%, p=0.028). Tacrolimus absorption increased from week 1-4 (1.1 +/- 0.53 vs. 1.73 +/- 0.97 nug/mL/mg, p < 0.0001) but was still showed high between- (41.6-70.4%) and within-subject (18.2-32.5%) variability, regardless of ethnicity, after stabilization. CONCLUSION: Non-white patients show higher tacrolimus variability and lower drug exposures after transplantation compared with W patients. Therefore, higher initial tacrolimus doses and intensive monitoring are recommended when administering tacrolimus-based immunosupressive therapy to NW patients of this transplant population.

Rejeiçäo aguda como fator de risco para sobrevida e sua incidência reduzida por ciclosporina entre HLA-idênticos / Acute rejection as a risk factor of long-term survival and a lower rejection incidence in cyclosporine-treated HLA identical patients

Considerando que fatores dependentes de aloantígenos e näo-dependentes de aloantígenos associam-se ao desenvolvimento de nefropatia crônica do enxerto (NCE) e à reduzida sobrevida do enxerto renal, este trabalho objetivou analisar 1.544 transplantes renais quanto à incidência de rejeiçäo aguda (RA) de acordo com três protocolos imunossupressores: (1) azatioprina (AZA) mais prednisona (PRED); (2) AZA mais PRED mais ciclosporina (CSA); e (3) AZA mais PRED mais ciclosporina microemulsäo (CSAm). Além disso, fizeram-se análises uni e multivariadas dos fatores potencialmente associados à sobrevida funcional do enxerto. A incidência de RA foi menor entre pacientes que utilizaram protocolos com ciclosporina quando comparada a pacientes que receberam AZA mais PRED. Entre os pacientes com RA, a sobrevida de cinco anos do enxerto foi significativamente menor que aqueles sem RA. Receptores com RA apresentaram menor sobrevida livre de NCE em cinco anos que aqueles sem RA. As variáveis que apresentaram associaçäo significativa com o risco de perda do enxerto foram: compatibilidade HLA; número de episódios de RA; idade do doador e idade do receptor.Fatores relacionados à resposta imunológica representam maior risco para perda do enxerto renal.(au)