Risk assessment score in pre-kidney transplantation: methodology and the socioeconomic characteristics importance

Introduction: Kidney transplantation is performed in emergency conditions in a population with high perioperative risk. Instruments for risk assessment before transplantation in this population are scarce. Objective: To develop a score with pretransplant variables to estimate the probability of success of kidney transplantation, defined as survival of the recipient and the graft with creatinine < 1.5 mg/dl at 6 months. Methods: Analysis of variables of patients from a unique kidney transplantation center in São Paulo. Logistic regression was used to construct an equation with variables able to estimate the probability of success. Integer points were assigned to variables for score construction. Results:Of the 305 patients analyzed, 176 (57.7%) achieved success. Of the 23 variables identified by univariate analysis, 21 were included in the logistic regression model and 10 that remained independently associated with success, were used in the score. Four of these 10 variables were socioeconomic. It was great (area under the ROC curve 0.817) the power of discrimination between groups success and not success and adequate (Hosmer and Lemeshow = 0.672) the agreement between frequencies of the probabilities estimated by equation and frequencies of probabilities actual observed. There were correlation (0.982) between the estimated probability via the scoring system and the estimated probabilities via logistic regression. Conclusion: Point score simplified risk stratification of transplant candidate according to their probability of success. Socioeconomic variables influence the success, demonstrating the need for creation of prognostic tools utilizing clinical and demographic variables of our population.Introdução: O transplante renal é realizado em condições de urgência em uma população com elevado risco perioperatório. Instrumentos de avaliação de risco pré-transplante nesta população são escassos. Objetivo: Construir um escore com variáveis pré-transplante para estimar a probabilidade de sucesso do transplante renal, definido como sobrevida do receptor e do enxerto, com creatinina < 1,5 mg/dl no 6º mês. Métodos: Análise das variáveis de pacientes de um centro único e especializado em transplante renal em São Paulo. A regressão logística foi utilizada para construção da equação com as variáveis capazes de estimar a probabilidade de sucesso. Atribuímos pontos inteiros às variáveis para a construção do escore. Resultados: Dos 305 pacientes analisados, 176 (57,7%) atingiram o sucesso. Das 23 variáveis identificadas pela análise univariada, 21 foram incluídas no modelo de regressão logística e as 10 que se mantiveram independentemente associadas com o sucesso foram utilizadas na construção do escore. Quatro destas 10 variáveis eram socioeconômicas. Foi ótimo (área sob a curva ROC = 0,817) o poder de discriminação entre os grupos sucesso e não sucesso e adequado (teste de Hosmer e Lemeshow = 0,672) o grau de concordância entre as frequências das probabilidades estimadas pela equação e as frequências das probabilidades reais observadas. Houve correlação (0,982) entre as probabilidades estimadas via sistema de pontuação e regressão logística. Conclusão: O escore de pontos apresentado simplificou a estratificação do risco do candidato ao transplante conforme a probabilidade de sucesso. As variáveis socioeconômicas exerceram influência no sucesso, demonstrando a necessidade da criação de instrumentos prognósticos utilizando as variáveis clínico-demográficas da nossa população.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Influence of deceased donor hemodynamic factors in transplant recipients renal function

INTRODUCTION: The incidence of delayed graft function (DGF) and unsatisfactory creatinine clearance (UCC) after renal transplantation is significantly higher in Brazil, when compared with that observed in United States or Europe. Deceased donor (DD) characteristics should directly influence the occurrence of these two outcomes. OBJECTIVE: This study aim to evaluate the influence of DD characteristics on DGF and UCC incidence in Brazil. METHODS: DD clinical and laboratory variables were correlated with outcome's incidence. RESULTS: We evaluated 787 DD whose organs were transplanted in 1298 patients. We noted a high prevalence of vasoactive drugs use (90.2%), hypernatremia (66.6%) and renal dysfunction (34.8%). The incidence of DGF and UCC was 60.6% and 55.2%, respectively. We observed a progressive increase in DGF risk for age groups over 30 years and for cold ischemia time (CIT) greater than 24 hours. DGF risk was two times higher in recipients of donor kidney final serum creatinine (Cr) over than 1.5 mg/dl. Hypertension and CIT over 36 hours was associated with an increasing of 82% and 99% in UCC risk, respectively. Donor age above 40 years was associated with a progressive increase in UCC risk. CONCLUSION: DD age, renal function, hypertension and prolonged CIT were associated with increased risk DGF and UCC.INTRODUÇÃO: A incidência de função tardia do enxerto (FTE) e função renal insatisfatória (FRI) após o transplante renal é significativamente maior no Brasil comparada com aquela observada nos Estados Unidos ou na Europa. Fatores relacionados ao doador falecido (DF) devem influenciar diretamente a ocorrência desses dois desfechos. OBJETIVO: Este estudo propõe-se a avaliar a influência das características do DF na incidência de FTE e FRI no Brasil. MÉTODOS: Variáveis clínicas e laboratoriais dos DF foram correlacionadas com a incidência de FTE e FRI. RESULTADOS: Foram avaliados 787 DF cujos órgãos foram transplantados em 1.298 pacientes. Notou-se elevada prevalência de uso de droga vasoativa (90,2%), hipernatremia (66,6%) e disfunção renal (34,8%). A incidência de FTE foi de 60,6% e de FRI foi de 55,2%. Considerando as características dos DF, observamos um aumento progressivo no risco de desenvolvimento de FTE para faixas etárias acima de 30 anos e a partir de tempo de isquemia fria (TIF) maior que 24 horas. O risco de FTE foi duas vezes maior em receptores de rim de doadores com creatinina sérica final (Cr) superior a 1,5 mg/dl. Hipertensão arterial (HA) e o TIF acima de 36 horas associou-se com aumentos de 82% e 99% no risco de FRI, respectivamente. A idade do doador acima de 40 anos associou-se com um aumento progressivo no risco de FRI. CONCLUSÃO: A idade, a função renal e a presença de hipertensão arterial no doador falecido, além do TIF prolongado, associaram-se com maior risco de FTE e FRI.Universidade Federal de São Paulo (UNIFESP)Fundação Osvaldo Ramos Hospital do Rim e HipertensãoUNIFESPSciEL

Mortality Predictors in Renal Transplant Recipients with Severe Sepsis and Septic Shock

Introduction: the growing number of renal transplant recipients in a sustained immunosuppressive state is a factor that can contribute to increased incidence of sepsis. However, relatively little is known about sepsis in this population. the aim of this single-center study was to evaluate the factors associated with hospital mortality in renal transplant patients admitted to the intensive care unit (ICU) with severe sepsis and septic shock.Methods: Patient demographics and transplant-related and ICU stay data were retrospectively collected. Multiple logistic regression was conducted to identify the independent risk factors associated with hospital mortality.Results: A total of 190 patients were enrolled, 64.2% of whom received kidneys from deceased donors. the mean patient age was 51 +/- 13 years (males, 115 [60.5%]), and the median APACHE II was 20 (16-23). the majority of patients developed sepsis late after the renal transplantation (2.1 [0.6-2.3] years). the lung was the most common infection site (59.5%). Upon ICU admission, 16.4% of the patients had = 2 organ failures at admission, and 27.9% experienced septic shock within the first 24 hours of ICU admission. the overall hospital mortality rate was 38.4%. in the multivariate analysis, the independent determinants of hospital mortality were male gender (OR = 5.9; 95% CI, 1.7-19.6; p = 0.004), delta SOFA 24 h (OR = 1.7; 95% CI, 1.2-2.3; p = 0.001), mechanical ventilation (OR = 30; 95% CI, 8.8-102.2; p<0.0001), hematologic dysfunction (OR = 6.8; 95% CI, 2.0-22.6; p = 0.002), admission from the ward (OR = 3.4; 95% CI, 1.2-9.7; p = 0.02) and acute kidney injury stage 3 (OR = 5.7; 95% CI, 1.9-16.6; p = 0.002).Conclusions: Hospital mortality in renal transplant patients with severe sepsis and septic shock was associated with male gender, admission from the wards, worse SOFA scores on the first day and the presence of hematologic dysfunction, mechanical ventilation or advanced graft dysfunction.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Hospital do RimUniversidade Federal de São Paulo, Unidade Transplante, Disciplina Nefrol, São Paulo, BrazilUniversidade Federal de São Paulo, Disciplina Anestesiol Dor & Terapia Intens, São Paulo, BrazilUniversidade Federal de São Paulo, Unidade Transplante, Disciplina Nefrol, São Paulo, BrazilUniversidade Federal de São Paulo, Disciplina Anestesiol Dor & Terapia Intens, São Paulo, BrazilWeb of Scienc

Lipid Profile Changes During the First Year After Kidney Transplantation: Risk Factors and Influence of the Immunosuppressive Drug Regimen

Aim. This study analyzed the incidence, time course, and risk factors associated with dyslipidemia during the first year after kidney transplantation among patients receiving various immunosuppressive regimens.Methods. the analysis included 474 kidney transplant recipients receiving cyclosporine (CSA) combined with sirolimus (SRL; n = 137) or mycophenolate (MMF, n = 58) or everolimus (EVR, n = 47); or SRL combined with MMF (n = 32); or tacrolimus (TAC) combined with SRL (n = 86) or MMF (n = 114). All patients received prednisone. We evaluated the influence of demographic features, clinical outcomes, and statin use on lipid profiles during the first year after transplantation. total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, TC:HDL-C, LDL-C:HDL-C, TG:HDL-C.Results. Lipid profiles were within the recommended ranges in 28% of patients pretransplantation and in 10% at 1 year; 27% of them received statins. At 1 year, LDL-C 100 mg/dL, almost 70% to 80% had other lipid fractions or ratios within target ranges. A logistic regression analysis showed age, gender, time on dialysis, diabetes, type of calcineurin inhibitor (CSA vs TAC), adjunctive therapy (SRL/EVR vs MMF) and prednisone dose to be associated with dyslipidemia.Conclusion. Dyslipidemia is frequent at 1 year after transplantation. the lack of agreement among changes observed in lipid fractions and ratios suggests that more studies are necessary to guide therapy besides targeting LDL-C concentrations as recommended by current guidelines.Universidade Federal de São Paulo UNIFESP, Div Nephrol, Hosp Rim & Hipertensao, BR-04038002 São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Div Nephrol, Hosp Rim & Hipertensao, BR-04038002 São Paulo, BrazilWeb of Scienc

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 ± 0.05 (0.25 mg), 0.73 ± 0.12 (0.5 mg), 3.26 ± 0.51 (1 mg), and 7.15 ± 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r² = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 ± 5.3% and ED50 = 0.48 ± 0.08 mg, r² = 0.94) or concentration (Emax = 78.3 ± 2.9% and EC50 = 0.59 ± 0.09 ng/ml, r² = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Hospital do Rim e HipertensãoNovartis PharmaceuticalsUNIFESP, EPM, Hospital do Rim e HipertensãoSciEL

Kidney transplantation in Brazil and its geographic disparity

The Brazilian National Transplantation System coordinates and regulates perhaps the largest public transplantation program worldwide. Since its implementation in 1997, the number of kidney transplantations increased from 920 (5.8 pmp) in 1998, to 4,630 (24.1 pmp) in 2010. This growth was primarily due to the increased number of effective donors (from 1.8 pmp in 1998 to 9.3 pmp in 2010), with a corresponding increased number of kidneys transplanted from deceased donors (3.8 pmp in 1999 versus 9.9 pmp in 2010).The number of kidney transplantations from living donors has not increased significantly, from 1,065 (6.7 pmp) in 1998 to 1,641 (8.6 pmp) in 2010, either as a consequence of the observed increase in the deceased donor program or perhaps because of strict government regulations allowing only transplantations from related donors. From 2000 to 2009, the mean age of living donors increased from 40 to 45 years, while it increased from 33 to 41 years for deceased donors, of whom roughly 50% die of stroke. There are clear regional disparities in transplantation performance across the national regions. While the state of São Paulo is ranked first in organ donation and recovery (22.5 pmp), some states of the Northern region have much poorer performances. These disparities are directly related to different regional population densities, gross domestic product distribution, and number of trained transplantation physicians. The initial evaluation of the centers with robust outcomes indicates no clear differences in graft survival in comparison with centers in the USA and Europe. Ethnicity and time on dialysis, but not the type of immunosuppressive regimen, decisively influence the measured outcomes. Since the implementation of national clinical research regulations in 1996, Brazilian centers have participated in a number of national and international collaborative trials for the development of immunosuppressive regimens. Besides the challenge of reducing the regional disparities related to access to transplantation, further improvements can be obtained by the creation of a national registry of the outcomes of transplanted patients and living donors, and also by the promotion of clinical and experimental studies to better understand the transplantation-related immune response of the Brazilian population.O Sistema Nacional de Transplantes (SNT) Brasileiro coordena e regulamenta o, provavelmente, maior programa de transplantes públicos do mundo. Desde o seu estabelecimento, em 1997, o número de transplantes renais aumentou de 920 (5,8 pmp), em 1988, para 4.630 (24,1 pmp), em 2010. Esse crescimento foi primariamente devido ao aumento no número de doadores efetivos (de 1,8 pmp em 1998 para 9,3 pmp em 2010), com aumento correspondente no número de rins transplantados de doadores falecidos (3,8 pmp em 1999 versus 9,9 pmp em 2010). O número de rins transplantados com órgãos de doadores vivos não aumentou significativamente, 1.065 (6,7 pmp), em 1998, para 1.641 (8,6 pmp), em 2010, tanto em consequência do melhor desempenho do programa de doadores falecidos, como talvez também devido a mais restrita regulamentação, permitindo apenas doação entre doadores vivos relacionados. De 2000 a 2009, a idade média dos doadores vivos aumentou de 40 para 45 anos, e a dos doadores falecidos, de 33 para 41 anos, com eventos cerebrovasculares sendo responsáveis por 50% dos episódios de óbito atualmente. Existem disparidades geográficas evidentes nos desempenhos entre as 5 regiões nacionais. Enquanto o estado de São Paulo ocupa a primeira posição em doação e captação de órgãos (22,5 pmp), alguns estados da região Norte apresentam pequena ou nenhuma atividade de transplante. Essas disparidades estão diretamente relacionadas à densidade populacional regional, ao produto interno bruto e ao número de médicos com treinamento em transplante. A avaliação inicial de desfechos clínicos robustos não indica diferenças nas sobrevidas do enxerto em comparação com as observadas nos EUA e na Europa. A etnia e o tempo em diálise, mas não o tipo de imunossupressão, apresentam influência decisiva nos desfechos medidos. A regulamentação nacional da pesquisa clínica foi implementada a partir de 1996, permitindo a participação de centros brasileiros em numerosos estudos clínicos nacionais e internacionais para o desenvolvimento de regimes imunossupressores. Acompanhando o desafio de atenuar as disparidades regionais no acesso ao transplante, o sistema pode ser aperfeiçoado pela criação de um registro nacional para receptores de transplante e de doadores vivos de rins e também pela promoção de estudos clínicos e experimentais voltados a melhor compreender a resposta imune relacionada ao transplante em nossa população.Universidade Federal de São Paulo (UNIFESP)Santa Casa de Misericórdia de Porto AlegreFaculdade de Medicina de São José do Rio PretoUniversidade Federal do CearáUniversidade de São PauloUNIFESPSciEL

Clinical manifestations and evolution of infection by influenza A (H1N1) in kidney transplant recipients

INTRODUCTION: The emergence of the pan>demic outbreak of influenza A (H1N1) in April, 2009, represented a logistic challenge for public health. Although most infected patients presented clinical and evolutionary manifestations which were very similar to seasonal influenza, a significant number of individuals developed pneumonia and severe acute respiratory failure. The impact of influenza A (H1N1) in immunocompromised patients is not well established yet. METHODS: This study aimed to analyze the clinical presentations and evolution of influenza A (H1N1) in 19 kidney transplant recipients. Influenza A (H1N1) infection was confirmed by RT-PCR in all patients. Treatment included antiviral therapy with oseltamivir phosphate and antibiotics. RESULTS: The studied population was compounded mostly of white people (63%), males (79%), at a mean age of 38.6 ± 17 years and patients with at least one comorbidity (53%). Influenza A (H1N1) infection was identified 41.6 ± 49.6 months after transplantation. Common symptoms included cough (100%), fever (84%), dyspnea (79%), and myalgia (42%). Acute allograft dysfunction was observed in 42% of the patients. Five patients (26%) were admitted to the Intensive Care Unit, two (10%) required invasive ventilation support, and two (10%) required vasoactive drugs. Mortality rate was 10%. CONCLUSIONS: Acute renal allograft dysfunction was a common finding. Clinical, laboratory, and evolutionary characteristics were comparable to those in the general population.INTRODUÇÃO: A emergência do surto pandêmico de influenza A, subtipo H1N1, em abril de 2009, representou um grande desafio para a logística de saúde pública. Embora a maioria dos pacientes infectados apresente manifestações clínicas e evolutivas muito semelhantes às observadas na influenza sazonal, um número significativo de indivíduos evolui com pneumonia e insuficiência respiratória aguda severa. O impacto da infecção pelo vírus influenza A, subtipo H1N1, em pacientes imunossuprimidos não é determinado. MÉTODOS: Neste estudo, foram analisadas a apresentação clínica e a evolução da influenza A, subtipo H1N1, em 19 receptores de transplante renal. Os pacientes receberam confirmação diagnóstica pela técnica de RT-PCR. O manejo clínico incluiu terapêutica antiviral com fosfato de oseltamivir e antibióticos. RESULTADOS: A população estudada foi predominantemente de indivíduos do sexo masculino (79%), brancos (63%), com idade média de 38,6 ± 17 anos e portadores de pelo menos uma comorbidade (53%). A infecção por influenza A, subtipo H1N1, foi diagnosticada em média 41,6 ± 49,6 meses após o transplante. Os sintomas mais comuns foram: tosse (100%), febre (84%), dispneia (79%) e mialgia (42%). Disfunção aguda do enxerto foi observada em 42% dos pacientes. Cinco pacientes (26%) foram admitidos em Unidade de Terapia Intensiva, dois (10%) necessitaram de suporte com ventilação invasiva e dois (10%) receberam drogas vasoativas. A mortalidade foi de 10%. CONCLUSÕES: A disfunção aguda do enxerto renal foi um achado frequente, e as características clínicas, laboratoriais e evolutivas foram comparáveis às da população geral.Universidade Federal de São Paulo (UNIFESP) Departamento de MedicinaUNIFESP, Depto. de MedicinaSciEL

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1%, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20% (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3%) and cytomegalovirus disease (4.3%) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.Universidade Federal de São Paulo (UNIFESP) Hospital do Rim e Hipertensão Divisão de NefrologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de PatologiaUNIFESP, Hospital do Rim e Hipertensão Divisão de NefrologiaUNIFESP, Depto. de PatologiaSciEL