Survival analysis and associated factors to mortality of renal transplant recipients in a University Hospital in Maranhão

INTRODUCTION
Renal transplantation is regarded as the best treatment for patients with Chronic Kidney Disease. Factors associated to survival of renal transplant recipients must be evaluated in order to implement appropriate conducts in these patients.


AIMS
To analyze the renal transplant patients survival and associated factors to their mortality.


METHODS
Observational, retrospective cohort study, including all the 215 patients who underwent kidney transplantation in the Renal Transplant Service of the Hospital Universitário da Universidade Federal do Maranhão (HUUFMA), from March 18, 2000 to September 18, 2008, with a follow-up ranging from 12 to 101 months. Demographic and clinical characteristics were observed. The Kaplan-Meier method was used for construction of survival curves, and they were compared by log-rank test. The Cox proportional hazards model was used for identification of factors associated to mortality.


RESULTS
The prevalence of deaths was 10,6%. The survival rates at 1, 3 and 5 years for living donors recipients were 97,8%, 94,1% and 92,9%, respectively and for deceased donors recipients, 95,6% and 95,6%, at 1 and 3 years, respectively. Factors statistically associated to a lower survival were: recipient age above 40 years (RR = 6.19; p = 0.001; 95% CI = 2.01-18.99) and surgery complications (RR = 4.98; p = 0.041; 95% CI = 1.07-23.27).


CONCLUSIONS
Kidney recipients survival rates at HUUFMA were similar to the rates related in other, Brazilian and international studies. Recipient age above 40 years and surgery complications were significantly associated to mortality in this study.


IntroductIon
Kidney transplantation (KT) is an ideal therapeutic approach for most patients with terminal chronic kidney disease (CKD), as it improves quality of life, reduces mortality, and offers a higher life expectancy when compared to dialysis. 1 This holds true even when considering certain patient groups, such as diabetics and the elderly, for whom such procedures were not permitted in the past. 2 With improvements in immunopharmacology and the clinical handling of patients, a decrease in the mortality rate after KT has been observed over time, although this decrease has not been followed by changes in the causes of death in this population.Cardiovascular diseases (CVD) have maintained their status as the main cause of death after KT. 3 The prevalence of cardiovascular risk factors is high among KT recipients; many recipients present with prior CVD, diabetes mellitus (DM), hypertension (H), or dyslipidemia at the time of the transplant 4 , and these patients have an annual risk of 3.5-5% for CVD-related death. 5nfections are important risk factors for mortality in KT recipients, who are susceptible to a large variety of pathogens, particularly bacteria, fungi, and viruses, as a consequence of immunosuppressive therapy. 6This immunosuppression-infection binomial frequently implies an impaired inflammatory response in the host, making it difficult to diagnose the infectious process and delaying adequate treatment for reducing the associated morbimortality. 7Additionally, some infections, Survival and associated factors to mortality of renal transplant recipients in a University Hospital in Maranhão particularly by viruses, may contribute to dysfunction and/or rejection of the graft and the development of systemic diseases and some neoplasms. 6alignant neoplasms are responsible for a high proportion of late mortality cases following KT, varying between 10% and 47%; survival increases both after transplantation and during the follow-up period. 8he main objective of this study was to identify the factors that had an impact on the survival of patients that underwent KT at the Kidney Transplant Center of the University Hospital of the Federal University of Maranhão (HUUFMA) between March 18, 2000 and  September 18, 2008.

Methods
The study was a retrospective cohort observational assessment study.All 215 patients who underwent KT at HUUFMA between March 18, 2000 and  September 18, 2008, with a live or deceased donor of any age or sex, with a minimum follow-up period of 12 months and a maximum follow-up period of 101 months, were analyzed.The study was conducted between January 2008 and December 2009.
Demographic, clinical, laboratory, pretransplantation, and evolutionary clinical data after KT were obtained from patient records.
The definitions used in the study are as follows: H, systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg; 9 anemia, hemoglobin level < 12 g/dL or use of recombinant human erythropoietin; 10 hypercholesterolemia, total cholesterol level ≥ 200 mg/dL; 11 hypertriglyceridemia, triglyceride level > 150 mg/dL; 11 hyperuricemia, uric acid level > 7 mg/ dL; 12 obesity (defined according to the classification by the World Health Organization [WHO]), 13 body mass index (BMI) ≥ 30 kg/m 2 ; left ventricular hypertrophy (LVH; defined according to the criteria of the American Society of Echocardiography [ASE]), normal values of the left ventricle mass index of up to 110 g/m 2 for women and up to 134 g/m 2 for men; 14 induction, use of intense immunosuppression in the initial stages of the transplant with the goal of immediately decreasing the immune response to the allograft; 15 monoclonal-anti interleukin-2 (IL-2), basiliximab, and polyclonal, antithymocyte globulin (ATG) antibodies (used in moderate-tohigh immunological risk patients according to the center criteria); surgical complications, surgical complications of any etiology, which presented at any time after the transplant.
Standard antibiotic prophylaxis using cefazolin was conducted for all surgical procedures.
Numerical variables are presented as mean and standard deviation (mean ± SD), and categorical variables are presented as frequency and percentage.
Patient age was categorized as ≤ 40 years and > 40 years.Dialysis time was categorized as ≤ 3 years and > 3 years.These categories were determined by the mean values of each of the 2 variables in order to calculate risk ratios (RRs).
Comparisons between the demographic and clinical characteristics of the patients who died and those of the patients who survived were conducted using the chi-squared (chi 2 ) test of association or, when indicated, Fisher's exact test.
Survival was analyzed considering follow-up time, that is, the time (in months) between the transplant date and death directly or indirectly attributed to KT. Patients who experienced kidney graft loss, died due to external causes, or were alive until the end of the study were excluded.
Survival curves stratified according to the demographic and clinical characteristics of the patients were calculated by the Kaplan-Meier method and the differences between the curves were assessed using the bilateral log-rank test.
To identify the factors linked to mortality, the Cox proportional hazards model was used. 16he variables with a p value of < 0.20 in the univariate analysis or those with a p value ≥ 0.20, yet clinically significant according to the literature, were included in the multivariate analysis.Only the variables with p-values of < 0.05 remained in the final model.The RRs and its respective 95% confidence intervals (CIs) were also estimated.
Statistical analyses were conducted using the Stata version 10.0 statistical package (StataCorp, College Station, TX, USA).In all of the analyses, a significance level of 0.05 was considered. In

results
Throughout the study period, 215 kidney transplants were performed at our center, all of which were included in the review.
A comparison of the demographic characteristics of the patients who died with the characteristics of the surviving patients is shown in Table 1.Mixed race (64.7%) and male gender (55.3%) were the most prevalent characteristics; however, there was no statistically significant difference between these 2 groups in this regard.Additionally, no significant differences were observed with regard to underlying disease, dialysis time, type of donor, and induction therapy (Table 1).
Most patients showed a prior dialysis time of ≤ 3 years, both in the death group (72.7%) and the survival group (72.0%; p = 0.94).The average dialysis time in the death group was 35.9 months (0−120 months) and that of survivors was 32.5 months (0−142 months; data not shown).
There was a predominance of KT from live donors (87%).
Induction immunosuppressive therapy was used in 49 patients (23%), of which 34 (69%) were treated with basiliximab and 15 (31%) with ATG.However, no significant link to death and infectious diseases, CVD, or other causes was demonstrated in the comparison between the death and survivor groups (p = 0.78).On the other hand, the association between induction and the type of donor was statistically significant (p < 0.001); ninety-six percent of the transplants from deceased donors received induction vs. 13% of those from a live donor (data not shown).
Kidney graft function loss occurred 45 patients (20.9%), and the most frequent causes were death of the functioning graft (38%); chronic graft nephropathy (CGN; 31%), and acute rejection (AR; 13%).The CGN and AR diagnoses were confirmed through biopsy, and cell-mediated rejection was prevalent (data not shown).
Death following KT occurred in 22 patients (10.6%); the average survival time of these patients was 14.4 (± 16.4) months.Among these patients, 12 (54.5%)died in the first year after the transplant, with 10 deaths occurring in the first 6 months (45.4%).Only 1 patient (4.5%) died 5 years after the transplant; the remaining 9 patients (40.9%) died after the first year and before the 5-year anniversary of the transplant.
Table 2 shows the causes of death.Infectious conditions were the most frequent cause (60%), followed by cardiovascular, cerebrovascular, and peripheral vascular complications (22%).
Among the infection-related deaths, 84.6% (11/13) were due to septic shock, 7.7% were due to cerebral toxoplasmosis, and 7.7% were due to complications from varicella.Among the 13 deaths attributed to infections, 10 (76.9%) occurred in patients who showed some type of surgical complication; among these patients, 9 (69.2%)underwent reoperation.Septic shock was responsible for half of the deaths occurring in the first year post-transplant (6/12), of which 5 cases (45.4%) were secondary to surgical reintervention.
There was only 1 death due to neoplasm (lung cancer), which occurred in the 34th month after the KT.
Table 3 shows the comorbid conditions of the patients.There was no significant difference between the 2 groups with regard to any comorbidity.The most prevalent conditions in the death and survivor groups, respectively, were H (73% vs. 86%, p = 0.10), hypertriglyceridemia (41% vs. 53%, p = 0.27), and DM (27% vs. 29%, p = 0.86).In the death group, DM was present in almost a third of the patients, and the deaths were related to infection in all 6 cases; of these patients, 67% (4/6) died in an average period of 159 (± 124) days.Only 1 of these patients received a graft from a deceased donor (1/6).
The clinical complications following KT are shown in Table 4 and include both immunological and non-immunological conditions.None of these complications obtained statistical significance in the comparison between the groups.The most prevalent infections were those of the urinary tract (UTI), bacterial and fungal, in the airways, herpes simplex, and varicella-zoster (data not shown).The survival rates of patients that received grafts from live donors 1, 3, and 5 years after the transplant were 97.8%, 94.1%, and 92.9%, respectively.For those that received transplants from deceased donors, the survival rates for 1 and 3 years were 95.6% and 95.6%, respectively.
The differences in the survival rate between the groups that received transplants from live and deceased donors were not statistically significant for any of the periods taken into consideration, e.g., 1 year (p = 0.52) and 3 years (p = 0.69).Table 5 shows the univariate analysis results with RRs and the respective 95% CIs.In patients aged > 40 years, surgical complications and reoperation were statistically significant factors, which were included in the multivariate analysis.After an adjusted analysis, the factors linked to decreased patient survival that remained were as follows: age > 40 years (RR = 6.19, p = 0.001, 95% CI = 2.01−18.99)and surgical complications (RR = 4.98, p = 0.041, 95% CI = 1.07−23.27).
Figure 1 shows the survival curves of the variables that remained significant in the adjusted analysis.Recipients > 40 years of age showed lower survival rates relative to younger recipients (p = 0.001).The same result was observed for those who presented surgical complications (p = 0.041).

dIscussIon
In this study, the demographic and clinical characteristics of 215 patients who underwent KT at HUUFMA over an 8-year period were analyzed.
8][19] This situation is common and may represent a failure of the health system in terms of early detection and adequate handling of CKD, even when considering a future post-transplant follow-up.
Most deaths (12/22) occurred in the early period after the KT (< 1 year), and half of these deaths were the result of septic shock (6/12).In São Paulo, De Marco et al. 20 reported a mortality rate of 78.5% due to septic shock in a group of 14 KT recipients (May 2000 to December 2001), of which 11 were in the first year post-transplant.In our study, infectious complications were the most prevalent causes of death at any time after the transplant (60%), followed by cardiovascular, cerebrovascular, and peripheral vascular causes (22%).21,22 Linares et al. 21reported mortality rates due to CVD of 38%, 29% due to infection, and 12% due to neoplasm in a cohort of 1,218 KT recipients between 1995 and 2004 in Spain.In our country, as well as in other developing nations such as Thailand 17 and India, 22,23 mortality associated with infection after KT shows a greater impact in relation to all other causes of death.This may be explained by the unfavorable social and economic conditions that exist in a large portion these areas, climatic conditions, and the coexistence of endemic diseases.
A study that included 1,676 kidney transplant patients conducted between January 1998 and March 2004 at the Kidney and Hypertension Hospital and the São Paulo Hospital showed a 49% prevalence of infectious complications in the first year after transplantation, notably respiratory, herpetic, and UTIs. 19In our study, these were also the most prevalent infections.
Several studies have linked pre-transplant dialysis time to negative post-transplant outcomes 5,[24][25][26] .Cosio et al. 24 assessed the impact of this factor on patient survival, with an 84 ± 14-month follow-up, by comparing 3 groups: the first without prior dialysis (preemptive), the second with a time of up to 2 years in dialysis, and the last group with 3 years of dialysis; the mortality rates reported were 7%, 23%, and 41%, respectively.In their multivariate analysis, patient survival rates differed significantly between the 3 groups.Goldfarb-Rumyantzev et al. 25 concluded that a prolonged dialysis time is linked to unsatisfactory outcomes, both for the graft and the survival of the patient following the KT.
In our study, the average dialysis time was 32.9 (± 30.3) months, and there was no statistically significant association between dialysis time and mortality following the KT.Arend et al., 26 in the Netherlands, and Kimura et al., 27 in Japan, did not report an association between these factors either.
At HUUFMA during the study period, 87% of the transplants were obtained from live donors, possibly due to the lack of an effective policy for transplants in the State, which can be well demonstrated by the numbers of the Brazilian Transplant Records (RBT) of the Brazilian Association of Organ Transplant (ABTO). 28owever, in Brazil as a whole, the number of KTs obtained from deceased donors has only surpassed the number of live donors as of 2008. 29According to the most recent Brazilian Transplant Records, the number of deceased donors in Maranhão was greater than the number of live donors in 2008, 2009, and 2011. 28,30,31In our State, all of the steps of the donation-transplant process lack a structure that allows for a more effective operation.Such unfair distribution of the transplantation activity in Brazil is due to the great structural differences between the many regions of the country. 28,29n this work, there was no significant association between induction therapy and mortality by any cause (p = 0.78, chi 2 ).Twelve percent (6/49) of the patients who received induction died: 4 due to infections, 1 due to cerebral vascular accident, and 1 due to hypovolemic shock.However, considering that less than a third of the patients received induction, the apparent lack of such a link to mortality is not consistent.According to Meier-Kriesche et al. 32 , induction of treatment with antibodies represents a significant risk of late death in general (RR = 1.1, p < 0.001).For deaths occurring up to 6 months post-transplant, the risk is also significant in the case of death by infection (RR = 1.32, p < 0.001) and CVD (RR = 1.27, p < 0.001). 32n our study, H was present in 72.7% of the patients who died and 87.5% of the surviving patients (p = 0.06).H is considered the most important cardiovascular risk factor in this population.According to Ojo, 5 H is present in more than half of dialysis patients, and after transplantation, it affects 75−90% of the recipients, which is in agreement with our findings.H results particularly from the condition of H prior to transplantation and the addition of CIN after the transplant as a maintenance immunosuppressant.Shirali & Bia 33 stated in 2008 that CIN, especially CsA, contributes to H through vasoconstriction and saline retention mechanisms.In our study, all 182 patients with H used at least 1 CIN as an initial immunosuppressant; among these patients, 113 (62%) used cyclosporine, which was significantly associated with H (p = 0.009, chi 2 ).Marcén 34 stated that any immunosuppressant regimen should maximize graft survival and minimize rejection, nephrotoxicity, cardiovascular risk, and other adverse effects.Thus, CIN and corticosteroids have an important impact on cardiovascular risk such as an increase in the severity of H, dyslipidemia, and DM.
The presence of DM constitutes, in many studies, 3,5,32,[34][35][36] an independent risk factor for patient survival after KT since it increases cardiovascular risk.In our case series, 28.8% of the patients were diabetic (7.4% from underlying diseases and 21.4% with posttransplant DM); when comparing deaths vs. surviving patients (27.3% vs. 29.0%,respectively, p = 0.86), DM did not significantly impact the survival of the patients, which contradicts the data in the literature.Approximately 10% of our diabetic patients died (6/62) in the same proportion as those who died and were not diabetic (16/153).In patients with DM, the deaths were linked to infections in all 6 cases and not to CVD.
Cosio et al. 36 reported that the recipients with DM show a significantly higher mortality rate linked to CVD and infection, but not to malignancy, when compared to nondiabetics.Similarly, Soveri et al. 37 , over a 5-year follow-up period, reported an all-cause mortality rate of 10.4% in nondiabetics and 24.6% in diabetics (p < 0.0001).Orsenigo et al. 35 , in a multivariate analysis of the factors affecting graft and patient survival after KT, identified DM and age of the recipient as significant predictors of mortality in the final model.
The age of the recipient has been reported as the main determinant in KT outcomes. 35,38In our study, 77.3% of the patients who died were aged > 40 years, and the relative mortality risk was 6.19 for these patients.This finding is similar to that of Arend et al., 26 in the Netherlands, who determined that in a cohort of 1002 patients, the relative mortality risk is greater in patients aged > 40 years after the first transplant.Similarly, Gentil et al., 39 using multivariate analysis, indicated that male sex, age > 39 years, DM, and previous dialysis time were prognostic factors of higher risk for mortality in KT recipients.Oniscu et al. 40 conducted a study in Scotland with 1095 patients and demonstrated that the relative risk of death adjusted to the comorbidities of all patients, aged 18 to > 65 years, was significantly higher in patients > 50 years of age than in younger patients.In our study, the patient age was > 40 years in 45% of the deaths due to infection and in 80% of the cardiovascular-related deaths.
According to the 2008 annual report from the United Network for Organs Sharing (UNOS)41 that was based on the relative data of kidney transplants in the United States between 1997 and 2007, the respective survival rates of patients at 1, 3, 5, and 10 years post-transplant were 98.9%, 96.4%, 92.9%, and 79.3% from a live donor; the respective rates in the case of deceased donors were 96.4%, 91.3%, 84.7%, and 62.7%.According to the 2011 Brazilian Transplant Record of the ABTO based on the record started on January 1, 2010, the 1-year survival rate for patients with live donors is 97%, and this rate is 91% for those with a deceased donor. 28he Kidney and Hypertension Hospital of the UNIFESP, which has developed the largest KT program in the world, showed respective 1-and 2-year patient survival rates of 97.5% and 95.3% with live donors and of 98.7% and 88.3% with deceased donors for all 2,364 kidney transplants performed between January 2003 and December 2006. 18In 2011, Ferreira et al. 42 of the Kidney Transplant Center of the University of São Paulo, reported survival rates Survival and associated factors to mortality of renal transplant recipients in a University Hospital in Maranhão after 1, 5, and 10 years for next-of-kin live donors of 96%, 91.6%, and 89.1%, respectively; for unrelated live donors these rates were 95.3%, 92.4%, and 84.7%, respectively.
In Botucatu, São Paulo, in a series with 108 patients, the respective survival rates of the patients at 1, 3, and 5 years were 92.4%, 92.4%, and 89.2% with live donors, and 82.6%, 77.8%, and 77.8% with deceased donors; these differences were not statistically significant (p = 0.09).In that same study, the main causes of death were cardiovascular factors (38.5%) and infection (38.5%), and most deaths (84.6%) occurred in the first year of follow-up, 43 similar to our results.
The survival rates recorded in the KT center of the HUUFMA were 97.8%, 94.1%, and 92.9% for 1, 3, and 5 years, respectively, with a live donor, and 95.6% and 95.6% with a deceased donor for 1 and 3 years, respectively.At our institution, the KT program started in March of 2000 with only the modality of living donors.In 2005, the modality with deceased donors was initiated, which is why the 5-year survival rates were not reported for this segment of the cohort.Some studies regarding patient survival after KT in the northeast region of Brazil were negative, thus it was impossible to compare our studies on a regional level, particularly because of characteristics that are peculiar and common to the states in the northeast in relation to the states in the south-southeast axis.We observed that many northeastern states are prominent nationwide in terms of transplantation activity, particularly in the management of the donation-transplant process, which has been reflected in the numbers of the ABTO records.
In this study, only age > years and surgical complications were factors associated with decreased survival of KT recipients.
However, the study is limited due to its design, which did not enable the establishment of a significant link between mortality in KT recipients and other factors such as DM, coronary artery disease, LVH, anemia, dyslipidemia, obesity, chronic infections by hepatitis B and C viruses, and dialysis time, which have been reported as significant factors of mortality in this patient population in the literature.Therefore, further studies are required in this regard.
Infectious complications constituted the main cause of death in this study.More effective clinical strategies of control, both for the early detection of infection as well as for treatment, will benefit KT recipients and decrease mortality.
Finally, it was possible to conclude that the survival rates of KT recipients in Maranhão were similar to those found in other national and international studies, and that recipients aged > 40 years and with surgical complications showed a higher mortality risk.These findings suggest that clinical measures that are directed at these patients should be adopted while considering the short-and long-term qualitative improvement of KTs in Maranhão.

references
Survival and associated factors to mortality of renal transplant recipients in a University Hospital in Maranhão

tAble 2 causes
Of death in renal transPlantPatients at huufma, between 03.18.2000 and 09.18.2008