Objectives: In many countries, some kidney transplants are performed in small centers, from which clinical data are rarely specifically reported. The aim of this study was to describe patient and graft survival rates and their correlates in a low-activity kidney transplant center.

Materials and Methods: We performed a retrospective cohort study of all patients who underwent transplant between January 2002 and May 2012 at a university hospital. Patient, graft, and death-censored graft survival rates were assessed with Kaplan-Meier analyses and compared by log-rank test, with associated factors analyzed by Cox proportional hazards modeling.

Results: Among a total of 162 patients, the mean age was 41.8 ± 13.5 years, and 92% received a living-donor graft. At 1, 3, and 5 years, patient survival was 88.6%, 86%, and 82.9%. Graft survival was 86.9%, 83%, and 77%, and death-censored graft survival was 98.1%, 96.6%, and 92.9% at the same time points. Most graft losses were due to patient death from infection and occurred within the first year after transplant. After adjustment, age over 42 years (hazard ratio of 3.94; 95% confidence interval, 1.39-11.13), deceased donor graft (hazard ratio of 11.41; 95% confidence interval, 1.2-108.35), and higher average education (hazard ratio of 4.96; 95% confidence interval, 1.01-24.32) were independently associated with graft loss.

Conclusions: The observed patient and graft survival rates were similar to those described in large databases; however, early mortality remains a major challenge. Improving posttransplant care is a key issue to increasing survival in small transplant centers.

Key words : Graft survival, Mortality, Patient survival, Risk factors

Introduction

Graft survival is a key outcome for evaluating the results of kidney transplants.¹ The transplant com­munity tracks these results through large databases from different sources and organized by various organizations, including the Collaborative Transplant Study, the United Network for Organ Sharing, and the Australia and New Zealand Dialysis and Transplant Registry. The currently applied methodology provides a broad overview of graft survival and allows general epidemiologic comparisons.^2-4

Some studies have indeed shown differences in demographics of dialysis patients and end-stage renal disease treatment practices across countries.^5,6 In the transplant field, some authors have also reported differences in transplant activity and late outcomes.^7-9 Despite these observations, the compiled results do not regularly show differences in transplant center characteristics, which limit the sharing of specific experiences and debates about local challenges. Low-activity transplant centers contribute to the overall results of large databases and account for a substantial portion of the total number of transplant centers. However, their specific results are not typically individually reported and could differ from those of the general studied population.^10-12

Reports are scarce regarding kidney transplant outcomes from low-activity centers. In addition, controversy remains as to whether kidney transplant outcomes from low-activity centers are worse or better than outcomes shown in the general data.^12-14 In fact, these low-activity centers have particular characteristics, such as limited staff and well-organized health care facilities. Nonetheless, a lower number of patients could also result in a more individual and efficient treatment approach. The geographic distribution of transplant centers ordinarily reflects sociocultural and socioeconomic disparities, resulting in a concentration of services in some regions.^1,7 A decentralization of this dis­tribution has the potential to increase the number of transplants, as the wait list continues to grow.¹⁵ A potential solution is to increase the number of procedures in low-activity centers, thus covering a broader area and larger population.

The main concern of the global transplant community is to increase the absolute number of kidney transplants and reduce access disparities while still maintaining satisfactory outcomes. This goal includes equal access for all patients with kidney disease independent of a country’s wealth.¹⁶ Today, Brazil is second in the world in absolute number of transplants. This transplant activity is based on a public health system that ensures funding throughout the process of organ procurement, allocation, and transplant.^17,18 However, Brazil faces many regional socioeconomic inequalities, including in transplant centers.¹⁷ Because many kidney transplant service providers perform fewer than 50 transplants per year,¹⁰ increasing the number of transplant procedures in low-activity centers could increase the total number of transplants. As an additional consideration, small low-activity centers could be more effective at caring for a limited number of patients, keeping them closer to home and dispensing more personalized care.^10,16

In this context, a better knowledge of the challenges and transplant outcomes in these low-activity centers can lead to better allocation of resources and adoption of specific measures to improve clinical outcomes. The aim of the present study was to describe patient, graft, and death-censored graft survival of a cohort of patients from a university-affiliated low-activity transplant center and to assess correlates of these outcomes.

Materials and Methods

Study design
This single-center retrospective cohort study included all patients who underwent transplant and were followed at our center from January 1, 2002, to May 30, 2012.

Sample setting and data collection
Pertinent data were collected from a database created to manage basic information related to transplant outcomes (the Brazilian National Transplant Registry). All transplants performed and followed during the study period at our center, Núcleo Interdisciplinar de Estudos, Pesquisas e Tratamento em Nefrologia of the Federal University of Juiz de Fora, Brazil, were considered eligible. Inclusion criteria were patient age of at least 18 years and having registered information in the database. A substantial amount of patient information was missing from the database. The minimum data to be included in the study were date of transplant, sex, age, type of donor, and date of last follow-up. From a total of 173 eligible patients, 3 were not included because of age and 8 because of data insufficiency, resulting in a total of 162 evaluated patients (Figure 1). All analyses considered data included at May 30, 2014, with a minimum follow-up of 2 years.

Variables and measurements
Demographic and clinical variables were collected from the database and consisted of age (years; by categories), sex, race (self-defined; white, or other), follow-up time (years), primary cause of chronic kidney disease, type of renal replacement therapy (hemodialysis, peritoneal dialysis, or preemptive), time on dialysis (0 vs > 0, < 1, 1-3, > 3 y), number of blood transfusions (0, 1-5, > 5), donor type (deceased or living), donor age (years), donor sex, HLA compatibility (identical, haploidentical, distinct, or deceased), initial immunosuppression regimen (cyclosporine vs tacrolimus, tacrolimus + myco­phenolate vs other), marital status (married or not), education (< 8, 8-11, > 11 y), city of residence (same as transplant center vs other), distance from home to the transplant center (≤ or > 100 km), and human development index of the city of residence.¹⁹

Acute rejection was defined per clinical parameters or biopsy-proven results. Return to dialysis for more than 30 days or retransplant was defined as graft loss. Dialysis within the first 7 days after transplant was defined as delayed graft function. Patients were classified as lost to follow-up if they were transferred to another center or absent from office visits for 6 consecutive months. Outcomes were patient, graft, and death-censored graft survival at 1, 3, and 5 years.

Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the local institutional research committee (approval number 290/2011) and in accordance with the Helsinki Declaration (1964) and Declaration of Istanbul on Trafficking and Transplant Tourism (2008). For this retrospective study, formal consent was not required.

Statistical analyses
Categorical variables were described according to their frequencies, and numerical variables were described as mean ± standard deviation or median (minimum to maximum), after assessing normality with the Kolmogorov-Smirnov test. The log-rank test and logistic regression were used for inferential statistical analyses related to age (< and ≥ 42 y), sex, race (white or not), marital status (married or not), education (< 8, 8-11, > 11 y), number of transfusions (0, 1-5, > 5), type of renal replacement therapy (dialysis or preemptive; preemptive, hemodialysis, or peritoneal dialysis), time on dialysis (< 1, 1-3, > 3 y), HLA compatibility (identical, haploidentical, distinct, or deceased), delayed graft function, initial immuno­suppression regimen (tacrolimus + myco­phenolate or other), acute rejection, distance to transplant center (≤ or > 100 km), and human development index (< or ≥ that of the transplant center city [0.779]). Patient, graft, and death-censored graft survivals were all estimated by Kaplan-Meier curves, and the association of risk factors was established by Cox regression analysis. Variables with P < .20 in the univariate analysis were included in the final multivariate model. Statistical software SPSS 19.0 (Chicago, IL, USA) was used, applying a 5% level of significance.

Results

Demographics
Among a total 162 kidney transplant recipients evaluated, most were recipients of living-donor donations (92%), 65.9% were white, and 68.5% were men, with a mean age of 41.8 ± 13.5 years. Most patients had received hemodialysis (74.8%), with a median time on dialysis of 1.8 years (range, 0-17 y), but 11.9% had a preemptive transplant. Almost 70% had never received a blood transfusion. Median follow-up was 5.87 years (range, 0-11.8 y). Two-thirds of patients were married, and 46.8% had less than 8 years of education. Only 28.8% lived in the same city as the transplant center; however, most patients lived within 100 km. The median human development index of the cities where patients lived was 0.742 (range, 0.562-0.799) (Table 1). In the study period, 18 ± 3.5 kidney transplants were performed per year, on average, at our center.

Clinical characteristics
Most donors were relatives (84.7%), female (56%), and with a mean age of 40.7 ± 11.5 years. As expected, most donors were HLA haploidentical to the recipient (54.9%). The initial immunosuppressive drug was cyclosporine (52.4%) or tacrolimus (45.5%). Prevalence of delayed graft function was < 10% (Table 1).

Survival analyses
Overall graft survival was 86.9% at 1 year, 83% at 3 years, and 77% at 5 years. By censoring deaths, we observed a clear improvement to 98.1%, 96.6%, and 92.9% at 5 years, undoubtedly showing the effect of patient death on these results. Patient survival was 88.6% at 1 year, 86% at 3 years, and 82.9% at 5 years (Table 2 and Figure 2). The major cause of graft lost was patient death (70.2%), and 54.5% of deaths occurred within the first year after kidney transplant. Infections (23.4%) and cardiovascular diseases (14.9%) were the 2 most frequent causes of death (Table 3). As expected, results from living-donor kidney transplants were better than those with deceased graft donations, although this difference did not reach statistical significance (Tables 2 and 4).

In univariate analysis, we found that recipient age at the time of transplant and peritoneal dialysis as renal replacement therapy both were associated with poorer patient and graft survival. Delayed graft function was also correlated with decreased allograft outcome (Table 4). The multivariate model for patient survival again showed an association with recipient age, but deceased donor graft and the immuno­suppression regimen also showed independent association. Graft survival correlated with both recipient characteristics (age and education) and with donor type. However, after censoring deaths, only delayed graft function had a significant negative influence on graft survival (Table 5).

Discussion

In this retrospective study of a low-activity kidney transplant service involving low-risk patients, we found acceptable survival rates. However, death with a functioning graft caused by infection and within the first year after transplant was the main cause of graft loss. These findings illustrate the specific challenges of this type of center and also show feasible points that can be indeed overcome.

During the study period, our service performed 10 to 20 kidney transplants per year. In Brazil, 77% of all centers can be classified as small centers performing less than 50 engraftments per year. In 2013, one-third of all Brazilian kidney transplants were carried out in centers showing this profile of activity, thus contributing substantially to the overall as a representative sample of transplant population.¹⁰ Our sample, primarily young adults, white, and receiving a kidney from a living donor, is representative of most kidney transplant patients in Brazil.²⁰ The Brazilian organ donation system has become more efficient in recent years, and the number of deceased-donor kidney transplants has surpassed that of living-donor kidney transplants in 2008.^10,18 In our region, kidneys from deceased donors were available only after 2009, explaining the small percentage of kidney transplants from deceased donors in the studied sample. Two other relevant characteristics of the evaluated population are low potential immunologic risk, as most had never received blood transfusion, and limited health care access, highlighted by the need to travel to another city for kidney transplant and follow-up care.

Comparing our absolute numbers to the major databases, 1-year graft survival rates are close to that of the Collaborative Transplant Study but inferior to the United Network for Organ Sharing and the Australia and New Zealand Dialysis and Transplant Registry.^2-4 Because the Collaborative Transplant Study reports transplant outcomes worldwide and the United Network for Organ Sharing and the Australia and New Zealand Dialysis and Transplant Registry have a more specific epidemiology pattern, we considered the Collaborative Transplant Study our best match. The Brazilian Transplant Registry, which contains data from 2010 to 2013 for approximately 60% of all kidney transplants, mainly with living donors, has slightly better 1-year survival rates (95%).¹⁰ Comparisons of 3- and 5-year outcomes show the same profile. Arogundade and associates, who described results from 5 small kidney transplant centers in Nigeria, reported graft survival of only 83% at 1 year and 73.4% at 5 years.¹⁴ In contrast, Rogers and associates, in a cohort of Australian patients from a small kidney transplant center, reported 1-year graft survival close to 90% and 5-year survival of 80%, similar to our results.¹² We found only 2 prior reports of survival rates at other small Brazilian centers.^21,22 Peres and associates, in a cohort of 188 patients who underwent kidney transplant before 2001, found graft survival rates of 83.6% and 75.7% at 1 and 3 years, clearly lower than those of our present study.²¹ Another study,²² which included 211 individuals, reported only death-censored graft survival, which was 95.6% and 95.6% at 1 and 3 years for living donors, slightly lower than our results but comparable regarding deceased donors.

When deaths were censored, graft survival markedly increased, confirming that death was the primary cause of graft loss. These deaths mainly occurred during the first year after transplant, a time of greater immunologic risk and thus showing the collateral effects of excessive immunosuppression.²³ We previously investigated the relation between our immunosuppression regimen and deaths by infection but found no clear correlation.²⁴ Although the 3 most frequent causes of death found in this study were previously reported by others, we hypothesized that difficult to access (distance) and limited structural resources of our kidney transplant service could be reasonable explanations for the elevated incidence of death due to infection. However, the collected data did not confirm our hypothesis, as distance to the center and unfavorable socioeconomic profile, assessed by the human development index, were not associated with patient survival. The short follow-up of less than 10 years could explain the low frequency of loss due to chronic allograft injury.^25,26

After adjustment, poor patient and graft survival were related to being older than the mean age of 42 years. Older recipients are widely recognized as being at higher risk of death with a functioning graft. This risk is often reported to exist for individuals aged within the 6th or 7th decades and associated with cardiovascular burden, although this is a higher age range than in our study.²⁷ However, in the 2 other studies of small kidney transplant services in Brazil, age over 40 years was also a risk factor for decreased graft survival, which could potentially be explained by unfavorable social and economic conditions in the areas where the patients live as well the coexistence of endemic diseases.^21,22 Although recipients of deceased donations made up less than 10% of our study population, they performed significantly worse. Deceased-donor kidney transplants usually result in more complicated care, namely, by necessity of dialysis after transplant, increased risk of acute rejections, and many immunosuppression adjust­ments. Ischemia-reperfusion injury and a more intense alloimmune response are also determinants of reduced graft survival with deceased donor kidneys.^27,28 Delayed graft function, a consequence of ischemia-reperfusion injury, was the only parameter in the final model of graft survival after censoring deaths, highlighting its deleterious effect even in this cohort composed primarily of living-donor kidney recipients.^22,27,28 Many classical correlates, including HLA compatibility, number of transfusions, acute rejection, and immunosup­pression protocol, failed to influence graft survival, possibly due to the limited number of patients included in our study. The significant association between higher average education than the mean of the sample (between 8 and 11 y of education) and risk of graft loss may be related to a higher prevalence of nonadherence, a well-known risk factor for inferior allograft outcomes.²⁹ In a previous study involving a subgroup of the present cohort, applying a sensitive methodology, we found higher nonadherence rates to immunosuppressive treatment in recipients with more favorable cultural and socioeconomic profiles.³⁰

Limitations of this study include the reporting of data from a single center and evaluation of mainly living-donor kidney transplant recipients. Although our center shared the major characteristics of other small centers and the Brazilian transplant population,^20-22 studies involving many centers and from different geographic regions would be of interest. Even for low-activity centers, it is a broad recommendation of the Brazilian Association for Organ and Tissue Transplantation to register key kidney transplant outcome information for the critical evaluation of transplant programs. These results should be useful in directing the application of financial resources by the government in the scenario of a restricted budget.¹⁸ We also encountered a paucity of some data as a consequence of incomplete and careless medical chart recordkeeping. This finding highlights the need for better registry practices and the necessity of changing our clinical routine, key implications of the present study.

In conclusion, in our retrospective study evaluating a low-activity transplant center, patient and graft survival rates were similar to national and international rates. Early patient death in the first year after kidney transplant was the major cause of graft loss, and factors associated with increased risk of poorer outcomes were related to deceased-donor kidney transplants and a specific demographic profile (higher average education). These results reinforce the importance of kidney transplant service and provide insight to guide efforts to limit suboptimal factors and further increase the number of kidney transplants performed with better graft outcomes.

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