Objectives: Kidney transplant is the optimal treatment for children with end-stage renal disease. Multiple factors affect patient and graft survival. We assessed determinants of long-term patient/graft survival in our center by a retrospective review of pediatric living donor (< 18 years) kidney transplants from February 2003 to December 2016.

Materials and Methods: Donor and recipient demo-graphic data and immunosuppression use were gathered for analyses. Transplant outcomes included patient/graft survival, acute rejection, and 1-year estimated glomerular filtration rate. Patient/graft survival results were analyzed by Kaplan-Meier, and Cox proportional hazards regression model was used for risk factors (univariate/multivariate). P ≤ .05 was statistically significant.

Results: Ninety-nine patients were included. Age was 13.4 ± 3.08 years, 64.6% were male, and 88.9% were on dialysis with time of 17.1 ± 12.6 months. Mean donor age was 36.6 ± 7.7 years, and most were females (63.6%). Donor estimated glomerular filtration rate was 89.4 ± 16.9 mL/min/1.73 m². HLA match was 3.2 ± 1.05. Panel reactive antibody showed 8.6 ± 20.5%. Of total patients, 47.5% used induction, 88.9% used cyclo-sporine, and 100% used mycophenolate mofetil. Five- and 10-year patient survival rates were 93.2% and 93.2%. One-year acute rejection was 14.1%, with rate of 24.2% throughout follow-up. One-year estimated glomerular filtration rate was 76.4 ± 25.6 mL/min/1.73 m². Five- and 10-year graft survival rates were 62.6% and 43.3%. Multivariate analysis confirmed donor age and acute rejection episodes throughout follow-up as risk factors for graft survival (P < .05).

Conclusions: Acute rejection and donor age are important risk factors for 10-year graft survival in living-donor pediatric kidney transplant in our program.

Key words : Kidney transplantation, Outcomes, Patient survival, Risk factors

Introduction

Kidney transplant is the treatment of choice for children with end-stage renal disease (ESRD), providing longer patient survival (PS) than dialysis and improving recipient linear growth, overall health, and quality of life.^1-3 Pediatric kidney transplant recipients have a more pronounced benefit than those on wait lists and compared with adults,¹ and a functioning renal transplant enables children to attend school and improves cognitive development.³ In Latin America, pediatric kidney transplant accounts for approximately 5% of the total kidney transplants performed.⁴

Refinements in surgical technique, improvements in postoperative care, and better immunosup-pression practices have increased rate of graft survival (GS).⁵ In pediatric populations, living-donor kidney transplant offers numerous significant advantages, including shorter wait times for recipients, better quality kidneys, and opportunities for preemptive transplant.^2,6-8 Established inter-national registries and transplant programs have documented excellent 1- and 5-year PS and GS rates.^4,6,7

Despite these advances, data on long-term outcomes (10 years) after pediatric transplant are still limited,^3,9-12 since longitudinal follow-up data may not be available from childhood to adulthood in the same unit. Multiple factors could affect pediatric PS and GS, including donor age and size, recipient age, HLA match, and acute rejection (AR) episodes to name a few.^5,8,10-15 Knowledge of strong predictors of late GS can be beneficial to understanding how to improve clinical outcomes in these children. Infor-mation on long-term mortality and GS is crucially important for clinicians to improve management and to provide reliable prognosis and counseling to parents and families. Herein, we assessed deter-minants of long-term PS and GS in a single center that allows transition of care from childhood to adulthood.

Materials and Methods

We retrospectively reviewed medical records of all living-donor pediatric (< 18 years old) kidney transplants performed at our institution from February 2003 to December 2016. Our study received previous approval from our Institutional Review Board. Demographic data of donors and recipients included age, sex, body surface area (BSA) (Mosteller method),16 and donor-to-recipient BSA ratio. Recipient age was categorized as either preschool/school age (3-12 y) or adolescent age (12-17 y). Recipient dialysis status (preemptive/dialysis), time on dialysis, and ESRD cause were recorded for analyses. Donor creatinine level was obtained, and estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease formula.¹⁷ HLA match and panel reactive antibody (PRA) were checked, and negative cross-match (flow cytometry) was mandatory in all cases. Transplant of kidneys was intra-abdominally if recipients weighed < 25 kg and if kidney size-to-patient BSA ratio was disproportionate based on clinical judgment of the surgeon.

Immunosuppression
Due to the study time frame, different immunosup-pression regimens were used. Induction therapy was initiated in 2007 and has been mandatory since 2012. Thymoglobulin was used in patients with PRA > 20%, and basiliximab was used (20 mg if patient weighed > 35 kg and 10 mg if patient weighed < 35 kg) in patients with PRA < 20%. Mycophenolate mofetil (MMF) was calculated at 600 mg/m2 BSA twice daily (2 g maximum dosage) and used in all patients. If dose could not be exactly calculated by use of 500-mg capsules, MMF dose was approximated to calculated dose. Methylprednisolone (500 mg) was given intravenously on day of transplant and was rapidly tapered to 20 mg oral prednisone by postoperative day 6 in all recipients. Further prednisone reduction was performed in the outpatient transplant clinic. Cyclosporine was administered twice daily at 4 to 8 mg/kg in divided doses, with dosage adjusted to 12-hour blood trough levels between 100 and 300 ng/mL based on posttransplant follow-up. Tacrolimus was first used in 2012 at 0.1 to 0.15 mg/kg twice per day with dosage adjusted to 12-hour blood trough levels between 5 and 15 ng/mL based on posttransplant follow-up. Standard prophylactic therapies per practice for Pneumocystis species, cytomegalovirus, and oral candidiasis infections were administered.

Outcomes
Patient survival was defined as the time between date of transplant to date of death or last date of follow-up. Graft survival was defined as the time between date of transplant and either date of graft failure (return to dialysis) or last date of follow-up with a functioning graft. Acute rejection was presumed if one or more of the following were found: serum creatinine increase of > 20% from baseline, oliguria, graft enlargement, and/or tenderness and increased resistance index by Doppler ultrasonography. Acute rejection was confirmed by kidney graft biopsy. One-year recipient eGFR was estimated by the Schwartz formula.¹⁸

Statistical analyses
Data are expressed as means and standard deviation and range for continuous variables and frequency and percentage for categorical variables. Patient and graft survival rates were calculated by the Kaplan-Meier method, and log-rank test was used to compare differences in survival. Continuous variables were categorized for PS and GS using mean values since data were normally distributed. For univariate analysis, we used Cox proportional hazards regression model (95% confidence interval) to investigate potential risk factors that may affect PS and GS. Multivariate analysis was also performed with Cox proportional hazards regression model (95% confidence interval) to adjust the effect of confounding risk factors on PS and GS. Variables with P ≤ .05 were included in the multivariate analysis. P < .05 was considered statistically significant. Data were analyzed using SPSS software version 22 (Chicago, IL, USA).

Results

Donor and recipient demographics
Our study included 99 patients; mean age was 13.4 ± 3.08 years. Most patients were male (64.6%) and adolescents (69.7%). Most patients (88.9%) were on dialysis, and the most common cause of ESRD was unknown (n = 70 patients). Mean donor age was 36.6 ± 7.7 years, and donors were mostly females (n = 63). Mean eGFR was 89.4 ± 16.9 mL/min/1.73 m². Mean donor-to-recipient BSA ratio was 1.48 ± 0.45. Mean HLA match was 3.2 ± 1.05 (range, 0-6), with 92.9% (n = 92) sharing at least 1 haplotype. Mean PRA was 8.6 ± 20.5% (range, 0%-95%). Table 1 shows donor and recipient demographic results.

Immunosuppression
Induction therapy was used in 47 patients (47.5%). Basiliximab was used in almost all patients (95.5%). All patients received MMF, and cyclosporine was the most common calcineurin inhibitor administered (88.9%). Seven patients (7.6%) were steroid-free at 1 year post-transplant, and 8.9% used prednisone at < 5 mg/day.

Outcomes
Mean estimated PS was 156.7 ± 4 months (95% confidence interval, 148.8-164.6). Five- and 10-year PS rates were 93.2% and 93.2%, respectively (Figure 1). Five patients died during follow-up, giving 5.5% mortality rate in our study. Causes of death were mostly infections (80%, n = 4), with 1 patient (20%) having unknown cause. Recipients with an AR episode during year 1 posttransplant, 1 AR episode throughout follow-up, and 1-year prednisone dose > 5 mg had significantly worse PS (Table 2).

One-year AR rate was 14.1%, and AR rate throughout follow-up was 24.2%. There were no significant differences in 1-year AR between preschool/school age (15.9%) and adolescent age patients (10%) (P = .3) and AR rate throughout follow-up (preschool/school rate of 13.3% and adolescent rate of 28.9%; P = .07). One-year eGFR was 76.4 ± 25.6 mL/min/1.73 m² (range, 36-184 mL/min/1.73 m²). Mean estimated GS was 102.8 ± 8.2 months (95% confidence interval, 86.7-119). Five-year and 10-year GS was 62.6% and 43.3%, respectively (Figure 1).

Thirty-three patients (33.3%) lost their graft during follow-up. Graft loss causes were chronic allograft nephropathy/chronic rejection (n = 10, 10.01%), nonadherence (n = 8, 8.08%), AR (n = 5, 5.05%), urologic causes (n = 4, 4.04%), miscellaneous (n = 3, 3.03%), technical (n = 2, 2.02%), and neoplasia (n = 1, 1%). Recipients with BSA > 1.27 m², donor age > 36 years, donor BSA > 1.38 m², and AR episodes (either during first year posttransplant or throughout follow-up) had significantly worse GS (Table 2).

Risk factors for patient survival
Univariate analysis revealed that higher prednisone doses (especially > 5 mg/day) had a significant negative impact on PS (P < .05). Furthermore, univariate analysis showed that AR episodes (throughout follow-up and during year 1 post-transplant) were negatively related to PS (Table 3). Multivariate analysis did not confirm any of these factors for PS (Table 4).

Risk factors for graft survival
Univariate analysis revealed that recipient age, recipient BSA, donor age, AR during year 1 posttransplant, or any AR throughout follow-up were significantly related to GS (P < .05) (Table 3). Donor-to-recipient BSA ratio showed a statistically significant trend regarding GS risk (P = .051). Multivariate analysis confirmed donor age and AR episodes throughout follow-up as risk factors for GS (Table 4).

Discussion

This study presents long-term outcomes of a pediatric kidney transplant cohort over a 10-year period. This is one of the largest single-center reports on long-term outcomes in pediatric kidney trans-plant patients in Latin America and Mexico. In our study, 10-year PS rate was > 90%, 10-year GS rate was 43%, and AR (during first year or during follow-up) and donor age had strong negative impacts on GS (shown by Kaplan-Meier or Cox regression analysis). Mortality rates in children with ESRD are 30 times higher than same-age healthy children.³ According to the Australia and New Zealand Dialysis and Transplant Registry, 10-year survival rate among children on renal replacement therapy (dialysis/-kidney transplant) is 79%. Considering these data, a 10-year PS of > 85% to 90% and a mortality rate between 7% and 15% are considered favorable.^3,5,9,11,12 Causes of death vary from center to center; however, most are related to infectious episodes or to cardiovascular events and malignancies.^3,9,11,12 Causes of death were similar in our population with a tolerable 5% mortality rate; however, our 10-year PS rate was actually higher than 90%.

In contrast, our GS was lower than previously encountered in other reports. In Latin America, registries have only published 5-year GS, which range from 84% to 89%, but no longer follow-up results have been published.^4-6 Although 5-year GS was above 60% in our present study and as shown previously,7 this GS is still lower than the aforementioned registries. When examining 10-year GS in other studies, Turkish¹⁰ and Japanese¹¹ centers showed similar 10-year GS results (46% and 58%, respectively). Other studies^3,5,9,12 showed 10-year GS rates of between 67% and 78%, which are higher than ours. Nevertheless, we found that causes of kidney loss were similar to those previously described (chronic rejection, allograft nephropathy, lack of adherence, and AR),^3-6,9-12 prompting us to find possible risk factors for these graft losses. Of note, graft vascular thrombosis, which is an important cause of graft loss in several centers,^3,5,6 was not common in our center.

Previous studies have identified certain risk factors for PS and GS in pediatric kidney transplant recipients.^3,5,8,10-15 Diminished PS rates have been associated with younger recipient age,³ donor sex, acute tubular necrosis, cardiovascular events, malignancies posttransplant, and era of transplant.¹¹ We found certain associations with AR in univariate analysis, but these results were not confirmed by multivariate analysis. On the other hand, there are more risk factors identified with poor GS, including donor age,^10,14 adolescent recipient age,^3,5,14 donor type (deceased),^5,11 urologic cause of ESRD,⁵ low donor-to-recipient BSA ratio,¹⁵ and AR during transplant follow-up.^{3,10,11,13,14} Both preemptive transplant8 and induction utilization, especially with thymoglobulin,^12,14 have been linked to better GS. Our study confirmed older donor age (> 36 y) and AR as risk factors for poor GS by survival analysis (log-rank) and multivariate analysis.

The mechanism of how older donor age is a risk factor for GS in pediatric kidney transplant is based on the concept of graft filtration adaptation in pediatric recipients. Studies have shown that kidneys from adult donors down-regulate filtration after pediatric kidney transplant and may not increase function to meet growing child requirements.¹⁹ A comparison between short- and long-term renal function according to donor age in grafts from adult donors (living related or deceased) versus grafts from pediatric deceased donors in pediatric transplant concluded that adult grafts may adapt to pediatric recipients initially posttransplant, but graft function did not improve thereafter with body size increase of the recipient.²⁰ Moreover, according to hyperfiltration theory, when functional nephron mass is reduced, such as in transplants from an older donor kidney into a child, the graft may not be able to compensate for the metabolic demands of the individual, leading to hypertrophy, sclerosis, and diminished allograft survival.²¹

The strong negative effect of AR on GS deserves consideration. Based on our previous reports,^7,13 AR incidence has decreased in our center. Our current results showed that the accumulated AR incidence during year 1 posttransplant and beyond (24.2%) was not higher than other centers,^3,5 excluding the concept that repetitive AR episodes may harm the allograft. Acute rejection is influenced by other factors, such as histocompatibility (HLA/PRA),¹¹ immunosuppression (induction and choice of calcineurin inhibitor),^12,14 and recipient age^3,5,14; however, none of these significantly affected GS in our study. Adherence in this particular population has also been postulated as a cause of graft loss,^3-6,9-12 which might impact AR and chronic rejection development. In addition, substitutions from innovator to generic immunosuppressants in pediatric solid-organ transplants should be considered,²² as our program has evolved from innovator^7,13 to generic immunosuppression. The retrospective nature of our study failed to identify which patients received innovator or generic immunosuppression to clarify our AR influence. Unfortunately, we also did not examine recipient adherence and immunosuppression maintenance/-monitoring was not completely assessed, although all patients received a calcineurin inhibitor/MMF/steroid regimen with or without induction In conclusion, AR and donor age are important risk factors for 10-year GS in living-donor pediatric kidney transplant recipients in our program. Further attention to these factors might improve GS in our patients. Longer follow-up in our patients is warranted to identify other possible risk factors for PS and GS.

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