Key words : Cyclosporine, Pediatric transplant, Renal disease, Tacrolimus, Transplantation

Introduction

Kidney transplant is the treatment of choice for kidney function replacement in children and adolescents and has been shown to be associated with improved patient survival^1,2 and improved quality of life.³ However, transplant patients are at risk for rejection, return of the original disease, and infections that impair the transplant and threaten the patient’s life and reduce the quality of life with frequent hospitalizations. Over the past decade, infection has become the leading cause of death in kidney transplant recipients, exceeding cardiovas-cular causes.⁴ In the United States, although the number of hospital admissions for adults has decreased significantly, hospitalizations due to infectious causes have remained the same.⁵ In children and adolescents, infectious complications have been the main cause for postoperative hospitalization in kidney transplant recipients. Recent studies show an increasing trend in the hospitalization rate due to infections as the cause of graft failure among children and adolescents.^6,7 In addition, infection after kidney transplant in children and adolescents is the most common cause of death and hospitalization.⁸ Infection after transplant is the cause of 24% to 56% of deaths⁹ and 24% of hospitalization cases10 in patients with a history of kidney transplant. Therefore, the use of any method or tool to prevent such a complication is a crucial factor to improve the survival of the transplanted kidney and ultimately the survival of patients.

Calcineurin inhibitors (cyclosporine and tacrolimus) are widely used in kidney transplant to prevent acute transplant rejection. The United States Food and Drug Administration has approved both drugs for use in cases of acute rejection.¹¹ Studies in children and adults using an immunomodulator to reduce the risk rejection of acute allograft transplant have shown tacrolimus to have better results than cyclosporine.¹² Additionally, the risk of infection and its complications are higher after the use of stronger immunosuppressant agents.^13,14 In this study, we investigated the relationship between the use of 2 different types of calcineurin inhibitors (cyclosporine and tacrolimus) and the development of infections in pediatric recipients of kidney transplant. We hypothesized that, since tacrolimus is a stronger immunosuppressant,¹⁵ the risk of infection with this drug should be higher.

Materials and Methods

All patients that we included in this prospective cohort study (n = 105) were 4 to 18 years old and were candidates to receive a kidney transplant at the pediatrics department in Hazrat Rasoul Akram Hospital in Tehran in 2019 and 2020. Patients were assigned to each group according to different physicians’ preferences. We reviewed complete data files for transplant donors and recipients, including age at time of transplant, sex, race, urban or rural residence, presence or absence of previous transplant, history of pretransplant dialysis, Epstein-Barr virus and cytomegalovirus serological tests for donors and recipients before transplant, treatment regimen, and any change in the treatment regimen according to the infectious complications and noninfectious complications during treatment.

We reviewed the patient files and found 28 patients treated with the cyclosporine regimen and 77 patients treated with the tacrolimus regimen. All patients were treated according to the standard protocol with mycophenolate mofetil (MMF) and prednisolone. Oral cotrimoxazole was given daily to all patients in the first year after transplant as prophylaxis for urinary tract infection and Pneumocystis pneumonia. Oral nystatin was given for the prophylaxis of fungal infections in the first 3 months after transplant. All participants received oral valganciclovir for cytomegalovirus prophylaxis within 3 months of transplant.

Participants were routinely tested for cyto-megalovirus on a monthly basis for the first 3 months and every 3 months thereafter for the first year. The cytomegalovirus test was performed for all patients with clinical suspicion of cytomegalovirus, such as periods of fever, leukopenia, anemia, thrombocy-topenia, and chronic diarrhea. Transplant recipients were regularly tested for BK viremia on a monthly basis for the first 3 months after transplant and every 3 months thereafter for the first year by qualitative polymerase chain reaction (PCR). Bacterial infection was diagnosed according to clinical findings, culture results, and radiological findings.

Information collected from pediatric recipients included age at the time of transplant, sex, previous history of transplant rejection, history of dialysis, source of the donor (living or deceased), history of cytomegalovirus in recipients and donors, and immunosuppressive regimens. The results for graft rejection after infection were also recorded. Infection with cytomegalovirus or BK virus was defined as a positive PCR test. Cytomegalovirus was also defined as the appearance of any indicator signs and symptoms of infection (pharyngitis with fever, chronic diarrhea, pneumonia, cytopenia, chorioretinitis, and cytomegalovirus encephalitis) with positive results for a cytomegalovirus PCR test. The study endpoints were positive results by PCR test for infection, number and interval of acute transplant rejection, graft failure, and death.

Because treatment compliance is known to be suboptimal in pediatric patients, blood levels of the immunomodulator drug were checked during regular postoperative follow-up visits (every week during the first 2 months, every 2 weeks during months 3 and 4, every 3 weeks during months 5 and 6, every month from 6 to 12 months, and every 2 months after the first year). Any patient in whom the serum level of drug was suboptimal due to noncompliance was excluded from the study.

For statistical analyses, results were recorded as mean values (±SD) for quantitative variables and summarized by frequency (percentage) for categorical variables. Continuous variables were compared with a t test or the Mann-Whitney test whenever the data did not appear to have normal distribution or when the assumption of equal variances was violated across the study groups. P ? .05 was considered statistically significant. For the statistical analyses, we used the SPSS package (version 23.0, for Windows; IBM).

Results

In the cyclosporine group and the tacrolimus group, the average age of participants was 11.11 ± 2.97 years and 10.55 ± 3.61 years (P = .556) with the male-to-female ratio of 15/13 and 40/37 (P = .843), respectively, which indicated no significant differences between the 2 groups. As shown in Table 1, there were no significant differences between the cyclosporine group and the tacrolimus group with regard to graft rejection rate (P = .719), cytomegalovirus viremia (P = .112), BK viremia (P = .278), and bacterial infection (P = .897). The graft failure was significantly more frequent in male than in female patients (30.9% vs 8.2%; P = .004). However, there were no significant differences in the rates of cytomegalovirus, BK virus, or bacterial infections across the 2 sexes (Table 2). The rates of graft failure in pediatric patients with and without previous history of graft failure were found to be statistically similar (16.7% vs 20.4%; P = .825). In this regard, the rates of cytomegalovirus viremia in the groups with and without history of graft failure were 0.0% and 8.1%, respectively (P = .496).

As indicated in Table 3, history of cytomega-lovirus infection in donors had no relationship with graft complications after transplant, including graft rejection or viral or bacterial infections among recipients. Also, the rate of graft rejection in the recipients with and without a history of cytomegalovirus infection was found to be 17.4% versus 33.3%, respectively, which indicated no significant difference (P = .167).

Donors were either parents of the recipients (72 patients, 68.6%) or deceased donors (33 patients, 31.4%). For patients who received grafts from parents, 4 donors (5.56%) were fathers and 68 donors (94.4%) were mothers. The rate of graft rejection in patients who received kidneys from parents was 23.6% (17 of 72); in patients who received deceased donor kidneys, the rate of rejection was 12.1% (4 of 33). However, the difference was not significant (chi-square Fisher exact test, P = .197).

Discussion

Tacrolimus and cyclosporine are widely used after kidney transplant, so it is important to evaluate the safety of these treatment regimens. According to the Scientific Registry of Transplant Recipients, from 2002 to 2012, the use of cyclosporine after kidney transplant decreased from 22.4% to 3.5% and the use of tacrolimus conversely increased from 71.1% to 93.8%. However, regarding the rate of infection, which is an important potential complication after administration of these drugs, there was no alignment across the studies.

Cytomegalovirus is an important pathogenic cause of infection after kidney transplant in children and adults, and a prevalence of 8% to 32% has been reported in various studies.¹⁶ In our study, prevalence of cytomegalovirus infection in the tacrolimus group was not significantly different from the prevalence shown with conventional cyclosporine treatment. In contrast, in the study of Kizilbash and colleagues,¹⁷ the infection rate was significantly higher in the cyclosporine group. Because the study by Kizilbash and colleagues was retrospective and our study is prospective, some data recording biases may have been prevented in our study.

However, regarding other sequelae after transplant, including mortality or graft failure, the results shown in the 2 treatment regimens in our study are comparable to the results previously published by Kizilbash and colleagues. In a recent meta-analysis by Ravanshad and colleagues,¹⁸ tacrolimus was similar to cyclosporine with regard to the total effects on graft loss, acute rejection, and mortality rate, which is in agreement with our results.

There are several known risk factors for graft rejection, the most important of which is the rate of immunosuppression in the graft recipient.¹⁹ This factor includes the amount and type of immunosup-pressive drugs, infection with immunomodulatory viruses, and previous history of transplant rejection. In our study, the rate of graft rejection was not significantly different in the 2 groups, and the
rate of viral or bacterial infections (including cytomegalovirus) was similar in both treatment groups. In contrast, in the study of Kizilbash and colleagues,¹⁷ the chance of cytomegalovirus infection in tacrolimus patients was higher than in the cyclosporine group; however, we did not find a significant difference between the 2 groups, which might be the result of the use of a heavy prophylaxis regimen in our study and the prospective nature of our study, which is less susceptible to bias than a retrospective study.

Kidney transplant studies in adults have shown that the risks of transplant rejection and mortality in the first 100 days after transplant are more prevalent in patients with BK viremia and cytomegalovirus infection.²⁰ In our study, the prevalence of transplant rejection was not significantly different between patients with and without cytomegalovirus infection, similar to the findings of Kizilbash and colleagues.¹⁷ In our study, BK infection after transplant was present in 10.4% of patients in the tacrolimus group and in 3.6% of patients in the cyclosporine group, with no significant difference, and these results are also similar to the study by Kizilbash and colleagues.¹⁷ According to a recent laboratory study, cyclosporine may have direct antiviral effects against BK virus.²¹ This factor explains the lower prevalence of BK infection in patients in the cyclosporine group. In adults, the use of tacrolimus in combination with MMF can increase blood levels of MMF, which is not the case with cyclosporine.²² A similar dose of MMF in the tacrolimus and cyclosporine groups may have led to higher immunosuppression and a higher percentage of BK infection in the tacrolimus group in our study.

In our study, boys were more likely to have a graft rejection than were girls. Previous studies have shown that overall compliance with medications among boys is lower than the overall compliance among girls, which may explain the higher risk of rejection in this group.^23,24

Our study had some potential limitations. First, some differences between groups may be significant at higher sample sizes, and thus it is recommended that further studies be performed with larger sample sizes. Second, in this study, we did not examine the extent to which patients cooperated in the use of the drug. It is recommended that future studies examine the extent of patient involvement as a factor in the level of compliance with the drug treatment. Patients in the cyclosporine group may have exhibited suboptimal compliance in response to undesirable side effects and potentially lower tolerance known to be associated with cyclosporine. However, given the similar prevalence of graft rejection in the 2 groups, this possibility is unlikely.

Conclusions

According to the results of this study, tacrolimus and cyclosporine regimens have similar consequences in terms of graft rejection or viral and bacterial infections posttransplant. Although tacrolimus is a stronger immunomodulator than cyclosporine, the risks of infection and transplant rejection in patients with a history of transplant were not significantly different between the 2 groups.

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