EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Viral infections are the leading cause of posttransplant morbidity and mortality. We aimed to determine the effect on graft function, the risk factors, the frequency, and types of viral infections and to evaluate the effect of viral infections on kidney and patient outcomes in pediatric kidney transplant patients.

Materials and Methods: Records of children undergoing kidney transplant in our center during the period February 1, 2010, to December 31, 2023, were retrospectively evaluated. Demographic and laboratory data, kidney failure etiologies, donor types, immunosuppression treatments, acute rejection episodes, accompanying viral infections, glomerular filtration rate, and graft loss rate were analyzed.

Results: Seventy-nine pediatric kidney transplant recipients were included in the study. The number of patients who experienced viral infections was 18 (23%). In total, 25 infection episodes were identified, with 6 (24%) attributed to cytomegalovirus infection, 8 (32%) to BK virus infection, 6 (24%) to varicella zoster virus infection (4 cases of shingles, 2 cases of chickenpox), 4 (16%) to parvovirus B19 infection, and 2 (8%) to COVID-19. Of 25 infection episodes, rejection episodes were observed in 11 cases (44%), and infections manifested after rejection in 8 cases (32%). Viral infections occurred an average of 15 months after rejection episodes. For 15 (60%) of the 25 infection episodes, the glomerular filtration rate was observed to be <60 mL/min/1.73 m2 during viral infection. Two patients succumbed to viral infections; 1 was due to COVID-19, and 1 was due to coinfection with parvovirus B19 and cytomegalovirus.

Conclusions: Our data emphasized the significant effect of viral infections on pediatric kidney transplant recipients. Early diagnosis and treatment in kidney transplant recipients are important, and clinicians should be alert.

Key words : Children, Kidney transplantation

Kidney transplant is the optimal treatment that greatly enhances survival, growth potential, and quality of life in children with end-stage kidney failure.¹ In recent years, despite the success achieved through advancements in immunosuppression therapies to prevent graft losses, immunosuppression remains a significant cause for concern. Immunosuppression therapy has facilitated the occurrence of viral infections in kidney transplant recipients.²

In kidney transplant recipients, viral infections have been reported to increase from 10% to 30% within the first 6 months after transplant.³ In these patients, viral infections may involve agents that are either well-known (cytomegalovirus [CMV], BK virus [BKV]), rare (parvovirus B19 [PVB19], varicella-zoster virus [VZV]), or newly emerged (SARS-CoV-2/COVID-19).

The primary objective of this study was to identify the risk factors leading to viral infections in pediatric kidney transplant recipients. The secondary objectives were (1) to determine the frequency and types of viral infections experienced by this patient population and (2) to assess the effect of these viral infections on kidney and patient outcomes.

Materials and Methods

This study is a single-center retrospective study conducted at Ba?kent University Adana Dr. Turgut Noyan Research and Training Center, involving pediatric patients who underwent kidney transplant from February 1, 2010, to December 31, 2023.

The study was approved by the Ethics Committee of Ba?kent University Faculty of Medicine, with approval number KA24/143. All study procedures were conducted according to the principles outlined in the Helsinki Declaration.

The data were collected from the medical records of the patients. Demographic characteristics of the patients, types of kidney donors, duration and type of pretransplant renal replacement therapy, primary diseases causing end-stage kidney disease (ESKD), immunosuppression therapy, episodes of acute rejection, and estimated glomerular filtration rate (eGFR) were recorded. The eGFR values were calculated using the modified Schwartz formula.⁴ Microbiological evaluations were performed on patients with clinical symptoms. Laboratory investigations for viral infections (CMV, BKV, parvovirus, SARS-CoV-2) including serology and polymerase chain reaction were documented. After kidney transplant, serial monitoring of viral infections, including CMV (serology) and BKV (blood quantitative polymerase chain reaction), was performed monthly for the first 3 months, every 3 months for the first year, and annually thereafter.

The immunosuppression therapy comprised induction with basiliximab. Maintenance immunosuppression included tacrolimus, mycophenolate sodium, and steroids. All patients received antibiotic prophylaxis to prevent infection of the surgical site in the immediate postsurgery period, trimethoprim/sulfamethoxazole for 1 year, valganciclovir for 3 months.

Statistical analyses

The data obtained in this study were statistically analyzed using SPSS (version 27.0). We used descriptive statistics to describe results, which included frequency distribution, mean (with SD), and median (with range). We compared continuous variables with the t test. We compared categorical variables with the chi-square test. Statistical significance was defined as P < .05.

A total of 79 pediatric kidney transplant recipients were included in the study, and 52 (66%) were male patients. The mean age at transplant was 12.7 ± 4 years, and the mean follow-up time was 4.2 ± 3 years. The median pretransplant dialysis duration was 2.4 years (range, 0.1-11 years). The most common cause of ESKD was congenital anomalies of the kidney and urinary tract in 42 patients (53%). Prior to transplant, hemodialysis was performed in 43 patients (54%), chronic peritoneal dialysis was performed in 25 patients (32%), and preemptive transplant was performed in 11 patients (14%). Kidneys from living donors were transplanted in 54 patients (68%). Demographic, clinical, and transplant-related data are summarized in Table 1. The patients were categorized according to their history of viral infection. Age, sex distribution, and follow-up period were similar between these groups. No significant differences were observed in primary diagnosis, kidney replacement therapy, dialysis duration, or donor type.

Graft rejection occurred in 33 patients (42%). A total of 41 rejection episodes were identified, with multiple rejections occurring in 5 patients. The rejection episodes consisted of 20 cellular (48%), 13 humoral (32%), and 8 mixed type (20%). The periods during which rejection episodes occurred were as follows: 12 (29%) within 0 to 3 months, 7 (17%) within 3 to 6 months, 4 (10%) within 6 to 12 months, and 18 (44%) after 12 months. At the time of patient discharge after transplant, the mean eGFR was determined to be 80 ± 24 mL/min; at 1 year it was 70 ± 22 mL/min, at 5 years it was 62 ± 30 mL/min, and at the last recorded visit it was 54 ± 27 mL/min.

Twenty-five episodes of infection were detected in 18 patients (23%). Of these, 6 (24%) had CMV infection, 7 (28%) had BKV infection, 6 (24%) had VZV infection (4 cases of shingles, 2 cases of chickenpox), 4 (16%) had PVB19 infection, and 2 (8%) had COVID-19. All donors and recipients were seronegative for CMV immunoglobulin M and seropositive for CMV immunoglobulin G during pretransplant evaluation. The frequencies, median times to viremia development, symptoms of each infection, and rejection episodes are summarized in Table 2. The median time after transplant when viral infections occurred was 23 months (range, 3-93 months). We observed that PVB19 viremia had the shortest median time to viremia and the lowest eGFR.

In 11 of 25 (44%) viral infection episodes, there was rejection, whereas viral infections occurred after rejection in 8 cases (32%). The viremia that developed most rapidly after rejection was BKV. Viral infections occurred an average of 15 months after rejection episodes. During viral infection, the mean eGFR of patients was 57.0 ± 30.5 mL/min/1.73 m2. In 15 (60%) of the 25 episodes, the mean eGFR was below 60 mL/min/1.73 m² (Table 3). Although there was no statistically significant difference, the rejection rate was found to be higher in the group with viremia. No differences were observed in graft outcomes between the groups with regard to graft loss rate, but eGFR was found to be lower in the group with viremia at 5 years after transplant and at the last visit. Two patients died from viral infections; 1 death was from COVID-19, and 1 death resulted from coinfection with PVB19 and CMV.

In this study, viral infections in pediatric kidney transplant recipients, predisposing factors, and the effects of these infections on patient and graft survival were investigated. A total of 23% of our patients developed viremias with BKV, CMV, VZV, PVB19, and COVID-19 viruses during a 13-year period. The incidence of viral infections had significantly increased by 10% to 30% after transplant, which is consistent with our findings in the literature.⁵

We identified BKV as the most prevalent infection in our patient group. Infection with BKV can be associated with a wide range of clinical manifestations, including asymptomatic viremia, urethral stricture, interstitial nephritis, and graft nephropathy.⁶ The viremia associated with BKV in our patients was detected by elevated serum creatinine levels. In our study, 7 patients (28%) had a plasma viremia level above 10⁴ copies/mL, which is a threshold considered significant with a positive predictive value of over 90% for BKV according to the standard established by Kidney Disease: Improving Global Outcomes.⁷ As previously reported, BKV nephropathy (BKVN) affects around 7% to 10% of transplant recipients, resulting in graft loss in 10% to 80% of cases.⁸ Diagnosis of BKVN typically involves immunohistochemical staining of renal biopsies with SV40 antigen-directed antibodies, although false-negative results may occur in early stages due to focal distribution. Routine kidney biopsies are often avoided in pediatric patients, so a plasma viremia level of 10⁴ copies/mL has been established as a treatment criterion, with over 90% positive predictive value for BKVN.⁹ Three patients underwent kidney biopsy at our center after an initial step of reducing immunosuppression therapy failed. Despite the high rate of graft loss associated with BKVN, none of our patients had yet experienced graft loss, with an average eGFR of approximately 60 mL/min/1.73 m².

Infection with CMV poses a significant clinical challenge in kidney transplant recipients, with considerable morbidity and mortality. Presentation of CMV infection can range from asymptomatic infection to severe organ involvement or dissemination, potentially resulting in allograft damage, allograft loss, or even death. Infection with CMV in transplant recipients can occur through primary infection or reactivation of latent viruses, with reported incidence rates ranging from 8% to 32% in renal transplant populations.¹⁰ Overall mortality attributed to CMV infection is estimated to be around 2%.¹¹ In our study, the prevalence of CMV infection was 24%, possibly influenced by the choice of seropositive donors in our population. The primary risk factor for CMV infection development in transplant recipients is the serology status of both the recipient and donor.¹² Notably, the highest risk is seen in donor-positive, recipient-negative CMV cases, with symptomatic infection observed in up to 60% of such recipients.¹³ In our study, all patients were donor-positive, recipient-positive CMV cases.

Our clinic follows a protocol for CMV infection surveillance in kidney transplant recipients wherein CMV prophylaxis is administered for the first 3 months after transplant, and CMV serology is tested every 3 months throughout the first year. We observed that our patients experienced CMV infection on average within 23 months after transplant. Although CMV infection is more common during the first year due to intensive immunosuppression therapy, CMV infection remains a clinical issue that can occur at any kidney transplant time.

Infection with VZV manifests in 2 forms: (1) primary varicella (chickenpox) in individuals with no prior exposure and (2) herpes zoster (the reactivation of latent infection) in those with previous exposure.¹⁴ The occurrence of primary varicella in kidney transplant recipients is rare, with rates estimated from case series or single reports. Kirnap and colleagues reported VZV infection in 2.5% of kidney transplant recipients, mostly herpes zoster (90%), occurring around 5 years after transplant.¹⁵ Reactivation rates of zoster disease have varied from 3.5% to 9.0% among kidney transplant recipients.¹⁴ In the epidemiological study by Gourishankar and colleagues, herpes zoster incidence was 7.4% among kidney transplant recipients.¹⁶ In our study, VZV infection was detected in 6 of 79 patients (7.6%), with 4 cases of herpes zoster and 2 cases of chickenpox, occurring around 30 months after transplant. Various factors contribute to VZV reactivation. A history of varicella illness in a recipient before transplant is associated with increased risk of zoster disease, whereas VZV seronegative status at transplant can increase susceptibility of a recipient to primary varicella. Pretransplant vaccination is recommended to mitigate these risks, providing immunity against posttransplant exposures.

In this study, PVB19 viremia was detected in 4 of 25 viral infection episodes involving 3 patients, 1 of whom had recurrent PVB19 viremia. Among them, 1 patient had coinfection with CMV and subsequently died. Infection with PVB19 resulted in anemia in 3 episodes and pancytopenia in the deceased patient. Limited data exist on PVB12 infection after kidney transplant, particularly in children, as most previously published studies comprise adult series and case reports.^17,18 The clinical spectrum of parvovirus infections varies from mild to life-threatening symptoms and is influenced by the age and immunological status of the host.¹⁹ Viral replication in erythroid progenitor cells leads to erythropoietin-resistant anemia and/or myeloid hypoplasia in kidney transplant recipients.^20,21 A strong humoral immune response is crucial to control and clear PVB19 viremia, with neutralizing antibodies conferring protective immunity.²² Persistent infection is associated with a lack of antibody response. Recurrent PVB19 infection in kidney transplant recipients may result from inadequate neutralizing antibody production. Treatment typically involves intravenous immunoglobulin administration and reduction of immunosuppression.³

In our study, we detected COVID-19 in 2 patients. One patient exhibited mild respiratory symptoms; however, the second patient experienced severe pulmonary manifestations that resulted in death. Infection with SARS-CoV-2, which causes COVID-19, may present less frequently with respiratory symptoms in children versus adults, with potentially milder disease courses.²³ However, COVID-19 progression may be worse in patients with systemic diseases.²⁴ Recent studies have indicated a higher risk of COVID-19 in kidney transplant recipients, with the disease typically manifesting more severely and leading to rapid progression, increased need for intensive care, and higher mortality rates compared with the general population.^25,26

In this study, the rejection rate did reach statistical significance in patients with viremia versus those without viremia. However, we observed a higher rejection rate among patients with viremia. This situation negatively affected graft function in the long-term, with lower graft function and higher graft loss seen in patients with viremia. Studies have reported that viral infections can trigger rejection and have a detrimental effect on long-term graft function.^27,28

In conclusion, we showed that viral infections can have a substantial effect on pediatric kidney transplant recipients. Consistent monitoring, prompt diagnosis, and timely intervention are paramount. Clinicians must remain vigilant and promptly assess any suspected viral infections in patients.

Volume: 22 Issue: 10 October 2024 - Supplement - 5

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