Key words : Complications, Immunosuppression, Outcomes, Renal transplantation

Introduction

Kidney transplant is the preferred treatment for patients with end-stage renal disease (ESRD).^1,2 Kidney transplant significantly improves patient survival and quality of life compared with lifelong dialysis. The 5-year graft survival rate for ESRD patients in the United States who receive a kidney from a deceased or living donor has been reported as 72% and 85%, respectively.³ A possible complication that may affect kidney transplant is posttransplant infection.

Particularly concerning infections include cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK polyoma virus, hepatitis B virus, hepatitis C virus, HIV, urinary tract infections (UTIs), Mycobacterium tuberculosis, and P jirovecii. Cytomegalovirus and EBV are associated with posttransplant lymphop-roliferative disorder, in which lymphocytes proliferate uncontrollably, ranging from benign enlargement of tissue to malignant lymphomas. Epstein-Barr virus is associated with 62% to 79% of patients with posttransplant lymphoproliferative disorder.^4-6

In kidney transplant recipients, UTI is the most common posttransplant infection.⁴ Recipient-related risk factors for UTIs include female sex, advanced age, history of recurrent UTIs, asymptomatic bacteriuria before surgery, pregnancy, or other comorbidities, such as diabetes mellitus, polycystic kidney disease, peripheral vascular disease, liver disease, or myocardial infarction.^7,8 Transplant-related factors include prolonged bladder catheterization or ureteral stent, prolonged hospitalization, problems with ureteral anastomosis, contaminated graft perfusion solution, episodes of acute graft rejection, delayed or reduced graft function, postoperative complications, CMV infection, and overimmunosuppression.^8,9

Donor-related risk factors include kidneys donated from a deceased donor or from an expanded criteria donor.⁸

The standard immunosuppression therapy includes a calcineurin inhibitor (CNI) immunosup-pression regimen, such as cyclosporine or tacrolimus and mycophenolate. However, these CNIs have nephrotoxic side effects, leading to worse renal function in a patient who has already received a kidney transplant because of ESRD. This results in physicians considering other immunosuppressive agents, such as belatacept. Belatacept was developed to improve long-term kidney transplant outcomes. It is a selective costimulation blocker approved by the US Food and Drug Administration in 2011 for organ rejection prophylaxis in kidney transplant recipients.^10,11 Belatacept is a high-affinity derivative of CTLA-4 immunoglobulin that inhibits T-cell activation. It binds to an antigen-presenting cell via ligands CD80 and CD86 (B7 costimulatory molecules), preventing binding to CD28 and activation of the T cell.^12-14

Belatacept has been reported to have a 43% lower risk of death or graft loss. Belatacept treatment has also shown preserved long-term mean estimated glomerular filtration rate compared with CNIs.8 However, minimal data are available to compare the infection rates for kidney transplant recipients on belatacept compared with standard immunosup-pression therapy. This study was undertaken to assess the outcomes and rates of infection in kidney transplant recipients on belatacept compared with kidney transplant recipients on standard immunosup-pression therapy.

Materials and Methods

Study design
We conducted a matched-pair case-control retros-pective analysis of a prospectively collected database of all adult kidney transplant recipients at a single center. We included data from January 1, 2016, to July 31, 2022. Data were collected from patients’ medical records from the hospital’s electronic medical record system (EPIC). Our inclusion criteria were deceased-donor kidney transplant recipients who received belatacept as initial immunosuppression treatment or were converted to belatacept (belatacept group) and deceased-donor kidney transplant recipients who received a standard immunosuppression regimen (standard immunosuppression group). Transplant recipients were followed for at least 90 days. Patients who later died, lost their graft, or stopped belatacept treatment during the study had their last parameters under belatacept recorded and were considered in the analysis. The most common indications for belatacept conversion were de novo synthesis of donor-specific antibody, CNI sparing due to toxicity, intolerance to tacrolimus, and chronic kidney tissue injuries, including antibody-mediated rejection and fibrosis.

One-year follow-up was defined from the conversion or start of belatacept for the belatacept group and 1 year after the kidney transplant for the standard immunosuppression group. Pediatric patients under 16 years old or multiorgan transplant patients, such as kidney-pancreas transplants, were excluded from the study. Patients who met the inclusion criteria were divided into the case group (with belatacept) and the control group (with standard immunosuppression).

The belatacept group included patients who started belatacept as the initial immunosuppressive medication or converted to belatacept and received ≥1 dose of belatacept. The control group included patients who started and received the standard immunosuppression treatment of tacrolimus, mycop-henolate mofetil, and prednisone after transplant. We matched the groups regarding age, sex, body mass index, KDPI, panel reactive antibodies, and cold ischemia time. Because the belatacept group had a mean of 413 days duration from time of transplant to conversion to the belatacept, infection incidents that happened during the second year after the transplant were recorded in the standard immunosuppression group to match the belatacept group. Early conversion was defined as all conversion done at <6 months after kidney transplant, and late conversion to belatacept was defined as conversion at >6 months after kidney transplant.

The attending transplant nephrologist deter-mined the belatacept conversion protocol. All infections were confirmed by the laboratory, and the type of microorganisms was identified with culture. Cefazolin (2 g for 1 dose) was used before kidney transplant in all patients as the preoperation prophylaxis. We identified infections based on clinical presentation and relevant laboratory studies, such as significant urine, wound, or blood cultures, consistent with routine medical practices. Urinary tract infections were identified by clinical symptoms, including dysuria, urinary frequency, and urgency, with a significant urinalysis culture showing ≥100?000 colony forming units/mL of at least a single uropathogen.

Results were reported and confirmed by the hospital laboratory. Cytomegalovirus viremia was defined as ≥1 serum CMV viral load >1000 IU/mL. BK viremia was defined as ≥1 blood BK polymerase chain reaction DNA count of ≥1000 copies/mL. Sepsis was defined as life-threatening organ dysfunction caused by a dysregulated host response to infection in accordance with the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) and was diagnosed based on the quick SOFA (qSOFA) score, which includes 1 point for each of 3 criteria: (1) respiratory rate ≥22 breaths/min, (2) altered mental status, and (3) systolic blood pressure ≤100 mm Hg. A qSOFA score ≥2 is suggestive of sepsis pneumonia, which was defined as an infection of the lung involving the alveolar space and was diagnosed based on the combination of the patient’s clinical characteristics and chest radiography.^15,16

Wound infection was defined as any type of skin and mucosal tissue abnormality with clinical signs of bacterial infection such as irritation, induration, pus accumulation, oozing, or pain, confirmed with a bacterial culture. Because the posttransplant time frame for the belatacept group was different (based on the belatacept infusion initiation date), we excluded the surgical site infection during the hospital stay in both groups due to the chance of sampling bias.

We did not include events of asymptomatic bacteriuria or insignificant urine cultures because of the high likelihood of spontaneous bacterial clearance.

Study outcomes
The primary objective of this analysis was to compare the rates of infection at 1 year posttransplant and the etiologies between the belatacept group versus the standard immunosuppression group.

Statistical analyses
The primary analyses compared baseline charac-teristics between the groups of interest. We used the t test in univariate analysis for continuous variables and the chi-square test and Fisher exact test for categorical variables. Categorical data are presented as proportions and percentages, and continuous data are presented as means and standard deviations. P < .05 was considered significant, and P < .1 was considered a trend.

Ethical compliance
All study procedures involving human participants were in accordance with the ethical standards of the institutional and national research committee and in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Results

The total number of patients who met the study inclusion criteria was 96. The patients were matched, paired, and divided into the belatacept group and the standard immunosuppression regimen group, with 48 patients in the belatacept group and 48 in the standard immunosuppression group. No graft failures were diagnosed or confirmed during the study period. Patients on the standard immuno-suppression regimen were converted to belatacept because of poor renal function an average of 13.⁷ months posttransplant. Table 1 lists the characteristics of the groups.

We found that 60.5% of patients in the belatacept group and 47.9% of patients in the standard immunosuppression group were diagnosed with an infectious disease during follow-up, but no significant difference was shown between the groups (P = .21). The distribution of infections for both groups is listed in Table 2 . With regard to posttransplant infectious disease prophylaxis, 17.2% of the patients in the belatacept group and 13% in the standard immuno-suppression group were on the standard post-transplant infectious disease prophylaxis, including trimethoprim-sulfamethoxazole, when the infectious disease was diagnosed. Interestingly, the prevalence of UTI among patients in the standard immuno-suppression group who were on trimethoprim-sulfamethoxazole prophylaxis was 76%, which was significantly higher than the UTI prevalence among patients in the belatacept group on trimethoprim-sulfamethoxazole prophylaxis (28.6%; P = .02). Urinary tract infections were the most common infection in both groups (41.8% in the standard immunosuppression group vs 50% in the belatacept; P = .42).

The rate of wound infection was also comparable between the belatacept group and the standard immunosuppression group (15% vs 4.7%; P = .09). The top 3 microorganisms that caused infections in the belatacept group were E coli (22%), Klebsiella pneumoniae (16%), and E faecalis (12%). The top 3 microorganisms that caused infections in the standard immunosuppression group were E coli (37.5%), S agalactiae (20.8%), and E faecalis (12.5%). Klebsiella species was identified in 8 infection episodes in the belatacept group, with 7 of 8 being UTIs (87.5%). We found no significant difference in terms of Pseudomonas-related infection between the groups (4.2% in the standard immunosuppression group vs 8% in the belatacept group; P = .55). Corynebacterium and P aeruginosa were positive in the wound culture of 50% of the wound infection episodes in the belatacept group and none in the standard immunosuppression group; however, the difference was not significant (P = .65).

There were 6 severe infections among the study patients, all of which met sepsis criteria, with 2 in the belatacept group and 4 in the standard immuno-suppression group. Of note, both sepsis events in the belatacept group occurred in the same patient. Only 1 patient in the standard immunosuppression group was admitted to the intensive care unit.

In the comparison of infection episodes between belatacept group patients with early and late conversion to belatacept, 73.9% of patients with early conversion to belatacept had an infection and 48% in the late conversion group (P = .06) (Table 3 ).

Discussion

In our case-control study comparing belatacept to the standard CNI immunosuppression therapy in kidney transplant recipients, no significant differences were shown between the 2 groups of kidney transplant recipients regarding posttransplant infection rate or etiology.

This study examined the rate and type of infections over 1 year of treatment to make potential improvements to the care of adult kidney transplant recipients. We reviewed patients’ medical records at 1 year after initiation of treatment and noted any diagnoses of infections and whether the patient was on prophylactic antibiotics at the time of diagnosis. The most common infections included UTIs, wound infections, pneumonia, COVID-19, BK polyoma virus, and CMV. We also identified and addressed a gap in the literature on belatacept and infections by including a control group on a standard immunosup-pression regimen.^17,18

The 2 groups did not significantly differ with regard to the type of infection. The standard immunosuppression regimen group had a similar rate of UTIs compared with the belatacept group (41.8% vs 50%; P = .42).

Because of the overall substantial number of UTI incidents, there is an argument to be made to tailor antibiotic prophylaxis and treatment against UTIs because of risk of worsening graft function. However, adjustments to antibiotic prophylaxis must be balanced with the risk of creating drug-resistant strains.¹⁹ The belatacept group had a higher rate of wound infections (15% vs 4.7%; P = .09, showing a trend). In the comparison of microorganisms that caused wound infections in both groups, we found that Corynebacterium and P aeruginosa were positive in the wound culture of 50% of the wound infection episodes in the belatacept group and none in the standard immunosuppression group.

Klebsiella species infection was more prevalent in the belatacept group (16% vs 4.2%), but it was not statistically significant (P = .13). In the belatacept group, Klebsiella species was identified in 7 of 8 UTI episodes and in a bacteremia infection.

To investigate the possible effects of late conversion to belatacept, we compared the incidence of infectious episodes in patients who converted to belatacept <6 months posttransplant versus those who converted >6 months posttransplant but found no significant difference between these patient groups. Although the wound infection rate was higher in the early conversion group, it was not statistically significant, which may be due to sampling size limitations.

Vincenti and colleagues²⁰ conducted a clinical trial to compare outcomes among patients on belatacept versus cyclosporin after kidney transplant. One secondary outcome was infection rates and etiologies in both groups. The overall infectious adverse incident rate was 70% in their study groups. Our study had a similar overall infectious adverse incident rate, with 47.9% in the standard immunosuppression group and 60.5% in the belatacept group, which was not significant. Although Vincenti and colleagues did not provide a P value for their comparison, the incidence rates of CMV and EBV infections and sepsis were similar in both groups, as shown in our study. In contrast, however, the UTI incident rate in the previous study was significantly lower, with an overall 25% of all infectious adverse incidents.

Ferguson and colleagues²¹ compared patient outcomes using belatacept versus tacrolimus and MMF. Although they avoided corticosteroids in their standard immunosuppression regimen group, they did not mention a significant difference in overall infectious adverse incidents and CMV and BK virus infections. However, their study did not report UTIs and wound infection incidents.

Gupta and colleagues²² assessed infection inci-dents in patients who were switched to belatacept. Similar to our findings, UTI was the most common infection in their patients. The sepsis and bacteremia incidents were similar to that shown in our belatacept group (5.7% vs 5%). However, UTI incident rate was lower in their study compared with that shown in our belatacept group (24.5% vs 41.8%).

Bertrand and colleagues conducted a retros-pective study to assess the rate of opportunistic infections after conversion to the belatacept.17 Our CMV infection rate in the belatacept group was similar to that shown in the previous study (3.3% vs 4.8%).

Our study had some limitations. First, our study was a single-center cohort study, and the number of cases was limited, mostly because belatacept was newly introduced as an alternative immunosup-pression therapy in kidney transplant patients. Second, during the study, although we matched cases between the 2 groups of interest, selection biases were inevitable. Third, similar to that shown by Bertrand and colleagues, we had a delay in belatacept conversion after kidney transplant, with average delay at 13.7 months versus 19 months, respectively.^17,18 This limitation may have affected the rate of infections while on prophylactic antibiotics. Therefore, future research should include a kidney transplant recipient group who is started immediately on belatacept or converted soon after kidney transplant. Currently, the number of studies focusing on infection incidents in patients who converted to belatacept compared with the standard immunosuppression treatment is limited. Rando-mized clinical trials with a meaningful cohort size are needed to eliminate possible biases.

Conclusions

Kidney transplant recipients on the standard immunosuppression regimen who were converted to belatacept because of poor renal function had a similar infection rate compared with recipients who remained on standard immunosuppression treatment. Neither the conversion to belatacept nor the timing of conversion changed the risk of infection after kidney transplant. Physicians may consider converting a kidney transplant recipient with poor renal function to belatacept without changing the patient’s risk of opportunistic infection.

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