EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Allograft dysfunction, Opportunistic infections, Quality improvement, Renal transplantation

Introduction
Cytomegalovirus (CMV) is a common opportunistic infection affecting kidney transplant recipients (KTRs).¹ The overall incidence is between 8% and 35%, with incidence peaking in the first 3 to 6 months posttransplant.² Cytomegalovirus infection is asso-ciated with allograft dysfunction and increased patient mortality. Cytomegalovirus infection ranges from asymptomatic viremia to full-blown CMV disease. Risk categories are stratified according to donor (D) and recipient (R) seropositivity for immunoglobin G (indicated by + or -). There are 4 risk categories (D+R-, D+R+, D-R+, and D-R-), with the highest risk of infection in the D+R- category.³ Strategies to prevent infection vary across transplant centers. Valganciclovir prophylaxis is commonly given for 6 months posttransplant for D+R- recipients. For D-R+ and D+R+ recipients, strategies include viral polymerase chain reaction (PCR) surveillance or preemptive antiviral prophylaxis for 3 months.⁴ Valganciclovir prophylaxis is also typically given after treatment with anti-thymocyte globulin and other lymphocyte-deleting agents for treatment of allograft rejection. Other risk factors for CMV infection include overimmunosuppression and leukopenia.^4,5 Drugs used as prophylaxis include valganciclovir, valaciclovir, and acyclovir. Valganciclovir should be dosed against the Cockcroft Gault creatinine clearance (CG CrCl) rather than the estimated glomerular filtration rate (GFR). If dosed against the latter, there is a risk of underdosing. Underdosing of valganciclovir after kidney transplant is a common scenario because of many factors, including frequent changes in graft function during the initial postoperative weeks.⁶ Stevens and colleagues showed that valganciclovir underdosing often resulted in increased breakthrough infections.⁷ Underdosing valganciclovir during prophylaxis has been reported to cause CMV disease with adverse outcomes.⁸ By using the SMART framework to formulate our objectives (specific, measurable, achievable, relevant, and timebound), we aimed to improve CMV infection rates in our KTRs during the first 6 months post-transplant. We conducted an initial baseline audit and then developed a quality improvement strategy to target multiple potential causative factors.

Materials and Methods Measurements
Cytomegalovirus infection was defined as detection of CMV viremia diagnosed by PCR, with PCR titer >log 3.2 as per local transplant and microbiology guidelines, with or without symptoms suggestive of viral syndrome or tissue invasive disease and/or requiring treatment with valganciclovir (this measure identified the burden of the problem). Dosing of valganciclovir in the transplant clinic according to the CG CrCl was assessed at 2, 4, and 8 weeks posttransplant. Our target was to achieve correct dosing in >80% of KTRs after 2 plan-do-study-act (PDSA) cycles. Before intervention, D+R- was the only category that received valganciclovir prophylaxis for 6 months.

Design
The Southwest Transplant Centre (Plymouth, UK) conducted the quality improvement project (QIP) over 20 months and included the following phases: a baseline audit (completed August 2021), review of results from the audit and planning interventions (completed December 2021), and implementation of change and performance of 2 PDSA cycles (January-June 2022 and July 2022-April 2023). In the baseline audit, 138 patients who received kidney transplants between January 2017 and January 2020 were included. We followed these patients for 6 months retrospectively and determined the incidence of CMV infection that necessitated treatment with valganciclovir. We also determined accuracy of valganciclovir dosing. We performed data entry and analysis with IBM SPSS version 29.

Ethical considerations
This QIP was registered locally as a clinical audit/QIP (No. CA_2021-22-189). We prepared the article by following SQUIRE (Standards for QUality Improve-ment Reporting Excellence) version 2.0 guidelines for quality improvement reports.⁹

Baseline data
Our baseline audit revealed a cumulative CMV incidence of 22.5% (31/138) across all risk categories. Table 1 details the incidence of CMV infection in the 4 different CMV risk categories. Valganciclovir prophylaxis was provided to 51 patients. Of the 51 patients, 15 (29.4%) developed CMV infection while on valganciclovir prophylaxis. Valganciclovir was dosed correctly against CG CrCl in 28 of 51 patients (54.9%) at 8 weeks, 23 of 51 (45.1%) at 4 weeks, and 25 of 51 (49.0%) at 2 weeks posttransplant. A review of our drug dosing table revealed that valganciclovir was frequently dosed against the estimated GFR (calculated by using the Modification of Diet in Renal Disease [MDRD] or the Chronic Kidney Disease Epidemiology Collaboration [CKDEPI] equations) rather than the CG CrCl. Table 1 shows the results of the baseline audit compared with the postinter-vention results. We presented these results at our regional transplant service governance meeting and com-municated the results by email to the wider transplant team. Meetings resulted in agreement of a series of interventions as part of the quality improvement strategy. Figure 1 illustrates the aims, primary and secondary drivers, and change ideas created, with details listed in Table 2.

Results Plan-do-study-act cycle 1 to determine impro-vement in drug dosing (January-June 2022)
During the 6-month period of PDSA cycle 1, drug-dosing interventions were introduced. Eight patients on valganciclovir prophylaxis were followed, and valganciclovir clinic dosing was assessed at 2, 4, and 8 weeks posttransplant. A significant improvement in drug prescription according to CG CrCl was shown at 2, 4, and 8 weeks (62.5%, 75%, and 88%, respectively).

Plan-do-study-act cycle 2 to determine improve-ment in drug dosing and reduction in cytomega-lovirus infection rates (July 2022-April 2023)
After PDSA cycle 1, 33 KTRs were followed to assess valganciclovir dosing according to CG CrCl. Of 33 KTRs, 28 (84.8%) were correctly dosed at 8 weeks, 26 (78.8%) were correctly dosed at 2 weeks, and 27 (81.8%) were correctly dosed at 4 weeks (Table 1). During the first 6 months posttransplant, 51 patients were followed up for CMV infection rates. Table 1 shows a comparison of preintervention and postintervention CMV infection rates. As shown in Table 1, all risk categories showed a significant decline in infection rates in the postintervention analysis. In addition, 6 of 33 KTRs (18.2%) developed varying degrees of leukopenia during the first 3 months.

Discussion
With the introduction of the above-mentioned interventions, we were successfully able to reduce the incidence of CMV infection in our KTRs during the first 6 months posttransplant. Our QIP raises important points for discussion regarding prevention of CMV infection in KTRs.

Accurate valganciclovir dosing
Appropriate valganciclovir drug dosing is important in the management and prevention of CMV infection.⁵ Suboptimal dosage increases the risk of resistance and treatment failure. Supratherapeutic doses increase the risk of complications. Hence, dose adjustment according to renal function is important.⁵ The CG CrCl has been widely used to dose valganciclovir. Prominent trials investigating valganciclovir use in KTRs (like VICTOR and PV16000) have used CG CrCl to dose valganciclovir.^10,11 Valganciclovir manufacturer inserts have also recommended the CG Cr Cl for dosing. Trevillyan and colleagues demonstrated that dosing valganciclovir and ganciclovir according to estimated GFR by using the MDRD equation resulted in subtherapeutic drug levels and hence underdosing in about 45% of solid-organ transplant recipients included in the study, which was because of an underestimation of renal function by about 20%.¹² Figure 2 presents one of our patients (50-year-old male KTR with creatinine level of 150 µmol/L and weight of 85 kg), showing valganciclovir under-dosing if not dosed against CG CrCl. We noticed a similar trend in our patient cohort in which dosing tables for valganciclovir were initially based on the estimated GFR using the CKDEPI or MDRD equations. This resulted in underdosing in about 50% of patients. Valganciclovir underdosing was reported as a frequent problem by Rissling and colleagues in their retrospective analysis of 635 KTRs.⁶ The study also identified that a substantial proportion of patients in the D+R- category continued on valganciclovir beyond 6 months (which is when prophylaxis should have stopped), as a result of the above-mentioned factor.⁶ The busy and complex nature of an outpatient transplant clinic can sometimes cause clinicians to overlook or forget this aspect of valganciclovir dosing. We recognized the issue of valganciclovir dosing and implemented measures as detailed in Figure 1 and Table 2. Implementation of the CG CrCl in our information technology system ensured that the CG CrCl results were readily available in the clinic. In addition, dosing cards (Figure 2) were made available in all transplant clinic rooms and inpatient ward areas. Our postintervention results showed a steady increase in the accuracy of valganciclovir prescription rates according to the CG CrCl. We noted a steep decline in the incidence of CMV infection for patients taking valganciclovir prophylaxis, highlighting the effects of accurate drug dosing.

Offering antiviral prophylaxis to recipients seropositive for cytomegalovirus
Kidney transplant recipients who are seropositive for CMV are at an increased risk of reactivation infection. In a study of the natural history of CMV before the era of effective CMV prevention in 477 KTRs, CMV infection occurred in 69% and 67% of CMV D+/R- and CMV R+ patients, respectively, and CMV disease occurred in 56% and 20% of CMV D+/R- and CMV R+ patients, respectively, within 3 months of transplant.² Guidelines from the British Transplant Society only recommend valganciclovir prophylaxis for seropositive recipients for 3 months, who have had lymphocyte-depleting agents, or after being treated for acute rejection.⁴ The international consensus guidelines on the management of CMV in solid-organ transplant recipients recommend either drug prophylaxis or preemptive therapy for 3 months, although practices should be guided by local CMV infection incidence, logistics of surveillance, and economic costs.⁵ Our baseline data revealed a substantial burden of CMV infection in seropositive recipients, exclusively, who contracted the infection within 3 months of transplant. Given the harmful effects of CMV on allograft and patient survival, we decided to offer prophylaxis to seropositive recipients for 3 months; our last PDSA cycle revealed a substantial reduction in CMV infection in both D+R+ and D-R+ patient categories.

Individualized reduction in immunosuppression
Maintaining a balance between over- and underim-munosuppression is extremely important in the management of KTRs. A major contribution to CMV infection is overimmunosuppression and lymphopenia.¹³ Hence, appropriately reducing immunosuppression based on white cell and lymphocyte counts is important in this setting. After review of our baseline data, a decision was made in our multidisciplinary meeting to reduce mycop-henolate mofetil dose in appropriate patients at 6 weeks posttransplant (taking into account immuno-logical risk). This was not implemented in all patients in the repeat PDSA cycles. The incidence of leukopenia during the first 3 months posttransplant following these interventions was 18%. The overall incidence of leukopenia with valganciclovir has been shown to be generally between 10% and 13% and was 11% in our baseline audit.¹⁴ Unfortunately, leukopenia is a common side effect of valganciclovir treatment, thus leading to a limitation of its use. However, this needs to be balanced against the risk of contracting CMV infection and the close follow-up in transplant patients to identify declining white cell counts.

Cost effectiveness of antiviral prophylaxis
Valganciclovir is an expensive drug. A 3-month prophylaxis course for a KTR with a CG CrCl between 25 and 60 mL/min could cost between £500 and £1500. A 2-week treatment course for a patient who develops CMV infection for this level of renal function could cost between £500 and £1000, although patients usually require a longer course and often require prophylactic valganciclovir to continue for a few weeks after viral PCR is undetectable. Cytomegalovirus infection in the early posttransplant period is associated poor allograft function at 1 and 2 years posttransplant and an increased risk of allograft rejection.^15-17 Treatment for these complications incurs extra cost and often involves hospitalization.¹⁸ Given our initial high burden of CMV infection and the steep decline thereafter with the formulated interventions, our QIP can potentially save costs. Antiviral prophyla-xis has been shown to reduce infection rates, with benefits extending beyond this, including a substan-tial reduction in cardiovascular death with a functioning graft.¹⁹ Antiviral prophylaxis has also been shown to be more cost effective, with a beneficial effect on a patient’s quality of life com-pared with preemptive strategy, as shown in a recent study.²⁰ The cost effectiveness of novel interventions to prevent or screen for CMV infections like the QuantiFERON-CMV assay have also shown promise.²¹

Need for a quality improvement strategy
Given the complex nature of transplant medication prescriptions, the role of an immunosuppression pharmacist is critical within transplant services. Indeed, many transplant centers have dedicated pharmacists who carefully monitor drug doses in dedicated clinics to avoid errors and underdosing.¹⁶ Our work also highlights the complex nature of CMV infection. Multiple factors feed into its occurrence, and all factors need careful targeting to improve infection rates, as demonstrated by our QIP. A systematic quality improvement initiative can improve medication safety in KTRs, which can lead to improved clinical outcomes, as evidenced by our work and a previous study.²²

Limitations
Our study had several limitations. We did not study improvement in infections after 6 months, which could be the target of future QIPs. Data collection was retrospective, which has the potential to introduce bias.

Conclusions
We were able to reduce the incidence of CMV infec-tion early posttransplant in all risk categories by adopting a multifaceted quality improvement stra-tegy targeting key factors identified on a baseline audit. Transplant centers should regularly survey CMV infection rates and adopt a quality impro-vement strategy to reduce infection rates, given its detrimental effect on allograft outcomes, patient well-being, and health care costs. Further studies investigating the cost effectiveness of novel inter-ventions to prevent or screen for CMV infection in the posttransplant period are required.

Volume: 23 Issue: 5 May 2025

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