Association between delayed graft function and cytomegalovirus infection after renal transplant

Introduction

Cytomegalovirus (CMV) infection represents one of the most prevalent and clinically significant viral complications in solid organ transplant recipients. Following primary infection, CMV establishes lifelong latency within the host and may be reactivated under immunosuppressive conditions, exerting both direct and indirect effects on transplant outcomes. Beyond its cytopathic impact, CMV is implicated in secondary infections, malignancy development, chronic allograft injury, and reduced long-term graft and patient survival (1). Established risk factors for CMV reactivation include donor seropositivity (D+/R−mismatch), intensified immunosuppressive regimens (e.g., antilymphocyte antibody therapy), and episodes of T-cell-mediated rejection (2,3).

Delayed graft function (DGF), clinically defined as the requirement for dialysis within the first seven days post-transplantation, complicates 25-30% of deceased donor kidney transplants in the United States (4,5). Pathophysiological mechanisms underlying DGF encompass ischemia-reperfusion injury, acute rejection, thrombotic microangiopathy, and technical/surgical complications (6). As DGF lacks definitive curative therapies, management often prioritizes graft preservation through augmented immunosuppression to mitigate hyperacute rejection risks (7). This therapeutic approach, combined with the systemic inflammatory milieu induced by allograft injury, may synergistically predispose DGF patients to opportunistic infections such as CMV.

Despite these pathophysiological intersections, the association between DGF and subsequent CMV infection remains poorly characterized in contemporary literature. To address this knowledge gap, we conducted a retrospective cohort study utilizing registry data to evaluate whether DGF independently correlates with an elevated risk of CMV infection in kidney transplant recipients. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-429/rc).

Methods

Study design

This was a single center, retrospective, cohort study to assess CMV infection outcomes in renal transplant recipients receiving prophylaxis with valganciclovir and experiencing DGF. DGF was defined as the need for dialysis within 1 week after kidney transplantation (4,8). Recipients were stratified into two groups: DGF Group: Patients with DGF, characterized by suboptimal early graft recovery necessitating dialysis intervention. Non-DGF Group: Patients achieving immediate graft function, defined as spontaneous decline in serum creatinine without dialysis requirement within the first postoperative week.

The donor organs were obtained from deceased brain-dead donors, and each case of brain-dead donors received informed consent from their families and approval from the Ethics Committee for civic organ donation. All donors were ≥18 years old at the time of donation. No living donors (related or unrelated) were included in this study, ensuring full adherence to the journal’s policy prohibiting transplantation from living unrelated donors. Organ allocation was conducted via the China Organ Transplant Response System (COTRS), a nationally regulated platform guaranteeing equitable and transparent distribution.

Electronic medical records for positive CMV test results, including viral cultures, histopathology, and viral load testing. All transplantations in patients aged ≥18 years who underwent kidney transplantation from January 2020 to November 2023 were eligible to be included. The inclusion criteria were (I) grafts obtained from deceased donation, (II) surgery performed as single-kidney transplantation, (III) and patients with complete data.

Ethical statement

This study was conducted with the informed consent of all kidney transplant recipients and in strict compliance with the ethical standards governing clinical medical research. It was approved by the Clinical Research and Application Ethics Committee of The Second Affiliated Hospital of Guangzhou Medical University (Approval No. 2024-hg-ks-46). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Immunosuppressive regimens

Rituximab, antithymocyte globulin or interleukin 2 receptor antibody blockers (basiliximab) with steroids were used as induction therapy based on immunologic risk factors. Our standard maintenance immunosuppressive protocol included with a calcineurin inhibitor, an antimetabolite, and prednisone.

CMV prophylaxis and diagnosis

During the study period, only CMV-seronegative patients receiving a kidney from a seropositive donor (D+/R−) were initiated on prophylactic ganciclovir 500 mg three times daily, or oral valganciclovir 450 mg once daily during the first 180 days after transplantation. Dose adjustments for renal impairment were based on drug use manual. The incidence of CMV disease, defined as clinical signs of CMV infection confirmed with a positive CMV quantitative polymerase chain reaction (PCR) (>1,000 copies/mL), was studied. Viral load assessment of CMV below laboratory detection limit was not included in the analysis. CMV pneumonia was defined by detailed clinical evidence of infection (fever, cough with or without sputum, chest distress, dyspnea, and hypoxemia) with definitive bronchoalveolar lavage results of fluorescence quantitative PCR.

Statistical analysis

Statistical analyses were performed by SPSS software version 26.0 (IBM SPSS Statistics, Chicago, IL, USA). Data were presented as median (range) and number (%). Categorical variables among patient groups were compared using the chi-squared and Fisher’s exact tests, and continuous variables were compared using the unpaired t-test and Mann-Whitney U test. Binary logistic regression was performed to assess the impact of significant DGF-related factors in univariate analysis. A two-sided P value <0.05 was considered statistically significant for all analyses.

Results

A total of 124 kidney transplant recipients (89 males, 35 females; mean age: 44.72±9.97 years) were included in this retrospective cohort study. Of these, 60 recipients (48.4%) developed DGF, while 64 (51.6%) maintained immediate graft function (non-DGF group). The predominant etiology of end-stage renal disease was glomerulonephritis (58.05%), followed by diabetes mellitus (10.55%) and chronic renal failure of unknown origin (31.4%). Immunosuppressive induction therapy comprised a triple-drug regimen: calcineurin inhibitor-based therapy with either cyclosporine (n=14, 11.29%) or tacrolimus (n=110, 88.71%), combined with mycophenolate mofetil and prednisone. Baseline demographic and clinical characteristics of the cohort are detailed in Table 1.

Posttransplant complications were stratified by DGF status (Table 2). Acute allograft rejection episodes occurred in 5 non-DGF recipients (7.8%) and 4 DGF recipients (6.7%), with no significant intergroup difference (P=0.80). However, cytomegaloviruria incidence within the first postoperative year was markedly higher in the DGF group (12/60, 20.0%) compared to the non-DGF group (4/64, 6.3%), achieving statistical significance (P=0.02). No significant differences were observed in urinary tract infection (P=0.63), CMV viremia (P=0.44), or CMV pneumonia (P=0.67) between groups.

Multivariate logistic regression analysis identified DGF as the sole independent risk factor for cytomegaloviruria [odds ratio (OR): 4.34; 95% confidence interval (CI): 1.20–15.72; P=0.02] (Table 3). To elucidate potential mechanisms underlying this association, immunological profiling was performed. Recipients without DGF exhibited significantly higher lymphocyte proportions (P=0.03) and absolute CD4⁺ T-cell counts (P=0.01) compared to the DGF cohort. Other immune factors did not differ remarkably between the two groups (Table 4).

Discussion

DGF is a common immediate postoperative complication after renal transplantation. In this single center study of 124 renal transplant recipients, we aimed to evaluate the risk of CMV infection in patients with DGF after kidney transplantation. The results of our study in kidney transplantation recipients showed that cytomegaloviruria incidence was significantly higher in DGF patients (20.0% vs. 6.3%, P=0.02), with multivariate analysis identifying DGF as an independent risk factor (OR: 4.34; P=0.02). Notably, the DGF group exhibited marked immunosuppression, evidenced by reduced lymphocyte proportions (P=0.03) and CD4⁺ T-cell depletion (P=0.01), both critical mediators of CMV-specific immune surveillance.

DGF is a common complication in kidney transplantation and is related to short- and long-term graft outcomes (9,10). In recent years, the incidence of DGF has increased with an incidence rate ranging between 20% and 45% because of the use of kidney allografts from expanded criteria donors (11-13). DGF is a major obstacle for allograft survival as it can be compounded by acute rejection and acute kidney injury. In a 3-year donation after cardiac death kidney registry analysis, Lim et al. (5) reported that recipients of donation after cardiac death kidneys with DGF experienced a higher incidence of overall and death-censored graft loss compared with those without DGF. A meta-analysis of 34 studies from 1988 through 2007 concluded that patients with DGF had a 41% increased risk of graft loss at 3.2 years of follow-up (14).

CMV infection is common in patients. When the immune system is weakened, CMV can be activated immediately. Especially for people who have had an organ, stem cell or bone marrow transplant, CMV infection can be fatal. CMV virus replication can occur locally in the affected organ compartment and can be detected by molecular viral load testing in the blood. A key element of successful treatment for CMV infection is the combination of early aggressive reduction of the immunosuppressive therapy.

To the best of our knowledge, the relationship between DGF and CMV infection is still unclear in kidney transplantation recipients. In a large population study, the findings suggested that DGF was an independent risk factor for developing CMV disease during the first three months after transplantation (15). Kleinherenbrink et al. (16) recently summarized and analyzed the data from 1300 renal transplant recipients who underwent a kidney transplantation in the Radboud University Medical Center between 2004 and 2015. This study demonstrated that recipients with DGF are at increased CMV infection risk. DGF also considerably increased the AR risk (7). In another study, Helanterä et al. (17) demonstrated that DGF predicted CMV recurrence in the logistic regression model analysis. However, Freedman et al. (18) did not find a higher rate of CMV infection in kidney transplantation recipients. In a retrospective study by Alshaikh et al., DGF was significantly associated with an increased risk of BK viremia and urinary tract infection but not CMV viremia or pneumonia (19).

The underlying mechanism of how DGF contributes to CMV infection has not been fully elucidated. One might think that the higher incidence of CMV infection could be due to the higher incidence of rejection, and associated anti-rejection therapy in patients with DGF. Acute tubular necrosis is a major determinant of renal ischemia-reperfusion injury and subsequent renal function, predisposing to DGF (20). DGF is known to be associated with innate immune responses, with complement activation and release of damage-associated molecular patterns, and with a higher incidence of rejection (21). A second possibility is explained by underexposure to ganciclovir, resulting from dose adjustments because of impaired renal function and bone marrow depression. Finally, the overall degree of immunosuppression is thought to be the most important factor. Low T cell subsets absolute counts may be regarded as a potential risk factor for developing opportunistic infections (22). This is consistent with our results showing that lymphocyte proportion and CD4⁺ T cells absolute counts were significantly lower in patients with DGF.

Although there is currently no definitive cure for DGF, the findings from our study offer critical insights that can inform clinical management strategies to mitigate one of its significant complications: an increased risk of cytomegaloviruria. We recommend implementing regular quantitative PCR-based monitoring of CMV in urine, particularly within the first year after transplantation, to facilitate early detection of viral replication. Our data also demonstrated that patients with DGF had significantly lower lymphocyte proportions and absolute CD4⁺ T-cell counts. Monitoring these immunological parameters may help identify DGF patients at the highest risk of opportunistic infections, enabling pre-emptive therapeutic interventions. Thus, upon diagnosis of DGF, clinicians should consider adopting intensified CMV surveillance protocols and ensuring optimal antiviral prophylaxis to reduce this risk.

Our findings should be interpreted in the context of several limitations. First, the relatively small sample size of this single-center retrospective cohort and the low incidence of CMV disease may limit the statistical power to detect rare outcomes or subtle associations. Second, the absence of pharmacokinetic data (e.g., therapeutic drug monitoring) for ganciclovir in this cohort precludes an assessment of whether suboptimal antiviral dosing contributed to CMV reactivation in patients with impaired renal function. Third, while we observed a significant association between DGF and cytomegaloviruria, our analysis could not establish causality or elucidate the precise mechanisms underlying these associations, particularly regarding DGF and systemic CMV manifestations such as viremia or pneumonia. Finally, residual confounding factors (e.g., CMV serostatus mismatch, human leukocyte antigen compatibility) may have influenced the observed outcomes but were not accounted for due to data availability constraints. Immunosuppressive drugs, such as antithymocyte globulin, rituximab, and IL-2 receptor blockers, as well as immunosuppressants, may all affect lymphocyte counts, potentially influencing the analysis of lymphocyte proportion and CD4⁺ T cell absolute counts in recipients from both groups. Future research should prioritize prospective multicenter cohorts with standardized virological monitoring (e.g., quantitative CMV PCR), immune profiling (e.g., CMV-specific T-cell assays), and longitudinal pharmacodynamic analyses to validate these findings and clarify the interplay between DGF, immunosuppression, and CMV pathogenesis.

Conclusions

This study demonstrated that renal transplant recipients with DGF are at increased cytomegaloviruria risk. In addition, lymphocyte proportion and CD4⁺ T cells absolute counts were significantly lower in patients with DGF. The results suggest that CMV should be monitored following the diagnosis and treatment of DGF in renal transplant recipients.

Acknowledgments

None

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-429/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-429/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-429/prf

Funding: This work was supported by a grant from the Guangdong Provincial Medical Research Fund Project (No. A2025270).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-429/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted with the informed consent of all kidney transplant recipients and in strict compliance with the ethical standards governing clinical medical research. It was approved by the Clinical Research and Application Ethics Committee of The Second Affiliated Hospital of Guangzhou Medical University (Approval No. 2024-hg-ks-46). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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