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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 2  |  Page : 125-130

Cytomegalovirus infection and kidney transplantation- A retrospective study of risk factors and long-term clinical outcome


Institute of Nephrology, Madras Medical College, Chennai, Tamil Nadu, India

Date of Submission17-Sep-2020
Date of Decision11-Jan-2021
Date of Acceptance24-Mar-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Dr. Aravinth Kumar Rajendiran
Institute of Nephrology, Madras Medical College, Chennai - 600 003, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_116_20

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  Abstract 

Aim: The aim was to study the clinical characteristics of postrenal transplant cytomegalovirus (CMV) infection and analyze its risk factors and its impact on graft and patient survival. Materials and Methods: We reviewed medical records of 739 renal transplant patients over 17 years (2002–2018). The demographic characteristics of patients were collected and compared with and without CMV infection. Multiple logistic regression analysis was done to identify risk factors for posttransplant CMV infection. Kaplan–Meier survival curve analysis was performed to analyze graft and patient survival by CMV infection. Results: The prevalence of CMV infection in our center was 12.4%. The most common presentation of CMV infection posttransplant is CMV syndrome. The use of antirejection therapy (hazard ratio [HR] 4.2, 95% confidence interval [CI] 2.6–6.9, P = 0.00), and new-onset diabetes after transplantation (NODAT) (HR 5.95, 95% CI 3.4–10, P = 0.00) was independently associated with postrenal transplant CMV infection. In Kaplan–Meier survival analysis, death-censored graft survival was significantly superior in patients without CMV infection/disease (CMV group: 55.4% vs. non-CMV group: 70.6% at 140 months P = 0.046). Patient survival was also significantly superior in patients without CMV infection (CMV group :59.8% vs. non-CMV group: 75.9% at 140 months P = 0.016). Conclusions: The use of antirejection therapy and NODAT are strong risk factors for developing CMV infection. Posttransplant CMV infection has a significant negative impact on graft and patient survival.

Keywords: Allograft rejection, cytomegalovirus infection, long-term graft survival, new-onset diabetes after transplantation


How to cite this article:
Rajendiran AK, Jeyachandran D, Gopalakrishnan N, Arumugam V, Thanigachalam D, Ramanathan S. Cytomegalovirus infection and kidney transplantation- A retrospective study of risk factors and long-term clinical outcome. Indian J Transplant 2021;15:125-30

How to cite this URL:
Rajendiran AK, Jeyachandran D, Gopalakrishnan N, Arumugam V, Thanigachalam D, Ramanathan S. Cytomegalovirus infection and kidney transplantation- A retrospective study of risk factors and long-term clinical outcome. Indian J Transplant [serial online] 2021 [cited 2021 Jul 24];15:125-30. Available from: https://www.ijtonline.in/text.asp?2021/15/2/125/319879


  Introduction Top


Infections remain the challenging offshoot of immunosuppression in renal transplant recipients. In developing countries like India, infection ranks first as the cause of death in patients with functioning allograft.[1] Cytomegalovirus (CMV) infection is the most common opportunistic infection occurring in renal transplant recipients. Risk factors for the development of CMV include seropositive donor and seronegative recipient, use of induction immunosuppression, simultaneous kidney–pancreas transplantation, older donors, presence of allograft rejection, and concurrent infection with other viruses.[2] Conversely CMV enhances the susceptibility to rejection, transplant renal artery stenosis, as well as bacterial, candida, and opportunistic infections like Pneumocystis carinii pneumonia and invasive aspergillosis.[3] There is a dearth of data regarding CMV incidence, risk factors, and its influence on graft and survival in renal transplant recipients in the Indian population. The aim of this research is to study the clinical characteristics of postrenal transplant CMV infection and analyze its risk factors and its impact on graft and patient survival.


  Materials and Methods Top


We retrospectively reviewed the medical records of kidney transplant recipients who were on regular follow-up at our institute. Nine hundred and thirty renal transplants (live-related and deceased donors) were done between 2002 and 2018. Seven hundred and thirty-nine patient records were available for analysis. The data were analyzed using case notes and follow-up records. All patients received triple immunosuppression including steroid, calcineurin inhibitors (CNI) (either cyclosporine/tacrolimus), and azathioprine or mycophenolate mofetil (MMF). Induction immunosuppression (either antithymocyte antiglobulin [ATG]/basiliximab) was utilized in deceased donor renal transplant (DDRT) recipients and live-related renal transplant (LRRT) recipients except in cases where either father or mother was the donor. ATG was given as a single dose of 1 mg/kg intraoperatively over 6 h. Basiliximab was given as 20 mg intravenous injection on day 0 and day 4. All patients received methylprednisolone 1 g intraoperatively, followed by 125 mg every 6 h for a total of 4 doses. Oral prednisolone 0.5 mg/kg was started after day 2 and tapered to 10 mg/day by end of 3 months. Cyclosporine was CNI of choice till 2013 after which it was replaced by tacrolimus. Cyclosporine and tacrolimus were initiated 1 day before transplant at doses of 5 mg/kg/day or 0.1 mg/kg/day in divided doses, respectively. The cyclosporine dose was titrated to maintain (C0) levels of 150–250 ng/ml till 6 months posttransplant and after that 100–150 ng/ml. The tacrolimus levels (C0) were maintained between 5 and 8 ng/ml till 6 months. After a period of 6 months, the level was maintained between 3 and 5 ng/ml. Oral valganciclovir (dose adjusted based on estimated glomerular filtration rate [eGFR]) prophylaxis was given in patients undergoing DDRT and as a secondary prophylaxis in patients receiving antirejection therapy. All patients received co-trimoxazole prophylaxis indefinitely posttransplant. All patients with acute graft dysfunction underwent allograft biopsy after ruling out reversible causes. Allograft rejection was diagnosed as per Banff classification (2017). Patients with acute T-cell mediated rejection received pulse methylprednisolone 1 g (500 mg on day 1 and 250 mg on days 2 and 3). Patients with active B-cell-mediated rejection received a combination of plasmapheresis, intravenous immunoglobulin, and pulse methylprednisolone. ATG was given only for refractory rejection episodes.

The following definitions were used to define CMV infection and disease.

Cytomegalovirus infection

Detection of viral antigens by CMV pp65 antigenemia or nucleic acid by CMV DNA NAT (nucleic acid amplification test) in any body fluid or tissue specimen regardless of symptoms or signs.

Cytomegalovirus disease

CMV infection is accompanied by clinical signs and symptoms. CMV disease is categorized into CMV syndrome and end-organ CMV disease.

Cytomegalovirus syndrome

Detection of CMV in the blood by NAT or antigenemia plus, at least two of the following: (1) Fever ≥38°C for at least 2 days (2) New or increased malaise or fatigue (3) Leukopenia or neutropenia on 2 separate measurements (4) 5% atypical lymphocytes (5) Thrombocytopenia 6. Hepatic aminotransferases increase to two times the upper limit of normal.

End-organ cytomegalovirus disease

CMV infection that is accompanied by organ involvement such as gastroenteritis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, and retinitis.

Patients with CMV syndrome were treated with oral valganciclovir 450 mg BD (dose adjustment according to eGFR). Patients with end-organ CMV disease and patients not tolerating oral valganciclovir were treated with intravenous ganciclovir 5 mg/kg BD for 21 days. In addition to antiviral treatment, MMF dose was reduced in severe infections. CNI dose was reduced only in life-threatening infections. Corticosteroids were generally continued to prevent adrenal insufficiency. All patients received secondary prophylaxis with oral valganciclovir 450 mg OD for a period of 3 months.

Statistical analysis

All data were entered in MS Excel. The statistical analysis was carried out by SPSS 20.0 version (IBM, New York, USA). Descriptions of quantitative endpoints were expressed as the mean ± standard deviation or as the median and interquartile range (IQR). A two-stage analysis was done to build a model for predictors/risk factors of postrenal transplant CMV infection. In the first stage, an association between continuous variables and CMV infection was assessed by univariate evaluation using independent sample t-test. Categorical variables were assessed by the Chi-square test and Fisher's exact test. In the second stage, variables found to be significant by univariate analysis (P < 0.05) were subjected to logistic regression analysis to build the final prediction model. Graft survival, death-censored graft survival, and patient survival were calculated using Kaplan–Meier survival analysis. Log-rank test was used to compare survivals between CMV and non-CMV cohorts. Statistical significance was considered at 5% level.

Patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

The study has been approved by the Institutional Ethics Committee of Madras medical College (ECR/270/Inst/TN/2013). Protocol was followed as per the Declaration of Helsinki.


  Results Top


A total of 739 allograft recipients were included in the study. The median follow-up period was 39.4 months (IQR 21–52 months). The demographic characteristics of renal allograft recipients are summarized in [Table 1]. Basiliximab induction immunosuppression was given in 111 (15%) patients, while 80 (10.8%) patients received ATG as induction agent. The most common maintenance immunosuppressive regimen was cyclosporine with azathioprine (45%), followed by tacrolimus with MMF (39.5%).
Table 1: Demographic characteristics of renal allograft recipients

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The characteristics of recipients and donors based on the presence of CMV infection/disease are shown in [Table 2]. Ninety-two allograft recipients (12.4%) developed CMV disease after a median interval of 6 months (IQR 4–12 months) after transplantation. The mean age was 31.8 ± 8.2 years. Seventy-three patients (79.3%) were men. Among who developed CMV disease, 66 (71.7%) were LRRT recipients and 26 (28.2%) DDRT recipients. Sixty-five patients (70%) in the CMV cohort did not receive any induction immunosuppression, while 18 patients (19.5%) received basiliximab, and 8 patients (8.6%) received ATG induction. The incidence of CMV disease was similar in CSA-based regimen (48, 12%) and tacrolimus-based regimen (39, 12.1%). Diabetes (44.5%) and HCV infection (15%) were the most common comorbid conditions.
Table 2: Demographic characteristics of recipients and donors, and transplant data according to cytomegalovirus status after transplantation

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A total of 106 episodes of CMV infection were noted in 92 patients. CMV syndrome was the common manifestation (60%) of CMV infection. Other clinical manifestations were gastroenteritis, pneumonitis, and cutaneous ulcers 19%, 8%, and 8%, respectively. Allograft viral involvement was noted in three patients.

On investigation of factors that could be potentially associated with the risk of CMV infection/disease postrenal transplant, we found in univariate analysis the presence of new-onset diabetes after transplantation (NODAT) (P = 0.00), antirejection therapy (P = 0.00), and posttransplant HCV infection (P = 0.02) as potential risk factors for CMV infection. Recipient age, donor age, type of transplant, and type of native kidney disease did not have a significant association with CMV infection. There was no significant association between induction agent and maintenance immunosuppression used and the development of CMV infection. In multiple logistic regression analysis [Table 3], the presence of NODAT and antirejection therapy were independently associated with postrenal transplant CMV infection (P = 0.00 and P = 0.00, respectively). Posttransplant HCV infection was not independently associated with CMV infection (P = 0.79).
Table 3: Logistic regression analysis

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In Kaplan–Meier survival analysis [Figure 1] and [Figure 2], death-censored graft survival was significantly superior in patients without CMV infection/disease (CMV group: 55.4% vs. non-CMV group: 70.6% at 140 months P = 0.046). A similar trend was also observed in patient survival rates, where patient survival was significantly superior in patients without CMV infection (CMV group: 59.8% vs. non-CMV group: 75.9% at 140 months P = 0.016).
Figure 1: Kaplan–Meier analysis for death censored-graft survival statistical significance. Log rank (Mantel-Cox) = 0.046, χ2 = 3.99

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Figure 2: Kaplan–Meier survival analysis curve for patient survival statistical significance. Log rank (Mantel-Cox) = 0.016, χ2 = 5.8

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  Discussion Top


CMV is an important cause of morbidity and mortality after renal transplantation.[4] We observed CMV infection in 12.4% of our renal allograft recipients. The difference in the preventive strategy used in different centers accounts for wide variability in the frequency of CMV infection after renal transplant. Studies have reported incidence from <10% to 80%.[5],[6] The median time between transplantation and occurrence of CMV disease was 6 months in our study which is consistent with previous studies.[7]

The most common presentation of CMV infection postrenal transplantation in various studies is CMV syndrome characterized by fever, malaise, arthralgia, leukopenia, and elevation of aminotransferase levels.[7],[8],[9],[10] Similarly CMV syndrome was the most common presentation (60%) in our study. Gastroenteritis was the mode of presentation in 19% of patients in our study. Gastroenteritis was observed in 18% and 27% of patients in studies by Cavdar et al.[11] and Durlik et al., respectively. We observed pneumonitis presentation in 8% of patients. Abott et al.[12] reported pneumonia in 17.1% and Durlik et al. in 9% of patients. Cutaneous ulcers are very rare manifestation of CMV disease.[13] In our center, we noted 8% of patients having cutaneous ulcers due to CMV. CMV involving renal allograft is not uncommon. We observed graft involvement in 3.2% of patients, while Bhadauria et al.[14] reported allograft involvement in 5.4% of patients.

The risk factors for CMV disease include donor-recipient serostatus (highest risk for D+/R‒ and lowest risk for D-/R‒), immunosuppression with CNI, use of lymphocyte depleting antibody (induction/antirejection therapy), acute rejection episodes, elderly age, and co-infection with tuberculosis, HCV, and other viruses.[6] The seroprevalence of CMV infection in a study done in voluntary blood donors in India was 95%.[15] Hence, majority of our patients can be considered to be at moderate risk of CMV reactivation posttransplant.

In our study, we found the use of antirejection therapy and NODAT to be independently associated with postrenal transplant CMV infection. Ollech et al.[16] reported that acute CMV infection was significantly more common among patients with NODAT than among non-NODAT group (12% vs. 8%, P = 0.004). John et al.[17] found that major infections occurred significantly higher rates in NODAT than in the non-NODAT group (41% vs. 25%, P = 0.07), even though CMV occurred in equal numbers in both groups.

Allograft rejection and enhanced immunosuppression deployed to treat rejection are major risk factors for CMV infection.[4],[18] Razonable et al.[19] reported that the risk of CMV infection is 6 times more when allograft rejection occurs. In our study, we found allograft rejection and antirejection therapy increased the risk of CMV infection by 4 times.

We did not find use of ATG as a risk factor for posttransplant CMV infection. This might be possibly explained by the finding that only small percentage of our patient cohort received ATG (10.8%). Bhadauria et al.[14] reported that CMV disease developed in 28% and 30.23% of recipients who received basiliximab and ATG as induction therapy, respectively. The difference was not statistically significant. In the study by Lebranchu et al.[20] CMV disease was seen in 6% and 12% of patients treated with basiliximab and ATG, respectively, but the difference was not statistically significant.

Tacrolimus and MMF were found to increase the incidence of posttransplant CMV infection in various studies.[21],[22] We found no significant association between the use of tacrolimus and MMF on CMV reactivation posttransplant. A similar observation of lack of difference in the incidence of CMV between tacrolimus versus cyclosporine and MMF versus azathioprine groups was made by Bhadauria et al.[14] and Razonable et al.[19]

The higher age of both donor[23] and receipient[24] was reported as a risk factor for CMV infection. We did not observe a similar trend may be because our transplant recipients and donors were relatively younger with a mean age of 31.3 ± 9 and 41.7 ± 11 years, respectively.

Although posttransplant HCV infection was significantly associated with CMV infection in univariate analysis, it was not a significant factor in logistic regression analysis. Radhakrishnan et al.[25] found a tendency toward increased CMV infection in patients with posttransplant HCV, but it was not statistically significant.

The striking observation of our study is the significant adverse impact of CMV infection/disease on the long-term graft survival and patient survival. Data regarding long-term graft and patient survival in patients with CMV infection are lacking. Kute et al.[3] reported patient and graft survival rates of 85.7% and 81% at 4 years. Bhadauria et al.[14] reported 90.5% graft survival at 1 year. However, there are no studies comparing graft and patient survival rates between CMV and non-CMV groups available. Our study is one with the longest follow-up period. At 140 months (11.6 years), we were able to demonstrate poor graft and patient survival in those with CMV infection/disease. Similar to our study, López-Oliva et al.[26] reported that at follow-up of 15.8 years, graft survival was poorer in CMV group (CMV group :68% vs. non-CMV group: 74.1%, P = 0.034). Similarly, patient survival was also poorer in CMV group (CMV group: 64.2% vs. non-CMV group: 76.9%, P = 0.019).

This is one of the largest studies of posttransplant CMV infections in India. We also analyzed long-term patient and graft outcomes in patients with posttransplant CMV infection which is another strength of this research work. The limitations include its retrospective nature and being a single-center study.

Limitations

It was a single centre study. Similar studies from other centres will help validate these findings.


  Conclusions Top


CMV infection is the most common opportunistic viral infection after renal transplantation. We found the use of antirejection therapy and NODAT as strong risk factors for developing CMV infection. Posttransplant CMV infection has a significant negative impact on graft and patient survival.

Acknowledgment

We acknowledge the immense support of all the postgraduates who helped in collecting data.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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