Cytomegalovirus Infectıon in Renal Transplant Recipients: One Center’s Experience Z. Bal, M.E. Uyar, E. Tutal, E. Erdogan, T. Colak, S. Sezer, and M. Haberal ABSTRACT Background. Cytomegalovirus (CMV) is the most common opportunistic viral infection that causes morbidity, graft loss, and mortality among renal transplant recipients (RTRs). The aim of this study was to evaluate the impact of CMV infection on allograft function, graft/ patient survival, and the possible asssociations between CMV infection and HLA typing. Method. This retrospective study included 162 RTRs who had at least 1 year regular post-transplantatioin follow-up between January 2007 and December 2011. Recipients who had positive quantative CMVepolymerase chain reaction (PCR) were assigned to the study group (n ¼ 17) and PCR-negative patients were assigned to the control group (n ¼ 145). To determine whether CMV infection was related to HLA specificities, the incidence of CMV infection was analyzed in relation to HLA-A, -B, and -DR typing. Results. Study groups were similar in terms of demographic, clinical, and basal laboratory findings. Duration of dialysis before transplantation was significantly longer in this study group (P ¼ .018). Although the total HLA mismatches of both groups were similar, we found that HLA-B51epositive recipients had a lower risk for CMV infection (P ¼ .018). CMV infection was more frequent in patients with a double-J stent (P ¼ .001). Although basal creatinine levels of the two groups were similar, the study group patients’ creatinine levels were significantly increased during the 1-year post-transplantation period compared to controls (P ¼ .0001). Frequency of acute rejection was significantly higher in the study group (41.2% vs 11%, P ¼ .001). Graft loss due to any cause was also significantly higher in the study group (29.4% vs 6.9%, P ¼ .01). Patients who had preoperative induction therapy and post-transplantatioin tacrolimus-based regimens were prone to CMV infection (P ¼ .0001, .006). Conclusions. Despite recent advances in prophylaxis, CMV infection is still a risk factor for RTRs. According to our data, long pretransplantation dialysis duration, being HLAB51enegative, having a double-J stent, preoperative induction therapy, and posttransplantation tacrolimus-based regimens might induce development of CMV infection by 1-year post-transplantation follow-up.
C
YTOMEGALOVIRUS (CMV) is the most common opportunistic viral infection that might increase morbidity, graft loss, and mortality rates in renal transplant recipients (RTR). The incidence of CMV infection in RTRs is estimated to be between 8% and 32% and it can occur acutely or as reactivation of latent virus.1 The presentation of CMV may be variable, ranging from asymptomatic infection to end organ or disseminated involvement.2 Donor seropositivity, especially in the absence of prior RTR infection, is the most important risk factor for posttransplantation infection. CMV seronegative recipients of
seropositive kidneys are at increased risk of invasive CMV disease, recurrent CMV, and ganciclovir (GCV)eresistant CMV infections.3e5 Other risk factors include type and From the Department of Nephrology (Z.B., M.E.U., E.T., E.E., T.C., S.S.), and the Department of General Surgery (M.H.), Bas¸kent University Faculty of Medicine, Ankara, Turkey. Address reprint requests to Emre Tutal, Associate Professor, Department of Nephrology, Bas¸kent University Faculty of Medicine, Besevler, Ankara, 06490, Turkey. E-mail: emretutal@gmail. com
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.098
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
3520
Transplantation Proceedings, 45, 3520e3523 (2013)
CYTOMEGALOVIRUS INFECTION
dosage of immunosuppressive drugs, older donor age, rejection episodes, and impaired transplant function.6,7 GCV and its oral pro-drug valganciclovir are the cornerstones of CMV treatment and are widely used for preventive and therapeutic measures in CMV infections.8 In the absence of prophylaxis, acute infection is most likely to occur between the first and third months after transplantation when immune suppression is at its maximum.2 The aim of this study was to evaluate the demographic features, risk factors, and effects of CMV infection on allograft function and survival and the possible asssociations between CMV infection and HLA typing in RTRs.
METHOD We retrospectively assessed the incidence of CMV infection and disease after transplantation in 162 consecutive RTRs at our institution between January 2007 and December 2011. We examined the serostatus of the donor and recipient before transplantation and diagnosis of CMV disease was based on detection of viral replication using a CMV DNA polymerase chain reaction. We studied risk factors associated with CMV infection, such as the use of rabbit antithymocyte globulin (ATG) for rejection or induction treatment and of three-drug immunosuppression, HLA DR mismatch, response to treatment, as well as effects of CMV infection on graft and patient survival rates. CMV infection was considered to be present if the patient had positive early antigen detection in blood or tissues and/or positive CMV antigenemia. CMV disease was diagnosed if CMV infection was accompanied by clinical signs and symptoms, such as fever, diarrhea, leukopenia, or any organ involvement. The definition of rejection was based on typical histopathological findings on a kidney biopsy using the Banff classification, or in few cases on increasing serum creatinine levels without any other explanation.9 Donor and recipient HLA typing at -A, -B, and -C loci was performed using molecular techniques with a minimum of antigen-split level resolution for HLA-A, -B, and -C and allele-level resolution at -DRB1. All recipients received induction treatment with methylprednisolone (500 mg) intravenously for 3 days. ATG (1.5 mg/kg body weight) was prescribed for high-risk patients. Maintenance immunosuppression consisted of prednisolone (20 mg/d tapered to 10 mg/ d at 1 to 3 months post-transplantation and continued thereafter), plus a calcineurin inhibitor (cyclosporine 3 mg/kg body weight/d or tacrolimus, 0.08 mg/kg body weight/d) and mycophenolate mofetil (1.5e2 g/d). All recipients recieved CMV infection prophylaxis (valgancyclovir 450e900 mg/d for 3 months), and Pneumocystis carinii treatment (trimethoprim/sulfamethaxazole 160/800 mg once a day for 6 months). Statistical analyses were performed by using SPSS software (Statistical Package for the Social Sciences, version 11.0, SSPS Inc, Chicago, Ill, United States). Normality of data was analyzed using a Kolmogorov-Smirnov test. All numerical variables with normal distribution were expressed as the means standard deviation (SD), whereas variables with skew distribution were expressed as medians and interquartile range. Categorical variables were expressed as percentages and compared using a chi-square test. Normally distributed numeric variables were analyzed by independent samples t tests. Skew distributed numeric variables were compared using the Mann-Whitney U test. A P value < .05 was considered to be statistically significant.
3521 Table 1. Comparison of Study Groups
Mean SD Median (IR)
Gender F/M Recipient age (y) Donor age (y) Living related donor (n, %) Pretransplantation dialysis duration (mo) Positive hepatitis B and C serology (n, %) Total HLA mismatches HLA-B51 carriers (%) Double-J stent (n, %) CRP level Blood lymphocyte count Urine leukcyte count Basal creatinine (mg/dL) 1-y creatinine (mg/dL) Change percentage of serum creatinine level (%) Frequency of acute rejection (n, %) Any cause of graft lost 1-year follow-up period (n, %) Induction therapy (n, %) Cyclosporin A (n, %) Tacrolimus (n, %)
Study Group Control Group (CMV Positive) (CMV Negative) (n ¼ 17) (n ¼ 145) P Value
6/11 34.6 11.4 41.8 19.2 12, 70.0 4.5 (6.5)
41/104 35.0 10.5 39.8 11.6 114, 78.6 2.45 (2.45)
.364 .911 .688 .288 .018
3, 17.6
9, 6.2
0.089
3.11 1.51 0 3, 17.6 36.7 (48) 1422 (1460) 12.8 (18) 1.52 0.45 2.30 (1.65) 38.8 (79.2)
3.41 1.05 25.5 3, 2.1 3.6 (3) 1833 (1730) 2.8 (1.5) 1.26 0.44 1.45 (0.70) 9.1 (38.5)
.370 .018 .001 .0001 .018 .0001 .05 .0001 .014
7, 41.2
16, 11
.001
5, 29.4
10, 6.9
.01
7, 41.2 7, 41.2 10, 58.8
8, 5.5 84, 57.9 36, 24.8
.0001 .189 .006
Abbreviations: IR, interquartile range; CMV, cytomegalovirus; CRP, C-reactive protein.
RESULTS
A comparison of study groups is shown in Table 1. Seventeen of 162 (10.4 %) patients had CMV infection. The mean recipient age of these 17 patients was 34.6 11.4 years with 64.7% (n ¼ 11) males and 35.3% (n ¼ 6) females. The mean donor age was 41.8 19.2 years. There were 12 living donor and 5 deceased donor recipients. All RTRs were administered follow-up examinations to a mean of 21.4 9.6 months. The control group (n ¼ 145) was statistically similar to study group in means of demographic, clinical, and basal laboratory findings. Duration of dialysis before transplantation was significantly longer in study group than the control group (P ¼ .018). All living donors and recipients were negative for CMV immunoglobulin M (IgM) and were positive for CMV IgG during pretransplantation evaluation. In 52% of the study group, the infection developed during the first 3 months after transplantation. Fever and malaise were the most common presenting symptoms (76.2%), followed by leukopenia (52.3%). In 47% (8 patients) of the study group, clinically significant CMV infections were diagnosed. Among the 8 patients who developed clinically significant infections, 4 had CMV pneumonitis, 2 had CMV gastritis, and 2 had CMV colitis. CMV infections were observed more frequently in patients with double-J stents (P ¼ .001). The mean total HLA mismatch was 3.11 1.51. Although total HLA mismatches from both groups did not have statistically differences, we found that
3522
HLA-B51epositive recipients might have a lower risk for developing CMV infections (P ¼ .018). There was a significant difference between the study and the control group by 12 months in mean CRP levels and blood lymphocyte and urine leukcyte counts (P ¼ .0001, P ¼ .018, and P ¼ .0001, respectively). Basal creatinine levels from the two groups were similar; however, patients in the study group exhibited a significant increase in serum creatinine levels from baseline to 1-year post-transplantation follow-up period (P ¼ .0001). In the control group, the change in the percentage of serum creatinine levels was significantly higher than that in the study group patients for the first post-transplantation year (P ¼ .014). We observed that the frequency of acute rejection was significantly higher in patients from the study group (n ¼ 7 [41.2%] vs n ¼ 16 [11%], P ¼ .001]. During the follow-up period, graft loss due to any cause was significantly higher for patients in study group (n ¼ 5 [29.4%] vs n ¼ 10 [6.9%], P ¼ .01]. Although immunsuppressive protocols for both groups were similar, patients who have been administered preoperative induction therapy with ATG or muromonab anti CD3 (OKT3) and post-transplantation tacrolimus users seemed to be prone to CMV infection (P ¼ .0001 and P ¼ .006, respectively).
DISCUSSION
CMV infection after renal transplantation is still a major clinical problem with significant morbidity and mortality. Moreover, RTRs with CMV appear to have reduced allograft survival.10 Incidence of CMV infection in the renal transplant population has been reported to be between 8% and 32%.1 In our study, the prevalence of CMV infection was 10.4%. We think that this low CMV prevelance in our population might be a result of our prophylaxis strategy and choice of seropositive donors for only seropositive recipients. Donor seropositivity, type and dosage of immunosuppressive drugs, older donor age, rejection episodes, and impaired transplant function were the risk factors for developing CMV infection. In the present study we showed that CMV-positive patients had a longer duration of dialysis before transplantation than CMV-negative recipients. This relationship could be explained by the longer time of exposure to the underlying uremic inflammation and endothelial dysfunction. In contrast to other studies, we could not find any association between CMV infection and patient gender, race, older donor age, and etiology of a chronic kidney disease (CKD) such as diabetes mellitus.11 Fever was found to be the most common manifestation of CMV infection accompanied by malaise, anorexia, and myalgia.12 Similarly, we found the same clinical manifestation with recipients who had CMV infection in our study. We suggest that a clinician should rule out CMV disease in a renal recipient who manifests with fever, especially during the first 6 months post-transplantation.
BAL, UYAR, TUTAL ET AL
The risk of CMV infection and disease after transplantation is strongly dependent on donor and recipient serostatus. CMV Dþ/R- patients are at the highest risk.7,13 In our study all patients were Dþ/Rþ for CMV. As considered before, this serostatus had moderate risk for developing CMV infection.14 To determine whether CMV infection was related to HLA specificity, our study took into account the HLA-A, -B and eDR typing. We found that the rate of CMV infection was higher in HLA-B51enegative recipients. A study by Boland et al described that the recipients of donors who were positive for HLA-B7 were especially at risk for developing active CMV infection and disease.15 In the present study, acute rejection episodes were observed more frequently in the CMV-positive group. Similar to our finding, Sagedal et al16 showed that CMV infection and disease are independent risk factors for the development of clinical acute allograft rejection in renal transplant recipients during the first 100 days posttransplantation. Beyond the acute allograft rejection, one of the most important effects of CMV on the RTR population is reduced allograft survival.17 We observed that the CMV-positive group’s graft loss due to any cause was significantly higher than that for the CMV-negative group. Furthermore, in the CMV-positive group, serum creatinine levels from baseline to 1-year post-transplantation follow-up period was significantly increased when compared to that of the CMV-negative group. This finding could be an indicator of chronic allograft nephropathy that is the main reason leading for end-stage CKD. Similarly, Sagedal et al17 observed that early asymptomatic CMV infection and early CMV disease significantly reduced graft survival when deaths with functioning grafts were included. Type and dosage of immunosuppressive drugs also influence the incidence and severity of CMV disease. An increased risk of CMV is associated with increased immunosuppressive exposure, especially to antilymphocyte antibodies (ATG or OKT3) all of which promote viral reactivation from latency.2 Similar to this study, we also showed that patients who have been administered preoperative induction therapy (ATG/OKT-3) developed CMV infection more frequently. Aditionally, we found that posttransplantation tacrolimus users seemed to be prone to CMV infection. In contrast to our findings, San Juan et al showed that use of cyclosporine increases the risk of CMV disease, whereas use of sirolimus seems to have a protective effect.6 Recently, Furhmann et al sugeested that tacrolimus could reduce T-cell polyfunctionality and cause an incresed infection risk in these patients.18 This could be a possible mechanism for our results. Despite recent advances in CMV prophylaxis, CMV infection is still a risk factor for clinical acute rejection and graft loss in kidney recipients. According to our data, long duration of dialysis time, absence of HLA-B51 gene locus, presence of a double-J stent, and a post-transplantation immunsuppresive regimen might predict the development of CMV infection.
CYTOMEGALOVIRUS INFECTION
REFERENCES 1. Patel R, Paya C. Infections in solid-organ transplant patients. Clin Microbiol Rev. 1997;10:86e124. 2. Green M, Avery R, Preiksaitis J. Guidelines for the prevention and management of infectious complications of solid organ transplantation. Am J Transplant. 2004;4(suppl 10), 10e17, 57e109, 160e163. 3. Brennan DC. Cytomegalovirus in renal transplantation. J Am Soc Nephrol. 2001;12:848e855. 4. Limaye AP, Corey L, Koelle DM, Davis CL, Boeckh M. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet. 2000;356:645e649. 5. Schnitzler MA, Woodward RS, Brennan DC, et al. The effects of cytomegalovirus serology on graft and recipient survival in cadaveric renal transplantation: implications for organ allocation. Am J Kidney Dis. 1997;29:428e434. 6. San Juan R, Aguado JM, Lumbreras C, et al. RESITRA Network of the Spanish Study Group of Infection in Transplantation. Impact of current transplantation management on the development of cytomegalovirus disease after renal transplantation. Clin Infect Dis. 2008;47(7):875e882. 7. Bataille S, Moal V, Gaudart J, et al. Cytomegalovirus risk factors in renal transplantation with modern immunosuppression. Transpl Infect Dis. 2010;12(6):480e488. 8. Hart GD, Paya CV. Prophylaxis for CMV should now replace pre-emptive therapy in solid organ transplantation. Rev Med Virol. 2001;11(2):73e81. 9. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753e760.
3523 10. Hartmann A, Sagedal S, Hjelmesaeth J. The natural course of cytomegalovirus infection and disease in renal transplant recipients. Transplantation. 2006;82(suppl):S15eS17. 11. Nemati E, Eizadi M, Lankarani MM, et al. Cytomegalovirus disease after kidney transplantation: clues to accurate diagnosis. Transplant Proc. 2007;39:987. 12. Rubin R, Cosimi B. Infectious disease syndromes attributable to cytomegalovirus. Their significance among recipients. Transplantation. 1977;24:458. 13. Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89(7):779e794. 14. Legendre C, Pascual M. Improving outcomes for solidorgan transplant recipients at risk from cytomegalovirus infection: lateonset disease and indirect consequences. Clin Infect Dis. 2008; 46(5):732e740. 15. Boland GJ, Hene RJ, Ververs C, de Haan MA, de Gast GC. Factors influencing the occurrence of active cytomegalovirus (CMV) infections after organ transplantation. 1993;94(2):306e312. 16. Sagedal S, Nordal KP, Hartmann A, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant. 2002;2:850. 17. Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int. 2004;66:329. 18. Fuhrmann S, Lachmann R, Streitz M, Hetzer R, Volk HD, Lehmkuhl H, et al. Cyclosporin A and tacrolimus reduce T-cell polyfunctionality but not interferon-g responses directed at cytomegalovirus. Immunology. 2012;136(4):408e413. http://dx.doi.org/ 10.1111/j.1365-2567.2012.03594.x.
C
YTOMEGALOVIRUS (CMV) is the most common opportunistic viral infection that might increase morbidity, graft loss, and mortality rates in renal transplant recipients (RTR). The incidence of CMV infection in RTRs is estimated to be between 8% and 32% and it can occur acutely or as reactivation of latent virus.1 The presentation of CMV may be variable, ranging from asymptomatic infection to end organ or disseminated involvement.2 Donor seropositivity, especially in the absence of prior RTR infection, is the most important risk factor for posttransplantation infection. CMV seronegative recipients of
seropositive kidneys are at increased risk of invasive CMV disease, recurrent CMV, and ganciclovir (GCV)eresistant CMV infections.3e5 Other risk factors include type and From the Department of Nephrology (Z.B., M.E.U., E.T., E.E., T.C., S.S.), and the Department of General Surgery (M.H.), Bas¸kent University Faculty of Medicine, Ankara, Turkey. Address reprint requests to Emre Tutal, Associate Professor, Department of Nephrology, Bas¸kent University Faculty of Medicine, Besevler, Ankara, 06490, Turkey. E-mail: emretutal@gmail. com
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.098
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
3520
Transplantation Proceedings, 45, 3520e3523 (2013)
CYTOMEGALOVIRUS INFECTION
dosage of immunosuppressive drugs, older donor age, rejection episodes, and impaired transplant function.6,7 GCV and its oral pro-drug valganciclovir are the cornerstones of CMV treatment and are widely used for preventive and therapeutic measures in CMV infections.8 In the absence of prophylaxis, acute infection is most likely to occur between the first and third months after transplantation when immune suppression is at its maximum.2 The aim of this study was to evaluate the demographic features, risk factors, and effects of CMV infection on allograft function and survival and the possible asssociations between CMV infection and HLA typing in RTRs.
METHOD We retrospectively assessed the incidence of CMV infection and disease after transplantation in 162 consecutive RTRs at our institution between January 2007 and December 2011. We examined the serostatus of the donor and recipient before transplantation and diagnosis of CMV disease was based on detection of viral replication using a CMV DNA polymerase chain reaction. We studied risk factors associated with CMV infection, such as the use of rabbit antithymocyte globulin (ATG) for rejection or induction treatment and of three-drug immunosuppression, HLA DR mismatch, response to treatment, as well as effects of CMV infection on graft and patient survival rates. CMV infection was considered to be present if the patient had positive early antigen detection in blood or tissues and/or positive CMV antigenemia. CMV disease was diagnosed if CMV infection was accompanied by clinical signs and symptoms, such as fever, diarrhea, leukopenia, or any organ involvement. The definition of rejection was based on typical histopathological findings on a kidney biopsy using the Banff classification, or in few cases on increasing serum creatinine levels without any other explanation.9 Donor and recipient HLA typing at -A, -B, and -C loci was performed using molecular techniques with a minimum of antigen-split level resolution for HLA-A, -B, and -C and allele-level resolution at -DRB1. All recipients received induction treatment with methylprednisolone (500 mg) intravenously for 3 days. ATG (1.5 mg/kg body weight) was prescribed for high-risk patients. Maintenance immunosuppression consisted of prednisolone (20 mg/d tapered to 10 mg/ d at 1 to 3 months post-transplantation and continued thereafter), plus a calcineurin inhibitor (cyclosporine 3 mg/kg body weight/d or tacrolimus, 0.08 mg/kg body weight/d) and mycophenolate mofetil (1.5e2 g/d). All recipients recieved CMV infection prophylaxis (valgancyclovir 450e900 mg/d for 3 months), and Pneumocystis carinii treatment (trimethoprim/sulfamethaxazole 160/800 mg once a day for 6 months). Statistical analyses were performed by using SPSS software (Statistical Package for the Social Sciences, version 11.0, SSPS Inc, Chicago, Ill, United States). Normality of data was analyzed using a Kolmogorov-Smirnov test. All numerical variables with normal distribution were expressed as the means standard deviation (SD), whereas variables with skew distribution were expressed as medians and interquartile range. Categorical variables were expressed as percentages and compared using a chi-square test. Normally distributed numeric variables were analyzed by independent samples t tests. Skew distributed numeric variables were compared using the Mann-Whitney U test. A P value < .05 was considered to be statistically significant.
3521 Table 1. Comparison of Study Groups
Mean SD Median (IR)
Gender F/M Recipient age (y) Donor age (y) Living related donor (n, %) Pretransplantation dialysis duration (mo) Positive hepatitis B and C serology (n, %) Total HLA mismatches HLA-B51 carriers (%) Double-J stent (n, %) CRP level Blood lymphocyte count Urine leukcyte count Basal creatinine (mg/dL) 1-y creatinine (mg/dL) Change percentage of serum creatinine level (%) Frequency of acute rejection (n, %) Any cause of graft lost 1-year follow-up period (n, %) Induction therapy (n, %) Cyclosporin A (n, %) Tacrolimus (n, %)
Study Group Control Group (CMV Positive) (CMV Negative) (n ¼ 17) (n ¼ 145) P Value
6/11 34.6 11.4 41.8 19.2 12, 70.0 4.5 (6.5)
41/104 35.0 10.5 39.8 11.6 114, 78.6 2.45 (2.45)
.364 .911 .688 .288 .018
3, 17.6
9, 6.2
0.089
3.11 1.51 0 3, 17.6 36.7 (48) 1422 (1460) 12.8 (18) 1.52 0.45 2.30 (1.65) 38.8 (79.2)
3.41 1.05 25.5 3, 2.1 3.6 (3) 1833 (1730) 2.8 (1.5) 1.26 0.44 1.45 (0.70) 9.1 (38.5)
.370 .018 .001 .0001 .018 .0001 .05 .0001 .014
7, 41.2
16, 11
.001
5, 29.4
10, 6.9
.01
7, 41.2 7, 41.2 10, 58.8
8, 5.5 84, 57.9 36, 24.8
.0001 .189 .006
Abbreviations: IR, interquartile range; CMV, cytomegalovirus; CRP, C-reactive protein.
RESULTS
A comparison of study groups is shown in Table 1. Seventeen of 162 (10.4 %) patients had CMV infection. The mean recipient age of these 17 patients was 34.6 11.4 years with 64.7% (n ¼ 11) males and 35.3% (n ¼ 6) females. The mean donor age was 41.8 19.2 years. There were 12 living donor and 5 deceased donor recipients. All RTRs were administered follow-up examinations to a mean of 21.4 9.6 months. The control group (n ¼ 145) was statistically similar to study group in means of demographic, clinical, and basal laboratory findings. Duration of dialysis before transplantation was significantly longer in study group than the control group (P ¼ .018). All living donors and recipients were negative for CMV immunoglobulin M (IgM) and were positive for CMV IgG during pretransplantation evaluation. In 52% of the study group, the infection developed during the first 3 months after transplantation. Fever and malaise were the most common presenting symptoms (76.2%), followed by leukopenia (52.3%). In 47% (8 patients) of the study group, clinically significant CMV infections were diagnosed. Among the 8 patients who developed clinically significant infections, 4 had CMV pneumonitis, 2 had CMV gastritis, and 2 had CMV colitis. CMV infections were observed more frequently in patients with double-J stents (P ¼ .001). The mean total HLA mismatch was 3.11 1.51. Although total HLA mismatches from both groups did not have statistically differences, we found that
3522
HLA-B51epositive recipients might have a lower risk for developing CMV infections (P ¼ .018). There was a significant difference between the study and the control group by 12 months in mean CRP levels and blood lymphocyte and urine leukcyte counts (P ¼ .0001, P ¼ .018, and P ¼ .0001, respectively). Basal creatinine levels from the two groups were similar; however, patients in the study group exhibited a significant increase in serum creatinine levels from baseline to 1-year post-transplantation follow-up period (P ¼ .0001). In the control group, the change in the percentage of serum creatinine levels was significantly higher than that in the study group patients for the first post-transplantation year (P ¼ .014). We observed that the frequency of acute rejection was significantly higher in patients from the study group (n ¼ 7 [41.2%] vs n ¼ 16 [11%], P ¼ .001]. During the follow-up period, graft loss due to any cause was significantly higher for patients in study group (n ¼ 5 [29.4%] vs n ¼ 10 [6.9%], P ¼ .01]. Although immunsuppressive protocols for both groups were similar, patients who have been administered preoperative induction therapy with ATG or muromonab anti CD3 (OKT3) and post-transplantation tacrolimus users seemed to be prone to CMV infection (P ¼ .0001 and P ¼ .006, respectively).
DISCUSSION
CMV infection after renal transplantation is still a major clinical problem with significant morbidity and mortality. Moreover, RTRs with CMV appear to have reduced allograft survival.10 Incidence of CMV infection in the renal transplant population has been reported to be between 8% and 32%.1 In our study, the prevalence of CMV infection was 10.4%. We think that this low CMV prevelance in our population might be a result of our prophylaxis strategy and choice of seropositive donors for only seropositive recipients. Donor seropositivity, type and dosage of immunosuppressive drugs, older donor age, rejection episodes, and impaired transplant function were the risk factors for developing CMV infection. In the present study we showed that CMV-positive patients had a longer duration of dialysis before transplantation than CMV-negative recipients. This relationship could be explained by the longer time of exposure to the underlying uremic inflammation and endothelial dysfunction. In contrast to other studies, we could not find any association between CMV infection and patient gender, race, older donor age, and etiology of a chronic kidney disease (CKD) such as diabetes mellitus.11 Fever was found to be the most common manifestation of CMV infection accompanied by malaise, anorexia, and myalgia.12 Similarly, we found the same clinical manifestation with recipients who had CMV infection in our study. We suggest that a clinician should rule out CMV disease in a renal recipient who manifests with fever, especially during the first 6 months post-transplantation.
BAL, UYAR, TUTAL ET AL
The risk of CMV infection and disease after transplantation is strongly dependent on donor and recipient serostatus. CMV Dþ/R- patients are at the highest risk.7,13 In our study all patients were Dþ/Rþ for CMV. As considered before, this serostatus had moderate risk for developing CMV infection.14 To determine whether CMV infection was related to HLA specificity, our study took into account the HLA-A, -B and eDR typing. We found that the rate of CMV infection was higher in HLA-B51enegative recipients. A study by Boland et al described that the recipients of donors who were positive for HLA-B7 were especially at risk for developing active CMV infection and disease.15 In the present study, acute rejection episodes were observed more frequently in the CMV-positive group. Similar to our finding, Sagedal et al16 showed that CMV infection and disease are independent risk factors for the development of clinical acute allograft rejection in renal transplant recipients during the first 100 days posttransplantation. Beyond the acute allograft rejection, one of the most important effects of CMV on the RTR population is reduced allograft survival.17 We observed that the CMV-positive group’s graft loss due to any cause was significantly higher than that for the CMV-negative group. Furthermore, in the CMV-positive group, serum creatinine levels from baseline to 1-year post-transplantation follow-up period was significantly increased when compared to that of the CMV-negative group. This finding could be an indicator of chronic allograft nephropathy that is the main reason leading for end-stage CKD. Similarly, Sagedal et al17 observed that early asymptomatic CMV infection and early CMV disease significantly reduced graft survival when deaths with functioning grafts were included. Type and dosage of immunosuppressive drugs also influence the incidence and severity of CMV disease. An increased risk of CMV is associated with increased immunosuppressive exposure, especially to antilymphocyte antibodies (ATG or OKT3) all of which promote viral reactivation from latency.2 Similar to this study, we also showed that patients who have been administered preoperative induction therapy (ATG/OKT-3) developed CMV infection more frequently. Aditionally, we found that posttransplantation tacrolimus users seemed to be prone to CMV infection. In contrast to our findings, San Juan et al showed that use of cyclosporine increases the risk of CMV disease, whereas use of sirolimus seems to have a protective effect.6 Recently, Furhmann et al sugeested that tacrolimus could reduce T-cell polyfunctionality and cause an incresed infection risk in these patients.18 This could be a possible mechanism for our results. Despite recent advances in CMV prophylaxis, CMV infection is still a risk factor for clinical acute rejection and graft loss in kidney recipients. According to our data, long duration of dialysis time, absence of HLA-B51 gene locus, presence of a double-J stent, and a post-transplantation immunsuppresive regimen might predict the development of CMV infection.
CYTOMEGALOVIRUS INFECTION
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3523 10. Hartmann A, Sagedal S, Hjelmesaeth J. The natural course of cytomegalovirus infection and disease in renal transplant recipients. Transplantation. 2006;82(suppl):S15eS17. 11. Nemati E, Eizadi M, Lankarani MM, et al. Cytomegalovirus disease after kidney transplantation: clues to accurate diagnosis. Transplant Proc. 2007;39:987. 12. Rubin R, Cosimi B. Infectious disease syndromes attributable to cytomegalovirus. Their significance among recipients. Transplantation. 1977;24:458. 13. Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89(7):779e794. 14. Legendre C, Pascual M. Improving outcomes for solidorgan transplant recipients at risk from cytomegalovirus infection: lateonset disease and indirect consequences. Clin Infect Dis. 2008; 46(5):732e740. 15. Boland GJ, Hene RJ, Ververs C, de Haan MA, de Gast GC. Factors influencing the occurrence of active cytomegalovirus (CMV) infections after organ transplantation. 1993;94(2):306e312. 16. Sagedal S, Nordal KP, Hartmann A, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant. 2002;2:850. 17. Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int. 2004;66:329. 18. Fuhrmann S, Lachmann R, Streitz M, Hetzer R, Volk HD, Lehmkuhl H, et al. Cyclosporin A and tacrolimus reduce T-cell polyfunctionality but not interferon-g responses directed at cytomegalovirus. Immunology. 2012;136(4):408e413. http://dx.doi.org/ 10.1111/j.1365-2567.2012.03594.x.
