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Association of the Outcome of Renal Transplantation with Antibody Response to Cytomegalovirus Strain—Specific Glycoprotein H Epitopes

  1. Kei Ishibashi1,2,
  2. Tadahiko Tokumoto3,
  3. Kazunari Tanabe3,
  4. Hiroki Shirakawa3,
  5. Koichi Hashimoto1,
  6. Nobuhiro Kushida2,
  7. Tomohiko Yanagida2,
  8. Naoki Inoue4,
  9. Osamu Yamaguchi2,
  10. Hiroshi Toma3, and
  11. Tatsuo Suzutani1
  1. 1Department of Microbiology, Fukushima Medical University, Fukushima
  2. 2Department of Urology, Fukushima Medical University, Fukushima
  3. 3Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
  4. 4Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
  1. Reprints or correspondence: Dr. Kei Ishibashi, Dept. of Microbiology, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan (keikun{at}fmu.ac.jp).

  1. Presented in part: 100th Annual Meeting of the American Urological Association, San Antonio, Texas, 21–26 May 2005 (abstract 1625); 12th International Conference on Immunobiology and Prophylaxis of Human Herpesvirus Infections, Osaka, Japan, 6–8 October 2005 (abstract P-15); and 26th International Herpesvirus Workshop, Seattle, Washington, 22–28 July 2006 (abstract 3.20).

 
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Abstract

Background. Cytomegalovirus (CMV) is the most important pathogen affecting the outcome of renal transplantation. The combination of CMV-seronegative transplant recipients with CMV-seropositive transplant donors places recipients at the highest risk of CMV disease. In cases of congenital CMV infection, existing immunity only partially protected mothers from reinfection with a different genotypic strain. The effect of differences in infected CMV strains between CMV-seropositive transplant donors and CMV seropositive transplant recipients on the outcome of transplantation remains unclear.

Methods. In this prospective multicenter study, the presence of antibodies against strain-specific glycoprotein H epitopes in 84 CMV-seropositive transplant donor/CMV-seropositive transplant recipient renal transplantation cases were determined, and their relationships to acute transplant rejection, CMV infection, degree of antigenemia, and CMV disease were evaluated.

Results. Among the 84 donor/recipient pairs, 45 and 32 had matched and mismatched strain-specific glycoprotein H antibodies, respectively. Acute transplant rejection in the mismatched group was more frequent than it was in the matched group (63% vs. 22%; P = .005). CMV disease was also more frequently observed in the mismatched group (28% vs. 9%; P = .026). The mismatched group had a higher level of antigenemia (P = .019).

Conclusions. Our results illustrate more adverse events in the cases with a CMV-seropositive transplant donor and a CMV-seropositive transplant recipient in which the glycoprotein H antibodies are mismatched, suggesting that reinfection with a different CMV strain results in more complications.

Although renal transplantation has been a valuable treatment for patients experiencing chronic renal failure, acute transplant rejection and cytomegalovirus (CMV) disease remain critical complications in transplant recipients [1]. CMV infection, which persists in the kidney in a latent state and is reactivated under immunosuppressive conditions, causes both direct and indirect effects on transplantation [2,3,4–5]. The role of CMV infection in acute transplant rejection after renal transplantation remains controversial, but several studies have suggested that CMV infection can lead to allograft rejection [6,7,8,9,10–11]. Because an episode of acute transplant rejection can lead to allograft loss and can affect the recipient's survival, it is crucial to prevent CMV infection after transplantation [7].

A recent meta-analysis described the importance of antiviral prophylaxis in solid-organ transplant recipients [12]. Although CMV prophylaxis can reduce the risk of CMV disease and associated mortality, its effects on allograft loss and acute transplant rejection have not been clearly established [12]. Many reports have demonstrated that CMV serostatus—that is, "seropositive or seronegative," as defined by conventional classifications—influences clinical outcome in renal transplantation [7, 8]. For example, the combination of CMV-seronegative transplant recipients (R-) with CMV-seropositive transplant donors (D+) led to the highest risk of CMV disease. Even in D+/R+ cases, ∼20% of recipients experienced CMV disease in the absence of any prophylaxis [13]. Interestingly, a recent report on congenital CMV infection provided clear evidence that exposure to CMV with a different genotype caused congenital infection, even in seropositive mothers [14], indicating that serostatus is a vague definition to evaluate preexisting immunity for protection against reinfection.

In this study, we examined the antibodies against CMV strain–specific neutralizing epitopes of glycoprotein H (gH) [14,15–16] in serum samples obtained from transplant donors and recipients, and we evaluated whether the presence or absence of antibodies against matched epitopes had any relationship with acute transplant rejection, CMV infection, degree of antigenemia, or incidence of CMV disease.

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Materials and Methods

Patients. This study, which was approved by the institutional ethics committees of Fukushima Medical University (Fukushima, Japan) and Tokyo Women's Medical University (Tokyo, Japan), included 114 pairs of consecutive donors and recipients who were receiving renal transplants from living, related donors, both at the Fukushima Medical University (Fukushima, Japan) and at the Tokyo Women's Medical University (Tokyo, Japan) from June 2002 through December 2004. All donors and recipients provided written, informed consent for participation. All transplant donors and recipients were screened for the presence of CMV antibodies, before transplantation was performed, to assess their CMV status. Data regarding the serostatus of the donors and recipients, episodes of rejection, CMV disease, and treatment protocols were stored in a database in our laboratory (Fukushima Medical University).

Immunosuppression. Immunosuppression for recipients consisted of triple-drug therapy (tacrolimus or cyclosporine, mycophenolate mofetile, and predonisolone). Tacrolimus was initiated intravenously at a dosage of 0.04 mg/kg daily for the first 4 days after transplantation, after which administration was switched to an oral route. Targeted plasma trough levels of the drug were 13–15 ng/mL for the first week, 5–10 ng/mL for the first month, and 5–8 ng/mL thereafter. Mycophenolate mofetile was administered at 1.5 g daily for the first month and was then decreased to 1.0 g daily. Prednisolone was administered at a dosage of 250 mg daily for the first 2 days, then the dosage was decreased in a tapering fashion to 60 mg daily by 1 week and to 12 mg daily by 1 month. Among the 114 transplantations, cyclosporin was used in 7 transplant recipients who experienced chest pain or hyperglycemia.

Diagnosis of rejection. Transplant rejection was suspected when serum creatinine levels increased to >25% of the baseline level in the absence of urinary tract obstruction or renal graft artery stenosis. Dehydration, infection, and nephrotoxic medication administration were excluded clinically. The first rejection episode was confirmed histologically using biopsy samples from the allografts.

For treatment of acute transplant rejection episodes, a basic dose of 500 mg of methylprednisolone was administered for 2 days. Steroid-resistant rejections were diagnosed if the maximum serum creatinine level did not decrease after the receipt of methylprednisolone treatment. Anti–lymphocyte globulin antibody or muromonab-CD3 was administered in cases of steroid-resistant rejection.

Monitoring of CMV antigenemia. Antigenemia using pp65 antibody was routinely evaluated weekly for 6 months after transplantation. When patients exhibited a positive antigenemia result or any sign of adverse event, such as infection or rejection, the assay was performed twice per week or more frequently. Detection of the pp65 antigen was performed as described previously [17]. In brief, 3.0 × 105 leukocytes were centrifuged onto microscope slides and fixed in acetone/methanol for 10 min at 4°C. Immunoperoxidase staining and monoclonal antibodies C10 and C11 (Clonab CMV; Biotest) against CMV pp65 were used to demonstrate the viral proteins in the leukocytes, and pp65 positive cells were counted.

Management of CMV infection and CMV disease CMV infection was defined as positive results of testing for antigenemia (e.g., ⩾1 pp65-positive cell per 3.0 × 105 leukocytes) during the monitoring period, irrespective of clinical manifestations. Patients with a low level of antigenemia (e.g., 1–9 pp65-positive cells per 3.0 × 105 leukocytes) were monitored frequently, and preemptive therapy was initiated if ⩾10 pp65-positive cells per 3.0 × 105 leukocytes were detected, as reported previously [18]. Irrespective of antigenemia results, patients who experienced CMV disease–related manifestations were treated immediately. CMV disease–related manifestations included unexplained fever (temperature, ⩾38°C, with no other source to account for it) for ⩾2 days, arthralgia, leukopenia (leukocyte count, ⩽4000 cells/mm3), the presence of ⩾3% atypical lymphocytes or thrombocytopenia (platelet count, ⩽100,000 cells/mm3), an increase in liver enzyme level, gastrointestinal ulceration or hemorrhage, and pneumonitis [17, 19]. Gancyclovir therapy was administered intravenously at a dosage of 5 mg/kg twice daily and was continued for at least 2 weeks after the receipt of negative antigenemia results. The dose was adjusted for renal function. Patients who exhibited any of the aforementioned CMV disease–related manifestations and/or who had received preemptive therapy were defined as the transplant recipients who developed CMV disease.

CMV-related serological findings and strain-specific ELISA. CMV serostatus was determined using a commercial ELISA kit (Enzygnost Anti-CMV/IgG, IgM; Dade Behring). To evaluate CMV strain–specific antibodies, the gH epitopes (amino acid position 32 to 42 of gH) from the AD169 and Towne strains were used for ELISA testing [14]. DNA fragments encoding the epitopes were prepared by annealing 2 synthetic oligonucleotides (Sigma Aldrich): strands A and B for AD169 and strands C and D for Towne (figure 1A). These were then cloned into the pGEX5x plasmid vector. Glutathione S-transferase (GST) proteins containing the gH epitopes were expressed in Escherichia coli DH5α and were purified using GSTrap FF (AmershamBioscience), according to the manufacturer's protocol.

Figure 1
Figure 1

A, Oligonucleotides containing cytomegalovirus (CMV) glycoprotein H (gH) epitopes from the AD169 and Towne strains that were used for the expression of gH epitopes (top of the oligonucleotides) as glutathione S-transferase (GST) fusion proteins. Each cassette has BamHI and EcoRI sites at the ends for cloning. B, Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of the purified GST fusion proteins containing the AD169-specific (lane 1) and Towne-specific (lane 2) gH epitopes. Size standards are shown on the left side of the gel. C, The results of ELISA using purified GST fusion proteins containing AD169- and Towne-specific gH epitopes. Reactivity of CMV-seronegative serum samples (closed triangles) and CMV-seropositive serum samples reacting with the gH epitopes that were specific to AD169 (closed circles) and Towne (open circles) were plotted. Dashed horizontal line, the cut-off optical density (OD) value.

ELISA using these purified recombinant proteins for the measurement of antibodies against the strain-specific gH epitopes was performed as described previously [20], with slight modification. In brief, microtiter plate wells (ELISA-PLATE 96w; Greiner Bio-One) were coated with 1 µg of purified recombinant gH-GST fusion proteins or of purified GST, and they were then blocked with 3% bovine serum albumin in phosphate buffered saline for 2 h at 37°C. Serum specimens were diluted 1 : 4 in PBS and were used to fill the wells. The plates were incubated at 37°C for 2 h. After washing with Tris-buffered saline (50 mmol/L Tris–hydrochloric acid [pH, 7.5] plus 150 mmol/L sodium chloride) containing 0.05% Tween 20, bound antibodies were incubated with horseradish peroxidase–conjugated rabbit antihuman IgG (DakoCytomation) for 2 h. The color reaction was developed for 30 min at room temperature with a commercially available ELISA POD Substrate ABTS kit (Nacalai). The plates were read at 450 nm using an ELISA plate reader. Optical density (OD) values specific to each strain-specific gH antigen were obtained by subtracting the OD values for GST. An arbitrary cutoff for the ELISA results (OD, 0.25) was defined as the mean plus 2 SDs of OD values obtained from a panel of 23 healthy, CMV-seronegative volunteers.

Statistical analysis. Fisher's exact test was used to evaluate the rate of CMV disease and CMV infection between different CMV status groups. Results were considered to be statistically significant if the P value was <.025 with a Bonferroni correction. The incidence of biopsy-proven acute rejection was calculated using the Kaplan-Meier method, and intergroup comparisons were performed using the log-rank test. Multivariate logistic regression analysis was used to estimate ORs and corresponding 95% CIs. The maximum numbers of pp65-positive cells in the antigenemia assay were depicted as box-plots and were compared using the Mann-Whitney test.

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Results

Performance of ELISA for strain-specific gH epitopes. GST fusion proteins containing the strain-specific gH epitopes (figure 1A) were expressed in E. coli and were purified by an affinity column (figure 1B). The results of ELISA using the GST-gH fusion proteins for detection of strain-specific antibodies were evaluated using a panel of serum samples obtained from 21 CMV-seropositive and 23 CMV-seronegative volunteers. Among the 21 serum samples from CMV-seropositive persons, 13 were AD169-specific, and 8 were Towne-specific (figure 1C). There was little ambiguity in distinguishing serum samples that reacted with AD169- from those with Towne-specific gH epitopes.

CMV strain–specific antibody responses of patients. Among the 228 participants of the 114 donor-recipient pairings in this study, 195 were CMV seropositive before renal transplantation. The 84 D+/R+ pairs were classified into 3 subgroups ("matched," "mismatched," and "D-") on the basis of the combinations of antibody responses against the strain-specific gH epitopes. figure 2 reveals the details of the combinations; the numbers of transplantation pairs and their characteristics are summarized in table 1. Because 7 donors did not have detectable antibodies against gH, they were excluded from the analysis. However, all of these donors exhibited antibody responses against glycoprotein B.

Figure 2
Figure 2

Classifications of the cytomegalovirus (CMV) seropositivity of donors (D) and recipients (R), according to conventional CMV serostatus (positive [+] or negative [-]) and CMV strain-specific antibodies against glycoprotein H (gH) epitopes. Details of the combinations based on strain-specific antibodies against gH epitopes are also shown. AD, AD169; mix, both AD169 and Towne; ND, undetectable; TW, Towne.

Acute rejection after transplantation. Thirty-one recipients (37%) of the 84 D+/R+ pairs and 5 recipients (21%) of the 24 D+/R- pairs experienced biopsy-proven acute rejection. Thus, there was no statistically significant difference in the acute rejection rate (P = .14). However, it was interesting to note that, among the 27 D+/R+ patients who experienced acute rejection and whose matching of strain-specific antibodies were known, 17 (53%) did not have matched strain-specific antibodies (figure 3A). This is a significantly higher rate than for those in the D+/R+ strain-specific antibody-matched group (22%; P = .0051) and for those in the D+/R- group (21%; P = .014). The mean time after transplantation to diagnosis of acute transplant rejection was 25 days for all patients who experienced acute rejection (figure 3A), and there were no statistical differences observed in incubation period for acute rejection among the 3 groups (D+/R-, D+/R+ with matched strain-specific antibodies, and D+/R+ with mismatched, strain-specific antibody groups). Multivariate logistic regression analysis was employed to identify any factors associated with acute rejection. Age, sex, number of human leukocyte antigen mismatches, immunosuppression protocols, total ischemia time, CMV disease and/or CMV infection, and CMV serostatus of recipients were used as parameters. For the analysis of the transplant recipients in the D+/R+ group, the strain-specific antibody serostatus was included in place of CMV serostatus. Analysis performed on samples obtained from all transplant recipients did not reveal any risk factors for acute transplant rejection. On the other hand, analysis of the 77 recipients of the D+/R+ group demonstrated that only CMV strain–specific antibody serostatus had a statistically significant interaction (P = .018) (table 2).

Figure 3
Figure 3

A, Summary of incidences of acute transplant rejection. aP = .014 vs. mismatched. bP = .0051 vs. mismatched. B, Kaplan-Meier curves for the cumulative probability of freedom from biopsy-proven acute rejection. The incidence of acute rejection in the cytomegalovirus (CMV) strain–specific antibody mismatched group was significantly higher than those in the CMV-seropositive donor and CMV-seronegative recipient (D+/R-) and strain-specific antibody-matched groups (P = .002). R+, CMV-seropositive transplant recipient.

Figure 4
Figure 4

Antigenemia among transplant recipients. The maximum number of pp65-positive cells during the 6-month monitoring period for each transplant recipient with cytomegalovirus (CMV) infection was plotted. Broken bars, the median of the pp65-positive cells. D+, CMV-seropositive transplant donor; R+, CMV-seropositive transplant recipient; R-, CMV-seronegative transplant recipient.

Table 1
Table 1

Baseline characteristics of renal transplant donor/recipient pairings.

Table 2
Table 2

Multivariate logistic regression analysis of rejection-related factors of the 77 transplant recipients in the cytomegalovirus (CMV)–seropositive transplant donor/CMV-seropositive transplant recipient (D+/R+) group.

CMV infection and CMV disease. Thirty-seven (48%) of 77 recipients in the D+/R+ group were found to be positive for CMV infection using the pp65 antigenemia assay (table 3). There were no statistical differences in the incidence of CMV infection between the CMV strain–specific antibody-matched and antibody-mismatched groups (51% and 44%, respectively). Among the 37 transplant recipients, 24 experienced infection without progression to CMV disease and had low levels of antigenemia (mean number of pp65-positive cell numbers, 2.2; range, 1–9). The remaining 13 recipients experienced CMV disease–related manifestations, including pneumonitis (1 patient), fever (3 patients), leukopenia (1 patient), fever and hepatitis (2 patients), gastrointerstinal ulceration (1 patient), and a high level of antigenemia alone (6 patients). Among these patients, 9 (28%) of 32 were in the CMV strain–specific antibody-mismatched group, and 4 (9%) of 45 were in the antibody-matched group. Consequently, CMV disease was significantly more prevalent in the mismatched group than in the matched group. The proportion of cases of CMV infection that progressed to CMV disease in the strain-specific antibody-mismatched and antibody-matched groups were 64% and 17%, respectively (P = .0038). Although we were unable to compare the severity and timing of various CMV-associated clinical manifestations in a uniform way, there appeared to be no significant differences in disease severity between these 2 groups.

Table 3
Table 3

Cytomegalovirus (CMV) infection and CMV disease after renal transplantation.

Sixteen (67%) of 24 recipients among the D+/R- pairs had CMV infection, and 13 (54%) of them developed CMV disease–related manifestations, including fever (7 patients), fever and hepatitis (3 patients), leukopenia (1 patient), or a high level of antigenemia alone (2 patients) (table 3). As expected, the incidence of CMV disease among the transplant recipients in the D+/R- pairs was statistically higher than the incidence among the transplant recipients in the D+/R+ pairs (P < .001).

CMV pp65 antigenemia. The maximum numbers of pp65-positive cells obtained during the weekly antigenemia assay are plotted in figure 4. The medians of the maximum positive cell numbers in the transplant recipients from the D+/R+ antibody-mismatched and the D+/R+ antibody-matched groups were 38 (range, 1–818) and 2 (range, 1–142), respectively. The difference in the maximum positive cell numbers between these 2 groups was statistically significant. The median maximum positive cell number measured in the transplant recipients in the D+/R- pairs was 113 (range, 1–3128). Although the maximum numbers of positive cells in the transplant recipients in the D+/R- pairs were statistically higher than those in the D+/R+ pairs (P = .0012), the difference between the D+/R- group and the antibody-mismatched group was not statistically significant. The incubation period from transplantation to detection of the first pp65-positive cells was 7–8 weeks in each group (table 3).

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Discussion

We analyzed cases of renal transplantation and found significant differences in the clinical outcomes, including degrees of antigenemia and incidences of acute rejection and CMV disease, between transplant recipient and donor pairs with mismatched and matched combinations of strain-specific antibodies against the gH epitopes. Our findings have some similarity with those that have been reported for congenital CMV infection in previously seropositive women [14]. Klein et al. [21] previously reported that the effective neutralization of CMV infection with clinical isolates required antibodies that were obtained from the matched patients. An attractive hypothesis to explain our findings is that antibodies in the transplant recipients could not protect against CMV disease caused by reinfection with a donor CMV strain containing different gH epitopes. To verify this working hypothesis, further study will be required to directly evaluate differences in the neutralizing activities of the recipients' serum, although the gH epitope locus that was used in this study was reported to be the target of the neutralizing immune response [15, 16]. Furthermore, determination of the gH sequences of the strains isolated from the donors and recipients is needed to support our serological findings. Those experiments are underway. In this study, CMV infection was not completely prevented, even in the matched patients, and there were no statistically significant differences in frequency of CMV infection between the matched and mismatched groups. Because glycoprotein B, glycoprotein M, and other glycoproteins can be additional targets for neutralization [22,23–24], it would also be interesting to see whether any strain-specific antibodies against these molecules affect the outcome of transplantation.

In our study, some of the CMV-seropositive serum specimens reacted with neither the AD169-derived gH antigen nor the Towne antigen. Plausible explanations for this could be a low sensitivity of strain-specific ELISAs and/or infection with some gH-epitope variant. Although we excluded 7 D+/R+ pairs from analysis because the donors did not have detectable strain-specific gH antibodies, classification of these 7 pairs into the mismatched group basically did not change the difference in the rates of acute transplant rejection and CMV disease, nor did it affect the maximum numbers of pp65-positive cells between the matched and mismatched groups.

Although additional studies are required to elucidate the mechanism of the relationship between strain-specific gH antibodies and the outcome of transplantation, this study indicates that some of the patients in the conventionally classified D+/R+ pairings experienced different outcomes after transplantation than was expected according to CMV strain-specific antibody matching. The use of preemptive management, rather than prophylactic management, might have resulted in a higher rate of CMV disease and acute transplant rejection. However, when compared with some other studies that used similar preemptive or deferred therapy, the incidences of acute rejection and CMV disease were not markedly higher [13, 25]. Given that 9 (69%) of 13 of the patients in the D+/R+ group who developed CMV disease after CMV infection had mismatched strain-specific antibodies, it would be important to retrospectively reevaluate the outcome of renal transplantation by applying strain-specific serological strategies.

Our working hypothesis implies that the combination of antiviral drugs and anti-CMV immunoglobulin with broad-strain specificity may be effective in minimizing the risk of CMV disease in cases of D+/R+ transplantation. In fact, several studies have reported the successful prevention of CMV disease in high-risk transplant recipients using passive immunization [26,27–28].

Although it is well documented that CMV can cause acute transplant rejection after renal transplantation [8, 29], the effect of prophylaxis on acute rejection and allograft loss remains controversial [12, 25, 30,31,32–33]. In this study, CMV infection and CMV disease were observed in only 18 (56%) and 8 (25%) of the 32 recipients who experienced acute transplant rejection during a 6-month follow-up period after transplantation, respectively. It is puzzling why the incidence of acute rejection in the mismatched antibody group was higher than that observed in the matched group, even though there were no differences between the matched group and the D+/R- group. It is possible that acute rejection is the consequence of strong recipient-derived cytotoxic T lymphocyte responses against ongoing CMV activities that had escaped humoral responses. It would be interesting to compare the frequency of CMV-specific cytotoxic T lymphocytes between the matched and mismatched groups. Additional studies with a larger number of cases are required to confirm our findings.

In conclusion, this study demonstrates that the occurrence of more adverse events in the cases of D+/R+ transplantation with mismatched gH antibodies. Our findings could be explained by the relationship between the degree of neutralization and outcome of transplantation in the D+/R+ setting.

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Acknowledgments

We thank all the subjects who participated in this study. We also thank Dr. Masayuki Saijo, Yuka Sato, and Miyuki Furusawa for their editorial assistance, provision of serum samples, and monitoring of the data, and Professor Tatsuya Okada for multivariate logistic regression analysis.

Financial support. Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research no. 16591609), the Research on Health Sciences Focusing on Drug Innovation program of the Japanese Human Science Foundation, and the Fukushima Society for the Promotion of Medicine.

Potential conflicts of interest. All authors: no conflicts.

  • Received January 30, 2007.
  • Accepted March 9, 2007.
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  1. Clin Infect Dis. (2007) 45 (1): 60-67. doi: 10.1086/518571
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