CMV-seropositive Kidney Transplant Research Articles

Cytomegalovirus-Responsive CD8+ T Cells Expand After Solid Organ Transplantation in the Absence of CMV Disease.

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in solid organ transplant recipients. Approximately 60% of adults are CMV seropositive, indicating previous exposure. Following resolution of the primary infection, CMV remains in a latent state. Reactivation is controlled by memory T cells in healthy individuals; transplant recipients have reduced memory T cell function due to chronic immunosuppressive therapies. In this study, CD8+ T cell responses to CMV polypeptides immediate-early-1 and pp65 were analyzed in 16 CMV-seropositive kidney and heart transplant recipients longitudinally pretransplantation and posttransplantation. All patients received standard of care maintenance immunosuppression, antiviral prophylaxis, and CMV viral load monitoring, with approximately half receiving T cell-depleting induction therapy. The frequency of CMV-responsive CD8+ T cells, defined by the production of effector molecules in response to CMV peptides, increased during the course of 1 year posttransplantation. The increase commenced after the completion of antiviral prophylaxis, and these T cells tended to be terminally differentiated effector cells. Based on this small cohort, these data suggest that even in the absence of disease, antigenic exposure may continually shape the CMV-responsive T cell population posttransplantation.

Response to “Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates”

Response to “Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates”

Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates

Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates

Association Between Individual and Combined SNPs in Genes Related to Innate Immunity and Incidence of CMV Infection in Seropositive Kidney Transplant Recipients

In this study, we assessed the association between single-nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the 12-month incidence of CMV infection in 315 CMV-seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T-allele genotypes of interleukin-28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p-value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll-like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38-0.96; p-value = 0.035), whereas the GG genotype of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18-2.94; p-value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC-SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV-seropositive KT recipients.

Cytomegalovirus prevention strategies in seropositive kidney transplant recipients: an insight into current clinical practice.

There is notable heterogeneity in the implementation of cytomegalovirus (CMV) prevention practices among CMV-seropositive (R+) kidney transplant (KT) recipients. In this prospective observational study, we included 387 CMV R+ KT recipients from 25 Spanish centers. Prevention strategies (antiviral prophylaxis or preemptive therapy) were applied according to institutional protocols at each site. The impact on the 12-month incidence of CMV disease was assessed by Cox regression. Asymptomatic CMV infection, acute rejection, graft function, non-CMV infection, graft loss, and all-cause mortality were also analyzed (secondary outcomes). Models were adjusted for a propensity score (PS) analysis for receiving antiviral prophylaxis. Overall, 190 patients (49.1%) received preemptive therapy, 185 (47.8%) antiviral prophylaxis, and 12 (3.1%) no specific intervention. Twelve-month cumulative incidences of CMV disease and asymptomatic infection were 3.6% and 39.3%, respectively. Patients on prophylaxis had lower incidence of CMV disease [PS-adjusted HR (aHR): 0.10; 95% confidence interval (CI): 0.01-0.79] and asymptomatic infection (aHR: 0.46; 95% CI: 0.29-0.72) than those managed preemptively, with no significant differences according to the duration of prophylaxis. All cases of CMV disease in the prophylaxis group occurred after prophylaxis discontinuation. There were no differences in any of the secondary outcomes. In conclusion, antiviral prophylaxis was associated with a lower occurrence of CMV disease in CMV R+ KT recipients, although such benefit should be balanced with the risk of late-onset disease.

Single Nucleotide Polymorphisms (SNPs) of IL28B Gene Are Associated With a Higher Incidence of CMV Infection in CMV-Seropositive Kidney Transplant Recipients (KTR).

Single Nucleotide Polymorphisms (SNPs) of IL28B Gene Are Associated With a Higher Incidence of CMV Infection in CMV-Seropositive Kidney Transplant Recipients (KTR).

Panresistant Cytomegalovirus in a Kidney Transplant Recipient

Cytomegalovirus (CMV) is an important pathogen often encountered after solid organ transplantation and is associated with increased morbidity and mortality. Resistance of CMV to antiviral agents is becoming more common but with few treatment strategies. Two specific mutations in the CMV genome--the UL97 and UL54 genes--correlate with antiviral drug resistance. We describe a 49-year-old, CMV-seronegative woman who received a CMV-seropositive donor kidney transplant and appropriate CMV prophylaxis. Approximately 1 month after transplantation, the patient developed CMV viremia that responded to valganciclovir. She was later diagnosed with recurrent CMV infection, CMV resistance, and both the UL97 and UL54 gene mutations. The patient responded to foscarnet and significant reduction of immunosuppression; she was negative for CMV viremia for the next 12 months. This case illustrates the importance of having heightened awareness for the possibility of panresistant CMV early and decreasing immunosuppression as the cornerstone of treatment.

Clonotype Analysis of Cytomegalovirus-Specific Cytotoxic T Lymphocytes

Cytotoxic T lymphocytes (CTL) control the replication of human cytomegalovirus (CMV). Previous studies assessed the clonotypic composition of CTL specific for individual immunodominant peptides within a certain HLA context. Such an approach has inherent limitations and may not assess the true clonal CTL response in vivo. Here, the clonotypic composition of CMV-specific CTL was determined in HLA-A2, CMV-seropositive kidney transplant recipients and healthy blood donors after stimulation of peripheral blood mononuclear cells with either a pp65 whole-peptide pool or a single immunodominant peptide. Even after stimulation with the whole peptide pool, CMV-specific CTL remained monoclonal or oligoclonal. Regarding intraindividual variation, the CDR3 motifs of the dominant clones were identical to those observed in CTL generated by the single immunodominant peptide. Sequencing of the CDR3 regions demonstrated significant interindividual variation; however, structural homology was observed for immunodominant clonotypes in three individuals. In conclusion, the highly focused T cell receptor repertoire found after stimulation with either a single immunodominant peptide or a peptide pool demonstrates a pivotal role for immunodominant epitopes in the generation of a clonal repertoire. These results provide new insights into the regulation of CMV clonal dominance and may contribute to the design and monitoring of adoptive immunotherapy.

CMV ANTIGENEMIA IS NOT ASSOCIATED WITH ADVERSE GRAFT OUTCOME OR CMV DISEASE IN INTERMEDIATE RISK TRANSPLANT RECIPIENTS.

P806 Aims: Pretransplant CMV seropositive kidney transplant recipients (KTR) carry a low risk for CMV disease unless they receive antilymphocyte therapy (ALT), however, administration of antiviral prophylaxis is a common management strategy with the theoretical objective of avoiding the indirect effects of CMV. In order to evaluate incidence of CMV infection/disease in a group of KTR [Donor CMV +or-/Recipient CMV+, (D+or-/R+)] and its impact in graft function in the absence of CMV prophylaxis, we performed this prospective study (Nov/01-Sep/03). Methods: Pretransplant CMV antibodies were determined by ELISA. CMV antigenemia (Ag) was assessed by monoclonal antibody against pp65: assay performed biweekly for the first 3 months posttransplant and then monthly up to 6 months. If positive (one antigen positive cell/150x103), the Ag assay was performed weekly. Ganciclovir IV was given only upon development of CMV disease. All KTR received triple or quadruple immunosuppressive Tx without ALT induction. Acute rejection (AR) clinically suspected was biopsy confirmed. Variables recorded: Transplant date, KTR age, gender, donor source, pretransplant CMV status, time to Ag+, and number of positive cells/assay. Follow-up visits: Clinical evaluation of CMV related symptoms, blood cell count, serum creatinine (SCr), liver function tests, and urinalysis. Results: We evaluated 75 KTR CMV+, mean age 33±3 y, 65% male; 84% received the kidney from living donors. Mean follow-up 522±227days. The incidence of CMV Ag+ was 36.8%. The time elapsed between the transplant and the first positive antigenemia was 60.3±36.3 days; the number of positive cells/assay fluctuated from 1 to 1900; and the mean duration of antigenemia before its spontaneous disappearance was 101±55 days. Only two Ag+ patients developed CMV disease (2.6 %). The incidence of AR episodes was 7.1 and 6.4 % for Ag+ and Ag- patients, respectively, p=0.7. Mean SCr for Ag+ patients was 1.63 ± 0.13 and 1.49 ± 0.11 mg/dl before the first positive antigenemia result (1 month posttransplant) and at 6 months, respectively. For those who remained Ag- during follow-up, the mean SCr was 1.31± 0.1 and 1.24 ± 0.04 at one month posttransplant and at 6 months, respectively. There were not differences between Ag+ vs Ag- patients regarding mean SCr at baseline and at 6 months. Conclusions: CMV transient antigenemia is a frequent finding in KTR with intermediate risk. In this group of patients the incidence of CMV disease is low and there is no impact on graft function. We believe that universal use of CMV prophylaxis in these patients is not necessary and treatment must be individualized.

Clinical Course of Cytomegalovirus (CMV) Viremia with and without Ganciclovir Treatment in CMV-Seropositive Kidney Transplant Recipients

This study was designed to evaluate the longitudinal history of cytomegalovirus (CMV) infection and to test the capacity of ganciclovir as effective therapy in CMV-seropositive renal transplant recipients. The CMV viremia was detected with CMV pp65 antigenemia assay in 153 renal transplants. The recipients were classified as having low-grade and high-grade CMV infections according to the severity of CMV infection. The recipients with low-grade CMV infections were observed without ganciclovir treatment, and the recipients with high-grade CMV infection were randomly assigned to ganciclovir-treated and untreated groups. The clinical course between low-grade and high-grade CMV infections was evaluated. All recipients with low-grade CMV infection (n = 62) showed spontaneous remission regardless of immunosuppresants. In high-grade CMV infection (n = 31), the ciclosporin A treated group (n = 11) showed no evidence of CMV disease, and the methylprednisolone-treated group (n = 8) showed CMV disease in 1 (25%) of 4 ganciclovir-untreated recipients. In the OKT3 group (n = 12), symptomatic CMV infection was observed in 6 (100%) ganciclovir-untreated recipients contrary to no CMV disease in the ganciclovir-treated group (p < 0.05). In conclusion, the CMV antigenemia assay is effective in monitoring CMV viremia, and ganciclovir treatment should be done during early CMV viremia in OKT3-treated recipients.