A prospective multicenter observational study of cell‐mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients

T cell immunity is essential for the control of cytomegalovirus (CMV) infection after transplantation. We evaluated a CMV‐specific peptide‐based enzyme‐linked immunosorbent spot (ELISPOT) assay to determine whether assay results could predict subsequent CMV events. Adult kidney transplant recipients at 43 centers underwent ELISPOT testing to enumerate interferon gamma (IFN‐γ) binding spot‐forming units (sfu) after stimulation of cells with an overlapping peptide pool of CMV phosphoprotein 65 (pp65) and immediate early‐1 (IE‐1) protein at the end of antiviral prophylaxis (EOP) and various time points thereafter. The primary outcome was a CMV event in the first posttransplant year. In 583 kidney transplant recipients (260 seropositive donor [D+]/seronegative recipient [R?] and 277 R+), CMV events occurred in 44 of 368 eligible patients (11.8%) at a median of 227 days (range 92‐360) posttransplant. A cutoff value of >40 sfu/2.5 × 10⁵ cells for either IE‐1 or pp65 was derived as a threshold for positivity, with a negative predictive value of >97% for CMV events. CMV events were significantly lower in assay positive vs assay negative patients (3.0% vs 19.5%, P < .0001 for pp65). Time to CMV event post‐EOP was significantly greater in those with sfu >40 at EOP (P < .0001). In this large, multicenter trial of kidney transplant recipients, we show that an assessment of CMV‐specific immunity using a novel ELISPOT assay is able to predict protection from CMV infection.     

Cytomegalovirus infections following renal transplantation – effects of antiviral prophylaxis: a report of the North American Pediatric Renal Transplant Cooperative Study

Post-transplant cytomegalovirus (CMV) infections are a source of significant morbidity. However, the extent of the problem and the benefits of various antiviral prophylactic therapies remain incompletely understood. The North American Pediatric Renal Transplant Cooperative Study registry was screened to identify patients hospitalized for CMV infections during the 1st post-renal transplant year between 1987 and 1993. Using a control group of transplant recipients, we performed a retrospective analysis of risk factors for CMV disease among these hospitalized patients and studied the effects of various viral prophylactic strategies on CMV risk, clinical manifestations, and outcome. We identified 142 patients hospitalized with CMV infections, the majority of which included major organ involvement. A CMV-positive kidney donor was the most significant risk factor for hospitalization [odds ratio (OR) = 5.2, P<0.0001] irrespective of recipient age or CMV immune status. As opposed to antiviral agents (acyclovir, ganciclovir) or pooled IgG, prophylaxis with enriched anti-CMV IgG significantly reduced the risk of CMV hospitalization (OR = 0.31, P = 0.03). The prophylactic use of antiviral agents was associated with a decreased risk of major organ involvement during the CMV infection (OR = 0.34, P<0.005). Among the patients with CMV, the 3-year graft survival was significantly better for those who received any form of prophylaxis compared with those who received none (88% vs. 52%, P<0.001). Our findings suggest a role for combined CMV-enriched IgG and antiviral agent prophylaxis for post-transplant CMV disease. Such an approach could diminish the incidence and severity of CMV infection and appears to have an independent favorable effect on graft outcome. Received November 14, 1996; received in revised form March 21, 1997; accepted April 11, 1997     

Prospective randomized study comparing everolimus and mycophenolate sodium in de novo kidney transplant recipients from expanded criteria deceased donor

The optimal immunosuppressive regimen for recipients of expanded criteria donor (ECD) kidneys has not been identified. In this single‐center study, 171 recipients of ECD kidney transplants were randomized to receive antithymocyte globulin induction, and delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r‐ATG/EVR, n = 88), or mycophenolate (r‐ATG/MPS, n = 83). No cytomegalovirus (CMV) pharmacological prophylaxis was used. The primary endpoint was the incidence of CMV infection/disease at 12 months. Secondary endpoints included treatment failure [first biopsy‐proven acute rejection (BPAR), graft loss, or death] and safety. Patients treated with EVR showed a 89% risk reduction (13.6 vs. 71.6%; HR 0.11, 95% CI 0.06–0.220, P < 0.001) in the incidence of first CMV infection/disease. Incidences of BPAR (16% vs. 5%, P = 0.021), graft loss (11% vs. 1%, P = 0.008), death (10% vs. 1%, P = 0.013), and treatment discontinuation (40% vs. 28%, P = 0.12) were higher in the r‐ATG/EVR, leading to premature study termination. Mean glomerular filtration rate was lower in r‐ATG/EVR (31.8 ± 18.8 vs. 42.6 ± 14.9, P < 0.001). In recipients of ECD kidney transplants receiving no CMV pharmacological prophylaxis, the use of everolimus was associated with higher treatment failure compared with mycophenolate despite the significant reduction in the incidence of CMV infection/disease (ClinicalTrials.gov.NCT01895049).     

1,25 Dihydroxyvitamin D circulating levels,calcitriol administration,and incidence of acute rejection,CMV infection,and polyoma virus infection in renal transplant recipients

Observation that 1,25‐Dihydroxyvitamin‐D3 has an immunomodulatory effect on innate and adaptive immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy‐proven acute rejection, CMV infection, BKV infection, with 1,25‐Dihydroxyvitamin‐D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=.04), CMV infection (3% vs 9%, P=.04), and BKV infection (6% vs 19%, P=.04) was significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25‐Dihydroxyvitamin‐D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<.005 and HR=3.25, P<.05), for CMV infection (HR=2.33, P<.05 and HR=2.31, P=.001), and for BKV infection (HR=2.41, P<.05 and HR=2.45, P=.001). After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<.05). Only one user developed polyomavirus‐associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2‐D3 deficiency circulating levels increased the risk of BPAR, CMV infection, BKV infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2‐D3 circulating levels.     

Circulatory follicular helper T lymphocytes associate with lower incidence of CMV infection in kidney transplant recipients

Primary infection and/or reactivation of cytomegalovirus (CMV) in kidney transplant recipients (KTR) favor rejection and mortality. T follicular helper cells (TFH) could contribute to protection against CMV. Circulatory TFH (cTFH) were studied pretransplant and early posttransplant in 90 CMV seropositive KTR not receiving antithymocyte globulin or antiviral prophylaxis, followed-up for 1 year. Patients who presented CMV infection had significantly lower cTFH and activated cTFH pretransplant and early posttransplant. Pretransplant activated cTFH were also lower within patients who developed CMV disease. Pre- and 14 days posttransplant activated cTFH were an independent protective factor for CMV infection (HR 0.41, p = .01; and 0.52, p = .02, respectively). KTR with low cTFH 7 days posttransplant (<11.9%) had lower CMV infection-free survival than patients with high cTFH (28.2% vs. 67.6%, p = .002). cTFH were associated with CMV-specific neutralizing antibodies (Nabs). In addition, IL-21 increased interferon-γ secretion by CMV-specific CD8⁺ T cells in healthy controls. Thus, we show an association between cTFH and lower incidence of CMV infection, probably through their cooperation in CMV-specific Nab production and IL-21-mediated enhancement of CD8⁺ T cell activity. Moreover, monitoring cTFH pre- and early posttransplant could improve CMV risk stratification and help select KTR catalogued at low/intermediate risk who could benefit from prophylaxis.     

Cytomegalovirus mismatch still negatively affects patient and graft survival in the era of routine prophylactic and preemptive therapy: A paired kidney analysis

The impact of cytomegalovirus (CMV) serostatus on kidney transplant outcomes in an era when CMV prophylactic and preemptive strategies are used routinely is not clearly established. Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, recipients with first deceased donor kidney transplant (≥18 years, 2010‐2015) were stratified into 4 groups in the main cohort: CMV‐seronegative donor (D?)/CMV‐seronegative recipient (R?), CMV‐seropositive donor (D+)/R?, D+/CMV‐seropositive recipient (R+), and D?/R+. In a paired kidney cohort, we identified 2899 pairs of D? kidney transplant with discordance of recipient serostatus (D?/R? vs D?/R+) and 4567 pairs of D+ kidney transplant with discordance of recipient serostatus (D+/R? vs D+/R+). In the main cohort, D+/R? was associated with a higher risk of graft failure (hazard ratio [HR] = 1.17, P = .01), all‐cause mortality (HR = 1.18, P < .001), and infection‐related mortality (HR = 1.38, P = .03) compared with D?/R?. In the paired kidney analysis, D+/R? was an independent risk factor for all‐cause mortality (HR = 1.21, P = .003) and infection‐related mortality (HR = 1.47, P = .04) compared with D+/R+. No difference in graft loss between D+/R? and D+/R+. CMV mismatch is still an independent risk factor for graft loss and patient mortality. The negative impact of D+/R? serostatus on mortality persists after fully matching for donor factors.     

Financial impact of delayed graft function in kidney transplantation

Increased utilization of suboptimal organs in response to organ shortage has resulted in increased incidence of delayed graft function (DGF) after transplantation. Although presumed increased costs associated with DGF are a deterrent to the utilization of these organs, the financial burden of DGF has not been established. We used the Premier Healthcare Database to conduct a retrospective analysis of healthcare resource utilization and costs in kidney transplant patients (n = 12 097) between 1/1/2014 and 12/31/2018. We compared cost and hospital resource utilization for transplants in high-volume (n = 8715) vs low-volume hospitals (n = 3382), DGF (n = 3087) vs non-DGF (n = 9010), and recipients receiving 1 dialysis (n = 1485) vs multiple dialysis (n = 1602). High-volume hospitals costs were lower than low-volume hospitals ($103 946 vs $123 571, P < .0001). DGF was associated with approximately $18 000 (10%) increase in mean costs ($130 492 vs $112 598, P < .0001), 6 additional days of hospitalization (14.7 vs 8.7, P < .0001), and 2 additional ICU days (4.3 vs 2.1, P < .0001). Multiple dialysis sessions were associated with an additional $10 000 compared to those with only 1. In conclusion, DGF is associated with increased costs and length of stay for index kidney transplant hospitalizations and payment schemes taking this into account may reduce clinicians’ reluctance to utilize less-than-ideal kidneys.     

Efficacy and Safety of Ultra-Low-Dose Valganciclovir Chemoprophylaxis for Cytomegalovirus Infection in High-Risk Kidney Transplantation Patients

IntroductionValganciclovir (VGCV) prophylaxis of 900 mg twice daily for 6 months is recommended to prevent cytomegalovirus (CMV) infection, which is a major cause of decreased graft and patient survival in kidney transplant recipients. However, recent studies have shown the efficacy of 900 mg once daily for 3 to 6 months. Maintaining VGCV compliance is difficult because of high drug costs and side effects, such as thrombocytopenia and leukopenia. Therefore, we studied the efficacy of ultra-low dose, short-duration VGCV (450 mg every other day for 3 months) in preventing CMV infection in ABO-incompatible (ABOiKT) and deceased donor kidney transplant (DDKT) recipients.MethodsWe retrospectively reviewed the medical records of all kidney transplant patients > 18 years old treated at Bong Seng Memorial Hospital from June 2009 to July 2016 who received ultra-low-dose VGCV prophylaxis (450 mg every other day for 3 months). The review included 74 CMV seropositive donor/seropositive recipient (D+/R+) ABOiKT and 78 CMV D+/R+DDKT recipients. The primary outcome was occurrence of CMV infection. Secondary outcomes were graft and patient survival and hematologic side effects.ResultsMean prophylaxis and follow-up were 3 and 98 months, respectively. CMV disease occurrence was significantly higher in DDKT than in ABOiKT (12 cases, 8.1%, vs 1 case, .7%, P < .01). There were no significant differences in patient survival rate, graft survival rate, or hematologic side effects between the groups.ConclusionUltra-low-dose VGCV prophylaxis to prevent CMV infection is effective in ABOiKT, but other treatment protocols are needed for DDKT patients.     

Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r‐ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end‐point was the incidence of first CMV infection/disease in the intention‐to‐treat population at 12 months. Patients treated with r‐ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037–0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13–0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound‐healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced‐dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate ( ClinicalTrials.gov NCT01354301).     

Cytomegalovirus prevention strategies and the risk of BK polyomavirus viremia and nephropathy

Polyomavirus BK (BKV) is the cause of polyomavirus‐associated nephropathy resulting in premature graft loss. There are limited data regarding the role of cytomegalovirus (CMV) infection and its prevention in developing BKV viremia and PVAN. In a prospective study, we analyzed 207 consecutive renal transplant recipients previously enrolled in 2 randomized trials evaluating different CMV prevention regimens with routine screening for BKV and CMV. Of these, 59 received valganciclovir and 100 valacyclovir prophylaxis; 48 patients were managed by preemptive therapy. At 3 years, the incidence of BKV viremia and PVAN was 28% and 5%, respectively. CMV DNAemia developed in 55% and CMV disease in 6%. Both BKV viremia (42% vs 23% vs 21%, P = .006) and PVAN (12% vs 2% vs 2%, P = .011) were increased in patients treated with valganciclovir prophylaxis compared to valacyclovir and preemptive therapy. Using multivariate Cox proportional hazard regression, valganciclovir prophylaxis was independent predictor of BKV viremia (hazard ratio [HR] = 2.38, P = .002) and PVAN (HR = 4.73, P = .026). In contrast, the risk of subsequent BKV viremia was lower in patients with antecedent CMV DNAemia (HR = 0.50, P = .018). These data suggest valganciclovir prophylaxis may be associated with increased risk of BKV viremia and PVAN. CMV DNAemia did not represent a risk for BKV.     

The risk of cytomegalovirus infection after treatment of acute rejection in renal transplant recipients

The risk of cytomegalovirus infection (CMV) after rejection treatment is poorly understood. To investigate this, we conducted a case/control (1:2) analysis of adult renal transplant recipients between January 1, 2005 and December 31, 2015, via incidence density sampling and survival analysis. Our objective was to evaluate the association of prior acute rejection with subsequent CMV, including epidemiology and outcomes. There were 2481 eligible renal transplants within the study period and 251 distinct CMV infections. Despite the use of antiviral prophylaxis rejection was a significant risk factor for CMV on unadjusted (HR 1.73 [1.34, 2.24] P < 0.05) and adjusted analysis (HR 1.46 [1.06, 2.04] P < 0.05). When matching cases to controls patients with CMV had significantly more rejection prior to CMV diagnosis (26.7% vs 14.2%, P < 0.01). CMV was associated with a twofold increased risk of prior rejection on unadjusted (OR 1.94, 95%CI: 1.28‐2.96, P < 0.01) and adjusted analysis (OR 2.16, 95% CI: 1.31‐3.58, P < 0.01). Patients with rejection preceding CMV had significantly increased graft loss (HR 2.89, 95% CI: 1.65‐5.09, P < 0.01) and mortality (HR 1.82, 95% CI: 1.12‐4.24, P = 0.03) as compared to those CMV cases without rejection. In conclusion, rejection is a risk factor for CMV infection that appears to persist for 1 year. Preceding rejection events increased risk of graft loss and mortality in CMV patients. Given this, prolonged surveillance monitoring for CMV after rejection may be warranted. Studies are needed investigating optimal monitoring strategies.     

Surgical Site and Early Urinary Tract Infections in 1000 Kidney Transplants With Antimicrobial Perioperative Prophylaxis

Surgical site infections (SSIs) and early urinary tract infections (UTIs) are well recognized postoperative kidney transplant complications. These complications seldom lead to graft loss, although they may result in significant morbidity with prolonged hospitalization. Thus, perioperative antibiotic prophylaxis (PAP) has traditionally been used in this setting. Between April 1988 and December 2012, we identified 1000 kidney transplant recipients (33 from living donors) who underwent prophylaxis with ceftriaxone before the surgical procedure. A retrospective analysis was conducted to evaluate both the incidence rate and outcome of SSIs and UTIs. Recipients who developed SSIs were also assessed to identify risk factors and potential correlations with different immunosuppressive regimens. A total of 20 SSIs (2%) and 93 UTIs (9.3%) were observed. The most significant risk factor for SSIs was urine leak (15.38%; odds ratio [OR], 12.3; P < .0001) followed by sirolimus-based maintenance immunosuppression therapy (5%; OR, 2.97; P = .04) and induction therapy with either antithymocyte globulin or basiliximab (3.18%; OR, 3.45; P = .01). Sex was identified as the only risk factor for UTI (female vs male, 17.1% vs 4.6%; P < .0001). We believe universal ceftriaxone-based prophylaxis is useful for preventing SSIs and UTIs, considering its effectiveness and safety profile.     

Cause of End-Stage Renal Disease Is Not a Risk Factor for Cytomegalovirus Infection After Kidney Transplant

BackgroundCytomegalovirus infection (CMV) after kidney transplantation leads to increased morbidity and mortality. Whether the cause of end-stage renal disease (ESRD) influences the risk of CMV infection post-transplant is not known.MethodsWe analyzed data from 2741 adult kidney transplant recipients from January 1993 through December 2014. The causes of ESRD included diabetes mellitus (n = 947), hypertension (n = 442), polycystic kidney disease (n = 549), and glomerulonephritis (GN) (n = 803). The primary outcome was incidence of CMV infection, defined as the first episode of detectable CMV DNA in the blood following transplant.ResultsThree hundred and thirty patients developed a CMV infection over a median follow-up of 4.5 years. Patients with diabetes mellitus (DM) as the cause of ESRD had a higher incidence of CMV infection post-transplant compared to patients with GN (2.37 vs 1.58/100 person-years, P < .005) whereas hypertension (HTN) and autosomal dominant polycystic kidney disease (PKD) were similar (2.17 and 2.07/100 person-years). DM was associated with a 35% higher risk of CMV infection compared to GN in unadjusted analyses [hazard ratio=1.35 [95% confidence interval 1.02–1.78], P = .04). However, after adjustment for age, the risk of CMV infection was similar in all groups (DM: age-adjusted hazard ratio 1.02 [0.78–1.39]; HTN: 0.96 (0.67–1.36); PKD: 1.08 [0.78–1.48]; compared to GN). The risk of CMV infection increased with age (adjusted hazard ratio=1.32 [1.18–1.47] for every decade of life, P < .001).ConclusionsOur study demonstrates that the cause of ESRD is not a significant risk factor for CMV infection in kidney transplant recipients once adjusted for age. Future studies are needed to identify risk factors for CMV infection to define patient-centered monitoring and prevention.     

Impact of Prophylaxis vs Pre-emptive Approach for Cytomegalovirus Infection in Kidney Transplant Recipients

Cytomegalovirus (CMV) is the most common viral infection during the post-transplant period, and it is one of the major causes of morbidity and mortality in kidney transplantation. In this study, the incidence and impact of pre-emptive and prophylactic approaches and long-term effects on graft and patient survival of CMV infection were investigated. Among 493 adult kidney transplant recipients, pretransplant CMV IgG-negative patients and patients with a follow-up shorter than a month were excluded. The patients were divided into 2 groups: pre-emptive group (n = 187, regular screening and acyclovir 400 mg twice daily for 6 months), and prophylaxis group (n = 275, valganciclovir 450 mg/d for 3 months). The pre-emptive group was screened for CMV with either pp65 antigenemia or CMV DNA. There were 462 patients, and mean follow-up was 37.7 months. There were more CMV infections in the pre-emptive group than in the prophylaxis group (n = 56, 30.1% vs n = 12, 4.4%, respectively; P < .001). Late CMV infections were significantly more frequent in the prophylaxis group (10 of 12, 83.3%) than in the pre-emptive group (8 of 56, 14.3%, P < .001). In multivariate analysis, valganciclovir prophylaxis was associated with a lower CMV infection (relative risk [RR]: 0.18, 95% confidence interval [CI] 0.08 to 0.39, P < .001). Delayed graft function was the only independent risk factor for graft loss during the follow-up on multivariate Cox regression analysis (RR: 2.66, 95% GA 1.17 to 6.04, P = .02). Valganciclovir prophylaxis was more protective against CMV infection than the pre-emptive approach. Neither prophylaxis/pre-emptive approaches nor CMV infection had negative effect on graft and patient survival.     

Association of sociocultural factors with initiation of the kidney transplant evaluation process

Although research shows that minorities exhibit higher levels of medical mistrust, perceived racism, and discrimination in healthcare settings, the degree to which these underlying sociocultural factors preclude end‐stage renal disease (ESRD) patients from initiating kidney transplant evaluation is unknown. We telephone surveyed 528 adult ESRD patients of black or white race referred for evaluation to a Georgia transplant center (N = 3) in 2014‐2016. We used multivariable logistic regression to examine associations between sociocultural factors and evaluation initiation, adjusting for demographic, clinical, and socioeconomic characteristics. Despite blacks (n = 407) reporting higher levels of medical mistrust (40.0% vs 26.4%, P < .01), perceived racism (55.5% vs 18.2%, P < .01), and experienced discrimination (29.0% vs 15.7%, P < .01) than whites (n = 121), blacks were only slightly less likely than whites to initiate evaluation (49.6% vs 57.9%, P = .11). However, after adjustment, medical mistrust (odds ratio [OR]: 0.59; 95% confidence interval [CI]: 0.39, 0.91), experienced discrimination (OR: 0.62, 95% CI: 0.41, 0.95), and perceived racism (OR: 0.61; 95% CI: 0.40, 0.92) were associated with lower evaluation initiation. Results suggest that sociocultural disparities exist in early kidney transplant access and occur despite the absence of a significant racial disparity in evaluation initiation. Interventions to reduce disparities in transplantation access should target underlying sociocultural factors, not just race.     

Cytomegalovirus transmission in mismatched solid organ transplant recipients: Are factors other than anti-viral prophylaxis at play?

Although antiviral prophylaxis has reduced cytomegalovirus (CMV) DNAemia and disease in seronegative solid organ transplant (SOT) recipients (R-) receiving seropositive donor organs (D+), its impact on CMV transmission is uncertain. Transmission, defined as CMV antigenemia/CMV DNAemia and/or seroconversion by year 2, and associated demographic risk factors were studied retrospectively in 428 D+/R- and 429 D-/R- patients receiving a SOT at our center. The cumulative transmission incidence was higher for lung (90.5%) and liver recipients (85.1%) than heart (72.7%), kidney (63.9%), and pancreas (56.2%) recipients (p < .001) and was significantly lower in living (50.1%) versus deceased donor (77.4%, p < .001) kidney recipients despite identical antiviral prophylaxis. In multivariate analysis, only allograft type predicted transmission risk (HR [CI] lung 1.609 [1.159, 2.234] and liver 1.644 [1.209, 2.234] vs kidney). For 53 D+ donating to >1 R- with adequate follow-up, 43 transmitted to all, three transmitted to none, and seven transmitted inconsistently with lungs and livers always transmitting but donor-matched heart, kidney or kidney-pancreas allografts sometimes not. Kidney pairs transmitted concordantly. CMV transmission risk is allograft-specific and unchanged despite antiviral prophylaxis. Tracking transmission and defining donor factors associated with transmission escape may provide novel opportunities for more targeted CMV prevention and improve outcome analysis in antiviral and vaccine trials.     

Universal Valganciclovir Prophylaxis Significantly Reduces Episodes of First-Year Cytomegalovirus Disease and Biopsy-Proven Acute Rejection in Kidney Transplant Recipients

Background

Cytomegalovirus (CMV) remains the most critical viral pathogen after kidney transplantation (KTx). The universal prophylaxis, but not pre-emptive therapy, could avoid the wide range of indirect effects induced by CMV infection. This study aims to examine the effect of universal prophylaxis with oral valganciclovir for the first year of CMV disease after KTx.

Methods

The universal prophylaxis therapy was started in May 2008. Patients who received KTx between January 2006 and September 2010 were included in the study. Oral valganciclovir (Valcyte) was used for 3 months with dosage adjusted by eGFR. CMV disease was defined by typical CMV syndrome with positive viremia or tissue proven. The study end points are episode of CMV disease and first-year biopsy-proven acute rejection.

Results

In total, 68 KTx patients who received universal prophylaxis for 3 months (study group) and another 50 KTx recipients without universal prophylaxis (control group) were enrolled. The incidence of CMV disease was 8.0% (4 of 50) in the control group. The universal prophylaxis significantly reduced the first-year episodes of CMV disease to 0% (0 of 68). There were 8 episodes of biopsy-proven acute rejection (8 of 50, 16%) within 1 year after KTx in the control group, but only 2 episodes of biopsy-proven acute rejection (2 of 68, 2.9%) in the treatment group (P < .05).

Conclusions

Universal prophylaxis with oral valganciclovir for 3 months significantly reduced episodes of first-year CMV disease and biopsy-proven acute rejection in kidney transplant recipients.     

Evaluation of a Cytomegalovirus Prophylaxis Protocol in Cytomegalovirus-IgG Positive Renal Transplant Recipients (R+)

BackgroundThe aim of the study was to evaluate the efficacy of a unique cytomegalovirus- (CMV) prophylaxis protocol in terms of CMV infection and disease progression in CMV IgG positive kidney transplant recipients.MethodsAchievement of negative CMV load, using concurrent prophylactic intravenous ganciclovir therapy during induction immunosuppression, combined with a 6-month prophylactic course of acyclovir, would yield a reduced incidence of early CMV infection and disease. CMV DNA was tested for at discharge, at the third, and sixth post-op months, and at the occurrence of any event that could be associated with CMV infection. CMV DNA positive patients received ganciclovir treatment until the viral load became negative. CMV replication was monitored using a quantitative PCR method capable of detecting as few as 42.5 copies/mL. All patients were given a maintenance dose of acyclovir.ResultThe file data of 267 patients who had undergone kidney transplantation between 2007 to 2016 were examined. Thirty-four patients were excluded from the study for various reasons, unrelated to the protocol. Of the remaining 233 patients, 42 (18%) had CMV DNA infection. Three patients had CMV disease (1.3%), 1of whom died of pneumonia. Diabetes mellitus (DM) was a risk factor for CMV DNA positivity (P < .004).ConclusionThe incidence of CMV infection and disease is low in renal transplant recipients whose CMV viral load is eliminated after concurrent ganciclovir administration with induction immunosuppression.     

Clinical and economic burden of infections in hospitalized solid organ transplant recipients compared with the general population in Canada – a retrospective cohort study

Infections continue to be a major cause of post‐transplant morbidity and mortality, requiring increased health services utilization. Estimates on the magnitude of this impact are relatively unknown. Using national administrative databases, we compared mortality, acute care health services utilization, and costs in solid organ transplant (SOT) recipients to nontransplant patients using a retrospective cohort of hospitalizations in Canada (excluding Manitoba/Quebec) between April‐2009 and March‐2014, with a diagnosis of pneumonia, urinary tract infection (UTI), or sepsis. Costs were analyzed using multivariable linear regression. We examined 816 324 admissions in total: 408 352 pneumonia; 328 066 UTI's; and 128 275 sepsis. Unadjusted mean costs were greater in SOT compared to non‐SOT patients with pneumonia [(C$14 923 ± C$29 147) vs. (C$11 274 ± C$18 284)] and sepsis [(C$23 434 ± C$39 685) vs. (C$20 849 ± C$36 257)]. Mortality (7.6% vs. 12.5%; P < 0.001), long‐term care transfer (5.3% vs. 16.5%; P < 0.001), and mean length of stay (11.0 ± 17.7 days vs. 13.1 ± 24.9 days; P < 0.001) were lower in SOT. More SOT patients could be discharged home (63.2% vs. 44.3%; P < 0.001), but required more specialized care (23.5% vs. 16.1%; P < 0.001). Adjusting for age and comorbidities, hospitalization costs for SOT patients were 10% (95% CI: 8–12%) lower compared to non‐SOT patients. Increased absolute hospitalization costs for these infections are tempered by lower adjusted costs and favorable clinical outcomes.     

Viral load,CMV‐specific T‐cell immune response and cytomegalovirus disease in solid organ transplant recipients at higher risk for cytomegalovirus infection during preemptive therapy

Despite advances in prevention, cytomegalovirus (CMV) recurrence is an important challenge in high‐risk organ recipients. The present study prospectively evaluates the impact of CMV‐specific T‐cell immune response and secondary prophylaxis on the risk of recurrence in a cohort of CMV high‐risk organ recipients and whether it is possible to determine a safe standardized viral load value below which CMV disease is unlikely. Thirty‐nine recipients were included. Thirty‐six had primary infections, and 88.9% recurred. Rate and duration of recurrent CMV infection was similar in patients with and without secondary prophylaxis: 57.9% vs. 53.6%, P = 0.770 and 16 vs. 15 days, P = 0.786, respectively. The only factor independently associated with no episodes of CMV recurrence was the acquisition of CMV‐specific T‐cell immune response (OR: 0.151, 95% CI: 0.028–0.815; P = 0.028). Cytomegalovirus diseases (N = 5) occurred in patients with CMV viral load above 1500 IU/ml who did not follow the planned monitorization schedule. Our observations suggest that episodes of recurrent CMV infection are common after preemptive therapy despite secondary prophylaxis and that CMV‐specific T‐cell immune response is associated with a decreased risk of recurrent infections. Preemptive therapy may be safe in patients at high risk for CMV infection with strict close monitoring of the CMV viral load.