Long-term results of CMV hyperimmune globulin prophylaxis in 377 heart transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) has emerged as the most important pathogen to affect the post-operative course after heart transplantation. We performed a retrospective analysis to evaluate the efficiency of CMV hyperimmune globulin (CMVIG) prophylaxis in preventing CMV disease in aggressively immunosuppressed patients after heart transplantation. METHODS: We studied 377 heart transplant recipients who received quadruple-immunosuppressive therapy and CMVIG as sole CMV prophylaxis. The study population was categorized into 4 groups according to donor and recipient CMV serology at the time of transplantation (D+/R+, D+/R-, D-/R+, D-/R-) and was monitored for CMV immediate early antigen in peripheral blood cells, in urine sediments, and in throat washings; for the presence of serum CMV immunoglobulin M and CMV immunoglobulin G; and for clinical evidence of CMV-related symptoms. In addition, we compared the incidence of cardiac allograft vasculopathy and infection among the groups. RESULTS: During the first 5 years after transplantation, CMV disease developed in 79 patients (20.96%). Comparison among the groups showed significantly increased risk for CMV disease in allograft recipients of organs from seropositive donors (D+, 27.31%; D-, 11.33%; p = 0.0003). We observed 6 CMV-associated deaths, all in CMV-antibody-negative recipients. Additionally CMV-positive recipients had a greater incidence of cardiac allograft vasculopathy (p = 0.048), and a greater overall infection rate (p = 0.0034). CONCLUSIONS: Cytomegalovirus hyperimmune globulin administration prevents CMV disease and infection in aggressively immunosuppressed heart transplant recipients. Because fatal CMV disease in CMV-negative recipients of organs from seropositive donors could not be prevented with CMVIG alone, we recommend the additional use of prophylactic ganciclovir in this CMV-mismatched population.     

Cytomegalovirus infection in simultaneous pancreas-kidney transplantation

INTRODUCTION: In this open-label multicenter study, 205 simultaneous pancreas-kidney (SPK) transplant recipients between 1998 and 2000 were randomly assigned to tacrolimus or cyclosporine-microemulsion (ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil and short-term corticosteroids. We report the 3-year data related to the occurrence, severity and effect of cytomegalovirus (CMV) infections. The type of CMV prophylaxis and treatment was at the discretion of the investigator. RESULTS: The overall incidence of CMV infection was 34% with no difference in incidence between the tacrolimus and cyclosporine-ME treatment arms. Statistically significant fewer CMV infections occurred among patients who received ganciclovir (22%) than those who did not receive prophylaxis (42%; P = .0075) or were treated with acyclovir (43%; P = .0066). The CMV infection rate according to donor recipient CMV serological status was: D-/R- group 11%, which was lower than the D-/R+ group at 40% (P = .0035), the D+/R+ group at 37% (P = .0024), or the D+/R- group at 52% (P = .00001). Among the last three groups, the infection rate was lower in patients on ganciclovir than those with no prophylaxis or on acyclovir (22% vs 64%; P = .00001). The incidence of acute rejection episodes was higher among patients without ganciclovir prophylaxis. No difference was observed in actuarial patient, kidney, or pancreas survival rates between patients with versus without infection. CONCLUSIONS: Ganciclovir prophylaxis effectively prevented CMV infection in SPK transplant recipients, especially in higher risk groups. An effect of CMV prophylaxis on the incidence of rejection is possible.     

Sirolimus exposure during the early post-transplant period reduces the risk of CMV infection relative to tacrolimus in renal allograft recipients

INTRODUCTION: There are limited data regarding the role of individual maintenance immunosuppressive agents in the development of cytomegalovirus (CMV) infection. We examined the association between exposure to sirolimus (SRL) and risk of CMV infection after kidney transplantation when compared with tacrolimus (TCL). METHODS: This is a retrospective observational study of adult renal allograft recipients transplanted between 2001 and 2005 at our center. Patients received anti-lymphocyte antibody induction, and mycophenolate mofetil with either SRL or TCL +/- prednisone. D+/R- patients received valganciclovir 900 mg/d and CMV + patients 450 mg/d for three months. CMV infection was diagnosed with pp65 antigenemia testing prompted by clinical suspicion. RESULTS: A total of 14 Cases with CMV infection and 129 Controls were identified for primary analysis, and 11 D+/R- Cases and 19 D+/R- Controls for secondary analysis. The groups were comparable in both analyses, except for D+/R- serostatus in the primary analysis. All 14 Cases were on TCL for at least three months prior to diagnosis of CMV infection. In the primary analysis, zero Cases, but 30.2% and 34.9% of Controls (p = 0.009 and 0.004), and in secondary analysis, zero Cases, but 31.6% and 42.1% of Controls (p = 0.046 and 0.013), were on SRL at one and three months, respectively. In the primary analysis, zero Cases vs. 45 Controls (p = 0.004), and in secondary analysis, zero Cases vs. eight Controls (p = 0.013), were on SRL for at least three months early post-transplantation. CONCLUSION: These findings suggest that SRL as a component of a multidrug immunosuppressive regimen decreases the risk of CMV infection after kidney transplantation when compared with TCL.     

Risk factors and impact of cytomegalovirus disease in simultaneous pancreas-kidney transplantation.

BACKGROUND: The relevance of cytomegalovirus (CMV) in simultaneous pancreas kidney (SPK) transplant recipients in the modern era of immunosuppression and antiviral therapeutics is largely unquantified. We sought to determine the risk factors of CMV disease and its impact on SPK transplant outcomes in recipients all receiving a consistent regime of maintenance immunosuppression and CMV prophylaxis. METHODS: This is a retrospective, single center study of 100 consecutive SPK transplant recipients. All received maintenance immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. CMV prophylaxis consisted of a short course of parenteral gancyclovir followed by oral gancyclovir. Recipients at high-risk (D+/R-) for CMV also received CMV hyperimmune globulin. Multivariate analysis of risk factors for CMV disease and risk factors for adverse outcomes in SPK transplantation were determined. The effect of duration of prophylaxis on timing and severity of CMV disease in high-risk (D+/R-) SPK transplant recipients was also evaluated. RESULTS: The actual 1-year rate of CMV disease was 17.0% (12.0% noninvasive, 5.0% tissue invasive); and according to donor and recipient CMV serological status was: D-/R+: 0%; D-/R-: 2.8%; D+/R+: 25.6%; and D+/R-: 40.6%. Multivariate analysis showed transplantation of organs from a donor with positive CMV serology to be predictive of CMV disease with a relative risk of 63.37 (P=0.0052). In the high-risk (D+/R-) subgroup, the duration of prophylactic therapy delayed onset of CMV disease, but had minimal effect on severity. Invasive CMV disease was an independent predictor of mortality but did not decrease kidney or pancreas allograft survival. CONCLUSIONS: Outcomes of SPK transplantation have improved in the current era of modern immunosuppression, yet CMV remains an important pathogen. The serological status of the organ donor and the duration of CMV prophylaxis are predictive of who and when CMV disease may occur. Nevertheless, new strategies that reduce risk and severity of CMV disease are still needed.     

Effect of donor-recipient cytomegalovirus serologic status on outcomes in simultaneous kidney-pancreas transplant recipients

Diabetic patients undergoing simultaneous kidney-pancreas transplantation (SKPT) may be at high risk for developing cytomegalovirus (CMV) infection. To study this issue, we analyzed 297 SKPT patients enrolled into a multicenter trial of two daclizumab dosing strategies versus no antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids. Complete donor (D) and recipient (R) CMV serology values were available in 294 cases and were distributed as follows: 86 (29%) D+/R-. Eighty-six (29%) D+R+; 45 (16%) D-/R+; 77 (26%) D-/R-; CMV antiviral prophylaxis was center specific, but 98% of patients received either ganciclovir or acyclovir. No differences existed in demographic or transplant characteristics or immunosuppressive regimens among the four groups except that more African-American SKPT recipients were CMV positive at transplant (P <.001). At 6 months, no differences were seen in patient and graft survival rates (GSR) and the incidence of acute rejection (AR) among the groups. However, the CMV D+/R- group had a significantly higher incidence of CMV infection/disease (14%) than the other groups collectively (4%, P <.05). Most cases of CMV infection/disease occurred greater than 3 months posttransplant when prophylaxis was discontinued. In the D-/R- group, the pancreas GSR was higher (94% vs 86% in the remaining three groups) and the incidence of AR was lower (16% vs 25% in the remaining three groups, both P =.09). Primary CMV exposure remains a major risk factor for CMV infection/disease, but does not have an adverse impact on short-term outcomes. Conversely, protective CMV seronegative matching may have a beneficial effect on outcomes.     

Predictive factors for cytomegalovirus infection after orthotopic liver transplantation using an ultrasensitive polymerase chain reaction assay

The predictive factors for cytomegalovirus (CMV) infection in de novo liver transplant patients were determined at 3 months posttransplantation. We included all consecutive patients except those who died or who had lost their graft within 1 month posttransplant. We recorded both donor (D) and recipient (R) data. Immunosuppression utilized tacrolimus, steroids, with or without mycophenolate mofetil, and/or induction therapy with anti-CD25 monoclonal antibodies. CMV prophylaxis was administered only to those at high risk of CMV infection, namely, D+/R- patients. These cases received intravenous ganciclovir at 500 mg/d for the first 2 weeks followed by oral ganciclovir at 500 mg for the following 3 months. The median time to CMV infection was 1 month. The significant predictive factors for CMV infection were D/R CMV status, (P = .002): D+/R+ versus other patients (P = .01), D-/R- versus other patients (P = .002), D+ versus D- (P = .009). In addition infection was associated with the original liver disease (hepatitis C virus infection or alcohol-related cirrhosis; P = .03), R+ vs. R- (P = .03), donor age (<45 or >45 years; P = .01), lymphocyte count at M2 (< or >1300/mm(3); P = .02), hemoglobin levels at 1 and 3 months, and platelet and white blood cell counts at day 7. The independent predictive factors were recipient CMV sero-status (R+ vs R-; odds ratio = 10.2), donor age >45 years (odds ratio = 11.4) and lymphocyte count at M2 <1300/mm(3) (odds ratio = 7.33). This study showed that the major factors associated with CMV infection were recipient CMV status, donor age, and lymphocyte count.     

Who among cytomegalovirus-seropositive liver transplant recipients is at risk for cytomegalovirus infection?

A vast majority of the transplant recipients are cytomegalovirus (CMV)-seropositive (R+). We sought to assess variables predictive of CMV infection, specifically in R+ liver transplant recipients. Study patients comprised 182 consecutive liver transplant recipients who survived at least 14 days after transplantation. Surveillance testing was used to detect CMV infection. Pre-emptive therapy was employed for the prevention of CMV disease, however, no antiviral prophylaxis was used for CMV infection. CMV infection developed in 32.5% (38 of 117) of R+ patients, 84.6% (33 of 39) of R-/D+, and 3.8% (1 of 26) of R-/D- patients. In R+ patients, Hispanic race (21.6% vs. 7.8%, P = 0.06), donor CMV seropositivity (73.7% vs. 45.6%, P = 0.005), and hepatocellular carcinoma (23.7% vs. 6.3%, P = 0.05) correlated with a higher risk of CMV infection. In a multivariate model, Hispanic race (OR: 3.5, 95% CI: 1.03-11.6, P = 0.045), donor CMV serostatus (OR: 4.0, 95% CI: 1.6-10.2, P = 0.003) and hepatocellular carcinoma (OR: 5.8, 95% CI: 1.6-20.5, P = 0.006) were all significant independent predictors of CMV infection. The aforementioned variables did not portend a higher risk of CMV infection in R-/D+ patients; donor CMV seropositivity overwhelmed all other risk factors in R- patients (P < 0.00001). In conclusion, CMV-seropositive liver transplant recipients at risk for CMV infection can be identified based on readily assessable variables. Preventive strategies may be selectively targeted toward these patients.     

Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection

BACKGROUND: Anticytomegalovirus (CMV) prophylaxis prevents the acute disease but its impact on subclinical infection and allograft outcome is unknown. We sought to determine whether CMV prophylaxis administered for three months after heart transplant would improve patient outcomes. METHODS: This prospective cohort study of 66 heart transplant recipients compared aggressive CMV prophylaxis (n = 21, CMV hyperimmune globulin [CMVIG] plus four weeks of intravenous ganciclovir followed by two months of valganciclovir); with standard prophylaxis (n = 45, intravenous ganciclovir for four weeks). Prophylaxis was based on pretransplant donor (D) and recipient (R) CMV serology: R-/D+ received aggressive prophylaxis; R+ received standard prophylaxis. Outcome measures were: CMV infection assessed by DNA-polymerase chain reaction on peripheral blood polymorphonuclear leukocytes, acute rejection, and cardiac allograft vascular disease (CAV) assessed by intravascular ultrasound. All patients completed one year of follow-up. RESULTS.: CMV infection was subclinical in all but four patients (two in each group). Aggressively treated patients had a lower incidence of CMV infection (73 +/- 10% vs. 94 +/- 4%; P = 0.038), and an independent reduced relative risk for acute rejection graded > or =3A (relative risk [95% CI] = 0.55 [0.26-0.96]; P = 0.03), as compared with the standard prophylaxis group. Aggressively prophylaxed patients also showed a slower progression of CAV, in terms of coronary artery lumen loss (lumen volume change=-21 +/- 13% vs. -10+/-14%; P = 0.05); and vessel shrinkage (vessel volume change = -15 +/- 11% vs. -3 +/- 18%; P = 0.03). CONCLUSIONS: Prolonged (val)ganciclovir plus CMVIG reduces viral levels, acute rejection, and allograft vascular disease, suggesting a role for chronic subclinical infection in the pathophysiology of the most common diseases affecting heart transplant recipients.     

A Trial of Valganciclovir Prophylaxis for Cytomegalovirus Prevention in Lung Transplant Recipients

Cytomegalovirus (CMV) infection is common after lung transplantation. We performed a prospective trial of valganciclovir prophylaxis in lung recipients with outcomes compared to matched historical controls. The valganciclovir group (n = 40) (including D+/R- and R+ patients) was prospectively enrolled, and received oral valganciclovir 900 mg once daily for 12 weeks. Historical controls (n = 40) received 12 weeks of daily intravenous ganciclovir if D+/R- or 12 weeks of oral ganciclovir if R+. CMV viral load testing was done at two-week intervals until 6 months posttransplant. Baseline demographics and immunosuppression were comparable in the two groups. The incidence of CMV viremia was 16/40 (40.0%) in the valganciclovir arm versus 18/40 (45%) in the ganciclovir arm (p = NS). The incidence of symptomatic CMV disease was 8/40 (20%) versus 7/40 (17.5%), respectively (p = NS). In both groups viremia, while on prophylaxis, was uncommon (valganciclovir: 0/40 and ganciclovir: 2/40). Peak viral load and time to viremia were similar in the two arms. High rates of viremia and symptomatic disease occurred in the D+/R- patients after discontinuation of prophylaxis. Genotypic CMV sequence analysis demonstrated low rates of ganciclovir resistance in both groups. Valganciclovir prophylaxis had similar efficacy to either intravenous ganciclovir (D+/R- patients), or oral ganciclovir (R+ patients) in lung recipients.     

Prophylactic Versus Preemptive Oral Valganciclovir for the Management of Cytomegalovirus Infection in Adult Renal Transplant Recipients

Prophylaxis reduces cytomegalovirus (CMV) disease, but is associated with increased costs and risks for side effects, viral resistance and late onset CMV disease. Preemptive therapy avoids drug costs but requires frequent monitoring and may not prevent complications of asymptomatic CMV replication. Kidney transplant recipients at risk for CMV (D+/R-, D+/R+, D-/R+) were randomized to prophylaxis (valganciclovir 900 mg q.d. for 100 days, n=49) or preemptive therapy (900 mg b.i.d. for 21 days, n=49) for CMV DNAemia (CMV DNA level>2000 copies/mL in >or=1 whole blood specimens by quantitative PCR) assessed weekly for 16 weeks and at 5, 6, 9 and 12 months. More patients in the preemptive group, 29 (59%) than in the prophylaxis group, 14 (29%) developed CMV DNAemia, p=0.004. Late onset of CMV DNAemia (>100 days after transplant) occurred in 11 (24%) randomized to prophylaxis, and none randomized to preemptive therapy. Symptomatic infection occurred in five patients, four (3 D+/R- and 1 D+/R+) in the prophylactic group and one (D+/R-) in the preemptive group. Peak CMV levels were highest in the D+/R- patients. Both strategies were effective in preventing symptomatic CMV. Overall costs were similar and insensitive to wide fluctuations in costs of either monitoring or drug.     

24-week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course

BACKGROUND: Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among kidney recipients. The highest risk of CMV infection occurs in CMV-naive recipients of kidneys from seropositive donors (D+/R-). Optimal CMV prophylaxis is not established. This prospective cohort study compared the safety and efficacy of prophylaxis with 12 versus 24 weeks of oral ganciclovir. METHODS: We prospectively administered 24 weeks ganciclovir to 31 D+/R- recipients. The control group comprised 39 patients transplanted in the immediately preceding era who received a 12-week course of prophylaxis. All patients received cytolytic therapy within the first month, as well as a tacrolimus-based maintenance regimen. A logistic regression model was fit to examine the relationship between 24 weeks ganciclovir prophylaxis and the odds of developing CMV infection by one year. RESULTS: Groups were matched, though the 12-week cohort had more delayed graft function than their 24-week counterparts (45% vs. 29%, P=0.04). CMV infection occurred in 31% and 7% patients in the 12-week and 24-week groups, respectively (P相似文献   

Gancyclovir prophylaxis in high risk patients

The aim of this study was to compare the incidence of cytomegalovirus (CMV) disease between seronegative recipients who received a CMV seropositive kidney (D+/R-) and seropositive recipients who received a CMV seropositive kidney (D+/R+). Among 42 patients included in the study, 26 were D+/R-, and the other 16 were D+/R+. Immunosuppression was based on cyclosporine (n = 12), tacrolimus (n = 28), or other agents (n = 2). Twenty-four seronegative patients were treated with gancyclovir for 3 months. The 16 D+/R+ patients did not receive CMV prophylaxis. Two D+/R- patients did not receive gancyclovir prophylaxis because of various health problems just after the surgery. Over the year post-renal transplant, there were 10 (23.8%) episodes of CMV disease. The two D+/R- patients who were not treated with gancyclovir developed CMV disease. The incidence of disease was higher in patients who were given cyclosporine (41.7% vs 17.9%). In conclusion, sero negative patients who received a kidney from a seropositive donor had greater risk of developing CMV disease. Despite gancyclovir treatment, the incidence was higher than in D+/R+ cases without treatment.     

Delayed-onset primary cytomegalovirus disease after liver transplantation.

Clinical practice guidelines recommend antiviral prophylaxis to cytomegalovirus (CMV) donor-positive/recipient-negative (D+/R-) liver transplant recipients. We assessed the outcome of this strategy by determining the incidence, clinical features, and risk factors of CMV disease among CMV D+/R- liver transplant recipients who received antiviral prophylaxis. Sixty-seven CMV D+/R- liver transplant recipients (mean age+/-standard deviation: 49.5+/-11.4 years; 75% male) received oral ganciclovir [n=9 (13%)] or valganciclovir [n=58 (87%)] prophylaxis for a median duration of 92 days (interquartile range: 91-100). No breakthrough CMV disease was observed during antiviral prophylaxis. However, primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylaxis was stopped. The incidence of delayed-onset primary CMV disease was similar between those who received oral ganciclovir and valganciclovir. Nine (47%) patients had CMV syndrome, 8 (42%) had gastrointestinal CMV disease, and 2 (11%) had CMV hepatitis. Female patients (P=0.01) and younger age at transplant (P=0.03) were associated with an increased risk, whereas diabetes mellitus (P<0.001) was significantly associated with a lower risk of delayed-onset primary CMV disease. Allograft loss or mortality occurred in 8 (12%) patients during the median follow-up period of 3.31 (range: 0.8-5.9) years. No significant association was observed between CMV disease and patient and allograft survival. In conclusion, CMV disease remains a common complication in CMV D+/R- liver transplant patients during the contemporary era of antiviral prophylaxis. Female patients and younger patients are at increased risk of delayed-onset primary CMV disease.     

A prospective study of the natural course of cytomegalovirus infection and disease in renal allograft recipients

BACKGROUND: Cytomegalovirus (CMV) infection is the single most frequent infectious complication in renal transplant recipients. Because no CMV-prophylaxis is given and ganciclovir is used only as deferred therapy for CMV disease at our center, we have been able to study the natural course of CMV infections. The aim was to assess risk factors for CMV infection and disease and thus identify subgroups of patients likely to benefit from CMV prophylaxis or preemptive therapy. METHODS: Between October 1994 and July 1997, 477 consecutive renal transplant recipients (397 first transplants and 80 retransplants) were included in the study. The patients were followed prospectively for 3 months with serial measurements of CMV pp65 antigen for monitoring activity of CMV infections. RESULTS: The incidence of CMV infections in first transplants was 68% in D+R- and D+/-R+ serostatus groups, whereas the incidence of CMV disease was higher in D+R- (56%) than in D+/-R+ (20%, P<0.001). No difference in severity of CMV disease in D+R- and D+/-R+ was seen except for an increased incidence of hepatitis in primary infections. One of 14 deaths could be associated with CMV disease in a seropositive recipient. Cox regression analysis showed that rejection (RR 2.5, P<0.01) and serostatus group D+R- (RR 3.9, P<0.001) were significant risk factors for development of CMV disease. The maximum CMV pp65 antigen count had significant correlation to disease only in CMV seropositive recipients, P<0.001. Conclusion. Renal transplant recipients can safely be given deferred ganciclovir therapy for CMV disease if they are intensively monitored for CMV infection. Patients with primary CMV infection (D+R-), CMV infected patients undergoing anti-rejection therapy and R+ patients with high CMV pp65 counts seem to have a particular potential for benefit from preemptive anti-CMV-therapy.     

Incidence and outcomes of cytomegalovirus in pancreas transplantation with steroid‐free immunosuppression

Cytomegalovirus (CMV) is a common opportunistic infection encountered after pancreas transplantation. The records of 407 pancreas transplant recipients (226 simultaneous pancreas and kidney transplant (SPK), 101 pancreas transplant after kidney (PAK), and 97 pancreas transplants alone [PTA]) performed at a single center with at least 1‐yr follow‐up were reviewed. Immunosuppression included rabbit antithymocyte globulin induction, steroid withdrawal, and maintenance therapy of tacrolimus and sirolimus (± mycophenolate). In addition, PTA recipients received a single dose of rituximab. All recipients received valganciclovir prophylaxis. Donor (D)+/recipient (R)− recipients received 6 months of prophylaxis; all others received 3 months. The overall CMV infection rate was 12%. The cumulative incidences of CMV infection at 3, 6, 9, and 12 months after transplant were 0.25%, 3%, 7%, and 8%, respectively. CMV infection rates were 20.2% in the D+/R− group, 16.5% in the D+/R+ group, 5.0% in the D−/R+ group, and 2.8% in the D−/R− group. Infections were less common in SPK recipients. Most infections developed at least 3 months post‐transplant, and 24% demonstrated tissue‐invasive disease. Immunosuppression was NOT reduced in 72% of patients with infections. Ganciclovir‐resistant CMV occurred in four patients. No patients died or lost their allografts due to CMV‐related infection; one graft was lost due to chronic rejection associated with a reduction in immunosuppression. In many cases, CMV infections may be treated in pancreas transplant recipients without necessarily reducing immunosuppression.     

Cytomegalovirus prophylaxis with intravenous polyvalent immunoglobulin in high-risk renal transplant recipients

Cytomegalovirus (CMV) seronegative renal allograft recipients (R-), particularly those with a graft from a CMV-seropositive donor (D+), are at high risk for primary CMV infection. CMV resistance to antiviral oral therapy is an emerging problem in renal transplantation, prompting development of new prophylactic strategies. We retrospectively studied the 1-year posttransplantation incidence of CMV infection in high-risk renal transplant recipients, in whom polyvalent intravenous immunoglobulins (IVIg) were used as prophylaxis. Forty R- patients received immunoprophylaxis by polyvalent IVIg (0.25 g/kg weekly for 8 weeks, starting on the operative day). CMV serological tests remained negative in eight patients (20%). Eight patients (20%) had asymptomatic CMV infection while 24 (60%) developed CMV syndrome and were treated with gancyclovir (10 mg/kg/day intravenously for 3 weeks). None had CMV disease or opportunistic infection. Six patients (15%) had biopsy-proven acute rejection, which followed CMV syndrome in three cases. One-year renal allograft and patient survivals were 95% and 97.5%, respectively. Mean serum creatinine level was 124 +/- 33 micromol/L at 1 year. Clinical tolerance of IVIg was excellent, without any episode of acute renal failure. Polyvalent IVIg provides effective prophylaxis in renal transplant recipients at high risk for CMV infection and is associated with excellent 1-year allograft survival. Because of their immunomodulatory functions, IVIg may have a beneficial effect on the incidence of acute and chronic rejection and allograft survival. A randomized prospective study is required to evaluate long-term effects of CMV prophylaxis with polyvalent IVIg compared to antiviral agents in renal transplant recipients.     

Leukopenia in kidney transplant patients with the association of valganciclovir and mycophenolate mofetil

Cytomegalovirus (CMV) is the most common viral infection after transplantation. Valganciclovir (VGC) is established for prophylaxis and treatment of CMV infections, but leukopenia which appears in 10% to 13% (severe in 4.9%) is the principal side effect. We have recently noted an increased incidence of leukopenia and severe neutropenia among our renal transplant patients and thought to identify the associated factors. We conducted a retrospective analysis of all kidney transplantations performed between January 2005 and December 2006. All patients received mycophenolate mofetil (MMF), tacrolimus, and steroids. VGC was used for targeted prophylaxis and preemptive therapy of CMV infection, with doses adjusted to renal function. Of the 64 patients undergoing renal transplantation 13 (20.3%) developed leukopenia within 3 +/- 2 months after transplantation with severe neutropenia in 5 (7.8%). All patients were on MMF and VGC (VGC 605 +/- 296 mg/d). Leukopenia was significantly associated with simultaneous liver-kidney transplantation and with second kidney transplantations (P < .01). The incidence of leukopenia was higher among patients under VGC since day 1 of transplantation (P = .008) with maximal incidence observed among patients prescribed 900 mg/d as opposed to those on lower doses (P < .01). There was no increase in CMV infection among patients with a low dose of VGC. No patient developed clinical CMV disease. In conclusion, VGC prophylaxis was associated with an increased frequency of leukopenia on MMF-tacrolimus treated patients or regimens. Low-dose VGC for CMV prophylaxis appeared to be as effective as high-dose treatment, and associated less frequently with leukopenia and neutropenia.     

Multivariate analysis of the influence of donor and recipient cytomegalovirus sero-pairing on outcomes in simultaneous kidney-pancreas transplantation: the South-Eastern Organ Procurement Foundation Experience

The purpose of this study was to determine if donor (D) and recipient (R) CMV sero-pairing at the time of simultaneous kidney-pancreas transplantation (SKPT) subsequently influenced outcomes in a large cohort of patients with long-term follow-up. Between January 1, 1997 and December 31, 1999 complete data were available on 723 primary SKPTs performed at South-Eastern Organ Procurement Foundation member institutions. For purposes of this study, four groups were defined: D+/R-, n = 203 (28%); D+/R+, n = 206 (28%); D-/R+, n = 156 (22%); and D-/R-, n = 158 (22%). Patient and graft survival rates for the study groups were computed by Kaplan-Meier estimates and tests of equality of survival curves were performed utilizing both the log-rank and Wilcoxon test statistics. A multivariate analysis was performed using a Cox proportional hazards model and logistic regression. A total of 56% of Ds were CMV+ and 50% of Rs were CMV-. D serostatus was not, but R serostatus was, a significant independent risk factor for patient and kidney, but not pancreas, graft survival rates in the uncensored analysis. When examining the CMV D/R groups in both univariate and multivariate fashion, CMV sero-pairing was not an independent risk factor for death, graft loss, or rejection. However, when considering CMV sero-pairing as a binary variable (D-/R- versus all other D/R groups), 6-year patient, kidney, and pancreas graft survival rates were significantly higher in the D-/R- group (P < .05). In conclusion, CMV seronegativity is present in half of diabetic patients at the time of SKPT, and protective CMV seronegative matching confers a long-term survival advantage.     

Cytomegalovirus infection in kidney transplant recipients: Evolution of approach through three eras

Cytomegalovirus (CMV) prophylaxis is recommended for high-risk patients, while preemptive therapy is considered acceptable for patients at moderate/low risk. After reviewing kidney transplant patients from 1992-1995 and 1996-1999, we decided to replace prophylaxis by preemptive therapy. Herein we have presented our data. From 1996-1999 we treated 129 patients with ganciclovir prophylaxis for 3 months if D+/R- or if they received depleting antibodies. The incidence of CMV was 13.2% versus 3.7% in the 1992-1995 cohort. The increase was associated with mycophenolate mofetil (MMF) use (P = .002). Forty-two percent of the D+/R- developed an infection with 89% of bouts occurring in the first month after cessation of prophylaxis. From 2002-2004, we never gave prophylaxis to 129 patients except when they received thymoglobulin. High-risk D+/R- patients were monitored by polymerase chain reaction (PCR) CMV for 3 months. The incidence of CMV was 17.1% with 54% of the D+/R- developing CMV. CMV infection occurred mostly during the first trimester posttransplantation. Creatinine at 1 year posttransplantation was worse in the presence of CMV infection (154.3 mumol/L-1.75 mg % versus 130.2 mumol/L-1.47 mg %, P = .03). Time to cure CMV infection was longer when MMF was discontinued: 36.7 days versus 69.9 days (P = .026). Our results indicated that CMV incidence is increasing: 3.7% (1992-1995) --> 13.2% (1996-1999) -->17.1% (2002-2004) and that it impairs 1 year graft function. Recovery was faster among patients still receiving MMF compared with those discontinuing MMF. Although MMF inhibits synthesis of anti-CMV IgM, it increases the anti-herpes virus effect of ganciclovir and may protect against chronic allograft nephropathy. Based on our experience, we plan to reintroduce prophylaxis in high-risk patients and to continue MMF when treating CMV infection.     

Impact of valganciclovir prophylaxis on the development of severe late-cytomegalovirus disease in high-risk solid organ transplant recipients

BACKGROUND: With the introduction of prolonged prophylaxis with valganciclovir in cytomegalovirus (CMV) donor/recipient serodiscordance (D+/R-) patients, concerns about a high incidence of late and invasive CMV disease associated with mortality have emerged. We compared the characteristics of CMV disease in D+/R- patients receiving prolonged valganciclovir prophylaxis with R+ patients. METHODS: We prospectively followed all solid organ transplant recipients from January 2004 to December 2005. CMV prophylaxis with valganciclovir or ganciclovir was administered as follows: donor- recipient serodiscordance (D+/R-), 12 weeks; induction with antithymocyte globulin or acute rejection episodes requiring steroid pulses, 15 to 30 days; and CMV R+ double kidney-pancreas, 15 days. Transplant characteristics and the development of CMV disease variables were collected for all patients. We defined 2 groups according to the risk of CMV disease: CMV donor/recipient mismatch (D+/R-) and recipient CMV-positive (R+) groups. RESULTS: During the study period we performed 481 solid organ transplantations: 237 kidney, 34 kidney-pancreas, 157 liver, 38 heart, 13 liver-kidney, and 2 heart-kidney. Overall, 36 patients developed CMV disease (7.5%). CMV donor-recipient mismatch (D+/R-) was associated with a greater risk of CMV disease compared with CMV-positive recipients (16% vs 7%; P = .036). Prophylaxis against CMV was longer in the D+/R- group (mean days 73 vs 15; P < .001). CMV disease appeared later in the D+/R- than in R+ group (mean days 123 vs 59; P < .001). We observed a trend toward a lower incidence of tissue-invasive CMV disease among the D+/R- group compared with the R+ group without significance (14% vs 41%; P = .382). Three patients died in the first 30 days after the onset of CMV disease, all of them in the R+ group. CONCLUSIONS: In our setting, high-risk patients (D+/R-) receiving prolonged prophylaxis with valganciclovir developed later CMV disease, but this was neither more tissue-invasive nor more life-threatening than in the R+ group.