Kinetic of the CMV-specific T-cell immune response and CMV infection in CMV-seropositive kidney transplant recipients receiving rabbit anti-thymocyte globulin induction therapy: A pilot study.

BACKGROUND: Some studies have suggested that rATG treatment may be associated with an increased incidence of CMV infection and delayed CMV immune response. However, the evidences supporting this matter are scarce. This study aims to characterize the kinetic of the CMV-specific T-cell immune response before and after rATG induction therapy and the relationship with the development of CMV infection in CMV-seropositive kidney transplant recipients. METHODS: An observational prospective study of CMV-seropositive kidney transplant patients that received rATG induction therapy was performed. A pretransplant sample was obtained before the surgery to determine the CMV-specific immunity. CMV viral load (by PCR) and CMV-specific T-cell immune response (by flow cytometry) were determined during the follow-up at 0.5, 1, 2, 3, 6, and 12 months post transplantation. RESULTS: A total of 23 patients were included in the study. CMV prophylaxis was administrated for a media of 90 days after transplantation. At the end of follow-up, 18 (78.3%) patients had CMV-specific immunity with a median value of 0.31% CD8+ CD69+ INF-γ+ T cells at a median of 16 weeks post transplantation. Five patients never acquired CMV-specific immunity. No statistically significant association between CMV infection and CMV-specific T-cell immune response (P = .086) was observed. However, patients with positive pretransplant CMV-specific immunity developed earlier immunity and achieved higher levels of CD8+ CD69+ INF-γ+ T-cell post-transplantation than patients with negative pretransplant immunity. CONCLUSIONS: CMV-specific immune monitoring in addition to CMV-serology may be useful to stratify patient's risk of CMV infection before transplantation.

l-Carnitine ameliorates the oxidative stress response to angiotensin II by modulating NADPH oxidase through a reduction in protein kinase c activity and NF-κB translocation to the nucleus.

l-Carnitine (LC) exerts beneficial effects in arterial hypertension due, in part, to its antioxidant capacity. We investigated the signalling pathways involved in the effect of LC on angiotensin II (Ang II)-induced NADPH oxidase activation in NRK-52E cells. Ang II increased the generation of superoxide anion from NADPH oxidase, as well as the amount of hydrogen peroxide and nitrotyrosine. Co-incubation with LC managed to prevent these alterations and also reverted the changes in NADPH oxidase expression triggered by Ang II. Cell signalling studies evidenced that LC did not modify Ang II-induced phosphorylation of Akt, p38 MAPK or ERK1/2. On the other hand, a significant decrease in PKC activity, and inhibition of nuclear factor kappa B (NF-kB) translocation, were attributable to LC incubation. In conclusion, LC counteracts the pro-oxidative response to Ang II by modulating NADPH oxidase enzyme via reducing the activity of PKC and the translocation of NF-kB to the nucleus.

Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients.

OBJECTIVES: The most frequent adverse events associated with valganciclovir treatment are hematological disturbances such as neutropenia. However, the consequences of neutropenia are unknown. We investigated the clinical impact of neutropenia during CMV preemptive therapy and its relationship with the length of antiviral therapy. METHODS: An observational, prospective cohort of 67 solid organ transplant recipients receiving CMV preemptive therapy was studied. RESULTS: Severe neutropenia occurred in 21.8% of the patients at a median of three weeks after initiating antiviral therapy. No association was observed between neutropenia and infection risk in these patients. Liver transplant recipients had 6.7 fold increased risk of neutropenia during CMV therapy compared to kidney transplant recipients (p = 0.012). Patients who developed severe neutropenia received antiviral therapy a median of six days longer than patient who did not (p = 0.457). CONCLUSIONS: Despite the frequency of neutropenia during CMV preemptive therapy, the incidence of infections is not increased. Adjusting the length of preemptive therapy during the episodes of viremia may be recommended, especially in patients with concurrent risk factors for neutropenia such as liver recipients. Further trials are warranted to confirm the safety of this approach.

Harmful effects of viral replication in seropositive hepatitis C virus renal transplant recipients.

BACKGROUND: Seropositivity for hepatitis C virus (HCV) predicts lower patient and graft survival after renal transplantation (RT). However, the influence of viral replication at transplantation on long-term outcome remains to be determined. METHODS: This was a retrospective study conducted in four Spanish hospitals, from 1997 to 2006. Data of all patients with RT, who displayed HCV+ (enzyme-linked immunosorbent assay), and with negative viremia at RT (NEG group) were collected (n=41). For each NEG patient enrolled, data of two patients with RT nearest in time, HCV+, and positive viremia (POS group) were also collected (n=78). RESULTS: The POS group showed a higher incidence of long-term liver disease (56.4% vs. 24.4%, P=0.0009) and episodes of transaminase elevation (38.5% vs. 7.3%, P=0.0003) and worse renal function (serum creatinine [sCr], 3.0 [2.7] vs. 1.9 [1.6] mg/dl, P=0.032; glomerular filtration rate, 43.7 [22.4] vs. 56.9 [27.9] ml/min, P=0.075). Noteworthy, 24.4% of NEG patients reactivated after RT, showing a worse patient survival (P=0.039). Active viral replication at RT and dialysis requirement in the first week remained as independent predictors of lower graft survival (death censored): hazards ratio, 3.11 (95% confidence interval, 1.34-7.19; P=0.009) and hazards ratio 3.13 (95% confidence interval, 1.53-6.37; P=0.002). CONCLUSIONS: This study shows that active viral replication at transplantation is an independent risk factor for graft failure in patients with positive serology for HCV.

Late evolution of kidney transplants in elderly donors and recipients receiving initial immunosuppressant treatment with daclizumab, mycophenolate mofetil, and delayed introduction of tacrolimus.

BACKGROUND: Organ transplants in elderly recipients have increased over the past few years. This situation poses specific problems both in terms of organs and recipients; therefore, immunosuppressant regimens must be adapted accordingly. A previous study demonstrated good initial results in kidney transplant cases in which older donors and recipients (average ages of 64.4 years and 61.3 years) had received initial immunosuppressant therapy with daclizumab and mycophenolate mofetil as well as delayed introduction of reduced-dose tacrolimus. In this study we reviewed the long-term results in the same group of patients. METHODS: An observational, retrospective multi-centre study carried out at a national level to determine survival rates and renal function in 126 patients included in the initial study (127 patients who survived the first year with a functioning graft, 123 treated according to protocol). We gathered data from the 2nd to the 6th year for 120, 118, 113, 102 and 62 patients, respectively. The evolution of renal function, relevant clinical data, and safety profiles were also analysed. RESULTS: After five years, most patients continued with the initial immunosuppressant regimen: 92% tacrolimus and 80% mycophenolate mofetil; 48% had abandoned steroids and proliferation signal inhibitors had been introduced in 3%. Patient and graft survival (adjusted for patient death) after five years was 93.1% and 93.8%, respectively. The main cause of death was neoplasia (in 7 out of 10 cases) whilst graft loss was mainly due to death with a functioning graft. The other causes of death were 2 acute myocardial infarctions and a gastrointestinal haemorrhage. Renal function was moderately but significantly reduced with the passing of time (P<.001): average creatinine levels in the overall group of patients rose from 1.60 ± 0.50mg/dl after the 1st year to 1.63 ± 0.70 mg/dl at the end of study. MDRD dropped from 46.28 ± 15.64 ml/min after the 1st year to 45.69 ± 15.44 ml/min at the end of study (P<.01). Only two acute rejections were observed after the 1st year. There were 19 cardiovascular events registered in 12 patients. CONCLUSIONS: The regimen used in our study was useful and appropriate for elderly donor-recipient pairs as demonstrated by the good long-term survival results, continued optimum renal function, and acceptable safety profile.

Impact of the new drugs in the cost of maintenance immunosuppression of renal transplantation. Is it justified?

BACKGROUND: The new immunosuppressive drugs control acute rejection better, and have potentially short-term economic advantages. However, their long-term cost-effectiveness must still be determined. The Spanish study of chronic transplant nephropathy provides data that facilitates the assessment of the economic importance of maintenance immunosuppression (MI). METHODS: We determined the frequency of use of the different MI drugs and their combinations in three renal transplantation cohorts performed in 1990, 1994 and 1998 (total: 3279), and their evolution over time. Based on the real costs found in a medium-sized service in our country at the end of 2000, the mean annual costs of MI drugs were calculated. We performed a multivariate analysis of graft survival in the 1998 cohort. RESULTS: In 1990 and 1994, cyclosporine (CsA) with or without azathioprine (AZA) was used almost exclusively as the initial MI drug. In 1998, 76% received mycophenolate mofetil (MMF) and 20% tacrolimus (TAC). During their follow-up, a growing number of patients from the 1990 and 1994 groups were converted to MMF (12 and 17%) and TAC (4 and 8%), while the treatment of those from 1998 remained stable. Using prices from the year 2000, the mean cost of the MI at the end of the first year in 1998 (5380) was almost double that of 1994 (2902) and 1990 (2855). In these two groups, the mean cost remained stable until 1996; afterwards, it increased in both, more rapidly in the 1994 (24.8%) than in the 1990 (17.3%) group, although it remained significantly inferior to that of 1998. Correction for the evolution of the drug prices and the peseta purchasing value lessened these changes in an important way. The new regimens allowed for the withdrawal of steroids in a greater proportion of cases; TAC was associated with a less frequent use of lipid-lowering drugs and antihypertensive drugs. In the whole patient group, the regimens with MMF and/or TAC showed a tendency to greater mean life of the organs, but without reaching statistical significance in the multivariate analysis of patients in 1998. CONCLUSIONS: The introduction of new drugs in the MI applied in Spain has had an important economic impact since 1996. Their cost-effectiveness is still pending confirmation in our country.

Medical management of pneumonia caused by Rhodococcus equi in a renal transplant recipient.

Rhodococcus equi is an animal pathogen that occasionally causes opportunistic infections in immunocompromised patients. The most common clinical picture is one of necrotizing pneumonia with a tendency toward cavitation and the formation of abscesses. We report a case of pneumonia caused by R equi in a renal transplant patient. An excellent response was shown to antibiotic treatment. Symptoms regressed, and the progressive disappearance of the lesion was confirmed on follow-up computed tomography scans. Surgical intervention or other invasive procedures were not required. To our knowledge, 14 cases of infection by R equi in solid-organ transplant patients have been described to date. Nine were recipients of a renal allograft. Surgery was required in many of these patients, and all the renal transplant recipients required the use of invasive therapeutic techniques, such as pleural drainage. This is the first case of a renal transplant recipient in whom radiologic presentation was as a solid nodule without ensuing cavitation that resolved exclusively with antibiotic treatment.