María José Santana

Pretransplant CD8 T-cell response to IE-1 discriminates seropositive kidney recipients at risk of developing CMV infection posttransplant.

Background Cytomegalovirus (CMV) infection is an ongoing clinical problem in solid-organ transplantation (SOT). Pretransplant CMV serology is currently the only tool for assessing the risk of CMV infection, although cellular immune responses driven by CMV-specific CD4 and CD8 T lymphocytes are important for controlling viral replication. Therefore, the analysis of CMV-specific T cells may be useful for estimating the risk of infection. Methods This is a prospective study of patients with kidney transplants and no prophylactic treatment for CMV replication. CD4 and CD8 T-cell responses to the major CMV pp65 and IE-1 antigens in 15 seropositive patients at intermediate risk of CMV infection were investigated, according to current algorithms. Intracellular flow cytometry was employed to determine IFN-&ggr; production as a functional readout. The response was analyzed in pretransplant samples and prospectively at 1 and 6 months and at 1 year posttransplant. Results It was observed that the CD8 responses to IE-1 antigen were practically absent pretransplant in patients who developed CMV infection posttransplant. Within the group of patients free of infection, CD8 responses to IE-1 were detected more frequently and were significantly higher (P=0.0083). In a receiver operating characteristics curve analysis (AUC=0.929; P=0.010; 95% CI: 0.078–1.0), low CD8 responses to IE-1 (⩽0.05%) pretransplant predicted the development of CMV infection under the immunosuppressive regime after transplant with 100% specificity and 85.7% sensitivity. Conclusions Assessment of IE-1-specific CD8 T-cell frequencies pretransplant may be a useful tool for identifying seropositive SOT patients at risk of developing CMV infection posttransplant.

The Natural History of Kidney Graft Cortical Microcirculation Determined by Real-Time Contrast-Enhanced Sonography (RT-CES)

Background Kidney transplantation is the therapy of choice for end-stage kidney disease. Graft’s life span is shorter than expected due in part to the delayed diagnosis of various complications, specifically those related to silent progression. It is recognized that serum creatinine levels and proteinuria are poor markers of mild kidney lesions, which results in delayed clinical information. There are many investigation looking for early markers of graft damage. Decreasing kidney graft cortical microcirculation has been related to poor prognosis in kidney transplantation. Cortical capillary blood flow (CCBF) can be measured by real-time contrast-enhanced sonography (RT-CES). Our aim was to describe the natural history of CCBF over time under diverse conditions of kidney transplantation, to explore the influence of donor conditions and recipient events, and to determine the capacity of CCBF for predicting renal function in medium term. Patients and Methods RT-CES was performed in 79 consecutive kidney transplant recipients during the first year under regular clinical practice. Cortical capillary blood flow was measured. Clinical variables were analyzed. The influence of CCBF has been determined by univariate and multivariate analysis using mixed regression models based on sequential measurements for each patient over time. We used a first-order autoregression model as the structure of the covariation between measures. The post-hoc comparisons were considered using the Bonferroni correction. Results The CCBF values varied significantly over the study periods and were significantly lower at 48 h and day 7. Brain-death donor age and CCBF levels showed an inverse relationship (r: -0.62, p<0.001). Living donors showed higher mean CCBF levels than brain-death donors at each point in the study. These significant differences persisted at month 12 (54.5 ± 28.2 vs 33.7 ± 30 dB/sec, living vs brain-death donor, respectively, p = 0.004) despite similar serum creatinine levels (1.5 ± 0.3 and 1.5 ± 0.5 mg/dL). A sole rejection episode was associated with lower overall CCBF values over the first year. CCBF defined better than level of serum creatinine the graft function status at medium-term. Conclusion RT-CES is a non-invasive tool that can quantify and iteratively estimate cortical microcirculation. We have described the natural history of cortical capillary blood flow under regular clinical conditions.

Incidence of Contrast-Induced Nephropathy in Kidney Transplant Patients

Introduction Kidney transplant patients are at risk of contrast-induced nephropathy. CT scan with contrast is a very common imaging test. Our objective is to study the incidence of acute kidney injury in kidney allograft patients who are made a CT scan with contrast. Materials and Methods Retrospective longitudinal study which includes patients with kidney transplant and a CT scan with hypoosmolar contrast, made between 2014 and 2016. All of the subjects received prophylaxis with saline solution, at a volume of 500-1000 ml depending on whether they had cardiology diseases or not respectively. Kidney function was analysed 5-7 days after the imaging test was made. Acute kidney injury was defined as an elevation in creatinine levels ≥ 0,3 mg/dl within 48 hours since the contrast was administered or as an increase of 150% from baseline values in 7 days not attributable to other causes. Results 4 in 61 patients had contrast-induced nephropathy (6.1%). This entity was more frequent in patients who were diagnosed of renal artery stenosis (p 0.027) and in those taking anticalcineurinics associated with a higher body mass index (p 0.043). 3 of 4 patients recovered their kidney function to previous baseline values. There was no association between contrast-induced nephropathy and diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or consumption or levels of anticalcineurinics. None of the subjects who were taking mTOR inhibitors developed this nephropathy. Also, no correlation was described in relation to ischemic heart disease, diabetes, peripheral artery disease, baseline creatinine or proteinuria. Conclusions with the administered prophylaxis, the incidence of hypoosmolar contrast-induced nephropathy in our population was lower than previously described (6.1%). 75% of acute kidney injuries were reversible. These results suggest that the risk of contrast-induced nephropathy is low in kidney transplant patients with prophylaxis, except for those in which renal artery stenosis is suspected or in the ones who take anticalcineurinics and have a higher body mass index.

Occult Hepatitis C Virus in Recipients of Kidney Transplantation: Prevalence and Clinical Implications

Background and Aim Occult HCV infection (OCI) is characterized by the presence of HCV- RNA in liver or in peripheral blood mononuclear cells in the absence of serological markers. Infection with HCV is and independent risk factor for graft loss and is associated with proteinuria, chronic rejection, transplant glomerulopathy, posttransplant diabetes and HCV- associated glomerulopathies. However, the prevalence and relationship between kidney outcome and OCI are unknown. The aim of the study is to know the prevalence of OCI in recipients of kidney transplantation and investigate possible clinical implications of OCI in a population of kidney transplantation recipients. Patients and Methods We randomized tested 133 anti HCV and serum HCV- RNA negative adult patients for the presence of OCI. All patients have al least one year of outcome from ingraft. HCV- RNA was tested by real-time RT- PCR in peripheral blood mononuclear cells and in 2 ml of plasma after ultracentrifugation. Results Occult HCV infection was positive in 20 patients (15%). Blood transfusions before kidney transplant was more frequent in patients with OCI (p<0.05). One year after ingraft, renal function and proteinuria were similar for both groups (plasma creatinine level 1.58 ± 0,48 mg/dL, 0.40 ± 0.62 gr/d, in the OCI positive group and 1,48 ± 0,88 mg/dL and proteinuria 0.30 ± 0.30 gr/d in the OCI negative group; p=0.42 and p=0.5). At the end of the follow-up, renal function tended to decline faster in the OCI positive group (plasma creatinine level 1.95 ± 1.08) and to have more proteinuria (0.86 ± 1.14) than in the OCI negative group (plasma creatinine level 1.78 ± 0.83, and proteinuria 0.63 ±1.41), although it was not statistical significant (p= 0.072, p=0.429). Conclusions The prevalence of OCI in recipients of kidney transplantation in our group is 15%, higher than in the general population. Blood transfusion before kidney transplant could be a risk factor for OCI. The presence of OCI could play a negative role in the outcome of kidney transplants, but more patients and longer follow up, are probably need, to make definitive conclusions. Fundacion Mutua Madrileña.

High Frequencies of CMV-specific CD8 and CD4 T Cell Subsets are Needed Pretransplant to Protect from CMV Replication in Kidney Transplant Recipients Treated with Thymoglobulin

Background Diagnostic of CMV-specific T cell immunity in solid organ transplant patients is showing to be a useful tool in predicting CMV infection after transplantation. Induction treatment with anti-lymphocyte polyclonal antibodies (thymoglobulin) causes lymphocyte depletion from the first week to beyond one-year post-trasplantation. Pretransplant immunological analysis in patients treated with thymoglobulin could guide the most appropriate prevention strategy. Methods We performed a prospective study of patients with kidney transplant who were treated with thymoglobulin as induction treatment and with universal prophylaxis for CMV infection. CD4 and CD8 T-cell responses to pp65 and IE-1 CMV antigens in 37 CMV-seropositive and 9 CMV-seronegative patients were investigated. Intracellular flow cytometry was employed to determine IFN-&ggr; production as a functional readout. The response was analyzed in pretransplant samples and at 1, 6, 12 and 24 months post-transplant. Results In CMV-seropositive patients who did not develop CMV infection post-transplant, pretransplant CD8 T-cell response to IE-1 (p= .004) and CD8 and CD4 T-cell responses to pp65 (p=.04 and p=.002, respectively) were significantly higher than it in patients with CMV replication (Figure 1) ROC curve analysis showed that low frequencies of IE-1-specific (< .13%) or pp65-specific (< .88%) CD8 T cells or pp65-specific (< .13%) CD4 T cells predicted the development of CMV infection (Figure 2). Figure. No caption available. Figure. No caption available. Conclusions Functional assessment of pretransplant CMV-specific CD4 and CD8 T-cell immunity in seropositive patients who are going to receive thymoglobulin allows the identification of patients at risk of developing CMV infection post-transplantation.

La infección por citomegalovirus postrasplante renal y pérdida del injerto a largo plazo

BACKGROUNDnDespite the use of prevention strategies, cytomegalovirus (CMV) infection is the most common viral complication after renal transplant and its impact on long-term outcomes is still open to debate.nnnOBJECTIVEnTo evaluate the incidence of CMV infection and disease during the use of prevention strategies in our centre and to analyse the association between CMV infection and long-term patient and graft survival and other potentially clinical events related with CMV.nnnMETHODSnWe reviewed the medical records of 377 recipients of kidney transplants performed between January 1998 and December 2008. Kaplain-Meier survival curve analysis was performed to analyse graft and patient survival by CMV infection/disease and Cox proportional hazards regression was used to identify factors associated with CMV infection/disease, graft loss and mortality.nnnRESULTSnThe incidence of CMV infection was 34.7% and CMV disease was 9.5%. Patient and graft survival was significantly lower in patients with CMV infection/disease. CMV infection/disease was associated with a higher risk of graft loss (HR 1.91, 95% CI 1.09-3.36, p=0.023), but not with a higher mortality (HR 1.29, 95% CI 0.7-2.38, p=0.4).nnnCONCLUSIONnCMV replication after renal transplant is a risk factor for long-term graft loss but not mortality. Prevention strategies decrease post-transplant CMV infection and disease.