Margarita Rufino

Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression.

Background. Immunosuppressive regimens based on low doses of cyclosporine A (CsA) or tacrolimus (TAC) may improve short-term outcome after kidney transplantation (KT), but the optimal immunosuppressive protocol is currently unknown. Methods. This study compared the 24-month efficacy and safety of two immunosuppressive regimens using reduced calcineurin inhibitors (CNIs) exposure with standard dosage of CsA in 240 patients who were randomized into three groups: group A (n=80): Thymoglobulin, CsA (4 mg/kg twice daily) plus azathioprine (1.5 mg/kg once daily); group B (n=80): basiliximab, CsA (2 mg/kg/ twice daily) plus mycophenolate mofetil (MMF; 1 g twice daily); and group C (n=80): basiliximab, TAC (0.05 mg/kg/ twice daily) plus MMF (1 g twice daily). Steroid administration was identical for all groups. Results. A significantly better creatinine clearance at 12 months, estimated by Cockcroft-Gault (57±12, 65.2±20, 73.5±27 ml/min, P=0.044), the Jelliffe-2 (51.5±16, 56±19, 59.4±19 ml/min/1.73 m2, P=0.041) and the Modification of Diet in Renal Disease equations (53±17, 58.5±20, 61.6±22 ml/min/1.73 m2, P=0.035), was observed in group C compared with group A. No significant differences were observed between groups B and C. The incidence of biopsy-proven acute rejection was similar between groups (15%, 13.8%, and 16.3%). In addition, patient and graft survival at 24 months were not different between groups. Adverse effects were similar among groups, but cytomegalovirus infections was significantly higher in group A (41% vs. 20% vs. 25%; P=0.008). Conclusions. Immunosuppressive regimens with reduced CNI exposure provide similar preservation of renal function compared with standard dose of CsA after KT and do not lead to underimmunosuppression.

Similar renal decline in diabetic and non-diabetic patients with comparable levels of albuminuria

BACKGROUND Diabetes is the main cause of ESRD, and albuminuria is a major determinant of adverse renal outcome. Likewise, albuminuria is an intermediate risk factor of chronic kidney disease (CKD) progression in diabetic patients. Our aim was to compare the rate of renal decline in diabetic and non-diabetic CKD patients (GFR < 50 ml/min) with comparable levels of albuminuria. METHODS In this observational study, 333 patients (age 67 +/- 15 years, 46% diabetics) were included during a 7.5-year period. The mean follow-up was 30 +/- 18 months (range 4-79). The influence of study variables was evaluated applying a time-dependent Cox model and slope-based outcome using a linear regression model. RESULTS The diabetes condition was associated with adverse outcome in univariate analysis, and after adjusting for age, sex and systolic blood pressure. However, when controlling for albuminuria (a time-dependent covariate), diabetes did not show any association with outcome. In addition, the mean slope of renal decline was similar in diabetic and non-diabetic patients when controlling for albuminuria. The urinary albumin-creatinine ratio was a robust predictor of poor outcome in uni- and multivariate models. In the diabetic group, time-varying glycosilated haemoglobin did not influence renal outcome in the Cox model, and time-varying albuminuria remained a strong predictor of outcome. CONCLUSIONS Diabetic patients have a poorer renal outcome, but at comparable levels of albuminuria renal decline is similar in diabetic and non-diabetic patients. Albuminuria is a risk factor for renal decline, and the main target to delay progression in patients, diabetics or non-diabetics, with moderate to advanced CKD.

A Novel Prognostic Index for Mortality in Renal Transplant Recipients After Hospitalization

Background. Prognostic indices that estimate long-term mortality are essential not only to compare different clinical studies and populations but also to perform the most appropriate therapeutic interventions. All-cause mortality is high after renal transplantation (RTx), but no prognostic index has focused on predicting mortality in RTx. We developed and tested a prognostic index for mortality in RTx after hospitalization. Methods. We retrospectively analyzed survival in 1,293 RTx recipients who were randomly assigned to two groups: a modeling population (n=646), used to create the new index, and a testing population (n=647), used to test this index. Patients were stratified into three risk groups (low, medium, and high) by combining peritransplant risk factors for mortality (&bgr;-coefficient), using a simple eight-point check list: age, pretransplant cardiovascular disease, renal dysfunction at discharge, cardiac hypertrophy, vascular calcification, diabetes, time on dialysis, and acute tubular necrosis. Results. Overall lower survival rates were observed with increasing risk classes in the testing population (log-rank test=18; P=0.0001). The 8-year survival rates ranged from 94% in the lowest-risk group to 59% in the highest-risk group. The area under the receiver operating characteristic curve was 0.63. Mortality risk (Cox analysis) significantly increased with increasing risk classes (medium risk: relative risk=3.8, 95% confidence interval=1.5–9.5, P=0.004; high risk: relative risk=6.3, 95% confidence interval=2.4–16.2, P=0.0001). Conclusions. This simple prognostic index applicable at the bedside may accurately predict survival in RTx recipients after discharge. Consequently, targeted treatment interventions may be indicated for minimizing mortality, especially in high-risk groups.

A novel risk score for mortality in renal transplant recipients beyond the first posttransplant year.

Background. All-cause mortality is high after kidney transplantation (KT), but no prognostic index has focused on predicting mortality in KT using baseline and emergent comorbidity after KT. Methods. A total of 4928 KT recipients were used to derive a risk score predicting mortality. Patients were randomly assigned to two groups: a modeling population (n=2452), used to create a new index, and a testing population (n=2476), used to test this index. Multivariate Cox regression model coefficients of baseline (age, weight, time on dialysis, diabetes, hepatitis C, and delayed graft function) and emergent comorbidity within the first posttransplant year (diabetes, proteinuria, renal function, and immunosuppressants) were used to weigh each variable in the calculation of the score and allocated into risk quartiles. Results. The probability of death at 3 years, estimated by baseline cumulative hazard function from the Cox model [P (death)=1−0.993592764exp(score/100)], increased from 0.9% in the lowest-risk quartile (score=40) to 4.7% in the highest risk-quartile (score=200). The observed incidence of death increased with increasing risk quartiles in testing population (log-rank analysis, P<0.0001). The overall C-index was 0.75 (95% confidence interval: 0.72–0.78) and 0.74 (95% confidence interval: 0.70–0.77) in both populations, respectively. Conclusion. This new index is an accurate tool to identify high-risk patients for mortality after KT.

Renin–angiotensin system blockade and kidney transplantation: a longitudinal cohort study

BACKGROUND The beneficial effect of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) in kidney transplant recipients on modern immunosuppression is not yet well established. Our objective was to investigate the impact of the use of ACEI/ARB on patient and graft survival in a cohort of kidney transplant recipients. METHODS A total of 990 patients, who received a single deceased donor kidney at our institution between 1996 and 2005, were included in this longitudinal cohort study. All-cause mortality and death-censored graft loss were the primary outcomes. We used traditional time-dependent Cox model (unweighted) and inverse-probability-of-treatment weighting of marginal structural models (weighted Cox model), controlling for time-dependent confounding by indication. RESULTS A total of 414 patients (42%) received ACEI/ARB through the study period (median duration 14 months, interquartile range 6-40 months). ACEI/ARB use was associated with reduction of risk for mortality in the crude [hazard ratio (HR) 0.627, 95% confidence interval (CI) 0.412-0.953] and adjusted Cox analysis (HR 0.626, 95% CI 0.407-0.963). Similar results were observed after adjusting for confounding by indication (HR 0.629, 95% CI 0.407-0.973). By contrast, ACEI/ARB use was not associated with significant improvement of graft survival after kidney transplantation. CONCLUSION ACEI/ARB prescription may be suggested as beneficial among multiple medications for reducing mortality in kidney transplant recipients, but its use was not associated with longer graft survival.

Early association of low-grade albuminuria and allograft dysfunction predicts renal transplant outcomes.

Background. Data on the combined associations of albuminuria and estimated glomerular filtration rate (eGFR) with renal transplant outcomes are limited. Our objective was to explore how renal transplant outcomes could be predicted by a combined variable of early low-grade albuminuria and allograft dysfunction. Methods. We studied a cohort of adult deceased-donor kidney transplant recipients who were subdivided into four groups according to median albuminuria (100 mg/day, interquartile range, 0–470 mg/day) and median eGFR (60 mL/min/1.73 m2; interquartile range, 30–73 mL/min/1.73 m2) at third month posttransplantation as follows: group I (albuminuria <100 and eGFR >60, n=238); group II (albuminuria ≥100 and eGFR >60, n=151); group III (albuminuria <100 and eGFR ⩽60; n=167); and group IV (albuminuria ≥100 and eGFR ⩽60, n=228). Results. Death-censored graft survival was significantly lower in group IV compared with the rest (P<0.0001). Multivariate Cox regression analysis using fixed and time-dependent covariates showed that the combination of low-grade albuminuria and lower eGFR was associated with graft failure (hazard ratio, 2.2, 95% confidence interval, 1.3–3.7; P=0.003). Likewise, but to a lesser extent, the risk of mortality was increased for group IV (hazard ratio, 1.7, 95% confidence interval, 1.01–2.8; P=0.042). Conclusions. Early association of low-grade albuminuria and allograft dysfunction represents an important risk factor of graft failure and mortality. This additive effect should be considered to identify individuals at risk for adverse kidney transplantation outcomes.

Disproportionately high incidence of diabetes-related end-stage renal disease in the Canary Islands. An analysis based on estimated population at risk

BACKGROUND An exceptionally high incidence of diabetes-related end-stage renal disease (DM-ESRD) has been reported in the Canary Islands. This phenomenon was attributed to an increased prevalence of diabetes in this community. We compared the incidence of DM-ESRD in the Canary Islands with the rest of Spain among the estimated number of individuals at risk (people with diabetes in the population). METHODS The population-at-risk was calculated using census population figures and estimates of self-reported diabetes prevalence from the Spanish National Health Survey in the years 2003 and 2006. The incidence of DM-ESRD for the same years was obtained through Spanish regional registries. The independent effect of age, community of residence and calendar year was estimated with a Poisson regression model. Age-standardized acceptance rate ratios were calculated for each community. RESULTS Overall DM-ESRD incidence in the Canary Islands population-at-risk was 1209.9 per million population (pmp) in 2003 and 1477.3 pmp in 2006. Rates for the remaining Spanish regions ranged from 177.3-984.9 pmp. The incidence was higher in the Canary Islands across all age groups, but was most striking for patients > or =75 years. Diabetes prevalence in the general population was greater in the two youngest age strata and diminished from 75 years on in the Canary Islands, in comparison with other areas of Spain. Using a cluster of three communities with the lowest incidence as a reference, the relative risk of DM-ESRD in the Canary Islands population-at-risk was 3.88 [95% confidence interval (CI): 3.07-4.89]. Age-standardized acceptance ratios (95% CI) in the Canary Islands were 2.21 (1.85-2.61) in 2003 and 2.73 (2.34-3.17) in 2006. CONCLUSIONS Individuals with diabetes in the Canary Islands present a disproportionately high incidence of ESRD. Diabetic Canary inhabitants are exposed to the disease for a longer time and therefore, may be more vulnerable to the development of chronic diabetes complications, including ESRD.

Type 1 Diabetes Increases the Expression of Proinflammatory Cytokines and Adhesion Molecules in the Artery Wall of Candidate Patients for Kidney Transplantation

OBJECTIVE Diabetes may accelerate atheromatosis in uremic patients. Our aim was to assess the influence of type 1 diabetes on the atheromatosis-related inflammation in patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS We analyzed the expression of proinflammatory cytokines and adhesion molecules in the inferior epigastric artery walls of type 1 diabetic patients with CKD (n = 22) and compared it with nondiabetic uremic patients (n = 92) at the time of kidney transplantation. We evaluated the expression of interleukin (IL)-6, monocyte chemotractant protein (MCP)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1, and the activation of nuclear factor-κβ p65 (NFkB-p65). Common carotid intima-media thickness (c-IMT) was determined by conventional echography. RESULTS IL-6, MCP-1, and VCAM-1 proteins were elevated in type 1 diabetic patients compared with nondiabetic subjects (P < 0.05). The nuclear localization of NFkB-p65 was higher in type 1 diabetic patients (P < 0.01) and correlated with the levels of MCP-1 in this group (r = 0.726, P < 0.001). Arterial fibrosis correlated with IL-6 and MCP-1 levels (r = 0.411, P < 0.001 and r = 0.378, P = 0.001). A significant correlation was observed between VCAM-1 levels and both the degree of arterial narrowing and c-IMT. CONCLUSIONS Type 1 diabetes produces a proinflammatory state in the arteries of end-stage CKD patients, with increased levels of IL-6, MCP-1, and VCAM-1, as well as a greater degree of p65 activation, which are associated with more severe vascular lesions and higher c-IMT. Although causality is not demonstrated, these findings support the major role of inflammation in type 1 diabetic patients with CKD.

Predicting delayed graft function and mortality in kidney transplantation

Kidney transplantation (KT) is the treatment of choice for end-stage renal failure, but such patients are increasingly older and have additional comorbid conditions leading to high mortality rates after transplantation. Delayed graft function is a common complication after KT, especially in recipients who receive expanded criteria donor, and these complications are associated with a poorer graft survival in the long term. Taken together, an appropriate assessment of comorbidity grouped in prognostic indexes could be a useful tool to make crucial therapeutic decisions at the time of transplant. Allocation systems based upon a recipient risk score, as well as identification of risk factors for delayed graft function, may improve outcomes after KT. The aim of this review is to assess the contribution and utility of comorbid conditions, grouped in prognostic indexes to predict and improve kidney transplant outcomes.

The GLUT-1 XbaI Gene Polymorphism Is Associated with Vascular Calcifications in Nondiabetic Uremic Patients

Background: Glucose transporters mediate the facilitative uptake of glucose into cells, with GLUT-1 being the predominant isoform in vascular smooth muscle cell (VSMC). Clones of human cells overexpressing the GLUT-1 transporter showed a high increase in intracellular glucose concentrations, mimicking the diabetic milieu. It is possible that high intracellular glucose together with uremic factors may play an important role in vascular calcification by transforming VSMC into osteoblast-like cells. The XbaI polymorphism in the GLUT-1 gene has been linked to variations in GLUT-1 expression, with consequent changes in intracellular glucose concentration. Methods: To assess the association between the GLUT-1 XbaI gene polymorphism and the presence of VC in nondiabetic uremic patients, a total of 105 nondiabetic patients on hemodialysis were studied. VC were evaluated by conventional simple X-ray. Mean values of serum calcium, phosphorous, cholesterol, triglycerides, HbA1c, PTH and insulin were measured. Height, weight, BMI and waist circumference were also determined. The GLUT-1 XbaI polymorphism in the second intron of the gene was ascertained by means of the polymerase chain reaction and restriction fragment length polymorphism analysis on DNA isolated from peripheral blood DNA. In the absence of an XbaI site, a fragment of 305 bp was seen (so-called x allele), whereas fragments of 232 and 73 bp were generated if the XbaI site was present (X allele). Results: Genotype distribution in all patients was similar to the Caucasian population. However, when the patients were grouped according to the presence or absence of VC, there were marked differences in the frequency of the GLUT1 genotypes: the xx GLUT-1 genotype was more prevalent in the group with VC (30.7 vs. 4.5%, p = 0.001). Stepwise logistic regression demonstrated that the xx GLUT-1 genotype was independently associated with the presence of VC after adjusting for other variables such as age, calcium × phosphrus product, BMI and time on dialysis (OR 7.68; 95% CI 1.28–45.7). Conclusions: GLUT-1 XbaI gene polymorphism is associated with vascular calcifications in nondiabetic uremic patients.