Ricardo Lauzurica

Epidermal dysplasia and neoplasia in kidney transplant recipients

BACKGROUND Established data confirm an increased incidence of skin cancer, mainly squamous cell carcinoma (SCC), in long-term kidney transplant recipients (KTRs). OBJECTIVE Our purpose was to investigate prospectively the type and frequency of neoplastic and preneoplastic skin lesions in KTRs during the first 3 years of immunosuppression, as well as the influence of potential risk factors. METHODS Eighty-one consecutive KTRs were examined every 6 months during the first 3 years after transplantation. All survival analyses were performed with the EGRET statistical software package. RESULTS After a median follow-up of 34 months, 25 skin cancers developed in 12 patients; the basal cell carcinoma (BCC)/SCC ratio was 3.1:1. The cumulative risk of skin cancer developing after 3 years of graft survival was 18.1%. Only age at the time of transplantation (p = 0.005) and occupational sun exposure (p = 0.048) had statistical significance as risk factors. CONCLUSION In carefully supervised KTRs, a high incidence of cutaneous malignancy, mainly BCC, exists in the early posttransplant period. Sun exposure and the patients age at the time of transplantation seem to be the most important risk factors.

Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil

Disseminated varicella zoster virus (VZV) infection is a rare complication after renal transplantation in adults. We report 4 cases diagnosed in our transplant patients. One of which was a primary infection (chicken pox) with multivisceral involvement (hepatitis, pneumonitis, myocarditis, and disseminated intravascular coagulation). The other 3 patients VZV-seropositive before transplantation suffered from disseminated zoster. No immunosuppressive drug was significantly associated with a higher risk of disseminated VZV infection. However, from our experience, we believe that mycophenolate mofetil (MMF), plays a part in the clinical presentation of the disease. Early treatment with high doses of acyclovir is fundamental in infection control. It is essential to perform a pretransplantation serological VZV study on all patients.

Prediabetes in patients receiving tacrolimus in the first year after kidney transplantation: a prospective and multicenter study.

Background. Tacrolimus-based immunosuppression, the most widely used regimen in kidney transplantation, increases the risk of new onset diabetes after transplantation (NODAT). However, the prevalence, evolution and risk factors of different prediabetic alterations: impaired fasting glucose, impaired glucose tolerance, and provisional diabetes, have not been established. Methods. In this multicenter and prospective study we evaluated 154 nondiabetic kidney transplant recipients receiving tacrolimus, mycophenolate mofetil and low dose steroids. An oral glucose tolerance test was performed 3 and 12 months after transplantation and prediabetes was defined by American Diabetes Association criteria. Results. Prediabetes was highly prevalent and showed little variation between 3 and 12 months (36% and 33%, respectively). Impaired glucose tolerance was the most frequent abnormality observed (23% and 25%, respectively) observed. In addition, 20% of recipients showed NODAT by 1 year. Multivariate analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.004–1.14), pretransplant body mass index (OR: 1.3, CI: 1.09–1.6) and triglyceride/high density lipoprotein-cholesterol ratio, a marker of insulin resistance, (OR: 1.4, CI: 1.05–1.9) were independent risk factors for prediabetes. Conclusion. One in two recipients with tacrolimus-based immunosuppresion showed prediabetes or NODAT by 1 year posttransplantation when properly investigated. Older age and high pretransplant body mass index and triglyceride/high density lipoprotein-cholesterol ratio were risk factors for prediabetes. These findings may help applying early interventions to prevent the disorder.

Adiponectin and risk of new-onset diabetes mellitus after kidney transplantation.

Background. New-onset diabetes mellitus after transplantation (NODAT) is a severe complication of kidney transplantation (KTx) with negative effects upon patient and graft survival. Several risk factors for NODAT have been described; however, the search for an early predictive marker is ongoing. It has recently been demonstrated that high concentrations of adiponectin (APN), which is an adipocyte-derived peptide with antiinflammatory and insulin-sensitizing properties, protect against future development of type 2 diabetes in healthy individuals. The purpose of this report was to study pretransplant insulin resistance and analyze pretransplant serum leptin and APN levels as independent risk factors for the development of NODAT. Methods. A total of 68 KTx patients were studied [mean age, 48±11 years; 70% males; body mass index (BMI), 25±3 kg/m2]; 31 KTx patients with NODAT and 37 KTx patients without NODAT (non-NODAT) with similar age, sex, BMI, immunosuppression, and posttransplant time were studied. All patients received prednisone and calcineurin inhibitors (75% tacrolimus and 25% cyclosporine A), and 76% of patients received mycophenolate mofetil. Family history of diabetes mellitus was recorded. Pretransplant homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated from fasting plasma glucose and insulin. Pretransplant serum leptin and APN levels were determined by radioimmunoassay. Results. NODAT patients showed higher pretransplant plasma insulin concentrations [NODAT, 13.4 (11–22.7) &mgr;IU/mL; non-NODAT, 10.05 (7.45–18.4) &mgr;IU/mL; P=0.049], HOMA-IR index [NODAT, 4.18 (2.49–5.75); non-NODAT, 2.63 (1.52–4.68); P=0.043], and lower pretransplant serum APN concentration [NODAT, 8.78 (7.2–11.38) &mgr;g/mL; non-NODAT, 11.4 (8.56–15.27) &mgr;g/mL, P=0.012]. Inverse correlations between APN and BMI (r=−0.33; P=0.014) and APN and HOMA-IR index (r=−0.39; P=0.002) and between APN and NODAT (r=−0.31; P=0.011) were observed. Multiple logistic regression analysis showed the patients with lower pretransplant APN concentrations to be those at greater risk of developing NODAT [Odds Ratio=0.832 (0.71–0.96); P=0.01]. Conclusion. Pretransplant serum APN concentration is an independent predictive factor for NODAT development in kidney-transplanted patients.

Pretransplant pregnancy-associated plasma protein-A as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events

Background. Cardiovascular disease and chronic allograft nephropathy (CAN) are two of the main complications observed in patients after renal transplantation. Both appear to be manifestations of the same process, in which inflammation plays a determinate role. Pregnancy-associated plasma protein A (PAPP-A) has been shown to be a marker of acute coronary syndrome and cardiovascular pathology. The objective of this study was to demonstrate whether or not serum concentration of pretransplant PAPP-A is a marker of CAN and a predictor of posttransplant cardiovascular events. Methods. In all, 178 renal transplants (65% males; 53±12 years of age) followed up over the course of 49.3±33.6 months were used in this study. During the follow-up period, 19 patients developed CAN (diagnosed by renal biopsy) and 27 patients had a cardiovascular event. Previous to transplantation, the following were determined: ultrasensitive C-reactive protein (CRP) (nephelometry); interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) (immunofluorimetric automatized method), and ultrasensitive PAPP-A (ELISA). Results. A positive correlation was found between PAPP-A and the inflammatory markers (PAPP-A vs. CRP, r=0.218; P=0.004; PAPP-A vs. IL-6, r=0.235; P<0.001; PAPP-A vs. TNF-α, r=0.372; P<0.001). The multiple regression analysis showed PAPP-A (relative risk [RR]: 6.4; 95% confidence interval [CI]:1.24-33.11; P=0.027) and CRP (RR: 6.05; 95% CI:1.21-29.74; P=0.028) to be predictors of posttransplant cardiovascular events and PAPP-A (RR: 4.27; 95% CI: 1.03-17.60; P=0.044) and TNF-α (RR: 5.6; 95% CI: 1.43-21.83; P=0.013) to be predictors of CAN. Conclusions. PAPP-A correlated with the inflammatory markers studied (CRP, IL-6 and TNF-α). Pretransplant serum concentration of PAPP-A is a predictor of posttransplant cardiovascular events and CAN.

Fluvastatin in the prevention of renal transplant vasculopathy: results of a prospective, randomized, double-blind, placebo-controlled trial.

Background. Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial. Methods. The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (&dgr;Vvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of &dgr;Vvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria. Results. A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The &dgr;Vvintima/artery was not different between treatment and placebo groups (6.9±8.2% vs. 6.9±7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (&kgr; 0.86 vs. 0.33). Conclusions. In summary, there were no differences in &dgr;Vvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.

Detection of Epstein-Barr virus in posttransplantation T cell lymphoma in a kidney transplant recipient: case report and review.

Posttransplantation T cell lymphomas (PTTLs) are rather unusual, and their etiology remains unclear. We describe a case of Epstein-Barr virus (EBV)-associated small bowel T cell lymphoma in a patient 5 years after kidney transplantation. EBV was detected in a biopsy sample by in situ hybridization, immunohistochemical staining, and polymerase chain reaction analysis. Eight previously reported cases of EBV-associated PTTL are reviewed, in which special attention is paid to the methods used for assessing EBV. This case of EBV-associated PTTL is believed to be the most completely studied from the point of view of the methods used for detection of EBV. The prognosis of PTTL is poor, but it has been reported that therapeutic approaches can be successful if they are given early in the course of the illness. Therefore, it is necessary to improve the diagnosis PTTL and to assess the precise involvement of EBV in posttransplantation lymphoproliferative disorders.

Unmasking Glucose Metabolism Alterations in Stable Renal Transplant Recipients: A Multicenter Study

BACKGROUND AND OBJECTIVES Emerging information indicates that glucose metabolism alterations are common after renal transplantation and are associated with carotid atheromatosis. The aims of this study were to investigate the prevalence of different glucose metabolism alterations in stable recipients as well as the factors related to the condition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A multicenter, cross-sectional study was conducted of 374 renal transplant recipients without pre- or posttransplantation diabetes. A standard 75-g oral glucose tolerance test was performed. RESULTS Glucose metabolism alterations were present in 119 (31.8%) recipients: 92 (24.6%) with an abnormal oral glucose tolerance test and 27 (7.2%) with isolated impaired fasting glucose. The most common disorder was impaired glucose tolerance (17.9%), and an abnormal oral glucose tolerance test was observed for 21.5% of recipients with a normal fasting glucose. By multivariate analysis, age, prednisone dosage, triglyceride/high-density lipoprotein cholesterol ratio, and beta blocker use were shown to be factors related to glucose metabolism alterations. Remarkably, triglyceride levels, triglyceride/high-density lipoprotein cholesterol ratio, and the proportion of recipients with impaired fasting glucose were already higher throughout the first posttransplantation year in recipients with a current glucose metabolism alteration as compared with those without the condition. CONCLUSIONS Glucose metabolism alterations are common in stable renal transplant recipients, and an oral glucose tolerance test is required for its detection. They are associated with a worse metabolic profile, which is already present during the first posttransplantation year. These findings may help planning strategies for early detection and intervention.

Ghrelin, glucose homeostasis, and carotid intima media thickness in kidney transplantation.

Background. Abnormalities in glucose homeostasis (AGH) frequently occur in kidney transplantation and favor vascular lesions. The purpose of this study was to analyze whether C-reactive protein (CRP), adiponectin, and ghrelin are markers of AGH and indicators of carotid atherosclerosis in kidney transplant patients with fasting plasma glucose below 126 mg/dL. Methods. This was a cross-sectional study of 85 kidney transplant patients (59 men; mean age: 52.4±11.6 years; median posttransplant follow-up 31 (range 3–61) months). All patients underwent an oral glucose tolerance test. Abnormalities in glucose homeostasis were diagnosed following American Diabetes Association criteria. CRP, adiponectin, and ghrelin levels were determined. Doppler ultrasound of the carotid artery was performed to determine intima media thickness (IMT) and atheromatous plaque. Results. A total of 50.5% of patients had AGH (12.9% were diagnosed with new-onset diabetes mellitus after transplantation and 37.7% had impaired glucose tolerance or impaired fasting glucose), whereas 49.4% were normoglycemic. Patients with AGH were older (P=0.002), had greater carotid IMT (P=0.022), and lower ghrelin concentrations (P=0.017) than normoglycemic patients. Logistic regression analyses showed ghrelin to be an independent marker for AGH (P=0.012) and AGH to be related to greater IMT (P=0.041). No differences in adiponectin or CRP were found in relation to AGH or atherosclerosis; however, there was a positive correlation between adiponectin levels and prednisone dose (r=0.240; P=0.044). Conclusions. A total of 50.5% of the study patients had abnormalities in glucose homeostasis. Patients with AGH had a higher percentage of preclinical atherosclerosis (greater carotid IMT). Ghrelin is an independent marker for abnormalities in glucose homeostasis.

Posttransplant Inflammation Associated With Onset of Chronic Kidney Disease

BACKGROUND Chronic allograft nephropathy (CAN), a major complication in renal transplant patients, is an important cause of graft loss. Inflammation as measured in the pretransplant and posttransplant phases, using various markers, has been associated with worse renal function and a greater risk of cardiovascular disease and of long-term graft loss. OBJECTIVE The objective of our study was to evaluate whether worsening inflammation in the first 3 months postoperatively was a risk factor for developing CAN. PATIENTS AND METHODS We performed a cross-sectional study in 207 patients. The following markers of inflammation (MIF) were determined pretransplant and at 3 months after grafting: C-reactive protein (CRP) (mg/L), interleukin (IL)-6 (pg/mL), IL-10 (pg/mL), tumor necrosis factor (TNF)-α (pg/mL), and its soluble receptor (ng/mL), soluble-IL2R (UI/mL), pregnancy-associated plasma protein A (PAPP-A; mUI/L), and IL-4 (pg/mL). We also calculated the ratio at 3 months versus the pre value of MIF. RESULTS CAN was diagnosed after the first year in 23 patients (11.3%) always by renal biopsy performed for clinical indications. Patients with CAN showed worse inflammation, eg, MIF ratios over one, with statistically significant differences for the ratios of TNF-α and PAPP-A (P=.032 and P=.051 respectively). Upon multivariate logistic regression analysis, using CAN as the dependent variable and age, sex, donor age, months on dialysis, acute tubular necrosis, acute rejection, and MIF ratios as covariates, we observed that an acute rejection episode (OR=13.03; CI=2.8-60.9; P=.001), CRP ratio (OR=1.36; CI=1.07-1.73; P=.013), and PAPP-A ratio (OR=1.80; CI=0.92-3.53; P=.005) were independent markers of CAN. CONCLUSIONS Among other factors, inflammation may determine the onset of CAN as diagnosed by renal biopsy.