Use of the new proliferation signal inhibitor everolimus in renal transplant patients in Spain: preliminary results of the EVERODATA registry.

Everolimus (Eve) has shown good efficacy and safety profiles in clinical trials in combination with low doses of cyclosporine but there is limited experience in other modes, especially with calcineurin inhibitor elimination. We developed a retrospective study to analyze its clinical use after approval in Europe in 2005. Herein we have presented the results of a series of 272 patients followed for the first 6 months after Eve introduction. In 93.8% of cases Eve was introduced after the first month posttransplantation (conversion use), and 6 months after introduction, the CNI had been eliminated in 75% of cases. The main indication for Eve introduction was the diagnosis of a malignant neoplasm (42%), whereas the combined indication of prevention and/or treatment of toxicity, especially nephrotoxicity, accounted for 46.3% of cases. Initial doses were low (1.37 mg/d), but were progressively increased up to 2 mg/d at 6 months. Renal function remained unchanged during the follow-up period, whereas proteinuria moderately increased. Only 5 cases (2%) of acute rejection episodes were observed with excellent patient and graft survivals at 6 months after conversion. Further analysis of this extensive series of patients with a longer follow-up is needed.

[Kidney transplant]. / Trasplante renal.

The kidney transplant is the therapy of choice for the majority of the causes of chronic terminal kidney insufficiency, because it improves the quality of life and survival in comparison with dialysis. A kidney transplant from a live donor is an excellent alternative for the young patient in a state of pre-dialysis because it offers the best results. Immunosuppressive treatment must be individualised, seeking immunosuppressive synergy and the best safety profile, and must be adapted to the different stages of the kidney transplant. In the follow-up to the kidney transplant, cardiovascular risk factors and tumours must be especially taken into account, given that the death of the patient with a working graft is the second cause of loss of the graft following the first year of the transplant. The altered function of the graft is a factor of independent cardiovascular mortality that will require follow-up and the control of all its complications to postpone the entrance in dialysis.

Preliminary results of the effect of treatment of hyperhomocysteinemia and its relationship with inflammation, coagulation status, and endothelial function after renal transplantation.

The aim of this study was to assess the relationship between total plasma homocysteine (tHC) and several markers of endothelial function, coagulation, and pro-inflammatory status in renal transplant recipients. Our own previous study demonstrated the efficacy of folic acid (FA) and vitamin B(12) (B(12)) treatment to reduce tHC. Using 70 stable recipients, 56 of whom showed hyperhomocisteinemia (HHC) (tHC > or = 14 micromol/L) and a control group (n = 14, tHC < 14 micromol/L), we treated 29 patients in the HHC group (10 mg FA and 500 mg B(12) daily) and determined their endothelial function, inflammatory activity, and coagulation status. We assessed plasma levels of von Willebrand Factor and fibrinogen as the prothrombotic profile and C-reactive protein and plasma albumin as inflammation markers. We performed Doppler sonography of the brachial artery to assess endothelial function. The mean value of plasma tHC of 19.05 +/- 3.70 micromol/L before treatment decreased to 13.45 +/- 3.25 micromol/L after 3 months of treatment (P < .001). The vWF was significantly correlated with tHC (P < .05) and was higher in the HHC patients (P < .05). The fibrinogen mean level was also significantly higher in HHC patients (P < .05). The C-reactive protein level was significantly higher and the albumin level was lower among patients with HHC. The endothelium-dependent dilation (EDD) correlated with baseline tHC (P < .05). In preliminary data we observed that homocysteine-lowering therapy may provide cardiovascular protection by enhancing endothelial function, limiting oxidative stress, and reducing procoagulation status.

Detection and treatment of post kidney transplant hyperglycemia: a Spanish multicenter cross-sectional study.

INTRODUCTION: The prevalence of diabetes mellitus (DM) is greater among patients with solid organ transplants than in the general population, although the factors associated with posttransplant DM (PTDM) are unknown. OBJECTIVES: The objective of this study was to estimate the prevalence of and assess the risk factors for PTDM. PATIENTS AND METHODS: We included outpatients with functioning isolated solid organ allografts (kidney, liver, heart, and lung). We collected demographic and posttransplant clinical data that included DM diagnostic ADA criteria, DM treatment, DM family history, presence of hepatitis C virus (HCV), immunosuppression treatment, hypertension, and dyslipidemia. RESULTS: A total of 2178 patients included, 1410 kidney recipients, 489 liver transplants, 207 heart transplants, and 72 lung recipients. Seventeen and four-tenths percent of the patients who did not have DM prior to transplantation, developed PTDM (median time: 79 days). A greater prevalence was observed among patients with a family history, HCV, and tacrolimus treatment (with or without steroids P < .05). By logistic regression analyses, OR for these factors were 1.51, 1.65, and 1.38, respectively. Of those patients who did not suffer PTDM, 55.2% showed basal blood glucose values under 100 mg/dL; only 68% presented with a hemoglobin Alc under 6. CONCLUSIONS: The prevalence of PTDM among kidney recipients was higher than that in the general population. DM family history, HCV positive, and tacrolimus were risk factors associated with this entity.

Generation of mouse cytolytic T cells against human concanavalin A blasts. Involvement of non-MHC determinants in the antihuman response.

Normal human peripheral blood lymphocytes (PBL) are incapable of eliciting a significant murine cytotoxic T cell (CTL) response either in vivo or in vitro. However, using a primary in vivo and secondary in vitro stimulation with lectin-activated PBL, Thy-l-positive cytotoxic cells were produced. The antigens that these T-cells identified were independent of the serum source employed in the culture medium used for lectin activation. The cells always preferentially lysed cells from the immunizing individual but were also able to lyse target cells from unrelated individuals, regardless of HLA identity or disparity with the immunizing individual, suggesting the presence of both a private (possibly class II antigens) and public specificity. Using the lymphoblasts of different family members as immunogen and targets there was slight preference of the CTL for HLA-identical targets with no apparent difference between the lysis exhibited against semiidentical and nonidentical subjects. Monoclonal antibodies directed against HLA DR or beta 2-microglobulin failed to inhibit the cytotoxicity observed in these experiments. It is suggested that under these circumstances of xenogeneic education, non-MHC-restricted T cells may become cytotoxic, and this model may serve as a useful probe to investigate some of the less-well-defined aspects of the T cell repertoire.

Localization of major histocompatibility complex (HLA-ABC and DR) antigens in 46 kidneys. Differences in HLA-DR staining of tubules among kidneys.

Biopsies from 46 kidneys that were subsequently transplanted were examined with monoclonal antibodies and the peroxidase-antiperoxidase technique to localize HLA-ABC and DR antigens. There was no variation in the expression of HLA-ABC which was present on all cells of the renal parenchyma. HLA-DR was found consistently on the endothelium of glomeruli and of intertubular capillaries but was only weakly expressed, or not expressed at all, on the endothelium of large vessels. The mesangium of glomeruli also stained for HLA-DR. But there was a striking variation in the expression of HLA-DR by proximal renal tubular cells in the 46 kidneys. HLA-DR was absent from tubules in 11 of 46 kidneys (23%) and probably absent or very weakly expressed in a further 8 kidneys (17%). The expression of HLA-DR in tubular epithelium was not related to the donor's age, sex, blood group, or ischemia times. However, the frequency of HLA-DR3 increased (55%) in donors of kidneys with tubular DR-negative kidneys, as compared with a frequency of 15% in donors of tubular DR-positive kidneys. Although this difference was not significant after a correction for the number of comparisons made, it suggests a genetic influence on the expression of tubular DR. The survival of tubular DR-negative kidneys was better at 1 year than that of tubular DR-positive kidneys (70% vs. 57%--not significant), and tubular DR-positive grafts may have had a higher rate of delayed function when transplanted in cases with a donor-specific positive B cell crossmatch. There was no obvious variation in the number of dendritic cells stained with antibodies to HLA-DR and the leukocyte common antigen despite prior administration of high doses of steroids to some donors before nephrectomy.

Mast cells in chronic rejection of human renal allografts.

An increased number of mast cells (MCs) is found in renal specimens of patients with diseases associated with persistent chronic inflammation. MCs proliferation is partly dependent on the presence of T lymphocytes. Both chronic inflammation and T-lymphocytes are essential in the development of chronic rejection (CR), and probably for the infiltration of MCs. MC-derived products such as heparin, histamine, and serine proteases may be responsible for endothelial proliferation and excess collagen production by fibroblasts. In this study, a quantitative evaluation of the MCs infiltration in kidney allografts with CR is performed. The extent of renal fibrosis was analysed in samples stained with Masson's trichrome. To evaluate the potential relationship between MCs and fibrosis in CR we analysed 30 kidneys with CR (25 from nephrectomies and 5 from autopsies). Ten transplanted kidneys obtained from patients died by causes not related with rejection were used as controls. CR was graded according to the Banff schema, which assesses the degree of vasculopathy, tubular atrophy, interstitial fibrosis and transplantation glomerulopathy. Giemsa-stained sections and immunohistochemistry using anti-MC tryptase and c-kit monoclonal antibodies were used to detect MCs. The mean number of MCs per 20 high-power fields (HPF) in the transplanted kidney with CR was 101.8+/-15.3 in the renal cortex and 46.60+/-6.52 in the medulla. MCs were significantly more numerous in CR with respect to normal kidneys, both in the cortex (P<0.01; Mann-Whitney U test) and in the medulla (P<0.01; Mann-Whitney U test). There was a positive correlation between the number of MCs and extent of fibrosis (P<0.01; Kruskal-Wallis one-way anova test) and tubular atrophy (P<0.01). These results suggest that MCs may play a role in the process of development of interstitial fibrosis in CR.

Benefits of a dietary intervention on weight loss, body composition, and lipid profile after renal transplantation.

The nutritional status of a group of 23 renal transplanted patients with a body mass index > 27, hyperlipidemia, and stable renal function were studied before and after 6 mo of dietary intervention with the American Heart Association (AHA) Step One pattern. The dietary records showed that the intake of total fat decreased from 42.2 +/- 5.5 to 33.0 +/- 4.2% (P < 0.001) and the intake of saturated fat decreased from 12.8 +/- 1.8 to 9.2 +/- 3.1% (P < 0.01) of total calories. The cholesterol intake fell from 352 +/- 10 to 221 +/- 12 mg/d. The mean weight loss was 3.2 +/- 2.9 kg (P < 0.001), followed by a significant decrease in mean body fat mass (%) measured by triceps skinfold (34.2 +/- 3.3 versus 32.9 +/- 3.7; P < 0.05), bioelectrical impedance (30.8 +/- 5.7 versus 26.5 +/- 5.9; P < 0.001), and infrared interactance (37.5 +/- 6.3 versus 34.7 +/- 5.5; P < 0.01). After the dietary intervention, lipid profile improved in all patients, with a decrease in the mean total cholesterol (237 +/- 32 versus 224 +/- 36 mg/dL; P < 0.05), which was higher in males. Also, low-density lipoprotein cholesterol was reduced in male patients (156 +/- 19 versus 136 +/- 11 mg/dL, P < 0.05), whereas in females low-density lipoprotein cholesterol levels remained unaltered. The high-density lipoprotein cholesterol and triacylglycerol values were not affected in both males and females by the dietary treatment. The reduction in serum cholesterol was inversely correlated with the initial values of triceps skinfold (r = 0.52, P < 0.01) and was lower in patients with a body mass index > 30 (5.7 versus 2.8%, NS). It is concluded that the obesity and hyperlipidemia following renal transplantation may be improved by dietary intervention and subsequent weight loss.

Kidney allograft biopsy: a valuable tool in assessing the diagnosis of acute rejection.

In order to determine the value of an isolated renal percutaneous biopsy in renal allografts with acute rejection, we studied 17 allograft nephrectomies, in which the histological degree of acute rejection of each of 30 Tru-cut cylinders, were compared with the histological degree of acute rejection diagnosed in 6 large fragments of each kidney considered as a whole. An accurate histological degree of acute rejection was made in 366 cylinders (71.8%). One hundred twenty-nine kidney cylinders (25.3%) were considered of a minor histological degree of acute rejection and 15 cylinders (2.9%) of a higher histological degree. We conclude that percutaneous renal allograft biopsy provides a representative picture of acute rejection histopathology but must be evaluated with other clinical and biochemical data for a correct clinical management.

De novo hemolytic-uremic syndrome/thrombotic microangiopathy in renal transplant patients receiving calcineurin inhibitors: role of sirolimus.

The aim of this study was to evaluate the outcome of ten renal transplant recipients who developed de novo hemolytic uremic syndrome/thrombotic microangiopathy (DnHUS) after treatment with calcineurin inhibitors among 3,862 patients transplanted during the period 2000-2001 in Spain, and the results of switching to sirolimus for resolution of this pathologic condition. No patient had end-stage disease due to primary HUS. The criteria of diagnosis were decreased renal function, biopsy-proven thrombotic microangiopathy, and no signs of acute rejection. Calcineurin inhibitors were completely removed and immediate treatment with sirolimus started after diagnosis. The follow-up period was 19.0+/-4.3 months, at least 12 months after diagnosis. One patient died of sepsis shortly after starting sirolimus therapy. The serum creatinine level in the series decreased from 5.2+/-2.6 mg/dL at the time of biopsy to 2.15+/-1.9 mg/dL 1 month later (P=.011). All but one of the nine recipients, who lost his graft 3 months later (80% success) maintained function, with a serum creatinine of 2.1+/-1.4 mg/dL and Cockroft index of 61.3+/-34 mL/min at the end of follow up. During this time, none of the patients experienced an acute rejection episode and sirolimus was maintained without any remarkable secondary effect. Sirolimus seems to be a promising alternative for the treatment of renal transplant patients who develop calcineurin inhibitor-induced DnHUS.

Autosomal-dominant polycystic kidney disease: high prevalence of graft loss for death-related malignancies and cardiovascular risk factors.

Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease with multiple extrarenal manifestations. It accounts for 7% to 11% of patients receiving dialysis or renal transplantation (RT) for end-stage renal disease (ESRD) in Europe. We analyzed retrospectively the causes of death, the prevalence of cardiovascular risk factors (CVRF) and the patient and graft survivals in 62 consecutive ADPKD patients who received 63 cadaveric grafts (29 men and 34 women), of the 600 RTs performed between 1980-2001. The diagnosis of ADPKD was established by family history and ultrasound techniques. At present, 50 patients (79.4%) have functioning grafts, with a mean follow-up of 84.7 months (range, 12-255), and 13 patients have lost their grafts. The main cause of failure was patient death with a functioning graft (9 cases). Malignancies occurred in 5 patients, including 2 lymphomas, 1 renal carcinoma, 1 pancreas sarcoma, and 1 lung cancer associated with infection. Three patients died of cardiocerebrovascular events, and 1 patient of pneumonia. One patient lost the graft after decreasing the immunosuppression for an obstructing colon cancer. Three additional patients now on dialysis lost their grafts due to chronic rejection in 2 cases and primary nonfunction in 1 case. The prevalence of cardiovascular risk factors among the 50 patients with functional grafts were: hypertension, 70%; hypercholesterolemia, 62%; hyperhomocysteinemia, 30%; hyperfibrinogenemia, 68%; increased lipoprotein (a), 18%; microalbuminuria, 22%; hyperuricemia, 48%; hyperparathyroidism, 24%; overweight status, 24%; and nonlethal myocardial infarction, 10%. We conclude that ADPKD patients have good graft and patient survivals, and that the presence of malignancy is the main cause of death and graft failure at our center.

Treatment of hyperhomocysteinemia after renal transplantation.

INTRODUCTION: Several epidemiologic prospective studies have provided strong evidence that hyperhomocysteinemia (HHC) is a risk factor for cardiovascular disease (CVD) due to its role in producing endothelial damage due to oxidation stress. Several studies show that combined folic acid (FA) and vitamin B12 (B12) treatment decreases fasting total homocysteine (HC) levels in renal transplant recipients (RTR). The aim of the study was to determine the efficacy and safety during one year of combined FA and B12 treatment in 89 RTR, as well as the relationship between HHC with other known risk factors for CVD and the intrinsic characteristics of the transplantation. METHODS: Among 193 RTR in whom we determined the baseline levels of HC, FA, B12, creatinine, and CV risk factors, 81 had normal (HC < 14 micromol/L) and 112 elevated (HC > or = 14 micromol/L) HC levels, 89 of whom were included in a treatment group (23 nontreated). Analytic measures were performed at baseline and 1, 3, and 12 months. RESULTS: We observed a decrease in HC levels among the treatment group (P<.05) after 12 months without differences in the other groups. There were no differences in age, hypertension, hypercholesterolemia, smoking, presence of diabetes, or type of immunosuppression between the groups. There was a significant correlation between basal creatinine and HC level (P<.05). A higher prevalence of CVD was observed in the HHC group (P<.05). CONCLUSION: HHC is associated with worse renal function and a higher prevalence of CVD. FA and B12 treatment normalize HC levels, representing a safe treatment that could improve the long-term vascular prognosis of RTR.

[Changes in the post-kidney transplantation body composition: different behavior between men and women]. / Cambios en la composición corporal postrasplante renal: diferente comportamiento entre hombres y mujeres.

A kidney transplant often leads to an increase in body weight, with an altered composition of the organism. This study assessed the body composition of a population with kidney transplant and an excess of weight (IMC > 25), using anthropometry, electric bio-impedance, and infrared interactance. The results were compared with the mean values (P50) for the Spanish population, and the differences between men and women were analyzed. The assessment of the body composition using anthropometry resulted in weight percentages, -mid-arm circumference, and -mid-arm muscle circumference of the upper arms, which were slightly higher than the P50, without there being any differences between the two sexes. The triceps fold showed values which were much higher than the average value, and this was more markedly seen in male. All patients showed an android type obesity pattern, and this was greater in men. The electric bio-impedance analysis and the infra-red interactance showed high fat levels for both sexes, without any statistically significant differences with respect to the percentages of fat mass, lean mass and water with both methods. The study has shown that the weight increase as a result of the kidney transplant, is mainly accompanied by an increase in the adipose tissue, and this is more marked in patients of the male sex, in such a way that the typical significant differences between both sexes with respect to the fat mass, commonly seen the general population, disappear.

[Multivariate analysis of the factors influencing the occurrence of surgical complications in renal transplantation]. / Análisis multivariado de los factores influyentes en la aparición de las complicaciones quirúrgicas en el trasplante renal.

Study of 307 renal corpse transplants performed in our centre, gathered in two series according to the immunosuppressive approach used, with and without cyclosporin A (Current and Historic Series, respectively). The surgical complications encountered are assessed and divided into urinary, vascular and other. Using a multivariate analysis, the factors influencing the occurrence of each of them are examined. In the Historic Series, the prognostic factors for the occurrence of urinary complications are the type of extraction and the duration of cold ischaemia. Regarding vascular complications, these factors are the type of anastomosis and the receptor's age. With respect to all other complications, the single influential factor is the initial delayed function. In the Current Series, the prognostic factors relative to urinary complications are the receptor's age, the duration of cold ischaemia, and the donor's age. No multivariate analysis is made of vascular complications due to their small number. The remaining complications are related, as in the other series, to the initial delayed function.

["De novo" malignant tumors in kidney transplant receptors]. / Tumores malignos "de novo" en receptores de trasplante renal.

Presentation of the "de novo" tumours developed in two series of renal transplant receptors over the last 16 years. The first series, Historic, comprises the group of 178 patients who were given Azathioprin or Cyclophosphamide plus Prednisone for immunosuppression. The second series, Current, includes 129 patients who received immunosuppressive therapy with Cyclosporin A. Overall incidence of these "de novo" malignant tumours was 4% (13/307), 9 of which corresponded to the Historic Series (incidence, 5%) and 4 to the Current Series (incidence, 3%). Mean time interval from transplantation to diagnosis was 87.3 months (range, 9-177) in the Historic Series and 34.5 (range, 8-67) in the Current Series, the difference being statistically significant (p = 0.02). By locations, skin and lip tumours represent 38.5%, followed in frequency by lymphoma (23%) and lung carcinoma (15%). No urological tumours were recorded.

[Adjusted survival of the graft in renal transplantation. Multivariate analysis of prognostic factors]. / Supervivencia ajustada del injerto en el trasplante renal. Analisis multivariado de los factores pronóstico.

Three hundred and seven first corpse transplantations performed in the Clínica Universitaria of Navarra since 1976 are analyzed. The cases are divided in two series, Current and Historic, depending on whether the immunosuppressive protocol included cyclosporin A. First, actual survival curves from both series were compared, obtaining a significantly improved survival in the cyclosporin A series (p). Then, the most influential prognostic features in each series are analyzed for the various post-transplantation periods. With regard to adjusted graft survival in the Historic Series, both initial function and the number of rejections have influence during the first post-transplantation year. HLA A + B identities and the donor's age influence during the immediate one-to-three months period. In the Current Series, time of cold ischaemia and number of rejections act during the earliest (first month) and the latest (between one to three years) periods. The donor's cause of death and the recipient's age influence during the first month of evolution. The initial function and the presence of surgical complications influence between the first month and the first year.

[Urologic complications in 237 recipients of cadaveric kidney transplantation]. / Complicaciones urológicas en 237 receptores de trasplante renal cadavérico.

We describe the urological complications occurred in 237 patients undergoing cadaveric renal transplant in 13 years. Two techniques of extravesical ureterocystoneostomy were used. Thirty patients (13%) presented 35 (15%) urological complications: 23 (9.7%) urinary fistula and 12 (5.1%) ureteral stenosis. The vast majority (80%) were early complications (before 90 days): 82% fistulas and 18% stenosis. All early complications were identified as technical deficiencies; all late complications were obstructive in nature. A new ureteral reimplant was performed in 15 patients, with successful results in 14. Six patients underwent nephrectomy and pyelostomy, 2 of these required a second operation. Seven patients underwent endo-urological procedures with good results. Three patients undergoing conservative treatment for urinary fistula required surgical drainage of an infected urinoma. No statistical difference was observed in the survival rates of both the grafts and the patients presenting or not urinary complications.

[Vascular complications in 237 recipients of renal transplant from cadaver]. / Complicaciones vasculares en 237 receptores de trasplante renal de cadáver.

Between July 1976 and June 1990, 244 transplantations were performed. Of the 237 patients monitored, 13 (5.4%) had vascular complications: 10 (77%) renal artery stenosis, 1 (7.7%) primitive iliac artery stenosis, 1(7.7%) renal artery thrombosis, 1 (7.7%) renal vein thrombosis. Six patients underwent surgery (Angioplasty was performed in three patients, re-anastomosis to the common iliac artery in one, by-pass of saphenous vein in another one, while in the last one it was tried a release of the vascular pediculus). Management with drugs was possible in one case. At present, 11 of the 13 patients are still alive and three of the grafts remain functional after a mean follow-up time of 83 months. According to a univariate study, the influential factors in the development of vascular complications are, the identity of Locus A, the type of extraction in Locus B, the length of cold ischaemia, the type of vascular anastomosis and the number of previous rejections. The factors with maximal influence in the development of complications are the type of vascular suture (with or without patch) and the number of previous rejections (according to a study of log regression models). The study demonstrates the significant influence vascular complications have on the graft's durability (p = 0.005).

[Prognostic value of initial function in graft and patient survival in cadaveric renal transplant; impact of cyclosporin A]. / Valor pronóstico de la función inicial en la supervivencia del injerto y del paciente en el trasplante renal de cadáver; impacto de la ciclosporina A.

This paper presents our experience with 237 primary renal cadaveric transplants and analyzes related factors to Initial Non-Function, its influence on graft and patient survival as well as the impact of cyclosporin A on graft survival. Our study shows better graft survival rates in patients treated with cyclosporin A and in patients with Immediate Initial Function.

[Effect of time of vascular anastomosis and of hot and cold ischemia, on survival of cadaver renal graft]. / Influencia de los tiempos de anastomosis vascular, isquemia caliente y fría, en la supervivencia del injerto renal de cadáver.

A retrospective study was performed on our series of 240 primary cadaveric renal transplant recipients to dissect the influence of vascular anastomosis time, warm ischemia time and cold ischemia time on ultimate graft survival. 177 patients received conventional immunosuppression with Azatioprine and steroids, and 63 patients received Cyclosporine A therapy. The data was analyzed for sub-groups of ischemia time and comparisons were performed using the method of Tarone-Ware. The present study fails to demonstrate a detrimental effect of ischemic insults on graft survival. The use of Cyclosporine A in the pre and post-transplant, monitoring periodically serum cyclosporine levels and the use of renal allograft biopsy, allows the use of this agent without a high incidence of nefrotoxicity.