Elevated serum gamma-glutamyltransferase and hypomagnesemia are not related with new-onset diabetes after transplantation.

BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) contributes to the risk of cardiovascular disease (CVD) and infection, reducing graft and patient survival in kidney transplant recipients. To reduce CVD and improve outcomes of kidney transplant recipients, it is of great interest to more precisely elucidate the risk factors that contribute to the development of NODAT. A previous study reported that hypomagnesemia is an independent predictor of NODAT. Elevated gamma-glutamyltransferase (GGT) activity increases the risk of incident type 2 diabetes in the general population. The objective of this study was to determine whether magnesium (Mg) and GGT were risk factors for NODAT among our population of kidney transplant recipients. METHODS: We retrospectively analyzed 205 non-previously diabetic kidney transplant recipients. GGT was measured before transplantation as well as at months 1, 2, and 12. Mg was measured at months 1, 2, and 12. NODAT was defined at month 12 and at the end of follow-up according to the "2003 international consensus guidelines." RESULTS: Although 36 patients (17.5%) developed NODAT at month 12, 55 patients (26.8%) displayed it at the end of follow-up. We did not observe any significant difference, either in mean Mg (month 1, 1.73±0.24 vs 1.75±0.30 [P=.824]; month 2, 1.71±0.22 vs 1.68±0.26 [P=.565]; month 12, 1.77±0.27 vs 1.80±0.24 [P=.596]) or GGT values (pretransplantation, 32 ± 27 vs 33±85 [P=.866]; month 1:39±24 vs 48±70 [P=.452]; month 2, 53±96 vs 48±83 [P=.739]; month 12, 40±37 vs 38±53 [P=.830]) between NODAT and non-NODAT patients at month 12 or at the end of follow-up. CONCLUSION: Hypomagnesemia and high GGT activity were not risk factors for NODAT development in kidney transplant recipients.

Determinants of resistive index shortly after transplantation: independent relationship with delayed graft function.

Measurement of the vascular resistive index (RI) by Doppler ultrasonography has been proposed as a non-invasive method to evaluate renal allograft dysfunction, but there are conflicting reports about its clinical utility. The aim of our study was to analyse the donor and recipient characteristics related to RI measured at days 2 and 3 after renal transplantation and the relationship between RI and allograft outcome. RI was measured by Doppler ultrasonography in 333 patients at days 2 or 3 post-transplantation. Donor and recipient variables and allograft outcome were collected from a prospectively maintained institutional database. In patients with RI higher than 0.7, donor age, recipient age, duration of renal replacement therapy, incidence of diabetes, hypertension and atherosclerosis in the recipient, pulse pressure, initial creatinine and the incidence of delayed graft function (DGF) were higher. After multivariate analysis, the only variables that remained significant for an increased risk of higher RI were recipient age over 55 years, presence of diabetes in the recipient and DGF. Recipient age, previous diabetes mellitus and DGF are the most important determinants of transplant kidney RI in the first days after transplantation. So both the graft recipient and the graft itself, but not the donor, determine intra-renal Doppler indices.

Correlation of C0 and C2 levels with cyclosporine side effects in kidney transplantation.

Cyclosporine has a narrow therapeutic window requiring close monitoring to ensure adequate immunosuppression while avoiding nephrotoxicity and other side effects. Pharmacokinetic studies have suggested that cyclosporine levels at 2 hours postdose (C2) is the best single time point to predict area under the concentration curve (AUC) in kidney transplant recipients. C2 also predicted acute rejection episodes and nephrotoxicity better than trough levels (C0). Targeting cyclosporine levels to minimize side effects while maintaining adequate immunosuppressive effects is of clinical interest. There are conflicting evidence and few reports about whether cyclosporine-related side effects are a dose-dependent phenomenon. The aim of this single center study was to ascertain whether cyclosporine side effects were dose-dependent and which single time point level (C0 or C2) was more closely related to them. We analyzed 225 patients on Neoral-based immunosuppression with C0 and C2 levels measured on the same day of 2 different visits. Serum creatinine, glucose, uric acid, potassium, total cholesterol, triglycerides, and 24-hour urinary sodium elimination were measured by routine biochemical analyses. Blood pressure was measured at each visit. A significant positive correlation was observed between C2 and C0 concentrations and levels of potassium (P < .001), total cholesterol (P < .001), systolic blood pressure (P < .001), and pulse pressure (P < .01). There was a significant negative correlation between C2 and uric acid (P < .001). AUCs of receiver operating characteristic (ROC) curves for both C2 and C0 levels were significant as predictors of hyperkalemia (P < .001), hyperuricemia (P = .001), hypercholesterolemia (P < .05), and high systolic blood pressure (P < .05). There were no significant differences between the capacities of C2 or C0 to predict these variables. In conclusion, potassium, total cholesterol, uric acid, and systolic hypertension were influenced by cyclosporine in a dose-dependent manner. Both C2 and C0 were useful to predict cyclosporine side effects.

[Dialysis and transplant. Spain in 2005]. / Informe de Situación de Diálisis y Trasplante en España, 2005.

In 2005, renal replace treatment (dialysis and transplant) was necessary for about 40,000 people, without being known the number accurate and either their basic characteristics, such as: time in treatment, modality or treatment changes. The presented data cover the 76% of the Spanish population and are the result of the cooperation among technicians of registries, nephrologists and transplant coordinations. 4,125 people started RRT in 2005, the total estimated acceptance rate for renal replacement therapy in adults in Spain was 126 pmp and regarding other European countries it locates us in an intermediate area. The incidence rate seems to keep stable in the last years although there were some differences among communities (from 104 pmp in Castile and Leon to 186 pmp in Canary Islands). Diabetes Mellitus is the most diagnosed cause of renal failure in 2005, more than 20% of patients, followed by vascular diseases. The estimated prevalence of renal replacement therapy in Spain at the end of 2005 was 903 pmp, with important variations among communities (from 806 pmp in Cantabria to 1056 pmp in Valencia Region). The 47% of prevalent RRT patients had a functioning transplant. Mortality on haemodialysis and peritoneal dialysis was 13.7% and 10.8% respectively. Mortality on transplant was 1.3%, one of the lowest values registered so far. Mortality on renal replacement therapy was around 5% among patients from 45 to 64 years, 11% between 65 and 74 years and 19% among the patients older than 75 years.

[Abscess colon diverticular disease produced for Actinomyces israelii in a renal transplant recipient]. / Diverticulitis abscesificante por Actinomyces israelii en un trasplante renal.

We present the case of a 53 years old man with a cadaveric kidney transplant under cyclosporin A and prednisolone therapy. Clinical transplant course was uneventful until 15 years after transplant, when he was admitted in our hospital with fever and a perirenal mass of unknown origin. Cyclosporin A was removed and a left sided colon was carried out and a abscess colon diverticular disease produced for Actinomyces israelii was diagnosed. The development was satisfactory after medical and surgical treatment.

Blood volume expansion with hyperoncotic colloids deteriorates allograft function in a canine model of renal transplantation.

PURPOSE: We investigated the effects of acute maximal hydratation with hemoce (H) and dextran-40 (D40) on the postoperative graft function, following renal transplantation (RT) in a canine model. METHODS: After induction of anesthesia with pentobarbital (5 mg/kg), 18 beagle dogs were randomized to receive either saline solution to increase the central venous pressure (CVP) to 5 mm Hg (GI); H solution to increase the CVP to 10 mm Hg (GII); or D40 to achieve 15 mm Hg (GIII), before reperfusion. A pulmonary artery catheter was used to measure CVP, mean pulmonary artery pressure, and cardiac output (CO). The surgical procedure consisted of autotransplantation of the dog's left kidney an hour prior to cold ischemia with University of Wisconsin solution, followed by contralateral nephrectomy. Diuresis, creatinine (Cr), and BUN levels were measure at 24 hours before RT, as well as 24, 48, and 72 hours after the procedure. RESULTS: Only in the treated groups did cardiac filling pressures and CO increase as a result of hydration. Only in the GI group did serum Cr and blood urea nitrogen significantly peak at the second postoperative day while it continued to increase at two (GII) and three (GIII) times greater than GI on the third day. Histological examination showed osmotic nephrosis like-lesions only among treated grafts. CONCLUSION: We concluded that maximal hydration with H and D40 colloid deteriorated postoperative graft function after RT. We believe that in the future the effects of any colloid solution should be tested in an animal model in the fashion as we have described, in order to know which one, and at what dose, is the safest to improve kidney allograft outcome.

Evaluation of the efficacy and safety of the conversion from a calcineurin inhibitor to an everolimus-based therapy in maintenance renal transplant patients.

Everolimus has recently been introduced into clinical practice with promising perspectives due to its efficacy, lack of nephrotoxicity, and antitumor effects. Experience in clinical trials associated with low-dose cyclosporine showed good results, but there is almost no experience in calcineurin inhibitor (CNI) elimination learning it as the primary immunosuppressant. We describe our experience in a series of 78 stable renal transplant patients who were switched to Everolimus with complete and quick elimination of the CNI: the procedure of conversion, pharmacokinetic results after conversion, evolution of renal parameters (renal function, proteinuria, and others), and safety data (acute rejection and adverse events). An initial dose of 3 mg/d was adequate to obtain the recommended trough levels between 5 and 10 ng/mL. Our results demonstrated that conversion to Everolimus was a simple, safe procedure that must be considered in patients CNI toxicity, especially those with malignant neoplasms and progressive deterioration of renal function due to chronic allograft nephropathy.

Cytokine polymorphisms and risk of infection after kidney transplantation.

INTRODUCTION: Infection remains a significant cause of morbidity and mortality after solid organ transplantation. Genetic background has an influence on the incidence of infection. The aim of our study was to analyze the relationship between cytokine polymorphisms and infection in our kidney transplant recipients. METHODS: DNA from 255 kidney transplant recipients was isolated routinely. Polymerase chain reaction sequence-specific primer was performed using commercially available cytokine genotyping primer packs to determine polymorphisms of interleukin (IL)-10, transforming growth factor-beta, tumor necrosis factor-alpha, interferon-gamma, IL-6, IL-4, IL-2, IL-12, IL-4R alpha, IL-1RA, IL-1R, IL-1 beta, and IL-1 alpha. The appearance and number of infections within the first year after transplantation were identified retrospectively. RESULTS: One hundred twenty-two patients experienced at least one episode of infection in the first year after transplant. The frequency of the -511 IL-1beta CC genotype and the frequencies of the -1188 IL-12 CA and CC genotypes were significantly higher among the infected patients compared with the noninfected patients. We failed to observe significant differences in the genotype distribution of the other analyzed cytokines regarding the incidence of infection. After adjusting, recipient IL-1beta (-511 CC) genotype (relative risk [RR] 2.67, 95% confidence interval (CI) 1.30 to 5.49, P = .007) and recipient IL-12 (-1188 CA and CC) genotypes (RR 2.57, 95% CI 1.22 to 5.38, P = .012) predicted independently the risk of infection in the first year after kidney transplantation. CONCLUSION: Kidney transplant recipients with -511 IL-1beta CC genotype or with -1188 IL-12 CA and CC genotypes were at higher risk of developing infections in the first year after transplantation. Patients with genetic susceptibility to infection may benefit from less potent immunosuppressive therapy and more intense preventive measures.

Diverticulitis abscesificante por Actinomyces israelii en un trasplante renal / Abscess colon diverticular disease produced for actinomyces israelii in a renal transplant recipient

Paciente de 53 años, trasplantado renal en tratamiento con Ciclosporina A y esteroides, con buena función renal, que ingresa 15 años después del trasplante por fiebre y una masa perirrenal a estudio. Al ingreso, se retiró la Ciclosporina A y, tras realizar diversas pruebas de imagen, se hizo una hemicolectomía izquierda detectándose una diverticulitis abscesificante por Actinomyces israelii con evolución favorable

We present the case of a 53 years old man with a cadaveric kidney transplant under cyclosporin A and prednisolone therapy. Clinical transplant course was uneventful until 15 years after transplant, when he was admitted in our hospital with fever and a perirenal mass of unknown origin. Cyclosporin A was removed and a left sided colon was carried out and a abscess colon diverticular disease produced for Actinomyces israelii was diagnosed. The development was satisfactory after medical and surgical treatment

Informe de situación de diálisis y trasplante en España, 2004 / Dialysis and transplant situation, Spain 2004

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Relevance of chronic kidney disease classification (K/DOQI) in renal transplant patients.

The National Kidney Foundation has developed guidelines for diagnosis and classification of chronic kidney disease (CKD) but it is not known whether they are applicable to renal transplant patients. This study analyzed the prevalence, the complications, and the influence of the CKD stage on the presence of complications in 506 stable transplant recipients. The mean age of the patients was 52.9 +/- 12 years, 34% were men, and the mean time after transplantation was 9.56 +/- 6.18 years. CKD was present in 90.3% with 9.9% were in CKD stages 4 or 5 with glomerular filtration rates lower than 30 mL/min per 1.73 m(2). The prevalence of anemia, phospho-calcium metabolism disorders, hypertriglyceridemia, and hypertension increased with the stage of CKD. We concluded that CKD and the complications of CKD were highly prevalent in renal transplant recipients. The classification of renal transplant patients by CKD stage may help clinicians to identify patients at increased risk and to target appropriate therapy to improve outcomes.

Conversion to everolimus in kidney transplant recipients: a safe and simple procedure.

To date there is a substantial experience with rapamycin conversion in stable renal transplant recipients with respect to the procedure of conversion, initial doses, and target blood levels as well as adverse events, but in the case of Everolimus there is almost no experience with conversion and calcineurin inhibitor (CNI) withdrawal. We describe an initial experience among 32 renal transplant recipients who were converted to Everolimus with complete suspension of CNI in two Spanish transplant centers. Our results emphasised the procedure for conversion, the target levels, the adverse events, and the initial efficacy, over the first month after conversion. Our conclusions were that conversion from CNI to Everolimus was a simple, safe procedure with a predictable profile of adverse events, which were, in general, of mild intensity. There was a good correlation between initial dose and blood level. Initial doses of about 3 mg/d combined with rapid reduction in CNI exposure seemed to be adequate. The target range levels between 5 and 10 ng/mL seemed to be sufficient for complete CNI elimination, especially in patients also receiving antiproliferative drugs (such as mycophenolate mofetil or azathioprine) in whom levels near the lower end of the range might be adequate.

Similar impact of slow and delayed graft function on renal allograft outcome and function.

Kidney transplant patients can be divided into three groups, according to the initial graft function. First-week dialyzed patients form the delayed graft function (DGF) group. Nondialyzed patients are divided into slow graft function (SGF) or immediate graft function (IGF) according to whether the day 5 serum creatinine was higher versus lower than 3 mg/dL, respectively. SGF patients showed worse graft survival, above higher incidence of acute rejection and lower renal function than IGF patients, although few reports have analyzed outcomes in these groups. We analyzed the impact of SGF on graft survival, first-year renal function, and incidence of acute rejection in 291 renal transplant patients. Creatinine was significantly worse at 12 months for SGF and DGF than for IGF patients (1.9 +/- 0.8 mg/dL, 1.8 +/- 0.7 mg/dL, 1.5 +/- 0.5 mg/dL, respectively; P < .05). There was no difference in first-year renal function between SGF and DGF. The acute rejection rate was higher among the SGF than the IGF group (45% vs 21%, P < .05), but not different from DGF patients (42%, P < .05). Graft survival was better among IGF than SGF or DGF patients, with no significant difference between the last two groups (3-year graft survival, 82%, 71%, 70%, respectively; log-rank test, P < .05). Kidney transplant recipients who develop SGF have a worse outcome than patients with IGF, similar to DGF patients. SGF patients show worse graft survival, worse renal function, and higher acute rejection rates than IGF patients, despite not needing dialysis.

Change in serum creatinine levels between 6 and 12 months and kidney graft survival: influence of proteinuria.

Renal function within the first year after transplantation has been shown to be an important parameter influencing long-term survival. In this study, we examined the relationship between long-term outcome in 365 renal transplants and renal function in the first year, expressed as serum creatinine (SCr) level at 6 months and at 1 year as well as namely deltaCr, the change in SCr between 6 months and 1 year. In addition, we examined the influence of the presence of proteinuria as a predictive factor for a worse evolution. Graft survival was worse among patients with higher deltaCr, especially among those who developed proteinuria. In a Cox regression analysis of long-term graft survival, both deltaCr and proteinuria were important predictors of half-life. The risk of graft loss when deltaCr >0.3 was 2.65 (1.8-3.8; P < .000), whereas the risk increased to 5.67 (3.3-9.4; P < .00) when proteinuria was present. In conclusion, deltaCr values predict long-term graft survival. Patients who developed proteinuria were at higher risk for graft loss compared with those without proteinuria. By using a combination of SCr and deltaCr with proteinuria, it is possible to identify a subset of transplant recipients with a predictably shortened half-life.

High initial blood levels of tacrolimus in overweight renal transplant recipients.

For the purpose of both efficacy and safety, exposure to tacrolimus and other immunosuppressive drugs must be monitored, since initial levels influence the development of acute rejection episodes, nephrotoxicity, and posttransplantation diabetes mellitus. The aim of this study was to identify risk factors for developing high initial tacrolimus blood levels. We analyzed clinical and biochemical parameters of 85 renal transplant recipients receiving tacrolimus-based immunosuppressive therapy by stratifying into subgroups of patients who displayed first tacrolimus concentrations higher and lower than 15 ng/mL. Patients with a first level of tacrolimus higher than 15 ng/mL were older (52 +/- 13 vs 40 +/- 12 years, P < .05) and had a larger body mass index (27 +/- 4 vs 23 +/- 3 kg/m2, P < .05) than patients with lower levels, despite receiving a lower weight-adjusted cumulative steroid dose (8.2 +/- 2.2 vs 9.3 +/- 2.5 mg/kg, P < .05). Upon logistic regression, age (RR 1.047, 95% CI 1.007 to 1.08, P = .021) and body mass index (RR 1.176, 95% CI 1.009 to 1.371, P = .036) remained significant risk factors for high initial blood levels of tacrolimus. As these subgroups of patients are most prone to develop posttransplantation glycemic disorders, attention must be paid to avoid high tacrolimus blood levels by diminishing initial tacrolimus doses or estimating them from ideal body weight.

Markers of fibrosis in early biopsies of renal transplants.

Many factors are involved in the development of chronic allograft nephropathy (CAN). Extracellular matrix turnover depends on the balance between fibrogenic and antifibrogenic cytokines. The aim of our study was to analyze the presence of transforming growth factor beta-1 (TGF-beta1), matrix metalloproteinase-2 (MMP-2), and mast cells in 53 early transplant biopsies using immunochemistry with specific monoclonal antibodies. We divided the patients into two groups depending on graft evolution (lost due to CAN versus functioning), renal function, presence of proteinuria, and graft survival. There were no differences in the demographic or immunological data. Renal function was worse and proteinuria greater among the group with CAN. The presence of mast cells was similar in both groups, but TGF-beta1 was expressed more and MMP-2 less in the CAN group. We observed a negative correlation between donor age and mast cells, and a positive correlation between TGF-beta1 and MMP-2. Grafts from younger donors showed better renal function, less proteinuria, greater graft survival, and less frequent development of CAN. According to our experience, cytokines involved in matrix turnover are expressed in early stages, correlating with donor age. The expressions of TGF-beta1 and MMP-2 seem to be important for the development of fibrosis in CAN.

Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus.

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.

Prevalence of anemia in renal transplant patients: results from MOST, an observational trial.

INTRODUCTION: Anemia is one of the most common complications of chronic renal disease. However, the incidence or prevalence of anemia in kidney transplant recipients has not been well studied. The aim of this study was to assess the prevalence of anemia in renal transplant in early and late posttransplant period and the influence of drugs (immunosuppressive and antihypertensive). METHODS: MOST is an observational, prospective trial of renal transplant receiving cyclosporine-based immunosuppressive regimen under condition of normal practice in de novo or maintenance recipients. We analyzed the Spanish data from 397 de novo recipients and 2102 maintenance recipients. RESULTS: In maintenance recipients mean hemoglobin levels were 12.8 +/- 1.6 g/dL (13.2 +/- 1.7 in men and 12 +/- 1.4 in women); 22.73% of men and 20.19% of women were found to be anemic. There was a significant correlation between hemoglobin and graft function (r = .14, P < .0001). The percentage of patients with anemia increased with the severity of chronic renal disease according to the KDOQI classification. Therapy with mycophenolate mofetil was also associated with a higher likehood of anemia as compared with other immunosuppressive therapies (azathioprine or sirolimus). There were no differences with angiotensin-converting enzyme inhibitors or ARB II. In de novo patients postransplant anemia was a frequent complication during the first 3 to 6 months. In patients with delayed graft function the recovery of anemia was slower. CONCLUSION: The prevalence of anemia in transplant recipients was remarkably high, especially in the early postransplant period, and appeared associated with impaired renal function and with immunosuppressive treatment.

Impact of HLA antibodies on transplant glomerulopathy.

The influence of humoral rejection on the development of chronic allograft nephropathy (CAN) is controversial, especially in relation to transplant glomerulopathy. The aim of our study was to analyse the influence of anti-HLA antibodies on the development of transplant glomerulopathy (cg0, cg1, cg2, and cg3; Banff'97). We selected all renal transplants patients from 1975 to 2003 who had a functioning graft for at least 6 months and a clinically indicated graft biopsy with CAN and chronic glomerular changes (case group). We studied the presence of anti-HLA antibodies (Ab) in the last serum taken while the graft was functioning and divided them into three groups according to the severity of glomerular lesions. We also selected 52 contemporary and comparable cases without transplant glomerulopathy (control group). A total of 77 case had transplant glomerulopathy: 39 cg1, 29 cg2, and 9 cg3. Pretransplant Ab titers and number of previous blood transfusions were higher among the subgroup with the most severe glomerulopathy. Patients who developed posttransplant anti-HLA Ab more frequently showed transplant glomerulopathy. Serum creatinine and proteinuria were higher among cases with chronic glomerulopathy, and more grafts were lost in that group. Thus, the presence of HLA-Ab is a key factor in the development of transplant glomerulopathy and chronic allograft rejection.