Variability of the Mammalian Target of Rapamycin Inhibitors Is Correlated With Long-Term Renal Graft Survival.

BACKGROUND: Many studies demonstrate the relationship between the high intrapatient variability of calcineurin inhibitor (CNI) levels and poor long-term renal graft outcome. Our objective is to analyze the intrapatient variability observed in the mammalian target of rapamycin inhibitors (mTOR-i) blood levels, to compare the variability of sirolimus (SRL) with that of everolimus (EVL) in kidney transplant patients converted to an mTOR-i, and to analyze whether the coefficient of variation (CV) was correlated with long-term graft survival. METHODS: We analyzed 279 adult renal transplant patients converted to an mTOR-i. CV was calculated using at least 3 blood trough levels between 3 and 18 months postconversion. RESULTS: The mean and median CV of the entire group was 25.54% and 23.7%, respectively. SRL and EVL mean CV was 23.8% and 27.1% (P = .03), respectively. The group of patients into the last tertile with CV> 28.52% presented a lower death-censored graft survival (75.26% vs. 93.01%, P < .0001) with a mean follow-up of 66.5 months. CONCLUSION: The CV of mTOR-i is correlated with long-term renal graft survival, so it should be considered a prognostic factor. SRL has a lower CV than EVL in renal transplant patients converted to mTOR-i in the stable posttransplant phase.

Diplopia secondary to orbital fracture in adults. / Diplopía secundaria a fractura orbitaria en adultos.

OBJECTIVE: To evaluate the incidence and evolution of diplopia as a complication of orbital fractures in adults. PATIENTS AND METHODS: A review was conducted on medical records of all consecutive adults with orbital fracture referred between January 2014 and December 2015. An analysis was made of the incidence of diplopia secondary to fracture in the acute phase and its evolution. A descriptive study was performed on the variables related to patients, fractures, and fracture and diplopia treatment. RESULTS: The study included 39patients with a mean age of 48years (17-85). Of all the patients, 17 (43.6%) presented with diplopia in the acute phase. Differences were found between the groups with and without diplopia in relation to muscle entrapment diagnosed by orbital computed tomography, duction limitation, and fracture surgery ≤1week (P=.02, P=.00, P=.04, respectively). Out of the 17patients with diplopia, 12 had a mean follow-up of 18weeks (1-72), and in 10 (83.3%) diplopia was resolved in a mean time of 10weeks (1-72). There were spontaneous resolution in 4 (33.3%) patients, and resolution after fracture surgery in 4 (57%) of the 7 that underwent surgery. In 4cases (33.3%) prisms were prescribed, and 2 (16.6%) required strabismus surgery. CONCLUSIONS: Diplopia secondary to orbital fracture in adults is frequent, but it is resolved in most cases spontaneously or after fracture surgery. A few patients will require prisms and/or strabismus surgery.

Antibody-Mediated Acute Vascular Rejection of Kidney Allografts: Fifteen-Year Follow-up.

BACKGROUND: Although acute vascular rejection (AVR) is associated with a high risk of graft loss, it remains unclear whether AVR with accompanied cellular or humoral rejection (AHR) has dissimilar outcomes. The aim of this study was to examine the association between subtypes of AVR and graft loss. METHODS: We assessed patients who provided biopsy samples for acute allograft rejection from 1998 to 2014. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology as well as donor-specific anti-HLA antibodies when available. RESULTS: A total of 1,004 patients were biopsied and included in the main analyses, of which 259 (32.87%) had acute biopsy-proven rejection. We identified three patterns of graft rejection defined according to the presence of peritubular capillaritis (ptc): a) T-cell-mediated acute vascular rejection if ptc free; b) humoral-mediated acute vascular rejection if ptc >0; and c) T-cell-mediated rejection if vasculitis = 0 and ptc = 0 (148 [57%], 70 [27%], and 41 [16%], respectively). At 5 years, graft survival was lower among patients with ptc-vascular rejection than those with T-cell vascular rejection (72.3% vs 83.2%; P = .010). T-cell-mediated rejection without vasculitis had similar survival compared with rejection absence (89.3% vs 8 9.2%; P = .698). Multivariate analysis adjusted by age and sex showed that risk of graft loss was higher in biopsies with high scores of glomerulitis (g2-g3); vasculitis (v2-v3), capillaritis (ptc2-ptc3), or interstitial inflammation (i2-i3). However, tubulitis and C4d were not statically significant. CONCLUSIONS: We conclude that antibody-mediated AVR involves a poorer prognosis than T-cell-mediated AVR. The presence of tubulitis does not seem to determine a poor long-term renal graft prognosis.

Presence of T-275A and C-2152T Polymorphisms of the Promoter Region of Uridine Diphosphate-Glucuronosyltransferase 1A9 Increases Mortality From Digestive Tumors: Results After 10 Years of Follow-up in a Renal Transplant Population.

BACKGROUND: The aim of this study was to determine the distribution of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) promoter region T-275A and C-2152T single-nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on the evolution of this population after 10 years of follow-up. METHODS: White renal transplant recipients (n = 873) were studied. The median time of follow-up was 91.8 months (P25-75 46-146). Amplification with specific "primers" to delimit the study area was performed for each polymorphism. Amplification was performed with the use of real-time polymerase chain reaction. RESULTS: T-275A promoter mutation was detected in 13% of patients and C-2152T in 12% of patients. Survival analysis was performed on 873 renal transplants, carried out between 2004 and 2013. We found a higher frequency of death from cancer among polymorphism carriers (P = .001). CONCLUSIONS: It appears that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region show a greater incidence of death from cancer, with a significantly higher cumulative incidence of death from gastrointestinal tumors.

Surgical Complications in En Bloc Renal Transplantation.

En bloc pediatric transplantation (EBPT) began with the aim of increasing the donor pool due to the existing high demand for donors. At its inception, it was considered a type of suboptimal transplantation due to its association with a high incidence of vascular, urologic, and immunologic complications. The main objective of this study was to update information on EBPT with the largest case series that exists on a worldwide scale. In a retrospective study, the results obtained from brain-dead donors (BDDs; n = 770) were compared to those of EBPT (n = 100) from January 1990 to December 2012. The median of follow-up was 12.8 years (interquartile range 8.1 to 17.2). The variables collected for analysis were demographic factors (age and sex of recipients, age and weight of donors), renal function, graft survival, recipient survival, surgical complications (thrombosis, lymphocele, urologic complications, and renal artery stenosis and need for revascularization with angioplasty and/or stents). Subsequently in a second analysis, we studied the association between graft survival, thrombosis, angioplasty, stents, and appearance of lymphoceles with the different factors that were considered to be related in accordance with published literature and our own experience. Graft loss due to surgical complications was more frequent in EBPT than in BDD (15% vs 2.2 % in BDD; P < .001), and interstitial fibrosis and tubular atrophy were more frequent in BDD (13% vs 2%; P < .001). EBPT offers a good survival rate after overcoming the possible surgical complications that may arise.

Risk Factors of Recurrence of Diabetic Nephropathy in Renal Transplants.

BACKGROUND: Renal transplantation has been established as the treatment of choice for end-stage renal disease (ESRD) due to diabetic nephropathy. This study aimed to investigate the risk factors for recurrence of diabetic nephropathy (RDN) in renal allografts. METHODS: We studied 1,011 renal transplant patients from 1986 to 2003, of which 95 had ESRD due to diabetic nephropathy. We retrospectively analyzed the clinical characteristics and outcomes of RDN after renal transplantation. RESULTS: Of the 95 recipients with ESRD due to diabetic nephropathy, 41 developed RDN and 11 of those 41 underwent graft biopsy. The mean durations from transplantation to RDN and to renal replacement therapy was 81.58 months (range, 54-120 mo), and 109.66 months (range, 27-188.4 mo), respectively. At 5 years, treatment on statins and renin-angiotensin-aldosterone system (RAAS) blockers were associated with a higher survival free from RND (82.2% vs 63.2% [P = .070] and 100% vs 80% vs 0.6% [P = .013], respectively). Compared with cyclosporine, tacrolimus was associated with a higher risk for RND (odds ratio [OR], 4.27; 95% confidence interval [CI], 1.75-5.13; P = .047). High doses of prednisone (>0.06 mg/kg) were also associated with a higher risk of RDN (OR, 3.03; 95% CI, 1.19-8.30; P = .029). The combination of calcineurin inhibitor and mammalian target of rapamycin inhibitor (mTORi) demonstrated the highest risk of RDN (OR, 14.08; 95% CI, 3.72-53.29; P < .01). CONCLUSIONS: Treatment with tacrolimus and mTORi is the most diabetogenic immunosuppressive regimen. Treatment with tacrolimus entails a greater risk of RDN than with cyclosporine. The administration of statins or RAAS blockers could delay the progression of RDN.

Minimal incision surgery in strabismus: Modified fornix-based approach. / Cirugía de mínima incisión en estrabismo: técnica base fórnix modificada.

OBJECTIVE: To evaluate the modified fornix-based technique as an approach for minimal incision surgery in strabismus. METHODS: The medical records of all consecutive patients that underwent strabismus surgery with fornix-based conjunctival incision between 2007 and 2012 were retrospectively reviewed. As a primary variable, an analysis was made of the wound size depending on the number of stitches. A descriptive study was performed on the variables related to patients and to the type of strabismus and surgery. RESULTS: Out of 153patients identified, 138 with 294 surgeries were included. In 200 (68%) interventions, the incision was sutured with one stitch, in 77 (26.2%) with 2, in 13 (4.4%) with 3, and in 4 (1.4%) with 4, with the mean number of stitches being 1.39±0.64. The mean age of the patients was 39years (2-80), and 36 (26.1%) had previous strabismus surgery, with topical anaesthesia being used in 35 (25.4%) cases. At 3months after surgery deviation was ≤10DP in 114 (82.6%) patients. There were no wound-related complications. CONCLUSIONS: The modified fornix-based technique is an effective and safe approach for minimal incision surgery in strabismus, in patients at all ages, with previous history of strabismus surgery and with topical anaesthesia.

Role of fibroblast growth factor 23 (FGF23) in the metabolism of phosphorus and calcium immediately after kidney transplantation.

INTRODUCTION: Persistence of inappropriately high serum levels of fibroblast growth factor-23 (FGF23), a recently discovered phosphaturic hormone, has been reported to play an important role in the pathogenesis of posttransplant hypophosphatemia. The aim of the present study was to evaluate FGF23 in the early posttransplant period and study the complex associations between FGF23, parathyroid hormone (PTH), 1,25(OH)(2) vitamin D, and phosphate in transplant patients. MATERIALS AND METHODS: We performed a cross-sectional observational study of 42 adult kidney recipients in the early posttransplant period (<6 months). Fasting serum samples and 24-hour urine samples were collected during a routine follow-up outpatient visit. Serum creatinine, calcium, phosphate, magnesium and urinary creatinine, calcium, magnesium, and phosphate were measured using standard assays. We also studied concentrations of 25 hydroxyvitamin D, 1,25(OH)(2) vitamin D, intact PTH, and circulating FGF23. RESULTS: Median values for the different parameters studied were as follows: 9.9 ± 0.6 mg/dL, phosphatemia 3.3 ± 0.7 mg/dL, estimated glomerular filtration rate (eGFR; 41.1 ± 14.0 mL/min, phosphate reabsorption rate 68.4% ± 10.7%, PTH 94.5 ng/L (53.8-199.5), calcitriol 33.0 pg/mL (24.0-44.1), calcidiol 27.3 ng/mL (17.0-38.0), FGF23 139 pg/mL (88-221), and calciuria 62.5 mg/d (40.3-101.3). The variables significantly associated with serum FGF23 levels were phosphate reabsorption rate (r = .493; P = .001), calcitriol (r = .399; P = .009), eGFR (r = .557; P < .001), PTH (0.349; P = .024). CONCLUSIONS: Elevated serum levels of FGF23 could explain the deficiency of calcitriol and elevated renal phosphorus wasting in the early posttransplant period. All treatments that can lead to increased serum phosphate levels (eg, oral medication or calcitriol) should be carefully evaluated, since increased phosphatemia could further stimulate secretion of FGF23 and prolong high phosphorus loss.

Anemia in kidney transplants without erythropoietic agents: levels of erythropoietin and iron parameters.

AIM: To study the association between hemoglobin, endogenous erythropoietin (EPO) levels and ferric parameters in kidney recipients not treated with EPO-stimulating agents. MATERIALS AND METHODS: Transverse study of 219 kidney transplant outpatients. The median time after transplantation was 54 months (P(25-75), 23-107). We assessed blood counts, ferric parameters, EPO levels, renal function (MDRD-4), and adjuvant treatment. We performed a linear regression analysis to predict hemoglobin. RESULTS: Median EPO values were 14.05 mUI/mL (P(25-75) = 10.2-19.7). Applying the formulas described by Beguin, kidney transplant recipients showed a low observed/expected ratio of erythropoietin and of transferrin. Considering anemia to be an hemoglobin of < 12 g/dL in women and < 13 g/dL in men, 24.2% of subjects were anemic (n = 53), including 2.3% with hemoglobin < 11 g/dL. Anemic patients displayed worse renal function (49.2 ± 18.5 versus 55.46 ± 16.58 mL/min/1.73 m(2) in nonanemic; P = .021). There were no differences in C-reactive protein. The patients receiving a combination of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) showed the highest prevalence of anemia compared with other groups (42.9%, P = .027). EPO levels were significantly lower among patients treated with these drugs (P = .041), without differences in transferrin and ferritin. The percentage of anemic patients treated with mammalian target of rapamycin inhibitors (mTORi) was 31% versus 22.2% among those not receiving these immunosuppressants (P = .23). Although there were no differences in hemoglobin levels, patients treated with mTORi, showed higher EPO levels (P = .005) and lower mean corpuscular volume (P < .001). Regarding the etiology of chronic kidney disease, less frequently anemic patients were those with polycystic kidney disease (8.6% versus 26.7% in the rest, P = .021). The formula obtained by multiple linear regression to calculate hemoglobin was: hemoglobin = 11829-0909 log (EPG level) - 0455 (if female) + 0.010 0.013 transferrin + 0.013 creatinine clearance (r = .424, P < .001). CONCLUSIONS: Treatment with ACEI and/or ARBs seemed to produce a defect in the synthesis of EPO, while those treated with mTORi, a hyporesponsive state.

Mammalian target of rapamycin signal inhibitors could play a role in the treatment of BK polyomavirus nephritis in renal allograft recipients.

UNLABELLED: BK virus (BKV) nephropathy is a common viral infection in renal transplant patients, with a prevalence of 1-9% at approximately 12 months after surgery. While it is widely agreed that reduction of immunosuppression should be the first intervention after diagnosis of BKV infection, there is no consensus on whether calcineurin inhibitors or antiproliferative drugs should be reduced first. Furthermore, target levels of immunosuppressive drugs are poorly defined, as are criteria for replacing one immunosuppressive agent with another. RESULTS: We report our series of 15 renal transplant patients who underwent surgery between September 2004 and March 2010 and who developed BKV infection. The first 8 patients were treated with reduction of immunosuppression; 7 of these patients received cidofovir and 6 received intravenous immunoglobulin. The remaining 7 renal transplant recipients received mammalian target of rapamycin inhibitors (imTOR). In this group, we observed faster and more efficacious BKV clearance in plasma and urine and a steady improvement in allograft function, with no episodes of acute allograft rejection during follow-up. The polymerase chain reaction assay for BKV in urine became positive in 2 patients in whom imTOR were stopped due to severe side effects. CONCLUSIONS: The use of imTOR should be considered a first step in the treatment of renal transplant recipients with BKV infection. In our experience, this change in treatment was safe and resulted in viral clearance.

De novo anti-HLA antibodies in renal allograft recipients: a cross-section study.

BACKGROUND: The occurrence of anti-HLA antibodies plays a well established role in solid organ rejection. The development of x-MAP multiple bead technology (Luminex) has enabled more accurate detection and definition of these alloantibodies. METHODS: In 267 kidney transplant patients with stable allograft function for ≥3 years, we analyzed the presence of anti-HLA antibodies by Luminex technology. These patients had no alloantibodies before transplantation, and the immunosuppression treatment was: tacrolimus, cyclosporine, mycophenolate mofetil, prednisone, everolimus, and/or sirolimus. RESULTS: Fifteen of the 267 patients showed anti-HLA class I antibodies and 12 showed anti-HLA class II antibodies, Seven patients had donor-specific antibodies (DSA): 1 anti-HLA class I, 5 anti-HLA class II, and 1 with both classes. No differences were found between DSA and the use or not of any specific therapy. However, in the retrospective review, we found a higher incidence of acute rejection episodes in the immediate posttransplant period among patients who developed class II DSA than those without DSA. CONCLUSIONS: The prevalence of patients with normal renal function who develop DSA beyond 3 years after transplantation was relatively low. Steroid or withdrawal replacement of calcineurin inhibitors with inhibitors of mammalian target of rapamycin seem to not be risk factors to increase the development of DSA. The finding that patients who developed DSA showed a higher rate of previous acute rejection episodes suggested that they should be monitored more frequently for HLA antibodies.

Incidence and risk factors for the metabolic syndrome and posttransplant diabetes in renal transplant recipients taking tacrolimus.

OBJECTIVES: We investigated the incidence and risk factors for the metabolic syndrome (MS) and posttransplant diabetes mellitus (PTDM) among renal transplant recipients on tacrolimus-based immunosuppressive regimens during the first year posttransplant. In addition, we studied the relationship between MS and PTDM with transplant renal function at 1 year. METHODS: We included the 100 patients who received a renal transplant in our unit between January 2007 and June 2008, collecting demographic, clinical and biochemical characteristics at 1, 6, and 12 months posttransplantation. We excluded 15% of patients with pretransplantation diabetes. MS was defined according to the National Cholesterol Education Program criteria and PTDM according to World Health Organization criteria. Insulin resistance at one year posttransplant was measured using the homeostasis model assessment (HOMA) index. RESULTS: Insulin therapy was required in 46% of patients during the first hospitalization and hyperglycemia was present in 65% of the cases. The incidence of PTDM decreased throughout the first year posttransplant, namely, 44%, 24%, and 13% at 1, 6, and 12 months, respectively. The incidence of MS increased to 33%, 48% and 50% at 1, 6, and 12 months, respectively. Age, body mass index, plasma fasting glucose levels at 1 month posttransplant, and pretransplant fasting triglyceridemia predicted PTDM. Rejection and in-patient hyperglycemia predicted MS. PTDM and MS were closely correlated (P=.004). The HOMA index was higher among patients with MS than other subjects at 1 year posttransplant: 3.2 (1.2) versus 2.3 (0.9; P=.035). Neither PTDM nor MS was associated with impaired plasma creatinine levels at 1 year after kidney transplantation. CONCLUSION: There was an high incidence of PTDM and MS among kidney transplant recipients treated with tacrolimus as the main immunosuppressive agent. The HOMA index was a good test of insulin resistance in this population. Screening and treatment of risk factors may avoid the development of these entities, which are related to poor cardiovascular outcomes.

Candiduria in renal transplant recipients: incidence, clinical repercussion, and treatment indication.

INTRODUCTION: The incidence of candiduria in renal transplant recipients is unknown. In clinical practice, the indications for antifungal therapy are not well established. Furthermore, there is the problem of the choice of the antifungal drug since some of them may select resistant Candida species, or interact with immunosuppressive agents or only be used intravenously. AIM: We sought to study the incidence, clinical repercussions and effectiveness of antifungal treatment to prevent recurrence of candiduria. MATERIALS AND METHODS: We examined all episodes of Candida-positive urine cultures (>50,000 cfu/mL) in 996 recipients over 2 years. We considered the Candida species, administered treatment, presence of fever, requirement for hospital admission versus outpatient case, occurrence of simultaneous bacterial urinary tract infection (UTI), antibiotic use during the week before candiduria, and presence of an indwelling urinary catheter. RESULTS: Among 996 subjects, 34 displayed 83 episodes of candiduria, yielding an accumulated incidence of 3.4% after 2 years. The frequency was higher among women (6.3% vs 1.7%, P<.001). Of the 45 outpatient episodes (54.2%), 17 were treated and one required hospitalization (5.9%). Of the 28 nontreated outpatients, two were hospitalized (7.1%, P=.68 vs treated patients). All cases of hospital admission presented simultaneous bacterial UTI, none developed candidemia, and two patients did not receive any antifungal therapy. With respect to the first episodes of each patient (n=34), 5/11 treated (45.5%) and 4/23 untreated (17.4%) patients developed recurrences (P=.095). Selection of more resistant Candida species was not observed. Fifty cases (60%) were associated with antibiotic therapy and 34 (41%) the presence of a urinary catheter. CONCLUSIONS: It does not seem necessary to treat candiduria in this setting. Antifungal therapy was not associated with either a reduction in recurrence or the appearance of more resistant species in this study. We observed no important clinical repercussions.

Changes in magnesium and potassium homeostasis after conversion from a calcineurin inhibitor regimen to an mTOR inhibitor-based regimen.

BACKGROUND: Transplant recipients treated with calcineurin inhibitors (CNIs) frequently show hyperkalemia, metabolic acidosis, and hypomagnesemia which could be deleterious for some patients. Conversion to inhibitors of mammalian target of rapamycin (mTOR) could improve these electrolytic disturbances. OBJECTIVE: To evaluate the potassium and magnesium changes due to converting patients from CNIs to mTOR inhibitors. METHODS: Retrospective review of 138 renal transplant patients who were converted from CNIs to mTOR inhibitors over a 6-month observation period. The following parameters were determined: potassium, sodium, chloride, magnesium, urea, glucose, and creatinine in blood and urine. We also analyzed plasma bicarbonate and calculated plasma and urine anion gap and plasma osmolarity. RESULTS: One month after conversion, a decrease was observed in serum creatinine (1.75±0.68 vs 1.61±0.61 mg/dL; P=.01), plasma potassium (4.60±0.52 vs 4.39±0.53 mEq/L; P<.001), calculated plasma osmolarity (308.7±8.5 vs 307.4±8.4 mOsm/L; P<.036), fractional excretion of sodium (1.55±0.69 vs 1.29±0.65%; P<.003), and fractional excretion of magnesium (7.15±4.08 vs 15.84±3.64%; P<.001), with an increase in serum magnesium (1.77±0.24 vs 1.95±0.29 mg/dL; P<.001). At 3 and 6 months, these differences remained unchanged. The transtubular potassium gradient did not change. CONCLUSIONS: We observed a decrease in serum magnesium due to renal magnesium wasting before switching from CNIs to mTOR inhibitors. After conversion, an increase in serum magnesium was observed together with a drop in the fractional excretion of this cation. A decrease in plasma potassium levels, plasma osmolarity, and fractional excretion of sodium consistent with minor aldosterone resistance was also detected after changing the immunosuppressive treatment.

Comparative analysis of adverse events requiring suspension of mTOR inhibitors: everolimus versus sirolimus.

BACKGROUND: Inhibitors of mammalian target of rapamycin (mTORi) have been suggested as an alternative to calcineurin inhibitors (CNIs) to treat stable renal transplant recipients. However, their use has been significantly limited owing to a high incidence of side effects. OBJECTIVE: To compare the rate of dropout (mTORi elimination and CNI reintroduction) caused by side effects among renal transplant patients converted to everolimus (EVL) or sirolimus (SRL). METHODS: Between October 1999 and February 2010, 409 subjects were converted to an mTORi at least 3 months after transplantation, including 220 (53.8%) to EVL and 189 (46.2%) to SRL. Most patients were under CNI therapy. Patients were followed for a median of 35 months (interquartile range [IQR], 18-50 months). RESULTS: mTORi treatment was prematurely eliminated due to adverse events in 112 patients. The median time between the initiation of mTORi and discontinuation was 5.7 months (IQR, 1.9-15.7 months; range, 0.2-48 months): 5.5 (IQR, 1.6-16.3) in the EVL group and 7.4 (IQR, 2.6-15.6) in the SRL group. In the EVL group, the drug was stopped in 69 patients (31.4%), and in the SRL group in 43 patients (22.8%; P=.051). The most important causes of discontinuation were severe infections (2.3% in EVL group and 4.8% in SRL group; P=.17), pneumonitis (6.8 % in EVL group and 4.8 in SRL group; P=.38), acute rejection episode (4.1% in EVL group and 1.6% in SRL group; P=.13), proteinuria (4.1% in EVL group and 1.6% in SRL group; P=.13), renal function deterioration (2.3% in EVL group and 2.1% in SRL group; P=.91), and severe dermal eruption (2.3% in EVL group and 0.5% in SRL group; P=.14). CONCLUSIONS: Although the overall incidence discontinuations due to side effects was higher in the EVL group, there was no greater frequency of severe side effects, such as pneumonitis, proteinuria, acute rejection episodes, renal function deterioration, or dermal eruptions.

Inadequate mycophenolic acid exposure and acute rejection in kidney transplantation.

INTRODUCTION: The clinical utility of predose levels of mycophenolic acid (MPA) monitoring among patients treated with mycophenolate mofetil (MMF) has been questioned. The aim of this study was to evaluate the impact of adequate MPA levels in the incidence of acute rejection episodes among a cohort of kidney transplant recipients. MATERIAL AND METHODS: In this retrospective study of 314 consecutive cases treated with tacrolimus, MMF, and steroids, evaluated 12-hour trough MPA samples during the first week as well as at 1, 3, 6, and 12 months as median values. RESULTS: During the first week, the median values of MPA were 1.6 microg/mL (p25-75 0.7-2.7 microg/mL) on mean doses of 1.84 +/- 0.38 g/d. The incidence of acute rejection was 28%. The mean MPA levels during the first week were significantly lower among patients who developed rejection than in nonrejectors (1.5 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P < .001). There were no significant differences in trough tacrolimus levels between rejectors and nonrejectors (11.2 +/- 0.4 vs 11.6 +/- 1.2 microg/mL; P < .78). Logistic regression analysis showed that one of the predictive factors of acute rejection was a 12-hour trough MPA <1.6 microg/mL (relative risk [RR] 2.6; CI [confidence interval] 95% 1.6-4.3; P < .001). CONCLUSIONS: Adequate MPA exposure is important to prevent acute rejection. Taking into account that the routine measurement of the area under the curve of MPA is impractical, at least the follow-up of trough MPA levels may help in the management of renal transplant recipients.

Graft outcome and mycophenolic acid trough level monitoring in kidney transplantation.

BACKGROUND: Large inter- and intrapatient variabilities have been observed in the pharmacokinetics of mycophenolic acid (MPA). As a consequence, the efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic drug monitoring. MATERIALS AND METHODS: In this retrospective study we analyzed; 7536 12-hour trough MPA samples obtained during the first year posttransplantation among 314 kidney recipients treated with tacrolimus, MMF, and corticosteroids. RESULTS: Despite taking similar MMF doses, patients with delayed graft function (DGF) showed lower 12-hour trough MPA levels than patients without DGF 1.4 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P = .001). There was a significant correlation between 12-hour trough MPA levels and creatinine clearance (r = .32; P < .001). Logistic regression analysis showed that creatinine clearance was a predictive factor of adequate 12-hour trough MPA levels (>1.6 microg/mL) at 7 days posttransplantation. Twelve-hour trough MPA levels at 7 days posttransplantation were lower among patients who developed an acute rejecton episode (1.5 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P < .001), whereas those with gastrointestinal side effects showed high levels (4.1 +/- 0.5 microg/mL). CONCLUSIONS: In patients with delayed or poor graft function, MMF doses greater than 2 g/d may be necessary to achieve adequate MPA levels. Therapeutic drug monitoring of MPA may be useful to prevent acute rejection episodes or toxicity.

Intracellular ATP levels in CD4+ lymphocytes are a risk marker of rejection and infection in renal graft recipients.

OBJECTIVE: The immune monitoring of transplant patients may allow us to minimize adverse events of immunosuppression and predict risks of rejection. Herein we have evaluated the capacity of an immune cell function assay to predict episodes of rejection and infections as well as its correlation with immunosuppressive drug trough levels and CD4, CD8, CD25, and DR cell counts. PATIENTS AND METHODS: This prospective study of 38 kidney transplant patients was performed from January to June 2008. Blood samples were obtained at several times posttransplantation until the sixth month. We measured intracellular adenosine triphosphate (iATP) levels following CD4 cell activation for comparison with the clinical courses. RESULTS: Patients with >or=525 ng/mL levels of iATP in the first week posttransplantation were 6.6 times more likely to develop an acute rejection episode (ARE) than those with lower immune response values (P = .014). Those who had an ARE with iATP < 525 ng/mL were generally highly sensitized (4/5). Statistically significant variations in iATP levels were observed among patients who had an ARE (P = .006). There was a relationship between infections and iATP levels also. Infections were more frequent with iATP

Sirolimus and everolimus induced pneumonitis in adult renal allograft recipients: experience in a center.

Mammalian target of rapamycin (mTOR) inhibitors induce pneumonitis, an unusual but potentially fatal side effect of this drug group. We retrospectively collected the cases of pneumonitis induced by sirolimus or everolimus among 1471 adult cadaveric renal transplant recipients who were grafted at our institution from 1980-2008. Due to chronic transplant dysfunction or tumor, 205 patients were switched from calcineurin inhibitors to sirolimus (n = 88) or to everolimus (n = 117). Six patients (2.9%) developed pneumonitis: 1 was associated with sirolimus and 5 with everolimus (5 males and 1 female; median age, 60 years [range, 47-73 years]). Median times from conversion to pneumonitis onset were 34 days in 4 patients (range, 24-46 days) and 491 days in 2 subjects (range, 454-528 days). The mean drug trough level at presentation was 8.2 microg/L (range, 5.5-13.8 microg/L). The most common symptoms were dry cough (n = 6), fever (n = 5), and dyspnea (n = 4). Imaging tests revealed lower lobe involvement in all patients. Bronchoalveolar lavage performed in 4 patients showed lymphocytic alveolitis. All patients completely recovered after drug withdrawal. Five patients received steroids, 5 were switched to a calcineurin inhibitor, and 1 was switched to the other mTOR inhibitor. In conclusion, mTOR inhibitor-associated pneumonitis is a rare disease. Sirolimus did not cause more cases of pneumonitis than everolimus. Pneumonitis development was not dependent upon the drug blood level. Lower lobe involvement and lymphocytic alveolitis were usually present. Discontinuation of the mTOR inhibitor with steroid prescription resulted in adequate outcomes. A change to the other mTOR inhibitor should be contemplated if patient circumstances require this type of immunosuppression.