A form of apolipoprotein a-I is found specifically in relapses of focal segmental glomerulosclerosis following transplantation.

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) following kidney transplantation occurs in a large percentage of patients. Accurate prediction of recurrence and elucidation of its pathogenesis are major therapeutic goals. To detect differential proteins related to FSGS recurrence, proteomic analysis was performed on plasma and urine samples from 35 transplanted idiopathic FSGS patients, divided into relapsing and nonrelapsing. Several proteins were detected increased in urine of relapsing FSGS patients, including a high molecular weight form of apolipoprotein A-I, named ApoA-Ib, found exclusively in relapsing patients. This finding was verified by Western blot individually in the 35 patients and validated in an independent group of 40 patients with relapsing or nonrelapsing FSGS, plus two additional groups: FSGS-unrelated patients showing different proteinuria levels (n = 30), and familial FSGS transplanted patients (n = 14). In the total of 119 patients studied, the ApoA-Ib form was detected in 13 of the 14 relapsing FSGS patients, and in one of the 61 nonrelapsing patients. Only one of the 30 patients with FSGS-unrelated proteinuria tested positive for ApoA-Ib, and was not detected in familial patients. Urinary ApoA-Ib is associated with relapses in idiopathic FSGS and warrants additional investigation to determine its usefulness as biomarker of relapse following transplantation.

The natural history of clinical operational tolerance after kidney transplantation through twenty-seven cases.

We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3%[p = 0.0455] and 96.7%[p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 ± 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.

Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients.

Prolonged-release tacrolimus was developed to provide a more convenient once-daily dosing that could improve patient adherence. We conducted a multicenter, prospective, observational, 12-month study to describe the efficacy, safety and patient preference of conversion from tacrolimus twice-daily to once-daily formulation in stable kidney transplant recipients in routine clinical practice. Conversion was made on a 1 mg: 1 mg basis (1 mg: 1.1 mg in patients with trough levels <6 ng/mL). The study included 1832 patients (mean age (± SD): 50.0 ± 13.4 years; 62.7% male). After conversion, a modest reduction in tacrolimus trough levels, necessitating an increase in daily dose, was observed (mean changes at 12 months of -9.1% and +1.24%, respectively; p < 0.0001). Mean glomerular filtration rate did not change significantly (56.5 ± 19.7 mL/min at conversion vs. 55.7 ± 20.6 mL/min at 12 months). Proteinuria, blood pressure, lipid, hepatic and glucose parameters remained stable. Eight patients (0.4%) had acute rejection and 34 patients (1.85%) discontinued treatment. Almost all patients (99.4%) preferred the once-daily formulation, because of less frequent dosing (66%) and improved adherence (34%). In conclusion, at similar doses to twice-daily tacrolimus, once-daily formulation provided stable renal function, a low acute rejection rate, and good tolerability in stable kidney transplant recipients in the routine clinical practice setting.

[Daclizumab in combination with mycophenolate mofetil and a late introduction of Tacrolimus at low doses, as a therapeutic approach in the elderly renal transplant donor-recipients pairs in kidney transplant]. / Daclizumab en combinación con Micofenolato Mofetil e introducción tardía de Tacrolimus a dosis bajas, como opción terapéutica en la pareja donante-receptor añoso en trasplante renal.

BACKGROUND: Nowadays, it is more frequent the use of kidneys from older donors in the renal transplantation. Moreover, it is also increasing the age of the recipients due to the ageing of the population treated with hemodialysis. This makes that recipients become older more commonly. This situation raises specific problems in the renal graft and in the recipient as well. In this manuscript we present the results of a multicenter study that analyzed an immunosuppressive strategy specifically designed to elderly renal transplant donor-recipients. METHODS: Patients > or =50 years were transplanted from donors > or =55 years. Immunosuppressive strategy consisted of daclizumab (2 doses of 1mg/Kg) in combination with steroids, mycophenolate mofetil (2g/daily during the first 45 days and then adjusted according to local practice) and Tacrolimus. Tacrolimus was introduced between 5 and 7 day post-transplantation, adjusting the predose levels between 4-8 ng/mL. Mean follow-up was 12 months. RESULTS: A total of 133 patients were included in the study. Mean age of recipients and donors was 61.3+/-6.2 years and 64.4+/-5.3, respectively. 42.9% of patients needed dialysis during the first week (median 4 days). Between first month and first year, serum creatinine improved from 2.0+/-1.0 mg/dl to 1.5+/-0.4 mg/dl. Similar improvements were observed when creatinine clearance (Cockroft-Gault) was calculated. The survival of patient and renal graft at 12 months was 97.7% and 96.1%, respectively. The acute rejection rate was 13.5%. Security profile was good, as expected. CONCLUSIONS: The Daclizumab and mycophenolate mofetil regimen with a late introduction of Tacrolimus at low doses is a good alternative in the elderly renal transplant recipients with a low immunologic risk.

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.

Effect of new immunosuppressive regimens on cost of renal transplant maintenance immunosuppression.

Although newer immunosuppressive drugs control acute rejection better and have short-term economic advantages, their long-term cost-effectiveness is unknown. We studied the frequency with which different maintenance immunosuppression regimens were used in 3 renal transplantation cohorts treated in 1990, 1994, and 1998 (total number, 3279). We calculated the mean annual immunosuppressive costs based on the true costs in a medium-sized hospital. Cyclosporine, with or without azathioprine, was used almost exclusively as the initial maintenance immunosuppressive therapy in 1990-1994. In 1998, 65% of patients received mycophenolate mofetil (MMF), and 20% received tacrolimus (Tac). A growing number of patients from 1990-1994 were converted to MMF (12%-17%) and Tac (4%-8%), while treatment of those from the 1998 cohort remained stable. According to year 2000 costs, the mean immunosuppressive cost at 1 year in 1998 (5380 euros) was almost twice that of 1994 (2902 euros) or 1990 (2855 euros). In these 2 groups the mean cost was stable until 1996, then increased faster in the 1994 cohort (24.8%) than in the 1990 cohort (17.3%), although it remained significantly lower than that in 1998. Correction of the evolution of drug prices and the purchasing value of the peseta greatly absorbed these changes. The MMF and Tac regimens showed greater mean graft life, but without reaching statistical significance in a multivariate study. The introduction of new immunosuppressive drugs has had an important economic effect since 1996; its cost-effectiveness is still pending confirmation in Spain.

Cost of renal transplant maintenance immunosuppression: effect of control of vascular risk factors.

In 3 renal transplant cohorts treated in Spain in 1990, 1994, and 1998 (total number, 3279), we studied the frequency of certain cardiovascular risk factors. Their effect on the cost of drugs was assessed from the data from 1 center; the mean cost of antihypertensive agents per patient-year was 349 euros, and of lipid-lowering drugs was 294 euros. Between 1990 and 1998 the frequency of use of antihypertensive agents at 2 years increased from 70% to 80%, and that of lipid-lowering agents from 12% to 46% (P < .001). Patients received various regimens of immunosuppression at the second year, as follows: (1) steroid-free: cyclosporine, 2.3%; tacrolimus, 9.9%; cyclosporine plus mycophenolate, 16.2%; and tacrolimus plus mycophenolate, 11.8% (P < .001); (2) antihypertensive agents: 74.9% of patients receiving tacrolimus, with or without mycophenolate, versus 80.7% of those receiving cyclosporine (P = .022); (3) lipid-lowering drugs: 28.4% of patients receiving tacrolimus, with or without mycophenolate, versus 51.1% of those receiving cyclosporine (P < .001). The increase in associated drug costs must be added to the recent large increase in the cost for immunosuppressive agents, which rose from 3854 euros per year, in 1990 to 5374 euros per year in 1998. A lower cost of associated drugs tends to lessen the overall cost of therapies with tacrolimus. Because cardiovascular disease is the main cause of death, these findings should be taken into account in the assessment of the long-term cost-benefit ratio.

Two doses of daclizumab with delayed introduction of low-dose tacrolimus in elderly recipients of cadaveric renal transplants from donors >55 years of age.

BACKGROUND: Renal transplants from elderly donors have a high incidence of delayed graft function, which can be increased by the initial use of calcineurin inhibitors. Our purpose was to assess the safety and efficacy of an immunosuppressive regimen using anti-IL-2R antibodies and MMF that allows delayed introduction of low-dose tacrolimus using elderly donors to elderly recipients. METHODS: This observational study involved 13 transplant centers. In total there were 119 patients (age 60.5 +/- 6.6 years, range 50 to 77) who received a kidney from a donor of mean age 64 +/- 5 years (range 55 to 76), 94% of whom died from a CVA. Immunosuppression consisted of daclizumab (1 mg/kg in two doses; preoperatively and on day 14) combined with steroids, mycophenolate mofetil (initial dose of 2 g/d), and tacrolimus (0.1 mg/kg per day). Tacrolimus was introduced before day 7 (mean 5.5 days) and adjusted to a target level of 5 to 8 ng/mL. The mean follow-up was 8 months. RESULTS: Two grafts were lost due to primary nonfunction and acute rejection and 48 patients (40%) required dialysis due to delayed graft function, although it was generally of short duration (median 4 days; only 2 cases >2 weeks). Acute rejection occurred in 16 patients (13.4%), of whom 13 were biopsy-confirmed (10.9%; Banff 1997 grades I and II). Three patients withdrew from the study, and three died (sepsis, accident, and cardiovascular event). The remaining 111 patients continued follow-up, with a median creatinine value of 1.5 mg/dL at 12-months. Eighty-six percent of patients had at least one episode of infection, half of which were urinary tract infections. There were 16 cases of CMV infection. CONCLUSIONS: Based on the initial results, our immunosuppressive regimen seems to offer good short-term renal function while maintaining an acceptable rejection rate and a low incidence of serious infections.

Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA.

BACKGROUND: Tuberculosis is unusual in transplant recipients. The incidence, clinical manifestations, and optimal treatment of this disease in this population has not been adequately defined. The present study was undertaken to assess the incidence, clinical features, and response to therapy of Mycobacterium tuberculosis infection in solid-organ transplant recipients. METHODS: We evaluated retrospectively the incidence, clinical characteristics, diagnostic procedures, antituberculous treatment, clinical course, and factors influencing mortality in 51 solid-organ transplant recipients who developed tuberculosis after transplantation. We also reviewed the world literature on tuberculosis in solid-organ transplantation. RESULTS: The overall incidence of tuberculosis was 0.8%. The localization was pulmonary in 63% of the cases, disseminated in 25%, and extrapulmonary in 12%. Tuberculosis developed from 15 days to 13 years after surgery (mean, 23 months). In one third of the cases, diagnosis was not suspected initially, and in three cases, diagnosis was made at necropsy. Fever was the most frequent symptom, followed by constitutional symptoms, cough, respiratory insufficiency, and pleuritic pain. Fifteen patients (33%) developed hepatotoxicity during treatment; hepatotoxicity was severe in seven cases. Hepatotoxicity was higher in patients receiving four or more antituberculous drugs (50%) than in patients receiving three drugs (21%; P=0.03). Serum levels of cyclosporine decreased in the 26 patients under the simultaneous use of rifampin. Nine of them (35%) developed acute rejection, and five (56%) died, in comparison with 3 of 17 patients (18%) who did not develop rejection after the use of cyclosporine and rifampin (P=0.03). Although microbiological response was favorable in 94% of the 35 patients who completed 6 or more months of treatment, 16 other patients (31%) died before diagnosis or in the course of treatment. None of the patients treated for more than 9 months died as a consequence of tuberculosis, whereas the mortality rate was 33% among those treated for 6 to 9 months (P=0.03). Use of antilymphocyte antibodies or high doses of steroids for acute rejection before tuberculosis was associated with a higher mortality rate. CONCLUSIONS: M tuberculosis causes serious and potentially life-threatening disease in solid-organ transplant recipients. Treatment with at least three drugs during 9 months or more, avoiding the use of rifampin, appears to be appropriate.

Safety and efficacy of delayed introduction of low-dose tacrolimus in elderly recipients of cadaveric renal transplants from donors over 55 years of age.

BACKGROUND: Renal transplants (RTs) from elderly donors show a high incidence of delayed graft function, which may be increased by the initial use of calcineurin inhibitors. OBJECTIVES: The purpose of this study was to assess the safety and efficacy of an immunosuppressive regimen using anti-IL-2R antibodies and mycophenolate mofetil (MMF) with delayed introduction of low-dose tacrolimus in RT from elderly donors to elderly recipients. METHODS: This observational study in 13 centers included 78 patients, aged 61+/-7 years (range, 50-77), who received a kidney from a donor with a mean age of 64+/-5 years (range, 55-76), 94% of whom had died from a cardiovascular accident (CVA). Immunosuppression consisted of 1 mg/kg daclizumab in two doses (pre-RT and on day 14) combined with steroids, mycophenolate mofetil (initial dose of 2 g/d), and tacrolimus (0.1 mg/kg per day). Tacrolimus was introduced before day 7 (mean, 5.5 days) and adjusted to a target level of 5 to 8 ng/ml. The mean follow up was 27 weeks. RESULTS: One graft was lost due to primary renal failure and 28 patients (36.4%) required dialysis due to delayed graft function, although it was generally of short duration (median, 4 days; only 2 cases >2 weeks). Acute rejection was seen in 11 patients (14%), with 9 of these confirmed by biopsy (11%, Banff 1997 grade I or II). Three patients withdrew from the study and two patients died (sepsis and accident). The remaining 72 patients continued follow up with a median 6-month creatinine value of 1.6 mg/dL. Sixty-seven percent of patients had at least one episode of infection, half of which were of urinary tract infections. There were nine cases of CMV infection. CONCLUSIONS: These initial results suggest that this immunosuppressive regimen offers good efficacy with regard to short-term renal function, while maintaining both an acceptable low rejection rate and incidence of serious infections.

[Isotopic renogram after captopril administration: clinical experience in the assessment of the hypertensive patient]. / Renograma isotópico después de la administración de captopril: experiencia clínica en la valoración del paciente hipertenso.

BACKGROUND: Isotopic renogram allows renal function to be estimated in both kidneys independently. The glomerular filtrate in ischemic kidneys is largely dependent on the tone of the efferent glomerular arteriolae and therefore on the concentration of circulating angiotensin II. METHODS: In 42 patients with severe high blood pressure in whom renal angiographic study was carried out for suspicion of vasculo-renal hypertension, an isotopic renogram using 99m Tc-DTPA as a tracer was performed in basal conditions and following the administration of 50 mg of oral captopril. RESULTS: In 21 patients both the angiographic examination and the post-captopril renogram were normal. In 16 patients in whom uni or bilateral stenosis higher than 50% of the lumen of renal artery was observed on angiographic examination, the post-captopril renogram showed changes. In 5 patients the angiography was normal while the renogram showed evaluable changes. No false negatives were observed in the post-captopril renogram, however the basal renogram was not demonstrative in 6 patients with stenosis of the renal artery. Sensitivity of the test was thus 100% and specificity 80%. The positive predictive value was 76% and the negative predictive value 100%. CONCLUSIONS: The post-captopril renogram may be a useful test in the functional study of renal behaviour in patients with vasculo-renal hypertension.

Native ureteropyelostomy in the treatment of obstructive uropathy in adult renal transplant. Experience and technical alternatives.

OBJECTIVE: To analyze and evaluate our experience in surgical treatment with the open approach of the complex ureteral stenosis after adult kidney transplantation in a tertiary level hospital in the last seven years. We have reviewed the different surgical options used. PATIENTS AND METHODS: A total of 589 consecutive adult renal transplants were performed from January 2005 to December 2012. Of these, 1.1% showed some degree of symptomatic obstructive uropathy which after initial urinary diversion required open surgical approach using the ipsilateral or contralateral native urinary tract. Characteristics of the patient, clinical examinations performed and surgical technique performed as well as their results are presented. RESULTS: During the period under review, in 5 men and 2 women who had ureteral stenoses after renal transplant, 7 reparative surgeries were performed by open ureteropyelostomy, using ipsilateral native ureter in 6 cases and contralateral ureter in the remaining case. In one case, uretero-calicial anastomosis was performed due to severe pyelic shrinkage. There were no significant complications. Native kidney nephrectomy was not required for further complications. All the patients operated on had optimum plasma creatinine levels with resolution of previous dilatation. CONCLUSIONS: The initial percutaneous nephrostomy followed by open surgical repair using native ureter represents a definitive, valid and optimal alternative in terms of safety and preservation of renal function.

Development and validation of a specific questionnaire for evaluating the impact of gastrointestinal symptoms on the health-related quality of life of transplant patients.

BACKGROUND: Transplant patients receiving immunosuppressant treatment suffer gastrointestinal symptoms (GIS) limiting their health-related quality of life (HRQOL) and causing dose redíuctions and discontinuations. METHODS: This observational, multicenter, cross-sectional study aims to develop and validate a questionnaire for detecting and quantifying the impact of GIS on the HRQOL of patients with functioning organ transplants. We developed a pilot version of the questionnaire SIGIT-QOL (Impact of Gastrointestinal Symptoms on Quality Of Life) and then evaluated the feasibility, validity, and reliability. We consecutively recruited 274 solid organ transplant patients from 20 hospitals. Sociodemographic and clinical data were collected. Patients completed the SIGIT-QOL and Gastrointestinal Quality of Life Index-GIQLI- questionnaires. RESULTS: Mean age was 52.7 (SD, 7.59) and 181 were male; 43.4% showed an episode of GIS since transplantation (3-12 months before). Of all patients, 95.3% completed the SIGIT-QOL. Mean time of completion was 6.49 minutes. Exploratory factorial analysis identified a 1-dimensional structure (42% of total variance). Internal consistency was high (Cronbach's alpha, 0.889). A significant association was found between the SGITI-QOL and the presence of GIS (P < .01). Finally, correlation coefficients between SIGIT-QOL and GIQLI were moderate-high except for Social Function. CONCLUSION: The brief SIGIT-QOL questionnaire can detect and quantify the GIS and their impact on the HRQOL of solid organ transplant patients.

Histological findings in two renal transplants accomplishing operational tolerance criteria.

Operational tolerance is defined as stable renal function in transplants without immunosuppression for at least 1 year. We present histological assessments of two patients with operational tolerance. The first withdrew immunosuppression in 2005 and presents stable renal function (creatinine 1.5 mg/dL) without proteinuria. The biopsy showed mild chronic tubulointerstitial changes without inflammation. The second withdrew immunosuppression in 2009 and maintains stable renal function (creatinine 1.6 mg/dL) with mild proteinuria. Histology showed chronic humoural rejection and Class II anti-human leukocyte antigen antibodies were detected. These cases suggest that a renal biopsy may be useful to rule out subclinical pathology in patients with operational tolerance.