The effects of mineral metabolism markers on renal transplant outcomes.

BACKGROUND: Hyperparathyroidism is a common complication of chronic renal failure. A functioning kidney graft improves hyperparathyroidism but it can persist to some degree for years. Persistent hyperparathyroidism associated with hypercalcemia and hyperphosphatemia have been associated with poor graft and patient survivals. The purpose of the present work was to assess the association between calcium/phosphate mineral metabolism markers and graft outcomes. PATIENTS AND METHODS: Among 389 renal transplantations performed in our center between January 2000 and June 2008, 331 patients had functioning grafts at 12 months, the subjects of this study. Measurements of intact parathyroid hormone (iPTH), serum calcium and phosphate, tubular phosphate reabsorption, and urinary calcium excretion were performed at 1, 3, 6, and 12 months. The mean follow-up was 84.0 ± 31.8 months. RESULTS: During the follow-up period, 63 grafts (19.0%) were lost, 30 patients (9.0%) died, and 80 recipients (24.2%) presented at least one cardiovascular event. Univariate Cox proportional analysis showed high iPTH levels at 1 and 12 months after transplantation to not be associated with worse patient or graft survival or an higher risk of cardiovascular events. Serum phosphate and calcium concentrations as well as calcium-phosphate products during the first year after transplantation were not associated with graft and patient outcomes or cardiovascular events. However, serum calcium at 12 months showed an inverse association with graft survival after adjusting for other variables (hazard ratio 0.61; 95% confidence interval 0.40-0.94; P = .026). CONCLUSIONS: iPTH levels and serum phosphate concentrations and calcium-phosphate products during the first year after transplantation were not associated with graft outcomes. The inverse association between adjusted calcium and graft survival should be studied further.

Validation of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation in advanced chronic renal failure.

INTRODUCTION: The aim of this work was to study the accuracy of the CKD-EPI equation to estimate the glomerular filtrate in patients with advanced chronic renal failure. OBJECTIVE: We compared the estimations of Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault (CG) equations to a glomerular filtration rate measured as the arithmetic mean of the urea and creatinine clearances (ClUrCr). MATERIAL AND METHODS: The study was made in 89 nondialyzed patients with chronic renal disease in stage 4 or 5. Serum creatinine values were recalibrated to standardized creatinine measurements. In each patient, the difference between each estimating equation and the measured glomerular filtration rate was calculated. The absolute difference expressed as a percentage of the measured glomerular filtration rate indicates the intermethod variability. RESULTS: Overall, the glomerular filtration rate measured as the ClUrCr was 14.5 ± 5.5 ml/min/1.73 m(2); and the results of the estimating equations were: MDRD 14.3 ± 5.5 (p = NS); CKD-EPI 13.6 ± 5.4 (p <0.01) and CG 16.8 ± 6.5 ml/min/1.73 m(2) (p <0.001). The variability of the estimating equations was 16 ± 12.2%, 16.7 ± 12,1% and 22 ± 15.6% (p <0.05), for MDRD, CKD-EPI and CG. The percentage of estimates within 30% above or below the measured glomerular filtration rate was 85% for MDRD, 88% for CKD-EPI and 70% for CG. The CG variability, but not MDRD variability or CKD-EPI variability, was influenced by gender (19.3 ± 15.1% in males vs 27.3 ± 15.5% in females, p <0.05) and showed a negative correlation with the glomerular filtration rate (r = -0.23, p <0.05) and the age (r = -0.24, p <0.05) and positive correlation with the body mass index (r = 0.37, p <0.001). In patients with chronic renal disease in stage 5, the variability of the different estimating equations was similar. CONCLUSIONS: We conclude that in our population with advanced chronic renal failure, the CKD-EPI equation is as accuracy as the MDRD equation. With standardized creatinine the CG equation has a lower accuracy and its utilization may be reconsiderated.

Utilization of elderly kidney donors (>70 years) does not affect graft survival in the medium term.

BACKGROUND: The need for organs for renal transplantation has encouraged the use of grafts from increasingly older donors. Earlier studies performed in Spain have shown the suitability of donors aged 60-65 years. In this single-center study, we evaluated our results using donors >70 years old. METHODS: We evaluated 401 primary transplantations performed from January 2000 to December 2009. Their initial immunosuppression was a tacrolimus-based (n = 324), cyclosporine-based (n = 70) or calcineurin inhibitor-free (n = 7) regimen patients. Recipients were classified according to the donors age: <50 (42.6%); 50-70 (39.7%) and >70 (17.5%) years. RESULTS: There were no differences in recipient or donor gender, time on dialysis, cold ischemia, delayed graft function, or acute rejection episodes. However, the mean age was higher among patients who received grafts from donors >70 years old; 42.5 ± 12.4 years for <50, 58.1 ± 8.2 years for 50-70, and 65.7 ± 7.2 years for >70; (P = .000). The serum creatinine at 12 months was increased according to the age of the donor; 1.4 ± 0.6, 1.8 ± 0.6, 70 and 1.7 ± 0.5 mg/dL, respectively (P = .001). The graft survival rates at 5 years were 81%, 74%, and 70%, respectively (P = .519). Upon multivariate analysis only HLA-DR mismatches, delayed graft function, and acute rejection episodes were associated with graft loss. Patient survival rates (86%) at 5 years were similar among recipients from donors aged 50-70 and >70 years, but higher (96%) for those who received a graft from a donor <50 years (P = .003). CONCLUSIONS: Nearly 20% of donors were >70 years old in our study. Their kidneys displayed excellent short-term outcomes.

Cholecalciferol supplements improve vitamin D deficiency in renal transplant recipients.

Most renal transplant recipients display vitamin D deficiency or insufficiency. The KDIGO guidelines suggest that this deficit should be treated as in the general population. Since there are few studies about the effects of cholecalciferol in de novo renal transplant recipients, we sought to assess these effects in long-term kidney graft recipients. Among 37 renal transplant recipients (19 males, 18 females) at a mean of 105±82 months posttransplantation, vitamin D insufficiency or deficiency was treated with cholecalciferol (400-800 IU/d) plus calcium supplements (600-1200 mg/d of elemental calcium). These subjects were compared with 37 untreated recipients for a period between 6 and 12 months. At baseline, there were no differences between the groups in age at transplantation, sex, length of follow-up after grafting, function measured by estimated glomerular filtration rate (44.4±16.8 treated vs 42.0±15.0 mL/min/1.73 m2 untreated; P=.527); iPTH (157±103 treated vs 176±118 pg/mL untreated; P=.461); 25OHD (14.7±4.7 treated vs 15.7±9.7 ng/mL untreated; P=.584); or 1.25OHD (34.1±26.0 treated vs 34.0±13.0 pg/mL untreated; P=.950). When compared with baseline values, iPTH (157±103 vs 144±89 pg/mL; P=.11) and 1.25OHD levels at 6 months (34.1±26.0 vs 35.9±26.3 pg/mL; P=.282) showed no change but 25OHD levels (14.7±4.7 vs 22.6±7.4 ng/mL; P=.000) and phosphate tubular reabsorption (64%±17% baseline vs 69%±14% at 6 months; P=.030) were increased in the treated patients. There were no differences in the parameters studied in untreated patients. Among the 27 recipients followed at 12 months, iPTH was decreased compared with baseline values (157±103 vs 124±62 pg/mL; P=.024) and 25OHD remained stable with respect to the values at 6 months (21.1±5.3 ng/mL). No adverse effects of cholecalciferol were observed such as those to increase urinary calcium excretion. Low doses of cholecalciferol improved vitamin D status and decreased iPTH levels at 12 months. Higher doses than those used in our study are needed to increase serum 25OHD concentrations above 30 ng/mL.

Evolution of rejection rates and kidney graft survival: a historical analysis.

INTRODUCTION: New immunosuppressive regimens have dramatically reduced rejection rates but this positive effect has not been followed by an improvement in long-term graft outcomes. The aim of the present work was to investigate the incidence of graft rejection and graft outcomes with various immunosuppressive protocols. PATIENTS AND METHODS: Included in our study were 1029 first renal transplantations performed at our unit between November 1979 and December 2007. Basal immunosuppression included azathioprine (AZA) in 198 recipients, cyclosporine (CsA) in 524 recipients, and tacrolimus (TAC) in 307 recipients. RESULTS: Recipient and donor ages increased progressively from the AZA to the TAC era. Delayed graft function was less frequent among AZA than CsA and TAC recipients (29.8 vs 39.3% vs 42.0%; P = .014). The incidence of acute rejection episodes was 68.7% on AZA, 38.2% on CsA, and 11.4% on TAC (P = .000). Graft survival rates at 1, 5, and 10 years were 69%, 56%, and 46% on AZA, 82%, 69%, and 54% on CsA, and 88%, 77%, and 60% on TAC, respectively (P = .001). However, the differences disappeared when only grafts surviving >12 months were analyzed. On multivariate analysis, the variables associated with worse graft outcomes after 12 months were older recipient age, male gender, longer time on dialysis, lower body weight, and higher serum creatinine level at 6 months. CONCLUSIONS: New immunosuppressants have decreased the incidence of acute rejection. But this was not followed by a significant improvement in graft outcomes after 12 months. The beneficial effects on rejection are possibly affected by the older age of donor and recipient and the worse early graft function.

Vitamin D deficiency in kidney transplant recipients: risk factors and effects of vitamin D3 supplements.

INTRODUCTION: The Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines in chronic kidney disease (CKD) give some recommendations about diagnosis and treatment of vitamin D deficiency. These guidelines may also be applied to renal transplant recipients. The aim of the present study was to assess the vitamin D status and the effects of vitamin D3 supplements among a cohort of kidney graft recipients. PATIENTS AND METHODS: Five hundred nine renal transplant recipients with a follow-up of more than 12 months were included in this retrospective cross-sectional study. A total of 189 patients were treated with vitamin D3 supplements, 171 with calcitriol (0.25 or 0.5 microg x 3 weekly) and 18 with cholecalciferol (400 IU/d). RESULTS: 25OHD deficiency was present in 38.3% of patients, insufficiency in 46.9%, and normal levels in 14.7%. There were no differences in the prevalence of deficiency or insufficiency between patients who were not treated or those who were treated with vitamin D3 supplements. Upon multivariate analysis, 25OHD concentrations correlated with gender, length of follow-up, season of 25OHD determination, iPTH and 1.25OHD concentrations, and treatment with ACEI/ARB (R(2) = 0.17; P = .000). CONCLUSIONS: 25OHD deficiency or insufficiency is frequent after renal transplantation even in sunny regions. The clinical significance of such a high prevalence of apparent 25OHD deficiency/insufficiency is unclear and requires further study.

Secondary hyperparathyroidism after kidney transplantation: a cross-sectional study.

INTRODUCTION: The purpose of the present study was to investigate the prevalence of hyperparathyroidism among a population of kidney graft recipients. PATIENTS AND METHODS: We investigated biochemical bone parameters of 509 renal transplant recipients with a mean follow-up of 113 +/- 76 months. Among these patients, 257 patients were treated with either vitamin D or calcium supplements or both. RESULTS: The mean estimated glomerular filtration rate (eGFR) was 47.2 +/- 18.4 mL/min/1.73 m(2) and the mean intact parathyroid hormone (iPTH) level was 144 +/- 149 pg/mL. A total of 70 patients (13.7%) had hypercalcemia defined by a corrected serum calcium >10.2 mg/dL. When the patients were classified according to iPTH concentrations following the Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines: 22.4% had iPTH <70 pg/mL; 30.8% between 70 and 110 pg/mL; 16.5% between 110 and 150 pg/mL; 24.3% between 150 and 300 pg/mL; and 6.9% >300 pg/mL. There were no differences in biochemical bone parameters between those that were or were not on calcium and vitamin D supplements, but there was a higher percentage of patients with normal iPTH among the treated group (28.0% vs 16.7%; P = 0.003). In patients not receiving calcium and/or vitamin D supplements, multiple linear regression demonstrated that only time on dialysis, eGFR, and serum 25-hydroxyvitamin D (25OHD) levels were significantly predictive of iPTH concentrations (R(2) = 0.21; P = .000). CONCLUSIONS: About 80% of patients displayed high iPTH concentrations. The persistence of hyperparathyroidism was associated with graft dysfunction, longer time on dialysis, and low concentrations of 25OHD. Treatment with vitamin D produced a slight improvement in the prevalence of hyperparathyroidism.

Comparative analysis of the hemodynamic and respiratory parameters during laparoscopic versus open living donor nephrectomy: an experimental model.

Increased intrabdominal pressure induced by pneumoperitoneum induces modifications in cardiovascular and respiratory systems. The aim of the study was to analyze the hemodynamic and respiratory modifications produced by pneumoperitoneum during living donor nephrectomy in a porcine experimental model. Twenty pigs underwent left nephrectomy, 10 by laparoscopy and 10 by an open approach. The following parameters were measured: mean arterial pressure (MAP), central venous pressure, cardiac output (CO), systemic vascular resistance (SVR), end tidal CO2 (ETCO2), minute volume (MV), respiratory airway pressure (RAP), and "compliance." Both groups were monitored for cardiac and respiratory systems at basal, 5, 30, and 60 minutes as well as postsurgery. The comparative analysis demonstrated increased CO with a higher difference at 30 minutes (4.33 +/- 0.73 vs 8.54 +/- 1.26 L/min, P < .001); decreased SVR (1118.81 +/- 302.52 vs 663.37 +/- 81.45 dinas x s x cm(-5), P < .001), and elevated MAP among the laparoscopic group (66.5 +/- 11.52 vs 80.25 +/- 2.49 mm Hg, P = .004). Analysis of respiratory modifications showed an initial increase in ETCO2 (44.3 +/- 2.6 vs 54.1 +/- 12.56 mm Hg, P < .035) and a higher MV administered (5.6 +/- 0.1 vs 7.01 +/- 0.96 L/min, P = .03) to the laparoscopy group. An increased RAP was observed at 5 minutes (22.11 +/- 2.76 vs 28.8 +/- 3.68 mm Hg, P < .001), in the laparoscopic group and lower levels of "compliance" at the same moment in that group (16 +/- 1.66 vs 14.9 +/- 4.07 cm H2O). Laparoscopic nephrectomy caused an increase in CO and MAP and decreased SVR. Likewise there were elevations of RAP, ETCO2, and MV and a slight decrease in the "compliance."

Mycophenolate mofetil levels in stable kidney transplant recipients.

The usefulness of mycophenolate mofetil (MMF) levels in stable kidney transplant patients is not well known. We measured MMF trough levels in 137 adult kidney recipients with more than 1 year of stable graft function. The MMF dose was adjusted according to hematological or gastrointestinal toxicity, it was 500 mg in 22 (16%) patients; 750 mg in 22 (16%); 1000 mg in 69 (50.5%); 1500 mg in 15 (11%); and 2000 mg in 9 (6.5%). We analyzed the total dose, virgule dose/kg, and MMF levels in relation to efficacy parameters (creatinine, proteinuria) and hematological toxicity (erythrocytes, leukocytes, and platelets) at the time of MMF level determinations and 3 months thereafter. Statistical analyses were performed with SSPS 12.0, including sensitivity and specificity analyses by ROC. Mean MMF levels were 3.68 mg/L (Pc25, 1.6-Pc75, 4.4 mg/L) with significant differences according to dose (P < .001). Trough MMF levels did not have discriminatory capacity in the area under the ROC for anemia, renal failure, or proteinuria at the time of determination or 3 months later. The percentage of patients without proteinuria was high among patients with MMF levels between 1.6 and 4.4 mg/L. The MMF levels were low in patients who had a major increase in creatinine (1.6 vs 3.8 mg/L, P < .05). In stable renal transplant patients the levels of MMF were related to the administered dose, and they are higher than those previously described in patients with less than a year follow-up with a functioning kidney. They did not have discriminatory value at the time of determination or 3 months later. Nevertheless, low MMF levels could help recognize patients at risk of developing chronic nephropathy.

High body mass index and posttransplant weight gain are not risk factors for kidney graft and patient outcome.

BACKGROUND: High body mass constitutes a significant risk factor for morbidity and mortality in the general population, but it has been associated with an increased survival among dialysis patients. Its effects on renal transplant outcomes are controversial. The aim of our present work was to investigate the impact of high body mass and posttransplant weight gain on patient and graft outcomes. PATIENTS AND METHODS: One thousand consecutive renal transplant recipients (631 men and 369 women) were included in the study. Their mean age was 42.9 years and the follow-up was at least 2 years. Basal immunosuppression was azathioprine (Aza) and steroids in 196 patients, cyclosporine (CsA) without or with antiproliferative agent in 557, and 239 were presented tacrolimus (Tac). RESULTS: At the time of transplantation the body mass index (BMI) was 23.7 +/- 3.9 kg/m2, namely, <18.5 kg/m2 in 6.3%; 18.5 to 25 in 61.7%; 25 to 30 in 25.4%; and >30 in 6.5%. Pretransplant obesity was associated with old age and female gender. Obese patients experienced a greater risk of delayed graft function (P < .01) and surgical wound complications (P < .01). After 1 year, 299 patients (29.9%) displayed weight gain >10% (mean 8.6% +/- 10.4% or 5.0 +/- 6.1 kg). Patients on Aza showed increased body weight by 11.9% +/- 10.9%; CsA patients by 9.5% +/- 10.3%, and Tac patients by 4.9% +/- 9.1% (P < .001). Univariate and multivariate analysis showed that pretransplant BMI had no effect on graft or patient survival either in the whole group or in the patients treated with CsA or TAC. Posttransplant weight gain above 5% or 10% did not influence graft or patient outcomes. CONCLUSIONS: The new immunosuppressive regimes reduce posttransplant weight gain. Pretransplant high body mass and 1-year posttransplant weight gain were not risk factors for graft or patient survival in our experience.

Prevalence of osteoporosis, osteopenia, and vertebral fractures in long-term renal transplant recipients.

BACKGROUND: Osteopenia and osteoporosis are frequent complications early after transplantation. Their long-term prevalences and associations with the risk of fractures are not well known. The objective of the present work was to determine the incidence of osteopenia and osteoporosis versus vertebral fractures in renal transplant recipients with stable graft function and with a follow-up of at least 10 years. PATIENTS AND METHODS: Forty renal transplant recipients, 24 men and 16 women, were included in the study. The mean age was 41.8 years and the follow-up was 130 +/- 14 months. Initial immunosuppression consisted of cyclosporine with or without an antiproliferative agent. Measurements of bone mass density (BMD) were performed by dual-energy X-ray absorptiometry (DEXA). The assessment of vertebral fracture using conventional radiography was evaluated by semiquantitative criteria. RESULTS: Eleven patients (27.5%) displayed lumbar spine osteoporosis (T-score < -2.5); 21 (52.5%), osteopenia (T-score > -2.5 and < -1) and 8 (20.0%), normal BMD. However, BMD was better preserved at the femoral neck: 14 patients (35.0%) had normal BMD; 20 (50.0%) osteopenia, and 6 (15.0%), osteoporosis. When analyzed together, patients with osteoporosis or osteopenia showed worse graft function at 1 and 8 years compared with normal BMD patients (1.75 +/- 0.634 vs 1.32 +/- 0.33 mg/dL at 1 year; P < .014) and (1.7 +/- 0.4 vs 1.2 +/- 0.2 mg/dL at 5 years; P < .01) and a greater number were prescribed vitamin D (50% vs 23%). Mild vertebral fractures were observed in 60.0% patients with osteoporosis; 70% with osteopenia; and 43% with normal lumbar BMD. Peripheral fractures were more common in patients with osteoporosis (P = .053). CONCLUSIONS: Osteoporosis and osteopenia are common among long-term renal transplant recipients are associated with poorer graft function. Lumbar spine BMD osteoporosis is associated with peripheral fractures. However, mild vertebral deformities are not associated with the presence of osteopenia or osteoporosis.

Mycophenolate mofetil tolerability and dose changes in tacrolimus-treated renal allograft recipients.

Mycophenolate mofetil (MMF) reduces acute rejection episodes (AREs) and may be associated with better renal graft survival than azathioprine. However, MMF-related adverse events are frequent; dose reduction or even withdrawal are quite common. Between 1999 and 2003, 115 renal transplantation patients were treated with tacrolimus, MMF, and steroids. An observational study was undertaken until graft loss (n = 7), death with a functioning graft (n = 2), or October 31, 2005 (mean follow-up-50 months). We assessed MMF dose reductions due to adverse events with the possible consequences on AREs and graft function. Treated acute ARE occurred in 11.3% of recipients, all of which were steroid-responsive. The median MMF initial daily dose was 1000 mg. In 44 patients (38.3%), the MMF dose was not changed; in 48 (41.7%) it was reduced; and in 23 (20%), withdrawn. The causes for dose modification were diarrhea (n = 33, 28.7% of all patients), leukopenia (n = 22, 19.1%), both of these (n = 7, 6.1%), or other events (n = 9, 7.8%). No AREs were attributed to MMF dose changes. Tacrolimus blood levels were higher at 3 years and serum creatinine values at 4 years among patients with dose changes (8.43 +/- 2.42 vs 7.37 +/- 2.23 ng/mL; P = .051 and 1.75 +/- 0.71 vs 1.48 +/- 0.38 mg/dL; P = .038, respectively). The need for MMF dose reduction or withdrawal was frequent in our patients with diarrhea or leukopenia during treatment with tacrolimus, MMF, and steroids. These adverse event-related changes were not associated with AREs, but produced deleterious effects on long-term graft function.

Conversion from calcineurin inhibitors to everolimus in kidney transplant recipients with malignant neoplasia.

Cancer has been reported to be more common among kidney transplant recipients than waiting-list patients or the general population. Use of anticalcineurin agents and azathioprine are relevant risk factors. Nine renal allograft recipients (seven men and two women) of mean age 67.6 (55-77) years and mean time after transplantation of 30.7 (58-216) months were switched to everolimus-based immunosuppression because of the presence of biopsy-proven malignancies (eight patients) or neurological tacrolimus toxicity (one patient). One patient with posttransplant lymphoproliferative disease also received chemotherapy with a good evolution at 6 months. He showed an initial increase in the protein to creatinine ratio (peak 3.3 mg/mg at 3 months) that was controlled by increasing the enalapril dose. One patient with skin cancer and severe atheromatosis (baseline SCr 2.5 mg/dL, creatinine clearance 17 mL/min, and protein to creatinine ratio 3.2 mg/mg), had cyclosporine and everolimus overlapped for 25 days, showing a continued poor evolution requiring dialysis initiation at 3 months after switch. The other six patients with recurrent skin cancers had good cancer evolution, with no new skin tumors and regression of skin lesions in three, including not biopsied actinic keratosis. Sudden switching from calcineurin inhibitors to everolimus is safe and may be used in long-term transplant recipients with malignancies. In patients with advanced chronic nephropathy this approach appeared to be less beneficial.

Pancreas islet transplantation in the genitourinary tract associated with renal transplantation: an experimental study.

Conceptually, pancreas islet transplantation (PIT) associated with renal transplantation (RT) should resolve not only chronic renal failure but also diabetes. Although the most frequently used site for PIT is the portal vein, genitourinary locations could be technically feasible during RT. Seventeen pigs (age 3 to 4 months; mean weight 34.5 kg) underwent the following experimental steps: On day 1 a left nephrectomy was performed and the kidney was perfused with cold Wisconsin solution. This was followed by a caudal pancreatectomy and islet isolation by means of digestion with intraductal collagenase. Islets were stained with Dithizone and cultured overnight al 37 degrees C and 5% CO(2). On day 2 a right nephrectomy and orthotopic RT of the preserved left kidney were performed. The islets were transplanted into four different sites: subcapsular in the kidney graft, in the bladder submucosa, in the testis by puncture, and in the testis by infusion through the vas deferens. On day 7 the animals were sacrificed. Islet viability was determined by histological examination with insulin immunostaining and determination of insulin in the blood of the veins draining the implantation sites. The mean weight of the pancreatic specimens was 27.8 g (13 to 46). The mean number of islets was 536,000 (16,600 to 1,5000,000). Islets were shown in the bladder submucosa and the testes after vas deferens infusion. The number of viable islets in the other implantation sites was very scarce. The insulin levels of the venous effluents were: 15.1 microU/mL for bladder submucosa, 10.2 microU/mL for intradeferential injection in the testis, 7.3 microU/mL for intratesticular injection by puncture, and 2.6 microU/mL for subcapsular implantation in the graft. In conclusion, the bladder submucosa and testis via the vas deferens might represent alternative sites for PIT. The latter route may benefit from the immunoprivileged and special trophic conditions of the testis. For the first time, the feasibility of the bladder submucosa as an implantation site for pancreas islets was demonstrated.

Lumbar bone mineral density after kidney transplantation: a three-year prospective study.

Osteopenia is a common complication after transplantation. However, prospective long-term studies are scarce and most were performed in patients on cyclosporine and high-dose steroids. In 65 patients with functioning grafts, 41 males and 24 females, 50 on tacrolimus-based immunosuppression and 15 on cyclosporine-based immunosuppression, bone mineral density (BMD) was measured in the lumbar spine (L2-L4) and femoral neck (FN) using dual X-ray absorptiometry (DEXA) in the first month after transplantation (baseline) and at 1, 2, and 3 years. At baseline, BMD was similar to the control population both in L2-L4 (z score = -0.421) and in FN (z score = -0.518). During the follow-up, 3 types of patterns were identified: BMD increased in L2-L4 in 25 patients (38.5%), remained stable in 20 patients (30.8%), and decreased in 20 patients (30.8%). BMD losses appeared mainly during the first year (0.964 +/- 0.162 baseline; 0.904 +/- 0.161 at 1 year, 0.886 +/- 0.140 at 3 years; analysis of variance [ANOVA] P < .001). However, the improvement was maintained throughout the follow-up (0.860 +/- 0.176 g/cm2 at baseline; 0.901 +/- 0.161 at 1 year; 0.954 +/- 0.178 at 3 years; ANOVA P < .001) and there was a parallel increase of BMD in FN (0.712 +/- 0.144 at baseline; 0.744 +/- 0.249 at 1 year; 0.826 +/- 0.184 at 3 years; ANOVA P < .01). There were no differences between both groups in graft function, intact parathyroid hormone (iPTH) levels, number of postmenopausal women, or steroid doses. About one third of patients had bone loss during the first year after transplantation. We were unable to identify any risk factor for this complication in patients on low-dose steroids.

Chronic kidney disease in renal transplant recipients.

UNLABELLED: The aim of the present study was to investigate the utility in renal transplant patients of the guidelines for the diagnosis and classification of chronic kidney disease (CKD) based on the estimated glomerular filtration rate (GFR) elaborated by the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation. PATIENTS AND METHODS: Four hundred forty-seven cadaveric kidney transplants performed between 1980 and 1994 with graft function at 12 months were included in the study. The GFR was calculated according to the MDRD equation. RESULTS: The mean GFR at 12 months was 54.5 +/- 20.3 mL/min/1.73 m(2): 23 patients (5.1%) had a GFR > or =90 mL/min/1.73 m(2); 136 patients (30.6%), 60-89; 246 (54.7%), 30-59; 35 patients (7.8%), 15-29; and 7 patients (1.6%), GFR <15. Similar distribution of CKD stages was observed at 5 and 10 years. Unadjusted graft survival at 10 years was better among patients with a higher GFR at 12 months: 87% in patients with GFR >90 mL/min/1.73 m(2); 83% of GFR 60-89 mL/min/1.73 m(2); 63%, GFR 30-59 mL/min/1.73 m(2); and 23%, GFR <30 mL/min/1.73 m(2) (P < .001). The association between GFR and graft survival persisted when adjusted by the age and gender of the recipients and donors, time on dialysis, body mass index, immunosuppression, delayed graft function, rejection, and HLA mismatches. The prevalence of complications, such as anemia, hypertension, dyslipidemias, and number of drugs increased as GFR declined. CONCLUSIONS: More than 60% of recipients presented chronic kidney disease. GFR was a predictive factor for graft survival at 10 years. The classification of renal transplant patients by CKD stages may help to identify patients with increased risk of graft loss and also to design strategies to improve outcomes.

Interaction between omeprazole and tacrolimus in renal allograft recipients: a clinical-analytical study.

Omeprazole is a proton pump inhibitor with a number of pharmacokinetic drug interactions due to interference with cytochrome P450. Some studies show absence of relevant interaction between omeprazole and cyclosporine, but little is known about possible interactions between omeprazole and tacrolimus. In vitro studies suggest such interference, but no clinical data are available so far. We assessed interactions between omeprazole and tacrolimus among patients fulfilling two criteria: (1) renal allograft recipients receiving immunosuppression based on tacrolimus and acid-related disorder prophylaxis with omeprazole 20 mg/d since the day of the transplant procedure and (2) stopped omeprazole when it was considered unnecessary. Fifty-one transplant recipients received concomitant immunosuppression with MMF-prednisone (n = 47) or azathioprine-prednisone (n = 1), or rapamycin-prednisone (n = 2) or only prednisone (n = 1). omeprazole was stopped after 6.2 +/- 3 months of treatment. Tacrolimus doses and levels were recorded during 3 outpatient visits before omeprazole withdrawal (Pre3/Pre2/Pre1), at the withdrawal visit (Susp), and at 3 visits after withdrawal (Pos1/Pos2/Pos3). Weight gain was significant (72.5 +/- 13 kg Pre3; 73.4 +/- 13 kg Susp; 74 +/- 12.9 kg Pos3, P < .0001) and serum creatinine (SCr) decreased (1.70 +/- 0.49 mg/dL Pre3; 1.63 + 0.49 Susp; 1.58 +/- 0.48 Pos3, P < .0001). The progressive decrease in tacrolimus doses and levels was significant (ANOVA including the 7 visits <0.01 in all cases); whereas the level/dose ratio remained constant. Tacrolimus doses and levels continued a slow, progressive and significant decrease without any relevant change between visits during on versus off omeprazole. This clinical-analytical study supported the conclusion that an omeprazole-tacrolimus interaction is not clinically relevant. Despite possible competition or interaction at the molecular level, clinical management was not significantly affected in renal allograft recipients.

Spanish experience with cyclosporine.

Our experience with cyclosporine (CsA) in de novo renal transplantation (RT) may be systematized in four consecutive periods. From February 1986 to December 1989, patient survival was higher among 128 consecutive CsA-prednisone-treated cadaver allograft recipients than in previous patients on azathioprine. One-year graft survival was significantly higher in CsA patients, a difference that was thereafter progressively reduced: at 10 years graft survivals were 50% versus 45%, and at 15 years 37% versus 35%, respectively. The most frequent cause of graft loss was death with a functioning graft. Acute rejection caused more graft losses among Aza-treated patients than CsA-treated ones. However, chronic allograft nephropathy produced more graft losses in CsA patients. After this initial experience with CsA-based immunosuppression we developed a second phase in which better results were obtained in 209 first cadaveric RT recipients. The use of lower initial CsA doses, more rapid steroid tapering, and a better approach to CsA nephrotoxicity or chronic nephropathy by substantial reductions in CsA exposure and delayed azathioprine addition, lead to these improvements. From March 1995 through 2000, we used the new microemulsion CsA formulation (Neoral) with steroids or azathioprine in 110 first de novo RT recipients. Mean donor and recipient ages were significantly higher in this phase than in previous ones; consequently, survival and function results were slightly worse. Blood CsA concentrations measured 2 hours after administration represent a more precise predictor of exposure than trough concentrations. The last step in optimizing Neoral use in RT on our service was application of reduced-dosage with C2 monitoring instead of classical C0 testing. Acute rejection and treatment failure rates were low and renal allograft function improved with respect to previous full-dose C0 experiences. CsA use has evolved in these two decades in four consecutive phases. Short-term results have improved or been maintained from phase to phase, even with expanded-criteria donors until excellent features during last years with C2 monitoring and combination with potent drugs such as MMF or everolimus. During the coming years, new drugs and protocols will allow even more optimized use.