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Background.In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. [ABSTRACT FROM PUBLISHER]

Background/aim: There is little information on the development of anemia in the early stages of chronic kidney disease. The aim of this study was to analyze the onset of renal anemia in a cohort of initially nonanemic chronic kidney disease patients followed up in nephrology clinics., Methods: This epidemiological, prospective, three-year, multicenter study enrolled patients aged 18-78 years with stage 3 chronic kidney disease without anemia. Interim analysis was performed on the data collected during the first 12 months., Results: The study included 432 patients, average age 63.6 years (range 22-78 years, 70% male). The main etiologies of chronic kidney disease were glomerular (11.6%), interstitial (10.4%), vascular (29.4%), and diabetic (16.9%). The percentages of patients with comorbidities were 33.8% diabetes (2.5% type 1), 69% dyslipidemia, and 93% hypertension. During the first year, 12.4% of patients developed anemia. The chronic kidney disease progression rate was low: proteinuria was 0.46 +/- 0.8 g/24 h at one year versus 0.67 +/- 1.0 g/24 h at baseline. Diabetic patients showed a greater prevalence of previous cardiovascular events (50.0% vs. 24.5%) and worse control of some modifiable cardiovascular risk factors: smoking (13.4% vs. 8.6%), obesity (BMI > 30 kg/m(2), 33.6% vs. 25.3%), target blood pressure (<130/80 mmHg, 21.0% vs. 27.9%), and proteinuria (0.8 +/- 1.1 vs. 0.6 +/- 0.9 g/day)., Conclusions: After one year, 12.4% of patients developed anemia. Diabetic patients had a higher cardiovascular risk and limited blood pressure control. The overall control of cardiovascular risk was unsatisfactory.

Background: Discontinuation of steroids has long been a goal of transplant teams. However, whether this strategy is associated or not with a higher risk of long-term graft loss has not been resolved., Methods: The authors analyzed a cohort of 91 renal allograft recipients who underwent transplantation between 1993 and 1997. They were treated with cyclosporine and mycophenolate mofetil (MMF) and then had steroids withdrawn. Inclusion criteria were as follows: serum creatinine lower than 133 microM, first or second renal transplants, no or only one acute rejection episode (borderline or Ia grade), and a peak of panel reactive antibodies under 50%. Prednisone was gradually tapered off and then discontinued over a period of 2 to 4 months., Results: There were no episodes of acute rejection after steroid withdrawal. Whether steroids were withdrawn before (early) or after (late) 6 months of renal transplantation did not influence outcome. By Kaplan-Meier analysis, patient survival was 93.6% and 100% at 5 years and 93.6% and 97.6% at 10 years in the early and late steroid withdrawal groups, respectively. Graft survival was 94.3% and 98.1% at 5 years and 87.6% and 82.4% at 10 years in the early and late steroid-withdrawal groups, respectively. Risk factors for graft loss in multivariate analysis were peak of panel reactive antibodies (relative risk, 1.074; 95% confidence interval, 1.017-1.134; P=0.01) and acute rejection (relative risk, 16.5; 95% confidence interval, 1.8-147; P=0.01)., Conclusions: Early and late steroid withdrawal in low-immunologic-risk renal allografts treated with cyclosporine and MMF can be achieved without risk of acute rejection and with excellent long-term results.

Background: Protocol biopsies performed in stable renal allografts show different degrees of acute and chronic lesions that have been related with graft outcome. However, the utility of protocol biopsies to manage baseline immunosuppression has not been well characterized., Methods: We performed a case-control study to compare histological lesions observed in protocol biopsies in 49 patients treated with tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone to 49 patients treated with cyclosporine Neoral (CsA), MMF, and prednisone. Histological lesions were graded according to 1997 Banff criteria. The analysis was done according to an intention-to-treat basis., Results: Patients treated with TAC displayed in the protocol biopsy a lower acute score (0.61+/-1.01 vs. 1.26+/-1.45; P=0.0115) and a similar chronic score (1.57+/-1.97 vs. 1.51+/-1.59; P=NS). Transplant glomerulopathy was also lower in TAC treated patients (0.02+/-0.14 vs. 0.20+/-0.41; P=0.0037). Univariate and multivariate logistic regression analysis showed that the presence of acute inflammation was associated with tacrolimus treatment (relative risk [RR]: 0.30, 95% confidence interval [CI]: 0.11-0.84; P=0.0211) and the time of biopsy (RR per month: 0.56, 95% CI: 0.32-0.97; P=0.0394). The presence of chronic lesions was only associated with serum creatinine at the time of biopsy (RR: 1.01, 95% CI: 1.00-1.02; P=0.0439)., Conclusions: The incidence of inflammatory lesions and transplant glomerulopathy is lower in patients treated with TAC than in patients treated with CsA. These data suggest that baseline immunosuppression could influence the severity of histological lesions in stable grafts.

Background: The addition of induction therapy with antilymphocytic antibodies to cyclosporine (CsA) based immunosuppression, has reduced acute rejection incidence and improved short-term survivals, but has not had well-established effects on long-term renal transplant survival., Patients: We analyzed the long-term allograft outcome of patients included in a prospective randomized clinical study conducted in our center 15 years ago by comparing two strategies: (A) horse antilymphoblast globulin (ALG) given at 10 mg/kg on alternate days to a maximum of 6 doses with low-dose CsA started at 8 mg/kg per day and prednisone at 0.25 mg/kg per day, versus (B) CsA started at 15 mg/kg per day and prednisone at 0.5 mg/kg per day. Diabetic and highly sensitized patients (PRA > 70%) were excluded from the study., Results: The characteristics of the 50 patients enrolled in each group were not different. Although patient survival was not different (88% in group A vs 77% in group B), recipients treated with ALG showed a lower incidence of acute rejection episodes (20% vs 44%, P = .01) and better death-censored renal allograft survival (57% vs 41%, P = .03). Among rejection-free patients, graft survival was 15% higher in group A (60% vs 45%, P = .12). Multivariate Cox regression analysis showed that an acute rejection episode (relative risk [RR]: 2.44, 95% confidence interval [CI] 1.36-4.39; P = .0029) rather than ALG immunosuppression (RR 0.74, 95% CI 0.41-1.33; P = NS) was an independent predictor of death-censored graft survival., Conclusions: In summary, we confirmed that concomitant induction therapy with ALG, CsA, and steroids improves long-term renal allograft survival., (Copyright 2004 Elsevier Inc.)

Protocol biopsies performed in stable renal allografts show different degrees of acute and chronic lesions. Histologic findings in protocol biopsies have been related to graft outcome. We evaluated histologic lesions observed in protocol biopsies performed in patients under different immunosuppression therapies. From June 1988 a protocol biopsy was performed at approximately 4 months in patients who fulfilled the following criteria: serum creatinine <300 micromol/L; stable renal function; and proteinuria <1 g/d. Histologic lesions were graded according to 1997 Banff criteria. For the present study we considered the following groups according to immunosuppressive schedule: (i) induction therapy with polyclonal or monoclonal antilymphocytic antibodies associated with cyclosporine and prednisone (n=201); (ii) cyclosporine, mycophenolate mofetil, and prednisone (n=127); and (iii) tacrolimus, mycophenolate mofetil, and prednisone (n=51). On protocol biopsy patients treated with tacrolimus displayed a lower acute score (0.61+/-1.01 vs 1.24+/-1.23 in group I, 1.28+/-1.41 in group II; P<.0001) and a higher proportion of normal biopsies (57.1% vs 41.9% in group I, 45.1% in group II; P=.016). A similar proportion of chronic lesions (chronic score of group I: 1.30+/-1.56; group II: 1.34+/-1.80; group III: 1.51+/-0.95; P=NS) was observed in the three groups. Protocol biopsies displayed fewer acute lesions in patients treated with tacrolimus. This result suggests that the efficacy of new immunosuppression schedules can be evaluated using the protocol biopsy as a surrogate marker of graft outcome.

Background: The minimum sample size to perform a clinical trial aimed to modify the natural history of chronic allograft nephropathy (CAN) is very large. Since the presence of chronic tubulointerstitial damage in renal protocol biopsy specimens is an independent predictor of late outcome, we evaluated whether protocol biopsies could facilitate the design of trials aimed to prevent or treat CAN., Methods: Two hundred eighty-two protocol biopsy specimens were obtained 3 months after transplantation in 280 patients with serum creatinine levels <300 micromol/L, proteinuria <1000 mg/day, and stable function. The specimens were evaluated according to the Banff criteria., Results: Graft survival depended on the presence of CAN and renal transplant vasculopathy (RTV). Thus, biopsy specimens were classified as: (a) no CAN (n=174); (b) CAN without RTV (n=87); and (c) CAN with RTV (n=21). Graft survival at 10 years was 95%, 82%, and 41%, respectively (P=0.001). Total serum cholesterol before transplantation was 4.5+/-1.1, 4.6+/-1.1, and 5.3+/-1.6 mmol/L, respectively (P=0.009) and it was the only predictor of RTV. Power analysis (beta=20%, alpha=5%) was done to evaluate whether protocol biopsies can facilitate the design of clinical trials aimed either to prevent or treat CAN. We showed that the most feasible approach would be to use the presence of CAN as the primary efficacy end point in a prevention trial. To demonstrate a 50% reduction in the incidence of CAN at 3 months, 570 patients would be required., Conclusions: Protocol biopsies may allow a reduction of sample size and especially the time of follow-up in a trial aimed to prevent CAN.

Background: Because of the shortage of kidneys available for transplantation, we began in 1985 to harvest kidneys from non-heartbeating (NHB) donors., Methods: We compared the results of a group of 66 kidney recipients from NHB donors (NHB group) with 122 kidney recipients from heartbeating donors (HB group). We analyzed, in the NHB group, the influence of ischemia times in graft survival and we tested the best cut-offs by receiver operating characteristic curves. We also studied, using a univariate and multivariate Cox hazard model, the capacity of different variables to predict graft loss., Results: Patient and graft survival were similar in both groups during the follow-up. The percentage of delayed graft function was the only significant difference between both groups (NHB group 62% vs. HB group 32%; P=0.0001). Delayed graft function, in the NHB group, is influenced by the warm ischemia time, which is directly related to the number of days to achieve a serum creatinine<300 mmol/L (P=0.0001). The best cut-off times in this group were 45 min for warm ischemia time and 22 hr for cold ischemia time. Recipients have a greater likelihood of losing the graft beyond those limits (P=0.017, relative risk: 7.3). The incidence of acute rejection was similar in both groups, and it was the only predictor factor of graft loss in the complete series of patients (P=0.0001), in the NHB group (P=0.007), and in the HB group (P=0.02)., Conclusions: Reducing the incidence of acute rejection and shortening ischemia time are conditions needed to guarantee a long graft survival of kidneys from NHB donors.

A longitudinal study of peripheral blood lymphocyte subsets was performed in 23 renal allograft recipients treated with prophylactic antilymphocyte antibodies, CsA, and steroids. At day 0 samples were obtained before transplantation (Tx), and afterwards at months +1, +3, +6, +9, +12, +24, +36, and +48. In all patients, after the depletion of lymphoid subsets during antilymphocyte antibody treatment, CD8+ lymphocytes recovered and reached higher values than those observed prior to Tx. This was mainly due to an increase in CD8+CD45RA+ lymphocytes; in contrast, the levels of "memory" CD4+ T cells and the CD4+CD62L+ subset remained low during all the follow-up period. In patients with preserved graft function (n=14) (with creatinine levels below 200 micromol/mL), the initial, relative decrease in CD4+ T cells was never reversed and the recovery of CD8+ lymphocytes started early. They also presented a peak of HLA-DR antigen expression at 1 month, not observed in those patients displaying a suboptimal graft function. At 1 month, the patients with suboptimal graft function (n=9) (with creatinine levels above 200 micromol/mL) showed higher number of CD4+ T cells, delayed recovery of CD8+ lymphocytes, and higher percentage of activated lymphocytes from month +3 on than well-functioning kidney recipients. Both CD8+ lymphocytes and HLA-DR+ T cells, found at month + 1 post-Tx, were negatively correlated with the concentration of creatinine along the follow-up. Interestingly, the mean percentage of CD4+CD25+ T cells found 36 and 48 months after Tx were positively correlated with creatinine concentration at these times. These findings indicate that variations in the distribution of lymphocyte subsets are related with a long-term graft outcome. Within the first month after Tx, a rapid recovery of CD8+ lymphocytes, but not of CD4+ T cells, and a peak of HLA-DR expression, are associated with a good graft function. In contrast, long-term expression of activation markers is related with renal dysfunction.

Our objective was to assess mean transit time (MTT) and initial uptake, both parameters derived from the renal retention function (RRF), in the study of renal function in patients with diabetic nephropathy. We studied 25 patients, 7 with type I diabetes mellitus and 18 with type II diabetes mellitus, all of whom fulfilled the criteria for diabetic nephropathy with proteinuria and/or retinopathy. We found a statistically significant correlation between initial uptake and the other biochemical and renographic parameters studied except proteinuria: serum creatinine (r = 0.66, P < 0.002), creatinine clearance (r = 0.61, P < 0.003), glomerular filtration rate (r = 0.74, P < 0.003) and effective renal plasma flow (r = 0.66, P < 0.003). The other renographic parameters studied (maximal activity of the conventional renogram and MTT of the deconvoluted renogram) did not show any correlation. Initial uptake is a semi-quantitative renographic parameter that can provide complementary information to biochemical data and it may be useful in the management of diabetic nephropathy, especially in patients with high serum creatinine or creatinine clearance.

Background: Acute rejection is an inherent risk of the withdrawal of steroids in renal allograft recipients. Mycophenolate mofetil is a potent immunosuppressant that, when given with cyclosporine (CsA), reduces the incidence of acute rejection and may facilitate discontinuation of steroids without increasing the risk of rejection., Methods: In an open pilot study, steroids were withdrawn from 26 adult cadaveric kidney transplant recipients. Corticosteroids were discontinued between 4 and 30 (mean 17) months after transplantation, and steroid-free follow-up ranged from 7 to 18 (mean 10) months., Results: Mean CsA doses, CsA blood levels, and serum creatinine at the time of steroid withdrawal and at last patient visit after cessation of steroids were 4.2+/-1.2 mg/kg/day and 3+/-0.8 mg/kg/day (P<0.001), 170+/-53 ng/ml and 113+/-34 ng/ml (P<0.001), and 133+/-36 microM/L and 130+/-37 microM/L (NS), respectively. No rejection episodes occurred after steroid withdrawal., Conclusions: This open study shows that corticosteroids can be safely and successfully withdrawn from renal allograft recipients receiving CsA and mycophenolate mofetil.

Clonal deletion or inactivation of donor-specific alloreactive cells are important mechanisms that are believed to account for acquired immune tolerance in allograft recipients. Serial assessment of precursor cytotoxic T lymphocyte frequencies (CTLpf) by limiting dilution analysis (LDA) provides information at the clonal level on changes in the alloimmune response of graft recipients. We performed a longitudinal study of 15 cadaveric kidney recipients before and every 3 months throughout the first year after transplantation (Tx). Pre-Tx values of donor CTLpf showed high interindividual variability without a predictive value for the clinical outcome. All patients with well functioning kidneys had decreased CDLpf at 3 months post-Tx in comparison with pre-Tx values. This decrease was donor-specific in four patients and was permanent in two cases throughout the study. Most patients presented decreased anti-donor CTLpf values from 6 to 9 months, whereas a partial recovery of donor CTLpf was observed in three patients. Reversible acute rejection was diagnosed in three patients, and it was associated with a marked increase in anti-donor CTLpf, returning to pre-Tx values by 9 months post-Tx. In addition, one patient with chronic rejection displayed a transient increase in CDLpf 6 months after Tx. The results of this sequential study indicate the establishment of a state of either hyporesponsiveness or functional clonal inactivation, transient or permanent, which could facilitate allograft acceptance.

In 661 renal transplantations, 2 potentially migrated tumours (0.38%), 5 preexisting neoplasias (0.76%), and 31 "de novo" tumours were seen in 29 patients (4.4&). Although of very low incidence, the likelihood of tumour migration from elderly donors, given the circumstances surrounding removal, offers a high risk. None of the preexisting neoplasias relapsed following transplant. The highest prevalence was seen in skin (40%), lung (13%), kidney (13%) and bladder (6.6%) "de novo" tumours. Incidence of lymphoma was low. Dominant etiological factors of the recipient were older age, effective and tolerated immunosuppression, viral infections, environmental agents and antigenic stimulation of the graft. Skin lesions have responded well to local treatment, without need to discontinue immunosuppression, a measure that is mandatory in other malignant tumours. Also, the conclusions of a round table during the 25th National Meeting of Urotransplantation of the Spanish Association of Urology held in 1994 on "Oncology and Renal Transplantation" are presented.

Cyclosporine (CsA) nephrotoxicity is partially mediated by renal vasoconstriction due to an imbalance between vasodilator and vasoconstrictor eicosanoids. LSL 90202 is a purified lysine salt of eicosapentaenoic acid which is a known inhibitor of renal eicosanoid synthesis. The aim of the present work was to determine if chronic dietary supplementation with LSL 90202 prevented CsA nephrotoxicity and to establish the role of thromboxane and prostacyclin in renal tissue. Thirty-three male Sprague-Dawley rats were divided into 4 groups: group 1, CsA in olive oil (n = 10); group 2, isovolumetric olive oil (n = 7); group 3, CsA in olive oil plus LSL 90202 (n = 8); group 4, isovolumetric olive oil plus LSL 90202 (n = 8). CsA and LSL 90202 were given at 20 mg/kg/day. Weight and creatinine clearance (CrCl) were determined before and on days 14 and 30. On day 30 whole-blood CsA was determined and renal tissue processed for renal malondialdehyde, thromboxane B2 and 6-keto-PGF1 alpha measurement and for conventional histology. CrCl was severely reduced in the CsA in olive oil group compared to olive oil and LSL 90202 control groups. On day 30, CrCl in the CsA in olive oil plus LSL 90202 group showed a slight decrease, but the mean CrCl was significantly higher than in the CsA in olive oil group. Trough whole blood CsA levels were not significantly different in both groups given the drug. No morphological differences were found between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to assess the immune mechanisms triggered by an immunosuppressive regimen consisting of prophylactic antilymphocyte globulin plus low-dose cyclosporine A and steroids, we studied the short-term evolution of both, anti donor in vitro alloresponse and peripheral blood T cell subsets in 21 recipients of a cadaveric kidney allograft. Spleen cells from cadaveric donors and peripheral blood lymphocytes from the respective recipients pretransplant (pre-Tx), at three and six months posttransplant (post-Tx) were obtained to perform one-way mixed lymphocyte cultures and flow cytometry analysis of lymphocyte subsets. The results indicated the development of donor-specific mixed lymphocyte culture (MLC) hyporesponsiveness as early as three months post-Tx, paralleled by a decrease in CD4+CD29+ helper-inducer cells and by an increase in CD8+CD45RA+ suppressor lymphocytes in peripheral blood. These changes were reflected in a very good clinical outcome of the patients. The present results further suggest that suppression of the immune system just before transplantation is a suitable method to induce early specific hyporesponsiveness to the allograft.

Forty-three biopsies were performed between 30 and 60 min after reperfusion. Patients (22 males/21 females, mean age 41 +/- 12 years, mean donor age 32 +/- 14 years) were treated either with antilymphocytic globulin, cyclosporin, and prednisolone (24 cases), or OKT3, cyclosporin, and prednisolone (19 cases). Ten patients had delayed post-transplant renal function (DPRF), defined as haemodialysis requirements after surgery, and seven patients had acute rejection 11 +/- 16 days post-transplant. Kidneys were perfused with a hypertonic solution containing mannitol. All patients were followed up for at least 30 months. During follow-up, five patients lost their grafts due chronic rejection, two patients due to noncompliance and one due to recurrence of focal segmental glomerulosclerosis. One patient died from heart infarction. Biopsies were stained with H&E, Masson's trichrome, periodic acid-Schiff (PAS) and silver methenamine. Interstitial fibrosis, interstitial oedema, tubular vacuolization, and peritubular capillary oedema were measured using a semiquantitative scale. Five 400 x magnification micrographs of cortical interstitium from silver-methenamine-stained sections were used to measure percentage of interstitial surface with a morphometer. Interstitial surface was 18.7 +/- 6.2% (range 3.2-35.3%). A positive correlation was found between interstitial surface and donor age (r = 0.469, P = 0.0015). No relationship was found between warm and cold ischaemia times and tubular vacuolization or peritubular capillary oedema.(ABSTRACT TRUNCATED AT 250 WORDS)

Different induction therapies have been used in renal transplantation to avoid cyclosporine (CsA) nephrotoxicity and early acute graft rejection. This study compares the efficacy of a short course of prophylactic OKT3 to that of antilymphocyte globulin (ALG) in preventing acute renal allograft rejection when administered concomitantly with CsA and steroids. Between March 1988 and December 1990, 140 first-cadaver renal transplant recipients were randomly allocated to two immunosuppression groups--ALG group (n = 68): ALG 15 mg/kg just before transplant surgery, ALG 12 mg/kg the first day after transplant, followed by four doses of 10 mg/kg on alternate days; and OKT3 group (n = 72): OKT3 5 mg just before transplant, followed by four doses of 5 mg/d. Both groups included low-dose CsA and steroids. The incidence of rejection during the first 3 months after transplantation was 15% in the ALG group and 19% in the OKT3 group (NS). Kaplan-Meier estimates of patients free of rejection at 2 years was 85% in the ALG group and 77% in the OKT3 group (NS). The 3-year actuarial graft survival was 82% and 85% (NS), and 3-year patient survival was 97% and 98% (NS), in the ALG and OKT3 groups, respectively. These results indicate that the concomitant association of CsA and ALG or OKT3 constitutes a safe and effective therapeutic strategy that provides a low incidence of rejection and gives good results for patient and graft survival.