Search

Transforming growth factor (TGF)-beta1 is a key profibrogenic cytokine associated with the pathogenesis of chronic allograft nephropathy (CAN). The primary aim of this study was to evaluate TGF-beta1 expression in protocol kidney graft biopsy in patients treated with different immunosuppressive regimens. Protocol kidney graft biopsies were carried out in 77 patients with stable graft function at 1 year after kidney transplantation, treated with a triple-drug regimen based on cyclosporin A (CyA; n = 49) or tacrolimus (TAC; n = 28). Morphological findings were assessed using the Banff 97 classification. TGF-beta1 expression was analysed using immunochemistry, and semiquantitatively scored in different renal structures (total score 0-18). Clinical data were analysed at the time of biopsy, and 12 months thereafter. No significant relation was found between the used immunosuppressive regimen and the histomorphological picture in the graft. TGF-beta1 expression within graft tissue was significantly higher in patients treated with CyA when compared with TAC (9.94 +/- 4.2 vs. 5.0 +/- 3.2; P < 0.001). Serum creatinine and glomerular filtration rate (GFR; Cockroft-Gault calculation) were comparable in both groups but, in the course of the next 12 months, GFR significantly decreased only in the CyA-treated group (from 1.03 +/- 0.33 to 0.96 +/- 0.37 ml/s) while not changing in the TAC-treated group. Patients treated with TAC had significantly lower diastolic blood pressure and serum cholesterol. The significantly lower TGF-beta1 expression in 1-year protocol kidney graft biopsy in TAC-treated patients with stable renal function, and the different development of graft function in both groups suggest a possible benefit of TAC for long-term graft acceptance.

This was a multi-center, open-label, randomized, dose-comparative study on 202 renal transplantation patients. We evaluated for the first time an alternative dosing regimen for basiliximab, consisting of a single 40-mg intravenous dose on day 1 post-transplantation plus triple therapy, in comparison with the conventional two-dose regimen (2 h before transplantation and on day 4) plus triple therapy. At 6 months, the incidence of acute rejection was low: 22.5% of patients in the basiliximab 2 x 20-mg group and 20.0% of patients in the basiliximab 1 x 40-mg group experienced an acute rejection episode ( P = 0.628) (biopsy-proven rejection: 19.6% and 17.0%, P = 0.585). There was no statistically significant difference in any of the secondary efficacy parameters. The incidence of graft loss by 12 months was 4.9% and 6.0% in the 2 x 20-mg and 1 x 40-mg group, respectively ( P = 0.73). No differences were observed between the dosage groups with regards to safety assessments (adverse events (AEs), infections, vital signs, laboratory safety evaluations, and physical examinations). The data reveal that basiliximab can be safely and effectively administered as a single 40-mg dose on day 1 after renal transplantation as a therapeutic option to the established 2 x 20-mg dosing regimen. This alternative dosing regimen may be of significant convenience under circumstances when a first dose of basiliximab was not given prior to transplantation. Both regimens can conveniently be used during the initial hospitalization of the patient.

Background: The role of nitric oxide (NO) after the cadaveric kidney transplantation has not been fully clarified yet. The aim of our study was to examine benefits of the administration of a NO precursor--L-arginine in the model of renal ischaemia and after the subsequent cyclosporine (CsA) treatment, which simulates the state resulting from the kidney transplantation., Methods and Results: 60 male rats of the Wistar strain were exposed to ischaemia for 45 minutes. Then they were divided into six groups: 1. Controls, 2. Rats administered by gastric sonde with 300 mg/kg of L-arginine since the first day after ischaemia, 3. Rats administered in a similar way with 10 mg/kg of cyclosporine A, 4. Group of rats receiving both drugs in the same doses, 5. Rats receiving 10 mg/kg of cyclosporine A since the first day after ischaemia and L-arginine in the dose 300 mg/kg since the seventh day, 6. Group of animals administered with L-arginine and cyclosporin A in the same doses with nonselective blocker of NO synthesis--L-NNA in the dose of 5 mg/kg. We examined renal functions (blood and urine levels of creatinine, urea, Na, K, Cl, osmolality, proteinuria), blood and urine levels of NO metabolites (NO2- and NO3-) in the fourth week after ischaemia. We found that L-arginine administration (when groups 1 and 2 were compared) decreased S-creatinine (< 0.05), it increased U-osmolality (p < 0.01), tubular resorption (p < 0.001), and blood levels of NO metabolites (p < 0.05). Changes in urine levels of NO metabolites (U-NOx/U-Cr) and in proteinuria were not found. In animals with renal ischaemia treated with cyclosporine (comparison of groups 3 and 4), L-arginine administration brought about a decrease of blood creatinine levels (p < 0.05), higher creatinine clearance (p < 0.05) and higher blood levels of NO metabolites (S-NOx; p < 0.01). However, differences in tubular functions, proteinuria and U-NOx/U-Cr were not detected. When L-arginine was added 7 days after the beginning of cyclosporine treatment, no significant difference was found between groups 5 and 3 and differences between groups 5 and 4 were similar to those between groups 4 and 3. Animals of the group 6 were not tested due to high mortality indicating high toxicity of the combination ischaemia + cyclosporine + L-arginine + L-NNA., Conclusion: Our study shows the benefits of L-arginine treatment in the renal ischaemia and during cyclosporine administration. The treatment should start immediately after the ischaemic period and at the same time as the cyclosporine administration. L-arginine added later has no positive effect.

Chronic rejection represents the most common cause of transplanted graft loss in the long term. Rapamycin (sirolimus), and it's derivate RAD, are new and potent, immunosuppressive drugs. They inhibit cell proliferation driven by various growth factors. These drugs were successfully tested in some experimental models of the chronic rejection. Results of the first clinical trials have defined rapamycin pharmacokinetics and proved immunosuppressive efficacy. Rapamycin acts synergistically with cyclosporin A. The side effects are a dose-dependent thrombocytopenia and leukopenia but the most frequent is hyperlipidemia. The question, if rapamycin and RAD inhibit development of chronic rejection in man, will be solved by the prospective clinical trials over years.

The last decade has witnessed an expansion of the arsenal of new immunosuppressive agents to include several novel drugs and antibodies. The main indication of all these immunosuppressive agents is organ transplantation. In terms of its action, tacrolimus resembles cyclosporin A and is employed as the mainstay immunosuppressant or for what is referred to as rescue therapy in refractory rejection. Mycophenolate mofetil is an anti-metabolite replacing azathioprine in immunosuppressive protocols. Sirolimus is an agent for prophylactic use, either as part of a cyclosporin-based regimen to enhance the effect of cyclosporin or as an alternative of non-nephrotoxic immunosuppression to cyclosporin-based regimens; its indications are still being specified. Gusperimus could be used for anti-rejection therapy; however, it is not being used in this country as yet. Recently, two monoclonal antibodies against the IL-2 receptor, chimeric basiliximab and humanized daclizumab, have been employed. Both agents are of non-depletion type and are indicated for induction therapy in the early post-transplant period.

Background: In renal transplant patients with stable graft function, triple-drug immunosuppression may not be necessary, while withdrawal of steroids may eliminate side effects. The primary aim of this study was to assess the risk of rejection after steroid withdrawal., Methods: A total of 88 patients with stable graft function and serum creatinine <160 micromol/l, treated with cyclosporin A, azathioprine and prednisone were randomized into group A (n=46) with a gradual prednisone reduction to zero in the course of 6 months, and group B (n=42) on triple-drug therapy without change. At the time of randomization, fine-needle aspiration biopsy (FNAB) was carried out in all of the patients. After stopping steroids, the patients were followed up for a period of 12 months., Results: Four patients failed to complete steroid withdrawal, three due to rejection, and one due to leukopenia. The proportion of rejection in three patients in group A (6.6%) was not significantly different from rejection in two patients in group B (4.8%). The mean value of serum creatinine was not significantly different in both groups in the course of follow-up. A finding of some degree of immunological activity in FNAB was made in four patients in each group, but none of these patients developed rejection. Compared with group B, significant decreases in serum cholesterol and blood leukocytes were observed in group A. Prednisone withdrawal did not have any influence on hypertension and serum triglycerides., Conclusions: Gradual withdrawal of steroids is not associated with a higher risk for rejection and has a beneficial effect on serum total cholesterol levels. FNAB was not a useful tool for predicting rejection.

Background: Triple-drug immunosuppression may not be necessary in a majority of stabilized patients over 1 year after kidney transplantation. In contrary steroid withdrawal may be beneficial for the patient by elimination of side-effects. The primary aim of this study was assessment of the risk of rejection after the prednisone withdrawal., Methods and Results: 88 patients 1 year after the first renal transplantation with stable graft function and serum creatinine < 160 mumol/l treated with cyclosporine-A, azathioprine and prednisone were randomized into group A (n = 46) with a prednisone withdrawal and group B (n = 42) on triple-drug therapy without change. At the time of randomization, fine-needle biopsy was carried out in all of the patients. In group A, the dose of prednisone was gradually reduced to zero in the course of six months and the patients were followed up for the next 12 months. In the group B, patients on triple-drug therapy were followed for the corresponding period of time. 3 patients (6.6%) in group A, and 2 (4.8%) in group B experienced rejection (NS). Mean values of serum creatinine were in the course of follow-up in both groups without any statistical difference. Suspect immunological activity or proved immunological activity in aspiration biopsy was present in 4 patients in each group, but one of them rejected the graft. In comparison with group B, a significant decrease of cholesterol and leukocytes was observed in group A. Prednisone withdrawal had no influence on hypertension and triglyceride., Conclusions: Gradual withdrawal of steroids is not associated with higher risks of rejection and has a beneficial effect on cholesterol levels. Aspiration biopsy was of no use for the prediction of rejection.

In a group of patients after transplantation of the kidney with stabilized graft function treated by Consupren sol. combined with prednisone and azathioprin in 20 patients (group A) Consupren sol. was replaced by Consupren S capsules, in 17 patients (group B) Consupren sol. therapy proceeded without any change. To maintain the cyclosporin blood concentration within the therapeutic range it was necessary after the change of drug form in group A to adjust the dosage of the drug in 12 patients of group A while in group B only in one patient (p<0.01). The mean doses and levels of Cy-A however did not change significantly during the three-month investigation period in the two groups and and the bioequivalence of the two preparations was evident. Conversion from Consupren sol. to Consupren S capsules is not associated with the risk of rejection or undesirable effects. It can be implemented at a ratio of 1:1 or 1: the closest dose divisible by 25 (the smallest capsules are 25 mg) and after conversion a check-up or possible modification of the dose is necessary.

The authors compared in a controlled clinical study two groups of patients after a first renal transplantation treated by triple drug immunosuppressive therapy. In a group of 31 patients the triple combination comprised Sandimmune Neoral. In the control group there were 30 patients who received Sandimmune. No differences were found between the two groups as regards the effectiveness of this treatment and the authors did not confirm a lower incidence of rejections described in patients treated with Sandimmune Neoral. They confirmed, however, a lower interindividual variability of Cy-A levels assessed specifically in patients treated with Sandimmune Neoral.

Background: The second part of the study was designed to assess Consupren side effects., Methods and Results: The groups of patients studied were described in Part I. Side affects typical of Cy-A were evaluated only in the CS group. Gastrointestinal intolerance, only mild and temporary, was observed in 31%, neurotoxicity in 44%, hypertrichosis in 37%, nephrotoxicity in 25%, and gingival hypertrophy in 19%. Mean values of systolic and diastolic blood pressure did not change significantly in the course of treatment. When changes in blood pressure were individually investigated in particular patients, they were found in 31% in the CS group and in none in the K group. Mean values of uric acid non-significantly increased in the CS group and, on individual investigation, hyperuricaemia was observed in 31%. Mean values of serum potassium did not alter significantly. Signs of possible hepatotoxicity were found in 37% patients of the CS group. In this group, there was a significant decrease in haemoglobin mean values and a decrease in haemoglobin of more than 25 g/l was observed in 44% of CS group patients. In the K group significant decrease in mean leukocyte count was noted, but no patient developed real leukopenia., Conclusions: The occurrence of side effects was comparable to data known from the literature.

Background: Withdrawal of cyclosporin-A from maintenance immunosuppressive therapy involves risk of rejection. The aim of the study was to reduce the risk of rejection and to evaluate the fine-needle aspiration biopsy in predicting rejection., Methods and Results: In 41 patients 14.4 +/- 2.6 months after the first transplantation of a cadaveric graft with good and stabilized function, cyclosporine was withdrawn from triple-drug therapy while the doses of azathioprine and prednisone were increased. Prior to the change fine-needle aspiration biopsy (FNAB) was performed and methylprednisolone 500-250-250 mg administered in 3 days. FNAB was repeated after 2 weeks. 39 patients fulfilling inclusion criteria but ineligible for the switch for different reasons served as a control group. Both groups were comparable in demographic and immunological parameters. Within 3 months after conversion, rejection was observed in 3 patients (7%) vs 2 patients (5%) of the control group over a comparable period of time: and within 6 months in 6 patients (15%) and 3 patients (8%) respectively (NS). No relationship between rejections before and after conversion was found. FNAB appeared to have some predictive value for rejection. In all of the 3 patients experiencing rejection, a rejection pattern was present in the 2nd biopsy., Conclusions: Incorporation of methylprednisolone into conversion therapeutic regime decreased the risk of rejection to 7%. The rejection pattern in the second FNAB after methylprednisolone administration may be predictive for further rejection development.

Background: Experience gained from recent studies shows, that Cyclosporine-A (Cy-A) may decrease proteinuria (PU) in some forms of chronic glomerulonephritis (GN) with the nephrotic syndrome. The aim of this study was to test the efficacy of Czech-made Cy-A, Consupren., Methods and Results: 30 patients with chronic GN, confirmed by biopsy and PU higher than 3 g/d, corticodependent or corticoresistant, were randomized according to the month of birth to either therapy with Consupren at an initial dose of 5 mg/kg/d (CS group, after dropout of 3 patients who did not finish the treatment, n = 16) or Cyclophosphamide at a dose of 1.5 mg/kg/d (K group, n = 11), and prednisone maintained at the original dose in both groups. The treatment was stopped after six months or after achieving remission. The main criterion of efficacy was PU. The decrease in mean values, statistically evaluated by Holm's procedure was highly significant in the CS group and non-significant in the K group. A similar evaluation of PU corrected by glomerular filtration rate was significant in both groups. Partial or complete remission was reached in 50% of CS group patients and in 34% of K group patients (NS). In the CS group a significant increase in the mean values of albumin and gama-globulin, and a decrease in cholesterol levels were observed. In the K group, these changes were non-significant., Conclusions: In patients with chronic GN and the nephrotic syndrome, the efficacy of Consupren treatment gives comparable, or even better results versus treatment with Cyclophosphamide.

Forty-five patients after transplantation of the kidney from a dead donor were treated by a triple combination of cyclosporin A, azathioprine and prednisone. In patients where during the first two days after transplantation the function of the graft was not restored, cyclosporin A was reduced and treatment supplemented by a combination of four by prophylactic administration of ATG for a period of 7 days. A total of 18 patients had a complete prophylactic dose of ATG. The results in this group were compared with a historical comparable group of 27 subjects treated only with the triple combination of drugs without reduction of cyclosporin A. In patients treated with ATG the mean initial function of the graft was reduced only insignificantly and the one-year survival of the graft was only insignificantly better than in the control group. During the first two months after transplantation there were significantly more leucopenic episodes in patients treated with ATG, however, no direct relationship with the latter was proved. The number of infectious complications in these patients was lower than in the control group.

Thirty-one patients with chronic mesangial-proliferative glomerulonephritis, histologically and clinically active, confirmed on biopsy, were included in a randomized therapeutic experiment. Of the total, 15 were treated by a combined prednisone, azathioprine, cyclophosphamide, Heparoid Spofa forte ling., Heparin retard Spofa and dipyridamole therapy. The control group comprised 16 untreated patients. One year later, a similar progression of glomerulonephritis was seen in both groups. Both treated and control patients exhibited a slight, but significant, decrease in proteinuria and a slow fall in the glomerular filtration rate. Despite a short period of follow-up, we succeeded to demonstrate, convincingly enough, that combined cyclophosphamide, azathioprine, prednisone, Heparoid ling., Heparin retard Spofa and dipyridamole therapy should not be indicated in chronic mesangial-proliferative glomerulonephritis.