Heide Sperschneider

Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation : results of the Atlas study.

Background. The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy. Methods. This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147). Results. The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 &mgr;mol/L (triple therapy), 134.7 &mgr;mol/L (Tac/MMF) and 135.8 &mgr;mol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively. Conclusion. Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.

Differential expression of β-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts

Background: The (3-chemokines MCP-1 (CCL2) and RANTES (CCL5) have been shown to play important roles in acute renal transplant rejection (AR) and chronic allograft nephropathy (CAN). The potential relationship of expression of these chemokines, their chemokine receptors CCR1, CCR2, CCR5, and the cell populations of inflammatory infiltrate, histological and clinical diagnoses were investigated in biopsies at the time of AR and compared with biopsies of CAN. Methods: In 24 renal transplant biopsies with AR (n = 15) and CAN (n = 9), the expression of MCP-1 and RANTES, their receptors CCR 1, CCR2, and CCR5 and the infiltration with monocytes/ macrophages and T cells were studied. Results: As previously described, chemokine and chemokine receptor expression was found mainly in mononuclear cells infiltrating the interstitium and glomeruli. In the tubulointerstitial area and glomeruli the expression of MCP-I, RANTES, and their receptors correlated with an infiltration by monocytes/macrophages. Biopsies with CAN revealed a lower expression of MCP-1, RANTES, CCR 1, CCR2 and CCR5 in tubulo-interstitial cells, and a significantly lower infiltration with MRP14-positive monocytes/ macrophages than biopsies with AR. In AR, MCP-1 and CCR1 showed a lower expression compared to RANTES, CCR2, and CCR5. Conclusions: The positive correlation between chemokines and chemokine receptors and infiltrating leukocytes during acute rejection, the lower but detectable expression of MCP-1, RANTES, CCR1, CCR2 and CCR5 in CAN, and the differences in the quantity of expression between the different chemokines and chemokine receptors point to a complex regulation of chemokine expression in renal allografts. Since chemokines are not only involved in inflammation but also in tissue regeneration, this could have impact on the development of CAN.

Vitamin Levels in Chronic Renal Failure and Need for Supplementation

Deficiencies of water-soluble vitamins may occur in uremic patients mainly because of restricted consumption and of loss during chronic hemo- and peritoneal dialysis. Although the daily requirement for most vitamins is not well defined in chronic renal failure supplementation of the vitamins thiamine, riboflavin, pyridoxine, pantothenic acid, niacin and ascorbic acid, the form of one multivitamin preparation without vitamin A as well as folic acid in dialysis patients after each dialysis is recommended. There is no need for vitamin B12, vitamin A and vitamin E.

Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: three-year observational results.

BACKGROUND The European tacrolimus versus ciclosporin A microemulsion (CsA-ME) renal transplantation study showed that tacrolimus was significantly more effective in preventing acute rejection and had a superior cardiovascular risk profile at 6 months. METHODS The endpoints of this investigator-initiated, observational, 36-month follow-up were acute rejection incidence rates, rates of patient and graft survival and renal function. An additional analysis was performed using the combined endpoints BPAR, graft loss and patient death. Data available from the original ITT population (557 patients; 286 tacrolimus and 271 CsA-ME) were analysed. RESULTS A total of 231 tacrolimus and 217 CsA-ME patients participated. At 36 months, Kaplan-Meier-estimated BPAR-free survival rates were 78.8% in the tacrolimus group and 60.6% in the CsA-ME group, graft survival rates were 88.0% and 86.9% and patient survival rates were 96.6% and 96.7%, respectively. The estimated combined endpoint-free survival rate was 71.4% with tacrolimus and 55.4% with CsA-ME (P <or= 0.001, chi-square test). Significantly more CsA-ME patients crossed over to tacrolimus during the 3-year follow-up: 21.2% versus 2.6%, P <or= 0.0001, chi-square test. Most patients in the tacrolimus arm discontinued steroids and received monotherapy and fewer tacrolimus patients remained on a triple regimen. Mean serum creatinine concentration was 145.4 +/- 90.9 micromol/L with tacrolimus and 149.0 +/- 92.1 micromol/L with CsA-ME. Significantly more CsA-ME patients had a classified cholesterol value >6 mmol/L (26.3% versus 12.6%, P <or= 0.0003, chi-square test). CONCLUSIONS Patients treated with tacrolimus had significantly higher combined endpoint-free survival rates and lower acute rejection rates with less immunosuppressive medication at 36 months.

Open prospective multicenter study of conversion to tacrolimus therapy in renal transplant patients experiencing ciclosporin-related side-effects

The hyperlipidemic and hypertensive effects of ciclosporin constitute a cardiovascular risk. Cosmetic side‐effects are known to reduce patients’ quality of life. This was a 6‐month, open, prospective, multicentre study in 296 adult kidney transplant patients to evaluate the conversion from ciclosporin to a tacrolimus‐based regimen. Primary indications for conversion were hyperlipidemia (n =77), hypertension (n = 72), hypertrichosis (n = 32) and gingival hyperplasia (n = 115). At month 6, hyperlipidemia and hypertension were at least moderately improved in 59.1% and 63.5% of patients, and strongly or completely resolved in 29% and 25%. Gingival hyperplasia and hypertrichosis were strongly or completely resolved in 73% and 72% of patients. Mean total cholesterol was reduced from 255 to 218 mg/dl. Mean systolic blood pressure (SBP) was reduced from 152.9 to 137.5 mmHg and mean diastolic blood pressure (DBP) from 90.7 to 85.8 mmHg. Ciclosporin‐related side‐effects resolved or improved after conversion to tacrolimus.

Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial.

Background Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation : one year observational results

Krämer BK, Klinger M, Wlodarczyk Z, Ostrowski M, Midvedt K, Stefoni S, Citterio F, Pietruck F, Squifflet J‐Paul, Segoloni G, Krüger B, Sperschneider H, Banas B, Bäckman L, Weber M, Carmellini M, Perner F, Claesson K, Marcinkowski W, Vítko Š, Senatorski G, Salmela K, Nordström J. Tacrolimus combined with two different corticosteroid‐free regimens compared with a standard triple regimen in renal transplantation: one year observational results.
Clin Transplant 2010: 24: E1–E9.

Influence of recombinant human erythropoietin therapy on in vivo chemotaxis and in vitro phagocytosis of polymorphonuclear cells of hemodialysis patients

Recombinant human erythropoietin (rhu-EPO) mainly stimulates erythropoiesis, but also influences the production and function of polymorphonuclear granulocytes (PAN). We evaluated the influence of rhu-EPO therapy in patients on maintenance hemodialysis without iron overload on both phagocytic and chemotactic activity of polymorphonuclear leukocytes (PMN) obtained from blood and a skin chamber. The study comprised 28 dialysis patients (15 females, 13 males, age 22-78 years, dialysis sessions three times weekly 4-5 h, mean duration of dialysis treatment 4-99 months) and 20 healthy subjects (9 females, 11 males, age 18-56 years). The absolute number of leukocytes in the peripheral blood, the leukocyte mobilization (chemotactic activity) and the phagocytic activity of PMNs were tested in patients before (n = 28), and after (n = 18) reaching the target hematocrit of 30% and during the follow-up period. No alteration in the total leukocyte number (PMN, monocytes, lymphocytes) in the peripheral blood during rhu-EPO therapy could be seen. The phagocytic activity of PMNs slightly improved during the follow-up period whereas the decreased chemotactic activity remained unchanged.

Serum vitamin E levels in patients with chronic renal failure.

27 patients with chronic renal failure, 21 patients on chronic intermittend dialysis treatment and 27 healthy controls were tested for serum level of vitamin E estimated spectrophotometrically. Both patient groups had significant higher mean values (12.1 ± 1.2 and 7.2 ± 0.8 μg/ml respectively) in comparison with normal controls (4.6 ± 0.7 μg/ml). No correlation was found to serum creatinine, hematologic values, protein and lipoprotein concentration, nor to mode and duration of treatment regimes. Vitamin E was not extracted from blood throughout dialysis. Under normal conditions of conservative or dialysis treatment of chronic renal failure patients vitamin E seems not to be a factor concerning uremic symptoms and there is no need for supplementation.

Der Einfluß von Diltiazem auf die Konzentration von Cyclosporin-Metaboliten bei mit Sandimmun® und Neoral® behandelten nierentransplantierten Patienten

BACKGROUND Diltiazem reduces the cyclosporine dose required for blood levels in the therapeutic target range by 30 to 40%. The effect of diltiazem on the pharmacokinetic disposition of cyclosporine after oral Neoral application is unknown and it is unclear whether or not the diltiazem-cyclosporine interaction is affected by the galenic cyclosporine formulation. PATIENTS AND METHODS Fifty-one stable renal allograft patients (19 females, 32 males) were enrolled in this prospective, randomized and double-blind study. The patients were assigned to 3 treatment groups: with diltiazem (I, n = 17), with nifedipine (II, n = 17) and without calcium channel blockers (III, n = 17). Nine patients in each group received Sandimmun and 8 patients Neoral. Blood concentrations of cyclosporine and its metabolites AM1 and AM9 were measured using HPLC for 12 weeks. The 3 treatment groups were not different in respect to age, gender distribution and serum creatinine concentration. Cyclosporine doses were adjusted on basis of the blood levels. RESULTS The cyclosporine doses required to achieve target blood levels were significantly lower in group I compared with group II (-43%) and group III (-33%; p < 0.0001). Although the cyclosporine blood concentrations in all groups were in the therapeutic range, the blood levels in group I showed a much lower variability. The blood concentrations of the metabolite AM1 in group I were significantly higher than those in groups II and III after dose correction (p < 0.0001), those of AM9 were significantly lower in group I than in groups II and III (p < 0.0001). The average dose, and the blood concentration of cyclosporine was not different when patients receiving Neoral were compared with those receiving Sandimmun within the groups. In the patients in group I, the blood concentration of metabolite AM1 was significantly higher after Sandimmun application than after Neoral. No other differences in the metabolite concentrations were detected within the groups comparing patients taking Sandimmun or Neoral. The incidences of acute rejection were lower in group I (17.6%) than in the other groups (II: 52.9%; III: 41%). CONCLUSION Diltiazem significantly reduced the necessary dose of cyclosporine. Compared with groups II and III, the blood concentrations were more stable in patients in group I. Diltiazem increased the blood concentration of AM1 in patients treated with Sandimmun to a larger extent than in patients taking Neoral. No additional pharmacokinetic differences of the 2 cyclosporine applications different with Sandimmun or Neoral were found.Zusammenfassung□ HintergrundDiltiazem reduziert die für therapeutische Blutspiegel erforderliche Cyclosporin-Dosis um 30 bis 40%. Der Effekt von Diltiazem auf die Pharmakokinetik von Cyclosporin nach Gabe von Sandimmun® ist bekannt, nicht dagegen, ob die Diltiazem-Cyclosporin-Interaktion durch die galenische Cyclosporin-Formulierung Neoral® beeinträchtigt wird.□ Patienten und Methoden51 stabile nierentransplantierte Patienten (19 Frauen, 32 Männer) wurden in eine prospektive, randomisierte, doppelblinde Studie einbezogen. Die Patienten wurden drei Behandlungsgruppen zugewiesen: mit Diltiazem (I, n=17), mit Nifedipin (II, n=17) und ohne Calciumblocker (III, n=17). Neun Patienten jeder Gruppe erhielten Sandimmun® und acht Patienten Neoral®. Die Blutspiegel von Cyclosporin und die Metaboliten AM1 und AM9 wurden über zwölf Wochen mittels HPLC gemessen. Die drei Behandlungsgruppen zeigten keinen Unterschied in bezug auf Alter, Geschlecht und Serumkreatinin. Die Cyclosporin-Dosierung wurde entsprechend dem Blutspiegel angepaßt.□ ErgebnisseDie erforderliche tägliche Cyclosporin-Dosis bis zum Erreichen des therapeutischen Blutspiegels war signifikant niedriger in Gruppe I (198,8±6,1 mg/Tag) im Vergleich zur Gruppe II (346,9 ± 10,2 mg/Tag; −43%; p < 0,0001) und Gruppe III (296,9 ± 6,7 mg/Tag; −33%, p < 0,0001). Die Cyclosporin-Konzentrationen im Blut lagen in allen Gruppen im therapeutischen Bereich, aber die Blutspiegel in Gruppe I zeigten eine viel geringere Variabilität. Die Konzentration des Metaboliten AM1 war nach Dosiskorrektur in Gruppe I signifikant höher, die von AM9 signifikant niedriger als in den Gruppen II und III (p < 0,0001). Zwischen den beiden Cyclosporin-Verabreichungsformen innerhalb der Gruppen gab es nach zwölf Wochen keinen Unterschied in der durchschnittlichen Dosierung und den Blutspiegeln von Cyclosporin. In Gruppe I war die Blutkonzentration von AM1 signifikant höher nach Sandimmun®-Gabe als nach Neoral®. Die Inzidenz von akuten Abstoßungen war in Gruppe I mit 17,6% niedriger als in den Gruppen II (52,9%) und III (41,2%).□ SchlußfolgerungDiltiazem reduziert signifikant die Cyclosporin-Dosis mit Konzentrationen im therapeutischen Bereich, führt zu stabileren Cyclosporin-Blutspiegeln und erhöht die Konzentration von AM1 besonders bei Patienten, die mit Sandimmun® behandelt werden. Darüber hinaus gab es keine signifikanten Unterschiede zwischen den beiden Darreichungsformen von Cyclosporin mit und ohne begleitend verabreichten Calciumantagonisten.Summary□ BackgroundDiltiazem reduces the cyclosporine dose required for blood levels in the therapeutic target range by 30 to 40%. The effect of diltiazem on the pharmacokinetic disposition of cyclosporine after oral Neoral® application is unknown and it is unclear whether or not the diltiazem-cyclosporine interaction is affected by the galenic cyclosporine formulation.□ Patients and MethodsFifty-one stable renal allograft patients (19 females, 32 males) were enrolled in this prospective, randomized and double-blind study. The patients were assigned to 3 treatment groups: with diltiazem (I, n=17), with nifedipine (II, n=17) and without calcium channel blockers (III, n=17). Nine patients in each group received Sandimmun® and 8 patients Neoral®. Blood concentrations of cyclosporine and its metabolites AM1 and AM9 were measured using HPLC for 12 weeks. The 3 treatment groups were not different in respect to age, gender distribution and serum creatinine concentration. Cyclosporine doses were adjusted on basis of the blood levels.□ ResultsThe cyclosporine doses required to achieve target blood levels were significantly lower in group I compared with group II (−43%) and group III (−33%; p < 0,0001). Although the cyclosporine blood concentrations in all groups were in the therapeutic range, the blood levels in group I showed a much lower variability. The blood concentrations of the metabolite AM1 in group I were significantly higher than those in groups II and III after dose correction (p < 0,0001), those of AM9 were significantly lower in group I than in groups II and III (p < 0,0001). The average dose, and the blood concentration of cyclosporine was not different when patients receiving Neoral® were compared with those receiving Sandimmun® within the groups. In the patients in group I, the blood concentration of metabolite AM1 was significantly higher after Sandimmun® application than after Neoral®. No other differences in the metabolite concentrations were detected within the groups comparing patients taking Sandimmun® or Neoral®. The incidences of acute rejection were lower in group I (17,6%) than in the other groups (II: 52,9%; III: 41,%).□ Conclusion:Diltiazem significantly reduced the neccessary dose of cyclosporine. Compared with groups II and III, the blood concentrations were more stable in patients in group I. Diltiazem increased the blood concentration of AM1 in patients treated with Sandimmun® to a larger extent than in patients takingNeoral®. No additional pharmacokinetic differences of the 2 cyclosporine applications different with Sandimmun® or Neoral® were found.