Search

Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3(+) regulatory T-cell (T(REG)) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T(REG) homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T(REG) homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4(+)CD25(+)FoxP3(+) T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25(+)FoxP3(+) T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4(+)FoxP3(+) T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4(+)FoxP3(+) T(REG) in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.

Background: Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients., Methods: Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups., Results: MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014)., Conclusion: A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.

Background: Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also beta-blockers are used. Tertatolol is a new beta-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients., Methods: We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured., Results: The mean arterial pressure was lower (P < 0.05) during atenolol (124 +/- 2 mm Hg) and tertatolol (125 +/- 2 mm Hg) treatment compared with washout (132 +/- 4 mm Hg). Also the heart rate was lower (P < 0.01) during atenolol and tertatolol (54 +/- 3 and 55 +/- 2 beats/min respectively) than in the wash-out period (65 +/- 3 beats/min). GFR and RPF were not changed by either beta-blocker., Conclusion: In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both beta-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.

In a randomised prospective trial, we studied the effects of replacement of prednisone (Pred) by azathioprine (Aza), 6 months after transplantation, in stable renal allograft recipients on cyclosporine and prednisone (CsA + Pred). Out of 83 patients, 42 started treatment with CsA + Aza and 41 continued therapy with CsA + Pred. CsA was dosed to achieve a level of 150 ng/ml, the Aza dose was 3 mg/kg per day and the Pred dose was 0.15 mg/kg per day. Eighteen months after randomisation, in the CsA + Aza group 18 of the 42 patients were effectively treated with CsA + Aza. In the main, anaemia, leuco- and thrombocytopenia, and hypocorticism necessitated the reintroduction of Pred in the remaining 24 patients. Compared to the continuation of CsA + Pred, conversion of Pred to Aza resulted in a reduced number of antihypertensive drugs needed, and in lower serum total, LDL and HDL cholesterol levels; the incidence of acute rejections and graft losses was no different. In conclusion, conversion of CsA + Pred to CsA + Aza is a safe option in renal transplant patients with contraindications to long-term corticosteroid treatment.

Background: The immunosuppressive drug cyclosporin is known to impair renal function. The degree of renal dysfunction is usually estimated from the clearance of creatinine (CCr). Theoretically however, a fall in CCr can be caused by a decrease of GFR, an inhibition of the tubular secretion of creatinine, or the combination of both. CsA has convincingly been shown to decrease GFR, but detailed information on the effects of CsA on tubular secretion of creatinine is lacking., Methods: We performed two studies to investigate the influence of CsA on tubular creatinine secretion. In study A we simultaneously measured CCr and GFR (using inulin) immediately before and 4 weeks after cessation of CsA therapy in 17 renal transplant patients. In study B, the rise in serum creatinine after administration of cimetidine, which blocks the tubular secretion of creatinine, was compared in renal transplant patients treated with either CsA (in whom secretion might already be inhibited) or azathioprine., Results: Study A: After cessation of CsA there was an increase of GFR (54+/-15 vs 63+/-16 ml/min/1.73 m2, PCr (71+/-21 vs 82+/-23 ml/min/1.73 m2; PCr and GFR (a measure of the relative contribution of tubular secretion to the clearance of creatinine) did not change significantly (1.33+/-0.21 vs 1. 32+/-0.30). Study B: In nine couples of patients matched for GFR the relative rises in serum creatinine after administration of cimetidine were 26+/-21% and 22+/-7% for CsA and azathioprine treated patients respectively (NS)., Conclusion: CsA does not substantially inhibit the tubular secretion of creatinine. A rise in serum creatinine after administration of CsA can thus be attributed completely to a fall in GFR.

Cyclosporine (CsA) and prednisone (Pred) are the mostly used drugs for immunosuppression after renal transplantation, but both drugs have marked side effects. Either replacement of CsA by azathioprine (Aza) or withdrawal of prednisone (Pred) resulting in CsA monotherapy can be employed to circumvent the adverse effects in the long run. Both treatment regimens were compared to this prospective randomized trial in patients who were treated with CsA and Pred during the first 3 months after renal transplantation (CsA: n=64, Aza-Pred: n=63, median duration of follow-up: 3.9 years). Estimated graft survival rates at 5 years after transplantation (in patients with a functioning graft at 3 months) were 78% in the CsA group and 87% in the Aza-Pred group. The incidence of a rejection within 3 months after start of steroid withdraw or conversion from CsA to Aza was 30% and 25% respectively (NS). At 2 years after transplantation, serum creatinine levels were lower in the Aza-Pred group (126+/-35 micromol/L) than in the CsA group (180+/-78 micromol/L; P>0.001). There were no differences in blood pressure or incidence of infections between the treatment groups. Treatment-related costs were measured during the first year after transplantation and were lower in the Aza-Pred group (DFL 40,882+/-18,895 vs. DFL 53,484+/-44,828; 1 DFL [Dutch guilder] is about US $0.60; P<0.005). In conclusion, CsA monotherapy and Aza-Pred treatment from 3 months after renal transplantation are comparably effective immunosuppressive treatment regimens, although Aza-Pred therapy results in better graft function. Withdrawal of steroids and replacement of CsA by Aza both carry a substantial risk of rejection. The previously demonstrated cost effectiveness of CsA-containing therapies seems to be limited to the first phase after transplantation. Conversion to Aza-Pred at 3 months after transplantation reduces costs.

The renal dysfunction induced by cyclosporine (CsA) has been demonstrated to be at least partially reversible after cessation of CsA therapy. The time course and magnitude of changes in various parameters of renal function after CsA withdrawal have not been studied in detail. We examined 12 renal transplant patients immediately before and 1, 2, and 4 weeks after replacement of CsA by azathioprine at 3 months after transplantation. Nine patients in whom CsA was continued during this period served as a control group. A significant increase in glomerular filtration rate ([GFR] 15 + or - 17%, p <0.01) occurred already in the first week after discontinuation of CsA. From 1 to 4 weeks after conversion, GFR did not significantly increase any further. A fall in serum creatinine (-7 + or - 9%, Ns) paralleled the rise in GFR (r = -0.76, p <0.01), but there was a further decrease of creatinine in the second to fourth week after conversion. Withdrawal of CsA induced a rise in serum magnesium in all patients (0.73 + or - 0.13 vs 0.86 + or - 0.12 mmol/l, p <0.001) as well as a marked decrease in the serum level of urate (0.39 + or - 0.09 vs 0.33 + or - 0.07 mmol/l, p <0.01) within one week. None of the observed changes took place in the control group. In conclusion, a major improvement of GFR occurs within one week after cessation of CsA therapy. Changes in the serum levels of magnesium and urate appear to be the most responsive markers of the renal effects of CsA.

Disturbances of lipid metabolism are frequently encountered after renal transplantation and have been ascribed to the use of cyclosporine (CsA) and corticosteroids, but the individual contribution of each of these drugs remains uncertain. The individual effects of CsA and prednisone (Pred) on serum lipid and (apo)lipoprotein levels were compared in a prospective randomized trial. All patients received CsA and Pred during the first 3 months after transplantation. Subsequently, they were allocated to either withdrawal of Pred or conversion from CsA to azathioprine (Aza). Serum lipids and (apo)lipoproteins, including lipoprotein(a) (Lp(a)), were measured at regular intervals during the first year after renal transplantation. Analysis of variance for repeated measures of the first year results showed higher values for serum triglycerides (P < 0.001) and lower high-density lipoprotein (HDL) cholesterol levels (P < 0.05) in the CsA monotherapy group (N = 59) as compared with the AzaPred group (N = 63). At 1 yr after transplantation, CsA-treated patients had significantly higher Lp(a) levels (CsA: median, 105 (interquartile range 42 to 340) mg/L; Aza-Pred: 46 (25 to 176) mg/L; P < 0.05). The withdrawal of Pred in the CsA group resulted in a large fall in HDL cholesterol (27 +/- 30% at 5 months after transplantation) and an increase in triglycerides (49 +/- 73% at 6 months). A reversion of these changes was observed in patients who were retreated with Pred. Multiple linear regression analysis showed an independent correlation between the use of Pred and HDL cholesterol level, whereas the use of CsA was independently associated with the concentration of Lp(a).(ABSTRACT TRUNCATED AT 250 WORDS)

This prospective, randomized study investigates the effect of two immunosuppressive treatment regimens on quality of life after renal transplantation. At 3 months after transplantation, patients treated with cyclosporine (CsA) and prednisone (Pred) were allocated to either withdrawal of Pred (n = 60) or to conversion of CsA to azathioprine (Aza) (Aza-Pred, n = 60). Quality of life was evaluated just before randomization, and at 6 and 12 months after transplantation using the Sickness Impact Profile (SIP), the Affect Balance Scale (ABS), the Center for Epidemiological Studies Depression Scale (CES-D), measures of satisfaction with several domains of life experience, and a population-specific physical symptoms questionnaire. In both groups, the overall SIP score as well as the scores on its physical and psychosocial dimensions improved continuously after transplantation, reaching levels that are comparable to those found in the general population. The occurrence of acute or chronic rejection had a significantly negative effect on SIP and CES-D scores. Intention-to-treat analysis showed no differences between groups for scores on SIP, ABS, CES-D, and satisfaction measures. Exclusion of 41 patients who did not strictly adhere to their originally designated therapy showed a tendency for better psychosocial SIP scores in CsA patients (P = 0.05), which mainly resulted from a difference on the category of social interaction (P = 0.01). This difference occurred despite a similar rejection rate and worse renal function in CsA-treated patients. Shortly after steroid withdrawal, a high proportion of CsA patients complained of stiff or painful muscles (CsA: 74%, Aza-Pred: 36%; P = 0.002). Our data indicate that if successfully completed, CsA monotherapy from 3 months after transplantation may lead to a higher degree of psychosocial well-being as compared with conversion from CsA-Pred to Aza-Pred. It seems likely that this advantage is related to the withdrawal of Pred.

Cyclosporine (CsA) impairs renal function, probably by preglomerular vasoconstriction. Vasodilating substances may therefore be of benefit to ameliorate CsA-induced renal dysfunction. We studied the acute effects on blood pressure and renal function of the dihydropyridine calcium antagonist nifedipine (10 mg orally) in 20 CsA-treated renal transplant patients. In addition, we compared the effects of nifedipine when given immediately before and 4 weeks after elective conversion from CsA to azathioprine. Compared with placebo (n = 14), administration of nifedipine led to a significant decrease in blood pressure and a strong natriuretic and diuretic response. Despite the reduction in blood pressure, glomerular filtration rate improved from 60 +/- 20 (mean +/- SD) to 69 +/- 24 mL/min/1.73 m2 (P < 0.001) and renal plasma flow (RPF) increased from 260 +/- 87 to 338 +/- 120 mL/min/1.73 m2 (P < 0.001). The combination of a decreased blood pressure with an increased RPF was reflected in a sharp decrease in renal vascular resistance (0.34 +/- 0.18 units v 0.23 +/- 0.10 units; P < 0.001). The conversion from CsA to azathioprine by itself led to significant increases in glomerular filtration rate (62 +/- 15 mL/min/1.73 m2 v 76 +/- 18 mL/min/1.73 m2; P < 0.05) and RPF (280 +/- 86 mL/min/1.73 m2 v 334 +/- 66 mL/min/1.73 m2; P < 0.05). During treatment with azathioprine an effect of nifedipine on glomerular filtration rate and RPF was no longer observed, although the natriuretic effect was similar on both occasions. The decrease in renal vascular resistance was larger during treatment with CsA than during treatment with azathioprine (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3+ regulatory T-cell (TREG) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for TREG homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on TREG homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4+CD25+FoxP3+ T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25+FoxP3+ T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4+FoxP3+ T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4+FoxP3+ TREG in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.Bone Marrow Transplantation (2007) 39, 537–545. doi:10.1038/sj.bmt.1705628; published online 12 March 2007 [ABSTRACT FROM AUTHOR]