Pentoxifylline reduces nephrotoxicity associated with cyclosporine in the rat by its rheological properties

BACKGROUND: The goals of this study were to evaluate whether administration of pentoxifylline (POF) reduces the nephrotoxicity associated with cyclosporine (CsA) in the rat, and whether the effect of POF is related to its rheological properties. METHODS: Mean arterial pressure was measured by an intraarterial catheter. Glomerular filtration rate and renal plasma flow were determined by measuring inulin and para-aminohippurate clearances, after double-blind coadministration for 10 days of CsA (25 mg/kg/day) with either vehicle or POF (45 mg/kg every 12 hr). These results were compared with those obtained in control rats. Blood viscosity and erythrocyte deformability were also evaluated after treatment using a cone plate viscometer and a filtration method, respectively. RESULTS: No changes were observed in mean arterial pressure in both groups compared with controls. Glomerular filtration rate was significantly lower in CsA-treated rats (0.3+/-0.1 ml/min/100 g) than in control animals (0.6+/-0.1 ml/min/100 g, P<0.02). The coadministration of CsA with POF normalized the glomerular filtration rate (0.6+/-0.1 ml/min/100 g). A parallel decrease in renal plasma flow was observed in CsA-treated rats compared with controls (CsA+vehicle: 1.5+/-0.2 vs. control: 2.2+/-0.1 ml/min/100 g, P<0.02), this effect completely reversed by cotreatment with POF (3.1+/-0.2 ml/min/100 g). Blood viscosity was significantly higher in CsA-treated rats than in the control group (CsA+vehicle: 5.6+/-0.7 vs. control: 5.0+/-0.4 m x Pa x s, P<0.05). This effect was associated with a lower erythrocyte deformability (CsA+vehicle: 1.2+/-0.2 vs. control: 1.5+/-0.3 ml/min, P<0.05). These rheological abnormalities were normalized by coadministration with POF (blood viscosity: 4.9+/-0.7 m x Pa x s and erythrocyte deformability: 1.9+/-0.4 ml/min, P<0.05). CONCLUSIONS: Our results show that administration of POF prevents the nephrotoxicity associated with CsA. This beneficial effect could be related to its rheological properties.     

Long-term renal function in heart transplant recipients receiving cyclosporine therapy

BACKGROUND: Immunosuppression with cyclosporine has improved allograft function and reduced both morbidity and mortality in organ transplantation. However, cyclosporine-induced nephrotoxicity still is a concern. The purpose of our study was to evaluate the effects of cyclosporine on renal function in orthotopic heart transplant recipients. METHODS: Thirty-nine patients who received transplants from 1985 to 1991 and had at least three yearly glomerular filtration rate measurements posttransplantation by 125I-iothalamate clearance method were included in the study. In addition, serum creatinine (before and after transplantation) and cyclosporine doses were analyzed. RESULTS: Maintenance immunosuppression at 1 year consisted of prednisone (0.1 mg/kg/day), azathioprine (2 mg/kg/day), and cyclosporine (12-hour trough level 100 to 150 ng/ml by fluorescence polarization immunoassay). The mean serum creatinine at 1 year was significantly higher than the mean pretransplantation serum creatinine (1.51 +/- 0.32 versus 1.28 +/- 0.38, p < 0.05) and stabilized after the first year. The mean glomerular filtration rate by 125I-iothalamate clearance method was 70.6 +/- 20.3 ml/min/1.73 m2 (range 32 to 105) at 1 year and remained relatively stable during the follow-up period of up to 7 years. Creatinine clearance calculated by the Cockcroft and Gault formula overestimated the true glomerular filtration rate after the third year. The mean cyclosporine dosage was significantly lower after the first-year dose of 3.9 +/- 1.8 mg/kg/day (p < 0.05). Three patients in 39 started hemodialysis at 5, 7, and 10 years after transplantation. CONCLUSION: Our data indicate that the adequacy of renal function is preserved with long-term cyclosporine therapy in heart transplant recipients.     

Cyclosporin does not inhibit the tubular secretion of creatinine

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.     

Effects of cyclosporine A on serum and urinary soluble interleukin-2 receptor in patients with lupus nephritis

OBJECTIVE: To evaluate the association of the level of urine and serum soluble interleukin-2 receptor (sIL-2R) with disease activity and response to cyclosporine A (CsA) therapy in patients with lupus nephritis (LN). METHODS: Sixteen hospitalized patients with LN were studied. At admission, fifteen patients had type IV-LN and one had type V-LN. All patients received CsA 6 mg/kg per day for 6-8 weeks, then tapered off gradually to 2 mg/kg per day. The levels of urinary and serum sIL-2R were determined by enzyme-linked immunosorbent assay (ELISA). Serum antinuclear antibody (ANA), anti-dsDNA antibody (A-ds-DNA), complement C3 and C4, total IgG, creatinine, urinary red blood cells and protein excretion, and lymphocyte subpopulations in the peripheral blood were also measured before and after CsA treatment. RESULTS: In LN patients, both urinary (534 +/- 101 U/ml) and serum SIL-2R levels (326 +/- 148 U/ml) were higher than those in normal controls. These findings were associated with higher levels of peripheral blood CD4 + and CD8 + lymphocytes (29.3 +/- 4.24 and 28.6 +/- 9.12%), higher titer of serum anti-ds-DNA, lower levels of serum complement C2 and C4 (0.98 +/- 0.23 and 0.24 +/- 0.12 g/L), as well as more proteinuria (Upro 2.99 +/- 0.76 g/24 hrs) and hematuria (URBC 83.9 +/- 95.2 10(4)/ml). These abnormalities were gradually ameliorated by CSA therapy. The changes in the levels of both serum (116 +/- 58.6 U/ml) and urine (136 +/- 43.2 U/ml) SIL-2R induced by CsA (at 8 weeks) were correlated with the changes in the levels of CD4 + and CD8 + cells (23.2 +/- 3.30 and 26.7 +/- 3.54%), degrees of immune abnormalities (serum C3 and C4 1.28 +/- 0.14 and 0.42 +/- 0.06 g/L), and renal injuries (Upro 1.07 +/- 0.46 g/24 hrs, URBC 5.82 +/- 3.15 10(4)/ml). CONCLUSIONS: These results suggest that serum and urinary sIL-2R are sensitive markers for the disease activity in patients with LN. CsA, a powerful immunosuppressive agent, significantly improves both immunologic disorders and renal functional impairments, the mechanism of which on patients with LN appears to inhibit the lymphocyte activation in the peripheral blood and renal tissues as indicated by the decrease in sIL-2R levels.     

Low-dose cyclosporine and mycophenolate mofetil in renal allograft recipients with suboptimal renal function

BACKGROUND: Cyclosporine (CsA) nephrotoxicity can be identified by functional changes and chronic renal damage. CsA-associated renal fibrosis has been related to the overproduction of transforming growth factor (TGF)-beta1, a fibrogenic cytokine. Mycophenolate mofetil (MMF) may allow CsA dose reduction without increasing the risk of rejection. METHODS: We studied the impact of CsA dose reduction in association with MMF on renal function and TGF-beta1, production in 16 long-term renal allograft recipients with suspected CsA nephrotoxicity. Two grams/day of MMF were introduced, and CsA dose was reduced to reach whole-blood levels between 40 and 60 ng/ml within 1 month. CsA dose and levels, renal function parameters, and platelet-poor plasma TGF-beta1 levels were evaluated before and 6 months thereafter. RESULTS: MMF allowed a decrease in both the mean dose of CsA (3.8+/-1.35 vs. 2.2+/-0.73 mg/kg/day; P<0.01) and CsA levels (148+/-36 vs. 53+/-19 ng/ml; P<0.001). The reduction of CsA was associated with a decrement of serum creatinine levels (210+/-46 vs. 172+/-41 micromol/L; P<0.001) and an increase in both the glomerular filtration rate (32.9+/-12 vs. 39.1+/-14 ml/min/1.73 m2; P<0.02) and renal plasma flow (195+/-79 to 218.6+/-74.02 ml/min/1.73 m2; P<0.02). There was a reduction in plasma TGF-beta1 levels (4.6+/-4.2 vs. 2.0+/-1.4 ng/ml; P=0.003) and CsA levels correlated with TGF-beta1 (r=0.536, P=0.002). No rejection episodes occurred, and an improvement in both systolic (149+/-13 vs. 137+/-12 mmHg; P<0.01) and diastolic blood pressure (89+/-14 vs. 83+/-10 mmHg; P<0.04) were observed. CONCLUSIONS: These short-term results show that MMF introduction allows a CsA dose reduction, which improves renal function, reduces TGF-beta1 production, and improves the control of hypertension, without increasing the incidence of acute rejection.     

The effect of felodipine on renal function and blood pressure in cyclosporin-treated renal transplant recipients during the first three months after transplantation

BACKGROUND: Due to their vasodilatory effect, calcium antagonist may have a renoprotective against cyclosporin (CsA)-induced nephrotoxicity and rise in blood pressure (BP) seen in renal transplantation. METHODS: In order to evaluate the effect of the calcium antagonist felodipine on renal function and BP during cyclosporin treatment, 79 CsA-treated renal transplant recipients were investigated during the first 3 months after transplantation in a randomized, double-blind, placebo-controlled study with two parallel groups. Felodipine (ER tablets, 10 mg) or placebo was given prior to transplantation and each day during the study period. The patients were assessed twice, i.e. at 4-6 weeks and at 10-12 weeks after transplantation. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by constant infusion technique. Tubular function was estimated from clearance of lithium. RESULTS: At 6 weeks after transplantation, felodipine caused a significantly higher RPF [felodipine: 219 +/- 70 ml/min; placebo: 182+/-56 ml/min (mean+/-1 SD); P=0.03]. No differences were found in GFR, filtration fraction (FF), tubular sodium handling, or sodium excretion. Felodipine lowered BP significantly. At 12 weeks after transplantation, felodipine caused a significantly higher GFR (felodipine: 49+/-18 ml/min; placebo: 40+/-16 ml/min; P=0.05) and RPF (felodipine: 225+/-77 ml/min; placebo: 175+/-48 ml/min; P<0.01). No difference was found in FF. Felodipine lowered BP significantly. No differences were found with regard to duration of primary anuria, hospitalization time, number of rejection episodes, plasma creatinine day 7 post-transplant, or treatment doses of CsA. CONCLUSIONS: It is concluded that in renal transplant recipients treated with CsA, felodipine significantly increased both GFR and RPF 3 months after transplantation when compared with placebo, despite a concomitant lowering of BP. A possible antagonizing affect of felodipine against CsA-induced nephrotoxicity in these patients is suggested.     

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy

BACKGROUND: Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS: Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS: At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS: These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.     

A randomized trial comparing cyclosporine induction with sequential therapy in renal transplant recipients

Calcium antagonists may reduce the nephrotoxicity of cyclosporine (CsA), allowing CsA to be introduced immediately after renal transplantation and thereby obviating the need for sequential induction therapy with a monoclonal or polyclonal antibody. To test this hypothesis, in a pilot feasibility trial 100 cadaveric or one-haplotype-mismatched living-related renal transplant recipients were randomized to either (1) sequential therapy with anti-thymocyte globulin (ATG) (ATGAM; Upjohn, Kalamazoo, MI) 20 mg/kg/d for 7 to 14 days until renal function was established and CsA (Sandimmune; Sandoz, East Hanover, NJ) was started, or (2) CsA 8 mg/kg/d begun immediately before surgery with diltiazem (Cardizem; Marion Merrell Dow, Kansas City, MO) 60 mg sustained release twice daily. Acute rejection episodes during the first 90 days were not different with ATG versus CsA induction (42% v 28%; P = 0.142 by chi-square analysis). Graft failures (10% v 16%; P = 0.372) and the incidence of delayed graft function (28% v 34%; P = 0.516) were also similar with ATG compared with CsA. ATG caused lower platelet counts (138 +/- 59 x 10(3) v 197 +/- 75 x 10(3) at 7 days; P < 0.001) and lower white blood cell counts (9.6 +/- 4.6 x 10(3) v 12.3 +/- 4.9 x 10(3) at 7 days; P = 0.003). Diltiazem reduced the dose of CsA required to maintain target blood levels (479 +/- 189 mg/d v 576 +/- 178 mg/d at 14 days; P = 0.015). There were no statistically significant differences between the groups in serum creatinine levels at days 1, 3, 5, 7, 14, 28, 60, or 90. The results of this pilot feasibility trial suggest that prophylactic treatment with CsA and diltiazem may be equally effective and less toxic than ATG induction after renal transplantation.     

Enhanced production of oxygen radicals in asthma

Cyclosporin A (CsA) is widely used to suppress graft rejection following transplantation and in the treatment of a variety of autoimmune diseases. Therapy with CsA is often accompanied by adverse effects which include hepatotoxicity, hypertension, and nephrotoxicity. The role of endothelin (Et) in CsA-induced nephrotoxicity has been the subject of recent investigations. BQ-123 is a recently discovered Et receptor antagonist which is selective for the EtA receptor. In the present study, BQ-123 was used to further characterize the role of Et in CsA-induced nephrotoxicity. All experiments were performed in Inactin (100 mg/kg, i.p.) anesthetized male Munich-Wistar rats (250 to 350 g). Animals were prepared for the recording of blood pressure (MAP) and heart rate (HR) as well as the measurement of urine volume (UV), UNaV, UKV, GFR and effective renal plasma flow (ERPF). GFR and ERPF were estimated from the clearance of 14C-inulin and 3H-PAH, respectively. On the day of the experiment, animals were randomly assigned to one of three groups and treated according to the following protocols: Group 1, pretreatment with BQ-123 (1 mg/kg, i.v. bolus with 0.1 mg/kg/hr i.v. infusion) followed by treatment with vehicle (cremophor; 0.15 ml, i.v.); Group 2, pretreatment with normal saline (1.0 ml/kg; plus 25 microliters/min infusion) followed by treatment with CsA (20 mg/kg, i.v.); and Group 3, pretreatment with BQ-123 (same as group 1) followed by CsA (20 mg/kg, i.v.). BQ-123 administration alone produced transient changes in several of the measured parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analysis of growth in five-sixths-nephrectomized rats

The present study was designed in an attempt to better define the pattern of growth in five-sixths-nephrectomized rats. Male Sprague-Dawley rats underwent two-stage (days 0 and 7) five-sixths nephrectomy (NX, n = 16) or sham surgery (SHAM, n = 9). At the time of sacrifice (day 21), renal failure (CRF) of NX rats was confirmed by elevated (p < or = 0.0001) serum concentrations (X +/- SEM) of urea nitrogen (SUN) (56 +/- 5 vs. 20 +/- 1 mg/dl) and creatinine (0.7 +/- 0.04 vs. 0.4 +/- 0.02 mg/dl) and reduced SUN (0.13 +/- 0.02 vs. 0.44 +/- 0.05 ml/min/100 g) and creatinine clearances (0.23 +/- 0.02 vs. 0.58 +/- 0.05 ml/min/100 g). As shown by lower cumulative gains of weight (41 +/- 6 vs. 74 +/- 4 g) and length (5.0 +/- 0.4 vs. 6.8 +/- 0.3 cm), NX rats grew subnormally. Detailed analysis of growth data revealed: (1) In spite of being identically matched in weight and length on day 0, at day 7, NX rats already weighed less than SHAM animals (147.1 +/- 2.3 vs. 153.4 +/- 1.9 g, p = 0.03). (2) From day 7 on, daily gain of weight was lower in the NX group only on days 8 (-6.08 +/- 0.52 vs. -1.60 +/- 0.69 g/100 g body weight) and 9 (-0.41 +/- 1.73 vs. 5.18 +/- 0.63 g/100 g body weight). (3) Following the early post-second-nephrectomy period, two subgroups of NX rats were clearly differentiated according to whether or not their daily growth rate was lower than that of SHAM animals. Maintained subnormal growth rate was observed in rats with severe CRF (SUN 73 +/- 5 mg/dl, range 54-90) but not in rats having milder uremia (42 +/- 3 mg/dl, range 31-51). Thus, growth in five-sixths-nephrectomized rats should be reported based on daily weight increments (g/100 g body weight). Subnormal growth can be attributed to CRF provided SUN is at least 3 times as high as normal while growth impairment of rats with less marked reduction of renal function is likely related to transient acute renal failure and postsurgical catabolic state.     

Is there a beneficial effect of the calcium channel blocker diltiazem on cyclosporine A nephrotoxicity in rats?

To investigate whether or not there is a beneficial effect of diltiazem (D) on cyclosporine A (CsA) nephrotoxicity, renal function, CsA blood levels, and effects of CsA on biotransformation in the liver and on lipid peroxidation were characterized in rats. A single administration of D (60 mg/kg b.wt.) reduced urinary volume (UV), GFR and excretion of Na+ and K+, whereas a single dose of CsA (60 mg/kg b.wt.) alone had no respective effects. P-aminohippurate excretion was almost equal in all groups. Lower doses of D (and CsA) were without effects. After repeated CsA treatment a retardation in body weight gain was seen, with little effect of a co-administration with D hereon. In all tests, thymus mass was reduced by CsA, the weight of spleen, liver, adrenal glands, and kidney were not generally affected by any of the treatments. Furthermore, after repeated administration of CsA and/or D, urinary volume, GFR and Na+ excretion were reduced by CsA, too. Electrolyte concentrations in plasma showed no evident changes by any of the treatments for Na+ and Ca2+. After long time treatment, CsA and CsA + D quite similarly led to higher K+ but lower Mg2+ concentrations in plasma. Only with 7 days highest dosage treatment PAH excretion was reduced significantly by CsA and CsA + D treatment. Surprisingly, CsA levels measured in blood and in kidney tissue, showed lower values after co-administration with D compared to CsA treatment alone. This could be caused by higher activities of monooxygenase functions revealed after pretreatment with D alone. Reduced glutathione (GSH) contents in kidney were elevated in CsA and CsA + D treated groups. In general no significant differences were to be observed concerning lipid peroxidation and stimulated H2O2 formation. Altogether evident protective effects of diltiazem on CsA nephrotoxicity in rats could not be proven.     

Cyclosporine increases local glomerular synthesis of reactive oxygen species in rats: effect of vitamin E on cyclosporine nephrotoxicity

BACKGROUND: We report an investigation of the effects of cyclosporine (CsA) on kidney function, the glomerular synthesis of reactive oxygen species, the peroxidation of lipids, and the levels of thromboxane B2 (TXB2). The effect of the simultaneous administration of the antioxidant vitamin E (Vit E) and CsA in rats was also evaluated. METHODS: Adult male Wistar rats were treated for 30 days with CsA (30 mg/kg/day), with Vit E (0.05 mg/ml), with CsA plus Vit E, or with the vehicle used for administration of CsA, namely 12.6% ethanol. RESULTS: CsA induced kidney failure and increased the glomerular synthesis of superoxide anion, H2O2, malonyldialdehyde, and TXB2. Vit E minimized the adverse effects of CsA on kidney function and the glomerular synthesis of these compounds. CONCLUSIONS: Our results suggest that the acute decrease in glomerular filtration rate induced by CsA might be mediated by the synthesis of reactive oxygen species and subsequent peroxidation of lipids, which increases the levels of TXB2. Treatment with Vit E prevented these effects, suggesting a possible role for antioxidants in the prevention of CsA nephrotoxicity.     

Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome

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.     

Interobserver variability in recognizing arousal in respiratory sleep disorders

BACKGROUND: The study was designed to investigate the influence of haemodialysis on the pharmacokinetics of the non-ionic contrast medium iopentol and the outcome of radiocontrast nephropathy in patients at risk undergoing angiography. METHODS: We prospectively studied 30 patients with reduced renal function (mean serum creatinine concentration (+/- SEM), 2.4 +/- 0.16 mg/dl (212 +/- 14 mumol/l)). Patients were randomly assigned to receive either a haemodialysis procedure for 3 h, started as soon as possible (63 +/- 6 min) after administration of contrast medium, or a conservative treatment. Serum concentrations of iopentol and creatinine were followed for up to 14 days. RESULTS: The extracorporal plasma clearance of contrast medium was 71 +/- 2.5 ml/min. The fraction of the dose eliminated was 32 +/- 3%. The rate of radiocontrast nephropathy (defined as serum creatinine increase of > or = 0.5 mg/dl (44 mumol/l) within 48 h) after administration of contrast medium was similar in both groups (53 and 40% in group 1 (haemodialysis) and group 2 (conservative treatment) respectively). The course of absolute changes in serum creatinine over the whole observation period was not different in both groups. CONCLUSIONS: The data indicate that haemodialysis eliminates contrast medium effectively, but it may not influence the incidence or outcome of contrast induced nephropathy.     

ICAM-1 antisense oligodesoxynucleotides prevent reperfusion injury and enhance immediate graft function in renal transplantation

BACKGROUND: Ischemia-reperfusion injury after organ transplantation is a major cause of delayed graft function. We showed earlier that antisense oligodesoxynucleotides (ODN) for intercellular adhesion molecule-1 (ICAM-1) ameliorate reperfusion injury after acute ischemia. This study tested the hypothesis that antisense ODN for ICAM-1 prevents ischemia-reperfusion injury and facilitates immediate graft function in a rat autotransplantation model. METHODS: Both kidneys were removed from male Lewis rats and re-implanted the left kidney after 30 minutes of cold ischemia time. The warm ischemia time was 60 minutes. Sham operated, uninephrectomized animals served as controls for renal function and histology. ICAM-1 antisense ODN (5 mg/kg), reverse ODN, or saline-vehicle were administered to donor animals i.v. six hours before autotransplantation. Glomerular filtration rate (insulin clearance), and serum creatinine concentrations were measured 24 hours post-transplantation. Tubular necrosis severity was assessed by histological grading scale. ICAM-1 expression was determined by immunohistochemistry and Western blot. RESULTS: Antisense ODN decreased ICAM-1 expression and leukocyte infiltration significant. Antisense ODN-treated animals showed significantly less tubular necrosis, than controls. Serum creatinine of antisense ODN-treated animals (N = 6) was 0.55 +/- 0.02 mg/dl compared to 1.92 +/- 0.07 mg/dl in reverse ODN-treated controls (N = 6; P < 0.01), 24 hours after transplantation. Antisense ODN-treated animals had normal GFR (0.93 +/- 0.07 ml/min/kidney wt) compared to sham-operated animals (0.95 +/- 0.09 ml/min/kidney wt), while autotransplanted animals treated with reverse ODN or saline-vehicle were all anuric. The ischemia-reperfusion-induced up-regulation of MHC class II was totally prevented by antisense ODN. CONCLUSIONS: ICAM-1 inhibition ameliorates ischemia-reperfusion injury and prevents delayed graft function. Antisense ODN-treatment of donors or donor organs for ICAM-1 may be useful for the prevention of reperfusion injury in human renal transplantation.     

Conversion from +Sandimmune to Neoral in kidney transplant recipients treated with cyclosporine and ketoconazole

BACKGROUND: Microemulsion cyclosporine is a new pharmaceutical form whose intestinal absorption is more constant, resulting in a better bioavailability. AIM: To assess dose adjustments and variability of blood levels after the conversion of cyclosporine to microemulsion cyclosporine in renal transplant recipients function receiving cyclosporine-ketoconazole. PATIENTS AND METHODS: Thirty four patients with more than one year after the transplantation, with stable renal function and receiving triple immunosuppression were studied. Conventional cyclosporine was changed to the microemulsion form maintaining the same daily dose. Drug serum levels, serum creatinine and blood pressure were measured within two to eight months after the conversion. Doses of microemulsion cyclosporine were adjusted to achieve serum levels of 150 +/- 40 ng/ml. RESULTS: Microemulsion cyclosporine induced a slight initial increase in blood cyclosporine levels. Afterwards, levels were more stable than with conventional cyclosporine (165-185 and 145-210 ng/ml respectively) and the dispersion of values were lower (standard deviations of 70 and 100 ng/ml respectively). Twenty three patients did not require dose adjustments, in four it was reduced and in five it was increased. There were no changes in serum creatinine or blood pressure after the conversion. CONCLUSION: More stable serum levels without adverse reactions were obtained with microemulsion cyclosporine. Doses of cyclosporine need not to be changed during the conversion.     

Prophylaxis of acute renal allograft rejection using FTY720 in combination with subtherapeutic doses of cyclosporine

BACKGROUND: In rodent transplant models, FTY720 exerts a synergistic affect with cyclosporine (CsA) to prolong allograft survival. The present experiments sought to test this combination in subhuman primates. METHODS: Cynomolgus monkeys were transplanted with kidney allografts that were incompatible in mixed lymphocyte culture reactions. The animals were treated with daily intramuscular injections of CsA using doses selected to maintain whole blood trough concentrations at therapeutic values between 40 and 200 ng/ml. The 4 experimental groups included CsA without or with 0.1, 0.3, or 1 mg/kg/day FTY720 delivered daily by intravenous bolus injection. Therapeutic effects were suggested both by the graft histology of biopsy within the first 10 posttransplant days and by the length of host survival. RESULTS: Whereas recipients treated with CsA alone rejected kidney allografts at a median survival time of 8.5 days (n=4), those treated with either 0.1 or 0.3 mg/kg/day FTY720 in addition to CsA showed significant prolongation of kidney allograft survival to 71 days (n=3; P<0.04) or 63 days (n=5; P<0.05), respectively. The hosts in the 1.0 mg/kg/day FTY720 group survived 48 days, with 2 of 5 recipients succumbing at 9 or 17 days postgraft, suggesting possible complications caused by overimmunosuppression. Biopsies of the 0.1 mg/kg/day FTY720 group on posttransplant day 7 documented mild to moderate rejection (grade I), indicated by multiple focal areas of tubular destruction. The histology results of transplants in the 0.3 or 1 mg/kg/day FTY720 group showed only minimal interstitial inflammatory infiltrates (borderline grade), with no evidence of tubular or arterial damage. Serum creatinine values among the animals in the 0.1 mg/kg/day FTY720 group showed increases in 2 of 3 recipients by day 20 and in the third by day 41 postgraft. Among the 0.3 mg/kg/day FTY720 group, 3 of 5 recipients maintained baseline creatinine values to 45 days postgraft; 1 recipient had stable kidney function for 120 days postgraft. CONCLUSIONS: Addition of FTY720 therapy to a subtherapeutic CsA immunosuppressive regimen delays the rejection of renal allografts in subhuman primates.     

Effects of P-glycoprotein modulators on etoposide elimination and central nervous system distribution

In this study, P-glycoprotein modulator effects on pharmacokinetics and central nervous system distribution of the chemotherapeutic agent etoposide were evaluated. The multidrug resistance transporter P-glycoprotein is expressed in normal tissues, and its physiological function is thought to be an excretory and/or protective one. To examine this further, we evaluated etoposide under steady-state and bolus dose conditions. In microdialysis infusion studies, etoposide 15 mg/kg/hr was administered to 12 rats. Rats received sodium cyanide (1 or 100 mM), trifluoperazine (30 mM) or cyclosporine (4.14 mM) via microdialysis probe at 3.5 hr after etoposide infusion initiation. High-dose sodium cyanide (100 mM) increased the etoposide BBR,corr from 0.09 +/- 0.03 to 0.85 +/- 0.35. Similarly, trifluoperazine significantly increased the BBR,corr (0.05 +/- 0.02 vs. 1.30 +/- 0.43), whereas cyclosporine had no effect. In bolus studies, etoposide (10-12 mg/kg) was given alone or concomitant to cyclosporine (5 mg/kg) or tamoxifen (13.5 mg/kg). Control etoposide total systemic clearance (ml/min/kg) was 29.3 +/- 13.0 vs. 16.0 +/- 1.9 and 22.6 +/- 5.3 for cyclosporine and tamoxifen treatments, respectively. Etoposide nonrenal clearance (ml/min/kg) values for cyclosporine (12.0 +/- 1.6) and tamoxifen (18.1 +/- 3.6) treatments was also decreased from controls (23.5 +/- 10.5). Etoposide renal clearance (ml/min/kg) values (5.7 +/- 2.5) were not significantly different from cyclosporine (4.0 +/- 0.7) or tamoxifen (4.6 +/- 1.7) treatments, respectively. In this study, the ability of sodium cyanide and trifluoperazine to alter etoposide BBR,corr, demonstrated that etoposide distribution into brain is partly controlled by an active transport process. Similarly, the results indicate cyclosporine inhibits etoposide transport at the canalicular membrane and/or etoposide P-450 metabolism.     

Systemic sclerosis complicated by procainamide-induced lupus and antiphospholipid syndrome

In order to estimate the effect of the long term administration of cyclosporine (CsA) on the shape change of erythrocytes, erythrocyte shapes which are observed with a scanning electron microscope were classified according to the nomenclature of Bessis for stomatocyte-echinocyte shape transformation. As a result of observing the erythrocyte shape of fifty-six patients with kidney transplantation treated with CsA, the morphological index of the erythrocytes of patients significantly increased to 0.0835+/-0.0085*** in comparison with 0.0004+/-0.0051 of those from healthy volunteers (control) (***: p<0.001, ANOVA). Such transformations had no relation to the subjects' sex or age. On the other hand, the erythrocytes of patients administered more than 100 ng/ml of CsA and posttransplanted within less than two years were transformed by CsA from the state of discocyte to echinocyte. In rats, the morphological index of erythrocytes of rats treated with 3 mg/kg/d or 5 mg/kg/d of CsA significantly increased in comparison with rats treated with saline (control). Furthermore, the erythrocytes of two patients were observed in terms of shape before the treatment with CsA. In both patients, the echinocyte type of erythrocyte increased by treatment with CsA. In vitro, the morphological index of the erythrocytes incubated with plasma containing CsA significantly increased, to 0.459+/-0.066*** in comparison with 0.064+/-0.029 of the control. It is suggested from these results that CsA treatment induces the echinocyte type of erythrocyte.     

Mechanism of the diabetogenic action of cyclosporin A

To investigate the mechanism of diabetogenic action of cyclosporin A (CsA), 7 male Wistar albino rats received 10 mg/kg/day of the drug for 4 weeks (CsA). The results were compared with controls (C); blood CsA levels measured weekly remained stable throughout the experiment (mean +/- SEM) (X = 2657.9+/-155.1 ng/ml). Intravenous glucose load (0.75 g/kg) performed after 2 weeks of CsA therapy showed glucose intolerance in treated animals as evaluated by the glucose area under the curve (CsA = 409.2+/-17.8 vs. C = 313.3+/-12.6 umol x ml(-1) x min(-1)) (p < 0.05) with insulin levels being similar in the two groups (CsA = 8603.9+/-1645.5 vs. C = 9571.9+/-828.5 pmol x ml(-1) x min(-1)). After 4 weeks of CsA administration, glucose intolerance was maintained (CsA = 398.6+/-35.6 vs. C = 301.7+/-23.0 umol x ml(-1) x min(-1)) (p < 0.05) associated with a significant decrease in insulin secretion (CsA = 4404.9+/-2392.0 vs. C = 10075.9+/-2861.0 pmol x ml(-1) x min(-1) (p < 0.05). These results suggest that CsA induced a state of insulin resistance preceding the failure of insulin secretion. After 4 weeks, the pancreatic insulin content was also decreased (CsA = 0.7+/-0.1 vs. C = 1.4+/-0.5 mU/mg) (p < 0.05). Maximal insulin binding to isolated adipocytes was not affected by CsA (CsA = 7.4+/-2.6 vs. C = 6.4+/-2.0%), although glucose transport and oxidation decreased after CsA treatment (p < 0.05). In conclusion, glucose intolerance induced by CsA in Wistar albino rats is due to decreased insulin production and impaired insulin action by a post-binding mechanism.