A randomized controlled trial of verapamil on cyclosporine nephrotoxicity in heart and lung transplant recipients

BACKGROUND: Cyclosporine (CsA) is a potent immunosuppressive drug widely used in organ transplantation and in the treatment of autoimmune diseases (1, 2). However, its common nephrotoxic effect is a major limiting factor. Short-term CsA treatment has been shown to cause reversible renal vasoconstriction, whereas long-term treatment can lead to an afferent arteriolopathy and chronic renal failure. METHODS: We performed a randomized controlled trial to examine the short-term renal effects of verapamil in 32 CsA-treated heart or lung transplant recipients. Sixteen patients each were randomized to receive a 6-week course of verapamil or control treatment (atenolol in hypertensive patients and placebo in normotensive patients) 1-2 months after transplantation. An 8-hr sequential clearance study of inulin and p-aminohippuric acid for estimating glomerular filtration rate and renal plasma flow, respectively, was performed at baseline and at completion of study. The integral area under the curve of the clearance parameter over 8 hr was then calculated to generate a clearance-time index. RESULTS: There was no difference in the clearance-time indices for inulin and p-aminohippuric acid between the two groups at baseline. However, at the completion of study, the within-group change in the glomerular filtration rate clearance-time index was different between the verapamil and control groups (48+/-20 vs. -35+/-17 ml/min/1.73 m2 x hr, respectively; P=0.0038). A similar trend was seen for renal plasma flow, but did not reach statistical significance. Mean arterial blood pressure and whole-blood CsA levels did not differ between the two groups during the study. Verapamil treatment was also associated with a decrease in CsA dose requirement (7.6+/-0.58 mg/kg/day at baseline vs. 4.6+/-0.40 mg/kg/day at completion; P<0.001) without any significant change in trough whole blood CsA levels. Rejection episodes did not differ between the two groups. CONCLUSIONS: The use of verapamil in the heart or lung transplant recipients may therefore provide both renal protective effects and cost savings.     

Enhancing the effect of secreted cyclophilin B on immunosuppressive activity of cyclosporine

BACKGROUND: Cyclophilin B (CyPB) is a cyclosporine (CsA)-binding protein, located within intracellular vesicles and secreted in biological fluids. In previous works, we reported that CyPB specifically interacts with the T-cell membrane and potentiates the ability of CsA to inhibit CD3-induced proliferation of T lymphocytes. METHODS: CyPB levels were measured in plasma from healthy donors and transplant patients. The role of extracellular CyPB on the distribution and activity of CsA was investigated first by studies on the uptake of free and CyPB-complexed drug by blood cells, and second by studies on the inhibitory effects of these two compounds on the CD3-induced proliferation of peripheral blood mononuclear cells. RESULTS: A significant increase in plasma CyPB level was observed for CsA-treated patients (13+/-6.4 nM, n=42) in comparison with untreated donors (4.3+/-2.1 nM, n=34). In vitro, extracellular CyPB dose dependently modified CsA distribution between plasma, erythrocyte, and lymphocyte contents, by both retaining the complexed drug extracellularly and promoting its specific accumulation within peripheral blood mononuclear cells. Moreover, the enhanced ability of CyPB-complexed CsA to suppress CD3-induced T-cell proliferation was preserved in the presence of other blood cells, implying specific targeting of the drug to sensitive cells. Furthermore, although a large interindividual variability of sensitivity to the drug was confirmed for 18 individuals, we found that CyPB potentiated the activity of CsA in restoring a high sensitivity to the immunosuppressant. CONCLUSION: These results suggest that plasma CyPB may contribute to the acceptance and the good maintenance of organ transplantation by enhancing the immunosuppressive activity of CsA through a receptor-mediated incorporation of CyPB-complexed CsA within peripheral blood lymphocytes.     

Recovery of blood mononuclear cell calcineurin activity segregates two populations of renal transplant patients with different sensitivities to cyclosporine inhibition

In vitro studies have shown that the immunosuppressive property of cyclosporine (CsA) depends on its ability to inhibit the phosphatase activity of calcineurin, a critical enzyme for T cell activation. Here we sought to investigate whether measurement of calcineurin activity in peripheral blood mononuclear cells (PBMC) from 30 renal transplant patients given CsA as a part of their immunosuppressive regimen would help in optimizing CsA therapy. We first documented that in PBMC from these patients complete inhibition of calcineurin phosphatase activity by in vitro addition of CsA occurs at concentrations that are easily achieved in vivo for a dose as low as 3 mg/kg/day orally, which corresponds to trough CsA blood levels of 100-150 ng/ml. However, ex vivo, at a blood CsA trough level of 250 ng/ml, calcineurin activity in PBMC was only inhibited from 40% to 70% as compared with controls. Patients on higher doses of CsA had a further inhibition of baseline calcineurin activity, although a complete suppression was never reached. A significant correlation was found between trough CsA concentration and the basal calcineurin activity (r=0.48; P=0.0085). To clarify the relationship between the daily exposure of patients to CsA and changes in the enzyme activity of calcineurin, we then correlated the pharmacokinetic profile of CsA in these patients with different CsA dosing (<4, 4-6, >6-8, >8 mg/kg/day) with the profile of calcineurin activity at different intervals from dosing. Each of the above CsA doses suddenly reduced calcineurin activity, with a nadir at 2 hr after maximum blood concentration. The degree of the inhibition was not a function of peak CsA blood levels. In all patients, CsA blood level returned to basal values 10 hr after dosing. By contrast, only in 50-70% of patients (depending on the dose) did calcineurin activity return to baseline at the same time point after dosing. In summary we have shown that (1) inhibition of calcineurin activity measured ex vivo in PBMC taken from CsA-treated transplanted recipients reflects the blood CsA trough level; (2) after CsA the time-course of inhibition of enzyme activity is relatively independent from CsA pharmacokinetics; (3) the rate of recovery of calcineurin activity 10 hr after CsA dosing segregates two populations of transplanted recipients -- one with complete recovery of the enzyme activity and another that never returns to the baseline calcineurin level.     

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.     

Differential suppression of dialysis patients' lymphocyte IFN-gamma production by glucocorticoids and cyclosporine

IFN-gamma is a potent pro-inflammatory cytokine involved in the immunologic rejection of transplanted organs. Having previously demonstrated differential suppressive effects of methylprednisolone (MP), prednisolone (P) and cyclosporine (CsA) on dialysis patients' lymphocyte proliferative responses to phytohaemagglutinin (PHA), we studied the effects of these drugs on dialysis patients' lymphocyte IFN-gamma production during mitogenic and allogeneic (MLR) stimulation. The mean +/- SEM 50% inhibitory concentration (ng/ml) on cell proliferation was significantly lower for MP than P in PHA-stimulated haemodialysis (HD) patients' (35 +/- 7 vs 152 +/- 25, P < 0.001) and peritoneal dialysis (PD) patients' (35 +/- 11 vs 134 +/- 33, P = 0.001) cultures and in HD patients' MLR cultures (15 +/- 3 vs 48 +/- 9, P < 0.001). The mean +/- SEM fractional responses (PHA or MLR + drug/PHA or MLR) in culture supernatant IFN-gamma concentrations were significantly lower with 10(-7) M concentrations of MP than P in HD (0.19 +/- 0.05 vs 0.31 +/- 0.06, P = 0.01) and PD (0.30 +/- 0.11 vs 0.46 +/- 0.11, P < 0.05) PHA cultures and in HD MLR cultures (0.15 +/- 0.04 vs 0.28 +/- 0.07, P = 0.01). CsA (400 ng/ml) alone not only caused less than 50% inhibition of IFN-gamma production in 15/27 HD PHA, 6/14 PD PHA and 4/13 HD MLR cultures, but actually stimulated it in 9 HD and 5 PD PHA cultures. The results suggest that: (1) MP has greater immunosuppressive potential than P for renal transplant recipients; (2) the stimulation of IFN-gamma by CsA in some patients could be harmful in patients with initial allograft dysfunction; and (3) pre-transplant in-vitro assessment of recipients' PBMC responsiveness to glucocorticoids and CsA may help individualize the post-transplant immunosuppressive regimen.     

Health related quality of life outcomes in patients treated for metastatic kidney cancer: a pilot study

The use of the immuno-suppressant cyclosporine A (CsA) after transplantation has been associated with less favorable plasma lipid profiles, which may contribute to the high incidence of cardiovascular morbidity and mortality in transplant recipients. Recent studies have suggested that oxidative modification of LDL plays an important role in the initiation and progression of atherosclerosis. It has also been demonstrated that CsA may facilitate lipid peroxidation in vitro and in vivo. Therefore, we determined several parameters of LDL oxidizability in renal transplant recipients who were switched from CsA to azathioprine (AZA)-based immunosuppressive treatment. The susceptibility of LDL to in vitro oxidation, LDL particle size, plasma titers of IgG and IgM antibodies against oxidized LDL and plasma LDL subclass patterns in 19 renal transplant recipients were determined during CsA treatment and 16 weeks after these patients were converted to AZA treatment. In addition, mean arterial pressure was recorded, and glomerular filtration rate and renal blood flow were estimated from the clearance of radiolabeled thalamate and hippurate. After conversion, the plasma concentrations of total cholesterol, LDL cholesterol and triglyceride decreased, while plasma HDL cholesterol did not change. During CsA therapy plasma LDL was significantly more susceptible to in vitro oxidation than during AZA, as reflected by a longer lag phase during in vitro oxidation (98.9 +/- 24.3 vs. 114.7 +/- 17.3 min, P = 0.031). In addition, the LDL size increased (236.5 +/- 7.3 vs. 240.7 +/- 6.8 nm, P = 0.00001), and the titers of IgM- and IgG-autoantibodies against oxidized LDL decreased significantly after patients were converted from CsA to AZA. The more atherogenic LDL subclass pattern B was present in 13 out of 19 patients during CsA. In five patients, pattern B changed into pattern A after conversion. The subclass B pattern was maintained in eight patients and subclass A pattern in six patients. In all patients the lag time of in vitro LDL oxidation increased, although the biggest changes were found in those patients in whom the LDL subclass changed from pattern B to pattern A. Mean arterial pressure decreased and renal function improved significantly after conversion. No correlation between parameters of lipid peroxidation and changes in blood pressure or renal function upon conversion, underlying renal disease, time since transplantation, or antihypertensive treatment was found. Our study demonstrates that treatment with CsA increases the susceptibility of LDL to in vitro oxidation, and also enhances the oxidation of LDL in vivo. In addition, conversion to AZA results in a more favorable lipid profile, which in combination with a lower arterial pressure and better renal function may decrease the risk for atherosclerosis. These factors may account for the cardiovascular complications during CsA treatment after organ transplantation, and also when CsA is used for other diseases.     

Additional inhibitory effects of intravenous immunoglobulins in combination with cyclosporine A on human T lymphocyte alloproliferative response in vitro

Intravenous immunoglobulins (IvIgG) are often used in patients receiving a basic immunosuppressive therapy with CsA either for prevention of infectious complications or as an additional prophylaxis of graft versus host disease in clinical bone marrow transplantation. As far as we know, the combined in vitro immunosuppressive effects of these 2 drugs have not been investigated yet. In this study, we compared the effect of CsA, IvIgG, and CsA combined with IvIgG on the proliferative capacity of peripheral blood mononuclear cells in a mixed lymphocyte culture system. The concentration-dependent inhibition of peripheral blood mononuclear cell proliferation in the mixed lymphocyte culture system by CsA is a well established phenomenon. By adding IvIgG to the cultures (n=20) containing CsA, we were able to show a significantly (P<0.0002) higher inhibition compared with the inhibitory capacity of CsA alone. Cyclosporine A was added to the cultures at concentrations ranging from 25 to 400 ng/ml, and IvIgG was added in 3 different fixed concentrations: 1.25, 2.5, and 5 mg/ml. These are all concentrations which one usually obtains in patients during therapy with these drugs. Even with a minimal concentration of CsA (25 ng/ml) plus IvIgG (1.25 mg/ml), we achieved a mean inhibition of 77.7 +/- 7.9%, which is in the range of the mean inhibition (84.3 +/- 4.7%) with the highest concentration of CsA (400 ng/ml tested. Our in vitro results could suggest that the additional therapy with IvIgG in patients receiving CsA might cause a CsA sparing effect. This might lead to a combined therapeutic regimen with a good immunosuppressive efficacy and minimal drug associated adverse effects.     

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.     

The specific antibacterial proliferation of reactive arthritis synovial T cells is not due to their higher proportion of CD45RO+ cells compared to peripheral blood

OBJECTIVE: To determine the role of synovial fluid (SF) compared to peripheral blood (PB) CD45RO+ T cells in patients with reactive arthritis (ReA) and undifferentiated oligoarthritis. METHODS: We examined SF and PB of 8 patients with a specific lymphocyte proliferation to Yersinia enterocolitica (n = 5) and Chlamydia trachomatis (n = 3). After depletion of the CD45RA+ T cell subset by dynabeads, the remaining T cells (> 95% CD45RO+) from PB and SF of these patients were again stimulated with these bacterial antigens. RESULTS: The mean stimulation index (SI) of these 8 patients with ReA (n = 5) and undifferentiated oligoarthritis (n = 3) was 30.3 +/- 21.86 in SF compared to 1.36 +/- 0.75 in PB. The enrichment of CD45RO+ cells influenced the antigen specific proliferative response of T cells neither in PB (SI = 1.75 +/- 1.35) nor in SF (26.1 +/- 24.05); the initial difference remained unchanged. CONCLUSION: Our findings suggest that the antigen specific lymphocyte proliferation obtained with SF cells is not due to abundance of nonspecific CD45RO+ T cells but can rather be taken as an indication of specific recognition of local bacterial antigens in ReA.     

Treatment with beta-blockers in patients with acute coronary syndrome

BACKGROUND: Immunosuppressive treatment with cyclosporin A (CsA) improves the survival of renal allografts, but is associated with renal vasoconstriction and hypertension. Previous reports suggest that the calcium-channel blockers nifedipine and amlodipine may improve graft function in CsA-treated patients. We have compared the effects of amlodipine (5-10 mg once daily) and nifedipine retard (10-40 mg twice daily) on renal function and blood pressure in renal transplant recipients treated with CsA. METHODS: This was a multicentre, two-way, crossover study in 27 evaluable hypertensive patients with renal insufficiency following renal transplantation, who were maintained on a stable dose of CsA. Patients received either amlodipine (5-10 mg once daily) or nifedipine retard (10-40 mg twice daily) for 8 weeks, and were then crossed over to the other treatment for a further 8 weeks. RESULTS: Trends were seen during amlodipine treatment towards larger improvements, in serum creatinine (by 8% of baseline on amlodipine vs 4% on nifedipine), lithium clearance (13% vs 2%), and glomerular filtration rate 11% vs 7%). Effective renal plasma flow was increased by 11% of baseline on nifedipine vs 9% on amlodipine. There were no significant differences between treatments. Amlodipine and nifedipine lowered systolic blood pressure to a similar extent (21 mmHg vs 15 mmHg respectively, P=0.25), but amlodipine was more effective than nifedipine in lowering diastolic blood pressure (13 mmHg vs 8 mmHg, P=0.006). Both treatments were well tolerated. CONCLUSION: Once-daily amlodipine is at least as effective as twice-daily nifedipine retard in controlling blood pressure and does not adversely affect graft function in hypertensive renal allograft recipients.     

CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.     

Sirolimus, a new, potent immunosuppressive agent

Sirolimus (SRL), a potent immunosuppressant, is currently being investigated in phase III trials for prophylaxis of renal transplant rejection. The mechanism of action of SRL is a blockade of the response of T and B cells to cytokines, thereby preventing cell cycle progression in G1 and consequently cell proliferation. There seems to be a good correlation between SRL concentrations, estimated as exposure by the area under the concentration versus time curve, and trough whole blood concentration, so that therapeutic monitoring may be done by trough levels only. Because of the low frequency of allograft rejection, there has been no documented correlation between trough concentrations and efficacy. Trough SRL concentrations of 15 ng/ml or higher seem to be associated with an increased frequency of adverse effects. Drug-associated toxicities include thrombocytopenia, leukopenia, and increases in cholesterol and triglyceride levels. The drug has synergy with cyclosporine (CsA) in vitro as well as in animal and clinical studies. In phase II trials the combination of SRL-CsA therapy reduced the frequency of acute rejection episodes, permit withdrawal of concomitant corticosteroid therapy, and allowed reduction of CsA dosages in nonblack patients.     

Duplex (thermotroph-psychrotroph) quadrant plates: convenient, error-avoiding tools for monitoring of HACCP-contained food lines and for epidemiological investigations under conditions of military or other constraints

The present study evaluated whether chronically administered low-dose (<5 mg/kg) ciclosporin A (CsA) affects renal haemodynamics and tubular function in renal transplant recipients (RTx) when studied at nadir CsA blood levels. The renal clearance of lithium was used as an index of proximal tubular outflow of sodium and water. Effective renal plasma flow, glomerular filtration rate, and renal clearance of lithium were studied in 67 stable non-diabetic RTx and 44 healthy controls. Forty-eight of the RTx were treated with CsA, prednisone, and azathioprine. Nineteen were treated exclusively with prednisone and azathioprine. In RTx with a good graft function (serum-creatinine <125 micromol/l), no specific CsA-induced renal haemodynamic and tubular dysfunctions were evident. In CsA-treated RTx with a slightly reduced renal function (serum creatinine 125-180 micromol/l) a decrease in fractional proximal tubular reabsorption was found. The renal clearances of urate and magnesium were comparable between RTx treated with or without CsA, and a significant correlation between glomerular filtration rate and renal clearance of urate was found. CsA-treated RTx had a significantly higher blood pressure, independent of glomerular filtration rate and segmental tubular function. In conclusion, at nadir CsA blood levels, no specific CsA-induced tubular dysfunction evaluated by the renal lithium clearance method could be demonstrated in RTx receiving chronically low-dose CsA. The hyperuricaemia commonly seen in RTx seems to be mainly caused by the reduced glomerular filtration rate.     

Von-Voss-Cherstvoy syndrome (DK-Focomelia): description of the first case in Spain and a literature review

Because hypercellularity is an important feature in acute serum sickness (AcSS), we quantified glomerular proliferation with immunoperoxidase staining using anti-proliferating cell nuclear antigen (PCNA Mab) and studied its relationship with lymphocyte infiltration (M108 Mab). AcSS was induced in 31 New Zealand White rabbits; group A (n = 14), with proteinuria, sacrificed 6-8 days after immunization; group B (n = 10), without proteinuria, sacrificed 6-7 days after immunization; group C (n = 7), sacrificed prior to development of AcSS. Four normal rabbits were included as controls. Intraglomerular proliferation (PCNA-positive cells/glomerular cross section) was increased in group A (12.2 +/- SEM, 1.84) but not in groups B (0.93 +/- 0.17) and C (0.37 +/- 0.05), which were similar to controls (0.66 +/- 0.06). Lymphocyte infiltration (lymphs/glomerular cross section) increased with time and was more prominent in rabbits with proteinuria (1.9 +/- 0.21, P < 0.001 vs controls). Lymphocyte infiltration was correlated with proliferative activity (Spearman correlation, r = 0.67, P < 0.0001). There was correlation between the severity of glomerular deposition of IgG and C3 and glomerular proliferation and proteinuria. These studies demonstrate a chronological association between lymphocyte infiltration and proliferative activity in AcSS.     

Tumor control of locally advanced prostate cancer following combined estramustine, vinblastine, and radiation therapy

Thalidomide (Thd) has been shown to have interesting immunosuppressive properties and strong action against TNF-alpha. It is used for treating a variety of immune-mediated pathology and inflammatory diseases. The purpose of this work was to evaluate the in vitro and in vivo immunosuppressive effects of Thd and its derivative, N-Hydroxythalidomide (H-Thd), alone and in combination with cyclosporin A (CsA), upon different in vitro lymphocyte activation pathways and in vivo local graft-versus-host-reaction (GvHR). At different concentrations, both Thd and H-Thd alone inhibited the lymphocyte proliferation induced by alloantigen (MLR), mitogens (Con A, PWM) and superantigen (SEB) with an activity of 50-75% that of CsA, however, in some tests, immunosuppressive potency of H-Thd was shown to be higher than that of Thd. In vivo using GvHR, Thd and H-Thd alone proved as active as CsA. The association in vitro and in vivo of each compound with CsA at different low concentrations, produced an additive effect as strong as CsA used alone at high therapeutic concentrations. In summarizing, this study revealed that: (1) despite its weaker potency in vitro than that of CsA, H-Thd presents interesting immunosuppressive properties similar to, and in some cases, better than Thd, and (2) the combination of H-Thd or Thd with CsA at suboptimal concentrations leads to high activity.     

Intratumoral blood flow in uterine myoma correlated with a lower tumor size and volume, but not correlated with cell proliferation or angiogenesis

OBJECTIVE: To investigate the correlation of intratumoral blood flow in uterine myoma with cell proliferation, angiogenesis, tumor size, and tumor volume. METHODS: Thirty-nine patients who had been scheduled for surgery because of symptomatic uterine myomas were evaluated by transvaginal sonography and color Doppler ultrasound before surgery. The largest dimension of each tumor and the volumes of myomas were determined ultrasonographically. Pulsatility index (PI) was determined by color Doppler ultrasound according to the maximum systolic, end-diastolic, and the mean flow velocities measured within the uterine nodules. After surgery, the paraffin-embedded slides containing representative leiomyoma tissues were stained with hematoxylin and eosin, proliferating cell nuclear antigen for measurement of cell proliferation, and factor VIII for quantitation of microvessel density. The ultrasonographic findings were correlated postoperatively with pathologic findings, and the data were analyzed by simple linear regression and Fisher r to z transformation. RESULTS: Simple regression analysis of the intratumoral PI values on the sizes of myomas showed a negative correlation (r = -0.47, P = .003; n = 39), whereas a less significant correlation between PI values and tumor volumes was observed (r = -0.42, P = .008). In contrast, no statistically significant correlation was observed between the intratumoral PI values and the values of the proliferating cell nuclear antigen index (r = 0.10, P = .547) or microvessel density counts (r = 0.18, P = .282). CONCLUSION: The intratumoral blood flow by transvaginal color Doppler ultrasound correlated with a reduced tumor size and tumor volume, but did not correlate with cell proliferation or angiogenesis.     

Myocardial viability. Concept, physiopathology. Methods and diagnostic value]

This study was designed to investigate the effect of tacrolimus (FK506) and of cyclosporine (CsA) on tubular function in renal graft recipients. Patients were randomised after renal transplantation to immunosuppressive treatment with FK506 (n = 8) or CsA (n = 8). Patients had a mean age of 45.7 +/- 3.4 yr; there was no difference in age, sex, HLA status or CMV mismatches. Neither was there any difference in the frequency of episodes of acute kidney failure between the groups, nor was there a significant difference in the frequency of episodes of kidney rejection within the first year. The mean FK506 level at the time lay at 14.7 +/- 14.4 ng/mL whole blood, and the mean CsA level at the time of study was 162 +/- 25 ng/mL whole blood. We performed renal function studies 6 months after transplantation: CIn, CPAH, NaHCO3 loading, and Na2SO4 loading. There was no significant impairment of GFR in patients treated with FK506 with 53.6 +/- 2.5 mL/min as compared to 58 +/- 6 mL in group 2. Plasma renin activity (0.6 +/- 0.4 ng/mL vs 2.3 +/- 3; p < 0.01) and aldosterone (69 +/- 17 vs 157 +/- 28.2 pg/mL; p < 0.05) were significantly decreased during treatment with FK506. Fractional HCO3 excretion was low in both groups, indicating that bicarbonate reabsorption in the proximal nephron was unimpaired. Distal renal tubular acidosis was demonstrated in 4 patients of group 1 but in only 1 of group 2. Potassium levels were slightly increased in patients treated with FK506 (5.4 +/- 0.2 mmoL/L) as compared to cyclosporine (4.9 +/- 0.3 mmoL/L; p < 0.05). Distal hydrogen ion secretion, evaluated by the ability to increase urinary pCO2 in a highly alkaline urine, was impaired in patients treated with FK506 (U-B pCO2: 16.1 +/- 4 vs 36 +/- 5.8; p < 0.05) as compared to patients treated with CsA. The maximum acidification capability (NAE) was slightly lowered during therapy with FK506 (67.5 +/- 11.8 versus 86.6 +/- 16.5 mumoL/min, ns). We conclude that FK506 administration results in a decrease in the rate of hydrogen ion secretion by the collecting tubules. This defect was disclosed by the finding of a subnormal pCO2 in a highly alkaline urine. These results show that FK506 is able to induce distal tubular acidosis. Distal tubular acidosis is part of FK506 induced nephrotoxicity, the pathogenesis of this type of hyperkalemic metabolic acidosis found in patients treated with FK506 after renal transplantation has to be further elucidated.     

Long-term outcome of a prospective randomized trial of conversion from cyclosporine to azathioprine treatment one year after renal transplantation

BACKGROUND: Since the introduction of cyclosporine (CsA), 1-year renal allograft survival has improved, but concern persists about the long-term adverse effects of CsA, especially with respect to renal function and blood pressure. This randomized controlled trial was set up to establish whether withdrawal of CsA would alter long-term outcome. METHODS: Adult patients who, at 1 year after renal transplantation, had a stable serum creatinine of less than 300 micromol/L and who had not had acute rejection within the last 6 months were eligible for entry. Patients were randomized either to continue on CsA (n=114) or to stop CsA and start azathioprine (Aza, n=102). All patients remained on prednisolone. Median follow-up was 93 months after transplantation (range: 52-133 months). RESULTS: There was no significant difference in actuarial 10-year patient or graft survival (Kaplan-Meier), despite an increased incidence of acute rejection within the first few months after conversion. Median serum creatinine was lower in the Aza group (Aza: 119 micromol/L; CsA. 153 micromol/L at 5 years after randomization, P=0.0002). The requirement for antihypertensive treatment was also reduced after conversion to Aza; 75% of patients required antihypertensive treatment at the start of the study, decreasing to 55% from 1 year after randomization in the Aza group and increasing to >80% in the CsA group (55% (Aza) and 84% (CsA) at 5 years after randomization, P<0.005). CONCLUSIONS: Conversion from CsA to Aza at 1 year after renal transplantation results in improvement in both blood pressure control and renal allograft function, and is not associated with significant adverse effects on long-term patient or graft survival.     

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.