CsA Patients Research Articles

Three novel mutations responsible for Cockayne syndrome group A.

Cockayne syndrome (CS) is a rare autosomal recessive disease, which shows diverse clinical symptoms such as photosensitivity, severe mental retardation and developmental defects. CS cells are hypersensitive to killing by UV-irradiation and defective in transcription-coupled repair. Two genetic complementation groups in CS (CS-A and CS-B) have been identified. We analyzed mutations of the CSA gene in 5 CS-A patients and identified 3 types of mutations. Four unrelated CS-A patients (CS2OS, CS2AW, Nps2 and CS2SE) had a deletion including exon 4, suggesting that there is a founder effect on the CSA mutation in Japanese CS-A patients. Patient CS2SE was a compound heterozygote for this deletion and an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, which resulted in a defective nucleotide excision repair. Patient Mps1 had a large deletion in the upstream region including exon 1 of the CSA gene. Our results indicate that a rapid and reliable diagnosis of CSA mutations could be achieved in CS-A patients by PCR or PCR-RFLP and that the Q106P mutation could alter the propeller structure of the CSA protein which is important for the formation of the CSA protein complex.

Immunosuppression impact on long-term cardiovascular complications after liver transplantation

Background: With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed. Objective: The objective of this study is to investigate at 3 years postliver transplant (OLTx) the incidence of hypertension (HTN), hyperlipidemia (HLIP), diabetes mellitus (DM), nephrotoxicity (NTX), and cardiovascular disease (MI, angioplasty, CHF, CVA, and seborth) as well as rejection in two cohorts of liver transplant recipients who received either tacrolimus (FK-506) or cyclosporine (CSA) and to analyze the consequences of these complications on mortality following transplantation. Methods: Eighty-seven sequential patients (CSA: n = 50, mean age 48 years, M/F 32/18; and FK-506: n = 37, mean age 45 years, M/F 22/15) who underwent OLTx between 1994 and 1998, were ≥18 years, and had a minimum of 3 years of complete follow-up were included in the analysis. All OLTx candidates over age 50, who had a history of alcoholic cirrhosis, or had a history of cardiac conditions/events underwent complete cardiac consultation including an echocardiogram with additional cardiac investigation as indicated prior to OLTx. Results: At 3 years following OLTx, the incidence of acute rejection (40% versus 19%, P < 0.05), HTN (62% versus 38%, P < 0.05), HLIP (14% versus 5%, P = 0.08), and cardiovascular disease (18% versus 0%, P < 0.001), were significantly greater for the CSA patients compared with the FK-506 patients. Eight (20%) of the CSA patients who died before 3 years had their death attributed to cardiovascular events versus none in the FK-506 group. Conclusion: Compared with CSA, FK-506 was associated with significantly less rejection and a reduced incidence of HTN and cardiovascular disease.

UVB radiation-induced cancer predisposition in Cockayne syndrome group A ( Csa) mutant mice

Cockayne syndrome (CS) is an inherited photosensitive neurodevelopmental disorder caused by a specific defect in the transcription-coupled repair (TCR) sub-pathway of NER. Remarkably, despite their DNA repair deficiency, CS patients do not develop skin cancer. Here, we present a mouse model for CS complementation group A. Like cells from CS-A patients, Csa −/− mouse embryonic fibroblasts (MEFs): (i) are ultraviolet (UV)-sensitive; (ii) show normal unscheduled DNA synthesis (indicating that the global genome repair sub-pathway is unaffected); (iii) fail to resume RNA synthesis after UV-exposure and (iv) are unable to remove cyclobutane pyrimidine dimers (CPD) photolesions from the transcribed strand of active genes. CS-A mice exhibit UV-sensitivity and pronounced age-dependent loss of retinal photoreceptor cells but otherwise fail to show the severe developmental and neurological abnormalities of the human syndrome. In contrast to human CS, Csa −/− animals develop skin tumors after chronic exposure to UV light, indicating that TCR in mice protects from UV-induced skin cancer development. Strikingly, inactivation of one Xpc allele (encoding a component of the damage recognition complex involved in the global genome repair sub-pathway) in Csa −/− mice resulted in a strongly enhanced UV-mediated skin cancer sensitivity, indicating that in a TC repair defective background, the Xpc gene product may be a rate-limiting factor in the removal of UV-induced DNA lesions.

Long-term results of kidney transplantation between HLA-identical siblings.

Long-term data on HLA-identical renal transplants are scarce, and the advantages of using cyclosporine (CsA) over azathioprine (AZA) have yet to be elucidated. In 68 recipients from HLA-identical donors (37 under AZA-steroids and 31 under CsA-steroids), we estimated the graft and patient survival to posttransplant 120 months, and compared the results between patients on different protocols. Episodes of rejection, causes of graft loss or patient death, and longterm complications were also compared retrospectively. The 10-year patient/graft survivals were comparable: 82.7/67.6% for the AZA and 78.4/63.5% for the CsA patients. The incidence of acute rejection during the first year after transplant was also comparable. We lost 25 grafts. The major causes of graft loss were patient death (7/13 in AZA and 5/12 in CsA patients) and chronic rejection (3/13 in AZA and 3/12 in CsA patients). Four grafts were lost due to poor compliance. We lost 12 patients due mostly to cerebrovascular disease and infections. There was no difference in the prevalence of complications between patients. In conclusion, the long-term outcome was excellent in this subgroup of transplant patients. We could not find any advantages of using CsA over AZA in these patients after a long-term follow-up. To achieve better results, continued attention should be paid to the prevention of poor compliance and complications.

Technical aspects and postoperative sequelae of spinal and epidural anesthesia: A prospective study of 3,230 orthopedic patients

Background and Objectives: Major complications after spinal or epidural anesthesia are extremely rare. The occurrence of less serious and transient sequelae and complaints may be underestimated if there is no established organization for the systematic and continuous surveillance of patients after anesthesia. This study was designed to evaluate the possible relationship between various block-related occurrences and the intra- and postoperative side effects and complaints. Methods: This prospective study included 3,230 orthopedic patients operated on under neuraxial block. The block was performed by single-dose (single-shot spinal anesthesia [SPIN], 80.6%), continuous spinal anesthesia (CSA, 10.3%), or combined spinal and epidural anesthesia (CSE, 9.1%) technique. The patient position during surgery and a detailed description of block performance and equipment, as well as all intraoperative problems, were immediately recorded. Every patient was given a standardized questionnaire to be completed and returned after 1 week. Results: The overall incidence of paresthesia was 12.8%, being most frequent during spinal catheter insertion with multiple attempts. Postoperative sensory disturbances (numbness, dysesthesia) occurred unrelated to paresthesia elicited by the puncture or catheterization. The failure rates (SPIN, 1.0%; CSA, 1.5%; and CSE, 1.0%) were quite low. Asystole with successful resuscitation, occurred in 1 patient with CSE but, overall, hemodynamic perturbations were more common with the continuous techniques. On the first postoperative day, decreased sensation of the skin was significantly more frequent after the continuous techniques, still present in 6.5% of SPIN patients, 6.1% of CSA patients, and 17.2% of CSE patients 1 week after surgery. These disturbances were also related to the use of a tourniquet and lateral position of the patient during surgery. The frequency of postdural puncture headache (PDPH) was similar for the different techniques (SPIN, 0.9%; CSA, 1.5%; and CSE, 1.7%). About one third of the patients reported strong postoperative pain on the day after the operation, and 5.6% continued to report this at 1 week. Conclusions: Although sensory changes were quite frequent, they were mild and transient. Rather than having been caused by the anesthetic technique, per se, a “nonanesthetic” reason (position, tourniquet, immobilization) should also be considered as their origin. Sensory disturbances, as well as strong pain for at least a week, were reported by several patients, and to become aware of these problems and improve the quality of treatment, a universal regional anesthesia follow-up system is recommended. Reg Anesth Pain Med 2000;25:488-497.

Liver transplantation for alcoholic cirrhosis.

Because of the donor shortage, there are concerns for liver transplantation in patients with alcoholic cirrhosis. We therefore analyzed patients transplanted for alcoholic cirrhosis at our center with respect to patient and graft survival, recurrence of disease, and postoperative complications. Out of 1000 liver transplantations performed in 911 patients, 167 patients were transplanted for alcoholic cirrhosis; 91 patients received CsA- and 76 patients FK506-based immunosuppression. Recurrence was diagnosed by patient's or relative's declaration, blood alcohol determination, and delirium. Diagnosis and treatment of acute and chronic rejection was performed as previously described. One- (96.8% versus 91.3%) and 9-year patient survival (83.3% versus 80%) compared well with other indications. Five of 15 patients died due to disease recurrence. Recurrence of disease was significantly related to the duration of alcohol abstinence prior to transplantation. In patients who were abstinent for less than 6 months (17.1%), recurrence rate was 65%, including four of the five patients who died of recurrence. Recurrence rate decreased to 11.8%, when abstinence time was 6-12 months and to 5.5%, when the abstinence times was > 2 years. Next to duration of abstinence, alcohol relapse was significantly related to sex, social environment, and psychological stability. The incidence of acute rejection compared well with other indications (38.1%); CsA: 40.1% versus 33.3% in FK506 patients. In all, 18.2% of CsA patients experienced steroid-resistant rejection compared with 2.6% of FK506 patients. Seven patients (7.6%) in the CsA group and one patient (1.3%) in the FK506 group developed chronic rejection. A total of 57.1% developed infections; 5.7% were life-threatening. CMV infections were observed in 14.3% (versus 25% for other indications). New onset of insulin-dependent diabetes was observed in 8.6% and hypertension in 32.4%. In conclusion, alcoholic cirrhosis is a good indication for liver transplantation with respect to graft and patient survival and development of postoperative complications. FK506 therapy was favourable to CsA treatment. Patient selection is a major issue and established criteria should be strictly adhered to. Patients with alcohol abstinence times shorter than 6 months should be excluded, since recurrence and death due to recurrence was markedly increased in this group of patients.

Endothelial dysfunction in renal transplant recipients maintained on cyclosporine

Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the L-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography. In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using L-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography. In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 micrograms/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to L-NMMA (4 mumol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (-39.5; -15.7 to -52.8; P = 0.056), and while controls vasoconstricted to the maximum dose of norepinephrine (240 pmol/min) as expected (-26.9; -1.4 to -38.6), CsA patients as a group tended to vasodilate (7.9; -36.8 to 92.6; P = 0.02). These data demonstrate impaired stimulated and basal NO production in CsA patients, indicating endothelial dysfunction. This may predispose patients to atherosclerosis and may be involved in the etiology of post-transplant hypertension.

Improved cyclosporine pharmacokinetics in maintenance renal transplant recipients converted to cyclosporine for microemulsion

Abstract Background: Variability in cyclosporine drug exposure of ≥ 20% has been shown to be a risk factor for the development of chronic renal allograft rejection. We tested the hypothesis that a cyclosporine microemulsion (CsA-ME) would result in reduced variability in stable maintenance renal transplant patients when compared with the original formulation of cyclosporine (CsA). Methods: The 31 maintenance renal transplant recipients were part of a multicenter, randomized, double-blind, prospective study comparing the CsA formulation with the CsA-ME formulation. Pharmacokinetics analyses were performed at two centers 1, 4, 12, and 52 weeks after patients were randomized to continue receiving CsA or to convert to CsA-ME. Results: The means of the week 1-, 4-, and 12-week areas under the concentration-time curves (AUC), and Cmax were significantly higher and the Tmax was significantly shorter in those patients converted to CsA-ME than in those remaining on CsA. There was no correlation between change in AUC after conversion and change in serum creatinine. The coefficient of variation values for dose-adjusted AUC, expressed as a percentage (%CVAUC), were lower in CsA-ME patients than CsA patients after both 12 and 52 weeks. Over the initial 12 weeks, %CVAUC values of ≤ 20% were seen in a significantly greater proportion of CsA-ME patients than CsA patients. Conclusions. Conversion of maintenance renal transplant recipients from CsA to CsA-ME resulted in improved absorption of cyclosporine. The CsA-ME formulation resulted in long-term reduction in the variability of cyclosporine exposure and more consistent pharmacokinetics.

Expression of LFA1 in biopsies of kidney recipients treated with an anti-LFA1 monoclonal antibody. Correlations with delayed graft function

354 Adhesion molecules (AM) are important intermediates in leukoendothelial interactions and it has been shown, in animal models of ischemia, that blocking AM responsible for strong leukocyte adhesion has a potential interest in the prevention of reperfusion injury. We have evaluated in human kidney transplantation the efficacy of Odulimomab (Pasteur Mérieux Imtix), an anti-LFA1 monoclonal antibody (Moab), administered as part of a quadruple sequential therapy, in the prophylaxis of acute rejection but our data also suggested that this Moab could have a protective effect of the transplant towards reperfusion injury. We have analyzed the expression of LFA1 in 9 systematic biopsies harvested between days 8 and 12 of a 10 day course of Odulimomab. They have been compared with biopsies from 5 patients under CsA triple therapy, harvested according to the same protocol. The magnitude of leukocyte infiltration in optic examination and the quantitative expression of LFA1 in immunohistology correlated with the presence of delayed graft function (DGF). In patients who required dialysis at the time of biopsy in the Odulimomab group, a moderate interstial infiltrate was present, that was not significantly decreased by comparison with CsA patients, who all had severe DGF. Furthermore, it was found that LFA1 sites on infiltrating leukocytes were not completely saturated, as the number of LFA1+ cells significantly (p<0.01) increased after the addition of exogeneous Odulimomab, by comparison with the number of cells coated in vivo with the therapeutic Moab. As, in other studies, we showed a complete saturation of LFA1 molecules on circulating lymphocytes and monocytes with the doses of Odulimomab used in the patients studied here, the assessment of the Moab biological efficacy on its blood monitoring only can be questioned. In Odulimomab treated patients having sustained transplant function, the biopsies were free of cellular infiltrate and leukocytes were saturated. These results suggest that DGF in patients treated with an anti-LFA1 Moab correlated with an incomplete blockade of intra-graft LFA1 molecules and bring further arguments for a role of LFA1 in reperfusion injury.

PREVALENCE OF CHRONIC ALLOGRAFT NEPHROPATHY AND ANALYSIS OF PREDICTIVE FACTORS: RESULTS OF 2-YEAR PROTOCOL BIOPSIES FROM A U.S. MULTICENTER STUDY.

15 This was a randomized, open label comparative study conducted at 19 centers in the U.S. Recipients of cadaveric kidney transplants were randomized to FK506 or CsA-based therapy. All patients also received antilymphocyte antibody induction, azathioprine and corticosteroids. Patients active in the trial at 2-years post-transplant were approached for a protocol biopsy. Biopsies were scored with the Banff Classification in a blinded fashion by one pathologist. The objectives of the protocol biopsy were to assess the prevalence of chronic rejection at 2-years post-transplant and to explore predictive factors of graft survival. Results: A total of 144 patients (41.3% of patients active at 2 years) had a protocol biopsy performed; 79 FK506 and 65 CsA. Demographic characteristics, serum creatinine levels and the incidence of acute rejection in the first year post-transplant were comparable between patients who did or did not have a protocol biopsy. Histologic evidence of acute rejection was low in both treatment groups; 8.9% in the FK506 group and 9.2% in the CsA group; all of the rejections were scored Grade I or II. Chronic allograft nephropathy (CAN) was prevalent in both groups; 49 (62.0%) FK506 patients and 47 (72.3%) CsA patients (p=0.155). There were no differences between treatments in the mean acute and chronic lesion scores and the mean lesion activity score. The proportion of patients who developed CAN was similar by patient age, race and sex, donor race and sex, the proportion of patients who experienced 1 ° nonfunction, cold ischemia time and number of HLA mismatches. CAN was found in 77.4% of patients who had acute rejection in the first year compared to 60.4% of patients who did not have rejection in the first year (p=0.045). This difference was most pronounced in CsA patients; 92.6% who experienced acute rejection in the first year developed CAN compared to 57.9% who did not have rejection. The occurrence of CAN was also significantly higher in patients who experienced nephrotoxicity (decreased renal function excluding rejection as a cause: p< 0.001) and CMV infection(p=0.038) in the first year. Conclusions: The rate of subclinical acute rejection was low at 2-years in both treatment groups suggesting that the FK506 and CsA dosing was therapeutically appropriate. Histologic evidence of CAN was prevalent but there were no apparent histopathologic differences between FK506 and CsA. While it is essential to reduce the occurrence and severity of acute rejection, these results also suggest that it is equally important to minimize episodes of drug nephrotoxicity and improve CMV prophylaxis to optimize longterm allograft survival.

TACROLIMUS USE IN KIDNEY-PANCREAS RECIPIENTS IS ASSOCIATED WITH LESS ACUTE RENAL DYSFUNCTION THAN CYCLOSPORINE

532 In many transplant programs tacrolimus (FK506) has replaced cyclosporine(CSA) for maintenance immunosuppression following kidney-pancreas transplantation. We reviewed all episodes of post-transplant acute renal dysfunction (ARD) in 89 combined kidney-pancreas transplant recipients from 1988-1996 to compare therapics. ARD was defined as a >20% increase in serum creatinine level from baseline. Demographics, transplant characteristics, diagnosis, management and outcome were assessed for each episode. There were 431 episodes ARD (4.8/patient); only 3% of patients had no ARD, 35% had 1-3 events, 44% had 4-7 events, and 18% had 8-12 events during an average follow-up of 1005 days. The median time post-transplant to ARD occurrence was 146 days (mean 521 days). There were no correlations with donor and recipient age, gender, and race when comparing patients with and without ARD. However, there were significantly more episodes of ARD in the 62 CSA patients compared to the 39 FK506 patients (4.7 vs. 3.2 events/patient, p<0.005); 12 patients received both therapies. There were no differences in either baseline serum creatinine (1.6 vs. 1.6 mg/dl), percent rise in serum creatinine (41% vs. 44%), and ARD creatinine (2.2 vs. 2.3 mg/dl) when comparing CSA and FK506 patients, respectively. There were 154 biopsies performed: the most common diagnoses were acute cellular rejection, CSA toxicity, and FK506 toxicity. 120 biopsies were in patients receiving CSA; the most common diagnoses were acute cellular rejection (49%) and CSA toxicity (23%). 34 biopsies were performed in FK506 patients with the most common diagnoses being FK506 toxicity (35%) and acute cellular rejection (29%). No differences in hospital admissions were observed when comparing CSA and FK506 patients (75% vs. 71%). In conclusion, FK506 use in kidney-pancreas transplant patients is associated with less ARD; the main cause of ARD in CSA-treated patients was acute cellular rejection while in FK506-treated patients ARD was most commonly related to nephrotoxicity.

Expression of LFA1 in biopsies of kidney recipients treated with an anti-LFA1 monoclonal antibody. Correlations with delayed graft function

354 Adhesion molecules (AM) are important intermediates in leukoendothelial interactions and it has been shown, in animal models of ischemia, that blocking AM responsible for strong leukocyte adhesion has a potential interest in the prevention of reperfusion injury. We have evaluated in human kidney transplantation the efficacy of Odulimomab (Pasteur Mérieux Imtix), an anti-LFA1 monoclonal antibody (Moab), administered as part of a quadruple sequential therapy, in the prophylaxis of acute rejection but our data also suggested that this Moab could have a protective effect of the transplant towards reperfusion injury. We have analyzed the expression of LFA1 in 9 systematic biopsies harvested between days 8 and 12 of a 10 day course of Odulimomab. They have been compared with biopsies from 5 patients under CsA triple therapy, harvested according to the same protocol. The magnitude of leukocyte infiltration in optic examination and the quantitative expression of LFA1 in immunohistology correlated with the presence of delayed graft function(DGF). In patients who required dialysis at the time of biopsy in the Odulimomab group, a moderate interstial infiltrate was present, that was not significantly decreased by comparison with CsA patients, who all had severe DGF. Furthermore, it was found that LFA1 sites on infiltrating leukocytes were not completely saturated, as the number of LFA1+ cells significantly(p<0.01) increased after the addition of exogeneous Odulimomab, by comparison with the number of cells coated in vivo with the therapeutic Moab. As, in other studies, we showed a complete saturation of LFA1 molecules on circulating lymphocytes and monocytes with the doses of Odulimomab used in the patients studied here, the assessement of the Moab biological efficacy on its blood monitoring only can be questioned. In Odulimomab treated patients having sustained transplant function, the biopsies were free of cellular infiltrate and leukocytes were saturated. These results suggest that DGF in patients treated with an anti-LFA1 Moab correlated with an incomplete blockade of intra-graft LFA1 molecules and bring further arguments for a role of LFA1 in reperfusion injury.

Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus.

We have evaluated the use of blood stem cell grafts for rapid hematopoietic recovery and tacrolimus (FK506) as GVHD prophylaxis to reduce early mortality after allogeneic transplantation. Eighty-five adults with advanced leukemia received high-dose thiotepa, busulfan, and cyclophosphamide as a preparative regimen in a prospective Phase II study. All donors were HLA-matched and related. Marrow (BMT) was used for 44 patients and filgrastim-mobilized blood stem cells (SCT) for 41 patients. GVHD prophylaxis consisted of cyclosporine (CsA) or FK506 with methotrexate (MTX) or methylprednisolone (MP). The median time to neutrophil recovery was earlier after SCT than after BMT (day 10 vs. 17, P<0.001), but this was due to the selective use of MTX only in the BMT patients. The risk of grades 2-4 GVHD was lower with FK506 than with CsA (16% vs. 45%, P=0.02) and was the same for SCT recipients as for BMT recipients (33% vs. 34%). Regimen-related toxicity was significantly lower after SCT than after BMT but did not differ between the FK506 and CsA patients. In comparison with those receiving the standard transplant (BMT with CsA and MTX), only the SCT recipients using FK506 and MP had a significantly higher survival at day 180 posttransplant (84% vs. 53%, P=0.014). In multivariate analyses, use of FK506 was associated with a lower risk of treatment-related mortality and a higher survival at day 180, while the diagnosis of acute lymphoblastic leukemia was associated with a higher risk of treatment-related mortality. These data suggest that the use of blood stem cell grafts and FK506 can reduce the early mortality after allogeneic transplantation for advanced leukemia.

A microemulsion of cyclosporine without intravenous cyclosporine in liver transplantation.

A microemulsion formulation of cyclosporine (CsA) has improved absorption compared with the original form. The purpose of this case control study was to assess the safety and efficacy of the microemulsion without intravenous CsA for induction immunosuppression in adult liver transplantation. Twenty-one consecutive patients receiving induction immunosuppression with the microemulsion 15 mg/kg/day were compared with 20 patients receiving intravenous CsA and the original oral form. Both groups received the same dose of methylprednisilone. Twenty of 21 patients receiving the microemulsion required no intravenous CsA to achieve target CsA levels. All patients receiving the original form received initial intravenous CsA. There was no difference in trough CsA levels between the two groups at 24 and 48 hours. The microemulsion group had 24 hr and 48 hr trough CsA levels of 227+/-15 and 520+/-300 ng/ml by monoclonal RIA while the intravenous CsA group had 24 and 48 hr trough levels of 293+/-18 and 405+/-91 ng/ml. CsA levels analyzed by HPLC were 20% lower than by RIA. The frequency of adverse events resulting in reduction of drug dosage was similar for the microemulsion and the original form: neurotoxicity (23 vs. 40%, P=.30); nephrotoxicity (25 vs. 45%, P=.32), and no patients required dialysis. There was no difference in septic complications. One patient required discontinuation of the microemulsion in an attempt to reverse severe neurotoxicity. A total of 75% of microemulsion patients were rejection free at 3 months while only 35% of CsA patients remained rejection free (P=0.02). These data suggest that the use of the microemulsion without intravenous CsA in liver transplantation is safe and efficacious, and may result in decreased episodes of acute rejection.

Loss of nocturnal blood pressure fall after liver transplantation during immunosuppressive therapy

Hypertension, which develops after organ transplantation during immunosuppression with cyclosporine (CSA), is often associated with a loss of nocturnal decrease in blood pressure. Few data correlate circadian blood pressure patterns before transplant with those observed at fixed time points after transplant, or address the role of alternate immunosuppressive agents such as FK506. FK506 is unrelated structurally to CSA and less often leads to hypertension early after transplant. The present study compared nocturnal blood pressure patterns in patients with end-stage liver disease (ESLD) before transplant to those of transplant recipients receiving either FK506 (0.15 mg/kg/day) plus prednisone or CSA (2 to 3 mg/kg/day) plus prednisone and azathioprine after orthotopic liver transplantation. Overnight ambulatory blood pressure profiles were studied in 13 pretransplant ESLD patients and in 34 patients (FK506: n = 13; CSA: n = 21) treated with different steroid doses (24 +/- 11 mg/day FK506; 34 +/- 3 mg/day CSA), according to protocol, 4 weeks (range, 2 to 7 weeks) after liver transplant. Mean blood pressure and heart rate values from awake and nocturnal 5-h time blocks were compared to 13 normotensive control subjects. Patients with ESLD were normotensive and maintained a normal nocturnal blood pressure fall (125 +/- 3/74 +/- 2 mm Hg awake; 109 +/- 3/60 +/- 2 mm Hg nocturnal). Awake ambulatory blood pressures were higher in CSA patients than in FK506 patients (148 +/- 3/95 +/- 2 v 128 +/- 3/78 +/- 2 mm Hg, respectively; P < .01), despite reduced glomerular filtration rates in both transplant groups. Both immunosuppressive regimens led to a loss of nocturnal blood pressure fall, as compared to ESLD patients or normotensive controls.(ABSTRACT TRUNCATED AT 250 WORDS)

THE EFFECT OF IMMUNOSUPPRESSIVE DRUGS ON QUALITY OF LIFE AFTER RENAL TRANSPLANTATION

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.

Causes of kidney allograft loss in a large pediatric population at a single center.

At our institution, 521 kidney transplants were performed in 429 children (mean age 8.7 +/- 5.6-years) between 1969 and 1991. Of these transplants, 408 were primary, 113 were retransplants, 347 were living related, 171 were cadaver, and 3 were living nonrelated. Immunosuppression consisted of prednisone, azathioprine, and Minnesota antilymphocyte globulin (non-CSA) in 339 patients, total lymphoid irradiation in 8, and, more recently, cyclosporine (CSA) in addition in 168 patients. Average follow-up was 8.8 +/- 6.0 years. Actuarial graft survival in the non-CSA versus CSA groups at 1 year was 77.0% versus 85.7%; at 5 years, 59.6% versus 71.9%. Of 136 non-CSA patients, causes of graft loss at 5 years included: chronic rejection in 55 (40.4%), acute rejection in 27 (19.9%), recurrent disease in 16 (11.8%), technical complications in 8 (5.9%), infectious complications in 4 (2.9%), other causes in 5 (3.7%), and death with a functioning graft in 21 (15.4%). Of 40 CSA patients, causes of graft loss at 5 years included: chronic rejection in 16 (40.0%), acute rejection in 8 (20.0%), recurrent disease in 6 (15.0%), technical complications in 3 (7.5%), other causes in 2 (5.0%), and death with a functioning graft in 5 (12.5%). The causes of graft loss did not significantly differ in the non-CSA and CSA groups. Chronic rejection was the most common cause of graft loss in both groups. Research focusing on chronic rejection is needed to improve graft outcome in pediatric kidney transplantation.

Temporary withdrawal of immunosuppression for life-threatening infections after liver transplantation.

Temporary withdrawal of immunosuppression for life-threatening infections after liver transplantation.

RENAL TRANSPLANT FUNCTION AFTER TEN YEARS OF CYCLOSPORINE

Although the nephrotoxic side effects of cyclosporine are well known, the impact of long-term CsA on renal transplant function is uncertain. We studied 5-10-year renal function in 347 CsA-treated patients, and in 64 randomly selected non-CsA-treated patients who had a minimum of 55 months of graft function. Non-CsA patients had a lower creatinine (Cr) level at one year than CsA patients (P = .001), with no change in renal function over time (P = .6). In CsA-treated patients there was also no suggestion of progressive renal damage, as evidenced by no change in Cr or 1/Cr. Simple linear regression models of 1/Cr vs. time for the first 10 years posttransplant were fit to the data for each patient. Analysis of the Y-intercept estimates from these regressions showed that age (P = .001), sex (P = .001), cyclosporine toxicity (P = .024), and initial cyclosporine dosage (P = .016) significantly affected the one-year serum Cr. Variables not affecting one-year Cr included donor source, early rejection episodes, late rejection episodes, ATN, diabetes, transplant number, HLA ABDR mismatch (for cadaver transplants), maximum PRA, and PRA at transplant. Analysis of the slope estimates from the regressions revealed that only age (P = .001) and late rejection episodes (P = .001) significantly affected the rate of change in 1/Cr over time. We conclude that, in long-term renal transplant patients, there is no evidence of progressive deterioration in renal function due to CsA nephrotoxicity.

THE IMPACT OF AZATHIOPRINE AND CYCLOSPORINE ON LONG-TERM FUNCTION IN KIDNEY TRANSPLANTATION

To assess the impact of cyclosporine on long-term kidney function in transplant patients, we retrospectively analyzed 273 patients on azathioprine and 308 on CsA with graft functioning at 1 year. To balance the length of follow-ups, the observation of patients was cut at 5 years. Actual graft survival rate at 5 years was similar in Aza and CsA (88% vs. 90%). Multivariate analysis in Aza pts showed that proteinuria (P = 0.006) and hypertension at 1 year (P = 0.002) increased the probability of irreversible graft failure by 2.47 and 2.85, respectively. In CsA patients, proteinuria (P = 0.007) and plasma creatinine higher than 2.5 mg/dl (P = 0.006) increased the probability of graft failure by 5.12 and 6.48, respectively. In both Aza and CsA patients with a follow-up of at least 5 years, plasma creatinine levels were significantly worse at 5 years vs. 1 year (P = 0.004). The slopes of plasma creatinine values plotted vs time were not different between the two groups. Chronic graft dysfunction (CGD) was defined as a stable increase of plasma creatinine of at least 50% above stable values at 1 year. The probability of remaining without CGD at 5 years was 75% for CsA and 80% for Aza patients (P = N.S.). Multivariate analysis of factors influencing the development of CGD showed that hypertension (P = 0.003) and proteinuria at 1 year (P = 0.081) increased the probability of developing CGD by 2.19 and 1.76, respectively, in Aza, while in CsA patients proteinuria only (P = 0.063) increased the probability of developing CGD by 2.29. Graft survival at 5 years after development of CGD was 34% in Aza and 53% in CsA-treated patients. These data confirm that in the long-term CsA does not cause a higher prevalence of CGD and show that, in the presence of CGD, CsA has a superior protective effect than Aza.