Association of gastrointestinal events with quality of life and treatment satisfaction in osteoporosis patients: results from the Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC OS).

The purpose of this study was to assess the association of GI events with HRQoL and treatment satisfaction. The effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D, OPAQ-SV, and treatment satisfaction scores among patients with vs without baseline GI events. The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis. INTRODUCTION: The goal of this study was to assess the association of gastrointestinal (GI) events with health-related quality of life (HRQoL) and treatment satisfaction in patients being treated for osteoporosis. METHODS: MUSIC OS was a multinational, prospective, observational study examining the impact of GI events on osteoporosis management in postmenopausal women. In this analysis, HRQoL and treatment satisfaction were assessed at baseline, 6, and 12 months and compared between patients with and without GI events. Covariate-adjusted scores were calculated using multivariate least-squares regression analysis, and differences between the mean scores of patients with and without baseline and post-baseline GI events were determined. RESULTS: Among the 2959 patients in the analysis, unadjusted scores at each time point were lower (i.e., worse) for patients with GI events than patients without GI events. In adjusted analyses, the effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D and OPAQ-SV scores at 12 months among patients with vs without baseline GI events (-0.04 for the EQ-5D utility score, -5.07 for the EQ-5D visual analog scale, -3.35 for OPAQ physical function, -4.60 for OPAQ emotional status, and -8.50 for OPAQ back pain; P ≤ 0.001 for all values). Decrements in month 12 treatment satisfaction scores were -6.46 for patients with baseline GI events and -7.88 for patients with post-baseline GI events. CONCLUSIONS: The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis.

Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset.

Type I diabetes may be an autoimmune disorder, although the evidence is largely circumstantial. The natural history of the disease after diagnosis includes partial remission in most patients, but only about 3 percent achieve transient insulin independence. beta Cell function, as indicated by the plasma concentration of C-peptide, is lost over 6 to 30 months and islet cell antibodies disappeared over 1 to 2 years. This article describes a pilot study in which 41 patients were treated with the immunosuppressive agent cyclosporine for 2 to 12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8 to 44 weeks after diagnosis, two achieved this state. These results indicate that a controlled trial of the effects of cyclosporine in type I diabetes should be conducted.

Two-hour post-dose cyclosporine levels in renal transplantation in Argentina: a cost-effective strategy for reducing acute rejection.

UNLABELLED: Monitoring of cyclosporine (microemulsion CsA) at 2 hours post-dose (C2), a measure of absorption and exposure, appears superior to trough (C0) monitoring for prediction of rejection risk. The purpose of this study was to determine whether C2 was cost-effective compared to C0 in Argentina. METHODS: A predictive decision model was adapted to Argentina to predict costs associated with C0 and C2 measurements in the first year after transplantation. Patients were treated with microemulsion CsA, steroids and azathioprine or MMF. Parameter estimates for the C0 strategy were based on event rates observed in published clinical trials. The model was adapted to Argentinean health system through local protocols and expert opinions; costs were valued in Argentinean pesos and converted to US dollars (1 USD = 2.85 ARS). RESULTS: Incidence of acute rejection was predicted to be 25.0% at 1-year among patients monitored by C0 and 18.0% by C2. Graft survival was predicted to be 1.4% lower in the C0 group. No important differences were identified in co-morbidity, C0 and C2 monitoring costs, and in ambulatory-based adverse events between C0 and C2 cohorts. The model predicted an average cost per patient of $16,269 for C0 and $16,343 for C2 testing (year 1). Sensitivity analyses indicated that the average daily dose of microemulsion CsA was the most important parameter leading to the incremental cost per patient. CONCLUSIONS: C2 is expected to provide a potentially important reduction in the risk of acute rejection without increasing the estimated cost of care in the first year post-transplant.

Primary acute renal failure ("acute tubular necrosis") in the transplanted kidney: morphology and pathogenesis.

"Acute tubular necrosis" (ATN) in the transplanted kidney, when properly differentiated from other causes of acute renal failure, appears to be a relatively benign condition. It has been widely assumed to be pathologically identical to ATN in the native kidney, but its histopathologic features have not been studied in detail. Because immunosuppressive therapy with cyclosporine adds an additional layer of complexity to the morphologic changes observed, in the present study we have confined our observations to patients immunosuppressed with steroids and azathioprine. Thirteen renal allograft biopsies from patients with ATN and 5 biopsies from patients with normal allograft function were compared with the previously obtained series of 57 native kidney ATN biopsies and 20 control biopsies. Both qualitative and quantitative differences between transplant and native kidney ATN were found. Compared with native kidney ATN, transplant ATN showed significantly less thinning and absence of proximal tubular brush border and less variation in size and shape of cells in individual tubular cross-sections. There were also significantly fewer casts and less dilatation of Bowman's space and a significantly greater number of polarizable crystals presumed to be oxalate in transplant ATN. In native kidney ATN the tubular injury sites were mostly characterized by desquamation of individual epithelial cells leaving areas of bare basement membrane (the "non-replacement" phenomenon). In transplant ATN, sites of tubular injury, although rare and affecting only short tubular segments, were characterized by the actual presence of identifiable necrotic tubular cells, a finding seldom seen in native kidney ATN. There also was a greater interstitial infiltrate of mononuclear inflammatory cells in transplant ATN compared to native kidney ATN. Electron microscopic studies of 9 transplant ATN biopsies showed a mild reduction in proximal tubular brush border compared with controls but this alteration was significantly less than that observed in native kidney ATN. There was no significant alteration in proximal or distal basolateral infoldings and this contrasted sharply with the marked reduction in basolateral infoldings of the plasma membrane observed in native kidney ATN. Disintegrated necrotic cells were found by electron microscopy in transplant ATN whereas these were not observed in native kidney ATN. There were significantly more cells with apoptosis (shrinkage necrosis) in transplant ATN than in native kidney ATN. There were significantly more cells with apoptosis (shrinkage necrosis) in transplant ATN than in native kidney ATN. On the other hand, there were significantly greater numbers of "non-replacement" sites in the distal tubules in native kidney ATN compared to transplant ATN.(ABSTRACT TRUNCATED AT 400 WORDS)

Detection and quantification of cyclosporine in body fluids using an interleukin-2 reporter-gene assay.

Different assays are employed to monitor the concentration of immunosuppressive drugs in biological fluids. None of these methods gives direct and precise information on the actual level of immunosuppression in the patient. Here we describe the use of an interleukin-2 (IL-2) reporter-gene assay (IL-2 RGA) to monitor the concentrations of immunosuppressants in body fluids. This assay is based on a chimeric gene construct in which the human IL-2 promoter drives the expression of a reporter gene. Upon mitogenic stimulation the reporter gene is expressed and can be easily quantified. The assay is very sensitive and selective for immunosuppressive compounds inhibiting IL-2 gene expression such as cyclosporine (CsA) and FK506, their active metabolites and derivatives, but not for others such as rapamycin. High reproducibility, fast performance time, and high capacity are additional characteristics of the assay. The assay was developed to monitor immunosuppressive drug levels in human volunteers or in animals receiving CsA analogues as the only immunosuppressive drugs. This assay is sensitive to CsA or ascomycin/FK506 analogues and metabolites, for which there are presently no specific monoclonal antibodies available. The IL-2 reporter-gene assay may be more suitable than other in vitro systems such as MLR or mitogen stimulated PBMC which were previously used to study the immunosuppressive activity of drugs in body fluids.

The cost impact of cytomegalovirus disease in renal transplant recipients.

A retrospective case controlled study was performed to determine the cost impact of cytomegalovirus disease in the first year following renal transplantation as a basis for the analysis of cost effectiveness of prophylactic and therapeutic regimens directed at CMV infection. Eleven sequential cases of organ-specific CMV disease were matched with 22 controls for age, diabetic status, and donor/recipient CMV serologic status from 119 consecutive first cadaveric renal transplant recipients performed at a single university-affiliated, solid organ transplant unit between January 1, 1988 and March 31, 1990. The groups were comparable for sex, HLA match and mismatch, incidence of initial graft dysfunction, and immunosuppression. Hospitalization data, resource utilization, and costs for all 33 subjects were obtained for a one-year period after transplantation. The mean initial hospitalization time was comparable for both CMV cases and controls (14.5 vs. 15.0 days, P = NS), but patients developing CMV disease averaged 59 hospital days during the first year posttransplant versus 22 days in the control group (P = 0.001). A mean of 31 days hospitalization was directly related to CMV disease. Mean total institutional costs, calculated in 1988 Canadian dollars, were 2.5 times higher for patients with CMV disease than for controls ($42,611 vs. $17,309, P = 0.001), reflecting predominantly a difference in general ward ($19,988 vs. $7484, P = 0.001), hotel ($2508 vs. $927, P = 0.001), clinical laboratory ($5420 vs. $2558, P = 0.0001), radiology ($1581 vs. $640, P = 0.05), and pharmacy ($4916 vs. $1782, P = 0.01) costs and utilization. Operating room, special ward, ancillary, and mean per diem costs ($719 vs. $790, P = NS) were not significantly different between the two groups. Functional graft survival at 1 year was 72% in patients with CMV disease compared with 86% in controls, reducing the mean calculated cost-effectiveness of transplantation by 2.9-fold. These data show that CMV disease has significant economic impact on renal transplantation as a result of extended hospitalization. In order to develop a cost effective management approach to CMV infection, this impact must be considered when assessing therapeutic and prophylactic regimens and protocols of organ allocation.

Economic analysis of basiliximab in renal transplantation.

BACKGROUND: Basiliximab is a chimeric monoclonal directed against the alpha-chain of the interleukin-2 receptor. International studies have shown that it is highly effective in preventing acute rejection in patients receiving Neoral, and causes no measurable incremental toxicity, but its economic value remains unknown. METHODS: This study employed an economic model to examine the potential economic benefit of basiliximab. Parameter estimates were derived from a randomized, prospective, double-blind study conducted in 21 renal transplant centers in seven countries in which 380 adult primary allograft recipients were randomized within center to receive basiliximab (20 mg i.v.) on days 0 and 4 or placebo in addition to dual immunosuppression with Neoral and steroids. Key clinical events included primary hospitalization, immunosuppressive drug use, patient and graft survival, graft rejection, treatment of rejection, dialysis, and repeat hospitalization. Health resources were valued via a comprehensive electronic cost dictionary, based upon a detailed economic evaluation of renal transplantation in Canada. Medication costs were calculated from hospital pharmacy acquisition costs; basiliximab was assessed a zero cost. RESULTS: The average estimated cost per patient for the first year after transplant was $55,393 (Canadian dollars) for placebo and $50,839 for basiliximab, rising to $141,690 and $130,592, respectively, after 5 years. A principal component of the cost in both groups was accrued during the initial transplant hospitalization ($14,663 for standard therapy and $14,099 for basiliximab). An additional $15,852 and $14,130 was attributable to continued care, graft loss, and dialysis in the two groups, whereas follow-up hospitalization consumed an additional $15,538 for placebo and $13,916 for basiliximab. The mean incremental cost of dialysis was $5,397 for placebo compared with $3,821 for basiliximab, whereas incremental costs of graft loss were $2,548 compared with $2,295 in the two treatment groups. The principal costs associated with repeat admission to the transplant ward and the general ward were marginally higher for placebo ($7,395 vs. $6,300 and $5,986 vs. $4,625). Treatment of acute rejection and maintenance immunosuppressive drug use were associated with only limited savings as a result of basiliximab (savings <$200 each). Sensitivity analysis indicated that the most influential parameters affecting the savings as a result of using basiliximab were a reduction in the duration of initial and repeat hospitalization followed by the reduced risks of acute rejection and graft loss. CONCLUSIONS: Before accounting for the cost of the therapy itself, basiliximab produces an estimated economic saving of $4,554 during the first year after transplant, of which $3,344 is attributable to the reduced costs of graft dysfunction, including graft loss and dialysis ($1,722) and follow-up hospitalizations ($1,622). When marketed, basiliximab is expected to cost approximately $3,000 per course (two doses of 20 mg), resulting in a net first-year saving of $1,554. Under these circumstances, basiliximab can be considered a dominant therapy in renal transplantation.

Inhibition of human in vivo cytotoxic T lymphocyte generation by cyclosporine following organ transplantation.

The effect of cyclosporine (CsA) on the in vivo cell-mediated immune response to donor antigens was examined sequentially following cadaveric renal transplantation in both immunologically naive and specifically sensitized allograft recipients. Cytotoxic T lymphocytes (CTL) exhibiting preferential specificity for donor antigens were detected in the peripheral blood of all patients receiving azathioprine (AZA) immunosuppression by two weeks posttransplant, disappearing progressively over the first three months with clinical quiescence. In contrast, the generation of donor-reactive CTL was significantly diminished in incidence (P = 0.05) and in magnitude (P = 0.004) in subjects receiving CsA. CTL were detected in only 36% of patients by two weeks posttransplant, and were not detectable in any CsA-treated patient after the sixth posttransplant week. The ability of CsA to inhibit clonal reexpansion of CTL was examined both in vitro and in vivo in subjects exhibiting prior sensitization to donor antigens. In vitro, CsA caused a dose-dependent inhibition of accelerated (72-hr MLC) CTL generation following restimulation with donor spleen cells, which was quantitatively identical to that in parallel cultures using responder PBL from non-sensitized individuals. In vivo, CsA produced a rapid disappearance of circulating CTL posttransplant in patients who exhibited specific cell-mediated sensitization to the graft donor, as evidenced by the presence of circulating donor-reactive CTL prior to transplantation. In contrast, in patients receiving AZA there was a rapid increase in donor-reactive CTL in the peripheral blood following transplantation. CTL persisted for six weeks or longer, and two of four patients lost the graft to irreversible acute rejection within the first four weeks.

Evidence for earlier stabilization of cyclosporine pharmacokinetics in de novo renal transplant patients receiving a microemulsion formulation.

Sequential cyclosporine pharmacokinetic assessments were performed at four centres within the context of a double-blind, multicenter clinical trial comparing the safety and tolerability of the conventional formulation with cyclosporine for microemulsion in de novo renal transplant patients. The initial average daily oral dose was 9.3 mg/kg given in two divided doses every 12 hr with subsequent dose reductions individually titrated to maintain trough concentrations within the target therapeutic range. Pharmacokinetic profiles were assessed at week 2, once between weeks 4-6, and at week 12 in 12 patients on the conventional formulation and 9 patients on the microemulsion. Over the study duration, cyclosporine daily doses were comparable in both study arms and were reduced in parallel from 9.2 to 6.9 to 4.7 mg/kg/day at the three successive pharmacokinetic visits. Dose-normalized peak and area-under-the-curve (AUC) increased between the week 2 and week 4-6 assessments for both formulations. Thereafter, these parameters continued to increase for the conventional formulation but exhibited a high degree of within-in patient stability for the microemulsion between week 4-6 and week 12. Between-formulation comparisons indicated that the rate and extent of cyclosporine absorption from the microemulsion were significantly higher over the study duration. Specifically, at week 2, 4-6 and 12, dose-normalized AUC was 49%, 63%, and 32% higher for the microemulsion. Intrasubject coefficients of variability for pharmacokinetic parameters of the conventional formulation ranged from 26.3% to 68.2%. Corresponding values for the microemulsion were reduced by approximately half, ranging from 13.1% to 38.7%. The correlation between predose trough concentration and AUC was stronger for the microemulsion (r(2)0.819 vs. 0.635) over the full range of systemic exposures attained throughout the study. These results provide initial evidence that, as doses are reduced with time posttransplant, the cyclosporine dose-exposure relationship from the microemulsion may stabilize earlier than that from the conventional formulation, allowing increased pharmacokinetic control over cyclosporine use in this critical posttransplant period.

Investigation of a possible interaction between ciprofloxacin and cyclosporine in renal transplant patients.

BACKGROUND: Bacterial infection is a common complication during the first few months after renal transplantation. Ciprofloxacin, a fluoroquinolone broad-spectrum antibiotic, is used frequently in treating infections in the early posttransplant period. Evidence from in vitro studies has suggested that ciprofloxacin can antagonize the cyclosporine (CsA)-dependent inhibition of interleukin-2 production. Such an effect in renal transplant patients could antagonize the immunosuppressive activity of CsA and lead to rejection of the graft. METHODS: To investigate the possibility of a pharmacodynamic interaction between ciprofloxacin and CsA, we conducted a case-control study in 42 patients who had received a kidney transplant and who were prescribed ciprofloxacin in the first 1-6 months after transplantation and in their matched controls (two per case) who did not receive ciprofloxacin during the study period. RESULTS: There was a twofold greater incidence (P=0.008) of ciprofloxacin use at 1-3 months (65%) than was observed at 4-7 months (35%) after transplantation. The proportion of cases experiencing at least one episode of biopsy-proven rejection 1-3 months posttransplant (45%) was significantly greater (P=0.004) than that of controls (19%). Furthermore, there was a marked increase (P<0.001) in the incidence of rejection temporally associated with ciprofloxacin use among cases (29%) compared with that experienced by the controls (2%). CONCLUSIONS: The possibility that ciprofloxacin increases rejection rates in renal transplant patients may be of clinical importance and therefore warrants further investigation.

Circulating lymphocyte subpopulations in experimental allergic neuritis.

T-cell subsets in the peripheral blood were analyzed using monoclonal antibodies during the development of experimental allergic neuritis in Lewis rats. Percentages of helper and suppressor cells and ratios of helper/suppressor cells did not exceed normal limits during the development of the disease.

The quality of initial function following renal transplantation determined by creatinine elimination kinetics. Comparison of Minnesota antilymphocyte globulin and cyclosporine induction immunosuppression.

To compare the effect of type of induction immunosuppression on the quality of initial renal allograft function, we identified 35 cadaver donor kidney pairs in which one recipient of a kidney from a given pair received induction immunosuppression with Minnesota antilymphocyte globulin (MALG group) while the recipient of the contra-lateral kidney received cyclosporine from day zero (CsA group). In the absence of an existing quantitative measure to assess and compare the status of those grafts that function primarily, we defined the half-life of creatinine elimination (t1/2SCr) as such an outcome measure based on a review of creatinine elimination kinetics. All organs were procured with in-situ perfusion and en-bloc removal. Total cold storage times, rewarm times, and perioperative management were comparable for the two groups. In the MALG group, the mean t1/2SCr) was not different from that in the CsA group (1.38 +/- 0.96 days vs 1.35 +/- 1.2 days P = NS). Multiple regression analysis performed on the differences in recipient age, number of DR-B locus matches, total cold ischemia time, rewarm time, and central venous pressure at reperfusion of a given donor pair demonstrated no significant impact of any of these differences on the difference in t1/2SCr for the same pair set in this sample. The nadir of serum creatinine achieved in the first five days posttransplant was somewhat higher in the CsA group (234 +/- 131 mumol/L) as compared with the MALG group (200 +/- 132 mumol/L) but the difference was not significant. A similar nonsignificant trend was observed in the comparison of mean serum creatinine values at 30 days posttransplant (MALG group: 158 +/- 62 mumol/L vs. CsA group: 200 +/- 141 mumol/L). Only one of seventy recipients (CsA group) was dialyzed within the first 5 days posttransplant for an overall incidence of ATN of less than 2%. Fourteen of 35 (40%) recipients in both groups received treatment for acute rejection. The mean time to first treatment for acute rejection episode was shorter in the CsA group than the MALG group (10 +/- 8 days vs 23 +/- 24 days, P = 0.055). Graft survival at one year was not different for the two groups (92% vs. 87% for the MALG and CsA groups respectively, P = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

The relationship of ischemia-reperfusion injury of transplanted lung and the up-regulation of major histocompatibility complex II on host peripheral lymphocytes.

OBJECTIVES: This study was designed to examine the relationship between ex vivo preservation time of the transplanted lung and the extent of injury and to relate this to the severity of rejection with and without allogenicity. METHODS: Single lung transplantation was performed on two groups of domestic swine. Group A (n = 7) and group B (n = 6) had ex vivo preservation times of 4 and 15 hours, respectively, at 4 degrees C hypothermia. Group C (n = 6) underwent 2 hours of warm ischemia via dissection and isolation of the left lung with ligation of its bronchial artery and crossclamping of the left pulmonary artery, vein, and bronchus without explantation. Assessment measures included lung function, antioxidant enzyme activities in the plasma and lung tissue, levels of inflammatory mediators in the recipient plasma, and quantification of major histocompatibility complex II HLA-DR-beta on host peripheral lymphocytes. RESULTS: All groups demonstrated increases in interleukin-10, lung weight, and HLA-DR-1beta expression and decreases in lung-tissue antioxidant enzyme activities, gas exchange, and lung compliance. There was a strong positive correlation between ex vivo preservation time and the expression of HLA-DR-beta and a negative correlation between ischemic time and lung-tissue superoxide dismutase. CONCLUSIONS: These results suggest that the intensity of the host immunogenic response is related to the severity of ischemia-reperfusion injury and is independent of tissue incompatibility and/or the type of ischemic insult. We conclude that the extension of ex vivo preservation time may predispose the transplanted lung to more severe rejection.

Successful paternity of twins following bone marrow transplantation with busulfan, melphalan and cyclophosphamide conditioning.

A 33-year-old man who had received previous chemotherapy with cytarabine, daunorubicin and mitoxantrone followed by an autologous marrow transplant after conditioning with busulfan, melphalan and cyclophosphamide, fathered sex-mismatched fraternal twins approximately 6 years post-transplant. HLA and DNA analyses showed the probability of paternity to be in excess of 99% for each twin. To our knowledge this represents the first documented case of paternity following conditioning with this combination of marrow ablative agents and the first report of twin paternity following autologous marrow transplantation.

Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation.

Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than adults, with an AUC of 861+/-805 vs 2629+/-1487 micromg x h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59+/-0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077+/-1551 microg x h/l compared to 1795+/-973 microg x h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These data suggest that 12 h postdose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT.

An introduction to utility measurement in health care.

Key decisions regarding the introduction and optimal use of health technologies often are made on an ad hoc basis. Quantitative information on effectiveness, if incorporated into the decision-making process, would establish a reasoned and defensible basis for the introduction and optimal use of therapeutic technologies. Utility measures provide a single summary score of effectiveness which, when combined with cost information, permits the calculation of cost-utility ratios for alternative technologies. A number of techniques have been developed to elicit utilities, including standard gamble, time trade-off, rating scales, the Quality of Well-Being Scale, and the Health Utility Index. No single method has been accepted yet as the gold standard. Selection therefore must be guided by the specific objectives of the assessment.

Cyclosporine: action, pharmacokinetics, and effect in the BB rat model.

Cyclosporine (Cy) was given to BB rats in an attempt to prevent the onset of diabetes. A dose of 15 to 20 mg/kg/d given orally or subcutaneously was associated with high Cy trough serum levels and caused nephrotoxicity and severe weight loss. Ten mg/kg/d of Cy was tolerated well. Forty rats were treated with Cy starting at 34 days of age. No Cy-treated rats developed diabetes by day 121, compared with 70% of the control rats. Once Cy was discontinued on day 121, 38% of female and 13% of male rats developed diabetes by day 169. Transient, spontaneously remitting hyperglycemia developed in nine rats. This occurred both in control rats and in rats on Cy, but it was more common in females than in males. Thus, Cy prevents diabetes mellitus in the BB rat when trough Cy serum levels greater than 100 ng/mL are achieved. Diabetes occurs in some rats after Cy is discontinued. In all treatment subgroups, diabetes occurred more frequently in females than in males.

Dialysis or transplant: an integrated approach to end-stage kidney disease management.

Technological and immunological developments within the last decade have evolved a variety of therapeutic modalities by which ESRD may be satisfactorily managed. With the exception of renal transplantation between identical twins, none of these modalities provide permanent and complete correction of the uremic state, however, and the challenge now facing those involved in the management of irreversible renal failure is to devise an individualized treatment program permitting optimal long-term physical and psychological well-being and the maintenance of a valuable and productive role in society. Such a goal is most effectively achieved by an integrated approach combining both dialysis and renal transplantation. In the program proposed and utilized at our institution, all therapeutic options are presented to the patient with incipient renal failure, and a rational long-term management strategy devised based on clinical status, psychological stability, convenience, and acceptability. Dialysis is normally employed as a limited term maintenance procedure pending renal transplantation from a living or cadaver donor, thus permitting optimal correction of the uremic state. Early rehabilitation and social reintegration are actively pursued to minimize disease impact and maximize quality of life. In subjects with chronic deterioration of graft function, retransplantation may be performed prior to requirement for dialysis, thus minimizing hospitalization time, cost, and social disruption. The definition of risk factors predicting graft success has facilitated the individualization of therapy within this integrated program. While allograft survival exceeding 90% may now be anticipated in the non-sensitized first-graft recipient, predicted outcome is poor in subjects who are highly sensitized following previous transplantation or with rapid loss of a prior graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of a biologically distinct EBV-related lymphoproliferative disorder following autologous bone marrow transplantation for an EBV-negative post-renal allograft Burkitt's lymphoma.

Post-transplant lymphoproliferative disorder (PTLD) is a known complication of both solid organ transplantation and allogeneic bone marrow transplantation (BMT) but is rarely seen following autologous BMT. We report the case of a 45 year-old female who developed Burkitt's lymphoma eight years after a renal allograft. This PTLD was found to have lambda light chain restriction, contained del(8)(q24) and add(14)(q32), and was negative for EBV on immunohistochemical and DNA-based PCR analyses. Immunoglobulin heavy chain (IgH) PCR studies revealed a prominent clonal rearrangement. She responded to intravenous cyclophosphamide and proceeded to high-dose chemoradiotherapy and mafosfamide-purged autologous BMT. Thirty-nine days post-BMT she presented with cough and fever and developed hepatic dysfunction; abnormal lymphoplasmacytoid cells were noted in the peripheral blood. Investigations revealed kappa light chain restriction, an oligoclonal IgH rearrangement, a normal karyotype and PCR studies for EBV were positive, consistent with a clinically and biologically distinct PTLD. She initially improved following discontinuation of immunosuppression, but then deteriorated abruptly and died 58 days post-BMT. It is likely that the two separate episodes of PTLD in this patient, one of which was atypical, arose as a result of both the chronic use of cyclosporine and the impairment of cell-mediated immunity associated with autologous BMT. The sequence of events in this patient should contribute to a better understanding of late-onset, EBV-negative PTLD.

Quality assessment of cyclosporine monitoring by 32 Canadian laboratories.

The Canadian Quality Assurance Program was initiated in June 1989, and is a voluntary program which currently encompasses all 32 laboratories involved in the measurement of cyclosporine (CsA) across Canada. Two whole blood samples from control or clinical patients (kidney, liver and heart) containing unknown concentrations of CsA are circulated to each participating laboratory monthly, and analyzed by all techniques employed within that laboratory. Four analytical methods are currently employed: HPLC (n = 4). Sandimmun SP (n = 3), CycloTrac SP (n = 27) and TDx (n = 3). Four laboratories reported survey results in more than one methodology. Results from all participating centers are analyzed monthly. The mean, SD, standard deviation index and range are reported to each laboratory with information coded to preserve confidentiality. Accuracy, precision, recovery, analytical specificity, linearity and blank studies have been performed. This report covers the period from June 1989 to April 1990.