High-Sensitivity Cardiac Troponin for Risk Assessment in Patients With Chronic Coronary Artery Disease.

BACKGROUND: Cardiac troponin is used for risk stratification of patients with acute coronary syndromes; however, the role of testing in other settings remains unclear. OBJECTIVES: The aim of this study was to evaluate whether cardiac troponin testing could enhance risk stratification in patients with chronic coronary artery disease independent of disease severity and conventional risk measures. METHODS: In a prospective cohort of consecutive patients with symptoms suggestive of stable angina attending for outpatient coronary angiography, high-sensitivity cardiac troponin I was measured before angiography, and clinicians were blinded to the results. The primary outcome was myocardial infarction or cardiovascular death during follow-up. RESULTS: In 4,240 patients (age 66 years [IQR: 59-73 years], 33% female), coronary artery disease was identified in 3,888 (92%) who had 255 (6%) primary outcome events during a median follow-up of 2.4 years (IQR: 1.3-3.6 years). In patients with coronary artery disease, troponin concentrations were 2-fold higher in those with an event compared with those without (6.7 ng/L [IQR: 3.2-14.2 ng/L] vs 3.3 ng/L [IQR: 1.7-6.6 ng/L]; P < 0.001). Troponin concentrations were associated with the primary outcome after adjusting for cardiovascular risk factors and coronary artery disease severity (adjusted HR: 2.3; 95% CI: 1.7-3.0, log10 troponin; P < 0.001). A troponin concentration >10 ng/L identified patients with a 50% increase in the risk of myocardial infarction or cardiovascular death. CONCLUSIONS: In patients with chronic coronary artery disease, cardiac troponin predicts risk of myocardial infarction or cardiovascular death independent of cardiovascular risk factors and disease severity. Further studies are required to evaluate whether routine testing could inform the selection of high-risk patients for treatment intensification. (Myocardial Injury in Patients Referred for Coronary Angiography [MICA]; ISRCTN15620297).

Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study.

BACKGROUND: Hyperglycemia alters the inflammatory response to infection and ischemia. We hypothesize that perioperative glycemic control could also influence the risk for allograft rejection. METHODS: Consecutive patients with established diabetes undergoing their first cadaveric renal transplantation and receiving steroid-sparing immunosuppression were identified (n=50). Records of capillary glucose observations over the first 100 hr following surgery and transplantation variables pertaining to graft function, acute rejection, and postoperative infection were identified and entered into multivariate analysis. RESULTS: Perioperative glycemic control was associated with an increased incidence of infection and acute rejection. Only 3 of 27 patients (11%) with optimal glycemic control during the 100 hr following surgery (mean<11.2 mmol/L) had rejection episodes compared with 58% of patients with poor control (>11.2 mmol/L). All patients with poor glycemic control experienced postoperative infection. CONCLUSIONS: This pilot study suggests that hyperglycemia may be associated with an increased risk of both allograft rejection and postoperative infection in patients with diabetes.

Four cases of CMV ureteritis: emergence of a new pattern of disease?

Although cytomegalovirus (CMV) infection is common in renal transplant recipients, urinary tract involvement has been rare. Only six cases of symptomatic ureteritis have been reported in renal transplant recipients and all within the last five years. We describe an additional four cases of CMV ureteritis. The presentation of CMV ureteritis is obstructive nephropathy often in the absence of systemic illness. Presentation may also mimic allograft rejection with minimal obstructive symptoms. We hypothesize that CMV ureteritis is an emerging complication of CMV disease, possibly due to changes in transplant practice.

Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes.

BACKGROUND: Patients with diabetes have an increased risk for allograft rejection, possibly related to peri-operative hyperglycaemia. Hyperglycaemia is also common following transplantation in patients without diabetes. We hypothesise that exposure of allograft tissue to hyperglycaemia could influence the risk for rejection in any patient with high sugars. To investigate the relationship of peri-operative glucose control to acute rejection in renal transplant patients without diabetes, all patients receiving their first cadaveric graft in a single center were surveyed and patients without diabetes receiving cyclosporin-based immunosuppression were reviewed (n = 230). Records of the plasma blood glucose concentration following surgery and transplant variables pertaining to allograft rejection were obtained. All variables suggestive of association were entered into multivariate logistic regression analysis, their significance analysed and modeled. RESULTS: Hyperglycaemia (>8.0 mmol/L) occurs in over 73% of non-diabetic patients following surgery. Glycaemic control immediately following renal transplantation independently predicted acute rejection (Odds ratio=1.08). 42% of patients with a glucose < 8.0 mmol/L following surgery developed rejection compared to 71% of patients who had a serum glucose above this level. Hyperglycaemia was not associated with any delay of graft function. CONCLUSION: Hyperglycaemia is associated with an increased risk for allograft rejection. This is consistent with similar findings in patients with diabetes. We hypothesise a causal link concordant with epidemiological and in vitro evidence and propose further clinical research.

Excellent long-term graft survival in low risk, primary renal allografts treated with prednisolone-avoidance immunosuppression.

Primary avoidance of oral corticosteroids for renal transplant recipients is uncommon. The South Australian renal transplant service used a double therapy (DT) regimen of cyclosporin and azathioprine from August 1986 to July 1996 for low risk (first graft, PRA < 50%) allografts. Oral corticosteroid, prednisolone (P), was reserved for severe rejection or two mild rejection episodes, but could be later withdrawn at the physician's discretion. This regimen is associated with more early acute rejection (Russ et al., Clin Transplant 1990: 4: 26). We have now analysed long-term patient survival (PS) and graft survival (GS) for this group. Of 448 transplants in South Australia between August 1986 and July 1996, 295 commenced DT regimen. Ninety-four (31.8%) never received P at any stage post-transplantation (group 1), 96 (32.5%) were placed on P and later weaned (group 2), and 97 (33%) remained on long-term P (group 3). Technical losses, eight (2.7%), within 30 d of transplantation, were excluded from sub-group analysis. PS for the total DT cohort at 1, 5 and 9 yr post-transplantation was 97, 88 and 74%, respectively. GS over the same time period was 88, 75 and 55%, respectively. There was no statistically significant difference in survival compared to other 'low risk' grafts in the rest of Australia during the same time period. Mean serum creatinine concentration (CrC) for the DT group at 3 and 6 months and 1, 3, 5 and 10 yr was not significantly different to the rest of the Australian 'low risk' grafts. In the DT cohort, there were 334 acute rejections ( < 90 d) in 206 patients (70%), but only 42 (12.5%) required anti-lymphocyte antibody therapy (OKT3 or ATG) for rejection. PS at 9 yr was not statistically significantly different between groups 1 and 2, but both groups survived better than group 3 (p < 0.0043). GS for group 1 at 1, 5 and 9 yr post-transplantation was 90, 81 and 73%, respectively; for group 2, 98, 87 and 66%, respectively; and for group 3, 84, 63 and 29%, respectively. Statistical significance was reached in group 1 versus 3 (p < 0.001) and group 2 versus 3 (p < 0.001). In summary, a DT regimen in low risk, first renal allografts gives excellent long-term patient and GS and minimises long-term P, despite a high rate of early acute rejection.

Towards safer drug prescribing, dispensing and administration in hospitals.

A multidisciplinary workshop was held in order to identify strategies likely to produce a reduction in adverse drug events, by targeting hospital systems involved in drug prescribing, dispensing and administration. Strategies identified at the workshop included: (i) improving the education and practice development of medical and nursing staff, concerning drug therapy and safe prescribing principles; (ii) introducing and using information technology and electronic prescribing processes; (iii) implementing the Australian Pharmaceutical Advisory Council (APAC) national guidelines to achieve the continuum of quality use of medicines between hospitals and the community; (iv) enhancing the importance of medication history taking as a routine part of the admission process; (v) instituting individual patient supply as the standard method of drug distribution in hospitals; and (vi) stimulating the hospital-based clinical pharmacy workforce.

Cutaneous necrosis from calcific uremic arteriolopathy.

Calcific uremic arteriolopathy (calciphylaxis) is an uncommon complication of chronic renal failure that is associated with high morbidity and mortality. We report 16 patients (13 female) who presented between 1985 and 1996. All patients developed painful livido reticularis that progressed to cutaneous necrosis and ulceration (11 cases on the proximal extremities and five cases on the distal extremities). Two patients with predominately distal leg disease survived; the cause of death in the other 14 patients was sepsis (six patients), withdrawal from dialysis (three), cardiac arrest (three), and gastrointestinal hemorrhage (two). Mesenteric ischemia from intestinal vascular calcification occurred in two cases. Clinical factors identified included the use of warfarin therapy in seven cases and significant weight loss (>10% body weight) in seven cases in the 6 months preceding the development of calcific uremic arteriolopathy. Skin pathology was studied in 12 cases, with all showing calcific panniculitis and small vessel calcification. Electron microscopic spectral analysis of the mineral content of the calcific lesions in the subcutaneous tissue showed only calcium and phosphorous. In two cases, substitution of low molecular weight heparin for warfarin therapy resulted in clinical improvement. Current theories of pathogenesis and treatment are reviewed. This study confirms the high morbidity and mortality of calcific uremic arteriolopathy producing ischemic tissue necrosis while drawing attention to significant weight loss and warfarin therapy as risk factors for the development of ischemic tissue necrosis. Hyperbaric oxygen therapy warrants further study.

A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group.

BACKGROUND: Three large-scale clinical trials conducted in North America, Europe, and Australia showed that mycophenolate mofetil (MMF) decreases the incidence of acute renal allograft rejection in the first 6 months after transplant compared with placebo or azathioprine. This study extends the randomized, prospective, double-blind trial of MMF conducted by the Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. METHODS: Patients (n=503) were randomized to receive 100-150 mg of azathioprine (AZA) (n=166), 2 g of MMF (n=173), or 3 g of MMF (n=164) per day, in conjunction with cyclosporine and prednisone from the time of transplantation. RESULTS: During the first 6 months, the incidence of biopsy-proven acute graft rejection (BPR) was reduced by approximately 50% in the MMF 2 g (19.7%) and MMF 3 g (15.9%) groups compared with the AZA group (35.5%). The incidence of treatment failure during the first 6 months, including BPR, death, graft loss, and early withdrawal without prior BPR, was significantly decreased: AZA, 50%, compared with MMF 2 g, 38.2% (P=0.0287), and MMF 3 g, 34.8% (P=0.0045). At 3 years after transplant, both intent-to-treat and on-study (censoring at 90 days after treatment) analyses of graft and patient survival showed a trend toward advantage for MMF 2 g and 3 g vs. AZA (intent-to-treat: 81.9% and 84.8% vs. 80.2%; on-study: 84.0% and 86.4% vs. 82.7%), although this trend did not reach statistical significance. Rejection was the principal cause of graft loss in all groups: AZA, 9.9%; MMF 2 g, 5.8%; and MMF 3 g, 3.0%. Graft function (intent-to-treat and on-study) was comparable in all three groups at 3 years. Gastrointestinal toxicity, leukopenia, and tissue-invasive cytomegalovirus disease were more common in the MMF 3 g group both during and after the first posttransplant year. Lymphoproliferative disorders were diagnosed in one AZA (0.6%), two MMF 2 g (1.2%), and three MMF 3 g (1.8%) patients. Other (non-lymphoproliferative disorders, noncutaneous) malignancies occurred in six AZA (3.7%), four MMF 2 g (2.3%), and nine MMF 3 g (5.5%) patients. Mortality was comparable in all three groups (AZA, 8.6%; MMF 2 g, 4.7%; MMF 3 g, 9.1%) by 3 years of follow-up. CONCLUSION: MMF significantly reduced the incidence of rejection in the first 6 months, but there was not a significant improvement in graft survival throughout the 3 years after cadaver kidney transplantation.

A cluster of haematuria cases in a pesticide-manufacturing plant.

In a pesticide manufacturing and formulating facility, 10 employees out of 48 were shown to have haematuria on dipstick testing. They included seven of the 27 production workers, all of whom had worked in both of two particular areas prior to the commencement of the routine urine testing. Five of the seven production workers with haematuria underwent further investigations, and in all five the haematuria was glomerular in origin. Two underwent renal biopsy, which showed irregular attenuation of the glomerular basement membrane (GBM) but no abnormality by light microscopy. Immunofluorescence studies were negative. This case series of glomerular haematuria is not readily explained by chance, false positive dipstick testing, or a recognizable non-occupational cause. Thin GBM disease, which is a benign condition, appears the likely explanation. Thin GBM disease is usually an autosomal dominant condition, but clustering of these genotypes in this small population is improbable.

Formulation of diltiazem affects cyclosporin-sparing activity.

OBJECTIVE: To consider the effect of changing from a conventional release formulation of diltiazem to the controlled diffusion diltiazem formulation on the cyclosporin-sparing effect in kidney transplant recipients. METHODS: Seven stable renal transplant recipients were studied on two separate occasions following at least 2 weeks stabilisation on either formulation. The order of administration of the two formulations was not randomised as all patients were already prescribed lower dosages of diltiazem before entering this phase of a larger study. The doses of diltiazem used were 90 mg (conventional release diltiazem) taken twice daily and 180 mg controlled diffusion diltiazem taken in the morning. RESULTS: Whilst there were no overall significant differences between the two formulations, the study demonstrated considerable interpatient variability when changing to the controlled diffusion formulation, particularly following the morning cyclosporin dose, with three patients showing a reduced cyclosporin AUC (30-60%) and one an increased cyclosporin AUC of 36%. CONCLUSION: A change in formulation of the cyclosporin-sparing agent may result in unpredictable alterations in cyclosporin concentrations and resultant clinical sequelae.

Diltiazem-cyclosporin pharmacokinetic interaction--dose-response relationship.

AIMS: To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and cyclosporin in kidney transplant recipients. METHODS: Eight stable kidney transplant recipients maintained on cyclosporin but not taking diltiazem, were given increasing doses of diltiazem to a maximum dose of 180 mg day(-1). Following a 2 week period on each dose of diltiazem, thirteen blood samples were taken over a 24 h period to allow morning and evening AUCs to be determined for cyclosporin, diltiazem and three metabolites of diltiazem. RESULTS: Mean cyclosporin AUC(0, 24 h) increased sharply following the lowest dose of diltiazem used (10 mg day(-1)), the rate of increase slowed after 30-60 mg day(-1) but continued to increase up to the maximum dose tested. The effect of a single morning dose of DTZ was evident over both morning (0-12 h) and evening (12-24 h) cyclosporin AUCs. There was considerable interpatient variation in response to DTZ. CONCLUSIONS: The dose of diltiazem required to increase cyclosporin AUC (and hence allow significant reduction in cyclosporin dose) is less than that currently used for many patients. Lower doses of diltiazem should result in fewer adverse effects and may allow its use in situations where it was hitherto contraindicated. Because of the significant interpatient variation in response, we recommend individual patient blood cyclosporin concentration monitoring both before and after the introduction of diltiazem.

The organ shortage: what are Australian organ sharing organizations doing about it?

A version of the Spanish model of organ donor generation is being trailed in Australia with early success. National implementation of this approach is underway, with the expectation that the current donor rate of 10.6 donors/pmp/year will be doubled.