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).

Glomerular lesions after renal transplantation.

Significant changes in glomeruli on light microscopy has been observed in 27 of 109 cadaveric renal allografts which functioned beyond 6 months. Tissue was available for study from all but two allografts. The histologic lesions were classified as follows: recurrent glomeruloneophritis, 9 cases (3 focal scierosis, 2 mesangial immunoglobulin A[IgA] disease, 2 mesangiocapillary glomerulonephritis, 1 dense deposit disease, 1 familial nephritis); de novo glomerulonephritis, 1 case (diffuse proliferative glomerulonephritis with crescents); and glomerular change of uncertain etiology, 17 cases (10 mesangiocapillary, 5 focal scierosis, 1 focal proliferative and 1 mesangial proliferative). These lesions were not distinguishable on light, fluorescent and electron microscopy from those in patients with spontaneous renal disease. All patients with glomerular lesions had proteinuria, and all but 3 had microscopic hematuria. Glomerular lesions were not significantly associated with early clinical rejection episodes or HLA compatibility. Presensitization of HLA antigens was significantly related to the occurence of a nonrecurrent glomerular lesion. Vescoureteral reflux was significantly more frequent in those with glomerular change (14 of 24) than in those without (13 of 48). Glomerular lesions were associated with a higher rate of graft loss due to renal transplant failure; renal function in survivors was significantly worse than in those without glomerular lesions.

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.

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.

Diltiazem in renal allograft recipients receiving cyclosporine.

Of 113 cyclosporine-treated primary renal allograft recipients, 60 were randomized to receive standard therapy without diltiazem (ND) and 53 received standard therapy plus diltiazem (D). There was no difference in CsA blood levels between ND and D at all intervals between 3 and 24 months follow-up, yet the D group required 35% less CsA than the ND group (measured at 12 months). At all intervals to 24 months there was no difference in blood pressure, renal function (as measured by serum creatinine), or in the number of grafts lost between the 2 groups (ND, 4 lost; D, 3 lost). There was no significant difference in the total number of rejection episodes in the 2 groups (ND, 89 episodes; D, 71 episodes). However, the severity of rejection episodes was greater in the ND group as evidenced by a significant difference in the usage of OKT3 (ND, 17 courses; D, 8 courses of OKT3, P < 0.05). Of the biopsy-proven episodes of rejection, there were more episodes of vascular rejection in the ND group (ND, 14 episodes; D, 3 episodes, P = 0.005). The incidence of primary nonfunction was less in the D group (ND, 16 patients; D, 5 patients, P = 0.05). It was concluded that the use of diltiazem was associated with a markedly reduced requirement for CsA without any adverse effect on graft function or graft outcome. Diltiazem with CsA was associated with fewer episodes of primary nonfunction and less-severe rejection episodes and in particular fewer episodes of vascular rejection.

A prospective randomized trial of low-dose versus high-dose steroids in cadaveric renal transplantation.

Low-dose steroid regimens, in combination with azathioprine, have become increasingly common for immunosuppression of renal transplant recipients. The change from conventional high-dose steroid regimens was prompted by the results of several prospective trials that showed similar graft survivals with high-dose and low-dose steroids, but a lower incidence of steroid-induced complications in low-dose-steroid--treated patients. However, the number of patients entered into the trials was small, and consequently there remained a possibility that a clinically relevant difference in graft survival could have remained undetected. A multi-center prospective trial was performed to compare graft survival with high-dose (91 patients) and low-dose (98 patients) oral steroids in combination with azathioprine. There was significantly worse graft survival in the low-dose group. The difference was largely due to a poor graft survival in patients receiving low-dose steroids and azathioprine less than 1.75 mg/kg/day. Graft survivals were similar in the high-dose and low-dose steroid patients who received azathioprine doses of greater than 1.75 mg/kg/day. The results indicate that the combination of low doses of both steroids and azathioprine provides inadequate immunosuppression in renal transplantation, although higher doses of azathioprine allow the use of low-dose steroids without significantly more graft losses than with high-dose steroids.

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.

Plasma 1,5-anhydro-D-glucitol concentration and its relation to other plasma components in renal failure and renal transplant recipients.

Plasma levels of 1,5-anhydro-D-glucitol (AG) were measured in non-diabetic patients with renal failure or following renal transplant. For patients with renal failure (n = 20) from various causes, the plasma level of AG was found to be positively associated with urate and negatively with both urea and prior dialysis. The results for seven renal transplant recipients, serially assessed during the post-transplant period, verified an increase in plasma AG with time, approaching normal levels (> or = 70 mumol/l) after 60 days, and which was adversely affected by rejection episodes. The actual mean rate of plasma AG rise ranged from 0.35 to 1.29 mumol/l per day. AG levels for long term (> 1000 days) surviving renal transplant recipients (n = 16) were predominantly related to renal function as assessed by plasma creatinine.

Effect of renal transplantation on left ventricular function in hemodialysis patients.

The effect of renal transplantation on left ventricular function was evaluated in 14 patients with end-stage renal disease requiring maintenance hemodialysis. They had no apparent clinical evidence of heart disease. Ischemic heart disease was excluded by history, electrocardiography and radionuclide ventriculography. Echocardiography and radionuclide ventriculography were recorded in the interdialytic periods. Sixty-four per cent of the patients had abnormal left ventricular function despite adequate hemodialysis. Left ventricular function was reassessed within the first two months after successful renal transplantation. All parameters improved shortly after the transplantation. Cardiac index increased by an average of 0.76 +/- 0.11/min/m2 (P less than 0.001), stroke volume by 23.9 +/- 0.5 ml (P less than 0.001), ejection fraction by 9.7 +/- 1.9% (P less than 0.001), mean normalized posterior wall velocity by 0.17 +/- 0.06 second-1 (P less than 0.01), mean velocity of circumferential fiber shortening by 0.28 +/- 0.02 circle/second (P less than 0.001), and mitral valve diastolic closure rate by 17.2 +/- 2.3 mm/second (P less than 0.01). Our findings support the existence of a specific uremic cardiomyopathy which is a functional defect probably related to poorly dialyzed uremic toxins.

Scanning electron microscopy of glomerular and non glomerular red blood cells.

Phase contrast microscopic examination of the urine has been recently shown to be of value in predicting whether hematuria is due to glomerulonephritis or lesions of the lower urinary tract. Glomerular red cells show variations in size and shape and have distorted surfaces. Non glomerular red cells are uniform in size and shape and have smooth surfaces. Scanning electron microscopy was performed on urine sediment containing either glomerular or non glomerular red cells to better define their surface characteristics. Glomerular red cells exhibited a variety of forms, most cells having lumpy projections from the surface, some showing fragmentation of the membrane and others showing gross distortion. In contrast non glomerular red cells show smooth surfaces and usually maintain the normal biconcave disc shape of peripheral red blood cells. Scanning electron microscopy can better define surface structural abnormalities of urinary glomerular and non glomerular red blood cells.

Bone disease in analgesic nephropathy.

Clinical, biochemical, radiological and bone biopsy findings were studied in 15 patients with end stage renal disease due to analgesic nephropathy and compared with data from age and sex matched controls who had end stage renal disease from other causes. Patients with analgesic nephropathy had significantly higher osteoid volume (P less than 0.04), reduced calcification fronts (P less than 0.001) and lower percentage mineralization (P less than 0.04). Serum alkaline phosphatase was significantly higher in the analgesic group (P less than 0.005). It is concluded that osteomalacia is more common and severe in the group of patients with end stage renal disease due to analgesic nephropathy. There was no relationship between osteomalacia and the duration of renal failure, acidosis, aluminium deposition or other serum biochemical abnormalities.

Glomerular transplant rejection: a distinctive pattern of early graft damage.

Five hundred seventy-six consecutive biopsy or nephrectomy specimens obtained during the first 6 months of transplantation from 300 grafts in 431 recipients were examined by light microscopy for focal or diffuse endocapillary hypercellularity. Forty-seven (8.2%) of the 576 specimens obtained from 37 (12.3%) of the 300 grafts exhibited segmental or global occlusion of capillaries by swollen cells in 40-100% of glomeruli per biopsy. The lesions occurred at any time after transplantation, but 34 (72.3%) were present by day 60 and 7 (14.9%) before day 10. Immunofluorescence in 39 affected biopsies revealed focal or segmental glomerular staining in 18 (46.2%), among which IgM was found most frequently, and was considered to be non-specific. Electron micrographs of 17 biopsies from 14 grafts revealed that glomerular capillaries were narrowed or occluded by mononuclear cells of uncertain type, possibly monocytes, as well as lymphocytes and a few neutrophils. Complement-fixing antibody titers to cytomegalovirus rose at least fourfold in 10 (45.5%) of the 22 patients studied, but glomerular lesions were no more severe in the seroconverters than in the non-converters, and there was no consistent temporal relationship between the occurrence of glomerular changes and seroconversion. Cellular or vascular rejection was present in most biopsies. One year graft survival was 34% among 35 accessed grafts with glomerular lesions, compared to 55% among 243 biopsied grafts with no glomerular changes. We consider that these lesions do not have a consistent association with cytomegalovirus infection and that they represent a distinctive form of glomerular rejection. Whether they indicate a poor graft survival, as the present results suggest but do not prove, requires further studies of other series of cases.

Recurrent focal glomerulosclerosis in renal transplants.

Among 431 renal transplants in 380 patients, 4 patients were identified with focal glomerulosclerosis characterized by presentation with corticosteroid-resistant nephrotic syndrome, early development of histological lesions, mesangial proliferation and rapid progression into chronic renal failure. After transplantation, all patients had early proteinuria and the 4 grafts surviving beyond 3 months developed recurrent glomerular lesions with severe nephrotic syndrome and progression to graft failure. In one patient, recurrent disease developed in two successive grafts. Focal glomerulosclerosis is a nonspecific glomerular lesion, but identification of specific clinical and pathological features may provide guidelines that will predict the risk of its recurrence in transplanted kidneys.

Beta 2-microglobulin excretion and urinary cytology in analgesic nephropathy.

Patients with analgesic nephropathy are at risk from uro-epithelial malignancy. Enhanced secretion of beta 2-microglobulin occurs from epithelial cancer cells. In order to find a screening test for malignancy in analgesic nephropathy, urinary levels of this protein were measured in patients with analgesic nephropathy with urine cytological abnormalities and were compared to a control group with glomerulonephritis. Mean fractional excretion of beta 2-microglobulin was higher (8.61 +/- 1.76 SEM) in patients with analgesic nephropathy than in those with glomerulonephritis (1.13 +/- 0.76) (P less than 0.025). Those patients with analgesic nephropathy who had malignant cells in the urine had higher mean fractional excretion (18.56 +/- 5.77) than those with only atypical cells (8.5 +/- 2.0) (P less than 0.05) who in turn had higher mean values than those with normal cytology (2.12 +/- 0.62) (P less than 0.0025). It is suggested that the increased beta 2-microglobulin excretion in analgesic nephropathy is due to secretion from abnormal urothelial cells as well as reduced tubular catabolism. Beta 2-microglobulin may be of use as a screening test for malignancy in analgesic nephropathy.

The effect of withdrawal of phenacetin-containing analgesics on the incidence of kidney and urothelial cancer and renal failure.

Incidence data for cancers of the kidney and urinary tract (1973-83) and for end stage renal failure (ESRF) due to analgesic nephropathy (1973-86) were examined by loglinear regression to determine the effect of the withdrawal of phenacetin from analgesic preparations in New South Wales and the Australian Capital Territory. Allowing for the altered age and sex structure of the population, the incidence rate between 1973-83 for ESRF due to analgesic nephropathy, in persons aged between 5 and 54 years, decreased by 4.2% per year while that for ESRF excluding patients with analgesic nephropathy or diabetes increased annually by 1.3%. The incidence rates in persons over 14 years of age for cancer of the renal parenchyma (3.4% per year), renal pelvis (5.5%) and bladder (2.1%) increased significantly more than that for cancer at all sites (1.2%). Thus the decrease in ESRF due to analgesic nephropathy had not, by 1983, been paralleled by a decrease in renal parenchymal or urothelial cancer.

Left ventricular function in uremia: echocardiographic and radionuclide assessment in patients on maintenance hemodialysis.

Echocardiography and radionuclide ventriculography were performed in 37 uremic patients on maintenance hemodialysis with no apparent coronary artery disease, pericardial effusion, valvular heart disease or heart failure. These non-invasive studies were performed during the interdialytic period (about 18 hours after a dialysis). Sixty-two percent of our patients had abnormal left ventricular function with one or more abnormal echocardiographic parameters. The significant abnormalities were enlargement of the left ventricular cavity, a reduction of myocardial contractility, and thickening of the left ventricular posterior wall. Similar findings were found in 10 undialyzed uremic patients. Measurement of cardiac index and ejection fraction were found to be inadequate for a full assessment of left ventricular function and other parameters such as the mean velocity of circumferential fiber shortening and mean normalized posterior wall velocity should be included. There is a significant number of hemodialysis patients (7/37) with congestive cardiomyopathic features on the echocardiogram. Their clinical features are no different from the other patients in this study, except they have a significantly higher prevalence of uremic hyperparathyroidism. Our findings support that the existence of a specific uremic cardiomyopathy and uremic hyperparathyroidism may play an important role in the pathogenesis.

Typing of intraglomerular mononuclear cells associated with transplant glomerular rejection.

To investigate the pathogenesis of glomerular injury in renal allografts, we have analyzed intraglomerular mononuclear cells from 20 biopsies with typical features of transplant glomerular rejection (TGR) (segmental or global occlusion of capillaries by swollen cells). Ten biopsies showing cellular rejection but no glomerular pathology were selected as controls. Microwave fixation and an avidin-biotin immunoperoxidase technique were used with the following monoclonal antibodies; Leu1 and OKT3 (pan T cell), Leu 3 a + b and OKT4 (helper T cell), OKT8 (cytotoxic T cell), OKB7 (B cell), OKM1 (monocyte) and OKDR (DR positive cell). The results showed a significant increase of T cells, helper T cells, cytotoxic T cells and monocytes in the patients with TGR compared with the controls (all p less than 0.001, Mann-Whitney U test). Of the T cell subsets, cytotoxic T cells outnumbered helper T cells by a mean ratio of 3.2:1. In the interstitium, the distribution of mononuclear cells was not different between the two patient groups. In both, T cells and monocytes were predominant and few B cells were found. The percentage of cytotoxic T cells was similar to that of helper T cells. In this study, there were at least four TGR patients without cytomegalovirus (CMV) infection and the distribution of intraglomerular mononuclear cells in these patients was indistinguishable from that of other TGR patients. There was no significant association of the distribution of mononuclear cells with the severity of glomerular damage. These results suggest that T cells, predominantly of the cytotoxic subset and monocytes are involved in the mediation of TGR.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Expanded polytetra fluoroethylene (PTFE) graft in hemodialysis.

Currently, PTFE grafts are regarded to be the alternative method of choice for patients with failed conventional fistulae. Observation over a longer period is necessary to assess the long term patency rate. Our experience in the use of PTFE grafts in providing vascular access for selected patients is reviewed. Thirty grafts were implanted in twenty-six patients over a sixteen-month period. Complications noted were thrombosis (six patients) and infection (two). Twenty patients were successfully hemodialysed without complications. Two additional patients had access provided for long term parenteral therapy or transfusion.