A successful scheme for reducing waiting times for arteriovenous fistula formation.

PURPOSE: In a bid to reduce waiting times for arteriovenous fistula (AVF) formation we introduced a scheme whereby nephrologists were able to place patients directly on the waiting list for surgery. This study evaluated the quality of these direct referrals and assessed the reduction in waiting times. METHODS: Fifty consecutive patients referred directly to the waiting list were compared with 50 patients placed on the waiting list after being assessed in our vascular access clinic. RESULTS: Forty-nine patients from the direct group and 47 patients from the clinic group underwent surgery. In the direct group 39 patients (80%) underwent the same procedure as they had been originally listed for, compared with 39 patients (83%) in the clinic group (p=0.80). A fistula suitable for needling was created in 37 patients (76%) of the direct group and 38 patients (81%) of the clinic group (p=0.62). The median wait from referral to surgery in the direct group was significantly lower than in the clinic group (62 vs.141 days; p<0.0001). CONCLUSION: This study demonstrates that nephrologists are able to effectively assess select patients for AVF formation. This significantly reduces waiting times for surgery, without an increase in cancelled operations, or a reduction in technical success.

Preparation of novel mesoporous carbons for the adsorption of an inflammatory cytokine (IL-1 beta).

Mesoporous carbons derived from two types of sulphonated styrene divinylbenzene copolymers (Macronet MN500HS and CT275, Purolite International Ltd) were produced and their adsorptive capacity for the proinflammatory cytokine IL-1 beta (MW 14.4 kDa) determined. The carbons produced had surface areas from 400 to 1200 m(2)g(-1) and pore volume between 0.2 and 1.4 cm(3)g(-1). The mechanical strength of the carbon beads with surface area values up to 800 m(2)g(-1) were robust. The highest adsorption value of IL-1 beta was 150 ng g(-1) for a mesoporous carbon with surface area around 900 m(2)g(-1) and pore volume around 1.3 cm(3)g(-1). However, there was a trade-off between adsorptive capacity and mechanical strength. When used in conjunction with existing treatment modalities, the materials produced have the potential to enhance the removal of uraemic toxins.

Albumin as an outcome measure in haemodialysis in patients: the effect of variation in assay method.

BACKGROUND: Serum/plasma albumin is an important predictor of future mortality/morbidity in haemodialysis (HD) patients and has been proposed as an important audit measure. Different methods of albumin assay give different results and the bias between methods may be greater in renal failure patients. METHODS: Albumin concentration in plasma was measured by three methods, two dye-binding methods (bromocresol green (BCG) and bromocresol purple (BCP)) and an immuno-turbidimetric (ITM) method, in 143 HD patients (group I) and 49 non-renal patients (group II). Comparisons were made between means, variation in differences across a range of albumin concentrations and on the percentage of patients within the normal range. RESULTS: In HD patients (group I), BCG over-estimated plasma albumin compared with the other two methods. The difference could be as much as 10 g/l and was more marked in hypoalbuminaemic patients. The BCP method gave results closer to the ITM method, particularly in HD patients. These differences were less marked in group II patients but both methods overestimated albumin compared with the ITM method. Using the BCG local laboratory normal range, 84% of HD patients had plasma albumin concentrations within the normal range but this fell to 57% if the BCP results were used. CONCLUSIONS: The method for determining albumin concentration has a marked effect on the results particularly in HD patients. BCG, the most commonly used method, gives higher results than other methods and correlates poorly with an immunological method. These differences make comparative audit between nephrology units difficult and have implications for other biochemical variables and other specialties.

Antioxidant vitamin concentrations and LDL oxidation in nephrotic syndrome.

The increased risk of atherosclerosis in nephrotic syndrome is attributable in part to the associated hyperlipidaemia. The importance of oxidation of LDL in the atherogenic process has been recognized over the last 15 years. However, there are few data on the balance of antioxidant defences and lipoprotein oxidation in nephrotic syndrome. Plasma antioxidant vitamin concentrations and indices of LDL oxidation (LDL lipid hydroperoxide content and the susceptibility of LDL to oxidation) were measured in two groups of patients; group I comprised 29 nephrotic patients and group II comprised 25 patients with haematuria. Plasma ascorbate concentration was significantly lower in group I (the nephrotic group) compared with group II (median 13.3 versus 22.2 micromol/L; P<0.001). Vitamin E concentrations were higher in group I but were not significantly different if corrected for total plasma cholesterol (6.12 versus 5.88 micromol/mmol; P=0.33). However, these changes resulted in a low ascorbate:vitamin E ratio in group I (0.19 versus 0.87; P<0.0001). Despite these changes in important antioxidant vitamin concentrations, we were unable to demonstrate any increased susceptibility to LDL oxidation in vitro or any difference in LDL lipid hydroperoxide content. These data suggest that there may be a relative defect of oxidant/antioxidant balance in nephrotic syndrome which could predispose to increased oxidative stress. However, measures of LDL oxidation were not significantly different between the two groups. LDL was protected from oxidation despite the severe hyperlipidaemia and the low circulating vitamin C concentrations.

A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients.

BACKGROUND: The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia and hyperlipidemia. Despite intensive research it is not clear at present what the causal links are between these pathological findings. METHODS: Stable isotope labeled amino acid tracer kinetic analysis was used to simultaneously investigate the metabolism of four apolipoprotein B-containing lipoproteins (VLDL1, VLDL2, IDL and LDL) and albumin in seven patients with nephrotic syndrome and marked hypercholesterolemia, in two additional nephrotic patients with concomitant renal failure and mixed hyperlipidemia, and in a matched group of normolipidemic controls. RESULTS: Increased concentrations of VLDL2, IDL and LDL were due to (a) impaired VLDL2 and IDL delipidation, (b) reduced LDL catabolism, and (c) a trend towards an increased rate of total apolipoprotein B production. The rate of fractional albumin elimination was three times higher in patients than in controls and the rate of albumin synthesis was increased by 45%. No correlations were detectable between rates of apolipoprotein B production and the rate of albumin synthesis. CONCLUSIONS: The results of this study suggest that hyperlipidemia in nephrotic syndrome is predominantly the result of delayed lipoprotein delipidation and catabolism. There is no evidence that it is driven by a general increase of the rate of hepatic protein synthesis.

The influence of familial factors on the progression of IgA nephropathy.

BACKGROUND: Vascular risk factors in first degree relatives of patients with insulin dependent diabetes mellitus are known to increase the risk of that patient developing diabetic nephropathy. We explored the influence of vascular risk factors in first degree relatives on patients with stable (serum creatinine < 150 mumol/l for > 5 years) and progressive (serum creatinine > 200 mumol/l, and > 150% serum creatinine at presentation, after minimum follow-up at 2 years) IgA nephropathy (IgAN). METHODS: We compared sodium-lithium countertransport activity (SLC Vmax), plasma lipoprotein(a) and von Willebrand factor (vWf) concentrations, incidence of vascular disease, and incidence of hypertension in 37 first degree relatives of 23 patients with stable IgAN and 33 first degree relatives of 17 patients with progressive IgAN. The two groups of relatives were comparable with respect to other risk factors: age, smoking, blood pressure, and plasma glucose, creatinine, cholesterol and triglyceride concentrations. RESULTS: SLC Vmax was higher in relatives of stable patients (mean 0.37 mmol/h/l RBC [S.D. 0.18] vs 0.30 [S.D. 0.09]; P = 0.034 two-sample t-test). There was no difference between the relatives of stable and progressive patients in plasma lipoprotein(a) concentration (median 11.5 mg/l vs 13.0: P = 0.45; 95% C.I. -12 to 3; Mann-Whitney test), plasma vWf concentration (149.4 IU/dl [S.D. 55.6] vs. 163.2 IU/dl [S.D. 57.3]; P = 0.31 two-sample t-test), or incidence of hypertension (13/37 [35.1%] vs 10/33 [30.3%]; chi 2 = 0.185; P = 0.667). Relatives of patients with progressive IgAN had a slightly higher incidence of vascular disease (10/33 [30.3%] vs 8/37 [21.6%]; chi 2 = 0.688; P = 0.407). CONCLUSIONS: Familial vascular risk may increase the likelihood of progressive renal failure in patients with IgAN but the influence is likely to be small and unrelated to the factors we measured. SLC Vmax was significantly higher in relatives of patients with stable disease which contrasts with data from other studies and is unexplained.

Prednisolone and chlorambucil therapy for idiopathic membranous nephropathy with progressive renal failure.

Twenty-one patients with membranous nephropathy, heavy proteinuria and progressive renal failure were treated with alternating monthly cycles of corticosteroids and chlorambucil for six months. Four patients received repeat courses. After a median period of follow-up of 39 months, three patients had died, six were receiving renal replacement therapy or had serum creatinine > 500 mumol/l, and one had progressive renal failure. Eleven patients had either stable or improved renal function, as judged by serum creatinine concentration. Of these eleven, four patients were in partial remission (daily protein excretion 0.2-2.0 g), and two were in complete remission. There was a tendency for those who received intravenous methylprednisolone to have a more favourable outcome. There was a high incidence of side-effects, with significant complications related to drug therapy observed in > 50% of subjects. Although individual patients appeared to respond well, sometimes dramatically, these results are less encouraging than other reports. We would urge caution in the use of this form of therapy, particularly in older patients who may have occult neoplasms, impaired glucose intolerance or pre-existing cardiac disease.

The relationship between urinary albumin excretion rate and serum cholesterol in primary glomerular disease.

The relationship between urinary albumin excretion rate (AER) and serum cholesterol was investigated in a group of 100 patients with primary glomerular disease. Patients were classified into four groups according to AER: 1. normal < 30 mg/24 h; 2. microalbuminuria 30-300 mg/24 h; 3. proteinuria 300-3000 mg/24 h; 4. nephrotic > 3000 mg/24 h. Serum cholesterol values for each patient were compared with the mean of two healthy controls matched for age, sex and weight. Although the albuminuric group had significantly increased serum cholesterol concentrations compared to controls (6.58 mmol/l sd 1.81 v. 5.91 sd 0.88; paired t, p < 0.003), this was almost entirely explained by the increase in the group with AER > 3000 mg/24 h (8.47 mmol/l sd 2.43 v. 6.18 sd 0.61; paired t, p < 0.02). However, there was a relationship between the log transformed values for serum cholesterol and AER which persisted even when those with AER > 3000 mg/day were excluded. These data suggest that albuminuria less than the nephrotic range has a minor influence on serum cholesterol in patients with primary glomerular disease.

Pathogenesis of lipid abnormalities in patients with nephrotic syndrome/proteinuria: clinical implications.

Hyperlipidaemia is an invariable complication of the nephrotic syndrome. The quantitative and qualitative changes in lipoproteins which occur may accelerate atherosclerosis. The pathogenetic mechanisms of the hyperlipidaemia are complex and poorly understood. Increases in lipoprotein production are compounded by reduced lipolysis of very low density lipoprotein and impaired catabolism of low density lipoprotein. Both proteinuria and hypoalbuminaemia have been implicated in the genesis of these abnormalities. The optimum treatment of the hyperlipidaemia has not been determined. 3-Hydroxy-3-methyl-glutaryl co-enzyme A reductase inhibitors appear to be the most effective lipid-lowering drugs, although their ability to reduce ischaemic events or prevent/delay renal failure remains to be proven.

Post-prandial lipoprotein metabolism in nephrotic syndrome.

Post-prandial lipaemia was investigated in a group of nine subjects with nephrotic syndrome by following the concentrations of triglyceride and retinyl palmitate in the d < 1.006 g ml-1 fraction of plasma after a standard oral fat load containing vitamin A. Lipoprotein lipase and hepatic triglyceride lipase activities were measured in post-heparin plasma. Subjects with other renal disease but insignificant proteinuria acted as controls. The time course of the lipaemic response was similar in both groups although individual patients demonstrated a prolonged lipaemia. Overall, there were no significant differences in the rise in triglyceride at 6 h (nephrotic--median 2.53 mmol l-1; range 0.87-4.76 vs. control 1.88; 0.38-4.12, P = 0.34), the peak concentration of retinyl palmitate (nephrotic 0.87 mg dl-1; 0.27-2.16 vs. control 0.65; 0.24-1.89, P = 0.97) or the areas under the curve from 0-24 h for triglyceride (nephrotic 10.5 mmol. h l-1; 2.9-43.6 vs. control 9.7; 4.3-27.0, P = 1.0) or retinyl palmitate (5.5 mg.h dl-1; 1.0-23.4 vs. 4.3; 1.5-12.4, P = 0.7). At baseline, the particles in the d < 1.006 g ml-1 fraction of plasma from nephrotic subjects had a higher free cholesterol:phospholipid ratio but this difference was no longer apparent 6 h after the test meal. There were no differences in total heparin-releasable lipase, lipoprotein lipase or hepatic triglyceride lipase activities between the two groups. These data suggest that impaired clearance of chylomicrons is not a major contributor to nephrotic hyperlipidaemia in man.

Effect of simvastatin on plasma lipid and lipoprotein concentrations and low-density lipoprotein metabolism in the nephrotic syndrome.

1. The effect of inhibiting the rate-limiting enzyme (3-hydroxy-3-methylglutaryl-CoA reductase, EC 1.1.1.88) in cholesterol synthesis on plasma lipid and lipoprotein concentrations was investigated in 16 patients with primary glomerular disease, heavy proteinuria, well-preserved renal function and hypercholesterolaemia. 2. Detailed studies of low-density lipoprotein metabolism were performed on eight patients before and after 12 weeks of simvastatin therapy. Radioiodinated tracers were used to quantify the fractional catabolic rate of low-density lipoprotein by apolipoprotein B/E receptors and alternative pathways. 3. Simvastatin produced consistent reductions in total plasma cholesterol concentration (median 36.9%), plasma low-density lipoprotein-cholesterol concentration (43.6%) and apolipoprotein B pool size (29.9%). 4. In contrast, the changes in kinetic parameters of low-density lipoprotein metabolism showed no clear pattern. Although an increase in the receptor-mediated catabolism of low-density lipoprotein was demonstrated in five patients, no change or a slight decrease was seen in three patients. Production rates were not significantly altered, although there was a slight decrease in the median value (from 12.4 to 9.7 mg day-1 kg-1). Plasma lathosterol concentration was reduced in all eight patients (range 34-71%), indirectly confirming significant inhibition of cholesterol synthesis. 5. These results suggest that, as in patients with primary moderate hyperlipidaemia, the significant cholesterol-lowering effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in the nephrotic syndrome is accompanied by variable changes in lipoprotein metabolism. The reasons for this heterogeneous response are unclear. This reflects our limited understanding of the metabolic basis of nephrotic hyperlipidaemia and the relationship between hepatic sterol synthesis and plasma lipoprotein kinetics.

Metabolism of apolipoprotein B-containing lipoproteins in subjects with nephrotic-range proteinuria.

Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise disturbances of lipoprotein metabolism which cause the elevated plasma lipid and lipoprotein concentrations have not been clearly defined in humans. This study examines the metabolism of apolipoprotein B-containing lipoproteins in patients with nephrotic-range proteinuria and in healthy controls. Two radioiodinated tracers of very low density lipoproteins (VLDL1, Sf60 to 400, and VLDL2, Sf20 to 60), were used to trace the metabolism of apolipoprotein B through the delipidation cascade from very low density lipoproteins (VLDL) to low density lipoproteins (LDL). The data from the apoB specific radioactivity curves and the pool sizes of apoB in four subfractions were analyzed by a multicompartmental modeling procedure using the SAAM 30 program. The main findings in the nephrotic group were: 1.) a consistent decrease in the fractional rate of apoB transfer from VLDL1----VLDL2 (median values-nephrotic 0.92 pools/day vs. controls 3.66, P less than 0.02) and from VLDL2----IDL (1.49 vs. 2.74, P less than 0.05); 2.) increased secretion of apoB into VLDL2 (14.5 mg/kg/day vs. 4.2, P less than 0.02); 3.) a trend towards decreased removal of IDL and LDL attributable to a defect in LDL receptor-mediated removal as previously shown (Metabolism 39:187-192, 1990). These findings suggest that catabolic defects of the apo B-containing lipoproteins are as important as increased hepatic synthesis in the pathogenesis of nephrotic hyperlipidemia in humans.

Combined renal and cardiac transplantation for severe left ventricular dysfunction in end-stage renal failure.

Successful treatment of severe cardiac failure in a patient with end-stage renal failure by combined renal and cardiac transplantation is described. The possible causes of myocardial disease in the dialysis population are discussed.

Primary hyperlipidaemia is not associated with increased urinary albumin excretion.

In a group of 141 otherwise healthy subjects attending a lipoprotein clinic, urinary albumin excretion was measured to determine whether primary hyperlipidaemia was associated with evidence of early renal dysfunction. There was no evidence of increased urinary albumin concentrations or albumin:creatinine ratios when compared with data for normal controls. There were no differences in these parameters when the values for the upper and lower quartiles of the cholesterol distribution were compared, and no relationship existed between plasma cholesterol and albuminuria. A weak association was shown between plasma triglyceride and urinary albumin concentration after log transformation of the data. We conclude that hyperlipidaemia per se is not associated with renal disease as measured by sensitive assays of albuminuria.

Low-density lipoprotein metabolism in the nephrotic syndrome.

Hyperlipidemia is a consistent feature of the nephrotic syndrome. In this study, low-density lipoprotein (LDL) metabolism has been investigated in nine patients with nephrotic syndrome and varying degrees of proteinuria. In subjects with moderate proteinuria (less than 10 g/d), total plasma cholesterol values were elevated to approximately 160% of normal due mainly to an increase in circulating LDL cholesterol. Metabolic studies showed that a defect in LDL clearance via the receptor pathway was responsible for its accumulation. The total amount of LDL apolipoprotein catabolized by this mechanism was only 55% of the value seen in controls; 60% more LDL was channelled into alternative, receptor-independent, catabolic pathways. Heavier proteinuria was associated with substantial increases in plasma triglyceride and very-low-density lipoprotein (VLDL) levels. The defect in LDL catabolism was aggravated by oversynthesis of the lipoprotein, which expanded the plasma LDL pool to 250% of normal. These observations indicate that the hyperlipidemia of the nephrotic syndrome is multifactorial in origin. The altered catabolism of LDL may be important in predisposing these subjects to premature atherosclerosis.