Grahame Wood

Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia

We have investigated the effects of two fibric acid derivatives, bezafibrate mono (400 mg daily) and gemfibrozil (600 mg b.d.), in 29 patients with type IIb hyperlipoproteinaemia. All patients received placebo and each drug for 8 weeks in randomised order in a double-blind, cross-over study designed to evaluate any different effects of the drugs on serum lipoproteins, cholesteryl ester transfer protein (CETP), cholesteryl ester transfer activity (CETA), plasma fibrinogen, plasminogen activator inhibitor-I (PAI-1) or paraoxonase. Serum cholesterol decreased (P < 0.05) with gemfibrozil, but the effect of bezafibrate on serum cholesterol did not achieve statistical significance (placebo 8.34 +/- 1.05 (mean +/- S.D.), gemfibrozil 7.70 +/- 1.23 and bezafibrate 7.8 +/- 1.37 mmol/l). Both drugs decreased the serum triglyceride concentration (both P < 0.001) (placebo 4.39 (3.13-5.75) (median (interquartile range)), bezafibrate 2.26 (1.89-3.89) and gemfibrozil 2.00 (1.30-3.30) mmol/l) and very low density lipoprotein (VLDL) cholesterol (both P < 0.001) (placebo 1.18 (0.74-2.30), bezafibrate 0.59 (0.34-0.85) and gemfibrozil 0.48 (0.34-0.68) mmol/l). Discontinuous gradient ultracentrifugation (DGU) revealed that Sf 60-400 (large VLDL) decreased by more than 50% and Sf 20-60 (small VLDL) by more than 30% with each of the drugs (both P < 0.001), neither of which affected the composition of these lipoproteins. Gemfibrozil decreased the concentration of Sf 12-20 lipoprotein (intermediate density lipoprotein; IDL) by 23% (P < 0.01), whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance. Neither drug altered the concentration of apolipoprotein B or of total Sf 0-12 lipoproteins (low density lipoprotein, (LDL)). Both, however, significantly increased the quantity of free cholesterol in Sf 0-12 lipoproteins (P < 0.05). Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU (Sf 0-12, Sf 12-20, Sf 20-60, Sf 60-400) on gemfibrozil treatment, but only in Sf 20-60 and Sf 60-400 on bezafibrate (all P < 0.05). Both drugs also increased serum high density lipoprotein (HDL) cholesterol (placebo 1.15 +/- 0.29, bezafibrate 1.27 +/- 0.38 (P < 0.01) and gemfibrozil 1.26 +/- 0.49 (P < 0.05) mmol/l) and HDL3 cholesterol concentration (placebo 0.59 +/- 0.12, bezafibrate 0.72 +/- 0.23 (P < 0.001) and gemfibrozil 0.70 +/- 0.24 (P < 0.01) mmol/l). Serum apolipoprotein A1 (apo A1) was increased (P < 0.05) by bezafibrate compared to gemfibrozil (placebo 103 +/- 26, bezafibrate 111 +/- 28 and gemfibrozil 102 +/- 25 mg/dl) and CETA from HDL to VLDL and LDL was decreased (P < 0.05) by bezafibrate compared to placebo, but the apparent decrease with gemfibrozil did not achieve statistical significance (placebo 39.6 +/- 17.7, bezafibrate 32.3 +/- 14.7 and gemfibrozil 33.8 +/- 15.0 nmol/ml/h). Neither drug affected the circulating concentration of CETP. Plasma fibrinogen was increased (P < 0.05) by gemfibrozil (placebo 4.16 (3.38-4.71) and gemfibrozil 4.65 (4.05-5.77) g/l) and was significantly lower (P < 0.001) on bezafibrate (3.60 (3.18-4.54) g/l) than on gemfibrozil treatment. There was a significant (P < 0.05) increase in PAI-1 activity with bezafibrate and a similar trend with gemfibrozil (placebo 41.2 (25.6-64.5), bezafibrate 50.5 (35.1-73.9) and gemfibrozil 48.5 (31.5-5.4 U/l). Neither fibrate influenced plasma concentrations of PAI-1 nor were the activities of lecithin:cholesterol acyl transferase or paraoxonase affected. The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemfibrozil in decreasing the overall serum concentration of Sf 12-20 lipoproteins and the triglycerides in Sf 12-20 and 0-12 lipoproteins. Bezafibrate, however, increased serum apo A1 concentration and significantly decreased CETA. The two drugs also had different effects on the plasma fibrinogen levels, which increased with gemfibrozil and tended to decrea

Presence of paraoxonase in human interstitial fluid.

Human serum paraoxonase (PON1) is postulated to have anti‐atherosclerotic properties through its ability to prevent lipid peroxide generation on LDL. However, in order to perform this role it must be present in interstitial fluid, to prevent LDL oxidation which takes place in the sub‐intimal space of the artery wall. The PON1 activity in interstitial fluid was 15.7 (2.3–183.0) (median (range)) nmol/min/ml compared to 105.3 (74.6–323.9) nmol/min/ml in serum. The PON1 concentration in interstitial fluid was found to be 20.2 (1.1–78.1) μg/ml (median (range)) compared to 109.6 (11.1–485.7) μg/ml in serum. Interstitial fluid PON1 concentration was dependent on the interstitial fluid apo AI concentration (r=0.690, P<0.005) indicating PON1 remained associated with HDL. However, the ratio of PON1 concentration to apo AI was lower in interstitial fluid (0.60±0.20) than in the serum (0.95±0.18) (P<0.001) indicating sequestration of PON1 in the sub‐intimal space. Therefore, PON1 is present and active in interstitial fluid where it can perform its anti‐atherosclerotic function.

Increasing Frequency of Pneumocystis jirovecii Pneumonia in Renal Transplant Recipients in the United Kingdom: Clonal Variability, Clusters, and Geographic Location

To the Editor—Pneumocystis jirovecii is a well-described opportunistic pathogen in human immunodeficiency virus (HIV) infection, but it is less commonly associated with pneumonia in other states of immunocompromise. However, outbreaks of P. jirovecii pneumonia (PCP) have been described in renal transplant recipients in both Europe and Asia [1–3]. Explanations for this, including the possible modes of transmission, have not been established, and risk factors for the development of PCP remain poorly understood. However, policies relating to immunosuppression and HLA matching have changed in recent years [4], and PCP prophylaxis guidance in renal transplant recipients has a poor evidence base [5]. We write to draw attention to the preliminary results of investigation of 2 concurrent outbreaks of PCP in renal transplant recipients in the Northwest of England, followed by a United Kingdom–wide surveillance questionnaire of renal units with responses suggesting that there has been a national upsurge in such cases. Between November 2008 and July 2010, 21 cases of PCP were diagnosed in renal transplant recipients attending the transplant unit at the Royal Liverpool University Hospital, compared with 1 case in the

Determinants of renal functional outcome in lupus nephritis: a single centre retrospective study.

BACKGROUND Lupus nephritis (LN) is a rare disease but is the strongest predictor of poor outcome in patients with Systemic Lupus Erythematosis (SLE). It is associated with significant morbidity, with 10-20% of patients developing end stage renal failure. As there is a paucity of randomized clinical trial data in LN, and no consistent literature regarding baseline factors that predict renal outcome, we were prompted to analyse our centres complete experience of managing LN. METHODS A retrospective analysis was undertaken of all patients presenting to our renal centre with biopsy proven LN from 1979-2003. Patients were divided into two categories, those with stable or deteriorating renal function over time. Baseline parameters were correlated with renal outcome. RESULTS Complete clinical records were available for 45 (40 female) patients. Mean (SD) age of onset of SLE was 32 +/- 14 years, and mean age onset of LN was 36 +/- 13 years. Patients were followed up for an average of 74 +/- 56 months. Four patients (9%) had WHO Class II LN, 11 (24%) WHO Class III and there were 15 (33%) each in Class IV and V, respectively on renal biopsy. Five (11%) patients presented with acute renal failure and all had proliferative changes on biopsy. The chief arbiters of renal functional deterioration over follow up were longer time to development of LN (P = 0.04), a high platelet count and worse baseline renal function (both P = 0.05). There was a trend relating low haemoglobin or membranous histology to poor renal outcome, and Class IV histology to better outcome. CONCLUSION The study has identified that longer time to development of LN, high platelet count and poorer renal function at baseline suggest a worse renal outcome in LN. The study was small but LN is a rare condition. A combination of factors is likely to influence renal outcome in LN and larger prospective trials are required to ascertain consistent baseline prognostic markers.

Role of renal function and cardiac biomarkers (NT-proBNP and Troponin) in determining mortality and cardiac outcome in atheromatous renovascular disease

Background and Aims: Patients with atheromatous renovascular disease (ARVD) have high cardiovascular morbidity and mortality. The cardiac markers N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin (cTnT) are easily measured, yet not widely used in renal patients as they are thought to be inaccurate in renal disease. We aimed to see if these markers could be used as prognostic indicators of cardiovascular events (CVEs) and death in ARVD. Methods: Subjects with ARVD treated in 1 renal center in 2003 were prospectively followed up. NT-proBNP and cTnT at baseline were correlated with CVEs and death, echocardiographic findings and degree of renal artery stenosis. Cutoff levels of 0.03 ng/ml (cTnT) and 43 pmol/l (NT-proBNP) were used. Results: Eighty-two patients (mean ± SD age 69 ± 8 years, mean follow-up 40.2 ± 16.6 months) were suitable for analysis. Twenty-nine percent of patients suffered new CVEs, and 37.8% died. Renal function was a significant predictor of CVEs and death. Patients with a raised NT-proBNP were more likely to die than those in the same chronic kidney disease (CKD) category with normal levels (p < 0.0001) even after adjusting for multivariate factors (hazard ratio 8.3 for high proBNP vs. 3.6 for low proBNP in CKD stage 4–5). Conclusion: No study to our knowledge has looked at both NT-proBNP and cTnT as outcome markers in ARVD. Our study shows that renal function is more important as a marker of suffering a CVE. However, raised NT-proBNP is associated with a greater likelihood of death when subdivided by CKD stage. Early risk stratification by simple measurement of these biomarkers may aid in intensifying management in high-risk patients, although further studies to assess the value of this approach are warranted.

Proteinuria and severe mixed dyslipidemia associated with a novel APOAV gene mutation

Cardiovascular Research Group, School of Clinical & Laboratory Sciences, University of Manchester, Core Technology Facility (3 Floor), 46 Grafton Street, Manchester, M13 9NT, United Kingdom (Drs. Soran, Charlton-Menys, and Durrington); Robarts Research Institute, University of West Ontario, Ontario, Canada (Drs. Hegele and Wang); Department of Histopathology, Central Manchester and Manchester Children University Hospitals, Manchester, United Kingdom (Dr. Benbow); Department of Histopathology, John Radcliffe Hospital, Oxford, United Kingdom (Dr. Roberts); and Department of Nephrology, Hope Hospital, Eccles Old Road, Salford M6 8HD, United Kingdom (Dr. Wood)

Presentation of laboratory test results in patient portals: Influence of interface design on risk interpretation and visual search behaviour

BackgroundPatient portals are considered valuable instruments for self-management of long term conditions, however, there are concerns over how patients might interpret and act on the clinical information they access. We hypothesized that visual cues improve patients’ abilities to correctly interpret laboratory test results presented through patient portals. We also assessed, by applying eye-tracking methods, the relationship between risk interpretation and visual search behaviour.MethodsWe conducted a controlled study with 20 kidney transplant patients. Participants viewed three different graphical presentations in each of low, medium, and high risk clinical scenarios composed of results for 28 laboratory tests. After viewing each clinical scenario, patients were asked how they would have acted in real life if the results were their own, as a proxy of their risk interpretation. They could choose between: 1) Calling their doctor immediately (high interpreted risk); 2) Trying to arrange an appointment within the next 4 weeks (medium interpreted risk); 3) Waiting for the next appointment in 3 months (low interpreted risk). For each presentation, we assessed accuracy of patients’ risk interpretation, and employed eye tracking to assess and compare visual search behaviour.ResultsMisinterpretation of risk was common, with 65% of participants underestimating the need for action across all presentations at least once. Participants found it particularly difficult to interpret medium risk clinical scenarios. Participants who consistently understood when action was needed showed a higher visual search efficiency, suggesting a better strategy to cope with information overload that helped them to focus on the laboratory tests most relevant to their condition.ConclusionsThis study confirms patients’ difficulties in interpreting laboratories test results, with many patients underestimating the need for action, even when abnormal values were highlighted or grouped together. Our findings raise patient safety concerns and may limit the potential of patient portals to actively involve patients in their own healthcare.