Non-steroidal anti-inflammatory drug use and brain tumour risk: a case-control study within the Clinical Practice Research Datalink.

PURPOSE: The aetiology of primary brain tumours is largely unknown; the role of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin use and glioma risk has been inconclusive, but few population-based studies with reliable prescribing data have been conducted, and the association with meningioma risk has yet to be assessed. METHODS: The UK Clinical Practice Research Datalink was used to assess the association between aspirin and non-aspirin NSAID use and primary brain tumour risk using a nested case-control study design. Conditional logistic regression analysis was performed on 5,052 brain tumour patients aged 16 years and over, diagnosed between 1987 and 2009 and 42,678 controls matched on year of birth, gender and general practice, adjusting for history of allergy and hormone replacement therapy use in the glioma and meningioma models, respectively. RESULTS: In conditional logistic regression analysis, excluding drug use in the year preceding the index date, there was no association with non-aspirin NSAID use (OR 0.96, 95 % CI 0.81-1.13) or glioma risk comparing the highest category of daily defined dose to non-users; however, non-aspirin NSAID use was positively associated with meningioma risk (OR 1.35, 95 % CI 1.06-1.71). No association was seen with high- or low-dose aspirin use irrespective of histology. CONCLUSIONS: This large nested case-control study finds no association between aspirin or non-aspirin NSAID use and risk of glioma but a slight increased risk with non-aspirin NSAIDs and meningioma.

Anti-glomerular basement membrane antibody-mediated nephritis complicating transplantation in a patient with Alport's syndrome.

Loss of an allograft caused by anti-GBM antibody-mediated nephritis is a rare complication of renal transplantation in Alport's syndrome. We describe a patient in whom this occurred. He belongs to the subgroup of patients with hereditary nephritis and deafness with an abnormal Goodpasture antigen, and he developed a high level of circulating anti-GBM antibodies within 20 days of transplantation of a kidney with a presumably normal Goodpasture antigen. The antibody titer fell, only to rise again when he developed evidence of acute infection with CMV. Coincident with this second rise in antibody titer he developed an anti-GBM antibody-mediated crescentic nephritis with resultant loss of graft function and transplant nephrectomy. This case provides support for the hypothesis that the abnormality in the basement membrane in some patients with Alport's syndrome involves the Goodpasture antigen, and raises the possibility that viral infection may have triggered autoantibody production.

The use of vaccines in renal failure.

Renal insufficiency is characterised by impaired host defences, which are compromised further by each of the 3 modes of renal replacement--haemodialysis, continuous ambulatory peritoneal dialysis (CAPD) and renal transplantation. Reduced renal clearance of unknown toxins, possible development of nutritional deficiencies and administration of immunosuppressive medications lead to aberrant immune regulation early in the course of renal failure. This results subsequently in increased frequency and severity of infection. Vaccination plays an important role in attenuating this infection risk, but impaired cell-mediated and humoral immunity contraindicates the use of live vaccines and engenders suboptimal and short-lived antibody responses to inactivated vaccines. Reinforced vaccination schedules, increased vaccine dosage and concomitantly administered adjuvant immunomodulators have variably improved the defective antibody responses to certain vaccines. Immunisation against hepatitis B virus has resulted in a significant decrease in prevalence and incidence of this infection in haemodialysis units. Similarly, the inoculation of influenza vaccine in patients with uraemia and of polyvalent pneumococcal vaccine in special risk circumstances has been recommended because of perceived reductions in morbidity and mortality from infection with these agents. Cytomegalovirus (CMV) vaccine may attenuate CMV disease severity in recipients of renal allografts. Staphylococcus aureus vaccine, on the other hand, is ineffective in preventing peritonitis or exit site infections in patients receiving CAPD. Other killed vaccines have not been comprehensively studied, but generally have the same indications for use as in normal individuals. However, the protection that these vaccines afford may be either inadequate or transient, so that other infection control strategies should be simultaneously implemented.

Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations.

Augmentation of antioxidant defenses may help protect tissues against ischemia-reperfusion injury associated with operations involving cardiopulmonary bypass. In this study we examined the effect of pretreating patients with alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on injury to the myocardium. Seventy-six subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo-controlled randomized trial, receiving either placebo or both 750 IU dl-alpha-tocopherol per day for 7 to 10 days and 1 gm ascorbic acid 12 hours before the operation. Plasma alpha-tocopherol concentrations, raised fourfold by supplementation, fell by 70% after the operation in the supplemented group and to negligible levels in the placebo group. There were no significant differences between the groups with respect to release of creatine kinase MB isoenzyme over 72 hours, nor in the reduction of the myocardial perfusion defect determined by thallium 201 uptake. Electrocardiography provided no evidence of a benefit from antioxidant supplementation. Thus the supplementation regimen prevented the depletion of the primary lipid soluble antioxidant in plasma, but provided no measurable reduction in myocardial injury after the operation.

Parathyroid carcinoma associated with chronic renal failure and previous radiotherapy to the neck.

Carcinoma of the larynx was treated by irradiation followed by laryngectomy in a man who had been receiving regular haemodialysis for two years. At least one, and probably two, parathyroid glands were removed at this time, and the remaining two were removed three years later for tertiary hyperparathyroidism. A portion of one gland was implanted into the forearm. The forearm implant was resected the following year for recurrent hypercalcaemia. Six years later, again with recurrent hypercalcaemia, he died of bronchopneumonia. Metastatic parathyroid carcinoma was found in the apex of the left lung. The source of this parathyroid tissue and the possible role of irradiation in the pathogenesis of parathyroid cancer in this patient were investigated.

Tubular nephrotoxicity after cardiac surgery utilising cardiopulmonary bypass.

Markers of renal tubular injury were examined in 21 patients (16 male, 5 female, mean age 57.4 years) undergoing cardiac surgery utilising cardiopulmonary bypass. Postoperative urine outputs were very high (200-250 ml/h at 1-2 h), decreasing to 100 ml/h by 6 h. Although creatinine clearances did not vary significantly in the postoperative period (P = 0.16), significant changes were noted in the urinary concentrations of three tubular markers relative to creatinine concentration (P < 0.001). Urinary beta 2-microglobulin increased from negligible levels (median 0.01 mg/mmol creatinine) to peak at 4 h (median 4.55 mg/mmol), in part due to interference with its reabsorption by the plasma volume expander Haemaccel. Concentrations of the brush border antigen adenosine deaminase binding protein increased 6-fold, from a median of 5.03 arbitrary units (AU)/mumol to 31.2 AU/mumol at 48 h. The lysosomal enzyme N-acetyl-beta-D-glucosaminidase increased nearly 4-fold, from 0.68 units/mmol to 2.64 units/mmol at 48 h. Our results suggest that cardiac surgery utilising cardiopulmonary bypass is associated with acute tubular injury which can occur in the absence of overt changes in creatinine clearance.

Renal glomerular lesions in unselected patients with cirrhosis undergoing orthotopic liver transplantation.

Renal biopsies were obtained from 23 patients at the time of orthotopic liver transplantation. Twelve biopsies showed minor glomerular abnormalities, 2 exhibited IgA nephropathy and one showed mesangiocapillary glomerulonephritis type I. The remaining 8 patients had glomerular lesions diagnosed as hepatic glomerulosclerosis (HGS). Immunofluorescence, available in 6 of the 8 biopsies with HGS, revealed granular deposits of immunoglobulins and complement in glomerular capillary walls and/or the mesangium. IgA was seen in 5 biopsies with HGS, but the staining for this protein was no more intense than that for the other immunoglobulins in 4 of these. Electron microscopy in HGS revealed partial mesangial interposition, hypertophy of mesangial and endothelial cells, granular material in a widened subendothelial space, slender projections of endothelial cytoplasm extending into the subendothelial space, and clusters of vesicles in the mesangium and glomerular capillary walls. These ultrastructural abnormalities have not hitherto been reported as a group of associated pathological changes. The renal biopsies were obtained from patients with advanced hepatic disease not selected because of urinary abnormalities or renal dysfunction. The frequency of lesions in this group of patients therefore probably reflects the true incidence of glomerular lesions in cirrhosis and related conditions. Progressive decline in renal function was not observed in any patient during follow up which ranged from 11 days to 55 mths.

Poor response to a recombinant hepatitis B vaccine in dialysis patients.

Eighty-three dialysis patients were inoculated with 20 micrograms of the recombinant derived hepatitis B vaccine Engerix-B at o, I and 6 months. Twenty-seven (32.5%) became seropositive for anti-HBs antibody after the third inoculation. Of the 56 non-responders, 48 received a 40 micrograms booster dose of vaccine 6 weeks after completion of the initial course and a further eight seroconverted. Six months after the third inoculation only 18/71 patients retested (25.3%) had demonstrable antibodies. We were unable to identify clinical or laboratory parameters separating responders from non responders to the vaccine. We recommend regular checks of anti-HBs status of vaccinated patients as it cannot be assumed that even initial responders retain their immunity. Those infection control procedures known to have decreased the incidence of hepatitis B infection in dialysis units should not be relaxed.

Effect of withdrawal of folic acid supplementation in maintenance hemodialysis patients.

The requirement of patients on maintenance hemodialysis for dietary supplements of folic acid is controversial. High levels of folate carry the risk of toxicity as well as being unnecessary. We followed a group of 41 patients, not receiving erythropoietin, for 16 months after the cessation of folate supplementation (5 mg/day). Diet supplied 60-80 g protein and 120-260 micrograms folic acid/day. Red cell folate levels decreased linearly from a mean of 1931 +/- 888 micrograms/l (+/- SD) to 676 +/- 294 micrograms/l after 6 months before levelling off at 455 +/- 222 micrograms/l after 9 months. Mean values were unchanged 7 months later (491 +/- 319 micrograms/l). No patient developed folate deficiency. Hemoglobin values at 6, 9 and 16 months were slightly higher than the baseline value of 8.3 +/- 1.8 g/dl (p < 0.05). Mean corpuscular volumes were generally within normal limits, and vitamin B12 status was satisfactory. We conclude that folic acid supplements are unnecessary in adequately nourished hemodialysis patients who are not receiving erythropoietin.

Use of aminohydroxypropylidene bisphosphonate (AHPrBP, "APD") for the treatment of hypercalcemia in patients with renal impairment.

Aminohydroxypropylidene bisphosphonate (AHPrBP, "APD") is a relatively new bisphosphonate which has been shown to be effective for control of hypercalcemia due to a variety of causes. Renal impairment has been reported following the use of other bisphosphonates and pre-existing renal impairment has been regarded as a contraindication to the use of AHPrBP. We report the successful use of intravenous AHPrBP to control hypercalcemia in three patients with renal impairment, one of whom was dialysis-dependent. No significant side effects were noted; in particular, there was no further deterioration in renal function. Intravenous AHPrBP may be a safe and effective agent for the control of hypercalcemia in patients with renal impairment.

Influence of intraperitoneal dialyzate on blood pressure during continuous ambulatory peritoneal dialysis.

Blood pressure (BP) of patients on continuous ambulatory peritoneal dialysis (CAPD) must be well controlled. The present study tests a clinical impression that BP recordings are higher with dialyzate within the peritoneal cavity than after it is drained out. 8 CAPD patients had systolic BP, diastolic BP and heart rate measured both with dialyzate in situ and after drainage. Paired t-tests showed systolic BP and diastolic BP but not heart rate to be significantly (P less than 0.05) higher with dialyzate in situ. To avoid a false impression of good BP control it is recommended patients on CAPD measure BP with dialyzate in situ.

Dialysis-induced change in erythrocyte volume: effect on change in blood volume calculated from packed cell volume.

Blood volume (BV) change during hemodialysis is often monitored by packed cell volume (PCV). This assumes erythrocyte volume is constant. We tested this by dialyzing 5 patients for 2 hours against high (154 mmol/l), normal (140 mmol/l) and low (126 mmol/l) dialysate sodium concentrations. Erythrocyte water content, calculated from measured blood and plasma water contents, decreased with high and increased with low dialysate sodium concentrations. Erythrocyte volume, calculated from mean corpuscular hemoglobin concentration (MCHC) decreased 3.8% with high concentration dialysate and increased 2.5% when dialysate concentration was low. These changes correlated significantly (r = 0.80, p less than 0.01) with alterations in plasma sodium. Mean corpuscular volume (MCV), measured with a Coulter-S Plus Counter did not alter because of a methodological artefact. BV change can be calculated from PCV when plasma concentrations of osmotically active substances are changed only if allowance is made for altered erythrocyte volume.

In vitro pairing of Echinostoma revolutum (trematoda) metacercariae and adults, and characterization of worm products involved in chemoattraction.

In vitro pairing studies were done on chemically excysted metacercariae and on adults of Echinostoma revolutum maintained in vitro in agar-Locke's petri dish cultures at 39 +/- 1 C for up to 24 hr. Whereas newly excysted metacercariae did not pair, both immature and mature adults showed significant pairing. Adult echinostomes confined in dialysis sacs emitted excretory-secretory (EC) products which significantly attracted single echinostome adults in vitro. Only the lipophilic fraction of ES products was found to elicit attraction. Preparative TLC analysis of adult echinostomes produced three major bands as follows: I (phospholipids); II (free sterols); and III (free fatty acids + triglycerides). When tested in vitro, only the free sterol fraction significantly attracted single adult echinostomes. TLC and GLC analyses of free sterols of E. revolutum have indicated that cholesterol is the major free sterol.

A non-invasive continuous method of measuring blood volume during haemodialysis using optical techniques.

Hypotension during haemodialysis and fluid overload between treatments are major problems for haemodialysis patients. Clinical means of assessing hydration state can be relatively imprecise. We describe a non-invasive method of measuring absolute blood volume (BV) during a mock in vitro haemodialysis session which adds objective information to that assessment. As fluid is removed by ultrafiltration, haemoglobin concentration [Hb] rises proportionately with the fall in BV. An optical monitor clamped across the transparent dialysis tubing gives a continuous readout of near infra-red light transmitted through the blood, and this can be converted to [Hb] values. The net change in BV is the difference between the volume of fluid ultrafiltered and the volume which refills the vascular compartment from the extravascular space. By analysing the change in [Hb] and therefore the change in BV at two different rates of fluid removal, the absolute BV can be determined. The accuracy of this method was tested in vitro. This optical method accurately measures the change in BV over a range of [Hb] from 4 to 15 g/dl and blood circulation pump speeds of 150-300 ml/min. A series of 10 in vitro experiments was performed. The mean relative difference between the measured BV and the calculated BV, was 5.7 +/- 2.5%. This readily repeatable technique can accurately measure BV during a mock in vitro haemodialysis session, thus providing information for the clinical assessment of the hydration state. Information from these experiments will assist in future in vivo studies.

Increased skeletal uptake of Tc-99m methylene diphosphonate in milk-alkali syndrome.

A case of milk-alkali syndrome is described in a 34-year-old man taking an over-the-counter antacid preparation for gastroesophageal reflux. A Tc-99m MDP bone scan performed in the initial investigation of the hypercalcemia was markedly abnormal with a "metabolic" pattern of tracer uptake similar to that seen in hyperparathyroidism and humoral hypercalcemia. Following withdrawal of the antacid and calcium, the bone scan appearance returned to normal, as did the biochemical markers of his disease.