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Bleeding and thrombosis are well known major causes of morbidity and mortality in patients with myeloproliferative disorders (MPD) but the relationship between these clinical events and the commonly found platelet function abnormalities have not been established. In this study we performed simultaneous laboratory evaluations in 54 patients with MPD to investigate abnormalities in platelet aggregation and cyclooxygenase activity, the latter by using an in vitro aspirin inhibition test; the studies were repeated in 22 patients 1-27 months later. We have found platelet hyper- and hypofunction co-existing in some patients (9/54), and change of platelet function during the course of the disease (7/22) with platelet hypofunction being the only constant abnormality over time. These results may explain the lack of correlation between the clinical events and the limited assessment of platelet function in the hitherto published studies, and also suggest the need for repeated evaluations to properly assess the relative risk for bleeding and thrombosis.

We describe a 31-year-old patient with pure red cell aplasia of pregnancy, successfully managed with regular blood transfusions. In vitro studies showed specific inhibition of day 14 erythroid colonies (BFU-E) using serum and purified immunoglobulin G (IgG) obtained from the patient at diagnosis (before blood transfusion). The inhibition of BFU-E disappeared when haematological remission occurred 3 weeks after delivery and she remains clinically well with a normal haemoglobin 4 years later.

was statistically significantly stronger than with outpatient systolic BP (r=0.25, 95% confidence Background. Left ventricular hypertrophy (LVH ) is both common and an important predictor of risk of interval 0.23-0.27). The same was true for the correla- tion between LVMI and mean 24-h ambulatory dia- death in end-stage renal failure ( ESRF ). In mild to moderate chronic renal failure (CRF ), the timing of stolic BP (r=0.42, 95% confidence interval 0.40-0.44), and outpatient diastolic BP (r=0.22, 95% confidence onset of LVH and the factors involved in its initial development have not been fully elucidated. The pre- interval 0.20-0.24). Conclusions. Twenty-four hour ambulatory BP record- sent study was undertaken to examine the prevalence and potential determinants of echocardiographically ing and echocardiography are required for accurate diagnosis of inadequate BP control and early LVH in determined LVH in this connection, and to compare 24-h ambulatory blood pressure ( BP) recordings with patients with chronic renal impairment, independent determinants of which are hypertension, male sex, BP measured at a previous clinic visit. Methods. From a cohort of 120 non-diabetic patients BMI, and anaemia. who had been attending a nephrology clinic, 118 agreed to participate in the study. Of these we selected for chronic renal failure (CRF ); hypertension; left ventri- analysis 85 stable patients (37 male). Patients with cular hypertrophy ( LVH ) known cardiovascular disease, those with a history of poor compliance with antihypertensive medication, and those in whom such medication had been changed in the previous 3 months were excluded. Clinic BP, Introduction 24-h ambulatory BP, echocardiography, body mass index (BMI ), serum creatinine (SCr), creatinine clear- Cardiovascular disease is the leading cause of death in ance (CrCl ), haemoglobin ( Hb), fasting cholesterol patients on renal replacement therapy (1-3). Left vent- (CHOL), triglyceride TRlGL), plasma glucose, calcium ricular hypertrophy (LVH ) is a strong predictor of (Ca), phosphate ( PO 4 ), alkaline phosphatase (ALK myocardial infarction, cardiac failure, sudden death, PHOS ), parathyroid hormone (PTH ) concentrations, and stroke in patients with essential hypertension and and 24-h urinary protein were assessed in all patients. normal renal function and those with end-stage renal Seventy-seven per cent were on antihypertensive disease ( ESRD) (4-7). LVH is common in ESRD and medication. frequently predates the initiation of dialysis treatment Results. LVH was detected in 16% of patients with (7-9 ), suggesting that the factors responsible may be CrCL >30 ml/min, and 38% of patients with CrCl present in early renal impairment. Information regard

A randomized controlled study of iron supplementation in patients treated with erythropoietin. In view of current uncertainty regarding the optimum route for iron supplementation in patients receiving recombinant human erythropoietin (EPO), a prospective randomized controlled study was designed to investigate this issue. All iron-replete renal failure patients commencing EPO who had a hemoglobin concentration < 8.5 g/dl and an initial serum ferritin level of 100 to 800 µg/liter were randomized into three groups with different iron supplementation: Group 1, i.v. iron dextran 5ml every 2 weeks; Group 2, oral ferrous sulphate 200mg tds; Group 3, no iron. All patients were treated with 25 U/kg of EPO thrice weekly subcutaneously. The hemoglobin concentration, reticulocyte count, serum ferritin, transferrin saturation, and EPO dose were monitored every two weeks for the first four months. Thirty-seven patients entered the study (12 i.v., 13 oral, 12 no iron). The three groups were equivalent with regard to age, sex, and other demographic details. Even allowing for dosage adjustments, the hemoglobin response in the group receiving i.v. iron (7.3 ± 0.8 to 11.9 ± 1.2 g/dl) was significantly greater than that for the other two groups (7.2 ± 1.1 to 10.2 ±1.4 g/dl and 7.3 ± 0.8 to 9.9 ± 1.6 g/dl for Groups 2 and 3, respectively; P < 0.005 for both groups vs. Group 1 at 16 weeks). There was no difference between the groups supplemented with oral iron and no iron. Serum ferritin levels remained constant in those receiving i.v. iron (345 ± 273 to 359 ± 140 µg/liter), in contrast to the other two groups in which ferritin levels fell significantly (309 ± 218 to 116 ± 87 µg/liter and 458 ± 206 to 131 ± 121 µg/liter for Groups 2 and 3, respectively; P < 0.0005 for Group 1 vs. Group 2, and P < 0.005 for Group 1 vs. Group 3 at 16 weeks). Dosage requirements of EPO were less in Group 1 (1202 ± 229 U/kg/16 weeks) than in Group 2 (1294 ± 314 U/kg/16 weeks) or Group 3 (1475 ± 311 U/kg/16 weeks; P < 0.05 vs. Group 1). The results of this study suggest that, even in iron-replete patients, those supplemented with i.v. iron have an enhanced hemoglobin response to EPO with better maintenance of iron stores and lower dosage requirements of EPO, compared with those patients receiving oral iron and no iron supplementation.

Four hundred consecutive episodes of continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis in 105 patients were analysed. Of these episodes 161 (40.25%) were caused by coagulase-negative staphylococci (CNS). Thirty-seven patients developed recurrent attacks (3-10) of peritonitis and CNS accounted for 72 (60%) of these episodes. Classification of reinfection or relapse in 67 of these recurrent episodes of peritonitis was based on clinical criteria alone. This was compared with the results of three typing methods of CNS strains: biotyping plus antibiograms, immunoblotting and 35S-methionine-labelled protein patterns (radio-PAGE). Radio-PAGE was the most discriminatory method followed by biotyping with antibiograms and then immunoblotting. There was total agreement between clinical diagnosis and the three typing methods in 67.2% of episodes but there was total disagreement between the clinical diagnosis and the three typing methods in 11.9%, suggesting inaccurate clinical diagnosis, and in 20.8% typing by at least one method differed from the clinical criteria. Thus, clinical criteria alone are inadequate for the accurate distinction of reinfection from relapse in recurrent CNS peritonitis. This distinction is desirable for optimal management and accurate assessment of different therapies. We suggest that CNS strains from peritoneal dialysate are stored for future typing should the patient develop repeated episodes of peritonitis, to aid in the diagnosis and management of such patients.

In vitro hemostatometry and assessment of thrombolysis was carried out in three groups of 72 renal transplant recipients. In one (triple, n = 21) immunosuppression was with cyclosporine, azathioprine, and prednisolone, while a second group (CsA, n = 29) received cyclosporine and prednisolone alone, and the third group (Aza, n = 22) azathioprine and prednisolone. Results were compared with those in 30 normal controls. A statistically significant increase in hemostasis compared with controls was seen in the triple group and in patients in the CsA group studied within 2 years of transplantation. Hemostasis in the Aza group did not differ from normal. All patients in this group had been transplanted more than 2 years before study. Thrombolysis times were significantly prolonged compared with controls in all three groups. Cyclosporine treatment is associated with enhanced hemostasis and reduced thrombolysis, especially during the first 2 years after renal transplantation. If these in vitro findings reflect events in vivo, this may throw light upon the pathogenesis of the obliterative arteriolopathy that is a feature of cyclosporine nephrotoxicity.

Atherosclerotic renal artery stenosis (RAS) is a recognized cause of renal impairment. RAS is often overlooked in unexplained chronic kidney disease (CKD). A retrospective analysis of renal angiograms was performed to determine the prevalence of occult renovascular disease in 64 (M:F, 46:18; ages 21-81 years [median 60 years]) patients with unexplained CKD. Twelve patients had diabetes mellitus (type II: 11) and 43 were smokers. Median serum creatinine was 5.2 mg/dl (range 1.5-10.6 mg/dl). Group A included patients with unexplained CKD and with no risk factors for RAS and Group B had patients with increased risk for RAS. A narrowing of the renal vessel, main artery or branch, by >50% on renal arteriography was used as diagnostic criteria for RAS. 31/64 patients had positive angiographic findings. Thirteen patients had unilateral RAS, 9 had bilateral RAS, 5 had unilateral stenosis with occlusion on the opposite side, 3 had unilateral occlusion and 1 had a solitary kidney with RAS. 19/34 (54%) in Group A and 12/30 (40%) in Group B had a positive renal angiogram. In 10 patients with a rise in serum creatinine on recent introduction of ACE inhibition, 2 had evidence of RAS on renal arteriography. Eleven patients underwent angioplasty and 2 reconstructive surgeries. In 4 patients, blood pressure control improved and anti-hypertensive drug requirements were reduced, whilst renal replacement therapy was postponed in 4, by 2-24 months. In 18 patients, the lesions were not amenable to angioplasty or reconstructive surgery. Four patients did not benefit in any form with intervention. Occult atheromatous renal vascular disease is a common, not readily predictable and potentially correctable etiology of unexplained CKD.

The anticoagulant effect of warfarin should be kept at an international normalised ratio (INR) of about 2.5 (desirable range, 2.0-3.0), although a higher level may be better in a few clinical conditions. The risk of bleeding increases exponentially with INR and becomes clinically unacceptable once the INR exceeds 5.0. Warfarin therapy should be continued for around six weeks for symptomatic calf vein thrombosis, and for 3-6 months after proximal deep vein thrombosis (DVT) that occurs after surgery or limited medical illness. Therapy for six months or longer could be considered for DVT occurring without an obvious precipitating factor, proven recurrent venous thromboembolism (VTE), or if there are continuing risk factors. Oral anticoagulants prevent ischaemic stroke in atrial fibrillation (AF). Maximum efficacy requires an INR2.0, but some benefit remains at an INR of 1.5-1.9. Patients aged over 75 years are at greatest risk of intracranial bleeding during warfarin therapy for AF, and the target INR may be reduced to 2.0-2.5, or perhaps as low as 1.5-2.0, in such patients. Warfarin should be withheld if it is more likely to cause major bleeding than to protect from stroke (e.g., in young people with isolated AF where the annual baseline risk of stroke is1%). In patients with AF, aspirin is less effective than warfarin (much less effective after such patients have had a stroke or transient cerebral ischaemia). In people with prosthetic heart valves, an INR of 2.5-3.5 is probably sufficient for bileaflet or tilting disc valves, but a higher target INR is necessary for caged ball or caged disc valves. The addition of aspirin (100 mg/day) further decreases the risk of embolism but increases the risk of gastrointestinal bleeding.

The prevalence of sensorineural hearing loss, measured by pure tone audiometry, was determined in 66 patients with chronic renal failure and threshold changes following haemodialysis were measured in 31 patients. The incidence of hearing loss was 41% in the low, 15% in the middle and 53% in the high frequency ranges respectively. No correlations with weight changes, haematocrit, metabolic bone disease or ototoxic drug history were found. Of 62 ears studied, 38% had a decrease in low frequency threshold after dialysis and 9% had an increase. Threshold in 22/31 ears with pre-existing low frequency loss altered after dialysis with little change in other frequencies and no correlation with weight changes. In conclusion, we find a high incidence of low and high frequency hearing losses in chronic renal failure patients. Fluctuation in low frequencies with dialysis is common. Possible mechanisms include treatment induced changes in fluid and electrolyte composition of endolymph.

The 20210A prothrombin mutation has recently been associated with an increased risk of venous thrombosis, but the mechanism of the increased thrombotic risk in affected persons has not been elucidated. We report on a thrombophilic family in which the proband presented with cerebral vein thrombosis and homozygosity for the 20210A prothrombin mutation as her only identifiable risk factor for venous thrombosis. Extended genotyping of family members revealed seven other affected, but asymptomatic, first-degree relatives (one A/A homozygote and six G/A heterozygotes). Plasma levels of prothrombin, prothrombin fragments 1 + 2 and thrombin-antithrombin complexes were highest in A/A homozygotes, intermediate in G/A heterozygotes and lowest in those with the G/G homozygous normal genotype, while D-dimer levels were elevated only in A/A homozygotes. Our results suggest that the 20210A prothrombin mutation is associated with activation of coagulation and increased thrombin generation, not only in patients with a past history of thrombosis but also in otherwise healthy asymptomatic persons. In a similar fashion to the homozygous factor V Leiden mutation, patients with the homozygous 20210A prothrombin mutation could be at highest risk of thrombosis, as suggested by our patient who presented with unusual thrombosis.

The 20210 G/A prothrombin gene mutation is associated with an increased risk of venous thrombosis but whether there is an association of the mutation with premature coronary artery disease and acute myocardial infarction remains unclear. To further assess the role of the G/A genotype as a risk factor for arterial vascular disease, we performed a case-control study of 644 patients aged less than 50 years with angiographically proven coronary artery disease, 402 of whom had myocardial infarction, and 679 unrelated healthy control subjects aged less than 50 years, randomly selected from the electoral roll. The prevalence of the G/A genotype was 2.5% in patients with coronary artery disease, and 3.2% in control subjects (odds ratio 0.8; 95% confidence interval 0.35 to 1.83). The mutation was not more frequent among patients with a history of myocardial infarction (2.2%, odds ratio 0.7; 95% confidence interval 0.27 to 2.05), and there was no evidence of an interaction between the prothrombin mutation and conventional cardiovascular disease risk factors. There was no association between genotype and extent of angiographic coronary artery disease (p=0.73). We conclude that the 20210 G/A prothrombin gene mutation is not a major risk factor for premature coronary artery disease in our predominantly Caucasian Australian population.

Adult polycystic kidney disease has been found in association with pathological dilatation of the seminal vesicles in six patients. These men appeared normal on clinical examination, but had azoospermia or severe oligozoospermia. They were investigated by scrotal exploration with vasography, renal and transrectal ultrasound scans (TRUS), and percutaneous puncture of the seminal vesicles in one case, before and after resection of the ejaculatory ducts. This revealed that the gross dilatation of the seminal vesicles was not caused by obstruction, but appeared to be due to atonicity (megavesicles). These ultrasonic appearances, when described previously, were incorrectly thought to be due to seminal vesicle cysts.

Summary Four patients with idiopathic membranous glomerulonephritis, heavy proteinuria and progressive renal failure received azathioprine and prednisolone. Renal function improved in all four and proteinuria declined sharply in three. We suggest that treatment with azathioprine and prednisolone may be of benefit in this form of idiopathic membranous glomerulonephritis.

Eighteen patients aged 60-84 years with acute myeloid leukemia were treated with low-dose combination chemotherapy comprising cytarabine, etoposide, and mitozantrone or 6-thioguanine; seven of these patients had a pre-existing myelodysplastic syndrome. Nine patients achieved a complete remission, and five had a partial remission. The duration of survival in these 14 responding patients has ranged from 2+ to 19+ months. Myelotoxicity occurred regularly, with time to recovery (neutrophilsor =0.5 x 10(9)/L, plateletsor =50 x 10(9)/L) from nadir being 10-14 days in 12 of the 14 patients. This novel approach with an overall response rate of 78% appears to be a simple and effective form of therapy for elderly patients.

Background Technetium-99m methoxy isobutyl isonitrile (Tc-99m MIBI) scintigraphy has been reported to be at least as reliable as thallium-technetium subtraction imaging in the preoperative localization of hyperplastic parathyroid glands in patients with renal failure. Reports have suggested that 50% of glands can be identified correctly by this method. The aim of this study was to improve on previous results and demonstrate that Tc-99m MIBI imaging has an important place in the preoperative work-up of these patients. Methods Eighteen patients on renal replacement therapy were studied. All had tertiary hyperparathyroidism and had Tc-99m MIBI imaging prior to parathyroidectomy. A refined reporting method was employed. The imaging results were compared to the subsequent surgical and histological findings. Results In the 12 patients in whom serum parathyroid hormone levels fell postoperatively to within or below the normal range, 38 of 46 glands (82.6%) were correctly identified and located in the correct quadrant of the thyroid gland. There were two false positive results where the imaging predicted glands not subsequently found by the surgeon. In the patients who had post-operative hyperparathyroidism, repeat Tc-99m MIBI imaging was able to locate accurately the site of the residual parathyroid tissue. Conclusions Tc-99m MIBI imaging is able to identify more than 80% of hyperplastic parathyroid glands in renal failure patients if this reporting process is used, and locate them in the correct quadrant of the thyroid gland. Tc-99m MIBI imaging is of particular value when re-exploration of the neck is required for post-parathyroidectomy hyperparathyroidism. These results represent a significant improvement on the sensitivity of this imaging technique when compared to previous published data.

Objective To investigate the effect, if any, of renal failure upon prostate-specific antigen (PSA) levels and the validity of PSA estimation as a marker of prostatic disease in renal failure. Patients and methods PSA was measured in 65 men (median age 67 years, range 39–84) on regular haemodialysis and 37 men (median age 70 years, range 42–77) on continuous ambulatory peritoneal dialysis (CAPD). Patients with a PSA level >4 ng/mL underwent prostatic biopsy guided by transrectal ultrasonography. Results There was no evidence of an artefactual elevation of PSA attributable solely to renal failure. All eight patients with a PSA level > 4 ng/mL had prostatic disease. Conclusion PSA measurements in patients with end-stage renal failure treated by dialysis remain a useful marker of prostatic disease.

Parathyroid tissue is sometimes auto-transplanted into the forearm after 'total' parathyroidectomy in patients with renal failure. Recurrent hyperparathyroidism demands identification of the source of PTH secretion which cannot be assumed to be the forearm. To this end, Tc-99m methoxy isobutyl isonitrile (MIBI) scintigraphy was used to identify functioning auto-transplanted parathyroid tissue in seven patients undergoing renal replacement therapy (five with functioning renal transplants and two on haemodialysis). Serum PTH was estimated in venous blood taken proximal and distal to the forearm graft and from the contralateral arm, and subsequent Tc-99m MIBI scanning was carried out without knowledge of the PTH results. Five patients had a significant gradient in PTH levels between sites proximal and distal to the graft, and between the proximal site and the contralateral arm, suggesting functioning parathyroid tissue in the graft. Subsequent Tc-99m MIBI scintigraphy confirmed the activity of the auto-transplanted parathyroid tissue in these five patients. In the remaining two patients without a significant PTH gradient between the sampling sites, Tc-99m MIBI scintigraphy did not identify any functioning forearm parathyroid tissue. The scan results therefore correlated well with the gradients in PTH levels, suggesting that MIBI scintigraphy can be used to identify functioning auto-transplanted parathyroid tissue. The results also indicate that any patient who has undergone auto-transplantation of parathyroid tissue must have blood samples taken from veins proximal to the graft and either distal to it, or from the contralateral arm when parathyroid status is re-assessed, particularly when surgery is being considered for recurrent hyperparathyroidism.

AIMS--To differentiate between reinfection and relapsing infection with Staphylococcus epidermidis in a middle-aged woman with defective opsonisation and procidin function in serum. METHODS--Microbiological typing was done by biotyping, phage typing, and polyacrylamide gel electrophoresis of radiolabelled bacterial proteins (radioPAGE method). Polymorphonuclear cell function was assessed in vitro by phagocytosis and killing of Candida albicans; measurement of neutrophil random locomotion and chemotaxis; reduction of nitroblue tetrazolium after stimulation by opsonised Candida and a radiometric saccharomyces opsonisation assay. The effect of plasma infusions on opsonic activity was assessed by chemiluminescence using control polymorphonuclear leucocytes with a laboratory strain of S epidermidis opsonised with either patient or control serum. RESULTS--Recurrent reinfection with different strains of Staphylococcus epidermidis rather than relapsing infection was confirmed as having occurred by typing bacterial strains. The RadioPAGE method detected all the S epidermidis strains involved in this patient's illness. The patient's serum was shown to be defective in both opsonin and procidin function. The defects were correctable in vitro by the addition of normal serum. Clinical recovery occurred after repeated infusions of normal fresh frozen plasma and prolonged antibacterial treatment; antibacterial treatment alone was insufficient. CONCLUSIONS--The radioPAGE method is useful in distinguishing recurrent reinfection with S epidermidis from relapsing infection with this organism. Elucidation of the nature of, and underlying predisposition to, infection in the patient studied allowed a rational treatment plan of plasma infusion combined with antibacterial treatment to be devised which ultimately proved successful.

Although the haemostatic defects that occur in uraemia are complex, a major factor is the anaemia of renal failure. This may now be corrected by recombinant human erythropoietin (rHuEpo) therapy rather than by repeated blood transfusion. Platelet reactivity to shear stress and collagen was measured using non-anticoagulated blood to study the effect of erythropoietin or blood transfusion on platelet function. Twenty dialysis patients were commenced on 25-50 U/kg rHuEpo twice weekly. The dose was adjusted after 3 months to maintain target Hb 10-10.5 g/dl. A further 15 patients were studied before and 10-12 days after receiving blood transfusion. Baseline platelet reactivity was subnormal in both groups versus control (P < 0.0001). In the rHuEpo group, a significant increase in platelet reactivity was observed at 2 months (P < 0.005) which disappeared at 3 months. This was not related to the increase in Hb (7.3 +/- 0.3 to 10.2 +/- 0.3 g/dl, P < 0.0001). There was no change in platelet reactivity after transfusion, despite an increase in Hb (6.2 +/- 0.2 to 8.8 +/- 0.2 g/dl, P < 0.0001) similar to that occurring in the rHuEpo group. We conclude that after rHuEpo therapy but not after transfusion a transient increase in platelet reactivity occurs which is dissociated from changes in platelet and red cell numbers.

Increasing numbers of patients in the developed world are exposed to contrast medium during cardiac catheterisation procedures, and the pressure to increase cardiac laboratory throughput of patients with suspected coronary disease is unrelenting. For this reason, the problem of radiocontrast induced nephropathy (RCIN) assumes greater and greater importance. How is the fallout from contrast exposure to be minimised? Radiocontrast use in all branches of medicine is reported to be the third most common cause of new onset renal failure in hospital patients.1 Although varying definitions of nephropathy have been employed in the literature, including a 25% rise, a 50% rise or a doubling of serum creatinine concentration, it is clear that this is a common complication of cardiac catheterisation. In the recent epidemiological report by McCullough and colleagues, 1826 unselected patients undergoing coronary intervention were found to have a 14.5% incidence of acute contrast induced renal failure as defined by a 25% rise in serum creatinine.2 This may seem a relatively small decline in renal function but it has important consequences in terms of prolonged in-patient stay and cost.3 More severe derangements in renal function increase morbidity, mortality, and the risk of developing end stage renal failure.3 4 Of the McCullough group, 7.7 per 1000 required renal replacement therapy, an outcome that was associated with a 36% in-hospital mortality and a two year survival of less than 20%. The incidence of RCIN is likely to be higher following interventional procedures than after angiography alone but is certainly not confined to the former. The pathogenesis of RCIN is likely complex.5Currently, it is widely accepted that ischaemic damage to the renal medulla and a direct toxic effect of contrast medium upon renal tubular cells is of importance. Patients most …

1. Twelve patients receiving haemodialysis for end-stage renal failure were studied at a single dialysis session. Platelet cytosolic calcium concentration, plasma ionized calcium concentration and serum parathyroid hormone concentration were measured before dialysis, mid-dialysis and 30 min after dialysis. 2. Plasma ionized calcium concentration increased towards dialysate calcium concentrations, falling insignificantly after cessation of dialysis. Serum parathyroid hormone concentration fell by 39% during dialysis, with incomplete recovery afterwards. There was no overall change in platelet cytosolic calcium concentration. 3. Patients were divided into two subgroups: low parathyroid hormone (serum parathyroid hormone concentration < 10 pmol/l) and high parathyroid hormone (serum parathyroid hormone concentration > 10 pmol/l). Before dialysis, values of platelet cytosolic calcium concentration or plasma ionized calcium concentration were not statistically different between the subgroups, but the platelet cytosolic calcium concentration was higher in the high-parathyroid hormone subgroup during and after dialysis. 4. Before haemodialysis there was a linear correlation between plasma ionized calcium concentration and platelet cytosolic calcium concentration, which disappeared during dialysis. In contrast, there was no relationship between serum parathyroid hormone concentration and platelet cytosolic calcium concentration before dialysis, but after dialysis a hyperbolic relationship was evident. 5. These results suggest that uraemic toxins may interfere with cytosolic calcium homoeostasis, allowing passive diffusion of extracellular calcium to influence the resting concentration, and that this effect is reversible by haemodialysis.

Bleeding due to impaired primary haemostasis is common in uraemia. However, thrombo-embolic episodes are also a clinical problem in dialysis patients. Platelet reactivity to shear stress (haemostasis, H1 and H2), exposure to collagen fibre (thrombus growth) and coagulation of flowing blood (clotting time, CT1 and CT2) were measured in non-anticoagulated blood samples taken immediately before and 18-24 h after haemodialysis (n = 26) and from patients maintained on continuous ambulatory peritoneal dialysis (CAPD, n = 30). H1 (p < 0.001), H2 (p < 0.01), percent thrombus growth rate (p < 0.03), CT1 (p < 0.01 and CT2 (p < 0.05) were restored towards normal after haemodialysis. Results obtained in the CAPD patients demonstrated that the mean values for formation of the haemostatic plug lay between the pre- and posthaemodialysis values; however, CT1 (p < 0.01) and CT2 (p < 0.05) were prolonged in CAPD compared with values after haemodialysis. These data, which indicate platelet function from non-anticoagulated blood and coagulation under flow conditions, (1) confirm that there is impaired haemostasis in uraemia; (2) demonstrate an improvement in haemostasis after haemodialysis; (3) show that peritoneal dialysis results in a haemostatic profile which falls between the pre- and posthaemodialysis pattern, and (4) show that neither dialysis modality returns haemostasis to normal.

We identified twenty patients maintained on continuous ambulatory peritoneal dialysis who suffered repeated episodes of peritonitis caused by coagulase-negative staphylococci. We documented hand and exist-site coagulase-negative staphylococcus-associated peritonitis over a total period of 32 months, and compared hand and exit-site strains with strains isolated from dialysate fluid using three typing methods: biotyping using the API Staph kit plus antibiograms, immunoblotting using sera raised in rabbits to three standard strains of coagulase-negative staphylococci, and 35S-methionine-labelled coagulase-negative staphylococcal profiles separated on sodium dodecylsulphate polyacrylamide gel electrophoresis and visualised by autoradiography (radioPAGE). In 5 of 84 episodes, strains isolated from skin were indistinguishable by all three typing methods from the dialysate strain. In a further two episodes, hand or exit-site isolates were indistinguishable by all three typing methods from the dialysate strain isolated in the subsequent, but not the same, episode. Thus in the majority of episodes, no inference of hand or exit-site origin of dialysate infection could be drawn.

Histologic evidence of bone disease is present early in the evolution of chronic renal failure. Prevention of bone disease and hyperparathyroidism with vitamin D metabolites appears logical, but the few prospective, placebo controlled studies published involved patients with end stage renal failure [1]. Consequently, our double-blind study followed patients with mild to moderate renal impairment in an attempt to determine whether a beneficial effect upon serum biochemistry and histological abnormalities can be obtained without deleterious effects on renal function.

We have described 4 patients with chronic renal failure receiving regular haemodialysis treatment who underwent total parathyroidectomy with autotransplantation of parathyroid fragments into the forearm musculature for hypercalcaemic hyperparathyroidism. In all, there was an immediate and profound fall in plasma calcium levels. Hypercalcaemia recurred 1-5 years post-operatively and was resistant to resection of the autograft. In 3 cases, thallium-technetium subtraction scanning and multiple venous sampling for estimation of parathyroid hormone levels suggested multiple sites of hypersecretion of parathyroid hormone in the neck. In 1 case, these investigations revealed a mediastinal adenoma which was successfully removed. These cases reinforce previous suggestions that total parathyroidectomy is frequently incomplete and undermine the procedure of total parathyroidectomy with autotransplantation in patients with persisting uraemia.

1,25(OH) 2 D 3 administration in moderate renal failure: A prospective double blind trial. This study represents the first randomized prospective, double-blind, placebo-controlled trial of the efficacy of 1,25(OH) 2 D 3 on bone histology and serum biochemistry in patients with mild to moderate renal failure. Sixteen patients with chronic renal impairment (creatinine clearance 20 to 59 ml per min) received either 1,25(OH) 2 D 3 , at a dose of 0.25 to 0.5 µg daily (eight patients), or placebo. Transiliac crest bone biopsies were performed before entrance into the study and after 12 months of experimental observation. None of the patients were symptomatic or had radiological evidence of bone disease. Of the thirteen patients who completed the study, initial serum 1,25(OH) 2 D levels were low in seven patients and parathyroid hormone levels were elevated in seven patients. Bone histology was abnormal in all patients. 1,25(OH) 2 D 3 treatment was associated with a significant fall in serum phosphorus and alkaline phosphatase concentrations as well as with histological evidence of an amelioration of hyperparathyroid changes. In contrast to previous reports, no deterioration of renal function attributable to the treatment occurred, perhaps because a modest dose of 1,25(OH) 2 D 3 was employed combined with meticulous monitoring. Further investigation is required to determine whether alternative therapeutic strategies (smaller doses or intermittent therapy) may avoid the potential for suppressing bone turnover to abnormally low levels in the long term.

1. The clearance of isotopically labelled sodium diatrizoate by haemodialysis was measured in vitro, with simulated extracellular fluid, and in vivo in eleven patients, at varying rates of fluid or plasma flow. Clearance was also measured in five patients undergoing peritoneal dialysis. In all instances simultaneous measurements of urea clearance were made and the diatrizoate/urea clearance ratio was calculated. 2. In haemodialysis studies, diatrizoate and urea clearances showed a linear increase with increasing ‘extracellular fluid’ or plasma flow through the dialyser while the diatrizoate/urea clearance ratio fell. 3. The clearance of diatrizoate in vivo was slightly less than clearance in vitro at corresponding flow rates, but the diatrizoate/urea clearance ratio showed no significant difference. 4. Diatrizoate and urea clearances during peritoneal dialysis were very much lower than during haemodialysis but the diatrizoate/urea clearance ratios were within the same range. 5. The rapid removal of diatrizoate in patients with renal failure requires haemodialysis.

Fibrinogen/fibrin degradation products (FDP) have been measured in serum by radioimmunoassay for fragment E (FgE), one of the terminal fragments in plasmic digestion of fibrinogen, and the results compared with those determined by both a tanned red cell haemagglutination inhibiton immunoassay (TRCHII) and a latex particle agglutination inhibition immunoassay. The detection limit of the FgE assay was 0.8 ng/ml, that of TRCHII was 625 ng/ml and the latex particle agglunitaion inhibition immunoassay was 10 mug/ml. All the samples measured had detectable levels of FDP with the FgE assay, whereas only 88% were measurable with the TRCHII and 2% by the latex particle agglutination inhibition immunoassay. A comparison of those samples giving a positive result with both the TRCHII and FgE assay showed overall agreement between the results of the two types of assay, but there was considerable scatter of FgE levels at each point of the TRCHII. The major advantages of the radioimmunoassay system are greater sensitivity, specificity and reproducibility.

A number of conditions have been assessed for the collection of serum samples for the measurement of fibrin(ogen) degradation products using a radioimmunoassay for degradation fragment E, which permits precise quantitation of differences. Blood should be collected using minimal venous occlusion into glass tubes containing 10 mg/ml of epsilon amino caproic acid and allowed to clot at 4 to 20 degrees C for at least 4 hours before centrifugation. The serum may be stored at 4 or -20 degrees C. Samples from patients receiving anticoagulant therapy should be treated with 10 IU of thrombin per ml.

Summary. Twenty-two patients with accelerated hypertension and varying degrees of renal involvement have been studied in order to assess the significance of microangiopathic haemolytic anaemia (MAHA) and the possible pathogenic role of intravascular fibrin deposition in this condition. Vascular damage was assessed by retinal photography including fluorescein angiography. Haematological investigations including examination of peripheral films and assessment of red cell fragmentation were carried out. Fibrinogen catabolism was measured using radio-iodine labelled fibrinogen. No correlation between the degree of vascular damage in the retinal vessels and the blood pressure, degree of red cell fragmentation or evidence of renal damage was found. There was a significant increase in red cell fragmentation when the creatinine clearance was 20 ml/min or less. Fibrinogen derivatives were demonstrated in the serum in the minority and in the urine of the majority of those patients with MAHA. Fibrinogen catabolism was normal in all cases. The significance of microangiopathic haemolytic anaemia in accelerated hypertension is discussed. It is suggested from these data that the red cell fragmentation occurs predominantly within the kidney and that there is no evidence that fibrinogen deposition plays an important role in red cell damage, or that it is an important pathogenic factor in producing accelerated hypertension.

Summary. Fibrinogen catabolism has been studied in six patients with microangiopathic haemolytic anaemia, three patients with fragmentary haemolytic anaemia following the insertion of valve prostheses into the heart and ten control patients. Increased rates of catabolism of 131 I-fibrinogen were found in the patients with microangiopathic haemolytic anaemia. Evidence of enhanced fibrinolysis was not present. This finding suggests that intravascular coagulation is a feature of some cases of microangiopathic haemolytic anaemia and supports the hypothesis that the interaction of red cells with fibrin may result in the characteristic morphological appearances in these cases.

Summary. Twelve patients are described who developed well-marked micro-angiopathic haemolytic anaemia in association with metastatic carcinoma. The tumours originated in the stomach in six cases, in the breast in two cases, in the lung in one case and the origin was uncertain in three cases. All 11 tumours studied were found to be mucin-secreting adenocarcinomas. Ten out of the 12 patients were thrombocytopenic. Fibrinogen metabolism was studied in four patients and in each patient the catabolism of fibrinogen was found to be greatly increased despite normal or near normal plasma fibrinogen levels and an absence of overt fibrinolysis. Fibrin degradation products were demonstrated in the serum of five out of six patients. Hyaline thrombi were seen in the small blood vessels in the kidneys and suprarenals in one patient and in the myocardium in two patients, while changes suggestive of organized thrombi were present in the interlobular arteries of the kidneys in three patients. It is thought likely that the microangiopathic haemolytic anaemia develops secondarily to intravascular coagulation brought about by thromboplastins derived from mucin-forming tumour cells which have entered blood vessels, and that contact between circulating red cells and tumour emboli within blood vessels may be an additional cause of red-cell damage.

1. Tamm—Horsfall (T—H) glycoprotein has been measured by a specific radioimmunoassay method in the urine of patients with chronic renal failure, cadmium nephropathy and Lignac—Fanconi syndrome, and in renal and bladder calculi. 2. Total T—H glycoprotein excretion/24 h was markedly reduced in patients with chronic renal failure compared with normals. A highly significant correlation was observed between T—H excretion rate and creatinine clearance corrected for surface area, in both normals and patients with renal impairment. However, the mean T—H excretion per functioning nephron unit did not differ significantly in patients with renal failure compared with normals. 3. Total T—H excretion/24 h was in the normal range in patients with cadmium nephropathy despite reduced glomerular filtration rates, owing to a highly significant increase in T—H excretion per functioning nephron unit. Similar findings were obtained in a group of children with Lignac—Fanconi syndrome whose T—H excretion per functioning nephron unit was much higher than that of normal children in the same age range. This indicates an increased T—H glycoprotein excretion per functioning nephron unit in both these conditions. 4. T—H glycoprotein content of bladder and renal calculi ranged from 0002 to 5.07 mg/g of calculus. There was no correlation between T—H glycoprotein content and either the total protein content or the qualitative inorganic composition of the stones.