Anti-CD20 antibody in thrombotic thrombocytopenic purpura refractory to plasma exchange.

Thrombotic thrombocytopenic purpura is a rare condition characterized by microangiopathic haemolytic anaemia, thrombocytopenia, altered neurology, renal impairment and fever. While plasma exchange has reduced mortality from more than 90% to between 10 and 30%, a proportion of cases fail to respond. Rituximab may be efficacious in the management of refractory cases of thrombotic thrombocytopenic purpura. We present two cases in which rituximab was used with successful outcomes. Treatment resulted in resolution of severe clinical and haematological abnormalities in both patients. There has been no relapse after 16 months follow up. Our experience supports the use of rituximab in difficult cases of TTP. Ongoing evaluation of its use is in progress at our institution.

Randomized, placebo-controlled trial of intramuscular vitamin B12 for the treatment of hyperhomocysteinaemia in dialysis patients.

BACKGROUND: Plasma homocysteine is elevated in patients with end-stage renal disease (ESRD) and is a risk factor for cardiovascular disease. Folic acid has been shown to partially reduce homocysteine levels in dialysis patients. It is not known whether vitamin B12 reduces homocysteine independent of folic acid in patients who are not vitamin B12 deficient. AIM: To determine whether 1 mg vitamin B12 lowers homocysteine in stable, chronic, haemodialysis patients independent of folic acid. METHODS: Twenty-eight haemodialysis patients were randomized to receive three doses of 1 mg vitamin B12 or 1 mL saline placebo in a double-blind fashion at 1-month intervals. Fasting plasma total homocysteine, folic acid, red-cell folate, vitamin B12 and haemoglobin levels were determined prior to each dose and 4 weeks after the final injection. The study was powered to detect a 30% reduction in homocysteine over the 3 months. RESULTS: Both the two groups were well matched with respect to total homocysteine levels, folic acid, red-cell folate and vitamin B12 levels. Serum vitamin B12 levels were significantly higher in the treatment group compared to placebo (217.7 pmol/L; 95% confidence interval (CI) 103.0-332.5; P < 0.001) at the end of the trial but homocysteine levels were not significantly different (3.08 micromol/L; 95% CI -4.44-10.61; P= 0.406). CONCLUSIONS: The administration of intramuscular vitamin B12 over a 3-month period does not result in any reduction of plasma homocysteine levels in haemo-dialysis patients independent of folate status, however reductions of <30% cannot be excluded by the present study. High-dose folic acid remains the treatment of choice in reducing homocysteine, but whether this results in a reduction in cardiovascular events remains to be determined.

Carotid artery intima-medial thickness is increased in chronic renal failure.

1. Chronic renal failure (CRF) is associated with rapidly progressive atherosclerotic vascular disease. In the present study, carotid arterial intima-medial thickness (IMT) was assessed in a large cohort of patients with CRF and matched controls and related to risk factors. 2. A total of 159 subjects with CRF (serum creatinine > or =0.40 mmol/L) aged > 50 years (mean (+/-SD) 63.8+/-7.7 years) and 159 healthy controls matched for age, sex and smoking status were studied. 3. The IMT was determined using B-mode ultrasound measurements of the far wall of both common carotid arteries and presented as the mean IMT. Fasting plasma homocysteine (tHcy) was measured in the CRF group. 4. Intima-medial thickness was significantly greater in CRF patients than controls (0.89+/-0.17 vs 0.73+/-0.13 mm, respectively) after matching for age, sex and smoking status. Heart rate and pulse pressure were also significantly increased. The tHcy was increased two-fold in the CRF group (27.7+/-11.3 micromol/L; normal < 13.0 micromol/L) and did not correlate with carotid IMT. 5. Compared with controls after adjusting for traditional risk factors, patients with CRF exhibit significantly increased IMT.

A study of the interactive effects of oral contraceptive use and dietary fat intake on blood pressure, cardiovascular reactivity and glucose tolerance in normotensive women.

OBJECTIVE: To investigate the interactive effects of oral contraceptive pill use and dietary fat intake on cardiovascular haemodynamics and metabolic parameters in young normotensive women. DESIGN: Thirty-two women participated, of whom 16 were taking oral contraceptive pills (ethinyl-oestradiol plus levonorgestrel) and 16 were age-matched and weight-matched controls not taking such pills. Subjects consumed either a high-fat or a low-fat diet for 2 weeks in an open, randomized, crossover study lasting 6 weeks. Investigations were performed at the end of each diet during the luteal phase of the menstrual cycle. METHODS: Blood pressure was measured by 24 h ambulatory recording; cardiovascular reactivity was determined by examining blood pressure responses to systemic infusions of noradrenaline and angiotensin II and to the cold pressor test; and carbohydrate metabolism was investigated by an intravenous glucose-tolerance test. RESULTS: Plasma triglyceride levels were significantly higher in women taking oral contraceptive pills compared with non-users on both diets; however, responses of lipoprotein levels to the two diets did not differ between study groups (total and low-density lipoprotein cholesterol levels decreased by 15 and 17% in oral contraceptive pill users and by 14% each in non-users, on the low-fat compared with the high-fat diet). Fasting plasma insulin levels, the insulin-production response to administration of glucose (insulin area under the curve) and resting clinic and night-time systolic blood pressures were all significantly reduced on the low-fat diet, but only in non-users. Blood pressure responses to noradrenaline and maximal heart rate response to cold were significantly attenuated during the low-fat diet in oral contraceptive pill users. During the low-fat diet, resting systolic, 24 h systolic and diastolic blood pressures and insulin area under the curve were all significantly higher for women taking the oral contraceptive pills. Users of these pills also exhibited a greater systolic sensitivity to administration both of noradrenaline and of angiotensin II and had a higher plasma renin activity irrespective of dietary phase. CONCLUSIONS: These results confirm that oral contraceptive pills have the potential to cause adverse effects on blood pressure, cardiovascular reactivity and the insulin-production response to administration of glucose and suggest that some of the beneficial effects of a low-fat diet on these parameters may be negated in women taking oral contraceptive pills.

PIP: The interactive effects of combined oral contraceptive (OC) use and dietary fat intake on cardiovascular hemodynamics and metabolic parameters were investigated in a comparative study of 16 normotensive OC users from Australia and 16 age- and weight-matched nonuser controls. The 6-week study's crossover design allocated women to consume either a high- or low-fat diet for 2-week periods. Analyses were performed at the end of each diet during the luteal phase of the menstrual cycle. Plasma triglyceride levels were significantly higher in OC users than nonusers in both diet groups; however, responses of lipoprotein levels to the 2 diets did not differ between study groups. Total and low-density lipoprotein cholesterol levels decreased by 15% and 17%, respectively, in OC users, and by 14% each in non-OC users on the low-fat, compared to the high-fat, diet. Fasting plasma insulin levels, the insulin production response to administration of glucose, and resting clinic and night-time systolic blood pressures were all significantly reduced on the low-fat diet, but only in nonusers. In OC users, blood pressure responses to noradrenaline and maximal heart rate response to cold were significantly attenuated by the low-fat diet. During the low-fat diet, resting systolic, 24-hour systolic, and diastolic blood pressures and areas under the curve were significantly higher in the OC group. OC users also demonstrated a greater systolic sensitivity to administration of both noradrenaline and angiotensin II, and had a higher plasma renin activity, regardless of diet. Overall, these findings confirm that OCs can cause adverse effects on blood pressure, cardiovascular reactivity, and the insulin production response to glucose administration, and negate some of the beneficial effects of a low-fat diet.

Antithyroid and antiadrenal autoantibodies in antiglomerular basement membrane disease, thin basement membrane disease and Alport syndrome.

The basement membranes of the glomerulus, thyroid and adrenal all contain the Goodpasture antigen, the target of autoantibodies in antiglomerular basement membrane (GBM) disease. Antithyroid antibodies can be associated with antiGBM disease, and there have been occasional reports of antithyroid antibodies in Alport syndrome, an inherited kidney disease where the GBM lacks the Goodpasture antigen. The aim of this study was to determine how often antithyroid and antiadrenal autoantibodies occurred in antiGBM disease, Alport syndrome and a related condition, thin basement membrane disease (TBMD). Sera from patients with antiGBM disease (n = 19), Alport syndrome (n = 5) or TBMD (n = 13) were tested for antithyroglobulin, antithyroid microsomal and antiadrenal antibodies. Five of the patients with antiGBM disease (5/19, 26%, P NS) had antimicrosomal, and one had antithyroglobulin, antibodies (1/19, 5%, P NS). No patient with Alport syndrome had antithyroid antibodies. One with TBMD (1/13, 8%, P NS) had antithyroglobulin and antimicrosomal antibodies at titres of 1/400 and 1/25,600, respectively. Both patients with antithyroglobulin antibodies had previously been diagnosed with hypothyroidism. No one with antiGBM disease, Alport syndrome or TBMD had antiadrenal antibodies. Antithyroid microsomal antibodies do not occur significantly more often in patients with antiGBM disease than in normals, and antithyroid and antiadrenal antibodies are not associated with Alport syndrome or TBMD.

Remission of transplanted melanoma--clinical course and tumour cell characterisation.

The recipient of a cadaveric kidney was found to have donor melanoma within the graft together with metastatic spread. After cessation of immunosuppression, the kidney rejected and was removed. One month later there was both clinical and radiological evidence of remission and at autopsy 5 months later there was no histological evidence of melanoma. The outcome for recipients of other organs from the same donor was varied. Tumour cells expressed HLA class 1 antigens mismatched in the recipient and mRNA for the costimulator B7, and the cytokines GM-CSF, IL-1 alpha and beta. These characteristics may have been important in the host immunological response.

Ocular abnormalities in thin basement membrane disease.

AIM/BACKGROUND: Alport syndrome is an X linked disease that results in renal failure, deafness, and ocular abnormalities including a dot and fleck retinopathy and anterior lenticonus. The ultrastructural appearance of the glomerular basement membrane in thin basement membrane disease (TBMD) resembles that seen in some patients with Alport syndrome, and in some cases this disease is inherited too. The aim of this study was to determine whether patients with TBMD have any ocular abnormalities. METHODS: The eyes of 17 unrelated individuals with TBMD were studied by slit-lamp, including biomicroscopic fundus examination with a 78 D lens, by direct ophthalmoscopy, and by fundal photographs. The findings were compared with those in patients with IgA glomerulonephritis or Alport syndrome, and in normals. RESULTS: No patient with TBMD had a dot and fleck retinopathy or anterior lenticonus. A corneal dystrophy (n = 2) or pigmentation (n = 1), and retinal pigment epithelial clumping and maculopathy (n = 1) were noted. Corneal, lens, and retinal dots were found in five (29%), three (18%), and 16 (94%) patients, respectively, but these were also demonstrated in individuals with other renal diseases and in normal individuals. CONCLUSIONS: The dot and fleck retinopathy and anterior lenticonus typical of Alport syndrome do not occur in TBMD. The protein abnormality and genetic defect in TBMD are not known, but the lack of ocular lesions suggests that the abnormal protein in this disease is more sparsely distributed or less important in the basement membranes of the eye than of the kidney. Alternatively, the protein may be less affected by the mutations responsible for TBMD.

Microscopic polyarteritis following a suppurative wound infection.

Bacterial and viral infections may be associated with the onset of a number of autoimmune diseases and relapses of these conditions. We describe a patient in whom there was a close temporal relationship between a suppurative wound infection and the onset of microscopic polyarteritis. The clinical features of this disease responded to treatment with high dose prednisolone and cyclophosphamide. The patient had several further infective episodes while being treated, but there were no disease exacerbations or relapses related to these. Anti-neutrophil cytoplasmic antibodies (ANCA) were never demonstrated in this patient. Thus while it is likely that the infection precipitated the onset of the systemic vasculitic illness, this occurred independently of ANCA.