Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE.

INTRODUCTION: The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. AIMS: The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. METHODS: Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. DISCUSSION: If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5.

Secondary hyperparathyroidism complicated by parathyromatosis.

Secondary hyperparathyroidism is a common complication of chronic renal disease. Clinical signs and symptoms tend to be severe and often are not controlled with medical measures. When medical therapy fails, parathyroidectomy becomes necessary. Recurrent hyperparathyroidism is not uncommon following surgery. One cause of surgical failure is parathyromatosis, which has been described as multiple nodules of hyperfunctioning parathyroid tissue scattered throughout the lower neck, superior mediastinum, or the arm if autotransplantation has been performed. Five cases of parathyromatosis in patients with chronic renal failure were identified. Clinical characteristics, course, and prognosis of the patients are reported. All patients had evidence of renal osteodystrophy and complained of severe pruritus and bone and/or joint pain. Three of the five patients had evidence of soft tissue calcification, two complained of muscle weakness, two had multiple fractures, and two eventually died of complications resulting from parathyromatosis. In four of five cases, surgical and medical management were ineffective. The patients described illustrate the severe morbidity and mortality associated with the parathyromatosis in the setting of end-stage renal disease. The pathogenesis remains controversial. Although primary prevention appears to be the most effective means of avoiding this complication, it is mandatory that meticulous care be taken during surgical manipulation. If such measures fail, calcium supplementation, calcitriol, and phosphate restriction may be tried.

Safety and efficacy of recombinant human erythropoietin in correcting the anemia of patients with chronic renal allograft dysfunction.

Recombinant human erythropoietin (rHuEPO) is effective in correcting anemia in hemodialysis, peritoneal dialysis, and predialysis patients. Limited studies in patients with failing renal allografts suggest a similar efficacy but provide little information concerning benefits, dose requirements, or adverse events. This study examined these considerations in a group of 40 patients (18 men; 22 women) aged 40.3 +/- 13.8 yr with stable, chronic renal allograft failure. All patients had a hemoglobin < 95 g/L and a serum creatinine > 250 mumol/L at baseline. Patients received rHuEPO (50 U/kg sc) three times weekly for 24 wk along with iron po if serum ferritin was < 100 micrograms/L. Mean hemoglobin rose from 78.9 +/- 10.4 to 102.6 +/- 18.4 g/L after 24 wk. Mean rHuEPO dose at 24 wk was 129.8 +/- 81.9 U/kg per week. With oral iron supplementation only, serum ferritin fell throughout the 24 wk, whereas serum iron, transferrin saturation, and total iron-binding capacity remained stable. Quality of life was assessed by use of the general Sickness Impact Profile and the disease-specific Transplant Disease Questionnaire measures at baseline and every 8 wk during rHuEPO therapy. Significant improvement was noted in global Sickness Impact Profile scores and in four of five dimensions of the Transplant Disease Questionnaire. Serious adverse events were infrequent. No change in mean systolic or diastolic blood pressure was noted, although there was a significantly increased need for antihypertensive drugs in 18 patients (P = 0.0002). A significant inverse correlation was noted between baseline renal function and maintenance rHuEPO dose (r = -0.45; P < 0.05). Twelve patients returned to dialysis during the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Fish oil in lupus nephritis: clinical findings and methodological implications.

Our objective was to determine the effects of fish oil on renal function, symptoms, and serum lipids in patients with lupus nephritis. A double-blind, randomized crossover trial of fish oil versus placebo (olive oil) was done on 26 patients with confirmed systemic lupus; 21 completed the study. Intervention was fish oil or placebo, 15 g/day, for one year followed by a 10 week wash-out period, and then the reverse treatment for one year. At baseline and six month intervals, we measured platelet membrane fatty acids, indices of renal function, a disease activity index, serum lipid levels, blood pressure, serum viscosity and red cell flexibility. We found that platelet membrane phospholipids were uniformly affected by fish oil supplementation (P < 0.001) but with significant carry-over effects despite a 10 week wash-out period. Glomerular filtration rate and serum creatinine were not affected. A non-significant reduction in mean (SE) 24-hour proteinuria occurred, from 1424.1 mg (442.7) on placebo to 896.7 mg (352.2) on fish oil (P = 0.21). Fish oil lowered serum triglycerides from 1.89 (0.25) mmol/liter to 1.02 (0.11) mmol/liter (P = 0.004). VLDL cholesterol decreased markedly whether patients initially received fish oil or placebo (P = 0.004). The size of the reduction was affected by the order of treatment (P = 0.03), but parallel comparisons were significant before the crossover (P = 0.0006). With the possible exception of bleeding time, no other treatment effects were shown with fish oil. However, treatment order effects were seen in urinary IgG excretion (P = 0.03), whole blood viscosity (P < 0.0001), red cell flexibility (P = 0.004), and bleeding time (P = 0.06). In conclusion, one year of dietary supplementation with fish oil in patients with stable lupus nephritis did not improve renal function or reduce disease activity, but did alter some lipid parameters. Hitherto unreported carry-over effects and treatment order effects caused by the olive oil created a risk of type II error, and bear methodologic consideration in the design of future studies.

The role of aluminium and parathyroid hormone in erythropoietin resistance in haemodialysis patients.

Recombinant human erythropoietin (rHuEpo) is an effective therapy for anaemia in most patients with end-stage renal disease (ESRD). However, there remain a minority of patients with ESRD who are resistant to the effects of rHuEpo. The present study examined the role of aluminium overload and hyperparathyroidism of the biological effects of rHuEpo. Twenty-two patients aged 26-74 (mean 53 +/- SD 15.5) received rHuEpo 50-200 U/kg per week for 16.5 +/- 8.0 months (range 3-27). Haemoglobin was maintained at 11.5-13.0 g/dl by appropriate dose adjustment. Iron supplements were provided to maintain serum ferritin greater than 200 ng/ml. The mean time to rHuEpo response (Hb greater than 2 g/dl over baseline) was 6.1 +/- 2.6 weeks. Mean pretreatment serum aluminium correlated with time to Hb response (r = 0.48; P less than 0.05) and pretreatment mean corpuscular volume (r = 0.43; P less than 0.05) but not with eventual rHuEpo maintenance dose. PTH did not correlate with either Hb response or eventual maintenance rHuEpo dose. In summary, elevated serum aluminium concentrations were associated with an initial resistance to the biological effects of rHuEpo but had no effect on long-term dose requirements. In contrast, no impact of PTH on either immediate or long-term rHuEpo dose was evident.

Removal of aluminum during hemodialysis: effect of different dialyzer membranes.

Aluminum toxicity is now widely recognized as a major cause of morbidity in patients on maintenance hemodialysis. Desferrioxamine (DFO) chelation therapy has been suggested as a method of AI removal in such patients, though the most appropriate treatment schedule is yet to be established. In the present study, AI removal following DFO infusion was evaluated using two different dialyzer membranes to test the hypothesis that polyacrilonitrile (PAN) membranes permit better AI clearance. All patients studied had significantly elevated plasma AI concentrations (1.22 to 9.45 mumol/L; normal less than 0.56 mumol/L). Plasma AI did not correlate with estimated total AI intake. During hemodialysis with a cuprophane membrane, AI clearance ranged from 33.5 to 42.1 mL/min. Total AI removal was 192.2 +/- 90.4 mumol during cuprophane dialysis. During hemodialysis with a PAN membrane, AI clearance ranged from 35.7 to 54 mL/min. Total AI removal was 154.2 to 93.9 mumol during PAN dialysis. The differences in AI clearance and total AI removal were not statistically significant. It is concluded that use of a PAN membrane does not significantly enhance DFO-AI clearance.

Ultrafiltration studies in vitro of serum aluminum in dialysis patients after deferoxamine chelation therapy.

Using gel filtration chromatography, we evaluated aluminum bound to albumin, transferrin, and other plasma proteins in the serum of patients on maintenance hemodialysis. The proportion of dialyzable aluminum, as determined by selective membrane ultrafiltration and flameless atomic absorption spectrometry, increased by more than fourfold on treatment with the metal chelator, deferoxamine. This ultrafiltration technique may prove useful for monitoring the proportion of aluminum mobilized during such therapy.