eprodisate and Kidney-Diseases

Amyloid A (AA) amyloidosis is a complication of chronic inflammatory conditions that develops when proteolytic fragments of serum amyloid A protein (SAA) are deposited in tissues as amyloid fibrils. Amyloid deposition in the kidney causes progressive deterioration in renal function. Eprodisate is a member of a new class of compounds designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils and deposition of the fibrils in tissues.. We performed a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of eprodisate in patients with AA amyloidosis and kidney involvement. We randomly assigned 183 patients from 27 centers to receive eprodisate or placebo for 24 months. The primary composite end point was an assessment of renal function or death. Disease was classified as worsened if any one of the following occurred: doubling of the serum creatinine level, reduction in creatinine clearance by 50% or more, progression to end-stage renal disease, or death.. At 24 months, disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of 94 patients given placebo (40%, P=0.06); the hazard ratio for worsening disease with eprodisate treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P=0.02). The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m(2) of body-surface area per year in the eprodisate and the placebo groups, respectively (P=0.02). The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94). The incidence of adverse events was similar in the two groups.. Eprodisate slows the decline of renal function in AA amyloidosis. (ClinicalTrials.gov number, NCT00035334.)

Topics: Amyloidosis; Arthritis, Rheumatoid; Creatinine; Disease Progression; Double-Blind Method; Familial Mediterranean Fever; Female; Glycosaminoglycans; Humans; Kaplan-Meier Estimate; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Propane; Proportional Hazards Models; Proteinuria; Serum Amyloid A Protein; Sulfonic Acids

The amyloidoses constitute a group of diseases in which misfolding of extracellular proteins plays a fundamental role. The aggregation of normally soluble proteins into insoluble unbranching fibrils is the basic underlying pathology in amyloidosis. The process of amyloid formation generates toxic insoluble (in saline) protein aggregates that are deposited in tissues in the form of β- pleated sheets of fibrillary material. The amyloidoses are considered to be part of the so-called protein storage diseases (protein thesauroses). In addition, due to the unusual protein folding associated with amyloid, this group of diseases has been referred to as conformational and protein folding disorders. For many years amyloidosis was considered an extremely rare, somewhat mysterious disease. However, in recent years its pathogenesis, particularly that of renal amyloidosis, has been carefully dissected in the research laboratory using in vitro and, to a lesser extent, in vivo models. These have provided a molecular understanding of sequential events that take place in the renal mesangium leading to the formation of amyloid fibrils and eventual extrusion into the mesangial matrix, which itself becomes seriously damaged and, in due time, replaced by the fibrillary material. Amyloid, once considered to be an 'inert' substance, has been proven to be involved in crucial biological processes that result in the destruction and eventual replacement of normal renal constituents. Although there are more than two dozen recognized amyloid precursor proteins (and new ones being added to the list) that can be involved in the genesis of amyloid fibrils, the pathophysiologic mechanisms that occur in the renal mesangium are likely to be very similar, if not the same, regardless of the type of amyloidosis. Likewise, the same is true of amyloid formation in the renal vasculature. Mesangial cells are essentially smooth muscle cells and the events that take place in the mesangium and vasculature (where smooth muscle cells and/or pericytes are present) in the entire body responsible for the formation of amyloid are the same. In the renal interstitium, fibroblasts likely participate in the formation of amyloid, following a similar sequence of events as smooth muscle cells. Although much of the information gathered has been from in vitro systems, an in vivo model of renal amyloidosis has recently been designed to study renal amyloidogenesis. Crucial steps in the cascade of events that result i

Topics: Amyloid; Amyloidosis; Genetic Therapy; Glomerular Mesangium; Humans; Kidney Diseases; Mutation; Propane; Protein Precursors; Sulfonic Acids

Topics: Amyloidosis; Colchicine; Familial Mediterranean Fever; Humans; Kidney Diseases; Kidney Failure, Chronic; Propane; Proportional Hazards Models; Sulfonic Acids