Dialysis-related amyloidosis: challenges and solutions.

Amyloidosis refers to the extracellular tissue deposition of fibrils composed of low-molecular-weight subunits of a variety of proteins. These deposits may result in a wide range of clinical manifestations depending upon their type, location, and the amount of deposition. Dialysis-related amyloidosis is a serious complication of long-term dialysis therapy and is characterized by the deposition of amyloid fibrils, principally composed of ß2 microglobulins (ß2M), in the osteoarticular structures and viscera. Most of the ß2M is eliminated through glomerular filtration and subsequent reabsorption and catabolism by the proximal tubules. As a consequence, the serum levels of ß2M are inversely related to the glomerular filtration rate; therefore, in end-stage renal disease patients, ß2M levels increase up to 60-fold. Serum levels of ß2M are also elevated in several pathological conditions such as chronic inflammation, liver disease, and above all, in renal dysfunction. Retention of amyloidogenic protein has been attributed to several factors including type of dialysis membrane, prolonged uremic state and/or decreased diuresis, advanced glycation end products, elevated levels of cytokines and dialysate. Dialysis treatment per se has been considered to be an inflammatory stimulus, inducing cytokine production (such as interleukin-1, tumor necrosis factor-α, interleukin-6) and complement activation. The released cytokines are thought to stimulate the synthesis and release of ß2M by the macrophages and/or augment the expression of human leukocyte antigens (class I), increasing ß2M expression. Residual renal function is probably the best determinant of ß2M levels. Therefore, it has to be maintained as long as possible. In this article, we will focus our attention on the etiology of dialysis-related amyloidosis, its prevention, therapy, and future solutions.

Atherosclerotic renovascular disease: medical therapy versus medical therapy plus renal artery stenting in preventing renal failure progression: the rationale and study design of a prospective, multicenter and randomized trial (NITER).

BACKGROUND: Many studies suggest a major prevalence of atherosclerotic renovascular disease (ARVD), caused by mono or bilateral renal artery stenosis (RAS). Unfortunately, there is no definite therapy to cure this disease to date; therefore, ARVD is burdened by important clinical complications with high social and economic costs. The last few years have seen important advancements in both medical therapy and in interventional radiology (for example, percutaneous transluminal renal artery stenting (PTRS)). All of them could affect, in some way, the natural history of ARVD, but to date the optimal strategy has not been established. METHODS: The protocol of a prospective, multicenter, randomized trial "Nephropathy Ischemic Therapy (NITER)" is presented. It enrolls patients with stable renal failure (glomerular filtration rate (GFR) >or=30 ml/min) and hypertension, and hemodynamically significant atherosclerotic ostial RAS (>or=70%) diagnosed by duplex Doppler (DD) ultrasonography and confirmed by magnetic resonance angiography (MRA). This study aims to evaluate whether medical therapy plus interventional PTRS is superior to medical therapy alone according to the following combined primary endpoint: death or dialysis initiation or reduction by >20% in estimated GFR after 0.5, 1, and 2 yrs of follow-up and an extended follow-up until the 4th year. Medical therapy means drugs to control hypertension, improve dyslipidemia and optimize platelet anti-aggregant therapy. The sample size is estimated in 50 patients per group to achieve a statistical significance of 0.05 in case of a reduction by 50% in the combined endpoints.

Insulin therapy in uremic diabetic patients on continuous ambulatory peritoneal dialysis; comparison of intraperitoneal and subcutaneous administration.

OBJECTIVE: To compare, in diabetic uremic patients on continuous ambulatory peritoneal dialysis (CAPD), the effects of two patterns of insulin administration, four times daily subcutaneous (SC) injections and intraperitoneal (IP) route, on blood glucose, insulin, lactate, beta-hydroxybutyrate and glycerol levels. PATIENTS AND METHODS: We examined 6 uremic insulin-dependent diabetic patients on CAPD. The two insulin regimens, SC and IP, were tested successively in randomized sequence in each patient. At the end of each treatment period we determined the 24-hour profiles of blood glucose, free insulin, lactate, beta-hydroxybutyrate, and glycerol. RESULTS: Mean blood glucose over 24 hours (SC 7.21 +/- 0.61 mmol/L, IP 7.49 +/- 0.93 mmol/L), Schlichtkrull's M value, an index of glycemic control and stability (SC 10 +/- 3, IP 10 +/- 5), and the blood intermediate metabolites beta-hydroxybutyrate, lactate, and glycerol were similar in both groups. Mean serum free insulin was significantly higher during subcutaneous treatment (SC 257.4 +/- 127.2 pmol/L, IP 170.4 +/- 83.4 pmol/L, p < 0.001). Insulin requirements were 2.5 times greater for the intraperitoneal route (SC 51 +/- 4 U/24 hours, IP 130 +/- 43 U/24 hours). CONCLUSIONS: In uremic diabetic patients on CAPD, good glycemic control may be achieved either with subcutaneous intensive insulin therapy or with intraperitoneal insulin administration. The latter method allows reduction of circulating free insulin levels, but requires a higher dose of insulin per day.