Light chains removal by extracorporeal techniques in acute kidney injury due to multiple myeloma: a position statement of the Onconephrology Work Group of the Italian Society of Nephrology.

Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is associated with increased short-term mortality. Additionally, even a single episode of AKI can eventually lead to end-stage renal disease (ESRD), significantly reducing quality of life and long-term survival. In the setting of multiple myeloma, severe AKI (requiring dialysis) is typically secondary to cast nephropathy (CN). Renal injury in CN is due to intratubular obstruction from precipitation of monoclonal serum free light chains (sFLC) as well as direct tubular toxicity of sFLC via stimulation of nuclear factor (NF)κB inflammatory pathways. Current mainstays of CN treatment are early removal of precipitating factors such as nephrotoxic drugs, acidosis and dehydration, together with rapid reduction of sFLC levels. Introduction of the proteasome inhibitor bortezomib has significantly improved the response rates in multiple myeloma due to its ability to rapidly reduce sFLC levels and has been referred to as "renoprotective" therapy. As an adjunct to chemotherapy, several new extracorporeal techniques have raised interest as a further means to reduce sFLC concentrations in the treatment of CN. Whether addition of extracorporeal therapies to renoprotective therapy can result in better renal recovery is still a matter of debate and there are currently no guidelines in this field. In this positon paper, we offer an overview of the available data and the authors' perspectives on extracorporeal treatments in CN.

Atrial fibrillation in end stage renal disease patients: influence of hemodialysis on P wave duration and atrial dimension.

BACKGROUND: Prevalence and incidence of atrial fibrillation (AF) are high in hemodialysis (HD) patients. Intra-atrial conduction velocity slowing plays an important role in AF onset. The aim of our study was to measure P wave duration (Pwd), expression of intra-atrial conduction velocity, in HD patients with and without a history of AF. METHODS: The study was performed in 47 end stage renal disease (ESRD) patients, subdivided into four groups: 19 patients within the first 6 months from starting HD therapy (HD1); the same patients studied 18 ± 3 months later (HD2); patients with no history of AF and long dialytic age (HD3, n = 13); and patients with sinus rhythm but history of AF (HDAF, n = 15); and 18 healthy controls. In all patients P wave high resolution recording and electrolyte plasma values were obtained before and after a HD session, and atrial diameter was assessed by echocardiography. RESULTS: Patients with the shortest dialysis vintage showed the shortest Pwd [131.2 ± 11.0 (HD1) vs. 139.8 ± 11.7 (HD2), 142.1 ± 7.2 (HD3), 152.3 ± 15.0 (HDAF) ms; p < 0.05], while Pwd was prolonged in patients with AF history when compared to all other groups (p < 0.03). At multivariate analysis atrial dimension was independently related to Pwd (R = 0.40, p < 0.02). HD session induced a significant increase of Pwd (141 ± 14.0-152 ± 17.0 ms, p < 0.001), that was correlated to modifications of K(+) concentration (R = 0.8, p < 0.0001). CONCLUSIONS: HD therapy prolongs Pwd. HD patients with a history of AF have prolonged Pwd compared to patients without, suggesting that increased Pwd is a marker of AF risk in patients with ESRD. HD session acutely increases Pwd, creating conditions favoring AF onset.

Kinetic modelling of haemodialysis removal of myoglobin in rhabdomyolysis patients.

An extended two compartment model is proposed to describe the dynamics of myoglobin in rhabdomyolysis patients undergoing dialysis. Before using clinical data to estimate the model's unknown parameters, structural identifiability analysis was performed to determine the parameters uniqueness given certain clinical observations. A Taylor series expansion method was implemented which found that the model was structurally globally/uniquely identifiable for both on- and off-dialysis phases. The fitted model was then used in a predictive capacity showing that the use of Theralite high cut-off (HCO) or HCO 1100 dialyser gave a significant reduction in myoglobin renal exposure compared to standard haemodialysis (HD).

Polymethylmethacrylate membrane and serum free light chain removal: enhancing adsorption properties.

INTRODUCTION: Polymethylmethacrylate (PMMA) membranes can adsorb a wide variety of uremic toxins including serum free light chains (sFLC). However, limited data are available regarding the clinical use of PMMA in multiple myeloma patients and its maximum adsorption capacity in this setting. AIM: This study aimed to measure the capacity of PMMA to adsorb sFLC and identify strategies to improve its efficiency in clinical practice. METHODS: Ten patients with dialysis-dependent renal failure and high levels of sFLC were included in the study. Five patients received standard PMMA hemodialysis (HD; n = 18), while in the other 5 patients a new technique called enhanced adsorption dialysis (EAD) was used, which involves PMMA dialyzer replacement after 2 h (n = 19). In all patients, sFLC were measured at the beginning and at the end of each dialysis session to calculate the difference between start and end of treatment and the percentage removal. RESULTS: PMMA membranes reduced sFLC in both the PMMA HD and EAD groups. PMMA HD showed similar efficiency on κ and λ percentage removal (22.3 and 21.0%, respectively, n.s.) but, in contrast, had a significantly greater effect on the delta of sFLC in κ [1,555 mg/l (-511 to +6,027)] versus λ [390 mg/l (120-650)] treatments (p = 0.007). EAD treatments only partially increased percentage removal of κ sFLC (22.3-31.0%, p = 0.38), while they had a significantly great effect on λ (21.0-53.1%, p = 0.003). A positive linear correlation was found between delta sFLC and pre-HD sFLC concentrations in PMMA HD κ treatments (r = 0.68, p < 0.02) but not for λ treatments (r = 0.54, p = 0.21), while the analysis of patients receiving EAD demonstrated a strong positive correlation for both κ and λ subtypes (r = 0.81 and r = 0.85, respectively, p < 0.008). In EAD sessions, a positive linear correlation was shown between blood flow during treatment and percentage removal of sFLC (r = 0.58, p = 0.02); however, with PMMA HD such a correlation was not observed (r = 0.28, p = 0.25). CONCLUSIONS: PMMA membranes can efficiently adsorb sFLC, but the process is limited by membrane saturation and is different between κ and λ sFLC. The new EAD technique can greatly improve λ removal but only partially act on κ sFLC. Therefore, EAD should be considered a valid economic treatment option without side effects in particular subsets of patients for the removal of sFLC.

Ultrastructural aspects of cynomolgus atherosclerotic carotid artery lesions on cholestyramine 'regression' treatment.

The carotid artery lesions of atherosclerotic cynomolgus monkeys treated with cholestyramine and studied with scanning electron microscopy appeared to be less bulging and largely covered by endothelial cells. With transmission electron microscopy these lesions showed an evident disappearance of cells and of extra- and intracellular lipid; a marked relative increase of fibrous material in the intercellular matrix, chiefly collagen and elastin fibers, was noted.

[Preliminary observations, at the ultrastructural level, on the reactivity of cerebral arteries from New Zealand rabbits to combined atherogenic stimuli (hypercholesterol diet and hypertension)]. / Osservazioni preliminari, a livello ultrastrutturale, sulla reattivita' delle arterie cerebrali di coniglio New Zealand a stimoli aterogeni combinati (dieta ipercolesterolica e ipertensione).

Both in monkeys (Rhesus and Cynomolgus) and in New Zealand rabbits fed an atherogenic diet, a marked delay in the appearance of atherosclerotic lesions of the cerebral arteries in comparison with other arterial districts has been observed. This appearance has been described in monkeys as relatively earlier if hypertension is added to the atherogenic diet. Preliminary observations on a little group of rabbits on a 3 months hypercholesterolic diet, subjected to Goldblatt aortic coarctation, have shown an increase of blood pressure and a severe gross atherosclerotic involvement of aorta, resembling the one obtainable after 6 months of atherogenic diet. Histologically, the aorta predominantly shows lesions of the fatty streaks type with necrotic areas in the deep; the carotid lesions show some lipid in smooth muscle cells disseminated in a sub-endothelial "edematous" space (rich in protein). The cerebral arteries do not show any lesion. At TEM, the aortic lesions look sometimes as advanced plaques with an initial fibrosis at the surface; the carotid lesions are characterized by a granular deposit in the sub-endothelial space in which some smooth muscle cells (with lipid in the cytoplasm) are present; in the cerebral arteries only the presence of collagen fibers among the smooth muscle cells of the media, never observed in the animals fed the atherogenic diet alone, has sometimes been noted.

An ultrastructural comparison of diet-induced atherosclerosis of arteries supplying the central nervous system in cynomolgus and rhesus monkeys.

The carotid lesions of cynomolgus and rhesus monkeys fed an 8- to 12-months atherogenic diet are very severe. However, the basilar, vertebral and middle cerebral arteries of the same atherosclerotic monkeys look instead, at SEM examination, similar to the control ones. At TEM examination, these arteries of the atherosclerotic monkeys show only minimal lesions in the subendothelial space ('edema' and presence of fragments of basilar membrane) and sometimes necrobiosis of endothelial cells. The smooth muscle cells, which are also present in the controls in these arteries in the subendothelial space, are sometimes surrounded by a nest of basement membrane beads and do not contain lipid droplets.

[Preliminary data on the different endothelial reaction to Con A at different levels of the arterial tree in rabbits and in Cynomolgus monkeys]. / Dati preliminari sulla diversa reazione endoteliale alla Con A, a differenti livelli dell'albero arterioso, nei conigli ed in scimie cynomolgus.

Delayed appearance of atherosclerotic lesions in cerebral arteries has been observed not only in man but also in monkeys and rabbits submitted to atherogenic diets. Previous observations of ours had shown a Con A positive reaction ("glycocalyx" or "surface coat") at the luminal surface and in the plasmalemmal vesicles of aortic endothelial cells of rabbits an other laboratory animals. The "surface coat" is now reputed the site of lipoproteinlipase activity whose importance in atherogenesis has recently been stressed. In our present observations, the endothelial cells Con A reactivity after Bernhard and Avrameas which was not previously studied in the cerebral arteries of rabbits and monkeys has resulted always lacking in this arterial district. Those observations may help explaining delayed appearance of atherosclerotic lesions in cerebral arteries.

Aortic surface coat scanning electron-microscopic modifications after short-term hypercholesterolic diet, visualized in rabbits by con A-haemocyanin reaction.

Modifications of the aortic endothelial surface coat have been visualized at SEM with the use of the Con A-haemocyanin method. After fifteen days of an atherogenic diet, a strong increase of the reactive coat was evident in areas near the orifice of the collateral branches. In other areas, the reaction appeared to be intensely diminished.

Regression of arteriosclerotic lesions in rhesus monkey aortas after regression diet. Scanning and transmission electron microscope observations of the endothelium.

Scanning and transmission microscopy were used to study aortic intima atherosclerotic lesions in Rhesus monkeys during both progression and regression phases. Scanning micrographs of severely atherosclerotic lesions showed areas of disjunctive endothelium and discontinuous basement membranes, frequently accompanied by red blood cells and other circulating elements adhering to the surface. Transmission micrographs also showed occasional areas of endothelial cell damage and loss with lipid-laden smooth muscle cells and foam cells beneath. Regressed lesions (affected by low-fat, low-cholesterol diet with or without cholestyramine) showed endothelial changes suggestive of reparative processes. Scanning micrographs showed flattened residual lesions with continous endothelial lining, while transmission microscopy disclosed interdigitated intercellular tight junctions and frequently reduplicated basement membranes.

Aortic endothelial and sub-endothelial lesions in early stages of experimental atherogenesis and in scurvy.

The endothelial and sub-endothelial lesions during early stages of experimental atherogenesis and scurvy have been studied by means of scanning EM and transmission EM, making use also of the Con-A reaction. The surface coat modifications were accompanied by formation of vacuoles in the endothelial cells and by sub-endothelial 'oedema', not only in rabbits fed a hypercholesterolic diet but also in scorbutic guinea pigs. The endothelial lesions were sometimes found even before clear modifications of the Con-A surface reactive layer were apparent.

Repair of early cholesterol-induced aortic lesions in rabbits after withdrawal from short-term atherogenic diet. Scanning electron-microscopical (SEM) and transmission electron-microscopical (TEM) observations.

Signs of repair of early atherosclerotic lesions after withdrawal of rabbits from a short-term atherogenic diet have been observed by means of scanning and transmission electron microscopy. The endothelial lining was lacking over large portions of the plaques during early atherogenesis. During the regression phase, hematic cholesterol values returned to normal, the smooth muscle cells of the plaques lost a large part of the lipids they had accumulated, while the surface of the plaques was covered by a continuous layer of endothelial cells.

Prevention by methylprednisolone of the endothelial lesions in rabbits on a hypercholesterolic diet or submitted to immunologic injury.

Methylprednisolone injections inhibit the thickness increase of the Concanavalin A reactive coat at the endothelial cell surface both in rabbits on a hypercholesterolic diet or submitted to pig aortic homogenate injections.