Middle molecule removal

Sieving coefficients of marker solutes such as vitamin B12 (MW = 1355 Da), inulin (MW = 5200 Da), and myoglobin (MW = 17,200 Da) are reported more often than sieving coefficients of known uremic toxins. Nevertheless, they serve as a useful tool in comparing potential middle molecule removal. 

In order to remove the endogenous toxicosis, we have applied various methods of detoxification in 22 patients. In 14 cases, one or two sessions of plasmapheresis were performed. Biochemical markers used for determining the level of toxemia were middle molecules . In six cases, against the background of intensive care, oral sorption (enterosorption) was administered 2-3 days after operative intervention. 

The first hemodialysis devices utilized natural cellulose (cuprophan) membranes, which possessed predominantly small pores. These membranes permitted the removal of excess fluid, ions, and small molecules, but prohibited the removal of substances above approximately 1200 Da in size. Larger molecules, such as P2-microglogulin (P2M, ll.SkDa), accumulated in the blood and were thought to contribute to many of the additional health problems and high mortality of patients on dialysis. This idea, coined the middle molecule hypothesis by Bapp et al. [342], led to the development of new synthetic polysulfone or polyacrylonitrile dialysis membranes that possessed larger pores and, in combination with equipment to control transmembrane pressure, permitted more efficient elimination of middle molecules. 

Fresh high-flux dialysis membranes achieve approximately 23—37% reductions in plasma P2M levels [344]. However, dialyzer reuse significantly impairs the removal of P2M [345]. Indeed, it has been recognized that non-specific adsorption of middle molecules on the surface of these synthetic high-flux membranes, rather than difiusion through the membrane, can account for significant amounts of the device s clearance [346, 347]. With the surface area of membranes in the dialysis device amounting to less than 2 m, the adsorption capacity of the device is obviously too small. 

There are at least three different types of uremic solutes which are potentially toxic and which can be characterized [Miyata, 2000 5576]. These inclnde (a) small water soluble compounds, such as urea and creatinine [Vanholder, 1998 5605] (b) middle molecules (c) protein-bound compounds. Most of the small water soluble compounds, such as urea and creatinine, are not particularly toxic and are easily removed with dialysis. 

Winchester JE Audia P. (2006). Extracorporeal strategies for the removal of middle molecules. Semin Dial 19, 110-114. 

While current therapy is believed to be effective in the clearance of small solutes such as urea, improved removal of middle molecules and protein-bound solutes is desirable. Henderson et al. (2001) point to the importance of quantifying the removal of larger toxic solutes in the fight of increasing evidence that shows a positive correlation between survival and middle molecule clearance in hemodialysis patients. A number of studies are underway to enhance the removal of middle molecules. These studies include (1) variations in modes of dialysis, (2) changes in dialyzer design to improve internal filtration, (3) targeted removal of specific molecules, and (4) increased frequency of dialysis. 

Immunoadsorption is another way to remove middle molecules, either specifically or nonspecificaUy. Adsorptive processes can be carried out either by chemically modifying a hemodialysis membrane to create adsorption sites or by the use of an add-on device during hemodialysis. It should be mentioned that the 1 to 2-m membrane surface area on the hollow-fiber lumen is much smaller than the surface area within the porous membrane structure and may be insuBicient to provide significant toxin removal. However, one could argue that adsorptive sites within the membrane wall offer httle benefit unless significant back filtration of a toxin is taking place because it makes no difference to the patient whether a toxin is adsorbed within the membrane walls or flushed away with the spent dialysate. 

Dialysis Treatment Time and Frequency Dialysis treatment time and frequency are important in the removal of middle molecules and other molecules that transport slowly within the human body. For small solutes such as urea, the transport gradient... 

A small number of proteins, and again insulin is an example, are synthesized as pro-proteins with an additional amino acid sequence which dictates the final three-dimensional structure. In the case of proinsulin, proteolytic attack cleaves out a stretch of 35 amino acids in the middle of the molecule to generate insulin. The peptide that is removed is known as the C chain. The other chains, A and B, remain crosslinked and thus locked in a stable tertiary stiucture by the disulphide bridges formed when the molecule originally folded as proinsulin. Bacteria have no mechanism for specifically cutting out the folding sequences from pro-hormones and the way of solving this problem is described in a later section. 

The middle spectrum Is recorded In CO-saturated SnCl./H.SO. after cycling the electrode potential through 1.2 V and tnen returning to 0.0 V. The spectrum Is virtually Indistinguishable from the first curve, which shows that the CO adlayer Is still saturated. This confirms that little, If any, adsorption of Sn adatoms occurs even after the initially adsorbed CO layer Is removed by oxidation. Instead, competitive adsorption of new CO molecules blocks the surface. 

Removal of the carboxyl group from a BS molecule leaves heneicosane (C21) which exhibits no liquid-crystalline phase, but does form two layered solid phases in which the C21 molecules are fully extended with the molecular axes normal to the layer planes [320]. In the higher temperature solid (Phase II), the molecules are hexagonally packed within and execute hindered rotations about their long axis. In the lower temperature solid (Phase I), the rotational motions are damped and the molecules are orthorhombically packed within a layer. Gauche defects in the preferred al -transoid conformations occur more frequently near layer ends than near the middle of layers... 

---