Methylamine Monomethylamine (MMA), dimethylamine (DMA) and trimethylamine (TMA) are the simplest compounds considered to be uremic toxins. Serum levels were reported to be two to three times higher in patients with ESRD compared with those with normal or near-normal renal function. 125,126
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Methylamine Monomethylamine (MMA), dimethylamine (DMA) and trimethylamine (TMA) are the simplest compounds considered to be uremic toxins. Serum levels were reported to be two to three times higher in patients with ESRD compared with those with normal or near-normal renal function. 125,126 However, available data and predictions based on their chemistry suggest that methylamines are poorly removed by dialysis, and early data suggest that they may even be produced in excess in uremic patients
A large volume of distribution may result in poor removal of methylamine by dialysis. These compounds are bases with a pKa ranging from 9 to 11. They therefore exist in a positively charged form at physiological pH. The lower intracellular pH compared to the extracellular pH should cause them to be preferentially sequestered intracellularly, with a volume of distribution exceeding that of body water. Indeed, measurements in experimental animals and humans confirm these predictions for DMA and TMA.
Because they circulate as small organic compounds that are not bound to proteins, these three amines are likely to be freely filtered. However, since they exist as organic cations, they also have the potential to be secreted by one or another family of organic cation transporters, and possibly also through Rh channels. 130,131 They therefore likely achieve clearances above GFR. The chemically similar exogenous compound tetraethylammonium has long been a prototype test solute for organic cation secretion, with clearance rates as high as (and in one study higher than) renal plasma flux. 132,133 Although formal renal clearance of DMA and TMA is not available, plasma disappearance of labeled compounds in rats results in total metabolic clearance of DMA and TMA approaching renal plasma flux. 128 In contrast, the urinary clearance of MMA in normal subjects is approximately one-third that of creatinine, indicating no net secretion of this amine. 127
The biochemical pathways leading to MMA, DMA, and TMA are not well described. Both host mammalian tissues and resident gut flora are thought to contribute to the net emergence of these amines. However, plasma MMA and DMA concentrations did not differ between ESRD patients with and without colon. 134 Dietary precursors of MMA, DMA, and TMA include choline and trimethylamine oxide (TMAO). 135–137 Production of these compounds may actually increase kidney failure, possibly caused by gut bacterial overgrowth. 127,129,138 Thus, fatty amine production may be increased in the face of impaired renal clearance.