Thermodynamic and Electrochemical Characteristics of Urine Protein Molecules That Affect the Formation of Stones

Pathogenetic development of urolithiasis (UL) can be divided chronologically into prestone phase and stone phase. Specifically, the stone phase (SP) occurs from the moment when Randall plaque (RP), which is calcium phosphate (CaP) in 100% of cases, having destroyed the epithelial layer of the papilla in the renal calyx, comes into direct contact with urine, which is saturated not only with numerous inorganic microelements but also with various organic molecules, which always leave “traces of protein.” The study of the composition of the stone shows that, in addition to inorganic substances, there is always a protein component, the role of which has not yet been fully disclosed. The most unclear question remains why urinary proteins (uromodulin, osteopontin…) are able to both inhibit stone growth and act as promoters of stone formation. No less intriguing is the question of why calcium oxalate (CaOx) is the most common calculus in the urinary system. Objective. To determine the features of thermodynamic (TD) and electrochemical (EC) mechanisms that promote the growth of urinary calculus on the calcium phosphate (CaP) template already formed in the renal papilla in the form of RP and to establish the role of the protein (organic) component in this process as well as to find out the reasons why CaOx is the most common calculus in the urinary system. Materials and methods. A metaanalysis of TD and EC mechanisms promoting the growth of urinary calculus on the already formed CaP “seed” in the form of RP was performed, and the effect of the isoelectric point (pI) of proteins deposited on this CaP template was determined. Considering that CaOx stones are the most common (60–80%), the рI of urinary protein molecules affecting their growth was compared with the features of circadian urine pH fluctuations. An analogy of the adhesive theory of electrical and electron formation of complex compounds that determine metal−ligand homeostasis is presented. Results and discussion. Proteins (peptides, amino acids) are weak electrochemical molecules, on the outer surface of which (depending on the pH of the external environment) a cationic or anionic charge prevails. An individual feature of any protein is its specific рI, in which the protein loses its EC activity and precipitates. Subsequently, the corresponding inorganic substances floating in the urine settle on the already aggregated protein layer. As a rule, рI of any protein is located within narrow limits of pH fluctuations not exceeding 1 unit (∆рН < 1), while, for the aggregation of the protein, in addition to its stay in рI, time is needed, which determines the rate; i.e., a long stay of the protein in pI is necessary for the formation of an organic layer on the RP. The range of physiological fluctuations in urine pH during the day varies from 5.0 to 8.0 (∆pH ≈ 3). Obviously, with such a 1000-fold range of proton (H⁺) oscillations, none of the proteins present in the urine have time to aggregate, and, accordingly, the entire colloid-crystalloid system of urine is in a dissolved state. In those pathological cases when the urine pH is within narrow limits for a long time (10–15 days), not exceeding one (isoaciduria), it is possible that some protein (whose pI is within these specific limits) loses its activity (solubility) and precipitates on the RP, creating an organic layer. A layer of prosthetic metal ions and salts of various acids (often oxaloacetic…), present in the urine, is then formed on the surface of this protein matrix. Daily fluctuations in urine pH are not distributed evenly (≠const) in accordance with the Gauss−Laplace law, and the most common (60–80%) values are located in the range from 6.0 to 7.0 (∆pH < 1). The urine pH in patients with the initial stage of urolithiasis (including renal tubular acidosis) is in the same slightly acidic range, and the main thing is that, with CaOx stones, urinary proteins with pI located in exactly this range (from 6.0 to 7.0) are found with high reliability (p = 0.04)! This explains the well-known fact that, in 60–80% of cases of urolithiasis, stones of this particular type, CaOx, are found. Conclusions. During urolithiasis, RP formed at the apex of the papilla enters into unimpeded contact with urine and serves as a template for further stone growth, the process of aggregation of proteins located at the isoelectric point (pI), which is largely individual for each specific protein, begins to play a primary role. Since pI has its own narrow range of acidity (ΔpH < 1) for all protein molecules, then, consequently, with fluctuations in urine pH exceeding the limits of two units (ΔpH > 2), aggregation of any proteins on the RP is fundamentally impossible, and, in the absence of a protein layer (matrix), regardless of the degree of salt concentration, the possibility of subsequent formation and growth of any calculus (organo-mineral substrate—OMS) is excluded!