FO003
PREDICTING THE SAFETY AND EFFICACY OF BUFFER THERAPY TO CONTROL ACIDEMIA IN UREMIC PATIENTS

INTRODUCTION AND AIMS: Metabolic acidosis, one of the many complications associated with the progression of CKD, is characterized by a disequilibrium in acid-base homeostasis, resulting in bicarbonate depletion with acid retention, increased protein catabolism, and worsening of the already present CKD bone mineral disorder (CKD-BMD)—leading to increased morbidity and mortality. The aim of this study is to develop a simple, but realistic, dynamic model of the physiological regulation of an HCO₃⁻/CO₂ buffering system that allows us to investigate the effects of various therapeutic treatments of metabolic acidosis.

METHODS: The model uses the HCO₃⁻/CO₂ buffering system with Henderson-Hasselbalch mass-action kinetics. The model also incorporates body production of both CO₂ and H⁺, loss due to non-bicarbonate buffering, and physiological regulation of the HCO₃⁻/CO₂ buffer system through ventilation and renal filtration. The model is parametrized to normal arterial physiological values of pCO₂ = 40 mm Hg, HCO₃⁻ = 24 mmol/L, and pH = 7.4 (other model parameters, such as those involved with renal filtration, ventilation and reaction kinetics, are obtained from literature data).

RESULTS: We simulate normal physiological condition, metabolic and respiratory disorders (acidosis and alkalosis). The model accurately predicts the observed clinical responses, both in terms of pH and secondary compensations. That is, in the simulated respiratory disorders, changes in ventilation (resulting in acidosis or alkalosis) cause changes in CO₂, which alters HCO₃⁻ and H⁺ levels, before the renal compensation affects the amount of reabsorbed HCO₃⁻ and restores pH close to the normal physiological range. In metabolic disturbances, we do not observe such effective respiratory compensation; as a result, the pH never returns to the normal range. Furthermore, we compare in silico results with clinical data on acid-base homeostasis in patients with acetazolamide-induced, NH₄Cl-induced, renal tubular, uremic, and mixed acidemia. The simulated serum HCO₃⁻ with respect to CO₂ (secondary respiratory compensation) is within the 95% confidence interval of the clinical data. Moreover, comparing the given secondary respiratory compensation predicted by the model with that of the clinical values, we obtained a linear relationship, where the regression line, with a slope of 0.903 and intercept of 2.13, has an R² of 0.928 as compared to identity line with R² of 0.917. Given the performance of the model, we can investigate the efficacy of various therapies including bicarbonate, alkali and TRC101 (a novel sodium-free non-absorbed hydrochloric acid binding agent to treat CKD-associated metabolic acidosis, see Bushinsky et al., Clin. J. Am. Soc. Nephrol. 13 (2018): 26-35, CJN-07300717), and other hypothetical therapies.

CONCLUSIONS: The model has been used to accurately simulate serum pH in normal conditions and acid-base disorders. It can also be used to provide pathophysiologic insights and to assess the safety and efficacy of different therapeutic intervention strategies to control or correct these disorders, e.g., metabolic acidosis.