Acute hypercapnia may develop during periodic breathing from an imbalance between abnormal ventilatory patterns during apnea / hypopnea and compensatory ventilatory response in the inter-event periods. However, transition of this acute hypercapnia into chronic sustained hypercapnia during wakefulness remains unexplained. We hypothesized that respiratory - renal interactions would play a critical role in this transition. As this transition cannot be readily addressed clinically, we modified a previously published model of whole body CO₂ kinetics by adding respiratory control and renal bicarbonate kinetics. We enforced a pattern of 8 hours periodic breathing (sleep) and 16 hours of regular ventilation (wakefulness) repeated for 20 days. Interventions included varying initial awake respiratory CO₂ response and varying rate of renal HCO₃^- excretion within the physiological range. The results showed that acute hypercapnia during periodic breathing could transition into chronic sustained hypercapnia during wakefulness. While acute hypercapnia could be attributed to periodic breathing alone, transition from acute to chronic hypercapnia required either slowing of renal bicarbonate kinetics, reduction of ventilatory CO₂ responsiveness, or both. Thus, the model showed that the interaction between the time constant for HCO₃^- excretion and respiratory control result in both failure of [HCO₃^-] to fully normalize prior to the next period of sleep and persistence of hypercapnia through blunting of ventilatory drive. These respiratory/renal interactions create a cumulative effect over subsequent periods of sleep that eventually results in a self perpetuating state of chronic hypercapnia.