Although the primary acid base disorder in patients with CF is caused by impaired ventilatory gas exchanges leading to CO₂ retention and chronic respiratory acidosis, the presence of metabolic alkalosis has been well documented in patients with CF for the last 5 decades (8–10). The preponderance of data has pointed to vascular volume depletion as the driving force in the generation of metabolic alkalosis in CF (8–10).

Recent studies have examined the pathogenesis of metabolic alkalosis in animal models and individuals with CF. These studies were mainly focused on acid base homeostasis in response to HCO₃ ^- loading. The first study in 2018 demonstrated that kidneys of CF mice had an impaired ability to excrete excess HCO₃ ^- during bicarbonate loading (4). In addition, there was a reduced expression of the HCO₃ ^- secreting transporter, pendrin (Slc26a4), in the kidneys of CF mice (4). Separate experiments in CF mice showed impaired HCO₃ ^- secretion in microperfused kidney collecting duct tubules (5). Follow up studies revealed that the kidney secretin receptor (Scrt) in the collecting duct is dysregulated in CF mice (5, 6), thus impairing the signal between the secretin secretion from the small intestine to a change in function of the kidney collecting ducts; and therefore, hampering the ability of the kidney to eliminate excess HCO₃ ^- (5–7). Whether the expression levels of secretin receptor are decreased in kidneys of either CF mice or patients with CF remain unknown.

There are no studies that have comprehensively looked at those CF individuals who have not been subjected to an oral HCO₃ ^- load, and yet present with metabolic alkalosis with increased frequency.

Published studies indicate that the two most common acid base disorders in cystic fibrosis are:

The authors of the above study (8) concluded that metabolic alkalosis contributes to acute hypercapnic respiratory failure in adult CF individuals.

In a study examining acid base disorders in patients with chronic pulmonary dysfunction, the authors investigated acid base homeostasis in individuals with CF vs. chronic obstructive pulmonary disease (COPD) (12). The authors reported that in patients with comparable forced expiratory volume in 1 second (FEV1), majority of patients with CF, but not those with COPD, had metabolic alkalosis (12).

The analysis of acid base parameters in individuals with CF (12) revealed the presence of a primary metabolic alkalosis in 57% (8/14) of subjects, and a mixed metabolic alkalosis along with respiratory acidosis in 28% (4/14) of participants. The authors concluded that stable patients with CF lung are more prone to display metabolic alkalosis than in COPD patients (12).

In an original study, children in the Tucson area that had been diagnosed as having CF before the age of 12 months were examined to ascertain the prevalence of metabolic alkalosis as a major presenting manifestation of the disease (13). Five of eleven infants (46%) in whom CF had been diagnosed between 1 and 12 months of age were initially seen with metabolic alkalosis, hypokalemia, and hypochloremia, unassociated with major pulmonary and/or gastrointestinal symptoms. Two infants had repeated episodes of metabolic alkalosis; for one of these infants, both episodes of metabolic alkalosis occurred before the diagnosis of CF (13). Ground breaking studies had convincingly demonstrated that individuals with cystic fibrosis could lose vast amounts of salt (Cl^- and Na⁺) in sweat, specifically in hot weather (14–16), which would precipitate vascular volume depletion. The enhanced loss of salt through sweat in individuals with CF was shown to be primarily due to a defective route of transcellular Cl^- uptake in sweat duct epithelium (17). It was postulated that chronic loss of sweat electrolytes together with mild gastrointestinal or respiratory illness may predispose young individuals with CF to develop a severe electrolyte and acid-base disturbance (13). Taken together the above studies indicate that metabolic alkalosis is a frequent occurrence in cystic fibrosis and may be independent of the presence of lung damage or infection.

The excess loss of chloride (salt) through sweat (CF), gastric content (vomiting), or kidney (in individuals with Bartter Syndrome or treated with loop diuretics) is a well-known factor that results in vascular volume depletion and precipitates metabolic alkalosis (18–20). Unlike patients who suffer from gastric acid loss (vomiting) and present with volume depletion and a very low urine chloride, patients with Bartter Syndrome present with volume depletion, metabolic alkalosis, and increased urine chloride (18, 21). Patients with CF can exhibit volume depletion and increased (but not decreased) urine chloride, a phenomenon which has been referred to as Pseudo Bartter Syndrome (22). It should be noted that in severe instances of volume depletion, patients with CF could present with a low urine chloride consistent with enhanced absorption of chloride in more proximal nephron segments (11).

The expression of CFTR in collecting duct cells varies according to cell type. It is most abundantly expressed in HCO₃ ^- secreting B-intercalated cells, followed by principal cells, and with the lowest levels found in acid-secreting A-intercalated cells (23). In an original study in 2018, the expression of the apical Cl^-/HCO₃ ^- exchanger, pendrin, was found to be significantly reduced, which resulted in impaired HCO₃ ^- excretion in response to an oral HCO₃ ^- load (4). These studies were confirmed by other investigators (5, 6). It was concluded that patients with CF are prone to the development of metabolic alkalosis when subjected to oral HCO₃ ^- loading secondary to the inactivation of the bicarbonate secreting transporter, pendrin in their kidneys (4–6). Additional investigations have shed more light on the link between oral HCO₃ ^- loading and the impaired ability of the CF kidney to eliminate excess HCO₃ ^- (5, 6). These experiments conducted in CF mice demonstrated dysregulation of Scrt (secretin receptor) in kidney B-intercalated cells (6). Taken together, these studies indicated that SCTR plays an important role in linking the circulating secretin with pendrin activation in kidney B-intercalated cells (5, 6).

Pendrin plays a dual role in acid-base and vascular volume regulation by secreting HCO₃ ^- into the lumen of the collecting duct in exchange for absorbing chloride (24–32). As such, pendrin is critical to both vascular volume regulation and acid base homeostasis (28–32). Increased circulating aldosterone, either as a primary event or consequent to vascular volume depletion, increases pendrin function in part through its translocation to the apical membrane from the subapical region (28, 30–32). In pendrin-deficient mice, imposing vascular volume depletion was associated with the inability to absorb chloride and secret HCO₃ ^-, thus resulting in the generation of metabolic alkalosis (28, 30–33). In a remarkably similar manner, CF mice developed a significantly higher serum HCO₃ ^- concentration vs. wildtype (WT) animals when placed on a salt deficient diet (with the serum HCO₃ ^- concentration increasing to 29.2 mEq/L in CF mice vs. 26.7 in WT; p<0.03) further supporting the critical role that pendrin plays in both volume regulation and acid base balance (4).

Figure 1 , left panel, is a schematic diagram depicting acid (H⁺) and base (HCO₃ ^-) secretion in A and B intercalated cells, respectievely, and electrolyte and water transport in principal cells in kidney collecting duct cells. As indicated in Figure 1 , right panel, pendrin mediates chloride absorption and HCO₃- secretion in B intercalated cells and shows overactivation in volume depleted state. As such, the impaired ability of pendrin to absorb luminal chloride and secret HCO₃ ^- results in an excessive loss of chloride into urine in the setting of vascular volume depletion, thus worsening the magnitude of alkalosis (Pseudo Bartter Syndrome).

Cystic fibrosis affects the integrity and functional properties of epithelial cells of several organs, including the respiratory tract, exocrine pancreas, intestine, vas deferens, hepatobiliary system, and exocrine sweat glands.

Published studies indicate that:

The activation of CFTR in pancreatic duct cells, airway epithelia, and the intestine enhances HCO₃ ^- secretion. Intense research on the role of CFTR activation in HCO₃ ^- secretion has identified several apical Cl^-/HCO₃ ^- exchangers from the anion transporting SLC26 family that physically interact and function in tandem with CFTR, thus contributing to enhanced HCO₃ ^- transport into the lumen of epithelial cells (46, 47). These apical Cl^-/HCO₃ ^- exchangers include SLC26A3 (DRA), SLC26A4 (pendrin) and SLC26A6 (PAT1) (48–50) and interact with the CFTR molecule through their STAS domain (46–49). The schematic diagram in Figure 2 depicts a remarkable similarity between the molecular machineries that facilitate HCO₃ ^- and Cl^- secretion in response to CFTR activation in airway epithelia (A), pancreatic ducts (B), and enterocytes of small intestine (C). It is plausible that the kidney B-intercalated cells may exhibit a similar activating interaction between CFTR and the Cl^-/HCO₃ ^- exchanger, pendrin ( Figure 2D ). As noted, CFTR mutations result in a widespread HCO₃ ^- secretion defect in the epithelial cells of the airways, pancreatic ducts, intestines, and the kidney collecting duct (4–6, 34–45). In addition to interacting with and stimulating the SLC26 Cl^-/HCO₃ ^- exchangers, a large number of studies support the conclusion that CFTR, when activated, becomes permeant to both Cl^- and HCO₃ ^- (reviewed in 51). Recent publications indicate that permeability of CFTR to various anions can be modulated by the WNK-SPAK pathway (51). The schematic diagrams in Figures 2A–C depicts the dual functional roles of CFTR in transporting Cl^- and HCO₃ ^- ions in an activated state in the pancreatic duct, enterocytes, and alveolar cells.

Excess HCO₃ ^- intake in WT mice results in an enhanced expression of pendrin along with increased HCO₃ ^- excretion (26, 27). A similar maneuver in CF mice, which display significant downregulation of pendrin, resulted in impaired HCO₃ ^- excretion along with the development of metabolic alkalosis (4–6, 36). These results indicate that a functional pendrin plays a sizeable role in preventing the generation of metabolic alkalosis in response to oral HCO₃ ^- loading. Based on the critical role of SCTR in activating pendrin-mediated HCO₃ ^- secretion in kidney B-intercalated (B-IC) cells in response to oral base (e.g., HCO₃ ^-) loading, recent studies suggest that loss of SCTR in CF impairs the appropriate increase of renal base excretion during acute base loading and that SCTR is necessary for rapid correction of metabolic alkalosis (5, 36). Extrapolated from these studies (5–7), it was proposed that the prevalent metabolic alkalosis in patients with CF could be explained by the absence of secretin-induced urinary HCO₃ ^- excretion (36). It was further suggested that patients with CF could be given a urine pH test after oral HCO₃ ^- loading to validate the efficacy of CFTR modulators in treating cystic fibrosis. Recent studies point to the impaired ability of CF patients to increase their urine HCO₃ ^- excretion during the presence of metabolic alkalosis (52).

It should be noted that while CF mice do not recapitulate several phenotypic presentations of individuals with CF (such as airway defect or male infertility), the GI and kidney manifestations in CF mice mirror those defects in human CF. In a search for non-primate models of CF, studies show that the porcine CF model exhibits a strong phenotypic resemblance to humans with CF in that the porcine model shows bacterial colonization, as well as airway anomalies at birth and the impaired ability of CF piglets to clear bacteria (53, 54). It would be enlightening to examine the role of pendrin and HCO₃ ^- secretion pathways in kidneys of porcine CF models. This issue becomes critical because it can shed light on whether lung infection/injury plays any role in the generation of metabolic alkalosis in cystic fibrosis.

As discussed in this minireview, the major determinant of metabolic alkalosis generation in CF is the development of vascular volume depletion, a process that is unencumbered by and independent of oral HCO₃ ^- load (8–13). It should further be noted that due to multiple medical ailments, patients with CF may exhibit a false positive response (impaired excretion of HCO₃ ^-) to the oral base loading test due to CF-independent tubular abnormalities. Amongst these medical maladies are:

Taken together, there are multiple medical maladies, as listed above, that are independent of CF that can interfere with enhanced excretion of oral HCO₃ ^- load.

In the kidney collecting duct, the Cl^-/HCO₃ ^- exchanger, pendrin (SLC26A4), significantly contributes to the maintenance of systemic vascular volume and blood pH during vascular volume depletion by absorbing luminal chloride in exchange for HCO₃ ^- secretion. This important defensive mechanism is hampered in individuals with CF, thus making them prone to the development of metabolic alkalosis and worsening of vascular volume depletion by excessive loss of salt in their kidneys (Pseudo Bartter Syndrome). In addition, kidneys of patients with CF may be ill-equipped to unload excess blood HCO₃ ^- concentration via pendrin due to the impaired cross talk between the circulating secretin and kidney B-intercalated cells. Please see the schematic diagram in kidney B-intercalated cells ( Figure 2D ). While the optimal treatment for the correction of metabolic alkalosis would be via the rectification of the underlying defect in the CFTR, the treatment of systemic volume depletion will go a long way to ameliorate existing metabolic alkalosis in patients with CF.