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Study from Membranes researchers shows that defective renal acid-base handling causes hypoventilation in cystic fibrosis during alkalosis

Cystic fibrosis is one of the most common lethal genetic inherited diseases. It is caused by dysfunction of the ubiquitously expressed epithelial anion channel CFTR. Patients are affected by symptoms from most organ system, most severely by a reduced lung function. Electrolyte disorders, including alkalosis, are also frequent and metabolic alkalosis has been contributed a role in the ventilatory failure observed in the end stage of the disease. Peder Berg, Jens Leipziger and collaborators recently discovered an impaired renal base excretion ability in CF mice and patients that explain the occurrence of metabolic alkalosis in CF. A link between dysfunction of renal acid-base handling and ventilation had not previously been investigated. In this study, study they show that loss of CFTR in mice causes hypoventilation during an induced alkalosis.

Prof. Jens Leipziger (left) and Dr. Peder Berg (right).

Body acid-base homeostasis is controlled by the lungs and kidneys. CO2 (acid) is expired via the lungs and acids and bases are excreted by the kidneys. The actions of both organs are highly regulated to maintain a constant blood pH. The classic text-book understanding is that the kidneys need several hours to days to appropriately respond to acid-base disturbances. In contrast, the respiratory system acts instantaneously with either increased or decreased ventilation to either eliminate or retain CO2. Here, Peder and Jens show that the kidneys react rapidly, within the hour, to an acute base load. Specifically, this ability depends on the function of the base-secreting beta-intercalated cells of the kidneys’ distal segments, the collecting ducts. Disruption of this function by genetic knock-out of either the Cl-/HCO3- exchanger pendrin or CFTR impairs the renal ability to excrete base into the urine. An alkalotic challenge in these mice cannot be handled by the kidney resulting in retention of base in the blood, i.e. metabolic alkalosis which then suppresses ventilation. The study is published in PNAS.

The study is a collaborative effort between researchers within Membranes and Zoophysiology/AU.

Contact: Jens Leipziger, leip@biomed.au.dk