Metabolic alkalosis in cystic fibrosis: from vascular volume depletion to impaired bicarbonate excretion.

Cystic fibrosis (CF) is the most common life-threatening genetic disease in the United States and among people of European descent. Despite the widespread distribution of the cystic fibrosis transmembrane conductance regulator (CFTR) along kidney tubules, specific renal phenotypes attributable to CF have not been well documented. Recent studies have demonstrated the downregulation of the apical Cl-/HCO3 - exchanger pendrin (Slc26a4) in kidney B-intercalated cells of CF mouse models. These studies have shown that kidneys of both mice and humans with CF have an impaired ability to excrete excess HCO3 -, thus developing metabolic alkalosis when subjected to excess HCO3 - intake. The purpose of this minireview is to discuss the latest advances on the role of pendrin as a molecule with dual critical roles in acid base regulation and systemic vascular volume homeostasis, specifically in CF. Given the immense prevalence of vascular volume depletion, which is primarily precipitated via enhanced chloride loss through perspiration, we suggest that the dominant presentation of metabolic alkalosis in CF is due to the impaired function of pendrin, which plays a critical role in systemic vascular volume and acid base homeostasis.

Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC.

Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1/Car2 dKO mice vs. Tsc1/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.

Polyamine Catabolism and Its Role in Renal Injury and Fibrosis in Mice Subjected to Repeated Low-Dose Cisplatin Treatment.

Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/recovery phase) after the final treatment. RNA-seq analyses revealed increases in the expression of markers of kidney injury (e.g., lipocalin 2 and kidney injury molecule 1) and fibrosis (e.g., collagen 1, fibronectin, and vimentin 1) in RLDC mice. In addition, we observed increased expression of polyamine catabolic enzymes (spermidine/spermine N1-acetyltransferase, Sat1, and spermine oxidase, Smox) and decreased expression of ornithine decarboxylase (Odc1), a rate-limiting enzyme in polyamine synthesis in mice subjected to RLDC. Upon confirmation of the RNA-seq results, we tested the hypothesis that enhanced polyamine catabolism contributes to the onset of renal injury and development of fibrosis. To test our hypothesis, we compared the severity of RLDC-induced renal injury and fibrosis in wildtype (WT), Sat1-KO, and Smox-KO mice. Our results suggest that the ablation of polyamine catabolic enzymes reduces the severity of renal injury and that modulation of the activity of these enzymes may protect against kidney damage and fibrosis caused by cisplatin treatment.

Abiraterone-Associated Mineralocorticoid Excess: A Case Report.

Abiraterone acetate causes an adrenocorticotropic hormone (ACTH)-mediated mineralocorticoid excess. We present a 77-year-old man with prostate adenocarcinoma who developed signs and symptoms of mineralocorticoid excess while on abiraterone and discuss its pathophysiology and treatment options. The patient developed hypokalemia, metabolic alkalosis, and hypertension, indicative of increased mineralocorticoid activity, confirmed by elevated ACTH, corticosterone, and deoxycorticosterone levels. Abiraterone inhibits cytochrome P450c17 (CYP17A1), thus inhibiting testosterone and cortisol synthesis. Diminished cortisol synthesis, in turn, leads to excessive mineralocorticoid precursor production mediated by ACTH, leading to enhanced sodium absorption and potassium excretion. Abiraterone is often prescribed with low-dose prednisone to suppress ACTH; however, this strategy may not provide physiological glucocorticoid levels, resulting in ACTH-mediated mineralocorticoid excess in some patients. High-dose steroids or mineralocorticoid antagonists may activate mutant androgen receptors in prostate cancer tissue; therefore, amiloride is suggested for managing residual mineralocorticoid activity. This case highlights the importance of being vigilant for the signs and symptoms of mineralocorticoid excess in patients on abiraterone.

Acid base homeostasis and serum bicarbonate concentration in syndrome of inappropriate anti-diuretic hormone secretion (SIADH) with hyponatremia.

The Syndrome of Inappropriate ADH secretion (SIADH) presents with excess ADH release caused by a range of conditions; including pneumonia, brain tumors, certain lung cancers, and diseases of the hypothalamus. It presents with significant reduction in both sodium and chloride concentrations in the blood. However, reports examining the acid base status indicate a normal serum bicarbonate concentration and systemic acid base homeostasis. The mechanisms for the absence of abnormalities in acid base homeostasis remain speculative. This mini review is highlighting the recent advances in renal molecular physiology to provide answers for the maintenance of acid base status and serum bicarbonate in a physiological range.