Kidney metabolism and acid-base control: back to the basics

Abstract

Kidneys are central in the regulation of multiple physiological functions, such as removal of metabolic wastes and toxins, maintenance of electrolyte and fluid balance, and control of pH homeostasis. In addition, kidneys participate in systemic gluconeogenesis and in the production or activation of hormones. Acid-base conditions influence all these functions concomitantly. Healthy kidneys properly coordinate a series of physiological responses in the face of acute and chronic acid-base disorders. However, injured kidneys have a reduced capacity to adapt to such challenges. Chronic kidney disease patients are an example of individuals typically exposed to chronic and progressive metabolic acidosis. Their organisms undergo a series of alterations that brake large detrimental changes in the homeostasis of several parameters, but these alterations may also operate as further drivers of kidney damage. Acid-base disorders lead not only to changes in mechanisms involved in acid-base balance maintenance, but they also affect multiple other mechanisms tightly wired to it. In this review article, we explore the basic renal activities involved in the maintenance of acid-base balance and show how they are interconnected to cell energy metabolism and other important intracellular activities. These intertwined relationships have been investigated for more than a century, but a modern conceptual organization of these events is lacking. We propose that pH homeostasis indissociably interacts with central pathways that drive progression of chronic kidney disease, such as inflammation and metabolism, independent of etiology.

Fig. 1

Bicarbonate reabsorption and formation of new bicarbonate via ammoniagenesis in coordination with glutamine metabolism, gluconeogenesis, and activity of potassium channels in the proximal tubule. Secretion of H⁺ via NHE3 or H + -ATPase (not shown) leads to reabsorption of HCO₃⁻ via NBCe1 (and AE2 in the segment 3). Ammonia and HCO₃⁻ are formed from the metabolization of glutamine in the mitochondria, which provides precursors for gluconeogenesis. Glycerol and lactate are additional substrates of gluconeogenesis, but they have a minor role in response to metabolic acidosis in healthy kidneys. The transcription factor NRF2 regulates the expression of the main importer of glutamine into proximal tubular cells during acidosis, SNAT3. Potassium channels in the basolateral membrane control membrane potential impacting NBCe1 activity and ammoniagenesis. NHE3 (SLC9A3) sodium hydrogen exchanger 3, NBCe1 (SLC4A4) electrogenic sodium bicarbonate cotransporter 1, SNAT3 (Slc38a3) sodium-coupled neutral amino acid transporter 3, NRF2 (NFE2L2) nuclear factor-erythroid factor 2-related factor 2, TASK2 (KCNK5) TWIK-related acid-sensitive K( +) channel 2, KIR4.2 (KCNJ15) inward rectifier K⁺ channel KIR4.2, AQP7 aquaporin 7, CAII and CAIV carbonic anhydrase 2 and 4, respectively; SMCTs represent sodium-coupled monocarboxylate transporters 1 and 2 (SLC58 and SLC5A12); MCTs represent different monocarboxylate transporter members, most probably SLC16A1 and SLC16A; PDG (GLS) phosphate-dependent glutaminase, GDH (GLUD1) glutamate dehydrogenase, PEPCK (PCK1) phosphoenolpyruvate carboxykinase

Fig. 2

Summary of main renal metabolic pathways altered between kidney transplant recipients (KTRs) with or without acidosis. Bulk RNA sequencing data using RNA from kidney biopsies of KTRs identified genes altered between patients with or without acidosis, but with comparable eGFR. These genes participate in metabolic activities shown in this figure in black. Red lines show molecular pathways that had genes restored by alkali therapy. Blue arrows show direct biochemical reactions, and blue dashed lines show indirect biochemical reactions. Black arrows show movement of molecules. Data originally published in [59]. TCA cycle tricarboxylic acid cycle (also citric acid cycle or Krebs cycle), P5P pyridoxal-5′-phosphate, GSH glutathione, THF tetrahydrofolate

Fig. 3

Conceptual framework how chronic kidney disease, inflammation, and deranged metabolism form a vicious cycle involving metabolic acidosis as an engine. Nephron loss and impaired renal function reduce kidney capacity of eliminating acids and generating new bicarbonate which leads to accumulation of acids in the organism. Renal responses to acidosis exacerbate inflammation and deranged metabolism that ultimately reduce kidney function and kidney capacity of keeping pH homeostasis. Steps of this network are shown in continuous black boxes, and open questions related to each of these steps are shown next to it in dashed black boxes. Inflammation and metabolism domains are artificially delimited in different colors as some of these steps may belong to both domains