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Liver-Kidney Interaction


Objectives

This chapter will:

  • 1.

    Give the reader an overview of the liver as an acid-base organ.

  • 2.

    Describe the complexities of the liver-kidney interaction at the molecular level.

  • 3.

    Relate the pathophysiologic abnormalities of liver-kidney interactions to outcomes of kidney injury in patients with liver disease.

The kidney is the primary organ for body-wide homeostasis, and disruption to its multiple functions has significant impact upon on all organ systems. Correspondingly, the interaction between the liver and kidney is complex and currently poorly understood. Both organs have similar physiologic roles in metabolic and endocrine homeostasis, protein, carbohydrate, and lipid metabolism, and the clearance of many pharmaceutical agents. In particular, they share a combined role in the provision of acid-base balance in the body. Given the large number of shared functions, it is perhaps not surprising that kidney disease is associated with liver impairment and more commonly, liver disease is associated with kidney impairment. This is clinically relevant because critically ill patients with kidney and liver dysfunction have a significantly higher morbidity and mortality. In this chapter we provide an overview of the liver's role in acid-base balance and briefly present the clinical significance of acid-base balance abnormalities in the setting of liver disease.

Role of Ammonia and Glutamine

Traditionally, it was thought that ammonia (NH 3 ) has a key role in the acid-base balance because of its combination with hydrogen ions and subsequent formation of ammonium ions (NH 4 + ) that are excreted readily via urine for a net loss of acid. However, the ammonia precursor, glutamine, exists in its ionized form in vivo ( Fig. 127.1 ) and not the un-ionized form. Like other amino acids, it is a dipolar ion containing an anionic carboxylate group (-COO − ) and a cationic-substituted ammonium (-NH 3 + ) group. The formation and excretion of ammonia in this pathway are electrochemically neutral with no uptake or loss of protons and therefore do not appear to influence body-wide acid-base balance, so an alternative explanation is required.

FIGURE 127.1, Deamidation and deamination of glutamine in the kidney. A, The conventional Pitts formulation. NH 3 , derived from glutamine, moves into the lumen and combines with H + that was obtained from the body buffer, with generation of an equimolar amount of HCO 3 − , which moves into the blood. B, The chemically valid formulation, taking ionization into account. NH 4 + , rather than NH 3 , is the product of deamidation and deamination of glutamine, and excretion of NH 4 + has no effect on the body buffer.

After glutamine has been reduced by the removal of two NH 4 + groups, the remaining carbon skeleton, α-ketoglutarate, has two negatively charged carboxylate groups. Most of this α-ketoglutarate is metabolized within the kidney to glucose or CO 2 , and consequently two HCO 3 − ions are produced according to the conservation of charge. However, these changes do not correlate with other changes occurring in the setting of metabolic acidosis. During metabolic acidosis, renal utilization of metabolic fuels switches away from α-ketoglutarate and other carboxylate-containing bicarbonate precursors, including lactate, resulting in net normal bicarbonate generation in acidosis and alkalosis. More important, if an increase in renal bicarbonate production were to occur, it would not affect systemic acid-base balance. Glutamine that is not used in the kidney will be metabolized elsewhere ( Fig. 127.2 ). Metabolic acidosis, in addition to increasing renal glutamine utilization, deceases hepatic glutamine utilization. Regardless of the location of metabolism, two bicarbonate ions are generated from each molecule of glutamine, and the alkalinizing effect on the blood is the same in both cases.

FIGURE 127.2, Ammonium metabolism and bicarbonate homeostasis. NH 4 + and HCO 3 − generation are ultimately linked in a 1 : 1 stoichiometry during protein catabolism because of the irreversible elimination of both compounds via hepatic urea synthesis. Flux through the urea cycle is sensitively controlled by the extracellular acid-base status. The mechanisms involved adjust bicarbonate-consuming urea synthesis to the requirements of acid-base homeostasis. When urea synthesis decreases relative to the rate of protein catabolism in acidosis, bicarbonate is spared and NH 4 + is excreted as such in the urine; there is no net production or consumption of α-ketoglutarate (2-oxoglutarate, or 2-OG) in the organism. Numbers in circles refer to major points of flux controlled by the acid-base status. In metabolic acidosis, flux through the area cycle (reaction 1) and hepatic glutaminase (reaction 2) are decreased, whereas flux through hepatic glutamine synthesis (reaction 3) and renal glutaminase (reaction 4) are increased. This interorgan “team effort” between the liver and the kidney results in NH 4 + disposal without concomitant removal of HCO 3 − from the organism.

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