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Underlying Pathophysiology

Metabolic acidosis damages kidney, bone, and muscle4,6,20,34,35

There are multiple serious consequences of chronic metabolic acidosis4,6,20,34,35

  • The consequences of metabolic acidosis are wide-ranging and consistent with the observation that many critical cell functions require a normal pH1,20
Image depicting serious consequences of chronic metabolic acidosis Image depicting serious consequences of chronic metabolic acidosis

Metabolic acidosis is both a complication of CKD as well as an underlying cause of CKD progression1,4,10,17,20

  • As currently understood, the mechanism that links metabolic acidosis to the progression of kidney disease involves a cascade of events1,4,10,17,20
    • Patients with compromised kidney function cannot excrete adequate amounts of acid to maintain neutral acid-base balance
    • This imbalance and accumulation of acid leads to increases in the production of select peptides and hormones that, in turn, increase the secretion of acid through the proximal and distal tubules of remaining healthy nephrons
    • Sustained overproduction of hormones further damages the diseased kidneys, resulting in long-term consequences including proteinuria, inflammation, kidney fibrosis, and hallmarks of CKD progression to end-stage renal disease such as sodium and water retention
  • Though low serum bicarbonate level is widely accepted as a measure of metabolic acidosis, it may actually be a lagging indicator as there is evidence that metabolic acidosis may begin to develop before serum levels are affected4,36
    • As nephrons are lost over time, subclinical—or eubicarbonatemic—metabolic acidosis can develop and begin to accelerate the progression of CKD
    • With eubicarbonatemic metabolic acidosis, blood pH and serum bicarbonate levels remain normal, but acid retention builds in the interstitial compartments of the kidney and eventually may lead to an acid-base imbalance in the blood
Image depicting certain effects of decreased acid secretion by the kidneys in CKD patients

Hear from a Nephrologist

Donald Wesson, MD, MBA*:

How does metabolic acidosis cause chronic kidney disease progression?

*Dr Wesson is a paid consultant of TRICIDA, Inc.

Download Dr Wesson's presentation featured in this video

The pathophysiology of metabolic acidosis is associated with loss of bone mineral density1,20,36

  • Acid buffering by bone is induced by acid retention in CKD patients
    • The initial response is characterized by the physicochemical release of bone carbonates and phosphates to the extracellular fluid in order to buffer the acidity, which releases sodium, potassium, calcium, and phosphate in the process
    • Persistent acidosis activates mechanisms within osteoblasts—bone forming cells—to decrease bone formation and in osteoclasts—bone resorbing cells—to increase bone resorption. Both processes are mediated by cellular hydrogen ion sensors
  • Both short-term physicochemical dissolution and long-term resorption result in the loss of bone integrity and strength, making the bone more susceptible to fracture
Acid buffering by bone with increased acid retention.

Metabolic acidosis contributes to muscle wasting in CKD as a result of increased muscle catabolism1,20

  • Intracellular proton buffering utilizing anionic proteins from muscle help neutralize accumulating acid, which contributes to muscle wasting1,20
    • Skeletal muscle turnover is continuous and highly regulated. Over time, even a small increase in degradation will cause a loss in muscle mass
    Continuous skeletal muscle turnover. Small increase in muscle degeneration, and loss in muscle mass. Continuous skeletal muscle turnover. Small increase in muscle degeneration, and loss in muscle mass.
  • During metabolic acidosis, in addition to a fall of systemic pH, there is a reduction in the pH of the interstitial compartment of muscle. The fall in muscle pH results in impaired insulin signaling, activation of the ubiquitin-proteasome pathway, and activation of caspase-3 proteolysis, resulting in muscle protein degradation1,20
    • This muscle protein degradation is believed to contribute to muscle wasting in patients with CKD

    PUTATIVE MECHANISMS THAT CONTRIBUTE TO MUSCLE WASTING IN PATIENTS WITH CKD AND METABOLIC ACIDOSIS1,20,46

    Pathophysiology of muscle wasting.

    This graphic was adapted from Kraut JA, Madias NE. Adverse effects of the metabolic acidosis of chronic kidney disease. Adv Chronic Kidney Dis. 2017;24(5):289-297.

  • Decreasing systemic pH also increases secretion of pro-inflammatory cytokines by macrophages, which can further contribute to muscle wasting1,20
  • These processes help to buffer the retained acid during the initial stages of CKD and begin to occur even before a fall in serum bicarbonate is apparent1,20

Hear from a Nephrologist

David A Bushinsky, MD:

How does metabolic acidosis impair muscle and bone health?

†Dr Bushinsky is a paid consultant of TRICIDA, Inc.

Download Dr Bushinsky's presentation featured in this video

Continue to the next page to learn more about how metabolic acidosis can impair physical function

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Kraut JA and Madias NE (2017):
Adverse effects of the metabolic acidosis of chronic kidney disease
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