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The purpose of this review article is to explain some of the experimental evidence linking uremic-related loss of muscle mass to metabolic acidosis-mediated responses.

Criteria for article selection not described.

Not specified.

Recruitment:  Search procedures and study quality assessment not described.  Studies involving both rats and humans cited.

Design:  Narrative Review.

Blinding Used (if applicable):  Not applicable.

Intervention (if applicable):  Not applicable.

Statistical Analysis:

Statistical analysis not completed.

Timing of Measurements

Not applicable.

Dependent Variables:

• Evidence relating both chronic and acute kidney failure to uremia, loss of lean body mass, negative nitrogen balance, and accompanying degradation of essential amino acids (EAA), branched-chain amino acids (BCAA), and muscle protein. 
• Relationship of EAA (particularly BCAA) degradation and muscle protein degradation to metabolic acidosis, with and without dietary protein restriction.
• Responses to metabolic acidosis and alleviation of negative responses via sodium bicarbonate (NaHCO3) supplements.

Independent Variables

Not applicable.

Control Variables

Not applicable.

Initial N:  There are 38 articles referenced in this paper.

Attrition (Final N):  38 references

Age:  Not mentioned

Ethnicity:  Not mentioned

Other relevant demographics:

Anthropometrics:

Location:  Worldwide studies

Increased morbidity and mortality associated with uremia:

Uremia blocks the ability to activate metabolic responses required to maintain protein stores.

Uremia is associated with malnutrition.

Poor nutritional status, especially hypoalbuminemia, is associated with increased morbidity and mortality.

Normal metabolic responses to restricted protein intake:

With decreased protein intake, two metabolic (ie, adaptive) responses should occur.  Oxidation of EAA is decreased, but to a limited capacity, in order to yield a more efficient use of dietary EAA to synthesize protein.  When intake is < 0.6 g protein/kg IBW/day (approximately), a second mechanism causes decreased protein degradation, to compensate for normal rates of protein turnover. 

BCAA and proteolytic pathyways activated in acidosis:

metabolic acidosis stimulates oxidation of BCAA and increases the rate of protein degradation in muscle by increasing the activity of the branch-chain ketoacid dehydrogenase enzyme.

metabolic acidosis blocks the second metabolic response to dietary protein restriction (ie, lack of adaptive mechanism).

metabolic acidosis stimulates the (glucocorticoid-related) ubiquitin-proteasome-dependent pathway, causing increased gene transcription related to a number of proteolytic processes.

muscle proteolysis has been directly correlated with serum concentrations of cortisol. 

Evidence that treating acidosis can curtail protein losses:

In rats with uremia/CRF

• Treatment with NaHCO3 eliminated accelerated breakdown of BCAA and eliminated the increase of muscle protein degradation.

In humans

• Studies showed that nonacidotic CRF patients fed either 1.0, 0.6, or 0.3 (+ ketoacid supplements) g protein/kg/day maintained appropriate metabolic response of low rates of both EAA oxidation and protein degradation after one year of therapy.
• Treating acidosis with NaHCO3 reduced the rate of oxidation of EAA, improved serum levels of BCAA, decreased ptotein degradation and improved nitrogen balance.
• Increased rate of protein degradation was not blocked by insulin.
• Induction of acidosis in normal subjects by feeding NH4Cl caused a negative nitrogen balance and inhibited albumin synthesis.

Loss of muscle mass is common in patients with acute or chronic renal failure, however, the mechanisms are not fully understood.  Uremia blocks metabolic responses that act to maintain protein balance when anorexia decreases dietary protein intake.  The adaptive metabolic responses include a sharp decrease in the degradation of essential amino acids and protein.

If these experimental results apply to patients with kidney disease, then acidosis activates genes encoding enzymes that degrade protein and amino acids by a glucocorticoid-dependent mechanism.  Understanding activation and regulation of the adenose-triphosphate-ubiquitin-proteasome system could provide insights into the catabolism associated with CRF and other catabolic diseases. 

University/Hospital:

Emory University School of Medicine

This short review emphasizes the importance of treating metabolic acidosis in renal failure to prevent muscle catabolism and to prevent protein malnutrition.