What is the relationship between uremia and the development of metabolic acidosis?

From the Guidelines

Uremia is a condition characterized by the accumulation of waste products in the blood due to kidney failure, and it commonly causes metabolic acidosis through several mechanisms, including the inability to excrete acid or reabsorb bicarbonate, leading to an acid-base imbalance, as noted in the KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease 1. When kidneys fail, they cannot adequately excrete acid or reabsorb bicarbonate, leading to an acid-base imbalance. Specifically, uremia causes metabolic acidosis because the kidneys can no longer effectively excrete hydrogen ions or regenerate bicarbonate, resulting in a net accumulation of acid in the body. Some key points to consider in the management of uremic acidosis include:

• The treatment of metabolic acidosis to delay progression of CKD has not been proven, however, it is recognized that acidosis can lead to exacerbation of nutritional issues, bone disease, and other consequences, as discussed in the KDIGO 2024 guideline 1.
• The threshold for aggressive intervention has been moved to <18 mmol/l from <22 mmol/l in the previous KDIGO guideline, highlighting the importance of monitoring and managing metabolic acidosis in patients with CKD 1.
• Patients with uremic acidosis typically require treatment with oral sodium bicarbonate supplements to neutralize excess acid, with a goal of maintaining serum bicarbonate at or above 22 mmol/L, as recommended in the clinical practice guidelines for nutrition in chronic renal failure 1.
• In more severe cases, especially during dialysis, intravenous sodium bicarbonate may be necessary, and managing the underlying kidney disease through dialysis or transplantation is ultimately essential for addressing uremic acidosis long-term.
• It is also important to note that the use of non–vitamin K antagonist oral anticoagulants (NOACs) in preference to vitamin K antagonists (e.g., warfarin) for thromboprophylaxis in atrial fibrillation in people with CKD G1–G4 is recommended, as stated in the KDIGO 2024 guideline 1. However, this is not directly related to the management of uremic acidosis. Overall, the management of uremic acidosis requires a comprehensive approach that takes into account the underlying kidney disease, as well as the potential consequences of metabolic acidosis, and should be guided by the most recent and highest quality evidence, such as the KDIGO 2024 clinical practice guideline 1.

From the FDA Drug Label

In a healthy adult with normal kidney function, practically all the glomerular filtered bicarbonate ion is reabsorbed; less than 1% is excreted in the urine. Plasma concentration is regulated by the kidney through acidification of the urine when there is a deficit or by alkalinization of the urine when there is an excess.

Uremia is not directly defined in the provided drug labels, but it can be inferred that it is related to kidney function.

• Uremia is likely a condition where the kidneys are not functioning properly, leading to an accumulation of waste products in the blood.
• Metabolic acidosis can occur when the kidneys are not able to regulate plasma concentration and remove excess hydrogen ions, leading to an imbalance in the body's acid-base status.
• The exact mechanism of how uremia causes metabolic acidosis is not explicitly stated in the provided drug labels, but it is likely related to the kidney's inability to properly regulate electrolyte and acid-base balance 2, 2.

From the Research

Definition of Uremia

• Uremia refers to the buildup of waste products, such as urea, in the blood due to chronic kidney disease (CKD) or acute kidney injury 3.
• Urea is a marker of uraemic retention in CKD and has been traditionally considered biologically inert, but recent studies suggest it may be toxic at concentrations representative of CKD 3.

Metabolic Acidosis in Uremia

• Metabolic acidosis is a common complication of CKD, characterized by a decrease in serum bicarbonate concentration and an increase in acid production 4, 5.
• The kidneys play a crucial role in regulating acid-base balance, and a decrease in renal function can lead to metabolic acidosis 4, 5.
• Metabolic acidosis in CKD can be classified as non-anion gap acidosis, high-anion gap acidosis, or both, and can be associated with muscle wasting, bone disease, hypoalbuminemia, inflammation, and increased mortality 4.

Mechanisms of Metabolic Acidosis in Uremia

• The decrease in serum bicarbonate concentration in CKD is usually absent until the glomerular filtration rate (GFR) decreases to <20-25 mL/min/1.73 m² 4.
• The acidosis can be associated with a positive acid balance, leading to a reduction in serum bicarbonate concentration 4.
• Urea itself can induce molecular changes related to insulin resistance, free radical production, apoptosis, and disruption of the protective intestinal barrier, contributing to the development of metabolic acidosis 3.

Treatment of Metabolic Acidosis in Uremia

• Administration of base, such as oral bicarbonate supplementation, may decrease muscle wasting, improve bone disease, and slow the progression of CKD 4, 5.
• The target serum bicarbonate concentration is unclear, but evidence suggests that increments in serum bicarbonate concentration >24 mEq/L might be associated with worsening of cardiovascular disease 4.
• Other treatments, such as increased fruit and vegetable intake and oral alkali supplementation, may also be effective in treating metabolic acidosis 5.