Metabolic Acidosis and the Link to CKD

The maintenance of a delicate acid-base balance in the body is essential for the health and proper functioning of organs, tissues and cells. Blood pH is kept within a narrow range of 7.36 to 7.44 by buffering systems in the body, primarily bicarbonate, or HCO3, and excretion mechanisms to remove excess volatile acid in the form of carbon dioxide, or CO2, through the lungs and non-volatile acids through the kidneys. Blood pH is defined by the ratio of serum bicarbonate (regulated by the kidneys) and CO2 (regulated by the lungs). Patients’ acid-base status can be diagnosed by measuring the level of bicarbonate in the serum of blood, which is part of a standard metabolic panel. Properly functioning kidneys will maintain a serum bicarbonate level of between 22 to 29 milliequivalents per liter, or mEq/L. A persistent serum bicarbonate level below 22 mEq/L indicates metabolic acidosis. Serum bicarbonate concentrations less than 22 mEq/L are associated with increased risk of CKD progression and increased risk of muscle wasting, loss of bone density and death.
Blood Bicarbonate Levels
In general, individuals produce between 50 and 100 mEq of acid each day through metabolic processes and the digestion of food (especially protein). This acid must first be buffered, and then excreted, by the kidneys. Patients with CKD continue to generate acid from their diet and metabolism but have a reduced ability to excrete acid via the kidneys. As a result, metabolic acidosis, characterized by a reduced serum bicarbonate concentration (i.e., below 22 mEq/L), can develop in patients with CKD.
Multiple Serious Consequences of Chronic Metabolic Acidosis

The imbalance and acid load accumulation in patients with CKD and metabolic acidosis leads to buffering of the acid by bone and muscle. This can result in bone demineralization, protein catabolism and reduced muscle mass, all of which may contribute to worsening physical function. In addition, in an attempt to compensate for the reduced acid secretion, select peptides and hormones, including endothelin-1, aldosterone and angiotensin II, increase the secretion of acid through the proximal and distal renal tubules of the remaining healthy nephrons. As currently understood, this sustained over-production of hormones exacerbates the damage in the diseased kidneys, resulting in long-term consequences, including renal fibrosis, proteinuria and inflammation, as well as sodium and water retention, which are hallmarks of the progression of CKD.

Multiple retrospective studies provide qualitative and quantitative evidence for the relationship between metabolic acidosis and the progression of CKD across a wide range of baseline eGFRs and serum bicarbonate levels. Prospective studies have shown that treating metabolic acidosis translates into a clinically meaningful slowing of CKD progression. In particular, four prospective trials (Garneata et al., 2016; de Brito-Ashurst et al., 2009; Phisitkul et al., 2010; Dubey et al., 2018) studying patients with Stage 3 to 5 CKD with metabolic acidosis demonstrated slowing of CKD progression following an increase in serum bicarbonate with three different interventions, comprising a very low-protein diet, oral sodium bicarbonate and oral sodium citrate. Increases in serum bicarbonate resulted in improved clinical outcomes, including fewer patients who progressed to ESRD and/or experienced significant declines of eGFR. Four large published retrospective database analyses show an association between higher serum bicarbonate levels and slower progression of CKD, independent of baseline eGFR and other factors such as age, sex, proteinuria, hypertension and diabetes (Dobre et al., 2013; Raphael et al., 2011; Shah et al., 2009; Tangri et al., 2011). In these four distinct large cohorts of patients with CKD, the analyses all demonstrate that clinical outcomes for patients with serum bicarbonate levels that are below normal (i.e., < 22 mEq/L) are significantly worse compared to patients with CKD with normal serum bicarbonate levels (i.e., 22 to 29 mEq/L).
Chronic Treatment of Metabolic Acidosis
There are no FDA approved therapies for the chronic treatment of metabolic acidosis. However, the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative, or KDOQI, guidelines and the Kidney Disease: Improving Global Outcomes, or KDIGO, guidelines recommend maintaining serum bicarbonate at levels above 22 mEq/L (the normal range of serum bicarbonate is 22 to 29 mEq/L.). Unapproved methods to increase serum bicarbonate include oral alkali supplements, such as sodium bicarbonate, which introduce significant amounts of sodium to patients. Yet approximately 90% of later-stage patients with CKD suffer from sodium-sensitive comorbid conditions, such as hypertension, cardiovascular disease, heart failure or edema and require a sodium-restricted diet. As such, the use of sodium-based supplements can lead to worsening serum pressure control and volume overload in this population. Given the significant limitations on the use of sodium-based supplements, there exists a significant unmet medical need for a chronic therapy for patients with CKD and metabolic acidosis. To chronically treat the broad population of patients with CKD and metabolic acidosis, physicians need an FDA-approved treatment that is proven to be safe, effective and easy to comply with. Tricida is a proud sponsor of the National Kidney Foundation, where you can find more information about awareness, prevention, and treatment of metabolic acidosis and CKD.