Metabolic Acidosis is a serious disease that
affects millions of Americans

Chronic Kidney Disease & Metabolic Acidosis

A Significant Global Health Issue

Chronic kidney disease, or CKD, is a serious condition characterized by the gradual loss of essential kidney functions over time. In patients with CKD, normal fluid and electrolyte balance can no longer be maintained, and the excretion of metabolic end products, toxins and drugs is impaired. Furthermore, production and secretion of certain enzymes and hormones are disturbed.

According to the Centers for Disease Control, or CDC, more than 30 million people in the United States are afflicted with CKD, representing an overall prevalence in the adult population of approximately 15%. The incidence of CKD is primarily driven by the increasing prevalence of diabetes and hypertension. CKD represents the ninth leading cause of death in the United States. The annual Medicare expense for CKD, including end-stage renal disease, or ESRD, exceeds $114 billion.

To help improve the diagnosis and management of kidney disease, the National Kidney Foundation, or NKF, has divided CKD into five stages. The severity of CKD at each stage is identified by the estimated glomerular filtration rate of the kidney, or eGFR. Treatment during the first four stages of CKD focuses on ways to preserve kidney function for as long as possible. ESRD is the fifth stage of CKD in which the patient typically requires renal replacement therapy, i.e., dialysis or a kidney transplant, for survival.

kidney transplant, for survival

The prevalence and severity of metabolic acidosis increases from CKD Stage 3 to Stage 5. We estimate the prevalence of metabolic acidosis to be 9% of the estimated 13.4 million patients with Stage 3a CKD, 18% of the estimated 5.7 million patients with Stage 3b CKD and over 30% of the estimated 2.5 million patients with Stage 4 and Stage 5 CKD, resulting in a total prevalence of approximately 3 million patients with CKD and metabolic acidosis in the United States.

Metabolic Acidosis and the Link to CKD

Diabetes and hypertension have long been recognized as modifiable primary risk factors for the progression of CKD. More recently, metabolic acidosis, a serious condition in which the body has accumulated too much acid, has also been identified as a key risk factor in the progression of 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 blood, which is part of a standard metabolic panel. Properly functioning kidneys will maintain a blood bicarbonate level of between 22 to 29 milliequivalents per liter, or mEq/L. A persistent blood bicarbonate level below 22 mEq/L indicates metabolic acidosis. Blood 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.

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 blood 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.

Chronic MA

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 blood 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 blood bicarbonate with three different interventions, comprising a very low-protein diet, oral sodium bicarbonate and oral sodium citrate. Increases in blood 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 blood 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 blood bicarbonate levels that are below normal (i.e., < 22 mEq/L) are significantly worse compared to patients with CKD with normal blood 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 International Society of Nephology’s Kidney Disease: Improving Global Outcomes, or KDIGO, guidelines recommend maintaining blood bicarbonate at levels above 22 mEq/L (the normal range of blood bicarbonate is 22 to 29 mEq/L.)

Unapproved methods to increase blood 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 blood 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.