Lactate: Synthesis, Metabolism, and Elevated Levels in CKD Patients

1. Basic Lactate Biochemistry - Where Does Lactate Come From?

Synthesis Pathway

Glucose → (glycolysis) → Pyruvate → (LDH) → Lactate + H⁺

• This reaction regenerates NAD⁺ from NADH, allowing glycolysis to continue even when oxidative phosphorylation is unavailable or overwhelmed.
• The reaction is reversible: lactate can be re-converted to pyruvate when oxygen is available.

• Skeletal muscle (major source, especially during exercise)
• Red blood cells (no mitochondria - always produce lactate)
• Skin, intestines, brain
• Renal medulla (naturally anaerobic environment)

Normal Lactate Levels and Clearance

• Liver (~60-70%) - converts lactate back to glucose (Cori cycle) or oxidizes it
• Kidney (~30%) - a major but underappreciated site of lactate clearance
• Heart and other muscles also consume lactate as fuel

2. The Kidney's Role in Normal Lactate Handling

Proximal Tubule - The Gluconeogenic Engine

• The proximal tubule is the primary gluconeogenic zone - it expresses phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase.
• Gluconeogenic enzymes are found almost exclusively in the proximal tubule.
• Overnight fasting: proximal tubule gluconeogenesis can account for up to 40% of whole-body gluconeogenesis.
• During liver transplantation, endogenous glucose release falls to only 50% of control levels within 1 hour of liver removal - demonstrating how significant renal gluconeogenesis is.

How the Kidney Processes Lactate (Concentration-Dependent)

1. Low concentration (<2 mmol/L): All lactate is oxidized to CO₂ to fuel transport and basal metabolism (generates ATP).
2. Moderate-high concentration (>2 mmol/L): Excess lactate is channeled into gluconeogenesis (Cori cycle participation).
3. Very high perfusate levels: Metabolic and synthetic rates approach maximum; some lactate is simply reabsorbed (conserved).

The Cori Cycle

• Brenner and Rector's The Kidney, Chapter 5 (Renal Gluconeogenesis and Lactate Handling)

3. Why Lactate Increases in CKD

3a. Loss of Renal Lactate Clearance Capacity

• Fewer functioning proximal tubule cells means reduced lactate-to-glucose conversion capacity
• The kidney's contribution to whole-body lactate clearance (~30%) diminishes progressively
• This creates a baseline shift toward higher circulating lactate

3b. Metabolic Acidosis Amplifies the Problem

• NaHCO₃ therapy, if given, stimulates phosphofructokinase, which increases glycolytic flux and lactate generation
• Metabolic acidosis causes protein catabolism, releasing amino acids that fuel anaerobic pathways

3c. Glycolytic Reprogramming in CKD (New Mechanism)

• In CKD, the expression of PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3) is positively correlated with the severity of renal fibrosis
• PFKFB3-driven glycolytic reprogramming in renal tubules generates excess lactate
• This lactate then promotes histone lactylation (H4K12la), activating NF-κB and driving further fibrosis
• This creates a pathological feed-forward cycle: CKD → lactate → lactylation → more fibrosis → worse CKD

3d. Lactylation - A New Concept (2025)

• Lactate is not merely a metabolic waste product - it acts as a signaling molecule and protein modifier (post-translational modification of histone lysine residues)
• In diabetic nephropathy, elevated lactate enhances H3K14la (histone H3 lysine 14 lactylation), promoting KLF5 expression and driving epithelial-mesenchymal transition (EMT) - a key mechanism of fibrosis
• These epigenetic modifications contribute to AKI-to-CKD progression

3e. Type B Lactic Acidosis - Multiple CKD-Associated Causes

• Frameworks for Internal Medicine, p. 438; Harrison's 22E, Section 58

3f. Specific Warning: Metformin in CKD

• Metformin accumulates due to reduced renal clearance
• Inhibits hepatic mitochondrial Complex I → blocks lactate clearance → metformin-associated lactic acidosis (MALA)
• MALA carries up to 50% mortality

4. Clinical Consequences of Elevated Lactate in CKD

Acid-Base Disturbance

• Lactic acid dissociates: lactate⁻ + H⁺ → raises the anion gap
• Anion gap = Na⁺ - (Cl⁻ + HCO₃⁻); normal ~8-12 mEq/L; elevated when >12 mEq/L
• In advanced CKD, the acidosis is mixed: both high-AG (uremic anions + lactate) and normal-AG components can coexist

Consequences of Acidosis in CKD

• Increased protein catabolism (muscle wasting)
• Bone disease (buffering H⁺ with carbonate from bone)
• Insulin resistance
• Increased cortisol and PTH
• Faster CKD progression (acidosis increases ammoniagenesis → tubulointerstitial injury)
• Elevated fibrosis via lactate-mediated histone lactylation

5. Management: Correcting Acidosis and Lactate in CKD

Bicarbonate Supplementation

• Target serum HCO₃⁻ ≥22 mEq/L (some guidelines suggest 22-23 mEq/L)
• Harrison's 22E notes: "Recent studies suggest that this replacement should be considered when the serum bicarbonate concentration falls below 20-23 mmol/L"
• Oral NaHCO₃ tablets or Shohl's solution
• Correction of acidosis has been shown to slow GFR decline in multiple RCTs (Brenner & Rector's The Kidney, Chapter 47)
• Diet rich in fruits and vegetables is an alternative alkali source

Caution with NaHCO₃ in Frank Lactic Acidosis

• If lactic acidosis is present (pH <7.00), alkali therapy is controversial - NaHCO₃ paradoxically depresses cardiac performance and stimulates phosphofructokinase, which can worsen lactate production
• Target: raise pH to no more than 7.2 and HCO₃⁻ to no more than 12 mmol/L acutely
• Volume overload is a significant risk in the oliguric CKD patient

Treat Underlying Causes

• Stop metformin if eGFR <30 (or 45 in high-risk)
• Correct sepsis, hypoperfusion (Type A component)
• Thiamine supplementation in malnourished dialysis patients
• Dialysis (hemodialysis clears lactate directly in MALA)

Summary Table: Lactate in CKD at a Glance

• Brenner and Rector's The Kidney, Chapters 5 & 47 (Renal Gluconeogenesis, Lactate Handling, and CKD Progression)
• Harrison's Principles of Internal Medicine 22E, Chapters 36 & 58 (Metabolic Acidosis, High-AG Acidoses)
• Frameworks for Internal Medicine, p. 438 (Uremic acidosis mechanism)
• The Washington Manual of Medical Therapeutics (Metabolic acidosis in CKD)
• Hou et al. (2025), "Lactate and Lactylation in AKI-to-CKD," Cell Proliferation (PMID: 40207870) - covers epigenetic mechanisms of lactylation in CKD