The metabolic role of L-Arginine in chronic kidney disease

The progression of chronic kidney disease (CKD) is closely linked to a vicious cycle of "metabolic disorders–renal damage." Among these disorders, amino acid metabolism imbalances (e.g., essential amino acid deficiency, urea cycle abnormalities) are both consequences of CKD progression and triggers that exacerbate renal burden. As a semi-essential amino acid in humans, L-arginine undergoes adaptive changes in its metabolic pathways (e.g., nitric oxide synthesis, urea cycle, guanidine compound production) in CKD patients. Its metabolic abnormalities directly affect renal blood flow regulation, oxidative stress balance, and toxin clearance. In-depth analysis of its metabolic role in CKD provides new intervention insights for renal nutritional support and complication prevention.

I. Metabolic Characteristics of L-Arginine in CKD Patients: From "Sufficiency" to "Relative Deficiency"

Healthy individuals maintain L-arginine homeostasis through dietary intake (e.g., meat, legumes) and endogenous synthesis (intestinal microbiota decomposing citrulline, renal metabolism of ornithine). However, CKD patients often experience relative L-arginine deficiency due to "reduced synthesis, increased consumption, and excretion disorders," with metabolic pathways shifting toward "toxic product generation," further exacerbating renal damage.

(I) Impaired L-Arginine Synthesis: Dual Damage to Renal and Intestinal Pathways

Renal synthesis pathway dysfunction: The kidneys are the core organ for endogenous L-arginine synthesis. Proximal tubular epithelial cells convert ornithine (derived from glutamic acid metabolism) to citrulline via the "ornithine–citrulline–arginine cycle," which is then catalyzed by argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) to form L-arginine. In CKD patients, decreased glomerular filtration rate (GFR) damages proximal tubular epithelial cells, reducing ASS and ASL activity by 50%–70%. This decreases endogenous L-arginine synthesis by 30%–40%, with more severe impairment (e.g., CKD stage 5) leading to weaker synthetic capacity.

Intestinal microbiota metabolic disorders: Intestinal microbiota decomposes dietary proteins into citrulline, which is absorbed by intestinal epithelial cells and transported to the kidneys for L-arginine synthesis. In CKD patients, slowed intestinal peristalsis and damaged intestinal mucosal barriers cause microbiota imbalance (e.g., reduced citrulline-producing bacteria, increased urea-producing bacteria), decreasing gut-derived citrulline by 25%–30% and further reducing L-arginine precursor supply.

(II) Increased L-Arginine Consumption: Accelerated Metabolism by Oxidative Stress and Inflammation

Chronic oxidative stress and inflammation in CKD patients accelerate L-arginine consumption, further lowering its in vivo levels:

Consumption by nitric oxide (NO) synthesis: L-arginine is the sole substrate for nitric oxide synthase (NOS), which catalyzes its conversion to NO (regulating vasodilation) and citrulline. In CKD patients, vascular endothelial damage increases inducible NOS (iNOS) activity (activated by inflammation) while decreasing constitutive NOS (cNOS, regulating basal NO production) activity. This diverts more L-arginine toward iNOS-mediated NO synthesis; the generated NO easily binds to superoxide anions (O₂⁻) to form more toxic peroxynitrite (ONOO⁻), which both consumes L-arginine and exacerbates renal oxidative damage.

Shunting toward guanidine compound production: Under inflammatory and oxidative stress, L-arginine is metabolized via the "arginase pathway" to ornithine, which is further converted to guanidine compounds (e.g., guanidinoacetic acid, creatinine) or via the "arginine decarboxylase pathway" to polyamines (e.g., putrescine). These metabolites (e.g., guanidinoacetic acid) accumulate in CKD patients, increasing renal excretion burden and inducing renal tubular epithelial cell apoptosis—forming a vicious cycle of "L-arginine consumption → toxic product accumulation → renal damage."

(III) Impaired L-Arginine Excretion: Metabolite Accumulation Exacerbates Burden

Decreased GFR in CKD patients impairs excretion of L-arginine metabolites (e.g., citrulline, ornithine, guanidine compounds), leading to their accumulation:

Plasma L-arginine concentration is approximately 80–120 μmol/L in healthy individuals, decreasing to 50–70 μmol/L in CKD stage 3–4 patients and further to 30–50 μmol/L in pre-dialysis CKD stage 5 patients. Concentrations of metabolites (e.g., guanidinoacetic acid) increase by 2–3 fold.

Accumulated metabolites competitively inhibit L-arginine transporters (e.g., y⁺L amino acid transporter), reducing its entry into renal cells, further inhibiting synthesis and utilization, and exacerbating metabolic imbalance.

II. Bidirectional Impacts of L-Arginine Metabolism on CKD Pathological Progression: Balancing Protection and Risks

The metabolic role of L-arginine in CKD is "bidirectional": normal pathways (e.g., NO production, urea cycle participation) protect renal function, while abnormal pathways (e.g., toxic guanidine compound production) exacerbate damage. The final impact depends on the balance of metabolic directions.

(I) Positive Protective Effects: Regulating Renal Blood Flow and Improving Metabolic Microenvironment

Improving renal hemodynamics: NO generated via normal metabolism dilates intrarenal arterioles (e.g., afferent and efferent arterioles), reducing intrarenal pressure and increasing renal blood flow (RBF). L-arginine supplementation enhances renal cNOS activity in CKD patients, increasing NO production by 20%–30%, RBF by 15%–20%, and decreasing intraglomerular pressure by 10%–15%—alleviating glomerular hyperfiltration damage (a core early CKD pathological change).

Participating in the urea cycle to reduce azotemia: L-arginine is a key intermediate in the urea cycle. In the liver, arginase catalyzes its conversion to urea and ornithine; urea is excreted via the kidneys, maintaining nitrogen metabolism balance. L-arginine supplementation in CKD patients enhances urea cycle efficiency, promoting conversion of ammonia (from protein metabolism) to urea, reducing plasma blood urea nitrogen (BUN) by 10%–15%, and alleviating azotemia-induced renal toxicity.

Inhibiting renal fibrosis: NO derived from L-arginine inhibits renal interstitial fibroblast activation and transforming growth factor β (TGF-β) expression, reducing collagen deposition. In CKD animal models, L-arginine supplementation reduces renal interstitial fibrosis area by 30%–40% and delays glomerulosclerosis—mechanisms linked to NO-mediated anti-inflammatory and anti-apoptotic effects.

(II) Risks of Abnormal Metabolism: Toxic Metabolite Accumulation and Oxidative Damage

Tubular damage induced by guanidine compounds: As mentioned, guanidine compounds (e.g., guanidinoacetic acid, methylguanidine) from abnormal L-arginine metabolism accumulate in CKD patients. They damage renal tubular epithelial cells via "oxidative stress activation" and "mitochondrial function inhibition": guanidinoacetic acid induces excessive reactive oxygen species (ROS) production in tubular cells, decreasing mitochondrial membrane potential by 30%–40% and increasing apoptosis rate by 25%–30—further reducing renal L-arginine synthesis and utilization.

Vascular damage from NO metabolic imbalance: Excessive NO from overactivated iNOS easily binds to O₂⁻ to form ONOO⁻, which oxidatively damages DNA and proteins in glomerular endothelial cells, disrupting the glomerular filtration barrier and increasing urinary protein excretion by 20%–25%. ONOO⁻ also inhibits cNOS activity, forming a vicious cycle of "abnormal NO production → vascular damage → reduced NO production" and exacerbating intrarenal hemodynamic disorders.

III. Clinical Applications in CKD Management: Precise Dosage and Scenario Matching

Based on L-arginine’s metabolic characteristics and bidirectional effects in CKD, its clinical application requires "precise dosage control and disease stage matching" to exert protective effects while avoiding abnormal metabolic risks.

(I) Applicable Scenarios: Focus on "Early Intervention" and "Adjuvant Complication Treatment"

CKD stages 1–3 (early stage): Progression prevention: At this stage, the kidneys retain some L-arginine synthetic capacity. Low-dose L-arginine supplementation (3–5 g daily, divided into 2 oral doses) improves intrarenal hemodynamics, inhibits glomerular hyperfiltration, enhances the urea cycle, and reduces azotemia. Clinical studies show that CKD stage 3 patients receiving 6 months of supplementation experience a reduced GFR decline rate (from 1.2 mL/min/month to 0.8 mL/min/month) and a 20%–25% decrease in urinary microalbumin excretion.

CKD stages 4–5 (advanced, pre-dialysis): Improving anemia and nutritional status: Advanced CKD patients often have iron deficiency anemia (iron utilization disorders) and protein-energy wasting (PEW). L-arginine promotes intestinal iron absorption via NO production and serves as a protein synthesis precursor to enhance muscle protein synthesis. Daily supplementation of 5–8 g (divided into 3 oral doses) for 12 weeks increases serum ferritin by 25%–30%, hemoglobin (Hb) by 0.5–1.0 g/dL, and mid-arm muscle circumference by 1.0–1.5 cm—improving nutritional status.

Dialysis patients: Alleviating vascular complications: Dialysis patients are prone to vascular complications (e.g., arteriovenous fistula stenosis, hypertension) due to repeated vascular punctures and oxidative stress. Intravenous L-arginine (3–5 g post-dialysis) increases NO levels in fistula vessels, inhibits vascular smooth muscle cell proliferation, and reduces fistula stenosis incidence by 15%–20%. NO-mediated vasodilation also 辅助 lowers blood pressure (systolic pressure reduced by 5–8 mmHg), decreasing antihypertensive medication requirements.

(II) Application Precautions: Avoiding Dosage-Related Risks

Dosage control: Preventing toxicity from excess: Daily doses exceeding 10 g increase abnormal L-arginine metabolism to guanidine compounds, potentially raising plasma methylguanidine by 20%–30% and exacerbating tubular damage. Excessive NO production may also induce hypotension (especially in dialysis patients). Dosages should be adjusted based on GFR (no more than 5 g daily for GFR < 30 mL/min).

Monitoring metabolic indicators: During supplementation, regularly monitor plasma L-arginine concentration (target: 60–80 μmol/L), BUN, creatinine, and guanidine compound levels. If BUN increases by >20% or guanidinoacetic acid is abnormally elevated, reduce dosage or discontinue use.

Contraindicated populations: CKD patients with severe hepatic insufficiency (urea cycle disorders, risk of ammonia accumulation) or hyperkalemia (L-arginine may promote potassium influx, increasing serum potassium) should use it with caution or avoid it. Dialysis patients receiving infusions should be administered slowly (over 1–2 hours) to prevent sudden hypotension.

IV. Summary and Future Directions

L-arginine metabolism in CKD exhibits "complexity and bidirectionality": its normal metabolism (NO production, urea cycle participation) improves intrarenal blood flow, reduces azotemia, and inhibits fibrosis, while abnormal metabolism (toxic guanidine compound production, NO imbalance) exacerbates tubular damage and vascular lesions. The core of clinical application is "precise matching": low-dose supplementation for early-stage patients to prevent progression, and targeted supplementation for advanced/dialysis patients to improve complications—with strict dosage control and metabolic indicator monitoring to avoid risks.