In a patient with chronic kidney disease stage 3, does supplementation with NAD⁺ precursors (nicotinamide riboside or nicotinamide mononucleotide) provide clinical benefit, and what dosing regimen is recommended?

NAD+ Supplementation in CKD Stage 3: Current Evidence Does Not Support Routine Use

Based on current evidence, NAD+ precursor supplementation (nicotinamide riboside or nicotinamide mononucleotide) cannot be recommended for patients with CKD stage 3, as no clinical trials demonstrate benefit in human CKD, and emerging safety concerns exist regarding accumulation of potentially cardiotoxic metabolites.

Absence of Guideline Support

No major kidney disease guidelines—including KDOQI, KDIGO, or diabetes-related CKD guidelines—recommend NAD+ precursor supplementation for CKD management 1. The 2020 KDOQI Nutrition Guidelines specifically address micronutrient supplementation in CKD but make no mention of NAD+ precursors, focusing instead on established interventions like vitamin D, B vitamins, and dietary modifications 1.

Standard CKD stage 3 management emphasizes blood pressure control (≤130/80 mmHg with albuminuria), ACE inhibitors or ARBs for patients with albuminuria >300 mg/24h, statin therapy for patients ≥50 years, sodium restriction to <2g daily, and plant-dominant Mediterranean-style diet 2.

Preclinical Evidence Shows Mixed Results

Animal Studies Demonstrate Context-Dependent Effects

The most recent 2025 preclinical study showed that nicotinamide riboside (NR) protected against CKD progression in an Alport syndrome mouse model by restoring fatty acid oxidation in proximal tubular cells and activating PPARα signaling 3. However, this represents a specific genetic model of kidney disease, not the typical causes of human CKD stage 3 (diabetes, hypertension, glomerulonephritis).

Critically, a 2021 study demonstrated that while NR supplementation prevented acute kidney injury in ischemia-reperfusion and cisplatin models, it completely failed to prevent CKD progression in two chronic kidney disease models (unilateral ureteral obstruction and chronic proteinuric disease) 4. This fundamental difference between acute and chronic kidney injury responses to NAD+ supplementation is essential for clinical decision-making.

Mechanism of NAD+ Depletion in CKD

NAD+ biosynthesis pathways are impaired in CKD, with de novo synthesis decreasing according to CKD stage while the salvage pathway remains relatively preserved 4, 5. A 2022 study identified that nicotinamide N-methyltransferase (NNMT) expression increases in CKD, contributing to NAD+ depletion and renal fibrosis through altered DNA methylation and inflammation 6.

Emerging Safety Concerns in CKD Patients

A critical 2025 publication raises serious safety concerns about NAD+ precursor supplementation in CKD patients 7. Patients with advanced CKD exhibit several-fold higher circulating concentrations of 2PY (N1-methyl-2-pyridone-5-carboxamide) and 4PY (N1-methyl-4-pyridone-5-carboxamide), which are terminal metabolites of NAD+ catabolism 7.

Cardiovascular Risk from Metabolite Accumulation

• Elevated 2PY and 4PY concentrations are independently associated with cardiovascular disease risk in humans 7
• CKD patients already have markedly elevated baseline levels of these metabolites due to impaired renal clearance 7
• NAD+ precursor supplementation further increases circulating 2PY and 4PY levels 7
• Given that cardiovascular disease is the leading cause of death in CKD patients, adding interventions that may increase CVD risk through metabolite accumulation is contraindicated 7

Clinical Translation Gap

Despite mechanistic plausibility and some positive preclinical data, no published human clinical trials have evaluated NAD+ precursor supplementation specifically in CKD stage 3 patients for clinically meaningful outcomes (mortality, cardiovascular events, dialysis progression, or quality of life) 3, 4, 5, 6.

The 2022 review on NAD+ metabolism in CKD acknowledges that while preclinical evidence is emerging, clinical studies remain limited and do not support therapeutic recommendations 5.

Dosing Information (Not Recommended for Clinical Use)

While specific dosing cannot be recommended due to lack of efficacy and safety data in human CKD:

• Preclinical studies used nicotinamide riboside at doses equivalent to approximately 250-500 mg/day in humans 3, 4
• No dose-finding studies exist for CKD populations 5
• Renal impairment likely alters pharmacokinetics of both NAD+ precursors and their metabolites, but this has not been systematically studied 7

Evidence-Based Alternatives for CKD Stage 3

Instead of unproven NAD+ supplementation, focus on interventions with established benefit:

• Blood pressure optimization: Target ≤130/80 mmHg if albuminuria present 2
• RAAS blockade: ACE inhibitors or ARBs for albuminuria >300 mg/24h 1, 2
• Statin therapy: For all patients ≥50 years with CKD stage 3 2
• Dietary modifications: Sodium <2g daily, plant-dominant Mediterranean diet 2
• Vitamin D supplementation: Only for documented 25(OH)D deficiency using cholecalciferol or ergocalciferol 1
• Bicarbonate supplementation: To maintain serum bicarbonate 24-26 mmol/L and reduce CKD progression 1

Critical Pitfalls to Avoid

• Do not use NAD+ precursors as a substitute for proven CKD therapies 2
• Avoid assuming that benefits in acute kidney injury models translate to chronic kidney disease 4
• Do not overlook the potential for cardiovascular harm from metabolite accumulation in patients with impaired renal clearance 7
• Recognize that proximal tubular energy metabolism dysfunction in CKD may not be reversible with simple NAD+ repletion in established disease 4, 6