Highlights: 

  • A recent mouse study showed that NMN promotes kidney inflammation and damage. 
  • Longevity scientist Dr. Brenner says this could potentially be from contaminated NMN. 
  • Many animal studies have shown that NMN is beneficial to the kidneys.

In a recent episode of The Optispan Podcast, host Matt Kaeberlein, PhD, asked guest Charles Brenner, PhD, about a recent preprint study showing evidence for kidney pathology in aged mice treated with NMN. Ultimately, Dr. Brenner suggests that the kidney toxicity was due to contamination of the NMN used in the study. 

Study Details

The study in question was done by Saleh and colleagues from the University of Washington who put 300 mg/kg of NMN in the drinking water of aged mice for 8 weeks. In a previous study of the same cohort of mice, NMN was shown to improve heart function, so Saleh and colleagues expected to see that NMN improves the kidneys. However, they found that NMN increased genetic markers for kidney inflammation and damage. This effect did not occur in the liver, suggesting organ-specific changes in response to NMN treatment.

Furthermore, Saleh and colleagues found that NMN increased metabolites like MNA (N-methyl-nicotinamide), 2-PY, and 4-PY, which were especially elevated in aged mice. A previous study showed that these metabolites were elevated in prediabetic, postmenopausal women who were administered 250 mg/day of NMN for 10 weeks. These metabolites come from the breakdown of NAD+ but at high levels are considered uremic toxins, which accumulate in the serum of individuals with chronic kidney disease. Moreover, a recent Cleveland Clinic study showed that these same metabolites are associated with cardiovascular disease (CVD) risk. 

Brenner’s Explanation 

Dr. Brenner mentions the Cleveland Clinic study showing an association between CVD risk and the 2-PY and 4-PY metabolites from niacin. He states that he thinks Saleh and colleagues proposed a similar mechanism for kidney damage in aged mice treated with NMN. He goes on to say that the MNA metabolite can be fed to mice and he doesn’t think it would cause kidney toxicity. Brenner then speculates that the NMN used by Saleh and colleagues might have been contaminated with toxins that could potentially lead to kidney inflammation and damage. 

In response to Brenner, Dr. Kaeberlein brings up that the NMN used by Saleh and colleagues came from leading NMN researcher Shino-Ichiro Imai, PhD. While he admits that impurities in the NMN are possible, Kaeberlein points out that NMN-induced kidney toxicity, particularly in aged mice, is at least plausible. Brenner then points out the various animal studies showing that nicotinamide and other NAD+ precursors protect against kidney damage and injury. For example, NR (nicotinamide riboside) has been shown to alleviate acute kidney disease.

Beneficial Effects of NMN on Kidney

Saleh and colleagues acknowledge that “previous studies focused on NMN supplementation in the kidney uniformly reported beneficial effects.” They also say that these studies “used acute toxic challenges or disease models rather than normative aging.” However, Saleh and colleagues cite a study showing NMN restores NAD+ levels in the kidneys of normally aged mice. The same study showed that NMN restores kidney sirtuins, enzymes associated with beneficial effects like DNA repair. 

In another study cited by Saleh and colleagues, NMN was shown, in normally aged mice, to restore protein levels and peroxisomes, which help clear waste products from cells. Additionally, NMN was shown to improve the kidneys and survival rates of a diabetes mouse model, protect against kidney scarring, and prevent kidney damage in mice. Thus, it would appear that NMN improves kidney health in disease models, in rodents exposed to acute toxic challenges, as well as with normative aging. When it comes to the effect of NMN on the kidneys of humans, more studies are needed. Although, Saleh and colleagues say, 

“It is important to note that mice and humans possess differing levels and forms of some [NAD+] metabolic enzymes which can affect the impact of NMN or other NAD+ compounds in a species-specific manner.”

The University of Washington researchers also explain that the dose of NMN given to the mice in their study is equivalent to approximately 1.5 grams/day for humans, which is higher than the recommended dose. This implies that taking the recommended dose of NMN may not trigger kidney damage, if it does at all. 

Does NMN Trigger Kidney Damage in Humans? 

Ultimately, whether NMN triggers kidney damage in humans requires further study. It could be that the beneficial effects of NMN on the kidneys of rodents reported by multiple studies outweigh the findings of Saleh and colleagues. However, human studies have shown an association between elevated NAD+ metabolites and CVD risk and kidney disease. These NAD+ metabolites could potentially be elevated by any NAD+ precursor, including NMN, NR, nicotinamide, and niacin. However, animal studies have shown that these NAD+ precursors exert beneficial effects on the kidneys. Therefore, future clinical studies of NAD+ precursors should measure markers of kidney damage, when possible, to elucidate this conundrum.