An orally available NAD+ precursor NR relieves acute kidney injury but not chronic kidney disease.(peterschreiber.media | iStock)
Kidney disease occurs when the fist-sized, bean-shaped organs on each side of your body become damaged and can’t filter blood as well as they should. This often is the result of alterations in the function of the cell’s power generator, the mitochondria, and a shortage in a vital molecule called nicotinamide adenine dinucleotide (NAD+) that fuels its function. However, the role of NAD+ deficiency in chronic kidney disease is not clear.
A research article published by Faivre and colleagues in the journal Nephrology Dialysis Transplantation shows that a major pathway for the synthesis of NAD+ is downregulated in biopsies from the short-term phase (acute phase) of ischemia in kidney transplant patients and in over 200 biopsies from long-term (chronic) kidney disease patients of diverse causes. This observation was reproduced in rodent models of acute kidney injury and chronic kidney disease, and replenishing the supply of NAD+ with a highly potent orally available NAD+ precursor nicotinamide riboside (NR) alleviated kidney damage in rodent models of acute kidney injury. However, using NR to bring up NAD+ levels did not efficiently prevent chronic kidney disease progression in rodent models of chronic kidney disease. The investigators conclude that NR could be used to prevent acute kidney injury in high-risk patients and before kidney donation or transplantation.
Acute kidney injury is a major risk factor for progression to chronic kidney disease, a worldwide health problem leading to decreased quality of life, increased mortality, and a large financial burden. Mitochondrial dysfunction is part of what causes acute kidney injury and may lead to chronic kidney disease progression.
NAD+ is a molecule found in every cell of the body and is critical to mitochondria, controlling their formation and function. NAD+ can be generated from tryptophan, an essential protein building block called an amino acid found in turkeys and many other foods, by a process called de novo NAD+ synthesis. It can also be made from precursors like nicotinamide, nicotinic acid, or nicotinamide riboside (NR) through what is known as the salvage pathway.
Deficient de novo NAD+ synthesis plays an important role in acute kidney injury. Whether alterations of de novo NAD+ synthesis is also a player in chronic kidney disease progression and fibrogenesis is unknown. For these reasons, pinpointing the pathway used by the kidney for generating NAD+ is an important therapeutic target that is being explored currently to curb kidney injury and disease. So, Faivre and colleagues studied the levels of key enzymes that participate in the synthesis of NAD+ in biopsies from kidney transplant patients and chronic disease patients of diverse causes.
Biopsies from transplanted human kidneys, which model acute kidney injury, revealed that NAD+ de novo synthesis is impaired whereas the salvage pathway is stimulated. In human biopsies from chronic disease patients, the NAD+ de novo synthesis pathway was impaired according to chronic kidney disease stage, with better preservation of the salvage pathway. “To our knowledge, we are the first to report alterations of NAD+ synthesis in all kidney compartments in human chronic kidney disease patients, with a severity proportional to the chronic kidney disease stage,” said the investigators in the article.
The decrease in de novo NAD+ synthesis was confirmed in several mouse models of acute kidney injury and chronic kidney disease. The investigators also assessed the effect of adding NR to mouse models with acute kidney injury or chronic kidney disease. NR supplementation showed beneficial effects in mice with acute kidney injury but did not prevent chronic kidney disease progression.
Altogether, these results indicate that chronic kidney disease is, at a minimum, less responsive than acute kidney injury to NAD+ restoration, at least using NR as an NAD+ precursor. “We show in mouse models that NR is able to prevent acute kidney injury but does not attenuate chronic kidney disease progression,” said the scientists in their study.
The investigators also suggest that, given their observations in kidney transplant recipients, administration of NR before donation may improve kidney recovery. In chronic kidney disease, more studies are needed to identify which NAD+ replenishment therapy should be used and which subpopulations are likely to benefit most, given the lower response observed experimentally with NR.