Kidney Disease and the Regulation of NAD+

Chronic kidney disease (CKD) is a debilitating condition affecting millions worldwide, characterized by progressive loss of renal function and severe metabolic disturbances. Recent scientific advancements have uncovered a fascinating connection between kidney dysfunction and the dysregulation of nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in cellular energy production, DNA repair, and mitochondrial health. A study led by Hongquan Guan and Yuting Geng provides compelling evidence that NAD+ depletion plays a central role in the progression of kidney disease, offering new insights into potential therapeutic interventions (Imai et al., 2025). Understanding this relationship is essential, as it not only sheds light on the molecular mechanisms underlying CKD but also opens doors to innovative treatments that could slow or even reverse kidney damage.

​NAD+ is indispensable for maintaining cellular homeostasis, serving as a key player in redox reactions, energy metabolism, and signaling pathways mediated by sirtuins and poly(ADP-ribose) polymerases (PARPs) (Cantó et al., 2015; Xu et al., 2021). Its levels naturally decline with age, a phenomenon exacerbated in metabolic disorders such as diabetes and hypertension, which are major contributors to CKD. The kidneys, being highly metabolic organs, are particularly vulnerable to NAD+ deficiency. They rely on this coenzyme to sustain tubular function, filter toxins, and regulate electrolyte balance.

When NAD+ levels drop, the consequences are severe: mitochondrial function deteriorates, leading to reduced ATP production and impaired nutrient reabsorption; oxidative stress increases due to diminished activity of antioxidant enzymes like superoxide dismutase; and inflammation escalates as NAD+-dependent sirtuins, which normally suppress pro-inflammatory pathways, become less active. These disruptions create a vicious cycle, accelerating kidney damage and fibrosis. Guan and Geng demonstrated that CKD is associated with a significant decline in renal NAD+ levels, primarily due to dysregulation in its biosynthesis (Imai et al., 2025). The salvage pathway, which converts nicotinamide into NAD+ via the enzyme nicotinamide phosphoribosyltransferase (NAMPT), is particularly affected (Cantó et al., 2015; Xu et al., 2021). In CKD, NAMPT expression is suppressed, crippling the kidney’s ability to replenish NAD+ stores (Xu et al., 2021). Compounding this issue is the overactivation of PARPs, enzymes that consume NAD+ to repair DNA damage—a common occurrence in stressed renal cells (Bai et al., 2011). As NAD+ is diverted to DNA repair, less is available for essential metabolic processes, further exacerbating cellular dysfunction (Bai et al., 2011). Additionally, damaged kidneys may excrete NAD+ precursors like nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) in urine, creating a systemic deficiency that extends beyond renal tissues (Xu et al., 2021; Imai et al., 2025).

​The implications of these findings are profound. Using experimental models, Guan and Geng showed that restoring NAD+ levels through NMN supplementation could mitigate kidney injury (Imai et al., 2025). Mice treated with NMN exhibited improved mitochondrial function, reduced oxidative stress, and slower progression of fibrosis (Bhargava & Schnellmann, 2017; Imai et al., 2025). These effects were linked to the activation of sirtuins, particularly SIRT3, which plays a critical role in maintaining mitochondrial integrity and suppressing inflammatory responses (Cantó et al., 2015; Bai et al., 2011). This aligns with earlier research showing that NAD+ repletion protects against acute kidney injury and diabetic nephropathy, suggesting a broad therapeutic potential for NAD+-boosting strategies in various forms of kidney disease (Xu et al., 2021).

​Given these discoveries, several promising interventions are being explored. Nicotinamide riboside (NR) and NMN, both precursors to NAD+, have shown efficacy in preclinical and early clinical trials, improving renal function and reducing markers of oxidative stress (Cantó et al., 2015). Sirtuin activators like resveratrol are also under investigation, as they enhance mitochondrial biogenesis and counteract inflammation (Bai et al., 2011). Another intriguing approach involves PARP inhibitors, which could prevent excessive NAD+ depletion in response to DNA damage, thereby preserving cellular energy reserves (Xu et al., 2021). However, challenges remain. The bioavailability of oral NAD+ precursors is limited, and their long-term safety in humans requires further study (Xu et al., 2021). Additionally, the heterogeneity of CKD—arising from diverse causes such as diabetes, hypertension, and genetic predispositions—means that treatments may need to be tailored to individual patients (Bhargava & Schnellmann, 2017).

​Looking ahead, the next critical step is translating these findings into clinical practice. Large-scale human trials are needed to confirm the benefits of NAD+ supplementation in CKD patients and to determine optimal dosing regimens (Imai et al., 2025; Xu et al., 2021). Combining NAD+ boosters with existing therapies, such as anti-inflammatory or antifibrotic drugs, could enhance their efficacy (Bhargava & Schnellmann, 2017). Moreover, advances in drug delivery systems, such as nanoparticle-based formulations, may improve the bioavailability of NAD+ precursors, maximizing their therapeutic impact (Imai, 2025).

​The study by Guan and Geng underscores the pivotal role of NAD+ in kidney health and disease (Imai et al., 2025). By elucidating the mechanisms linking NAD+ depletion to renal dysfunction, it provides a scientific foundation for novel treatments that could transform the management of CKD. As research progresses, NAD+ modulation may emerge as a cornerstone of nephrology, offering hope to patients grappling with this chronic and often devastating condition. The intersection of aging, metabolism, and kidney function is a fertile ground for discovery, and the insights gained from studying NAD+ could have far-reaching implications, not only for CKD but also for other age-related diseases. In a world where the prevalence of kidney disease continues to rise, such innovations are not just scientifically intriguing—they are urgently needed.


​References

​Bai, P., Cantó, C., Oudart, H., Brunyánszki, A., Cen, Y., Thomas, C., Yamamoto, H., Huber, A., Kiss, B., Houtkooper, Riekelt H., Schoonjans, K., Schreiber, V., Sauve, Anthony A., Menissier-de Murcia, J., & Auwerx, J. (2011). PARP-1 Inhibition Increases Mitochondrial Metabolism through SIRT1 Activation. Cell Metabolism, 13(4), 461–468. https://doi.org/10.1016/j.cmet.2011.03.004
Bhargava, P., & Schnellmann, R. G. (2017). Mitochondrial energetics in the kidney. Nature Reviews Nephrology, 13(10), 629–646. https://doi.org/10.1038/nrneph.2017.107
Cantó, C., Menzies, Keir J., & Auwerx, J. (2015). NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metabolism, 22(1), 31–53. https://doi.org/10.1016/j.cmet.2015.05.023
Imai, S. (2025). PPDPF: Preventing kidney disease through NAD +regulation. Science Advances, 11(12). https://doi.org/10.1126/sciadv.adw6815
Xu, J., Kitada, M., & Koya, D. (2021). NAD+ Homeostasis in Diabetic Kidney Disease. Frontiers in Medicine, 8. https://doi.org/10.3389/fmed.2021.703076