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Abstract: PO2241

Differential Role of NAD+ Deficiency in Acute and Chronic Kidney Disease

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Faivre, Anna, Universite de Geneve, Geneva, GE, Switzerland
  • Katsyuba, Elena, Ecole Polytechnique Federale de Lausanne, Lausanne, VD, Switzerland
  • Verissimo, Thomas, Universite de Geneve, Geneva, GE, Switzerland
  • Heckenmeyer, Carolyn, Universite de Geneve, Geneva, GE, Switzerland
  • Legouis, David, Universite de Geneve, Geneva, GE, Switzerland
  • De Seigneux, Sophie M., Universite de Geneve, Geneva, GE, Switzerland
Background

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been shown in acute kidney injury (AKI), but few is known about chronic kidney disease (CKD).

Methods

We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from allograft patients during reperfusion, mimicking AKI, and in patients with CKD at different stages. We used ischaemia–reperfusion injury (IRI) and cisplatin injection to model AKI, unilateral ureteral obstruction (UUO) and tubulointerstitial fibrosis induced by proteinuria (POD-ATTAC) to investigate CKD in mice. Then we assessed the effect of a potent NAD+-replenishment therapy, the nicotinamide riboside (NR), in both AKI and CKD models.

Results

RNA-sequencing analysis of human kidney allograft biopsies during reperfusion showed that the NAD+ de novo synthesis is impaired in the immediate post-transplantation period. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury.
In biopsies from CKD patients, the NAD+ de novo synthesis was impaired according to CKD stage, with better preservation of the salvage pathway (Figure 1). Similar alterations in gene expression were observed in UUO and POD-ATTAC mouse models. NR supplementation did not prevent CKD progression in contrast to its efficacy in AKI.

Conclusion

Impairment of NAD+ synthesis seems to be a hallmark of AKI and CKD. An oral NR supplementation showed protective effects on AKI but had no effect on CKD in mouse models. This study shows the dual role of NAD+ deficiency in AKI and CKD and the potential of NAD+-replenishment therapies as a preventive strategy for human AKI.

Funding

  • Private Foundation Support