Cell stress response impairs de novo NAD+ biosynthesis in the kidney.

The biosynthetic routes leading to de novo nicotinamide adenine dinucleotide (NAD+) production are involved in acute kidney injury (AKI), with a critical role for quinolinate phosphoribosyl transferase (QPRT), a bottleneck enzyme of de novo NAD+ biosynthesis. The molecular mechanisms determining reduced QPRT in AKI, and the role of impaired NAD+ biosynthesis in the progression to chronic kidney disease (CKD), are unknown. We demonstrate that a high urinary quinolinate-to-tryptophan ratio, an indirect indicator of impaired QPRT activity and reduced de novo NAD+ biosynthesis in the kidney, is a clinically applicable early marker of AKI after cardiac surgery and is predictive of progression to CKD in kidney transplant recipients. We also provide evidence that the endoplasmic reticulum (ER) stress response may impair de novo NAD+ biosynthesis by repressing QPRT transcription. In conclusion, NAD+ biosynthesis impairment is an early event in AKI embedded with the ER stress response, and persistent reduction of QPRT expression is associated with AKI to CKD progression. This finding may lead to identification of noninvasive metabolic biomarkers of kidney injury with prognostic and therapeutic implications.

Percutaneous cannulation for extracorporeal membrane oxygenation (ECMO): A method for pig experimental models.

Pigs are often used for experimental models of cardiogenic shock, cardiac arrest or acute lung injury with veno-arterial (VA) or veno-venous (VV) extracorporeal membrane oxygenation (ECMO) implementation. Percutaneous (as opposed to surgical) cannulation in experimental models has potential advantages, including, less surgical trauma or stressful stimuli and less bleeding complications when compared to open chest cannulation. However, pig anatomy can also be a challenge because of the deep location and angled anatomy of the femoral artery. The Seldinger technique and the use of a percutaneous cannulation kit is feasible in pigs. Summarized here we present (Graphical Abstract):•Percutaneous ECMO cannulation method for non-cardiac surgeon.•Establishment of this simple and rapid methods for pig experimental models.•Predictable complications of this method.

Real-Time and Non-invasive Monitoring of the Activation of the IRE1α-XBP1 Pathway in Individuals with Hemodynamic Impairment.

Many stressors that are encountered upon kidney injury are likely to trigger endoplasmic reticulum (ER) stress, subsequently activating transcriptional, translational and metabolic reprogramming. Monitoring early cellular adaptive responses engaged after hemodynamic impairment yields may represent a clinically relevant approach. However, a non-invasive method for detecting the ER stress response has not been developed. We combined a metabolomic approach with genetic marker analyses using urine from individuals undergoing scheduled cardiac surgery under cardiopulmonary bypass to investigate the feasibility and significance of monitoring the ER stress response in the kidney. We developed an original method based on fragment analysis that measures urinary levels of the spliced X-box binding protein 1 (sXBP1) mRNA as a proxy of inositol-requiring enzyme 1α (IRE1α) activity because sXBP1 is absolutely sensitive and specific for ER stress. The early engagement of the ER stress response after ischemic stress is critical for protecting against tissue damage, and individuals who mount a robust adaptive response are protected against AKI. The clinical consequences of our findings are of considerable importance because ER stress is involved in numerous conditions that lead to AKI and chronic kidney disease; in addition, the detection of ER stress is straightforward and immediately available in routine practice.