Renal Denervation Exacerbates LPS- and Antibody-induced Acute Kidney Injury, but Protects from Pyelonephritis in Mice

Significance Statement The advent of second-generation radiofrequency ablation has renewed interest in renal denervation (RDN) to treat patients with drug-resistant arterial hypertension. In this study, we demonstrate that RDN-induced alterations in glomerular perfusion and filtration have hitherto unknown consequences for inflammatory kidney diseases. Denervated kidneys are more susceptible to immune complex GN or endotoxin-induced renal inflammation. In contrast, the improved GFR of denervated kidneys provides relative protection against pyelonephritis, at the cost of higher susceptibility of the contralateral kidney. These effects need to be kept in mind when RDN is considered in patients with hypertension and other conditions. Our findings suggest that unilateral RDN might allow enriching drugs in one kidney. Background Renal denervation (RDN) is an invasive intervention to treat drug-resistant arterial hypertension. Its therapeutic value is contentious. Here we examined the effects of RDN on inflammatory and infectious kidney disease models in mice. Methods Mice were unilaterally or bilaterally denervated, or sham operated, then three disease models were induced: nephrotoxic nephritis (NTN, a model for crescentic GN), pyelonephritis, and acute endotoxemic kidney injury (as a model for septic kidney injury). Analytical methods included measurement of renal glomerular filtration, proteinuria, flow cytometry of renal immune cells, immunofluorescence microscopy, and three-dimensional imaging of optically cleared kidney tissue by light-sheet fluorescence microscopy followed by algorithmic analysis. Results Unilateral RDN increased glomerular filtration in denervated kidneys, but decreased it in the contralateral kidneys. In the NTN model, more nephritogenic antibodies were deposited in glomeruli of denervated kidneys, resulting in stronger inflammation and injury in denervated compared with contralateral nondenervated kidneys. Also, intravenously injected LPS increased neutrophil influx and inflammation in the denervated kidneys, both after unilateral and bilateral RDN. When we induced pyelonephritis in bilaterally denervated mice, both kidneys contained less bacteria and neutrophils. In unilaterally denervated mice, pyelonephritis was attenuated and intrarenal neutrophil numbers were lower in the denervated kidneys. The nondenervated contralateral kidneys harbored more bacteria, even compared with sham-operated mice, and showed the strongest influx of neutrophils. Conclusions Our data suggest that the increased perfusion and filtration in denervated kidneys can profoundly influence concomitant inflammatory diseases. Renal deposition of circulating nephritic material is higher, and hence antibody- and endotoxin-induced kidney injury was aggravated in mice. Pyelonephritis was attenuated in denervated murine kidneys, because the higher glomerular filtration facilitated better flushing of bacteria with the urine, at the expense of contralateral, nondenervated kidneys after unilateral denervation.