Regulation of renal perfusion and oxygenation in sepsis-induced acute kidney injury

• Applicant: Dr. Erdmann Seeliger, since 2/2015
• Subject Area: Anatomy and Physiology ; Nephrology
• Term: from 2011 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 152203169

• Final Report Year: 2019

Final Report Abstract

The hypothesis that renal tissue hypoperfusion and hypoxia are pivotal elements of the pathophysiological chain of events that leads to AKI of various origins was corroborated by in vivo studies in rats utilizing both, methods of integrative physiology and parametric MRI (in close cooperation with Projects 9 and 5). Based upon our results, we proposed a unifying theory regarding the multifaceted pathophysiology of contrast-induced AKI. To test the hypothesis, that nitrite alleviates AKI, we first established a protocol for low-dose nitrite administration that results in significant vasodilation in hypoxic tissue areas, but does not result in unwarranted hypotension or methemoglobin levels. This low-dose nitrite administration greatly alleviated renal tissue hypoperfusion and hypoxia in rat AKI; as the safety of comparable low-dose nitrite administration in humans has already been shown, it might well constitute a reasonably specific measure to prevent or alleviate AKI in patients. Our studies showed that the use of a standard set of reversible (patho-)physiologically relevant test procedures (including the newly developed ones) as well as the addition of near-infrared spectroscopic measurements to our standard setup of physiological probes enables comprehensive determination of the regulation of renal hemodynamics and oxygenation in vivo. The feasibility of iron oxide nanoparticles as contrast agent was also proven. Utilizing the hybrid MR-PHYSIOL approach, in close cooperation with Project 9 we found that the relationship between parameters relevant for renal (patho-)physiology such as renal tissue partial pressure of oxygen and blood oxygenation level-dependent MRI is confounded by a number of factors. Therefore, the impact of these confounders in several (patho-)physiological scenarios must be quantified, before a stand-alone MRI protocol for renal hemodynamics and oxygenation can be established.

Publications

• Early effects of an x-ray contrast medium on renal T2*/T2 MRI as compared to short-term hyperoxia, hypoxia and aortic occlusion in rats. Acta Physiol (Oxf) 208: 202-213, 2013
  Arakelyan K, Cantow K, Hentschel J, Flemming B, Pohlmann A, Ladwig M, Niendorf T, Seeliger E
  
• High temporal resolution parametric MRI monitoring of the initial ischemia/reperfusion phase in experimental acute kidney injury. PLoS ONE 8: e57411, 2013
  Pohlmann A, Hentschel J, Fechner M, Hoff U, Bubalo G, Arakelyan K, Cantow K, Seeliger E, Flemming B, Waiczies H, Waiczies S, Schunk WH, Dragun D, Niendorf T
  
• Detailing the relation between renal T2* and renal tissue pO2 using an integrated approach of parametric magnetic resonance imaging and invasive physiological measurements. Invest Radiol 49: 547-560, 2014
  Pohlmann A, Arakelyan K, Hentschel J, Cantow K, Flemming B, Ladwig M, Waiczies S, Seeliger E, Niendorf T
  
• Low-dose nitrite alleviates early effects of an x-ray contrast medium on renal hemodynamics and oxygenation in rats. Invest Radiol 49: 70-77, 2014
  Seeliger E, Cantow K, Arakelyan K, Ladwig M, Persson PB, Flemming B
  
• Detailing renal hemodynamics and oxygenation in rats by a combined near-infrared spectroscopy and invasive probe approach. Biomed Opt Express 6: 309-323, 2015
  Grosenick D, Cantow K, Arakelyan K, Wabnitz H, Flemming B, Skalweit A, Ladwig M, Macdonald R, Niendorf T, Seeliger E
  
• How bold is blood oxygenation-dependent (BOLD) magnetic resonance imaging of the kidney? Opportunities, challenges and future directions. Acta Physiol (Oxf) 213: 19-38, 2015
  Niendorf T, Pohlmann A, Arakelyan K, Flemming B, Cantow K, Hentschel J, Grosenick D, Ladwig M, Reimann H, Klix S, Waiczies S, Seeliger E
  
• Acute effects of ferumoxytol on regulation of renal hemodynamics and oxygenation. Sci Rep 6: 29965, 2016
  Cantow K, Pohlmann A, Flemming B, Ferrara F, Waiczies S, Grosenick D, Niendorf T, Seeliger E
  
• What Do BOLD MR Imaging Changes in Donors' Remaining Kidneys Tell Us? Radiology 281: 653-655, 2016
  Niendorf T, Flemming B, Evans RG, Seeliger E
  
• Low dose nitrite improves reoxygenation following renal ischemia in rats. Sci Rep 7: 14597, 2017
  Cantow K, Flemming B, Ladwig-Wiegard M, Persson PB, Seeliger E
  
• Understanding and preventing contrast-induced acute kidney injury. Nat. Rev. Nephrol. 13: 169-180, 2017
  Fähling M, Seeliger E, Patzak A, Persson PB