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Kidney oxygenation under pressure
van der Bel, R.
Publication date
2017
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van der Bel, R. (2017). Kidney oxygenation under pressure.
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Chapter
7
Discussion | 119 | C ha pt er 7
discussion
Although not yet fully understood at the time, the conceptual framework introduced at the beginning of this thesis served as the pathophysiological basis for the development of cath-eter based renal sympathetic denervation (RDN) in the first decade of the two thousands 1,2. This technique aimed to interrupt the kidneys’ sympathetic innervation by severing the sym-pathetic nerves located along the vascular wall of the renal arteries using radiofrequency ablation, thereby taking away the sympathetic signal arising from the kidneys. Resulting in a decreased sympathetic tone, reduced renin/angiotensin activity, lowered blood pres-sure and potentially improved kidney oxygenation. This made RDN ideally suited for the treatment of therapy resistant hypertension, rapidly generating interest from clinicians who previously had been without adequate further treatment options such patients. However, after initial enthusiasm aroused by two open label trials that indicated therapeutic benefit, the sham controlled Symplicity HTN-3 trial failed to show treatment efficacy of RDN on the blood pressure goals 3,4. Now much controversy surrounds the use of the technique and the basis on which it was founded 5-7. Proposed reasons for the failure of RDN are muchvaried, from technique failure, the large Hawthorne effects, increased drug adherence and patient selection, to a flawed pathophysiologic rationale 6-11. This thesis investigates
several mechanisms related to (nephrogenic) hypertension. Some of their results question the pathophysiological rationale for RDN in humans, starting with a study into the relations between the sympatho-vagal balance and cardiovascular risk in the general population and an expanded repeat of one of the studies that founded the rationale for RDN 12.
The sympathetic nervous system is not uniquely affected in CKD
The study by Hering et al. suggested an altered renal chemoreflex response in CKD patients during oxygen supplementation, attenuating sympathetic activity and blood pressure during systemic hyperoxia. With this in mind, one would expect increased sympatho-vagal impair-ment with renal function decline compared to other cardio-metabolic risk factors. However, we found no such relation in baroreflex sensitivity analysis among almost 6,000 participants of the HELIUS study described in Chapter 2. Furthermore, we were unable to repeat the
results of these experiments in a group of 19 CKD patients in Chapter 3. In our hands, oxygen
supplementation causes a dose-dependent blood pressure increase in these patients, which was caused by an increase in systemic vascular resistance, likely as the result of hyperoxic vasoconstriction independent of baroreflex function in patients with an insufficient nitric oxide mediated vasodilatory response. Although, oxygen supplementation may alleviate pe-ripheral sympathetic activity 12, it presents a major cardiovascular stressor to CKD patients. The central hemodynamic effects overshadows any beneficial renal effect, if at all present. Whether sympathetic dysregulation in patients is cause or consequence of cardio-metabolic
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disease cannot yet be determined based on the studies so far, upcoming prospective data will provide the opportunity to make the distinction.
Kidney BOLD MRI associates most with the kidneys’ filtration fraction, not
with GFR
According to the conceptual framework the two determinants of tubular oxygen demand, kidney perfusion and thus oxygenation are sympathetic nerve and renin/angiotensin activity. However, the effect of sympathetic activity on kidney oxygenation has only been investigated in animal models 13. Non-invasive assessment of kidney oxygenation in humans using blood
oxygen level dependent (BOLD) MRI has rapidly developed over the past years. By compar-ing the effects of angiotensin II on kidney perfusion and oxygenation to gold standard GFR and effective renal plasma flow we were able to gather that kidney BOLD MRI associates most with the kidneys’ filtration fraction and not with GFR. As the FF is the product of both the GFR and renal plasma flow, we therefore conclude that simultaneous renal blood flow measurements are indispensable for the correct interpretation of renal BOLD (Chapter 4). In
the meantime, another group has substantiated this in CKD patients 14,15.
Sympathetic activation decreases kidney perfusion without a reduction in
oxygenation
With these insights we moved on to investigate the effects of sympathetic activation on kid-ney hemodynamics and oxygenation using lower body negative pressure (LBNP), in Chapter 5. Using LBNP as a selective sympathetic stimulant we found that it substantially increased renal vascular resistance and reduced kidney perfusion, similar to that achieved by angioten-sin II infusion. However, this was not accompanied by a reduction in kidney oxygenation, not in the cortex nor in the medulla. These exploratory data question the physiological concept that sympathetic hyperactivity per se decreases kidney oxygenation. In contrast to the conceptual framework, this implies that systemic sympathetic activation decreases kidney perfusion without a parallel reduction in oxygenation, at least in healthy humans. Conversely in patients, pre-existent metabolic dysregulation in the kidneys may cause hypoxia during increased sympathetic activity. This has yet to be investigated.Improving MRI based functional assessment of the kidneys
Current functional MRI of the kidneys is not yet capable to fully evaluate the complex rheo-logical attributes of the kidneys. On the one hand this can be overcome using innovative post processing techniques, and the implementation of new advanced MRI modalities on the other. Innovative post processing can for instance be used to visualize and quantify the oxygenation gradient within the kidneys, as shown in Chapter 4 16,17. Adoption of other MRI
modalities to quantify and map kidney perfusion could prove valuable in the future as the currently used phase contrast method only provides global kidney perfusion quantification
Discussion | 121 | C ha pt er 7 without mapping. Using arterial spin labeling 18,19 or intravoxel incoherent motion (IVIM) analysis of diffusion weighted imaging 20. Both techniques provide spatially differentiated perfusion data, however only IVIM analysis can potentially differentiate between blood and urine perfusion within the kidney. In Chapter 6, we used a kidney specific tri-exponential
approach to IVIM analysis to show its capability to track changes renal perfusion and GFR. Its further development might provide new opportunities for a non-invasive, spatially dif-ferentiated assessment of kidney perfusion and filter function in kidney disease.
IMPLICATIONS AND PERSPECTIVES
For the clinic
The role of kidney hypoxia in the pathophysiology and progression of chronic kidney disease and its relation to systemic sympathetic hyperactivity may not be as simple as previously thought 7,21 . Consequently, this could partially explain the inefficacy of RDN. Therefore, in-tervention in this pathway is not as appealing anymore. None the less, kidney hypoxia remains an attractive factor and potential therapeutic target to prevent CKD progression 7. For example, new compounds that intervene in the hypoxia inducible factor (HIF) pathways are becoming available in the near future. Although these compound have been developed as alternatives to erythropoietin, these are expected to have reno-protective effects as well. HIF stabilization may directly influence the metabolic efficiency of cells, thereby lowering oxygen consumption, alleviating tissue hypoxia and po-tentially reducing or halting the nephrosclerotic process. Several clinical trials in non-dialysis and dialysis CKD patients have reported positive outcomes 22-26. As therapeutic options targeting kidney hypoxia are underway, reliable methods for future therapy and patient evaluation will become indispensable for research and clinic. Multi-modal MRI seems ideally suited for such applications. To fully elaborate on the role of hypoxia in CKD in humans, further studies should focus on the effects of hypoxia reduction on CKD progression. Using the developed MRI techniques, patients’ current drug therapy may already be optimized to reduce the kidney metabolic demand and improve filtration fraction.
For research
The advent and eventual failure of RDN as an antihypertensive therapy may have been in part be a consequence of inappropriate human extrapolation of data obtained from animal studies. Our studies underlines the essential role of human studies to translate animal data to human (patho)physiology. Although such human studies may be intensive and/or use| Chapter 7 | 122 physically strenuous interventions, these will deliver true insight into human physiology and therefore will remain indispensable. Conducting human research relies heavily on the availability, development and application of safe, technically advanced and minimally invasive measurements. Therefore, the integra-tion of technology and clinic or physics and physiology becomes ever more important. This thesis is proof that the Technical Physician is very much at home in such an environment and can be a valuable asset to a multidisciplinary team of clinicians and engineers.
Discussion | 123 | C ha pt er 7
references
1. Schlaich MP, Sobotka PA, Krum H, et al. Renal sympathetic-nerve ablation for uncontrolled hyperten-sion. N Engl J Med. 2009; 361(9): 932-934.2. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009; 373(9671): 1275-1281.
3. Bakris GL, Townsend RR, Liu M, et al. Impact of renal denervation on 24-hour ambulatory blood pres-sure: results from SYMPLICITY HTN-3. J Am Coll Cardiol. 2014; 64(11): 1071-1078.
4. Kandzari DE, Bhatt DL, Sobotka PA, et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol. 2012; 35(9): 528-535.
5. Gulati R, Raphael CE, Negoita M, et al. The rise, fall, and possible resurrection of renal denervation. Nat Rev Cardiol. 2016; 13(4): 238-244.
6. Hiremath S, Froeschl M, Ruzicka M. Catheter-based renal sympathetic denervation: limitations to and gaps in the evidence. Curr Opin Cardiol. 2014; 29(4): 336-343.
7. Hirakawa Y, Tanaka T, Nangaku M. Renal Hypoxia in CKD; Pathophysiology and Detecting Methods. Front Physiol. 2017; 8: 99.
8. Burchell AE, Chan K, Ratcliffe LE, et al. Controversies Surrounding Renal Denervation: Lessons Learned From Real-World Experience in Two United Kingdom Centers. Journal of clinical hypertension (Green-wich, Conn). 2016; 18(6): 585-592.
9. Sharp AS, Davies JE, Lobo MD, et al. Renal artery sympathetic denervation: observations from the UK experience. Clin Res Cardiol. 2016; 105(6): 544-552.
10. Imnadze G, Balzer S, Meyer B, et al. Anatomic Patterns of Renal Arterial Sympathetic Innervation: New Aspects for Renal Denervation. J Interv Cardiol. 2016; 29(6): 594-600.
11. Froeschl M, Hadziomerovic A, Ruzicka M. Percutaneous renal sympathetic denervation: 2013 and beyond. Can J Cardiol. 2014; 30(1): 64-74.
12. Hering D, Zdrojewski Z, Krol E, et al. Tonic chemoreflex activation contributes to the elevated muscle sympathetic nerve activity in patients with chronic renal failure. J Hypertens. 2007; 25(1): 157-161. 13. Evans RG, Ince C, Joles JA, et al. Haemodynamic influences on kidney oxygenation: clinical implications
of integrative physiology. Clin Exp Pharmacol Physiol. 2013; 40(2): 106-122.
14. Khatir DS, Pedersen M, Jespersen B, et al. Evaluation of Renal Blood Flow and Oxygenation in CKD Using Magnetic Resonance Imaging. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2015; 66(3): 402-411.
15. Khatir DS, Pedersen M, Jespersen B, et al. Reproducibility of MRI renal artery blood flow and BOLD measurements in patients with chronic kidney disease and healthy controls. Journal of magnetic resonance imaging : JMRI. 2014; 40(5): 1091-1098.
16. Milani B, Ansaloni A, Sousa-Guimaraes S, et al. Reduction of cortical oxygenation in chronic kidney dis-ease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging. Nephrology Dialysis Transplantation. 2016.
17. Piskunowicz M, Hofmann L, Zuercher E, et al. A new technique with high reproducibility to estimate renal oxygenation using BOLD-MRI in chronic kidney disease. Magn Reson Imaging. 2015; 33(3): 253-261.
18. Cai YZ, Li ZC, Zuo PL, et al. Diagnostic value of renal perfusion in patients with chronic kidney disease using 3D arterial spin labeling. Journal of magnetic resonance imaging : JMRI. 2017; 46(2): 589-594.
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19. Mora-Gutierrez JM, Garcia-Fernandez N, Slon Roblero MF, et al. Arterial spin labeling MRI is able to detect early hemodynamic changes in diabetic nephropathy. Journal of magnetic resonance imaging : JMRI. 2017.
20. van Baalen S, Leemans A, Dik P, et al. Intravoxel incoherent motion modeling in the kidneys: Compari-son of mono-, bi-, and triexponential fit. Journal of magnetic resonance imaging : JMRI. 2016. 21. Liu ZZ, Bullen A, Li Y, et al. Renal Oxygenation in the Pathophysiology of Chronic Kidney Disease. Front
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25. Pergola PE, Spinowitz BS, Hartman CS, et al. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 2016; 90(5): 1115-1122.
26. Provenzano R, Besarab A, Sun CH, et al. Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. Clinical journal of the Ameri-can Society of Nephrology : CJASN. 2016; 11(6): 982-991.
