CardioPulse 4543 doi:10.1093/eurheartj/ehaa655 Josep Trueta and Renal Sympathetic Activation

The 80-year evolution from defining Renal Sympathetic Activation to Renal Denervation (RDN)

Josep Trueta, MD, was an innovative thinker whose advances in wound Downloaded from https://academic.oup.com/eurheartj/article/41/48/4543/5912222 by guest on 28 September 2021 care saved the lives of thousands of patients during the Spanish Civil war and World War II. He was also one of the first orthopaedic pio- neers to recognize the relationship between blood and bone. Trueta was a polymath with wide-ranging interests and one of his innovative studies during World War II contributed greatly to both our knowl- edge of the renal circulation and the pathogenesis of hypertension. Trueta was first and foremost a Catalan. He was born in Barcelona into a family with a long tradition of medical and military service.1 His appointment as chief surgeon and professor of surgery at the University of Barcelona coincided with the outbreak of the Spanish Civil War. He had the dubious distinction of witnessing and treating the sequelae of history’s first mass aerial attacks on a civilian popula- tion.1,2 As an inventive trauma surgeon, Trueta’s two major contribu- tions encompassed the concept of mass casualty evacuation/care and the publication of his classic paper, ‘The treatment of war fractures by the closed-plaster method’.2,3 Shortly after his arrival at Oxford, Trueta was invited to work in the newly furbished laboratory of Sir Howard Florey at the William Dunn School of Pathology. Trueta found working there heady and exciting Figure 1 Josep Trueta dressed in Oxford regalia with the Queen (Figure 1). The afternoon ‘teatime’ meetings of the many prominent Mother Elizabeth on the occasion of the dedication of a new building researchers with diverse investigative interests were exhilarating, lead- at the Nuffield Orthopaedic Centre, 27 October 1958 (photograph ing to cross fertilization of ideas and catalyzing research collaborations. provided courtesy of Ame`lia Trueta Llacuna). One of these discussions led to a collaboration by Trueta and his col- league John Barnes, with the biochemist Ernst Chain (Figure 2). Chain remembered the research of Alexander Florey with ‘Penicillium nota- tum’. Barnes and Trueta subsequently injected mice with staphylococci moved to the Nuffield Institute for Medical Research at Oxford and treated one half of the group with penicillin serum. Only the mice University to pursue his studies of the renal circulation in the labora- 1,6 which had been inoculated with penicillin survived. As Trueta later tory of the renowned physiologist Kenneth Franklin’. They were wrote, ‘A miracle had happened under our very eyes—the antibiotic soon joined by a radiologist, Alfred Barclay, and an expert pathologist, era was born’, (ref 1, page 150 ). Peter Daniel. This clearly exemplified multidisciplinary research at its 6 Trueta’s seminal contributions to the physiology of the renal circula- best. The four co-investigators initiated experimental studies on rab- tion and the pathogenesis of hypertension were almost an accident. In bits. Following the tying of a tourniquet on a rabbit’s hind leg, they March 1941, at a time when England was suffering heavily from injected India ink or other opaque fluids into its arteries to opacify the German air-raids, Bywaters and Beall published the first account of a vasculature and observed the results by X-ray. Trueta’s experiments condition they coined the ‘crush syndrome’.4 The condition was char- soon elucidated the pathogenesis of the ‘crush syndrome’: prolonged acterized by acute kidney failure developing in patients who suffered pressure on the leg arteries constricted adjacent blood vessels, pre- one or more limbs crushed for several hours under fallen debris in- sumably by provoking activation of sympathetic activity, with resultant 6 cluding stones or heavy beams. The pathogenesis of the acute renal impairment of renal perfusion. failure was the subject of debate. Many observers ascribed the renal Subsequent experiments with many different stimuli, including di- failure to toxic substances released by the crushed tissues. In contrast, rect electrical stimulation of the renal pedicle produced the same re- Trueta postulated that the crush injury to one or more limbs produced sult; as did severe haemorrhage, heavy doses of certain hormones (e.g. a spasm of the renal arteries, leading to renal ischaemia and an impair- adrenalin, pituitrin i.e. vasopressin), and injections of the toxins pro- ment of renal function.5 In retrospect, it is conceivable that rhabdomy- duced by staphylococcus. The investigators decided all of these stimuli olysis may have also contributed to the observed acute renal failure. activate nerves which constrict the kidneys’ blood vessels and divert As described in an article in Time magazine, ‘In order to elucidate the blood flow from the small vessels in the cortex to the larger ones the relationship between crushed limbs and renal failure, Trueta in the medulla (Figure 3). Lack of blood in the cortex, in turn, produced 4544 CardioPulse an increase in systemic blood pressure.6 As reported in Time maga- zine, Trueta’s group hopefully declared: ‘We believe that [the primary factors causing high blood pressure] will eventually be found in the central nervous system, even in the human mind itself, and that with their discovery will come a complete understanding of the condition known as “essential hypertension,” affording a new hope for the vic- tims of this disease of civilized man’.7 Of interest, from that point onward, the trajectory for Trueta’s sem- inal observations diverged into two separate investigational pathways: acute renal failure of diverse aetiology8 and hypertension. In retro- spect, it is readily apparent that Trueta’s pioneering studies to directly visualize the renal circulation had correctly foreshadowed the multiple Downloaded from https://academic.oup.com/eurheartj/article/41/48/4543/5912222 by guest on 28 September 2021 visual techniques that subsequently elucidated the pivotal role of intra- renal haemodynamics in renal ischaemia. During my research fellow- ship in John Merrill’s laboratory at the Peter Bent Brigham Hospital, I participated in the constellation of concomitant xenon washout stud- Figure 2 Josep Trueta (centre) at a reunion with his two Oxford ies, selective renal arteriograms, and open renal biopsies that provided colleagues and research collaborators, both of whom ultimately were awarded the Nobel Prize, Sir Ernst Chain (left) and Sir Hans Krebs compelling evidence to support the hypothesis that renal cortical is- (right). Barcelona, 1975 (photograph provided courtesy of Ame`lia chaemia constituted a determinant of acute renal failure of diverse Trueta Llacuna). aetiologies.8 It subsequently became readily ap- parent that the renal functional responses to renal nerve stimulation could contribute to hypertension. As detailed in the following paragraphs, the important parallel steps encom- passed:1 Murray Esler’s demonstration that renal sympathetic nerve activation (RSNA) was increased in hypertensive humans;2 renal denervation (RDN) could prevent or attenuate the blood pressure increase in myriad ex- perimental models of hypertension;3 RDN could reverse the blood pressure elevation in already established experimental models of hypertension. How might renal sympathetic activation cause essential hyperten- sion? Large bodies of experimental studies in various animal models of hypertension have demonstrated the importance of the renal sympa- thetic nerves in the development of hypertension . Activation of the renal sympathetic outflow mediates hypertension by (i) enhancing tu- bular sodium reabsorption, (ii) renin release, and a reduction in glo- merular filtration rate (GFR), and (iii) renal blood flow. Acting in concert, these multipronged mediators have the capacity to contribute to the development of hypertension.9,10 Renal denervation began with the seminal studies of Krum et al. in 2009.11 These investigators applied a revolutionary treatment principle to successfully test the renal sympathetic nerve hypothesis in patients with resistant (uncontrolled) hypertension. Their studies encompassed ablation of the renal sympathetic nerves with a radiofrequency- emitting catheter inserted percutaneously Figure 3 Radio micrographs of sections of right and left rabbit kid- into the femoral artery in the groin and ad- neys, demonstrating the effects of faradic stimulation of the nervous vanced proximally to lie in the lumen of plexus surrounding the left renal artery the ‘tree in winter’ effect. both renal arteries.11 Such an approach Colloidal bismuth had been injected during life via the aorta. (A) was feasible because sympathetic nerves Section of right (unstimulated) kidney. Contrast medium is seen filling the interlobular arteries extending to their terminations. A large num- enter the human kidneys in the walls of ber of cortical glomeruli are also opacified. (B) Section of left (stimu- the renal arteries and consequently lie lated) kidney depicting the absence of opacification of the cortical well within reach of ablative energy deliv- vasculature. Note the intense constriction of the peripheral segments ery. The initial aims of this multicentre of the interlobular arteries (photograph provided courtesy of Ame`lia Trueta Llacuna). CardioPulse 4545 study were several fold: (i) to establish that the procedure does pro- and safety of a procedure but they must also demonstrate its dura- duce RDN in humans; (ii) that it is safe; and (iii) that blood pressure is bility and favourable long-term clinical outcomes. The answers to lowered. All three objectives were confirmed.11 In order to demon- these questions will define how denervation will fit into clinical strate whether the catheter ablates renal sympathetic nerves, meas- practice. urements of renal norepinephrine spill over were made at baseline and at follow-up. Subsequent studies of catheter-based RDN for uncon- Acknowledgements trolled HTN using radiofrequency ablation in the main renal arteries The author thanks Drs James R. Oster and David L. Epstein for their showed that RDN was effective in lowering office blood pressure (BP). thoughtful discussions and Sally Baron for expert editorial support in 12–17 The clinical investigative follow-up has been extraordinary. The the preparation of this manuscript. I thank Ame`lia Trueta Llacuna for last few years have witnessed a resurgence of clinical investigative in- hergracioushospitalityandforrelatingdetailsofherfather’sacademic terest in RDN. Transcatheter RDN for treating hypertension is an career and research in Barcelona and in Oxford. emerging clinical procedure. In recent years, improved catheter design, Downloaded from https://academic.oup.com/eurheartj/article/41/48/4543/5912222 by guest on 28 September 2021 procedure technique, and medication use have confirmed its feasibility. Conflict of interest: The author declares no competing interests. Two recent randomized sham-controlled trials in patients not taking References antihypertensive drugs (SPYRAL HTN-OFF MED)14 or continuing to take drugs (SPYRAL HTN-ON MED)15 performed RDN with the References are available as supplementary material at European Heart second-generation radiofrequency ablation system using an ablation Journal online. protocol that included treatment of the distal renal artery as well as the branch renal arteries. These studies showed that RDN significantly reduced office and 24-h ambulatory BP compared with sham Murray Epstein MD FASN FASH Division of Nephrology and Hypertension treatment. University of Miami Miller School of Medicine P.O. Box 016960 (R-126), Miami, FL 33101, USA Important unanswered questions about RDN device-based ther- Phone: (305) 479-7201 E-mail: [email protected] apy for hypertension remain.16,17 It is readily apparent that future clinical trials should not only demonstrate antihypertensive efficacy doi:10.1093/eurheartj/ehaa716 Let us make this clear: Nomenclature for kidney function and disease

Kai-Uwe Eckardt MD, of KDIGO talks to CardioPulse about the need to clarify communication around kidney-related health

Kai-Uwe Eckardt is Professor of Medicine and Chief of Nephrology and Medical Intensive Care at the Charite´in Berlin, Germany. He is a founding member and past co-chair of Kidney Disease: Improving Global Outcomes (KDIGO). The non-profit organization set itself the goal of refining the nomenclature used to describe kidney function and disease along with developing a glossary for use by scientific journals and publications. He speaks to CardioPulse about the recommendations for uniformity in this field.

Why do we need to update/rationalize kidney nomenclature?

There is overwhelming evidence that kidney disease represents a global health burden of increasing relevance. However, the nomenclature that is currently used to describe kidney function and diseases has not been systematically developed and frequently lacks precision, consistency, and pa- tient-centredness.

What is Kidney Disease: Improving Global Outcomes and what does it do?

Kidney Disease: Improving Global Outcomes was established in 2003 by the National Kidney Foundation, a US organization experienced in devel- oping and implementing clinical guidelines. In 2013, KDIGO became an independently incorporated non-profit foundation and is governed by an