de Borst, Martin H

English

University of Groningen

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. [gfac017].https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-11-2022EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

A new era in cardio-renal risk management:overview of landmark papers published in NDT in 2021

Proceedings - University of Groningen

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. [gfac017].https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-10-2022EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. Article gfac017. Advance onlinepublication. https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 11-09-2023EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

Dissertations of the University of Groningen

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. [gfac017].https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 14-02-2023EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

ARTS repository - University of Groningen

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. Article gfac017. Advance onlinepublication. https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 01-11-2023EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. [gfac017].https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 30-04-2023EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

NARCIS 

A new era in cardio-renal risk management: overview of landmark papers published in NDT in 2021

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. Article gfac017. Advance onlinepublication. https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 10-09-2023EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

   University of GroningenA new era in cardio-renal risk managementde Borst, Martin HPublished in:Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association -European Renal AssociationDOI:10.1093/ndt/gfac017IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2022Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Borst, M. H. (2022). A new era in cardio-renal risk management: overview of landmark papers publishedin NDT in 2021. Nephrology, dialysis, transplantation : official publication of the European Dialysis andTransplant Association - European Renal Association, 37(6), 1003–1005. Article gfac017. Advance onlinepublication. https://doi.org/10.1093/ndt/gfac017CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-09-2023EDITORIALNephrol Dial Transplant (2022) 37: 1003–1005https://doi.org/10.1093/ndt/gfac017Advance Access publication date 31 January 2022A new era in cardio-renal risk management: overview oflandmark papers published in NDT in 2021Martin H. de BorstDepartment of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen,The NetherlandsCorrespondence to: Martin H. de Borst; E-mail: m.h.de.borst@umcg.nlThe World Health Organization Global Action Plan forthe Prevention and Control of Non-Communicable Diseases(NCDs) aims to reducemortality from cardiovascular diseases,cancers, diabetes and chronic respiratory diseases amongindividuals aged 30–70 years by 25% between 2010 and 2025[1]. Although some progress has been made over the pastdecade, focussing on just these four groups of NCDs maynot be sufficient. A recent study analysed premature deathscaused by NCDs that could be prevented through effectivepublic policies and health interventions at global, regionaland national levels. Although an overall global reductionin premature avertable mortality from NCDs was observed,the number of premature avertable deaths from chronickidney disease (CKD) and acute glomerulonephritis increasedin many countries and regions [2]. While alarming, recentdevelopments in the field of nephrology raise hope that thistrend will change soon. Several novel therapies have becomeavailable or are currently under development to better managecardiovascular complications, themain cause of death in CKD.This editorial will address emerging strategies and therapiesthat may contribute to improving cardiovascular outcomes inCKD, with a specific focus on five landmark articles publishedin Nephrology Dialysis Transplantation (NDT) in 2021.AVOIDANCE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM BLOCKADEDISCONTINUATIONSince the 1990s, angiotensin-converting enzyme inhibitors(ACEi) and angiotensin receptor blockers (ARB) havedemonstrated efficacy to reduce the risk of kidney failureand mortality in patients with CKD and form the cornerstonetherapy for these patients. Yet, for various reasons includingacute deterioration of kidney function, hyperkalaemia orhypotension, ACEi or ARB treatment may be discontinued. Arecent NDT study in a large cohort of US veterans with CKDshowed that ACEi/ARB discontinuation was associated witha 1.7–2.3 times increased risk of death [3]. Remarkably, thisassociation was already evident if ACEi/ARB was interruptedfor a short period (14–30 days). The observational natureof this and similar studies published previously precludesfirm conclusions on causality, but given trial data thatACEi treatment reduces the risk of mortality or kidneyfailure also in advanced CKD [4], there seems a strongbasis to further explore interventions that could facilitate itscontinuation. Recently, novel potassiumbinders patiromer andsodium zirconium cyclosilicate (SZC) have become available,theoretically making it possible to overcome hyperkalaemiaas a reason for ACEi/ARB discontinuation in some patients.Several studies with both compounds have demonstratedtheir efficacy for long-term normalization of potassium levelsin patients with CKD. Roger et al. addressed whether SZChad similar efficacy in patients with worse kidney function[estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2], comparedwith thosewithmildly impaired or normalkidney function (eGFR ≥30 mL/min/1.73 m2) [5]. The mainfinding was that proportions of patients with normokalaemiawere similar among both eGFR strata (82% and 90% at 1 year,respectively), although greater proportions of patients withbaseline eGFR <30 mL/min/1.73 m2 experienced adverseevents (83% versus 54%, respectively). Whether continuation,or even uptitration, of ACEi/ARB treatment facilitated bypatiromer or SZC leads to clinical benefits remains to bedemonstrated.SGLT2 INHIBITORS AND FINERENONEDecades after the landmark ACEi and ARB trials, severalpromising new therapies have recently emerged. Large ran-domized controlled trials with sodium-glucose cotransporter2 inhibitors (SGLT2i) including the Dapagliflozin and Pre-vention of Adverse outcomes in Chronic Kidney Disease(DAPA-CKD) [6] and Canagliflozin and Renal Endpointsin Diabetes with Established Nephropathy Clinical Evalu-ation (CREDENCE) [7] studies have demonstrated further© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 20220.4 0.6 0.8 1.0 1.2favors comparator favors placeboTrial name N Eligibility criteria Primary endpoint RefDAPA-CKD 4304 eGFR 25-75 mL/min/1.73 m2ACR 200-5000 mg/gKidney failure, ≥50% eGFR reducon, renal/CV death(6)CREDENCE 4401 eGFR 30-90 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(7)FIDELIO-DKD 5674 eGFR 25-75 mL/min/1.73 m2ACR 30-5000 mg/gKidney failure, ≥40% eGFR reducon, renal death(8)FIDELIO-DKD, CREDENCE-matched4619 eGFR 30-75 mL/min/1.73 m2ACR 300-5000 mg/gKidney failure, ≥57% eGFR reducon, renal/CV death(10)FIGURE 1: Comparison of the effect sizes of three large randomized controlled trials: DAPA-CKD (dapagliflozin), CREDENCE (canagliflozin)and FIDELIO-DKD (finerenone), and a subgroup of FIDELIO-DKD that matches the CREDENCE population and endpoints. From theoriginal publications, it may seem that the effect size of renoprotection by finerenone is smaller compared with the two SGLT2i trials. However,Agarwal et al. [10] performed a post hoc analysis accounting for differences in eligibility criteria and endpoints (FIDELIO-DKD, CREDENCEmatched population). The result is presented in the lowest row (open square symbol) and shows that the effect size of finerenone in a similarpopulation with a similar (cardio-renal) endpoint is in line with DAPA-CKD and CREDENCE. Data derived from referenced studies. CV,cardiovascular.cardio-renal risk reduction in patients with CKD on top ofACEi/ARB. Furthermore, two recent large trials [Finerenonein Reducing Kidney Failure and Disease Progression inDiabetic Kidney Disease (FIDELIO-DKD) and Finerenone inReducingCVMortality andMorbidity inDiabetic KidneyDis-ease (FIGARO-DKD)] reported cardio-renal protection by thenon-steroidal mineralocorticoid receptor antagonist (MRA)finerenone in patients with type 2 diabetes and CKD whoalready received ACEi or ARB treatment at the maximum tol-erated dose [8, 9]. In CREDENCE, DAPA-CKD and FIDELIO-DKD, the relative risks of the primary outcomes were reducedby 30% (95% confidence interval 18–41%), 39% (28–49%)and 18% (7–27%), respectively. It may therefore seem thatfinerenone had a smaller magnitude of effect than the SGLT2icanagliflozin and dapagliflozin (Figure 1). However, just com-paring the primary results of these trials does not take into ac-count that there were considerable differences in the design ofthe trials, their patient populations and primary endpoints. Ina recentNDT paper by a group of FIDELIO-DKD investigators[10], these differences were (partly) accounted for by selectinga subpopulation of FIDELIO-DKD participants with inclusioncriteria largely overlapping with the CREDENCE population(‘CREDENCE-matched’, Figure 1). The investigators alsoaccounted for differences in heart failure prevalence at baselineand analysed a modified primary endpoint corresponding asclosely as possible with CREDENCE. Interestingly, the mainresult of this post hoc analysis of the FIDELIO-DKD wasthat cardio-renal protective effects of finerenone were of asimilar magnitude to those of canagliflozin in the CREDENCEtrial. Therefore, both finerenone and the SGLT2i canagliflozinand dapagliflozin are novel therapies with similar potential toimprove the prognosis of patients with CKD. A subsequentquestion may be whether the combination of SGLT2i andMRA, on top of an optimally dosed ACEi or ARB, mightfurther enhance cardio-renal protection. On one hand, thismight seem feasible since side-effects of one drug might becounteracted by the other (e.g. hyperkalaemia, a common sideeffect of MRA, may be avoided or tempered by concomitantSGLT2i use [11]). On the other hand, other side effects suchas an acute decrease in kidney function have been observedfor both classes of drugs and may be more pronounced ifcombined. A secondary analysis of the DAPA-HF trial showedsimilar efficacy and safety of dapagliflozin in 3370 patientswith heart failure who were on MRA treatment [12]. InCKD patients, prior studies with ACEi, ARB and direct renininhibitors have shown that their combined use is only indicatedunder specific circumstances.Whether or not the combinationof SGLT2 and MRA may be safe and (more) effective in CKDremains to be addressed in dedicated clinical trials. At the sametime, further strategies should be explored to target additionalpathways deregulated in (advanced) CKD that further improvecardiovascular outcomes.BONE AND MINERAL DISEASEVascular calcification is a hallmark of advanced CKD and thepresence and extent of vascular calcification are associatedwith cardiovascular morbidity and mortality. Deregulations inmineral metabolism, including hyperphosphatemia and hy-perparathyroidism, are considered to drive vascular calcifica-tion in advanced CKD. The phosphaturia-inducing hormonefibroblast growth factor 23 (FGF23) is one of the earliesthallmarks of CKD-metabolic bone disorder (CKD-MBD) anda higher FGF23 level has been consistently associated withcardiovascular outcomes and mortality across stages of CKD.Interestingly, several studies have demonstrated bilateral cross-talk between aldosterone and FGF23 [13]. Aldosterone andangiotensin II induce expression of FGF23 in bone cells,the main source of FGF23 in the body, as well as in othercells including cardiomyocytes. Conversely, FGF23 can induceangiotensinogen expression and may increase angiotensin IIformation, in turn leading to higher aldosterone levels [13].Also, several studies have shown that MRA can reduce FGF23levels in animals and patients. Whether the cardiovascularbenefits of MRA treatment including finerenone are at leastin part mediated by a reduction in FGF23 remains to beaddressed.1004 M. H. de BorstDownloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022In addition to efforts aiming to reduce FGF23, otherinterventions targeting CKD-MBD with the aim to improvecardiovascular outcomes include phosphate binders and vi-tamin K supplementation. Although phosphate binders arewidely used to correct hyperphosphatemia in advanced CKDand kidney failure, evidence that these compounds can reducecardiovascular morbidity and mortality is limited. Recently, itwas demonstrated that phosphate binders can also bind vita-min K, a major inhibitor of vascular calcification. In a recentpreclinical study published in NDT, Neradova et al. showedthat combining phosphate binder treatment with high-dosevitamin K2 supplementation attenuated vascular calcification[14]. While these findings require prospective confirmation inhumans, this could imply that combination therapy is neededto overcome progressive vascular calcification in patients withkidney failure.CONCLUSIONNew treatments have emerged that will undoubtedly improvethe renal and cardiovascular prognosis of patients with CKD.Increasing our knowledge about the optimal positioning ofSGLT2i and MRA and their mechanisms of cardio-renalprotection may further advance patients’ outcomes in thecoming years. NDT will continue to publish cutting-edgeoriginal articles and review papers in this area to furthercontribute to these exciting developments.CONFLICT OF INTEREST STATEMENTM.H.d.B. has served as a consultant, received honoraria orresearch support (all to employer) from Amgen, AstraZeneca,Bayer, Kyowa Kirin Pharma, Pharmacosmos, Sanofi Genzymeand Vifor Pharma.REFERENCES1. World Health Organization. NCD global monitoring frameworkhttps://www.who.int/teams/ncds/surveillance/monitoring-capacity/gmf(20 January 2021, date last accessed)2. Martinez R, Lloyd-Sherlock P, Soliz P et al. Trends in prematureavertable mortality from non-communicable diseases for 195 countriesand territories, 1990–2017: a population-based study. Lancet Glob Health2020; 8: e511–e5233. Walther CP, Winkelmayer WC, Richardson PA et al. Renin-angiotensinsystem blocker discontinuation and adverse outcomes in chronic kidneydisease. Nephrol Dial Transplant 2021; 36: 1893–18994. Hou FF, Zhang X, Zhang GH et al. Efficacy and safety of benazeprilfor advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–1405. Roger SD, Lavin PT, Lerma EV et al. Long-term safety and efficacyof sodium zirconium cyclosilicate for hyperkalaemia in patients withmild/moderate versus severe/end-stage chronic kidney disease: compar-ative results from an open-label, Phase 3 study. Nephrol Dial Transplant2021; 36: 137–1506. Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin inpatients with chronic kidney disease. N Engl J Med 2020; 383: 1436–14467. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal out-comes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380:2295–23068. Bakris GL, Agarwal R, Anker SD et al. Effect of finerenone on chronickidney disease outcomes in type 2 diabetes.NEngl J Med 2020; 383: 2219–22299. Pitt B, FilippatosG,Agarwal R et al.Cardiovascular eventswith finerenonein kidney disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–226310. Agarwal R, Anker SD, Filippatos G et al. Effects of canagliflozin versusfinerenone on cardiorenal outcomes: exploratory post-hoc analyses fromFIDELIO-DKD compared to reported CREDENCE results. Nephrol DialTransplant 2021; Epub ahead of print. doi: 10.1093/ndt/gfab33611. Neuen BL, Oshima M, Perkovic V et al. Effects of canagliflozin onserum potassium in people with diabetes and chronic kidney disease: theCREDENCE trial. Eur Heart JEur Heart J 2021; 42: 4891–490112. Shen L, Kristensen SL, Bengtsson O et al.Dapagliflozin in HFrEF patientstreated withmineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021; 9: 254–26413. Epstein M, Freundlich M. The intersection of mineralocorticoid receptoractivation and the FGF23-Klotho cascade: a duopoly that promotes renaland cardiovascular injury. Nephrol Dial Transplant 2022; 37: 211–22114. Neradova A, Wasilewski G, Prisco S et al. Combining phosphate bindertherapy with vitamin K2 inhibits vascular calcification in an experimentalanimal model of kidney failure.Nephrol Dial Transplant 2021; Epub aheadof print. doi: 10.1093/ndt/gfab314Received: 20.1.2022; Editorial decision: 23.1.2022NDT 2021 cardio-renal landmark papers 1005Downloaded from https://academic.oup.com/ndt/article/37/6/1003/6517744 by University of Groningen user on 10 October 2022

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A new era in cardio-renal risk management:overview of landmark papers published in NDT in 2021

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