Advertisement
Canadian Journal of Cardiology

Cardiorenal Syndrome and Heart Failure—Challenges and Opportunities

  • Haran Yogasundaram
    Affiliations
    Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
  • Mark C. Chappell
    Affiliations
    Department of Surgery/Hypertension and Vascular Research, Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
    Search for articles by this author
  • Branko Braam
    Affiliations
    Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
  • Gavin Y. Oudit
    Correspondence
    Corresponding author: Dr Gavin Y. Oudit, Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: +1-780-407-8569; fax: +1-780-407-6452.
    Affiliations
    Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada

    Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
    Search for articles by this author
Published:April 12, 2019DOI:https://doi.org/10.1016/j.cjca.2019.04.002

      Abstract

      Cardiorenal syndromes (CRS) describe concomitant bidirectional dysfunction of the heart and kidneys in which 1 organ initiates, perpetuates, and/or accelerates decline of the other. CRS are common in heart failure and universally portend worsened prognosis. Despite this heavy disease burden, the appropriate diagnosis and classification of CRS remains problematic. In addition to the hemodynamic drivers of decreased renal perfusion and increased renal vein pressure, induction of the renin-angiotensin-aldosterone system, stimulation of the sympathetic nervous system, disruption of balance between nitric oxide and reactive oxygen species, and inflammation are implicated in the pathogenesis of CRS. Medical therapy of heart failure including renin-angiotensin-aldosterone system inhibition and β-adrenergic blockade can blunt these deleterious processes. Renovascular disease can accelerate the progression of CRS. Volume overload and diuretic resistance are common and complicate the management of CRS. In heart failure and CRS being treated with diuretics, worsening creatinine is not associated with worsened outcome if clinical decongestion is achieved. Adjunctive therapy is often required in the management of volume overload in CRS, but evidence for these therapies is limited. Anemia and iron deficiency are importantly associated with CRS and might amplify decline of cardiac and renal function. End-stage cardiac and/or renal disease represents an especially poor prognosis with limited therapeutic options. Overall, worsening renal function is associated with significantly increased mortality. Despite progress in the area of CRS, there are still multiple pathophysiological and clinical aspects of CRS that need further research to eventually develop effective therapeutic options.

      Résumé

      Le syndrome cardiorénal (SCR) est caractérisé par une dysfonction bidirectionnelle et concomitante du cœur et des reins dans laquelle l'un de ces deux organes déclenche, perpétue et/ou accélère le déclin de l'autre. Le SCR est fréquent dans l'insuffisance cardiaque et, dans tous les cas, laisse présager un pronostic plus défavorable. Malgré le lourd fardeau du SCR, son diagnostic et sa classification demeurent difficiles. Outre les causes hémodynamiques comme la diminution de l'irrigation rénale et l'augmentation de la pression dans la veine rénale, d'autres facteurs comme l'induction du système rénine-angiotensine-aldostérone, la stimulation du système nerveux sympathique, la perturbation de l'équilibre entre l'oxyde nitrique et le dérivé réactif de l'oxygène et l'inflammation jouent également un rôle dans la pathogenèse du SCR. Le traitement médical de l'insuffisance cardiaque, y compris par l'inhibition du système rénine-angiotensine-aldostérone et le blocage des récepteurs bêta-adrénergiques, peut atténuer ces processus délétères. La maladie rénovasculaire peut accélérer la progression du SCR. La surcharge volémique et la résistance diurétique sont fréquentes et compliquent la prise en charge du SCR. Lorsque l'insuffisance cardiaque et le SCR sont traités par des diurétiques, l'élévation du taux de créatinine n'est pas associée à une aggravation du problème si une décongestion clinique peut être obtenue. Un traitement d'appoint est souvent nécessaire pour contrer la surcharge volémique dans le SCR, mais les données probantes sur l'efficacité d'un tel traitement sont rares. L'anémie et la carence en fer sont associées de façon importante au SCR et pourraient amplifier le déclin des fonctions cardiaque et rénale. L'insuffisance cardiaque et l'insuffisance rénale terminales ont un pronostic particulièrement défavorable et leurs options thérapeutiques sont très limitées. Dans l'ensemble, la détérioration de la fonction rénale est associée à une augmentation significative de la mortalité. Malgré les progrès réalisés dans le traitement du SCR, il subsiste de multiples facettes de cette affection, tant physiopathologiques que cliniques, qui devraient faire l'objet de recherches dans le but de trouver des options thérapeutiques efficaces.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ronco C.
        • Cicoira M.
        • McCullough P.A.
        Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure.
        J Am Coll Cardiol. 2012; 60: 1031-1042
        • Damman K.
        • Testani J.M.
        The kidney in heart failure: an update.
        Eur Heart J. 2015; 36: 1437-1444
        • Damman K.
        • Tang W.H.
        • Testani J.M.
        • McMurray J.J.
        Terminology and definition of changes renal function in heart failure.
        Eur Heart J. 2014; 35: 3413-3416
        • Bagshaw S.M.
        • Cruz D.N.
        • Aspromonte N.
        • et al.
        Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference.
        Nephrol Dial Transplant. 2010; 25: 1406-1416
        • Campbell R.C.
        • Sui X.
        • Filippatos G.
        • et al.
        Association of chronic kidney disease with outcomes in chronic heart failure: a propensity-matched study.
        Nephrol Dial Transplant. 2009; 24: 186-193
        • Ezekowitz J.A.
        • O’Meara E.
        • McDonald M.A.
        • et al.
        2017 Comprehensive update of the Canadian Cardiovascular Society Guidelines for the management of heart failure.
        Can J Cardiol. 2017; 33: 1342-1433
        • Rangaswami J.
        • Bhalla V.
        • Blair John E.A.
        • et al.
        Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association.
        Circulation. 2019; 139: e840-e878
        • Bongartz L.G.
        • Cramer M.J.
        • Doevendans P.A.
        • Joles J.A.
        • Braam B.
        The severe cardiorenal syndrome: “Guyton revisited.”.
        Eur Heart J. 2005; 26: 11-17
        • McCullough P.A.
        • Kellum J.A.
        • Haase M.
        • et al.
        Pathophysiology of the cardiorenal syndromes: executive summary from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI).
        Contrib Nephrol. 2013; 182: 82-98
        • Ronco C.
        • Haapio M.
        • House A.A.
        • Anavekar N.
        • Bellomo R.
        Cardiorenal syndrome.
        J Am Coll Cardiol. 2008; 52: 1527-1539
        • Zannad F.
        • Rossignol P.
        Cardiorenal syndrome revisited.
        Circulation. 2018; 138: 929-944
        • Braam B.
        • Joles J.A.
        • Danishwar A.H.
        • Gaillard C.A.
        Cardiorenal syndrome--current understanding and future perspectives.
        Nat Rev Nephrol. 2014; 10: 48-55
        • Khwaja A.
        KDIGO clinical practice guidelines for acute kidney injury.
        Nephron Clin Pract. 2012; 120: c179-c184
        • Bellomo R.
        • Ronco C.
        • Kellum J.A.
        • Mehta R.L.
        • Palevsky P.
        Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
        Crit Care. 2004; 8: R204-R212
        • Mehta R.L.
        • Kellum J.A.
        • Shah S.V.
        • et al.
        Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.
        Crit Care. 2007; 11: R31
        • Damman K.
        • Valente M.A.
        • Voors A.A.
        • et al.
        Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis.
        Eur Heart J. 2014; 35: 455-469
        • Maisel A.S.
        • Mueller C.
        • Fitzgerald R.
        • et al.
        Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: the NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial.
        Eur J Heart Fail. 2011; 13: 846-851
        • Alvelos M.
        • Pimentel R.
        • Pinho E.
        • et al.
        Neutrophil gelatinase-associated lipocalin in the diagnosis of type 1 cardio-renal syndrome in the general ward.
        Clin J Am Soc Nephrol. 2011; 6: 476-481
        • Maisel A.S.
        • Wettersten N.
        • van Veldhuisen D.J.
        • et al.
        Neutrophil gelatinase-associated lipocalin for acute kidney injury during acute heart failure hospitalizations: the AKINESIS study.
        J Am Coll Cardiol. 2016; 68: 1420-1431
        • Damman K.
        • Masson S.
        • Hillege H.L.
        • et al.
        Tubular damage and worsening renal function in chronic heart failure.
        JACC Heart Fail. 2013; 1: 417-424
        • Jungbauer C.G.
        • Birner C.
        • Jung B.
        • et al.
        Kidney injury molecule-1 and N-acetyl-beta-D-glucosaminidase in chronic heart failure: possible biomarkers of cardiorenal syndrome.
        Eur J Heart Fail. 2011; 13: 1104-1110
        • Jungbauer C.G.
        • Uecer E.
        • Stadler S.
        • et al.
        N-acteyl-ss-D-glucosaminidase and kidney injury molecule-1: new predictors for long-term progression of chronic kidney disease in patients with heart failure.
        Nephrology (Carlton). 2016; 21: 490-498
        • Mascarenhas J.
        • Laszczynska O.
        • Severo M.
        • et al.
        Prognostic effect of renal function in ambulatory patients with heart failure and reduced ejection fraction: the kidney is a marker of cardiac function.
        Can J Cardiol. 2018; 34: 1325-1332
        • Hatamizadeh P.
        • Fonarow G.C.
        • Budoff M.J.
        • et al.
        Cardiorenal syndrome: pathophysiology and potential targets for clinical management.
        Nat Rev Nephrol. 2013; 9: 99-111
        • Damman K.
        • Navis G.
        • Smilde T.D.
        • et al.
        Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction.
        Eur J Heart Fail. 2007; 9: 872-878
        • Mullens W.
        • Abrahams Z.
        • Francis G.S.
        • et al.
        Importance of venous congestion for worsening of renal function in advanced decompensated heart failure.
        J Am Coll Cardiol. 2009; 53: 589-596
        • Tang W.W.
        • Kitai T.
        Intrarenal venous flow: a window into the congestive kidney failure phenotype of heart failure?.
        JACC Heart Fail. 2016; 4: 683-686
        • Damman K.
        • van Deursen V.M.
        • Navis G.
        • et al.
        Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease.
        J Am Coll Cardiol. 2009; 53: 582-588
        • Gottschalk C.W.
        • Mylle M.
        Micropuncture study of pressures in proximal tubules and peritubular capillaries of the rat kidney and their relation to ureteral and renal venous pressures.
        Am J Physiol. 1956; 185: 430-439
        • Braam B.
        • Cupples W.A.
        • Joles J.A.
        • Gaillard C.
        Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure.
        Heart Fail Rev. 2012; 17: 161-175
        • Iida N.
        • Seo Y.
        • Sai S.
        • et al.
        Clinical implications of intrarenal hemodynamic evaluation by Doppler ultrasonography in heart failure.
        JACC Heart Fail. 2016; 4: 674-682
        • Hene R.J.
        • Boer P.
        • Koomans H.A.
        • Mees E.J.
        Plasma aldosterone concentrations in chronic renal disease.
        Kidney Int. 1982; 21: 98-101
        • Kishimoto T.
        • Maekawa M.
        • Abe Y.
        • Yamamoto K.
        Intrarenal distribution of blood flow and renin release during renal venous pressure elevation.
        Kidney Int. 1973; 4: 259-266
        • Mori J.
        • Zhang L.
        • Oudit G.Y.
        • Lopaschuk G.D.
        Impact of the renin-angiotensin system on cardiac energy metabolism in heart failure.
        J Mol Cell Cardiol. 2013; 63: 98-106
        • Hostetter T.H.
        • Ibrahim H.N.
        Aldosterone in chronic kidney and cardiac disease.
        J Am Soc Nephrol. 2003; 14: 2395-2401
        • Reid I.A.
        Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure.
        Am J Physiol. 1992; 262: E763-E778
        • Levine B.
        • Kalman J.
        • Mayer L.
        • Fillit H.M.
        • Packer M.
        Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.
        N Engl J Med. 1990; 323: 236-241
        • Chu P.Y.
        • Zatta A.
        • Kiriazis H.
        • et al.
        CXCR4 antagonism attenuates the cardiorenal consequences of mineralocorticoid excess.
        Circ Heart Fail. 2011; 4: 651-658
        • Giam B.
        • Kaye D.M.
        • Rajapakse N.W.
        Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome.
        Heart Lung Circ. 2016; 25: 874-880
        • Nakagami H.
        • Takemoto M.
        • Liao J.K.
        NADPH oxidase-derived superoxide anion mediates angiotensin II-induced cardiac hypertrophy.
        J Mol Cell Cardiol. 2003; 35: 851-859
        • Heymes C.
        • Bendall J.K.
        • Ratajczak P.
        • et al.
        Increased myocardial NADPH oxidase activity in human heart failure.
        J Am Coll Cardiol. 2003; 41: 2164-2171
        • Weber K.T.
        Aldosterone in congestive heart failure.
        N Engl J Med. 2001; 345: 1689-1697
        • Ligtenberg G.
        • Blankestijn P.J.
        • Oey P.L.
        • et al.
        Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure.
        N Engl J Med. 1999; 340: 1321-1328
        • Klein I.H.
        • Ligtenberg G.
        • Oey P.L.
        • Koomans H.A.
        • Blankestijn P.J.
        Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure.
        J Am Soc Nephrol. 2003; 14: 425-430
        • Remuzzi G.
        • Perico N.
        • Macia M.
        • Ruggenenti P.
        The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease.
        Kidney Int Suppl. 2005; : S57-S65
        • Mori J.
        • Patel V.B.
        • Ramprasath T.
        • et al.
        Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity.
        Am J Physiol Renal Physiol. 2014; 306: F812-F821
        • Patel V.B.
        • Zhong J.C.
        • Grant M.B.
        • Oudit G.Y.
        Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure.
        Circ Res. 2016; 118: 1313-1326
        • Triposkiadis F.
        • Karayannis G.
        • Giamouzis G.
        • et al.
        The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.
        J Am Coll Cardiol. 2009; 54: 1747-1762
        • Schlaich M.P.
        • Socratous F.
        • Hennebry S.
        • et al.
        Sympathetic activation in chronic renal failure.
        J Am Soc Nephrol. 2009; 20: 933-939
        • Hasking G.J.
        • Esler M.D.
        • Jennings G.L.
        • et al.
        Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.
        Circulation. 1986; 73: 615-621
        • Goldsmith S.R.
        • Sobotka P.A.
        • Bart B.A.
        The sympathorenal axis in hypertension and heart failure.
        J Card Fail. 2010; 16: 369-373
        • Leineweber K.
        • Heinroth-Hoffmann I.
        • Ponicke K.
        • et al.
        Cardiac beta-adrenoceptor desensitization due to increased beta-adrenoceptor kinase activity in chronic uremia.
        J Am Soc Nephrol. 2002; 13: 117-124
        • Petersson M.
        • Friberg P.
        • Eisenhofer G.
        • Lambert G.
        • Rundqvist B.
        Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure.
        Eur Heart J. 2005; 26: 906-913
        • Cohn J.N.
        • Pfeffer M.A.
        • Rouleau J.
        • et al.
        Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON).
        Eur J Heart Fail. 2003; 5: 659-667
        • Schirmer S.H.
        • Sayed M.M.
        • Reil J.C.
        • et al.
        Improvements in left ventricular hypertrophy and diastolic function following renal denervation: effects beyond blood pressure and heart rate reduction.
        J Am Coll Cardiol. 2014; 63: 1916-1923
        • Nammas W.
        • Koistinen J.
        • Paana T.
        • Karjalainen P.P.
        Renal sympathetic denervation for treatment of patients with heart failure: summary of the available evidence.
        Ann Med. 2017; 49: 384-395
        • Bhatt D.L.
        • Kandzari D.E.
        • O’Neill W.W.
        • et al.
        A controlled trial of renal denervation for resistant hypertension.
        N Engl J Med. 2014; 370: 1393-1401
        • van Bilsen M.
        • Patel H.C.
        • Bauersachs J.
        • et al.
        The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.
        Eur J Heart Fail. 2017; 19: 1361-1378
        • Amann K.
        • Koch A.
        • Hofstetter J.
        • et al.
        Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers.
        Kidney Int. 2001; 60: 1309-1323
        • Bakris G.L.
        • Hart P.
        • Ritz E.
        Beta blockers in the management of chronic kidney disease.
        Kidney Int. 2006; 70: 1905-1913
        • Hering D.
        • Marusic P.
        • Duval J.
        • et al.
        Effect of renal denervation on kidney function in patients with chronic kidney disease.
        Int J Cardiol. 2017; 232: 93-97
        • Vonend O.
        • Marsalek P.
        • Russ H.
        • et al.
        Moxonidine treatment of hypertensive patients with advanced renal failure.
        J Hypertens. 2003; 21: 1709-1717
        • Rastmanesh M.M.
        • Braam B.
        • Joles J.A.
        • Boer P.
        • Bluyssen H.A.
        Increased SOCS expression in peripheral blood mononuclear cells of end stage renal disease patients is related to inflammation and dialysis modality.
        Eur J Pharmacol. 2009; 602: 163-167
        • Rastmanesh M.M.
        • Bluyssen H.A.R.
        • Joles J.A.
        • et al.
        Increased expression of SOCS3 in monocytes and SOCS1 in lymphocytes correlates with progressive loss of renal function and cardiovascular risk factors in chronic kidney disease.
        Eur J Pharmacol. 2008; 593: 99-104
        • Zimmermann J.
        • Herrlinger S.
        • Pruy A.
        • Metzger T.
        • Wanner C.
        Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
        Kidney Int. 1999; 55: 648-658
        • Yeun J.Y.
        • Levine R.A.
        • Mantadilok V.
        • Kaysen G.A.
        C-reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.
        Am J Kidney Dis. 2000; 35: 469-476
        • Torre-Amione G.
        • Kapadia S.
        • Benedict C.
        • et al.
        Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD).
        J Am Coll Cardiol. 1996; 27: 1201-1206
        • Colombo P.C.
        • Ganda A.
        • Lin J.
        • et al.
        Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome.
        Heart Fail Rev. 2012; 17: 177-190
        • Guo J.
        • Lu L.
        • Hua Y.
        • et al.
        Vasculopathy in the setting of cardiorenal syndrome: roles of protein-bound uremic toxins.
        Am J Physiol Heart Circ Physiol. 2017; 313: H1-13
        • Mittal M.
        • Siddiqui M.R.
        • Tran K.
        • Reddy S.P.
        • Malik A.B.
        Reactive oxygen species in inflammation and tissue injury.
        Antioxid Redox Signal. 2014; 20: 1126-1167
        • Virzi G.M.
        • Clementi A.
        • Ronco C.
        Cellular apoptosis in the cardiorenal axis.
        Heart Fail Rev. 2016; 21: 177-189
        • Arici M.
        • Walls J.
        End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link?.
        Kidney Int. 2001; 59: 407-414
        • Putko B.N.
        • Wang Z.
        • Lo J.
        • et al.
        Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.
        PLoS One. 2014; 9: e99495
        • Ter Maaten J.M.
        • Damman K.
        • Verhaar M.C.
        • et al.
        Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation.
        Eur J Heart Fail. 2016; 18: 588-598
        • Yogasundaram H.
        • Nikhanj A.
        • Putko Brendan N.
        • et al.
        Elevated inflammatory plasma biomarkers in patients with Fabry disease: a critical link to heart failure with preserved ejection fraction.
        J Am Heart Assoc. 2018; 7: e009098
        • Ward R.A.
        • McLeish K.R.
        Polymorphonuclear leukocyte oxidative burst is enhanced in patients with chronic renal insufficiency.
        J Am Soc Nephrol. 1995; 5: 1697-1702
        • Chung E.S.
        • Packer M.
        • Lo K.H.
        • Fasanmade A.A.
        • Willerson J.T.
        Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial.
        Circulation. 2003; 107: 3133-3140
        • Landmesser U.
        • Spiekermann S.
        • Dikalov S.
        • et al.
        Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase.
        Circulation. 2002; 106: 3073-3078
        • Ruiz S.
        • Pergola P.E.
        • Zager R.A.
        • Vaziri N.D.
        Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease.
        Kidney Int. 2013; 83: 1029-1041
        • Himmelfarb J.
        • Stenvinkel P.
        • Ikizler T.A.
        • Hakim R.M.
        The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.
        Kidney Int. 2002; 62: 1524-1538
        • Witko-Sarsat V.
        • Friedlander M.
        • Capeillere-Blandin C.
        • et al.
        Advanced oxidation protein products as a novel marker of oxidative stress in uremia.
        Kidney Int. 1996; 49: 1304-1313
        • Katoh M.
        • Egashira K.
        • Usui M.
        • et al.
        Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats.
        Circ Res. 1998; 83: 743-751
        • Bongartz L.G.
        • Braam B.
        • Verhaar M.C.
        • et al.
        Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease.
        Am J Physiol Regul Integr Comp Physiol. 2010; 298: R815-R823
        • Bongartz L.G.
        • Braam B.
        • Verhaar M.C.
        • et al.
        The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction.
        Am J Physiol Heart Circ Physiol. 2010; 299: H2037-H2045
        • Hare J.M.
        • Mangal B.
        • Brown J.
        • et al.
        Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study.
        J Am Coll Cardiol. 2008; 51: 2301-2309
        • Kane G.C.
        • Xu N.
        • Mistrik E.
        • et al.
        Renal artery revascularization improves heart failure control in patients with atherosclerotic renal artery stenosis.
        Nephrol Dial Transplant. 2010; 25: 813-820
        • Watson P.S.
        • Hadjipetrou P.
        • Cox S.V.
        • Piemonte T.C.
        • Eisenhauer A.C.
        Effect of renal artery stenting on renal function and size in patients with atherosclerotic renovascular disease.
        Circulation. 2000; 102: 1671-1677
        • Nerenberg K.A.
        • Zarnke K.B.
        • Leung A.A.
        • et al.
        Hypertension Canada’s 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children.
        Can J Cardiol. 2018; 34: 506-525
        • Messerli F.H.
        • Bangalore S.
        • Makani H.
        • et al.
        Flash pulmonary oedema and bilateral renal artery stenosis: the Pickering syndrome.
        Eur Heart J. 2011; 32: 2231-2235
        • Conlon P.J.
        • Little M.A.
        • Pieper K.
        • Mark D.B.
        Severity of renal vascular disease predicts mortality in patients undergoing coronary angiography.
        Kidney Int. 2001; 60: 1490-1497
        • Alyamani M.
        • Thomas J.
        • Shanks M.
        • Oudit G.Y.
        Resistant hypertension from renal artery stenosis leading to heart failure with preserved ejection fraction.
        J Investig Med High Impact Case Rep. 2018; 6 (2324709618816501)
        • Rundback J.H.
        • Murphy T.P.
        • Cooper C.
        • Weintraub J.L.
        Chronic renal ischemia: pathophysiologic mechanisms of cardiovascular and renal disease.
        J Vasc Interv Radiol. 2002; 13: 1085-1092
        • Wright J.R.
        • Shurrab A.E.
        • Cooper A.
        • et al.
        Left ventricular morphology and function in patients with atherosclerotic renovascular disease.
        J Am Soc Nephrol. 2005; 16: 2746-2753
        • Cooper C.J.
        • Murphy T.P.
        • Cutlip D.E.
        • et al.
        Stenting and medical therapy for atherosclerotic renal-artery stenosis.
        N Engl J Med. 2014; 370: 13-22
        • Bax L.
        • Woittiez A.J.
        • Kouwenberg H.J.
        • et al.
        Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.
        Ann Intern Med. 2009; 150: w150-w151
        • Wheatley K.
        • Ives N.
        • Gray R.
        • et al.
        Revascularization vs medical therapy for renal-artery stenosis.
        N Engl J Med. 2009; 361: 1953-1962
        • Mullens W.
        • Damman K.
        • Harjola V.P.
        • et al.
        The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology.
        Eur J Heart Fail. 2019; 21: 137-155
        • Ellison D.H.
        • Felker G.M.
        Diuretic treatment in heart failure.
        N Engl J Med. 2017; 377: 1964-1975
        • Mahtani K.R.
        • Heneghan C.
        • Onakpoya I.
        • et al.
        Reduced salt intake for heart failure: a systematic review.
        JAMA Intern Med. 2018; 178: 1693-1700
        • Heerdink E.R.
        • Leufkens H.G.
        • Herings R.M.
        • et al.
        NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics.
        Arch Intern Med. 1998; 158: 1108-1112
        • Gheorghiade M.
        • De Luca L.
        • Fonarow G.C.
        • et al.
        Pathophysiologic targets in the early phase of acute heart failure syndromes.
        Am J Cardiol. 2005; 96: 11-17
        • Schrier R.W.
        Role of diminished renal function in cardiovascular mortality: marker or pathogenetic factor?.
        J Am Coll Cardiol. 2006; 47: 1-8
        • Metra M.
        • Davison B.
        • Bettari L.
        • et al.
        Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function.
        Circ Heart Fail. 2012; 5: 54-62
        • van der Meer P.
        • Postmus D.
        • Ponikowski P.
        • et al.
        The predictive value of short-term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure.
        J Am Coll Cardiol. 2013; 61: 1973-1981
        • Valente M.A.
        • Voors A.A.
        • Damman K.
        • et al.
        Diuretic response in acute heart failure: clinical characteristics and prognostic significance.
        Eur Heart J. 2014; 35: 1284-1293
        • Felker G.M.
        • Lee K.L.
        • Bull D.A.
        • et al.
        Diuretic strategies in patients with acute decompensated heart failure.
        N Engl J Med. 2011; 364: 797-805
        • ter Maaten J.M.
        • Dunning A.M.
        • Valente M.A.
        • et al.
        Diuretic response in acute heart failure-an analysis from ASCEND-HF.
        Am Heart J. 2015; 170: 313-321
        • Hasselblad V.
        • Gattis Stough W.
        • Shah M.R.
        • et al.
        Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial.
        Eur J Heart Fail. 2007; 9: 1064-1069
        • Rao V.S.
        • Planavsky N.
        • Hanberg J.S.
        • et al.
        Compensatory distal reabsorption drives diuretic resistance in human heart failure.
        J Am Soc Nephrol. 2017; 28: 3414-3424
        • Martin P.Y.
        • Schrier R.W.
        Sodium and water retention in heart failure: pathogenesis and treatment.
        Kidney Int Suppl. 1997; 59: S57-S61
        • Sobotka P.A.
        • Mahfoud F.
        • Schlaich M.P.
        • et al.
        Sympatho-renal axis in chronic disease.
        Clin Res Cardiol. 2011; 100: 1049-1057
        • Kiyingi A.
        • Field M.J.
        • Pawsey C.C.
        • et al.
        Metolazone in treatment of severe refractory congestive cardiac failure.
        Lancet. 1990; 335: 29-31
        • Brisco-Bacik M.A.
        • Ter Maaten J.M.
        • Houser S.R.
        • et al.
        Outcomes associated with a strategy of adjuvant metolazone or high-dose loop diuretics in acute decompensated heart failure: a propensity analysis.
        J Am Heart Assoc. 2018; 7: e009149
        • Butler J.
        • Anstrom K.J.
        • Felker G.M.
        • et al.
        Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial.
        JAMA Cardiol. 2017; 2: 950-958
        • Konstam M.A.
        • Gheorghiade M.
        • Burnett Jr., J.C.
        • et al.
        Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial.
        JAMA. 2007; 297: 1319-1331
        • Chen H.H.
        • Anstrom K.J.
        • Givertz M.M.
        • et al.
        Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial.
        JAMA. 2013; 310: 2533-2543
        • Verbrugge F.H.
        • Dupont M.
        • Steels P.
        • et al.
        Abdominal contributions to cardiorenal dysfunction in congestive heart failure.
        J Am Coll Cardiol. 2013; 62: 485-495
        • Kazory A.
        • Ejaz A.A.
        • Ross E.A.
        The UNLOAD trial: a “nephrologic” standpoint.
        J Am Coll Cardiol. 2007; 50 ([author reply 820-1]): 820
        • Bart B.A.
        • Goldsmith S.R.
        • Lee K.L.
        • et al.
        Ultrafiltration in decompensated heart failure with cardiorenal syndrome.
        N Engl J Med. 2012; 367: 2296-2304
        • Costanzo M.R.
        • Negoianu D.
        • Jaski B.E.
        • et al.
        Aquapheresis vs intravenous diuretics and hospitalizations for heart failure.
        JACC Heart Fail. 2016; 4: 95-105
        • Costanzo M.R.
        • Ronco C.
        • Abraham W.T.
        • et al.
        Extracorporeal ultrafiltration for fluid overload in heart failure: current status and prospects for further research.
        J Am Coll Cardiol. 2017; 69: 2428-2445
        • Gheorghiade M.
        • Follath F.
        • Ponikowski P.
        • et al.
        Assessing and grading congestion in acute heart failure: a scientific statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine.
        Eur J Heart Fail. 2010; 12: 423-433
        • Jie K.E.
        • Verhaar M.C.
        • Cramer M.J.
        • et al.
        Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors.
        Am J Physiol Renal Physiol. 2006; 291: F932-F944
        • Scrutinio D.
        • Passantino A.
        • Santoro D.
        • Catanzaro R.
        The cardiorenal anaemia syndrome in systolic heart failure: prevalence, clinical correlates, and long-term survival.
        Eur J Heart Fail. 2011; 13: 61-67
        • Tang Y.D.
        • Katz S.D.
        The prevalence of anemia in chronic heart failure and its impact on the clinical outcomes.
        Heart Fail Rev. 2008; 13: 387-392
        • Cleland J.G.
        • Zhang J.
        • Pellicori P.
        • et al.
        Prevalence and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure.
        JAMA Cardiol. 2016; 1: 539-547
        • Young J.B.
        • Abraham W.T.
        • Albert N.M.
        • et al.
        Relation of low hemoglobin and anemia to morbidity and mortality in patients hospitalized with heart failure (insight from the OPTIMIZE-HF registry).
        Am J Cardiol. 2008; 101: 223-230
        • Cohen-Solal A.
        • Damy T.
        • Terbah M.
        • et al.
        High prevalence of iron deficiency in patients with acute decompensated heart failure.
        Eur J Heart Fail. 2014; 16: 984-991
        • McClellan W.M.
        • Flanders W.D.
        • Langston R.D.
        • Jurkovitz C.
        • Presley R.
        Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study.
        J Am Soc Nephrol. 2002; 13: 1928-1936
        • Jankowska E.A.
        • Rozentryt P.
        • Witkowska A.
        • et al.
        Iron deficiency: an ominous sign in patients with systolic chronic heart failure.
        Eur Heart J. 2010; 31: 1872-1880
        • van Veldhuisen D.J.
        • Ponikowski P.
        • van der Meer P.
        • et al.
        Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency.
        Circulation. 2017; 136: 1374-1383
        • Anker S.D.
        • Comin Colet J.
        • Filippatos G.
        • et al.
        Ferric carboxymaltose in patients with heart failure and iron deficiency.
        N Engl J Med. 2009; 361: 2436-2448
        • Avni T.
        • Leibovici L.
        • Gafter-Gvili A.
        Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-analysis.
        Eur J Heart Fail. 2012; 14: 423-429
        • Lewis G.D.
        • Malhotra R.
        • Hernandez A.F.
        • et al.
        Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial.
        JAMA. 2017; 317: 1958-1966
        • Kazory A.
        • Ross E.A.
        Anemia: the point of convergence or divergence for kidney disease and heart failure?.
        J Am Coll Cardiol. 2009; 53: 639-647
        • Swedberg K.
        • Young J.B.
        • Anand I.S.
        • et al.
        Treatment of anemia with darbepoetin alfa in systolic heart failure.
        N Engl J Med. 2013; 368: 1210-1219
        • Ghali J.K.
        • Anand I.S.
        • Abraham W.T.
        • et al.
        Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia.
        Circulation. 2008; 117: 526-535
        • Hewing B.
        • Dehn A.M.
        • Staeck O.
        • et al.
        Improved left ventricular structure and function after successful kidney transplantation.
        Kidney Blood Press Res. 2016; 41: 701-709
        • Wali R.K.
        • Wang G.S.
        • Gottlieb S.S.
        • et al.
        Effect of kidney transplantation on left ventricular systolic dysfunction and congestive heart failure in patients with end-stage renal disease.
        J Am Coll Cardiol. 2005; 45: 1051-1060
        • Knoll G.
        • Cockfield S.
        • Blydt-Hansen T.
        • et al.
        Canadian Society of Transplantation consensus guidelines on eligibility for kidney transplantation.
        CMAJ. 2005; 173: 1181-1184
        • Samarendra P.
        • Ramkumar M.
        • Sharma V.
        • Kumari S.
        Cardiorenal syndrome in renal transplant recipients—it’s the fistula at fault: a case series.
        Clin Transplant. 2018; 32: e13417
        • Nickel P.
        • Gul S.
        • Puhl G.
        • Poellinger A.
        • Schindler R.
        Acute cardiorenal syndrome by high flow arteriovenous fistula after kidney transplantation.
        J Vasc Access. 2013; 14: 394-396
        • Mehra M.R.
        • Canter C.E.
        • Hannan M.M.
        • et al.
        The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update.
        J Heart Lung Transplant. 2016; 35: 1-23
        • Cowger J.A.
        • Radjef R.
        Advanced heart failure therapies and cardiorenal syndrome.
        Adv Chronic Kidney Dis. 2018; 25: 443-453
        • Schaffer J.M.
        • Chiu P.
        • Singh S.K.
        • et al.
        Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.
        Am J Transplant. 2014; 14: 384-396
        • Walther Carl P.
        • Niu J.
        • Winkelmayer Wolfgang C.
        • et al.
        Implantable ventricular assist device use and outcomes in people with end-stage renal disease.
        J Am Heart Assoc. 2018; 7: e008664
        • Kirklin J.K.
        • Naftel D.C.
        • Kormos R.L.
        • et al.
        Quantifying the effect of cardiorenal syndrome on mortality after left ventricular assist device implant.
        J Heart Lung Transplant. 2013; 32: 1205-1213
        • Smith G.L.
        • Lichtman J.H.
        • Bracken M.B.
        • et al.
        Renal impairment and outcomes in heart failure: systematic review and meta-analysis.
        J Am Coll Cardiol. 2006; 47: 1987-1996
        • McAlister F.A.
        • Ezekowitz J.
        • Tonelli M.
        • Armstrong P.W.
        Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study.
        Circulation. 2004; 109: 1004-1009