Outline Cardiorenal Syndromes: New ° Definitions Insights into Combined Heart and Kidney Failure ° Complex, bidirectional pathogenesis ° Novel diagnostic targets Peter A. McCullough, MD, MPH ° Therapy FACC, FACP, FAHA, FCCP, FNKF ° Putting it all together History Outline •1913: Sir Thomas Lewis gave a clinical lecture on paroxysmal dyspnoea in cardiocardio--renalrenal patients with special reference to “cardiac” and “uremic” asthma •1951: the term cardiorenal syndromes (CRS) was coined by Ledoux [i] •1997 to present: Schrier in multiple papers summarized the impact of salt and ° Definitions water retention combined with neurohormonal activation in the pathogenesis of CRS. [ii] [iii] [iv] ° Complex, bidirectional pathogenesis •2003: Brammah and colleagues pointed out that treatment of bilateral renal arterial disease could result in improvement of both heart and kidney function. [v] •2005: Braam demonstrated in animals that organ dysfunction in one system ° Novel diagnostic targets influences that in the other. [vi] •2008: Ronco and colleagues proposed five distinct CRS according to the temporal sequence of organ injury and failure as well as the clinical context. [vii] ° Therapy •2008: Acute Dialysis Quality Initiative (ADQI) involving nephrology, critical care, cardiac surgery, and cardiology was convened. [viii] ° Putting it all together •2011: Karger launches “Cardiorenal Medicine” James Sowers, MD, Editor •2012: ADQI conducted a second consensus conference to review the spectrum of pathophysiologic mechanisms involved in CRS [i] University College Hospital, London, November 12th, 1913. BMJ 2: 1417–1420. Ledoux P. [Cardiorenal syndrome]. Avenir Med. 1951 Oct;48(8):149-53. [ii] Blair JE, Manuchehry A, Chana A, Rossi J, Schrier RW, Burnett JC, Gheorghiade M. Prognostic markers in heart failure-congestion, neurohormones, and the cardiorenal syndrome. Acute Card Care. 2007;9(4):207-13. [iii] Sarraf M, Masoumi A, Schrier RW. Cardiorenal syndrome in acute decompensated heart failure. Clin J Am Soc Nephrol. 2009 Dec;4(12):2013-26. [iv] Sarraf M, Schrier RW. Cardiorenal syndrome in acute heart failure syndromes. Int J Nephrol. 2011 [v] Brammah A, Robertson S, Tait G, Isles C. Bilateral renovascular disease causing cardiorenal failure. BMJ. 2003 Mar 1;326(7387):489-91. [vi] Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B. The severe cardiorenal syndrome: 'Guyton revisited'. Eur Heart J. 2005 Jan;26(1):11-7. [vii] Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008 Nov 4;52(19):1527-39. [viii] Ronco C, McCullough PA, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege H, House A, Katz NM, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P; Acute Dialysis Quality Initiative (ADQI) consensus group. Cardiorenal syndromes: an executive summary from the consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol. 2010;165:54-67. 1 Five Cardiorenal Syndromes Recognition of Cardiorenal Cardiorenal Syndrome (CRS) General Definition: Syndrome A pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ CRS Type I (Acute Cardiorenal Syndrome) Abrupt worsening of cardiac function (acutely decompensated congestive heart failure) leading to acute kidney injury CRS Type II ( Chronic Cardiorenal Syndrome) Chronic abnormalities in cardiac function (chronic congestive heart failure) causing progressive and permanent chronic kidney disease CRS Type III (Acute Renocardiac Syndrome) Abrupt worsening of renal function (acute kidney ischaemia or tubular injury) causing acute cardiac disorder (new or decompensated heart failure) CRS Type IV (Chronic Renocardiac Syndrome) Chronic kidney disease (diabetic nephropathy) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events CRS Type V (Secondary Cardiorenal Syndrome) Systemic condition (e.g. sepsis) causing both cardiac and renal dysfunction Ronco C, McCullough PA, Anker SD, et al; Acute Dialysis Quality Initiative (ADQI) consensus group. Cardiorenal syndromes: an executive summary from the consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol. 2010;165:54 -67. Definition of Acute Kidney Injury (KDIGO Guidelines 2012) 2 Risk of Worsening Renal Function (WRF) by Number of Risk Factors Characteristics Adjusted OR 6.0 Women 1.41 HTN 1.64 53% 5.0 Rales>Bases 1.28 HR >100 bpm 1.34 38% 4.0 SCr ≥1.5 mg/dL 1.77 SBP >200 mm Hg 1.63 29% 3.0 (%) 24% 2.0 Risk of WRF Risk 16% 1.0 0.0 ≤ 1 2 3 4≥ 5 No. of Risk Factors N=1,681, WRF, defined as a rise in serum creatinine of >0.3 mg/dl (26.5 µmol/l). Krumholz HM et al. Am J Cardiol . 2000;85:1110. Outline ° Definitions ° Complex, bidirectional pathogenesis ° Novel diagnostic targets ° Therapy ° Putting it all together 3 High Central Venous Pressure and Cardiorenal Syndrome JACC Vol. 53, No. 7, 2009 Cardio-Renal Syndrome Pathophysiology Venous Congestion and Glomerular CKD-Associated Myocardial Chan.es Systolic or Diastolic Dysfunction or oth Myocyte hypertrophy Myocyte dysfunction Altered Intra-renal Hemodynamics Filtration &&Inters,,al Fibrosis 2Capillary density &&L/ Mass Ele3ated serum troponin le3els Increased CKD-Associated /ascular Chan.es Decreased Perfusion 3enous Accelerated atherosclerosis pressure Renal &/ascular s,@ness Con.estion 2Smooth muscle density Precipitators Osteoblastic /SMC transformation Diuretics /asodilators Intra-and extracellular calcification Procedures Toxicity /ascocostriction Acute on Acute on Chonic Chronic Cardiac Acute Neurohoromonal Acti3ation Kidney Disease SNS+RAS+Aldosterone+ Endothelin+ADH+1 renal In0ury Chronic Neurohormonal 3asoconstriction 8adenosine9+prosta.landin DM+HTN + other CKD &SNS1 RAS1 Aldosterone dysre.ulation Renal hypoperfusion 2/itamin D Decreased GFR &PTH Resistence to diuretics &PO5 LV Failure Resistance to ANP/BNP Mechanisms Hypotestesteronism Na + H 2O retention • Pressure overload ANP/ locked 2EPO • Volume overload NP Natruretic Peptides Natriuresis Necrosis / apoptosis 2Fe u,li7a,on • Cardiomyopathy Fibrosis 2Na-K ATPase Humoral Anemia/Rela,3e 2Epo/Fe transport blocked Cytokine Biomarkers si.nallin. Incitin. E3ents secretion ↑BNP/NT-proBNP 2Medical compliance ↑ N-GAL IL-11 TNF- 2Tubulo- &Sodium intake ↑ KIM-1 Alpha Glomerular Ischemia Leukocyte Function ↑IL-18 Endothelial Arrhythmias 8AF9 Acti3ation Catalytic iron Dysfunction OSAS ↑Cysta,n-C &Cytokines1 &Adhesion Molecules1 &En7yma,c Ac,3a,on1 &Oxida,3e Stress &Crea,nine Added Insults -rine albumin NSAIDS1 T:Ds Many others McCullou.h PA1 Die7 J1 KDIGO 2010 Workshopt1 Adapted1 Courtesy Ronco1 C 2009 4 Tubular Recovery and Renal Reserve in AKI ~30% of In-hospital AKI results in permanent loss in eGFR (~5% ESRD) Outline ~70% must have had tubular recovery or compensation by the remaining nephrons ° Definitions ° Complex, bidirectional pathogenesis ° Novel diagnostic targets ° Therapy ° Putting it all together Adapted fromThadhani et al., N Engl J Med 1996 BOLD MRI History of Urine in Western Medicine Power Doppler ° Ancient Babylonian and Sumerian physicians Clinical Evaluation first inscribed their And Biomarkers evaluations of urine into clay tablets as early as Positron Emission Tomography 4,000 B.C. Figure: People showing for a diagnose a sample of their urine to the physician Constantine the African. Advanced Imaging Yoquinto, My Health Daily News, Aug 15 2011 5 Blood and Urine Biomarkers of Acute Kidney Injury G1 cell cycle arrest markers ([TIMP-2].[IGFBP7]) NGAL, IL-18, KIM-1, L-FABP Tubular Enzymuria GGT, AlkPhos, LDH Cr, Cystatin-C NAG, α/πGST, Adapted from Geraghty et al. Am J Physiol Renal Physiol. 1992; 263: 958-962, Westhuyzen, et al, NDT 2003, Endre Z, 2008, Kashani Crit Care 2013 Predicted AKI Detection Multimarker Panel Approach Diagnostic value of biomarker Single Combination Liangos et al., Biomarkers 2008 0.50-0.66 0.78 Han et al., Clin JASN 2009 0.59-0.68 0.80-0.84 Kashani K et al, Crit Care 2013 0.76-0.79 0.80 Inducers of G1 cell cycle arrest (Urine [TIMP-2].[IGFBP7]) AKI Cystatin C Creatinine KIMKIM--11 IL 18IL 18 NGALNGAL 0 h 4 h 8 h 12 h 24 h 48 h Adapted Courtesy Herget-Rosenthal 2010 24 6 Baseline Samples and Prediction of AKI NEPHRO CHECK ® Test System: (TIMP-2 x IGFBP-7 Product in Spot Urine): Sapphire Study the Astute Medical NEPHRO CHECK ® Test System has received 510(k) clearance through FDA’s de novo classification process. On 9/5/14 FDA: “Current laboratory tests can only assess whether a patient may already have AKI; often, the patient has progressed to moderate to severe AKI before the test results confirm the clinical diagnosis. NephroCheck detects the presence of insulin-like growth-factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2) in the urine, which are associated with acute kidney injury. Within 20 minutes, the test provides a score based on the amount of the proteins present that correlates to the patient’s risk of developing AKI within 12 hours of the test being performed. No other tests currently on the market are FDA- approved or cleared to assess the risk of developing AKI in at-risk patients.” 25 -rinary ATIMP-2BCAIGF P7B Discriminates Patients With AKI From Those Without AKI 8Topa7 Study9 ihorac et al1 AJRCCM 2015 7 NEPHRO CHECK ® AKIRisk™ NGAL is an endogenous bacteriostatic protein by Case #1 Positive Test Performed Score = 2.6 reducing available catalytic iron Day 1 Day 2 Day 3 Day 4 Day 5 Therapies Cardiac Surgery: 6 hrs. NGAL E. coli Pump timeE 1.5 hrs. Siderophore No Transfusion Serum Creatinine (SCr, mg/dL) 3x SCr Baseline 1.3 SCr Baseline Iron X Urine Output AKI (UO, mL/h) <0.5ml/kg/h for ≥12h 0.5 ml/kg/h bacterial without NGAL growth Fluid Balance +6.4L +9.5L +11.2L +12.5L (Cumulative) curves with NGAL Hours 0 12 24 36 48 60 72 84 96 108 Goetz et al.