Cardiorenal Syndrome

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1 Cardiorenal Syndrome Peenida Skulratanasak, M.D. Division of Nephrology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University

2 Definition of Cardiorenal syndrome (CRS) Structural and functional abnormality The disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other The 7th ADQI consensus conference. Nephrol Dial Transpl. 2010;25:1416e1420.

3 Classification of CRS Type 1 Acute Cardiorenal syndrome Acute worsening of cardiac function leading to renal dysfunction Acute Decompensated Heart Failure AKI Type 2 Chronic cardiorenal syndrome Chronic abnormalities in cardiac function leading to renal dysfunction Type 3 Acute renocardiac syndrome Acute worsening of renal function causing cardiac dysfunction Chronic renocardiac syndrome Chronic abnormalities in renal function leading to cardiac disease Type Chronic 4 Kidney Disease Cardiac dysfunction Type 5 Secondary cardiorenal syndromes Systemic conditions causing simultaneous dysfunction of the heart and kidney like amyloidosis, sepsis The 7th ADQI consensus conference. Nephrol Dial Transpl. 2010;25:1416e1420.

4 CardioRenal Syndrome type 2 Prevalence 25%

5 CRS type 3 Decreased GFR Na + H 2 O retention HT Volume expansion Increased pre-load Sympathetic activation Bilateral renal artery stenosis Humoral signaling RAA activation vasoconstriction Electrolyte, acid-base & coagulation imbalance Monocyte actigation Endothelial activation

urinary obstruction Acute decompensation Acute heart failure

6 CardioRenal Syndrome type 3 Glomerular disease Interstitial diseases Acute tubular necrosis Acute pyelonephritis Acute urinary obstruction Acute decompensation Acute heart failure Ischemic insult Arrythmia Decrease CO Biomarkers Troponin Myoglobin MPO BNP

7 CardioRenal Syndrome type 5

8 New classification pathogenesis of CRS Nat. Rev. Nephrol. 9, (2013)

9 CRS type 1 Acute Cardiorenal Syndrome

10 Cardiac conditions precipitate CRS type1 Acute decompesated heart failure (ADHF) ADHF 27-40% develop acute kidney injury Reduced or preserved ejection fraction Acute coronary syndrome Cardiogenic shock Pulmonary embolism, valve disease Cardiac surgery

11 Acute Renal Dysfunction Acute kidney injury Worsening renal failure Definitions: Increase in serum creatinine > 0.3 mg/dl Increase in serum creatinine > 25% from baseline Kidney International Supplement (2012) 2,

12 Early Recognized CRS type 1 Cardiac conditions risk Following with A reduction in diuretic response A rise in serum creatinine

13 Pathophysiology of CRS type 1 Hemodynamic abnormality Neurohormonal abnormality Ronco C, et al. J Am Coll Cardiol 2008;52:

14 Hemodynamic abnormality Low cardiac output Reduced renal blood flow Venous congestion High central venous pressure Increased intraabdominal pressure Contrib Nephrol. Basel, Karger, 2013, vol 182, pp

15 Venous Congestion Glomerular filtration pressure = Renal perfusion pr. Renal venous pressure Prowle, J. R. et al. Nat. Rev. Nephrol. 10, (2014);

16 Intra-abdominal pressure Increased IAP: IAP > 8 mmhg Intra-abdominal hypertension: IAP > 12 mmhg Abdominal compartment syndrome: IAP > 20 mmhg with organ failure Intensive Care Med (2007) 33:

17 Elevated IAP in ADHF IAP > 8 mmhg: 60% of patients with ADHF J Am Coll Cardiol 2008;51:300

18 Hemodynamic abnormality Blood Purif 2014;37(suppl 2):2 13

19 Neurohormonal abnormality Renin-angiotensin-aldosterone system Sympathetic nervous system Inflammation cytokines Impaired balance of ROS vs. NO production

20 Contrib Nephrol. Basel, Karger, 2013, vol 182, pp

21 A loss of autoregulation and the onset of worsened salt and water retention, reduction in renal filtration, and oliguria

22 The Acute Decompensted Heart Failure National Registry (ADHERE) Acute worsening of renal function during treatment of ADHF is a strong and consistent independent predictor of adverse outcomes Higher mortality Longer length of hospital stay Greater likelihood of readmission Am Heart J. 2005;149(2):

23 Biomarkers for Early Diagnosis Tubular damage markers Neutrophil gelatinase-associated lipocalin (NGAL) myocardiocytes, vascular wall cells, fibroblasts and neutrophils N-Acetyl-β-D-Glucosaminidase (NAG) Kidney injury molecule 1 (KIM-1) IL-18 Contrib Nephrol. Basel, Karger, 2013, vol 182, pp

24 Biomarkers for Early Diagnosis Neurohormonal activation marker Natriuretic peptides Mid-regional pro-adrenomedullin Copeptin c-terminal segment of preprovasopressin Hyponatremia poor prognosis marker Contrib Nephrol. Basel, Karger, 2013, vol 182, pp

25 Soluble ST-2 blood biomarker in the risk prediction of HF hospitalization and death ST2 is the receptor for interleukin-33 a cytokine with angiohypertrophic and antifibrotic effects on the myocardium Contrib Nephrol. Basel, Karger, 2013, vol 182, pp

26 Risk factors of CRS type 1 Older age Comorbid conditions (DM, uncontrolled HT, anemia) Drugs: NSIAD, Diuretic, ACEi, ARB, Aldosterone receptor antagonists Baseline renal dysfunction History of Heart failure / Impaired LVEF Prior myocardial infarction NYHA functional class High dose of diuretic Clin J Am Soc Nephrol. 2013;8(10):

27 Treatment Relieve congestion and improve symptoms while restoring renal and systemic perfusion Diuretics vs. Ultrafiltration Inotropic drugs and vasodilators

Diuretics Continuous infusion Greater urine output Less ototoxicity (tinnitus and hearing loss) Similar frequency of electrolyte disturbances

28 Diuretics Continuous infusion Greater urine output Less ototoxicity (tinnitus and hearing loss) Similar frequency of electrolyte disturbances Cochrane Database Syst Rev. 2005;(3) Blood Purif 2017;43:1 10. Higher dose associated with mortality Marker of disease severity Cause of adverse outcome

29 Diuretics RCT, 308 patients with ADHF Hx of chronic HF, on furosemide mg/d Furosemide, intravenous DOSE Bolus every 12 hours vs. Continuous infusion Low dose (1x of the previous oral dose) vs. High dose (2.5x of the previous oral dose) N Engl J Med 2011;364:

30 N Engl J Med 2011;364:

31 Death, re-hospitalization, emergency visit A high-dose strategy - A trend toward improved symptom relief - Increased worsening kidney failure events either bolus or continuous infusion

32 Adv Chronic Kidney Dis. 2017;24(4): Blood Purif 2017;43:1 10. Ultrafiltration

33 Diuretics vs. Ultrafiltration 200 patients with HF Ultrafiltration vs. intravenous diuretics Ultrafiltration Peripheral Fluid remove rate: up to 500 ml/h UNLOAD J Am Coll Cardiol 2007;49:675 83

34 At 90 days, the ultrafiltration group Fewer patients rehospitalized for HF Fewer rehospitalization days per patient Fewer unscheduled visits Diuretics limitation: dose of diuretic and clinical response J Am Coll Cardiol 2007;49:675 83

35 Diuretics vs. Ultrafiltration CARRESS 188 patients with ADHF and worsened renal function (increase serum Cr >0.3 mg/dl) Ultrafiltration vs. pharmacologic therapy with diuretics Ultrafiltration: fluid-removal rate of 200 ml per hour Intravenous diuretics: keep urine output 3 to 5 liters per day N Engl J Med 2012;367: Mean Cr mg/dl

36 At 96 Hr A stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration - for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches Limitation: Fixed rate UF N Engl J Med 2012;367:

37 Diuretics vs. Ultrafiltration What time point should UF be considered? Early or after inefficacy of diuretics (diuretic resistance) What is the optimal rate of fluid removal?

38 Vasodilator therapies Aim: to reduce central venous pressure Decrease net filtration pressure gradient between afferent and efferent arteriole Nitroglycerine Nitoprusside Nesiritide

39 Nesiritide A recombinant of B-type natriuretic peptide Vasodilatation and induction of natriuresis and diuresis Risk of worsening renal function

40 7141 patients with heart failure Nesiritide vs. Placebo: 24 to 168 hours Add on standard care ASCEND-HF N Engl J Med 2011;365:32-43.

41 Nesiritide Episode of hypotension Renal impairment N Engl J Med 2011;365:32-43.

42 Inotropic drugs To increase cardiac contractility For patients with low LVEF, hypotension, impaired tissue perfusion Dobutamine Dopamine Levosimendan

43 Levosimendan A calcium-sensitising drug that stabilises the troponin molecule in cardiac muscle Increase cardiac contractility Vasodilatation effect Not recommended in patients with SBP < 85 mmhg (ESC 2016)

44 Management CRS type 1

46 Management CRS type 4

47 CRS type 4

Traditional Age Male gender Family History DM Risk factors Uremia-related Hypertension Dyslipidemia Smoking Hyperhomocystinemia Oxidative

48 Traditional Age Male gender Family History DM Risk factors Uremia-related Hypertension Dyslipidemia Smoking Hyperhomocystinemia Oxidative stress Inflammation Low serum albumin Anemia High PTH High P Low GFR High CRP Albuminuria High ADMA Arterial Stiffness Accelerated Atherosclerosis

49 CRS type 4 Anemia, Uremic toxins Ca and P abnormalities Nutritional status, BMI Na + H2O overload Chronic inflammation

50 Anemia Target Hb CKD non-dialysis Hb mg/dl CKD stage 5 dialysis Hb mg/dl Iron status TSAT >30% Ferritin >500 ng/ml Kidney International Supplements (2012) 2,

51 CKD-MBD Avoid hypercalcemia Keep phosphate toward normal range Vascular calcification Accelerated atherosclerosis Restrict the dose of calcium-based phosphate binder Avoid aluminum containing phosphate binder Kidney International Supplements (2017) 7, 1 59

52 CKD-MBD Parathyroid level CKD stage 3-5ND optimal level is not known modifiable hyperp, hypoca, high P intake and vitamin D deficiency CKD stage 5D PTH 2-9x UNL Kidney International Supplements (2017) 7, 1 59

resistance Endothelial dysfunction Smooth muscle proliferation LDL oxidation, Oxidant stress Vascular

53 CRS type 4 CKD stage 5 dialysis Anemia, Nutritional status Ca and P abnormalities Soft tissue calcifiation Uremic toxins Na + H 2 O overload EPO resistance Artificial surface Contaminated Fluids Chronic inflammation Insulin resistance Endothelial dysfunction Smooth muscle proliferation LDL oxidation, Oxidant stress Vascular calcification Accelerated atherosclerosis Appetite Muscle metabolism Bone remodeling Acute phase reactants Adipocytokine production

54 Dialysis Strategies to Improve Cardiovascular Outcomes Uremic toxin

55 Dialysis technique Hemodiafiltration Diffusion and convection Biocompatible membrane Ultrapure water Frequent hemodialysis Short daily HD 2-2.5h, 6-7 days/wk Decrease LV mass Nocturnal HD 8h, 6-7 days/wk Remove middle molecule of uremic toxin Decrease inflammation Improve P and BP control

Cardiorenal Syndrome

SOCIEDAD ARGENTINA DE CARDIOLOGIA Cardiorenal Syndrome Joint session ESC-SAC ESC Congress 2012, Munich César A. Belziti Hospital Italiano de Buenos Aires I have no conflicts of interest to declare Cardiorenal