The Cardio-Renal Syndrome Stephen L. Rennyson MD

1. The Cardio-Renal SyndromeStephen L. Rennyson MD

2. Clinical Presentation • 68 y.o. man with iCMO admitted with volume overload consistent with CHF exacerbation • Admitted 2 weeks prior -- similar presentation • Discharged with appropriate CHF regimen, furosemide diuretic • Laboratory Studies • Sodium 132 • Creatinine 1.8 • Hemoglobin 9.8 • Albumin 2.2

3. Placed on BiPap in the ED, given 120 mg of iv Lasix, transferred to CICU . . . Started NTG gtt • Initial success of 500 cc urine output • Morning laboratory studies show creatinine rising • Midnight dose of lasix produced little urine output • Blood pressure falling . . .

4. Cardio-Renal Syndrome Background Pathophysiology Management Options Case

5. Congestive Heart Failure • Epidemiology changing from acute management to managing the chronicity of cardiac dysfunction • An indicence of 5 million persons • Responsible for over 1 million yearly hospitalizations • 280,000 deaths annually

6. Comorbid Conditions . . .Associated with a worse prognosis • Anemia (Hb < 10.0) • Cirrhosis • Peripheral Vascular Disease • Hyponatremia (<135) • Renal failure N Engl J Med 2006; 355:260-269July 20, 2006

7. Cardiovascular Outcomes with renal dysfunction • Stratified by GFR Cumulative incidence • Cardiovascular death • Unplanned ADHF admission reduced LVEF (LVEF<=40%) • Stratified by GFR LV systolic function (LVEF>40%) Hillege, H. L. et al. Circulation 2006;113:671-678

8. ADHERE Registry • Registry of Acute Decompensated Heart Failure (ADHF) • 105,000 patient registry • QOC study evaluating variations in CHF treatment • Best predictors of outcome: • BUN • Creatinine

9. Cardio-Renal Syndrome • Most Simplistic Description: • Associated loss of renal function in the setting of advanced CHF • CRS or RCS?

10. Subtypes • Type I, acute CRS • Type II, chronic CRS • Type III, acute renocardiac syndrome • Type IV, chronic renocardiac syndrome • Type V, secondary CRS -- sepsis, amyloidosis

11. Cardio-Renal Syndrome • CHF patients at increased risk for CRS: • Hypertension • Diabetes • Severe Vascular Disease • Elderly

12. Cardio-Renal Syndrome Background Pathophysiology Management Conclusions

13. Pathophysiology • Neurohormonal Factors: • SNS, RAAS, AVP System • Hemodynamics: • Loss of Cardiac Output • Transrenal perfusion pressure • Intrarenal hemodynamics

14. Neurohormonal Axis Adenosine

15. CHF Hemodynamics • Systolic or Diastolic CHF • Exacerbations -- Symptomatology seen objectively • Elevated PCWP • Elevations of INR, Alkaline Phosphatase • Elevations of Creatinine • Shift in paradigm

16. CVP and Renal Failure • 2,557 patients underwent RHC • Age 59 ± 15 years • 57% were men • Renal Function using estimatedGlomerular Filtration Rate (eGFR) Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

17. Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values Solid line = cardiac index <2.5 dashed line = cardiac index 2.5 to 3.2 dotted line = cardiac index >3.2 p = 0.0217 Central Venous Pressure Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

18. CVP and Renal Failure Kaplan-Meier Analysis of Event-Free Survival According to Tertiles of CVP Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

19. Renal Hemodynamics • Transrenal perfusion pressure • TRPP = MAP - CVP • CVP influenced: • PAP -- Oxygenation, Valve Dysfunction, CO • Volume Status • MAP -- Perfusion Pressure • Cardiac Output • Systemic Vascular Resistance

20. Renal Hemodynamics • Ultimately lack of adequate transrenal perfusion pressure: • Renal Hypoxia • Inflammation / Cytokine Release • Progressive loss of nephron function and structural • Activation of the Neurohormonal cascade

21. Cardio-Renal Syndrome Background Pathophysiology Management Options Case

22. The Cardio-Renal Syndrome • Treatment Goals • Same goals as ADHF • Removal of Volume • Optimizing Hemodynamics • Complicated by chronic renal failure and acutely worsening renal function

23. Removal of Volume • Loop Diuretics • Brain Naturetic Peptide • Arginine Vasopressin Antatonism • Adenosine Antagonism • Ultrafiltration

24. Loop Diuretics • Goal --> Deplete extracellular fluid volume • Balanced refilling interstitium to intravascular compartment • Reality --> Contraction of circulating volume --> Activation of neurohormonal response

25. Loop Diuretics • Furosemide • Blockage of the thick ascending loop Na/ K/ 2 Cl pump • Acts intraluminally • Travels Bound to albumin • High Na delivered to distal tubules • Chronic use -> cellular hypertrophy -> increased Na reabsorption -> Failure of diuresis

26. Diuretic Resistance • Inadequate dosing • Cellular Hypertrophy • Bolus vs Continuous Infusion • Double Diuretic Therapy • Nutritionally Deficient Patients

27. Loop Diuretic Dosing • Dose response curve is not smooth • Thus, no diruresis until threshold dose reached • If 20 mg IV once a day is insufficient; BID will be just as ineffective • Torsemide and Bumetanide vs Furosemide • Similar iv bioavailabiltiy • Improved Oral Bioavailablity

28. Braking Phenomenon • Short term tolerance after the first dose • Continuous Infusion • Limited Data • Cochrane Review • Improved safety • Improved diuresis • Shorter Hospital Stay • Lower Cardiac Mortality in a single study Cochrane Database Syst Rev. 2004. p. CD003178.

29. The DOSE TrialDiuretic Optimization Strategies Evaluation • DOSE Trial • 308 patients with ADHF • Low vs High Dose Furosemide • Continuous vs a12 hour dosing • Overall no significant difference among all groups • Patients symptoms • Creatinine • High Dose group had a greater diuresis with transient increases in creatinine N Engl J Med. 2011 Mar 3;364(9):797-805.

30. Diuretic Resistance • Double Diuretic Therapy or Sequential Nephron Blockade • Loop + Thiazide • Chlorothiazide 250 mg vs 500 mg IV / Metolazone 5-10 mg PO • Very Effective -- Weight loss and edema resolution • Double Sodium Excretion • CAUTION: Hyponatremia, Hypotension, Worsening renal function • Chronic use -> cellular hypertrophy -> increased Na reabsorption -> Failure of diuresis J Am Coll Cardiol, 2010; 56:1527-1534, doi:10.1016/j.jacc.2010.06.034

31. Diuretic Resistance • Travels bound to albumin --> Delivered to Glomerulus --> Filtered --> Acts luminal side of thick ascending loop • Advanced CHF / Chronically ill • Elevated catecholamines (Catabolic) • Low serum albumin • Decreased delivery of diuretic to renal tubules **Addition of salt poor albumin** Furosemide-Albumin dimer allows better drug delivery Clin Pharmacokinet. 1990 May;18(5):381-408

32. Brain Natriuretic Peptide LV volume overload --> Cardiac Myocytes secrete BNP precursor --> Converted to proBNP --> ProBNP cleaved into: • C-terminal BNP (biologically active) • Decrease in SVR and CVP • Increase natriuresis • N-terminal BNP or NT-proBNP (biologically inactive)

33. Nesiritide (Natrecor) • New to market in 2001 • Actions in ADHF • PCWP reduced within 15 minutes of administration • Resultant decreases in PA and RA pressure • Reduced SVRI • Resultant increase in CO • Enhances loop diuretic effects • Modest intrinsic natriuretic and diuretic effects • No tachyphylaxis • Blocks loop diuretic effects of aldosterone up-regulation • Cleve Clin J Med. 2002 Mar;69(3):252-6. Review • Clin Cardiol. 2010 Jun;33(6):330-6

34. ASCEND-HF • Over 7000 patients with ADHF -- standard therapy • Nesiritide infusion 24 hrs - 7 days vs placebo • Primary End points: • CHF mortality and readmission (30 days) • Self reported Dyspnea at 6 and 24 hours

35. ASCEND-HF

36. ASCEND-HF • Role of Natrecor: • Resolved Concerns: • Worsening mortality • Worsening renal function • No significant benefit compared to standard therapy • Improved Dyspnea Score ($500.00/day)

37. Arginine Vasopressin • Arginine vasopressin (AVP), secreted by posterior pituitary • V1 Vascular receptor • V2 Renal receptor • Proportional to the severity of HF • Contributes to fluid retention and hyponatremia

38. Hyponatremia

39. ACTIV Trial • Initial trial for Tolvaptan -- AVP antagonist • 319 patients with systolic dysfunction (<40%) admitted with exacerbation • Tolvaptan vs Placebo/ Standard Treatment • Greater loss of body weight • Greater urine output at 24 hours • Increase in serum sodium JAMA. 2004 Apr 28;291(16):1963-71.

40. EVEREST Trial • Efficacy of Vasopressin Antagonism in HF Outcome Study With Tolvaptan • Over 4000 patients in two separate study groups • EF < 40% • Tolvaptan (30mg) vs Placebo in combination with standard HF thearpy • Treatment time up to 7 days JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25

42. EVEREST Trial JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25

43. EVEREST Trial JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25

44. EVEREST Trial JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25

45. EVEREST Trial • No change over 24 month follow up: • All Cause Mortality • Cardiovascular Mortality • Heart Failure Hospitalization JAMA. 2007 Mar 28;297(12):1332-43. Epub 2007 Mar 25

46. Adenosine?? • Elevated levels seen in ADHF • Released locally in response to stress (Macula Densa) and sodium delivery to the DCT • Actions: • Afferent Arteriole Vasoconstriction • Decreased GFR • Sodium reabsorption • Tubuloglomerular feedback mechanism for regulation of GFR

47. Adenosine • Tubuloglomerular Feedback • Acute delivery of sodium to the distal tubules (Lasix) • Adenosine further released from the macula densa • Further renal dysfunction Br J Pharmacol. 2003 August 2; 139(8): 1383–1388.

48. Adenosine AntagonismBG9719 • 63 patients with ADHF • Compared Groups • Lasix Alone • Adenosine Antagonist Alone • Combination thearpy Circulation. 2002;105:1348-1353

49. Adenosine Circulation. 2002;105:1348-1353

50. Ultrafiltration • The removal of isotonic volume across a semipermeable membrane • Hemodialysis -- Removal of volume and solutes using a concentration gradient • UF does not decreasesodium presentation to the macula densa • Avoids neurohormonallymediated sodium and water reabsorption