Biomarkers, the Kidney and the Heart: Acute Kidney Injury

Transcription

1 Biomarkers, the Kidney and the Heart: Acute Kidney Injury 12th Annual Conference on Biomarkers in Heart Failure and Acute Coronary Syndromes: Diagnosis, Treatment and Devices San Diego May 13, 2016 Ravindra L Mehta MD, DM, FACP, FRCP University of California San Diego

2 The Cardio-Renal Syndrome

3 Cardio-Renal Syndrome Type 1 Definition Acute worsening of heart function leading to kidney injury and/or dysfunction. Key Features Epidemiology is challenging: Associated with heart failure, ACS, AMI Retrospective/second ary analyses Definition of worsening renal function (WRF) Variable observed time-at-risk

4 Cardio-Renal Syndrome Type 2 Definition Chronic abnormalities in heart function leading to kidney injury or dysfunction. Key Features Patients generally develop CKD Unclear rate of progression of CKD in patients with established CVD? Mechanistic link of heartkidney interaction and? synergistic interaction Effect of cardio-protective therapies on progression/exacerbation of CKD

5 Management Issues: CRS Type 1 Definition Acute worsening of heart function leading to kidney injury and/or dysfunction. Clinical Need Criteria for WRF Differential diagnosis of WRF Reversible hemodynamic change Structural damage Contributory factors Primary disorder Therapy for primary disorder Severity of renal dysfunction Nature and timing of intervention Response to intervention Prognosis

6 Management Issues: CRS Type 2 Definition Chronic abnormalities in heart function leading to kidney injury or dysfunction. Clinical Need Determine level of CKD Determine rate of progression of CKD? Mechanistic link of heart-kidney interaction and? synergistic interaction Effect of cardioprotective therapies on progression/exacerbati on of CKD

7 Clinical Need Determinants of renal function Contributory factors for WRF in heart failure

8 Determinants of renal function Cardiac output Renal blood flow Autoregulation Renal perfusion

9 Unique features of renal oxygenation Brezis, M et al, NEJM 1995 Inhomogeneous regional blood supply -Cortex receives nearly 20% of cardiac output, tissue PO mmHg -Medulla receives about 2.5% of cardiac output, tissue PO 2 of mm Hg -Medulla- brink of hypoxia

10 Corticomedullary junction: Critical zone of medullary hypoxia- O 2 delivery and O 2 consumption Bonventre JV et al, JCI 2011

11 Renal Compensatory Mechanisms Badr and Ichikawa NEJM 1988

12 Renal Compensatory Mechanisms Renal autoregulation of RBF and GFR. If MAP is in the range of ~80 to 180 mm Hg, fluctuations in blood pressure have only marginal effects on RBF and GFR. This is an intrinsic mechanism and can be modulated or overridden by extrinsic factors.

13 Determinants of renal function Cardiac output Renal blood flow Autoregulation Structural integrity Pressure gradients Autoregulation Renal perfusion GFR

14 AKI Pathophysiology Pressure gradients are needed for GFR Prowle, J. R. et al. Nat. Rev. Nephrol. 6, (2010);

15 Pathophysiology of AKI Murray P Eds: Intensive Care Nephrology

16 Tubuloglomerular Feedback Changes in the delivery of NaCl to the macula densa region of the thick ascending limb of the loop of Henle cause changes in the afferent arteriolar caliber. The response is mediated by adenosine or possibly ATP, and modulated by other locally produced agents, such as angiotensin II and nitric oxide. Increased macula densa NaCl delivery results in afferent arteriolar constriction, thereby reducing GFR.

17 Welch WJ: Adenosine A1 receptor antagonists in the kidney: effects in fluid-retaining disorders. Curr Opinion Pharmacol 2002;2(2): Summary of effects mediated by adenosine A1 and A2 receptors on the afferent arteriole. In normal conditions, the A1 receptor mediated constriction predominates and vasoconstriction of the afferent arterioles is seen.

18 Normal GFR Determinants of normal renal function Contributory factors for WRF Prevention strategies Wesson LG, ed. Physiology of the Human Kidney 1969:

19 Renal Reserve (Recruitable Nephrons) Baseline GFR depends on many factors, including diet and fluid intake. Each person has the capability to increase GFR in response to different stimuli. The difference between maximum GFR (Max GFR) and baseline GFR describes the renal functional reserve. When renal mass is lost, Max GFR declines in an almost linear function. RFR is still present any time the baseline GFR is lower than the Max GFR at a given value for functioning renal mass.

20 Serum Creatinine and GFR Relationships W Finn NDT 2006

21 Determinants of renal function Renal perfusion Cardiac output Renal blood flow Autoregulation Microcirculatio n GFR Structural integrity Pressure gradients Autoregulation Tubular Function Tubular reabsorption Water balance Acid excretion Divalent ions Hormones

22 Linear relationship of oxygen consumption (QO 2 ) to transport Majority of renal QO 2 is driven by Na reabsorption which is determined by GFR Tubular transport is among the principal determinants of intrarenal oxygenation. Thurau K, 1961

23 Increasing metabolic cost of Na transport along the nephron 0.4 cals/meq Na* 2.7 cals/meq Na* 1.4 cals/meq Na* 4.6 cals/meq Na* *Cohen JJ et al, 1981

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25 Clinical Need Determinants of renal function Contributory factors for WRF in heart failure

26 Clinical Need: Risk Assessment

27 Clinical Need: Risk Assessment Predictors of WRF during decompensated heart failure

28 Correlates of Worsening Renal Function (WRF) Characteristics Adjusted OR 95% CI P Value Women 1.41 ( ).003 HTN 1.64 ( ).003 Rales>Bases 1.28 ( ).03 HR >100 bpm 1.34 ( ).01 SCr 1.5 mg/dl 1.77 ( ) <.001 SBP >200 mm Hg 1.63 ( ).009 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.

29 Risk of Worsening Renal Function (WRF) by Number of Risk Factors Risk of WRF (%) % % 29% 38% 53% 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.

30 Impact of Worsening Renal Function (WRF) on Clinical Outcomes and Resource Consumption Outcomes % WRF Absent WRF Present Adj. Estimates In-hosp. mortality ( ) 30-d mortality ( ) 30-d readmission (all-cause) ( ) 30-d readmission (HF) ( ) 6-m mortality ( ) 6-m readmission (all-cause) ( ) 6-m readmission (HF) ( ) Length of stay (days) 7.5± ± ± (0.25) Hosp. Cost ($) 6,823±5,175 6,327±4,874 8,085±5,665 1,758±287.2 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.

31 Clinical Need: Contributory Factors for WRF Patient Factors Impaired renal compensatory mechanisms Underlying level of renal function RAAS inhibition Other agents

32 Pathophysiology of AKI Abuelo NEJM 2007

33 Clinical Need: Contributory Factors for WRF Patient Factors Impaired renal compensatory mechanisms Venous hypertension

34 Effects of increased CVP on renal blood flow and GFR Firth et al, Lancet 1988

35 Relationship between CV parameters and renal function Objective To determine whether venous congestion, rather than impairment of cardiac output, is primarily associated with the development of worsening renal function in patients with advanced decompensated heart failure. Methods Observational prospective study 145 consecutive patients admitted with acute decompensated CHF treated with intensive medical therapy guided by PAC were studied. Worsening renal function defined as an increase of serum creatinine 0.3 mg/dl during hospitalization. Mullens W et al J Am Coll Cardiol 2009;53:589 96

36 Impact of CVP on glomerular hemodynamics J Am Coll Cardiol 2009;53:597 9

37 Colombo et al, European Heart Journal (2014) 35, 4 30 mmhg above baseline valuee

38 Endothelial Glycocalyx determines vascular permeability Healthy Damaged Finfer and VincentL N Engl J Med 369;13, 2013

39 Becker et al: Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovascular Research (2010) 87,

40 Glycocalyx degradation induced by hypervolemia and atrial natriuretic peptide Glycocalyx VOLUME (%) Alb 5% Hémodil. Alb 5% hypervolémie HEA Hémodil. HEA hypervolémie -50% volume glycocalyx Rehm et al, Anesthesiology 2001, Anesthesist 2001

41 Glycocalyx degradation induced by. hypervolemia and atrial natriuretic peptide controls + ANP Increase vascular permeability Bruegger D et al. Am J Physiol Heart Circ Physiol 2005;289:H1993-H1999

42 Lung Injury and Barrier Dysfunction in acute heart failure Pappas et al, Am J Respir Crit Care Med Aug 1;190(3):342-5.

43 Increase intravascular volume in most patients with ADHF predicted normal total blood volume ranged from + 9.5% to + 107% on admission Na + Miller et al, J Am Coll Cardiol HF 2014;2:

44 ADHF = Inappropriate tubular Na + reabsorption Glomerular filtration ~180l/day mmol Na+ Inappropriate Na + reabsorption At the tubular level Daily Na+ intake < Diuresis Na + <100 mmol

45 The vicious circle of Na+ retention in heart failure Inappropriate tubular Na + reabsorption Low RBF Increase oncotic pressure in efferent arteriole Increase oncotic pressure in peritubular capillaries water and sodium reabsorption in proximal tubules Verbrugge et al, European Journal of Heart Failure (2014) 16, Bonventre & Yang,, J Clin Invest. 2011;121(11):

46 The vicious circle of Na+ retention in heart failure (1) Inappropriate tubular Na + reabsorption Afferent arteriole 1000ml/min Afferent arteriole 500ml/min Filtration fraction 20-25% Efferent arteriole Filtration fraction 45-45% Efferent arteriole Increase oncotic pressure In efferent arterioles

47 The vicious circle of Na+ retention in heart failure Inappropriate tubular Na + reabsorption Low RBF activation of renin angiotensin aldosterone system Increase oncotic pressure in efferent arteriole Increase oncotic pressure in peritubular capillaries water and sodium reabsorption in proximal tubules Verbrugge et al, European Journal of Heart Failure (2014) 16, 13 Bonventre & Yang,, J Clin Invest. 2011;121(11):

48 Clinical Need: Contributory Factors for WRF Patient Factors Impaired renal compensatory mechanisms Venous hypertension Anemia Process of Care Contrast Diuretics Other agents Cardiac surgery

49 Diuretics

50 Determinants of Diuretic Action Sodium Excretion Rate Dose Bioavailability Tubular secretory capacity Rate of absorption Time course of delivery A Threshold Maximal Response Altered dose-response relationship Braking phenomenon B Loop Diuretic Excretion Rate

51 Diuretic Therapy Significantly Decreases Glomerular Filtration Rate* Placebo GFR (% change) IV Furosemide Urine Output, 0-8 h (ml) N=16; NYHA II (19%) and III (81%) Mean baseline CrCl: 108 ± 51 µg/ml. *GFR estimated using 7-hour CrCl. Gottlieb SS et al. Circulation. 2002;105:1348. NYHA, New York Heart Association; CrCl, creatinine clearance.

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53 Felker et al: Diuretic Strategies in Patients with Acute Decompensated Heart Failure. N Engl J Med 2011;364: Creatinine Changes

54 Felker et al: Diuretic Strategies in Patients with Acute Decompensated Heart Failure. N Engl J Med 2011;364:

55 Felker et al: Diuretic Strategies in Patients with Acute Decompensated Heart Failure. N Engl J Med 2011;364:

56 Damman K et al: Volume Status and Diuretic Therapy in Systolic Heart Failure and the Detection of Early Abnormalities in Renal and Tubular Function. JACC Vol. 57, 2011: patients with chronic systolic heart failure in a presumed euvolemic state and on standard oral furosemide therapy (40 to 80 mg) were examined. At baseline, subjects were withdrawn from their loop diuretics.after 72 h, their furosemide regimen was reinstated, and patients were studied again 3 days later. Serum creatinine, atrial and B-type natriuretic peptide, urinary kidney injury molecule (KIM)-1, urinary N-acetyl-beta-Dglucosaminidase (NAG), and serum as well as urinary neutrophil gelatinase associated lipocalin (NGAL) were determined at various time points.

57 Damman K et al: Volume Status and Diuretic Therapy in Systolic Heart Failure and the Detection of Early Abnormalities in Renal and Tubular Function. JACC Vol. 57, 2011: patients with chronic systolic heart failure in a presumed euvolemic state and on standard oral furosemide therapy (40 to 80 mg) were examined. At baseline, subjects were withdrawn from their loop diuretics.after 72 h, their furosemide regimen was reinstated, and patients were studied again 3 days later. Serum creatinine, atrial and B-type natriuretic peptide, urinary kidney injury molecule (KIM)-1, urinary N-acetyl-beta-Dglucosaminidase (NAG), and serum as well as urinary neutrophil gelatinase associated lipocalin (NGAL) were determined at various time points.

58 Clinical Need: Therapeutic Interventions When the diagnosis is uncertain to define the type and nature of initial therapy CRS 1: whether patient has pre-renal state or has suffered structural damage Is the dysfunction due to the underlying disease or to the therapy CRS 2: Is the decline in kidney function chronic and stable or is new injury occurring What will be effect of choice of therapy on kidney function

59 Clinical Need: Therapeutic Interventions When the therapy is in place to define success Has renal function decline resolved Has a new steady state been achieved that is acceptable Is progression occurring

60 Renal Dysfunction in Heart Failure It s Complicated