Cardiorenal syndrome

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cardiorenal syndrome-a new emphasis

cardiorenal syndrome-a new emphasis

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  • 1. CARDIORENAL SYNDROME
    Dr.PraveenNagula
    Dr.Nagula Praveen
  • 2. Sir Arthur Guyton
  • 3. Case scenario
    71 yr old man complaints of severe SOB and chest pain.
    Past h/o HTN,CHF--NYHA IV,CKD.
    Temporary dialysis 3-4 times /week for acute on chronic CKD.
    b/lcrackles,pedal edema.
    CXR cardiomegaly,smallrt pleural effusion,pulmonary venous congestion.
    Echo –LVH,DD,EF 40%,PASP 45 mmHg.
    BUN -22 mmol/l s. creatinine was2.23 mg/dl
     CHF exacerbation–furosemide.
    Acute on chronic renal failure serum creatinine raised to 4.7 mg/dl –hemodialysis.
    Pericardial effusion and respiratory failure.
    Rx with milirinone,dopamine,dobutamine,furosemide,thoracocentesis,perciardiocentesis –patient improved.
  • 4. Cardiorenal syndrome
    type 2
  • 5.
  • Introduction
    CRS increasingly has been used without a consistent or well accepted defintion.
    Biomarkers can contribute to early diagnosis.
    CRS is defined as a condition characterised by the initiation and progression of renal insufficiency sec to heart failure , term is also used to describe the negative effects of reduced renal function on heart and circulation.
    Cluster of conditions complexity ---lack of clarity of with regard to diagnosis and management.
  • 17. Definition
    • CRS can be generally defined as a patho physiologic disorder of the heart and kidneys whereby acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other.
    - JACC;vol 52:no 19 ,2008
    • SEVERE CARDIORENAL SYNDROME :
    • 18. A pathophysiologic condition in which combined cardiac and renal dysfunction amplifies progression of the failure of the individual organ , so that CV morbidity and mortality in this patient group is at least an order of magnitude higher than in the general population
    -Eur Heart Journal :vol 26 :2008
  • 19.
    • Simplistic view of CRS relatively normal kidney is dysfunctional because of a diseased heart , with the assumption that in the presence of a healthy heart the same kidney would perform normally.
  • Mechanisms in CRS
    RAAS
    Increased SNA
    Reactive oxygen species
    Inflammation
    Endothelin effect
    Argininevasopressin effects
    BNP effects
  • 20. EPIDEMIOLOGY
    Age adjusted CVD mortality is about 30 times higher in CKD than in general population.
    Risk of dying because of cardiovascular causes in patients with ESRD – 65 times higher in pts with 45-54 yrs, 500 times higher than general population in young cohort.
    1/3 of patients with mild renal impairment –h/o overt CVD.
    Pretransplant CVD risk marker of post transplant CVD –loss of grafts.
  • 21. CLASSIFICATION
    World congress of nephrology
    Based on patho physiology
    5 sub types
    1.CRS type 1 : acute cardio-renal syndrome
    2.CRS type 2 : chronic cardio-renal syndrome
    3.CRS type 3 : acute reno-cardiac syndrome
    4.CRS type 4 : chronic reno-cardiac syndrome
    5.CRS type 5 : seconary cardio-renal syndrome
  • 22. Guyton model
    Extensively described normal physiological interactions between the control of extracellular fluid volume by the kidney and the systemic circulation by the heart.
  • 23.
  • 24. Cardiorenal connection
    When one of the organs fails , a vicious cycle develops in which the reninangiotensin system ,the NO-ROS balance,SNS ,inflammation interact and synergize ,here called the cardiorenal connection
  • 25. Important molecules
    NGAL—neutophilgelatinaseassosciatedlipocalin.
    Cystatin C
    Kidney injury molecule 1
    N acetyl β (D) glucosaminidase
    Netrin 1
    NHE –sodium hydrogen exchanger
    GST –glutathione s transferase
    L FABP –l type fatty acid binding protein.
    IL-6,8,18
  • 26. Anemia –a crucial factor in the vicious cycle of CRS
    Integral part of advanced renal failure.
    Independent effect on CVD in CKD
    Every 1 gm/dl drop in mean hemoglobin –risk of cardiac failure increases by 25%.
    Increases LVH by 42%,increases death risk by 14%.
    Erythropoietin levels barely go up –TNF,IL -6 .
    TNF – interferes with absorption of iron from gut.
    Proteinuria –loss of EPO ,Iron ,transferrin---anemia .
    Glycosylation of interstitial cells –EPO in diabetics.
  • 27.
  • 28.
  • 29.
  • 30. Blood pressure
    Blunting of nocturnal BP in uremics
    It is due to LVH or it leads to LVH
    High risk of vascular diseases in CKD.
    Decreased cardiac perfusion due to LVH –ischemia.
    At any given SBP –pulse pressure > 50 mm hg correlates with increased risk of death.
  • 31. Calcium phosphate product
    Prognephron loss- - phosphate retention , hypocalcemia- sec hyperparathyroidism.
    It is independent risk factor of CVD.
    >60 mg2/m2 ---metastatic calcification.
    Vascular calcification begins 10-20 yrs earlier in these patients.
    Calcium regulatory proteins deficiency -- x2 heremanschmidglycoprotein,matrix G1 a protein –extraosseus calcification.
  • 32. Proteinuria,hypoalbuminemia
    Hypoalbuminemia
    Hyperlipidemia
    Coagulation abnormalities following hyperfibrinogenemia , increase in factor III,vWBF.
    Microalbuminuria—marker of vascular endothelial dysfunction.
    Hypoalbuminemia—risk factor in HD pts.
    Hyperhomocysteinemia , impaired NO synthesis.
    Increased plasma volume in HD pts.
    Albumin-- Negative acute phase protein.
    Increased acute phase proteins in HD pts.
  • 33. MIA
    Malnutrition – inflammation – atherosclerosis syndrome.
    IL1 IL6 TNF increased 8-10 times in ESRD
    IL – 6 pro atherogenic cytokine.
    Reduced clearance of cytokines , accumulation of AGE, unrecognised persistent infections , graft and fistula infections.
    • IL-6 stimulate adhesion molecules VCAM,ICAM—attachment of leukocytes—endothelial dysfunction.
    • 34. Down regulates albumin mRNA.
    • 35. Inhibits albumin synthesis , inhibits appetite directly , indirectly through leptin.
    • 36. Sustained inflammatory response—ED-oxidative stress, complement activation—increased CV mortality.
  • Role of ADMA
    Asymmetric dimethylarginine
    New emerging CV risk factor in uremic patients.
    Competitive NO synthase inhibitor.
    Decreased NO availability.
    Degraded by dimethylargininedimethylhydrolase –renal tissue.
    ADMA accumulates with renal failure.
    Second strongest predictor of CV mortality after Age.
    Reduced by ACEI ,ARBs,insulin sensitizers.
  • 37. Angiotensin II
    RAAS –diabetics and HTN
    Angiotensin II –vasoactivepeptide,true cytokine that regulates cell growth,inflammation and fibrosis.
    Increases TNF alpha,IL-6,NF kB
    Stimulates superoxide lipid peroxidation and inactivation of NO producing oxidative stress.
    Promotes atherosclerosis.
    Endothelial cell apoptosis
    MMP 1,MMP-9 lead to proliferation,migration of smooth muscles cells—fibrosis.
  • 38. Hyperhomocysteinemia
    • Strong predictor of CVD in general population.
    • 39. Moderate levels 16-30umol/l in CKD.(4.4-10.8umol/L)
    • 40. Enhances vascular smooth muscle proliferation.
    • 41. Prothrombotic environment in coagulation.
    • 42. Activates factor V,X,XII.
    • 43. Decreased activation of protein C, thrombomodulin.
    • 44. Modualtion of annexin II.
    • 45. Oxidative stress --- ROS—binding to NO--- homocysteinatedacylated proteins—acc of S.-adenosylhomocysteine –inhibitor of transmethylation reactions.
  • lipids
    Reduced Apo A containing HDL.
    Increased Apo B VLDL,IDL.LDL.
    Preferential increase in IDL and small dense LDL.
    Decreased Apo A II /Apo C III ratio is hallmark.
    HD attenuates the dyslipidemia,PD aggravates it.
  • 46. CRP
    CRP –directly involved in atherothrombogenesis
    • Induces expression of adhesion molecules
    • 47. E selectin,VCAM -1 ICAM 1 by endothelial cells.—chemoattractant to monocytes,mediated by MCP 1.
    • 48. Opsonises LDL
    • 49. Activates complement via classical pathway.
    • 50. Decreases NO synthesis.
    • 51. Progression of atherosclerosis.
    • 52. Stimulates tissue factor—thrombogenesis.
  • CRS type 1
    Acute cardiac failure –worsening renal function.
    Mechanisms are:
    1. acute hypoperfusion leading to decreased GFR
    2. decreased oxygen delivery.
    3.resistance to ANP /BNP
    4.cell necrosis/apoptosis
    AKI severe in those with impaired LV EF than with preserved EF imparting the importance of perfusion of kidneys-- >70 %cardiogenic shock.
  • 53. CRS Type 1
    Ronco, C. et al. J Am Coll Cardiol 2008;52:1527-1539
    Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.
  • 54. Early diagnosis of CRS type 1 is important as serum creatinine rises when the AKI is already established.
    Novel biomarkers are needed –rise within few hours of onset of AKI
    NGAL –neutrophilgelatinaseassosiatedlipocalin –earliest and sensitive marker of ischemic/nephrotoxic injury detected in blood /urine.
    Kidney injury molecule 1 is a highly specific marker for ischemic AKI.
  • 55. Biomarkers in the diagnosis of AKI
  • 56. Management of CRS 1
    Diuretics–useful in volume overloaded non hypotensive patients.
    Loop diuretics ,thiazides
    Overzealous use –worsening renal function
    Exacerbates neuro hormonal activity , activates RAAS , Inc SVR ,worsens LVF .
    Inotropes --dopamine,dobutamine,milirinone
    Vasodialtors – nesiritide
    Wang et al –no effect of nesirtide on GFR, RPF,urine output ,sodium excretion
    Ultrafiltration(aquapheresis)
    Arginine vasopressin receptor antagonists—tolvaptan
    EVEREST trial
    Adenosine A1 receptor antagonists
  • 57. CRS type 2
    Chronic congestive cardiac failure –chronically reduced renal perfusion –chronic renal venous congestion—chronic renal dysfunction.
    Prevalence of renal dysfunction in CHF is approx .25%
    Pathophysiology is poorly understood.
    ESCAPE study –no relation between the pulmonary artery catheter measured blood variables and serum creatinine.
  • 58. Pathophysiology
    Low cardiac output--- activation of RAAS –SNS ---subclinical inflammation ---endothelial dysfunction—increased renal vascular resistance—accelerated atherosclerosis.
    Relative or absolute erythropoietin deficiency.
    Activation of the receptor of erythropoietin leads to reduced risk of apoptosis , inflammation and fibrosis.
  • 59.
  • 60. CRS Type 2
    Ronco, C. et al. J Am Coll Cardiol 2008;52:1527-1539
    Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.
  • 61. Management
    Diuretics – volume expanded state
    ACEI
    ARBs
    block RAAS ---decLVH,proteinuria,decrease progression of CKD .
    Vasodilators may also be useful.
  • 62. Cardiorenal syndrome type 3
    AKI --- RAAS , NO reactive oxygen species , SNS.---acute cardiac dysfunction by fluid overload and accelerated HTN ---manifested as acute pulmonary edema.
    Hyperkalemia---cardiac arryhthmias and SCD
    Metabolic acidosis –cardiac inotropy –pulmonary vasoconstriction –RHF.
    Acute uremia --- myocardial contractility affected.
    Renal ischemia --- SIRS –proinflammatory cytokines--- delayed cardiodepressant response.
    Cardiac troponins , NT pro BNP,TNF,IL—6,
    Myeloperoxidase ---early detection
  • 63. CRS Type 3
    Ronco, C. et al. J Am Coll Cardiol 2008;52:1527-1539
    Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.
  • 64. Management
    Rx of accelerated HTN ,hyperkalemia,metabolic acidosis.
    Hemodialysis.
    CRRT
  • 65. CRS 4
    Primary CKD –CHF
    Microalbuminuria ---increases CV risk by 2-4 times.
    Declining GFR – assosciated with increasing CV risk.
    Anemia, hypervolemia , HTN, abn calcium and phosphate metabolism,oxidative stress and inflammation,endothelialdysfunction,ADMA,hyperhomocystenemia,proteinuria
    Hypervolemia and hypertension – lvh –IHD—DCM
    Abnormal calcium and phosphate metabolism --- coronary artery calcification noted.
  • 66. CRS Type 4
    Ronco, C. et al. J Am Coll Cardiol 2008;52:1527-1539
    Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.
  • 67. Oxidative stress and inflammation : enzymes involved are NADPH oxidase,SOD,NOS,myeloperoxidase are capable of oxdizing LDL.
    Increased levels of inflammatory biomarkers like CRP,IL-6,fibrinogen –along with oxidized LDL – proatherogenic – endothelial dysfunction.
    Worsened by co existing hypoalbuminemia.---scavenger
    Increased production of AGE ---pentosidine N carbo methyl lysine --accelerated atherosclerosis.
    Endothelial dysfunction – ADMA
    ADMA –competitive inhibitor of NO synthase.renal tissue.
  • 68. Management
    Cessation of smoking,control of diabetes,HTN.
    Correction of anemia –iron supplements and erythropoietin
    Hb 11-12 gm % hct >36%
    Loop diuretics ,ACEI, ARB s,bb
    Calcium * phosphate ionic product to be kept below 50 mg2/m2
    Sevelamer –better one in retarding calcification.
    Statins --anti proteinuric effect
    Vitamin E
    N acetyl cysteine.
  • 69. CRS 5
    Cardiac and renal dysfunction due to acute or chronic systemic cause.
    Sepsis acutely.
    Diabetes,amylodiosis,SLE
    TNF alpha , IL 1B, IL – 6.
    Pathophysiology of CRS type 1 and 3 – sepsis
    CRS type 2 and 4 –chronic
  • 70. CRS Type 5
    Ronco, C. et al. J Am Coll Cardiol 2008;52:1527-1539
    Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.
  • 71.
  • 72. Management
    Treatment of underlying cause.
    Vasopressors
    Inotropes
    Diuretics
    Intensive renal replacement therapy in sepsis.
  • 73.
  • 74.
  • 75.
  • 76.
  • 77.
  • 78.
  • 79.
  • 80.
  • 81. New drugs
    Neutral endopeptidase NEP
    • An endothelial metalloproteinase– degradation of several regulatory peptides including natriuretic peptides.
    • 82. Inhibition augments vasodilation and natriuresis.
    NEP/ACEI – vasopeptidase inhibitors –omapatrilet.
    • Decreases protetinuria by 20 % in CKD.
    • 83. Major disadvantage is angioedema.
    Adenosine A1receptor antagonist BG 9719.
    Targeted renal delivery of drugs—fenoldopam ,nesiritide.
  • 84. Trials
    EVEREST trial
    ESCAPE study
    HOPE,HDFP,MRFIT,HOT ,framingham heart study--- increased cardiovascular risk begins early in renal insufficiency.
    SHARP trial—lowering of LDL by 1 mmol/l for for 4-5 yrs reduces risk of coronary event by 20%.
    EUPHORIA trial
    UNLOAD trial
  • 85. Future
    early diagnosis of the syndrome is needed.
    Pathophysiology of the syndrome to be known in detail.
    New alternative therapies other than diuretics are expected with results from large trials.
    The transplantation of organs to be encouraged.
    Diagnostic criteria to be developed.
  • 86. Take home message
    CRS is a pathophysiological condition.
    Treatment is to be individualized based on the etiology.
    Early diagnosis is important for better survival.
    Early novel biomarkers are to be used in diagnosis.
    Each patient with either CKD,CVD to be assessed with risk factors and followed up.
    Scope for research.
  • 87.
  • 88. References
    • Postgraduate medicine (recent advances in medicine)XXI
    • 89. Medicine update ,volume 20,2010.
    • 90. Oxford journals – guyton revisited SCRS
    • 91. JACC – vol 52,no.19 2008---cardiorenal syndrome.
    • 92. Medscape education.
    • 93. Experimental and clinical cardiology—pubmed.
    • 94. Circulation 2004 journal 1514-1517.
  • Thank you
    Sagittarian