Cardiorenal syndrome

Dr.Nagula Praveen

CARDIORENAL SYNDROMEDr.Praveen Nagula

Sir Arthur Guyton

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/l crackles,pedal edema. CXR cardiomegaly,small rt 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.

CARDIORENAL SYNDROME

TYPE 2

Introduction Definition Epidemiology Classification Pathophysiology Severe cardiorenal syndrome Diagnosis Treatment Prognosis Future Trials Take home message

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.

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 : 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

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

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.

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

Guyton model

Extensively described normal physiological interactions between the control of extracellular fluid volume by the kidney and the systemic circulation by the heart.

Figure 1 Pathophysiological basis of the severe cardiorenal syndrome.

Bongartz L G et al. Eur Heart J 2005;26:11-17

European Heart Journal vol. 26 no. 1 © The European Society of Cardiology 2004; all rights reserved.

Cardiorenal connection

When one of the organs fails , a vicious cycle develops in which the renin angiotensin system ,the NO-ROS balance,SNS ,inflammation interact and synergize ,here called the cardiorenal connection

Important molecules

NGAL—neutophilgelatinase assosciated lipocalin.

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

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.

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.

Calcium phosphate product

Prog nephron 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

hereman schmid glycoprotein,matrix G1 a protein –extraosseus calcification.

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.

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.

• Down regulates albumin mRNA.• Inhibits albumin synthesis , inhibits appetite directly ,

indirectly through leptin.• Sustained inflammatory response—ED-oxidative stress,

complement activation—increased CV mortality.

Role of ADMA

Asymmetric dimethyl arginine New emerging CV risk factor in uremic

patients. Competitive NO synthase inhibitor. Decreased NO availability. Degraded by dimethyl arginine dimethyl

hydrolase –renal tissue. ADMA accumulates with renal failure. Second strongest predictor of CV mortality after

Age. Reduced by ACEI ,ARBs,insulin sensitizers.

Angiotensin II

RAAS –diabetics and HTN Angiotensin II –vasoactive peptide,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.

Hyperhomocysteinemia

Strong predictor of CVD in general population. Moderate levels 16-30umol/l in CKD.(4.4-

10.8umol/L) Enhances vascular smooth muscle proliferation. Prothrombotic environment in coagulation. Activates factor V,X,XII. Decreased activation of protein C, thrombomodulin. Modualtion of annexin II. Oxidative stress --- ROS—binding to NO---

homocysteinated acylated proteins—acc of S.-adenosyl homocysteine –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.

CRP

CRP –directly involved in atherothrombogenesis Induces expression of adhesion molecules E selectin,VCAM -1 ICAM 1 by endothelial cells.—

chemoattractant to monocytes,mediated by MCP 1.

Opsonises LDL Activates complement via classical pathway. Decreases NO synthesis. Progression of atherosclerosis. 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.

Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Ronco, C. et al. J Am Coll Cardiol 2008;52:1527-1539

CRS Type 1

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 –neutrophil gelatinase assosiated lipocalin –earliest and sensitive marker of ischemic/nephrotoxic injury detected in blood /urine.

Kidney injury molecule 1 is a highly specific marker for ischemic AKI.

Biomarkers in the diagnosis of AKI

Biomarker Assosciated injury

Cystatin C Proximal tubule injury

KIM 1 Ischemia and nephrotoxins

NGAL Ischemia and nephrotoxins

NHE3 Ischemia,prerenal ,postrenal AKI

GST Proximal tubule injury ,acute rejection

GST Distal tubule injury,acute rejection

L-FABP Ischemia and nephrotoxins

Cyr 6 1 Ischemic ATN

NETRIN 1 Ischemia and nephrotoxins,sepsis

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

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.

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.



CRS Type 2

Management

Diuretics – volume expanded state ACEI ARBs block RAAS ---dec LVH,proteinuria,decrease

progression of CKD . Vasodilators may also be useful.

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



CRS Type 3

Management

Rx of accelerated HTN ,hyperkalemia,metabolic acidosis.

Hemodialysis. CRRT

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,endothelial dysfunction,ADMA,hyperhomocystenemia,proteinuria

Hypervolemia and hypertension – lvh –IHD—DCM Abnormal calcium and phosphate metabolism ---

coronary artery calcification noted.



CRS Type 4

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.

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.

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



CRS Type 5

Management

Treatment of underlying cause. Vasopressors Inotropes Diuretics Intensive renal replacement therapy in sepsis.

New drugs

Neutral endopeptidase NEP• An endothelial metalloproteinase– degradation of

several regulatory peptides including natriuretic peptides.

• Inhibition augments vasodilation and natriuresis. NEP/ACEI – vasopeptidase inhibitors –

omapatrilet.• Decreases protetinuria by 20 % in CKD.• Major disadvantage is angioedema. Adenosine A1receptor antagonist BG 9719. Targeted renal delivery of drugs—

fenoldopam ,nesiritide.

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

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.

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.

References

Postgraduate medicine (recent advances in medicine)XXI

Medicine update ,volume 20,2010. Oxford journals – guyton revisited SCRS JACC – vol 52,no.19 2008---cardiorenal

syndrome. Medscape education. Experimental and clinical cardiology—pubmed. Circulation 2004 journal 1514-1517.

Thank you

Sagittarian

Cardiorenal syndrome

Education

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