Case scenario<br />71 yr old man complaints of severe SOB and chest pain.<br />Past h/o HTN,CHF--NYHA IV,CKD.<br />Temporary dialysis 3-4 times /week for acute on chronic CKD.<br />b/lcrackles,pedal edema.<br />CXR cardiomegaly,smallrt pleural effusion,pulmonary venous congestion.<br />Echo –LVH,DD,EF 40%,PASP 45 mmHg.<br />BUN -22 mmol/l s. creatinine was2.23 mg/dl<br /> CHF exacerbation–furosemide.<br />Acute on chronic renal failure serum creatinine raised to 4.7 mg/dl –hemodialysis.<br />Pericardial effusion and respiratory failure.<br />Rx with milirinone,dopamine,dobutamine,furosemide,thoracocentesis,perciardiocentesis –patient improved.<br />
Take home message</li></li></ul><li>Introduction<br />CRS increasingly has been used without a consistent or well accepted defintion.<br />Biomarkers can contribute to early diagnosis.<br />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.<br />Cluster of conditions complexity ---lack of clarity of with regard to diagnosis and management.<br />
Definition<br /><ul><li>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.</li></ul> - JACC;vol 52:no 19 ,2008<br /><ul><li>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</li></ul> -Eur Heart Journal :vol 26 :2008<br />
<ul><li>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.</li></li></ul><li>Mechanisms in CRS<br />RAAS<br />Increased SNA<br />Reactive oxygen species<br />Inflammation<br />Endothelin effect<br />Argininevasopressin effects<br />BNP effects<br />
EPIDEMIOLOGY<br />Age adjusted CVD mortality is about 30 times higher in CKD than in general population.<br />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.<br />1/3 of patients with mild renal impairment –h/o overt CVD.<br />Pretransplant CVD risk marker of post transplant CVD –loss of grafts.<br />
CLASSIFICATION <br />World congress of nephrology<br />Based on patho physiology<br />5 sub types<br />1.CRS type 1 : acute cardio-renal syndrome<br />2.CRS type 2 : chronic cardio-renal syndrome<br />3.CRS type 3 : acute reno-cardiac syndrome <br />4.CRS type 4 : chronic reno-cardiac syndrome<br />5.CRS type 5 : seconary cardio-renal syndrome<br />
Guyton model<br />Extensively described normal physiological interactions between the control of extracellular fluid volume by the kidney and the systemic circulation by the heart.<br />
Cardiorenal connection <br />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<br />
Anemia –a crucial factor in the vicious cycle of CRS<br />Integral part of advanced renal failure.<br />Independent effect on CVD in CKD <br />Every 1 gm/dl drop in mean hemoglobin –risk of cardiac failure increases by 25%.<br />Increases LVH by 42%,increases death risk by 14%.<br />Erythropoietin levels barely go up –TNF,IL -6 .<br />TNF – interferes with absorption of iron from gut.<br />Proteinuria –loss of EPO ,Iron ,transferrin---anemia .<br />Glycosylation of interstitial cells –EPO in diabetics.<br />
Blood pressure<br />Blunting of nocturnal BP in uremics<br />It is due to LVH or it leads to LVH <br />High risk of vascular diseases in CKD.<br />Decreased cardiac perfusion due to LVH –ischemia.<br />At any given SBP –pulse pressure > 50 mm hg correlates with increased risk of death.<br />
Calcium phosphate product<br />Prognephron loss- - phosphate retention , hypocalcemia- sec hyperparathyroidism.<br />It is independent risk factor of CVD.<br />>60 mg2/m2 ---metastatic calcification.<br />Vascular calcification begins 10-20 yrs earlier in these patients.<br />Calcium regulatory proteins deficiency -- x2 heremanschmidglycoprotein,matrix G1 a protein –extraosseus calcification.<br />
Proteinuria,hypoalbuminemia<br />Hypoalbuminemia<br />Hyperlipidemia<br />Coagulation abnormalities following hyperfibrinogenemia , increase in factor III,vWBF.<br />Microalbuminuria—marker of vascular endothelial dysfunction.<br />Hypoalbuminemia—risk factor in HD pts.<br />Hyperhomocysteinemia , impaired NO synthesis.<br />Increased plasma volume in HD pts.<br />Albumin-- Negative acute phase protein.<br />Increased acute phase proteins in HD pts.<br />
MIA<br />Malnutrition – inflammation – atherosclerosis syndrome.<br />IL1 IL6 TNF increased 8-10 times in ESRD<br />IL – 6 pro atherogenic cytokine.<br />Reduced clearance of cytokines , accumulation of AGE, unrecognised persistent infections , graft and fistula infections.<br /><ul><li>IL-6 stimulate adhesion molecules VCAM,ICAM—attachment of leukocytes—endothelial dysfunction.
Inhibits albumin synthesis , inhibits appetite directly , indirectly through leptin.
Sustained inflammatory response—ED-oxidative stress, complement activation—increased CV mortality.</li></li></ul><li>Role of ADMA<br />Asymmetric dimethylarginine<br />New emerging CV risk factor in uremic patients.<br />Competitive NO synthase inhibitor.<br />Decreased NO availability.<br />Degraded by dimethylargininedimethylhydrolase –renal tissue.<br />ADMA accumulates with renal failure.<br />Second strongest predictor of CV mortality after Age.<br />Reduced by ACEI ,ARBs,insulin sensitizers.<br />
Angiotensin II<br />RAAS –diabetics and HTN<br />Angiotensin II –vasoactivepeptide,true cytokine that regulates cell growth,inflammation and fibrosis.<br />Increases TNF alpha,IL-6,NF kB<br />Stimulates superoxide lipid peroxidation and inactivation of NO producing oxidative stress.<br />Promotes atherosclerosis.<br />Endothelial cell apoptosis<br />MMP 1,MMP-9 lead to proliferation,migration of smooth muscles cells—fibrosis.<br />
Hyperhomocysteinemia<br /><ul><li>Strong predictor of CVD in general population.
Moderate levels 16-30umol/l in CKD.(4.4-10.8umol/L)
Oxidative stress --- ROS—binding to NO--- homocysteinatedacylated proteins—acc of S.-adenosylhomocysteine –inhibitor of transmethylation reactions. </li></li></ul><li>lipids<br />Reduced Apo A containing HDL.<br />Increased Apo B VLDL,IDL.LDL.<br />Preferential increase in IDL and small dense LDL.<br />Decreased Apo A II /Apo C III ratio is hallmark.<br />HD attenuates the dyslipidemia,PD aggravates it.<br />
CRP <br />CRP –directly involved in atherothrombogenesis<br /><ul><li>Induces expression of adhesion molecules
E selectin,VCAM -1 ICAM 1 by endothelial cells.—chemoattractant to monocytes,mediated by MCP 1.
Stimulates tissue factor—thrombogenesis.</li></li></ul><li>CRS type 1 <br />Acute cardiac failure –worsening renal function.<br />Mechanisms are:<br />1. acute hypoperfusion leading to decreased GFR<br />2. decreased oxygen delivery.<br />3.resistance to ANP /BNP<br />4.cell necrosis/apoptosis<br />AKI severe in those with impaired LV EF than with preserved EF imparting the importance of perfusion of kidneys-- >70 %cardiogenic shock.<br />
Early diagnosis of CRS type 1 is important as serum creatinine rises when the AKI is already established.<br />Novel biomarkers are needed –rise within few hours of onset of AKI <br />NGAL –neutrophilgelatinaseassosiatedlipocalin –earliest and sensitive marker of ischemic/nephrotoxic injury detected in blood /urine.<br />Kidney injury molecule 1 is a highly specific marker for ischemic AKI. <br />
Management of CRS 1<br />Diuretics–useful in volume overloaded non hypotensive patients.<br />Loop diuretics ,thiazides<br />Overzealous use –worsening renal function<br />Exacerbates neuro hormonal activity , activates RAAS , Inc SVR ,worsens LVF .<br />Inotropes --dopamine,dobutamine,milirinone<br />Vasodialtors – nesiritide<br />Wang et al –no effect of nesirtide on GFR, RPF,urine output ,sodium excretion<br />Ultrafiltration(aquapheresis)<br />Arginine vasopressin receptor antagonists—tolvaptan<br />EVEREST trial <br />Adenosine A1 receptor antagonists<br />
CRS type 2<br />Chronic congestive cardiac failure –chronically reduced renal perfusion –chronic renal venous congestion—chronic renal dysfunction.<br />Prevalence of renal dysfunction in CHF is approx .25%<br />Pathophysiology is poorly understood.<br />ESCAPE study –no relation between the pulmonary artery catheter measured blood variables and serum creatinine.<br />
Pathophysiology<br />Low cardiac output--- activation of RAAS –SNS ---subclinical inflammation ---endothelial dysfunction—increased renal vascular resistance—accelerated atherosclerosis.<br />Relative or absolute erythropoietin deficiency.<br />Activation of the receptor of erythropoietin leads to reduced risk of apoptosis , inflammation and fibrosis.<br />
Oxidative stress and inflammation : enzymes involved are NADPH oxidase,SOD,NOS,myeloperoxidase are capable of oxdizing LDL.<br />Increased levels of inflammatory biomarkers like CRP,IL-6,fibrinogen –along with oxidized LDL – proatherogenic – endothelial dysfunction.<br />Worsened by co existing hypoalbuminemia.---scavenger <br />Increased production of AGE ---pentosidine N carbo methyl lysine --accelerated atherosclerosis.<br />Endothelial dysfunction – ADMA <br />ADMA –competitive inhibitor of NO synthase.renal tissue.<br />
Management<br />Cessation of smoking,control of diabetes,HTN.<br />Correction of anemia –iron supplements and erythropoietin<br />Hb 11-12 gm % hct >36%<br />Loop diuretics ,ACEI, ARB s,bb<br />Calcium * phosphate ionic product to be kept below 50 mg2/m2<br />Sevelamer –better one in retarding calcification.<br />Statins --anti proteinuric effect<br />Vitamin E <br />N acetyl cysteine. <br />
CRS 5<br />Cardiac and renal dysfunction due to acute or chronic systemic cause.<br />Sepsis acutely.<br />Diabetes,amylodiosis,SLE<br />TNF alpha , IL 1B, IL – 6.<br />Pathophysiology of CRS type 1 and 3 – sepsis<br />CRS type 2 and 4 –chronic <br />
New drugs <br />Neutral endopeptidase NEP<br /><ul><li>An endothelial metalloproteinase– degradation of several regulatory peptides including natriuretic peptides.
Inhibition augments vasodilation and natriuresis.</li></ul>NEP/ACEI – vasopeptidase inhibitors –omapatrilet.<br /><ul><li>Decreases protetinuria by 20 % in CKD.
Major disadvantage is angioedema. </li></ul>Adenosine A1receptor antagonist BG 9719.<br />Targeted renal delivery of drugs—fenoldopam ,nesiritide.<br />
Trials<br />EVEREST trial<br />ESCAPE study<br />HOPE,HDFP,MRFIT,HOT ,framingham heart study--- increased cardiovascular risk begins early in renal insufficiency.<br />SHARP trial—lowering of LDL by 1 mmol/l for for 4-5 yrs reduces risk of coronary event by 20%.<br />EUPHORIA trial<br />UNLOAD trial<br />
Future<br />early diagnosis of the syndrome is needed.<br />Pathophysiology of the syndrome to be known in detail.<br />New alternative therapies other than diuretics are expected with results from large trials. <br />The transplantation of organs to be encouraged.<br />Diagnostic criteria to be developed.<br />
Take home message <br />CRS is a pathophysiological condition.<br />Treatment is to be individualized based on the etiology.<br />Early diagnosis is important for better survival.<br />Early novel biomarkers are to be used in diagnosis.<br />Each patient with either CKD,CVD to be assessed with risk factors and followed up.<br />Scope for research.<br />