Nephrology 02

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ABSTRACT:

The term “Cardiorenal syndrome” has gained wide attentionof physicians in recent times specially due to the increasingpresentations of patients with dual organ dysfunction resulting froma web of pathophysiological causation , the proper understandingof which might have important bearings on management andoutcome of these patients. This web of causation, though poorlyunderstood has been termed the cardio-renal connection and

in nutshell includes the Renin- Angiotensin- Aldosterone System(RAAS), Sympathetic Nervous system (SNS), Nitric Oxide ,inflammatory cytokines etc1.Recently in the World Congress ofNephrology the bi-directional nature of the Cardiorenal syndromewas emphasized and a classification based on pathophysiology wasproposed. Till now the management of the syndrome has metwith little success and no specific treatment strategy has beenestablished definitively. Diuretics, inotropes, vasodilators, renalreplacement therapy and others have all been tried with variable

success. More research and definitive clinical trials are requiredto further understand the pathophysiology and devise effectivemanagement strategies for the syndrome.

Key Words: Cardiorenal syndrome, RAAS, heart failure

Concomitant cardiac and renal dysfunction is the most simplisticview of cardio-renal syndrome. However the definition isambiguous as it lacks a direction of pathogenesis of the diseaseprocess. In fact the general view holds that renal injury occurssecondary to a diseased heart and in the presence of a normalcardiac function the same kidneys would perform normally (c.fHepato-renal syndrome) 2. However it is a known fact that primarydisorder of one of these two organs often causes secondarydysfunction of the other.3Hence a more comprehensive definitionthat encompasses the complete patho-physiology linking the twoorgans is required.

CARDIO-RENAL SYNDROME: DEFINITION

The cardio-renal syndrome includes a variety of acute or chronicdisorders where the primary failing organ can be either the heartor the kidney leading to the secondary dysfunction of the other. 4 (Fig.1)Thus according to the chronology of events the cardio-renal syndrome can be subdivided into 5 sub-types, namely4:

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: Secondary cardio-renal syndrome

CRS type 1: Acute cardio-renal syndrome is defined as acutecardiac failure leading to worsening of renal function. Within this isa spectrum of disorders involving the heart and the blood vesselsleading to acute heart failure which further causes Acute kidneyinjury through multiple mechanisms5. These mechanisms include:

1. Acute hypo perfusion leading to decreased G.F.R

2. Decreased Oxygen delivery

Khan SA, Gupta V, Haque SF, Aligarh

CARDIO-RENAL SYNDROME

Fig. 1 : Cardiorenal syndrome Pathophysiology

KIDNEY

INJURY

CARDIAC

FAILURE

RAAS, SNS,

NO-ROS,

Inflammatory

Mediators

C ARDI O-RE NAL S Y NDR OM

E


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3. Resistance to ANP/BNP

4. Cell Necrosis/ apoptosis

In fact AKI tends to be more severe in patients with impairedLeft Ventricular ejection fraction, being >70% in patients withcardiogenic shock 6.

Early diagnosis of kidney injury in CRS 1 and also CRS 3 (discussedlater) is important , but still remains difficult as serum creatininerises when the AKI is already established. Recently, novelbiomarkers which rise within first few hours of onset of AKIhave been discovered. Of these Neutrophil Gelatinase AssociatedLipocalin (NGAL) is one of the earliest and highly sensitive markerof ischemic/nephrotoxic kidney injury detected in the blood/urine. Similarly Kidney Injury Molecule is a highly specific markerfor ischemic AKI. Table 1 lists important biomarkers for the earlydetection of AKI.

Thus by using a combination of assay of these biomarkers Type 1CRS can be diagnosed early with timely intervention to preventongoing renal damage.

Management: While diuretics, both loop and thiazides have beenuseful in volume overloaded non-hypotensive patients, thereoverzealous use is associated with worsening of renal function7.Also diuretic therapy exacerbates neurohormonal activity, activatesthe RAAS, increases systemic vascular resistance and worsensleft ventricular function8 9. Besides, inotropes like dobutamine,dopamine, milrinone may be judiciously used in patients withimpaired cardiac output although their role is still controversialas they have been associated with increased mortality and cardiac

events

10

.Vasodilators like Nesiritide have been used favourably inthe treatment of Acute Decompensated Heart Failure where anon hypotensive, low cardiac output state is combined with coldextremities and increased peripheral vascular resistance due toexcessive vasoconstriction. In fact Nesiritide has been shown toreduce both systemic and pulmonary pressures and increase thecardiac and stroke volume indices11. However in the context ofcardiorenal dysfunction Wang and colleagues found that nesiritidehad no effect on GFR, renal plasma flow, urine output, or sodium

excretion12.

Patients who have diuretic resistant volume overload may stillrespond to ultrafiltration13.

Newer promisimg approaches in the management include theArginine Vassopressin Receptor antagonists like Tolvaptan(EVEREST trial) 14 15and Adenosine A

1 receptor antagonists.

CRS type 2: Chronic cardio-renal syndrome involves ChronicCongestive cardiac failure causing progressive kidney dysfunctionset on a background of chronically reduced renal perfusionand chronic renal venous congestion. The prevalence of renaldysfunction in chronic HF has been reported to be approximately25% 16. In fact the pathophysiology of renal dysfunction in thissyndrome is poorly understood. The ESCAPE study found nolink between pulmonary artery catheter measured hemodynamicvariables and serum creatinine17.The different putative mechanismsinclude low cardiac output causing activation of RAAS andsympathetic nervous system, subclinical inflammation, endothelialdysfunction, increased renal vascular resistance and acceleratedatherosclerosis. Recently it has been found that these patientshave relative/absolute erythropoietin deficiency causing moresevere anaemia than can be accounted for by renal failure alone18.In fact erythropoietin receptor activation in the heart may reducethe risk of apoptosis, inflammation and fibrosis19 20.

Management: Although diuretics are helpful in managing avolume expanded state, the key drugs in treating left ventricularsystolic dysfunction are the Angiotensin-Converting EnzymeInhibitors and Angiotensin Receptor Blockers. They by blockingthe RAAS not only affect cardiac remodeling and cause regressionof LVH but also retard proteinuria and progression of CKD.Due to the presence of excessive vasoconstrictor mediators inchronic heart failure, vasodilators might be of use in reducing the

congestion and improving renal perfusion.CRS type 3: Acute renocardiac syndrome is Acute Kidneyinjury leading to acute cardiac dysfunction through differentpathophysiological mechanisms involving three main systems: theRAAS, Nitric Oxide-Reactive oxygen species and the sympatheticnervous system. Fluid overload and accelerated hypertensioncan lead to acute pulmonary edema. Hyperkalemia can lead tolife threatening cardiac arrhythmias and sudden cardiac arrest.Metabolic acidosis can affect cardiac inotropy21 and causepulmonary vaso-constriction leading to right sided heart failure22.Acute uremia may cause depression of myocardial contractilitywhile uremic pericarditis may act as a mechanical hindrancefor the same. Myocardial ischemia frequently complicates AKI

which is due to a reduced coronary reserve which fails to meetincreases in myocardial oxygen demand. Renal ischemia alsoinduces a Systemic inflammatory response syndrome producinga number of pro-inflammatory cytokines leading to a delayedcardiodepressant response23.

A variety of markers of cardiac dysfunction/injury includingCardiac Troponins, NT-Pro BNP, cytokines like TNF α, IL-6 andmyeloperoxidase may be utilized for early detection of this

Table 1 : Lists important biomarkers for the early de-

tection of AKI.

Biomarker Associated Injury

Cystatin C Proximal tubule injury

KIM-1 Ischemia and nephrotoxins

NGAL Ischemia and nephrotoxins

NHE3 Ischemia, pre-renal, post-renal AKI

α-GST Proximal Tubular injury, Acute rejection

π-GST Distal Tubular injury, Acute rejection

L-FABP Ischemia and nephrotoxins

Cyr61 Ischemic ATN

Netrin-1 Ischemia and nephrotoxins,sepsis

GST = glutathione S-transferase; IL = interleukin; KIM = kidney in-

jury molecule; L-FABP = L-type fatty acid binding protein; NGAL =

neutrophil gelatinase-associated lipocalin; NHE = sodium-hydrogen

exchanger;Cyr61=Cysteine rich protein 61.


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syndrome.

Management: Adequate treatment of accelerated hypertension,hyperkalemia and metabolic acidosis reduces the risk of cardiacinjury. At the same time hemodialysis can be used in removingthe uremic toxins as well as treating the pericarditis effectively.In patients with hemodynamic instability Continuous renalreplacement therapies may offer better outcomes.

CRS type 4: Chronic Renocardiac syndrome is characterized byprimary chronic kidney disease contributing to the developmentof cardiac dysfunction resulting in increased cardiovascularmorbidity and mortality. While microalbuminuria is known to

increase the Cardiovascular risk 2-4 times, declining GFR per seis associated with increasing CV risk as shown in Table 2 24.

Besides the traditional risk factors, uremia and related novel riskfactors are responsible for the development of cardiovasculardisease, especially in CKD stages IV and V.25These include (1)Anemia (2) Hypervolemia and hypertension (3) Abnormal Calciumand phosphate metabolism (4) Oxidative stress and inflammation(5) Endothelial dysfunction (6) ADMA (7) Hyperhomocystenemia(8) Proteinuria

1. Anemia: For every 1g/dl decrease in mean haemoglobin therisk of cardiac failure increases by 25% 26 .Anemia furthercauses reduced viscosity, increased venous return and ag-gravation of sympathetic activity leading to Left ventricularhypertrophy.

2. Hypervolemia and hypertension: Fluid overload as well ashypertension increases the risk of cardiac failure. It is fur-ther associated with Left Ventricular hypertrophy, develop-ment of Ischemic Heart Disease and cardiomyopathy.

3. Abnormal Calcium and phosphate metabolism: CKD pa-tients have increased disturbances of calcium and phosphatemetabolism as early as stage 3 and are associated with ac-celerated calcifying atherosclerosis and arteriosclerosis. InESRD patients , extensive vascular, in particular coronaryartery calcication can be observed in young age group

and they are strong predictors of Cardiovascular Disease

and all cause mortality27. The secondary hyperparathyroid-ism along with hyperphosphatemia and increased Calcium –Phosphate ionic product are independent risk factors forCardiovascular disease28.

4. Oxidative stress and inammation: CKD is a state of chron-ic inammation and increased oxidative stress. Various en-zymes involved in production of reactive oxygen species :NADPH Oxidase, Superoxide Dismutase, Nitric Oxide Syn-

Table 2 : Chronic Kidney Disease and CV Risk

Stage CKD GFR(ml/min) CV Risk (OR)

1 >90 ??(proteinuria)

2 60-89 1.5

3 30-59 2-4

4 15-29 4-10

5 20

thase, Myeloperoxidase are capable of oxidizing LDL Be-sides there are increased levels of inammatory biomarkers

like CRP,IL-6, brinogen which along with Oxidised LDL are

proatherogenic and also lead to endothelial dysfunction.The situation is further worsened by coexisting hypoalbu-minemia which is a scavenger for these oxidants29.Oxidativestress also increases the production of Advanced Glycation

End Products –Pentosidine and N CarboxyMethyl Lysinewhich may contribute to accelerated atherosclerosis.

5. Endothelial Dysfunction: In CKD various factors includinginammation ,ADMA , oxidative stress, hypertension result

in endothelial dysfunction leading to accelerated athero-sclerosis and increased cardiovascular mortality30

6. Proteinuria: Urinary ACR is independently associated withthe presence and severity of cardiovascular disease in non-diabetic population.

7. Hyperhomocysteinemia: The prevalence of hyperhomo-cysteinemia in ESRD patients exceeds 90%.However theirexact relationship with Cardiovascular disease is still notclear31.

8. ADMA: A competitive inhibitor of NO synthase, causes de-creased NO bioavailability. ADMA is degraded by dimethylarginine aminohydrolase –an enzyme found in renal tissue.With advancing CKD, ADMA accumulates and leads to en-dothelial dysfunction and is strongly associated with CVmortality32.

Management: The primary prevention of CRS type 4 consistsof cessation of smoking, adequate control of Diabetes andhypertension,.

• Correction of anemia using iron supplements and Erythro-

poietin to maintain a Haemoglobin between 11-12g% and apacked cell volume >36%33.

• Control of volume overload and hypertension by using loop

diuretics as well as blocking the overactive RAAS by usingACE inhibitors and ARB’s. ACE inhibitors and ARB’s shouldbe used even if the patient is not hypertensive because theyare antiproteinuric and retard the progression of kidneydisease34.Since CKD is a state of sympathetic overactivityβ blockers as well as central sympatholytics are useful notonly in controlling the blood pressure but also reducing thesympathetic drive.

• Hyperphosphatemia and secondary hyperparathyroidism

have to be controlled and the Calcium * Phosphate ionicproduct should be kept below 50mg2/m2 by dietary phos-phate restriction and use of phosphate binders. Moreovernewer non-calcium containing phosphate binders likeSevelamer are known to reduce the progression of coro-nary and aortic calcication better than the calcium con-taining phosphate binders35.

• CKD patients are high risk cardiovascular individuals, hence


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Statins should be used to achieve a LDL cholesterol levelof less than 100 mg/dl (K/DOQI guidelines).Besides Statinsalso have modest antiproteinuric effect36.However thereuse should be judicious in view of recent reports that theymay favour development of renal brosis37

• Antioxidants like Vitamin E and acetylcysteine have been

shown to have a benecial effect on cardiovascular eventsin recent small studies and require further authentication.

CRS type 5: It is characterized by cardiac and renal dysfunctiondue to acute or chronic systemic cause. While in the acute settingsepsis is the most important cause, chronic conditions consist ofdiabetes, amyloidosis, SLE etc. The acute or chronic inflammatorystates acting through various cytokines like TNF α,IL-1β,IL-6 etc.may affect the functioning of both these organs38 39.Thereafterthe pathophysiological mechanisms of both Type 1 and Type 3CRS apply in sepsis while those of Type 2 and Type 4 CRS forchronic conditions.

Management: Treatment is directed at the prompt identificationand treatment of the underlying cause while supporting organfunction , both cardiac and renal by judicious use of vasopressors, inotropes and diuretics. In septic patients, preliminary studiessuggest that intensive renal replacement therapy may have a rolein improving myocardial performance while providing optimalsmall solute clearance 40.

Conclusion: Thus the concept of Cardiorenal syndrome is stillin its preliminary stages of development with further researchneeded to clarify its pathophysiology and adequate methodsof management. Till then individualization of each patient with judicious use of drugs is the best line of management.

REFERENCES

1 Mahapatra H S, Lalmalsawma Robert, Singh N P, Kumar M, Tiwari S CCardiorenal syndrome. Iranian Journal of Kidney Diseases 2009 Vol-ume 3 Number 2

2 Bongartz L.G., Cramer M.J., Doevendans P.A., Joles J.A. , Braam B., Thesevere cardiorenal syndrome: ‘guyton revisited.’, Eur Heart J 26 (2005),pp. 11–17.

3 Schrier R.W., Cardiorenal versus renocardiac syndrome: is there a dif-ference?, Nat Clin Pract Nephrol 3 (2007), p. 637

4 Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenalsyndrome. J Am Coll Cardiol. 2008;52:1527-39.

5 Liang K.V., Williams A.W., Greene E.L. and Redeld M.M., Acute decom-pensated heart failure and the cardiorenal syndrome, Crit Care Med36 (2008), pp. S75–S88

6 Jose P., Skali H. , Anavekar N. et al., Increase in creatinine and cardiovas-cular risk in patients with systolic dysfunction after myocardial infarc-

tion, J Am Soc Nephrol 17 (2006), pp. 2886–28917 Weinfeld MS, Chertow GM, Stevenson LW. Aggravated renal dysfunc-

tion during intensive therapy for advanced chronic heart failure. AmHeart J. 1999;138:285–90

8 Bayliss J, Norell M, Canepa-Anson R, Sutton G,Poole-Wilson P. Un-treated heart failure: clinical and neuroendocrine effects of introducingdiuretics. Br Heart J. 1987; 57:17-22.

9 Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN.Acute vasoconstrictor response to intravenous furosemide in patients

with chronic congestive heart failure. Activation of the neurohumoralaxis. Ann Intern Med. 1985;103:1-6.

10 Felker GM, O’Connor CM. Inotropic therapy for heart failure: an evi-dence-based approach. Am Heart J.2001;142:393 401.

11 [No authors listed]. Intravenous nesiritide vs nitroglycerin for treat-ment of decompensated congestive heart failure: a randomized con-trolled trial. JAMA. 2002;287:1531-40

12 Wang DJ, Dowling TC, Meadows D, et al. Nesirit ide does not improve

renal function in patients with chronic heart failure and worsening se-rum creatinine. Circulation. 2004;110:1620-5.

13 Jaski BE, Miller D. Ultraltration in decompensated heart failure. CurrHeart Fail Rep. 2005;2:148–54

14 Gheorghiade M, Konstam MA, Burnett JC, Jr, et al. Short-term clini-cal effects of tolvaptan, an oral vasopressin antagonist, in patients hos-pitalized for heart failure: The EVEREST Clinical Status Trials. JAMA.2007;297:1332–43

15 Konstam MA, Gheorghiade M, Burnett JC, Jr, et al. Effects of oral tolvap-tan in patients hospitalized for worsening heart failure: The EVERESTOutcome Trial. JAMA. 2007;297:1319–31

16 Hillege H.L., Nitsch D. ,Pfeffer M.A et al., Renal function as a predictorof outcome in a broad spectrum of patients with heart failure, Circula-tion 113 (2006), pp. 671–678.

17 Nohria A., Hasselblad V. ,Stebbins A. et al., Cardiorenal interactions—

insights form the ESCAPE trial, J Am Coll Cardiol 51 (2007), pp. 1268– 1274.

18 Jie K.E, Verhaar M.C. and Cramer M.J. et al., Erythropoietin and thecardiorenal syndrome: Cellular mechanisms on the cardiorenal con-nectors, Am J Physiol Renal Physiol 291 (2006), pp. F932–F944

19 Fu P. ,Arcasoy M.O., Erythropoietin protects cardiac myocytes againstanthracycline -induced apoptosis, Biochem Biophys Res Commun 354 (2007), pp. 372–378

20 Riksen N.P., Hausenloy D.J., Yellon D.M., Erythropoietin: ready forprime-time cardioprotection, Trends Pharmacol Sci 29 (2008), pp. 258– 267.

21 Brady J.P. and Hasbargen J.A., A review of the effects of correction ofacidosis on nutrition in dialysis patients, Semin Dial 13 (2000), pp. 252– 255

22 Figueras J., Stein L., Diez V., Weil M.H. , Shubin H., Relationship between

pulmonary hemodynamics and arterial pH and carbon dioxide tensionin critically ill patients

23 Prabhu SD Cytokine mediated modulation of cardiac function. Circ.res.2004;95;1140-45

24 Schiffrin E.L et al. Chronic Kidney Disease: Effects on the Cardiovascu-lar System Circ 2007;116:85

25 Muntner PHJ, Astor BC, Folsom AR, Coresh J:Traditional and non-tra-ditional risk factors predict coronary heart disease in chronic kidneydisease:Results from the atherosclerosis risk in communities study. JAm.soc. Nephrol 2005;16:529-538

26 Levin A et al Left ventricular mass index increasing in early renal dis-ease and impact of decline in hemoglobinAJKD 1999;34(1):1225-34

27 Blacher J,Guerin JP, Pannier B et al Arterial calcications, artrerial stiff -ness, and cardiovascular risk in end – stage renal disease. Hypertension2001:38:938-942

28 Block GA, Hulbert Shearon TE, Levin NW, Port FK: Association of se-rum phosphorus and calcium * phosphate product with mortality riskin chronic haemodialysis patients: Am j Kidney disease 1998;31:607-617

29 Himmelfarb J , Stenvinkel P, Ikizler TA, Hakim RM :The elephant ofuremia:Oxidative stress as a unifying concept of cardiovascular diseasein uremia. Kidnay Int 2002;62:1524-1538

30 Stam F, van GC, Becker A, et al. Endothelial dysfunction contrib-utes to renal function-associated cardiovascular mortality in a popula-


5/5

Cardio-Renal Syndrome

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tion with mild renal insufciency: the Hoorn study. J Am Soc Nephrol(2006) 17:537–545

31 Suliman M , Barany P,Kalanther Zadeh K,et al Homocysteine in uremia:A puzzling and conicting story. Nephrol Dial transplant 2005;20:16-21

32 Fliser D. Asymmetric Dimethyl arginine : A cardiovascular risk factor inrenal disease ? Kidney Int2002:62 (Suppl.82):S12-22

33 Locatell i F, Aljama P,Barany P, et al: Revised European best practice

guidelines for the management of anemia in patients with chronic renalfailure. Nephrol Dial Transplant 2004;19 (Suppl 2):ii 1-47

34 Wilmer WA, Rovin BH,Hebert CJ, et al :Management of glomerularproteinuria: A commentary. J Am Soc Nephrol 2003;14:3217-3232

35 Chertow GM, Burke SK, Raggi P :Sevalamer attenuates the progressionthe progression of coronary and aortic calcication in hemodialysispatients.Kidney Int.2002:62:245- 252

36 Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in

patients with chronic kidney disease: meta-analysis and meta-regres-sion of randomised controlled trials BMJ 2008;336:645-651

37 Theodoros I. Kassimatis, Panagiotis A. Konstantinopoulos Statins inPatients With Chronic Kidney Disease: A Double-Edged Sword? J AmColl Cardiol, 2008; 52:1679

38 Cunningham P.N., Dyanov H.M., Park P., Wang J., Newell K.A. and QuiggR.J., Acute renal failure in endotoxemia is caused by TNF acting directlyon TNF receptor-1 in kidney, J Immunol 168 (2002), pp. 5817–5823

39 Kumar A, Paladugu B, Mensing J, Kumar A. , Parrillo J.E., Nitric oxide-de-pendent and independent mechanisms are involved in TNF-α induceddepression of cardiac myocyte contractility, Am J Physiol Regul IntegrComp Physiol 292(2007), R1900–R1906

40 Honore P.M., Jamez J. , M. Wauthier et al., Prospective evaluation ofshort-term, high-volume isovolemic hemoltration on the hemody-namic course and outcome in patients with intractable circulatoryfailure resulting from septic shock. Crit Care Med 28 (2000), pp. 3581– 3587

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