Cardio renal care-An integated best Practice Approch

Declaration of Disclosure

It is the policy of the National Kidney Foundation to ensure balance, independence, objectivity, and scientific rigor in all CME/CE activities. Any individuals who have control over CME content are required to disclose to learners any relevant financial relationship(s) they may have with commercial interests supporting this activity or whose products or devices are discussed in this activity. If, on the basis of information disclosed a conflict exists, resolution will be achieved based on established policy by the NKF.

Faculty Disclosures

Refer to handout in participant folder

Learning ObjectivesDistinguish among the different cardio-renal syndromes (CRS) to make an

accurate diagnosis in high risk patients

Evaluate strategies to facilitate organ protection in patients with CRS and patients at risk for CRS

Incorporate a best practice approach to cardio-renal care in high risk patients to improve patient outcomes

AgendaWelcome and Introduction

Case Study Presentation Overview of Cardiorenal Syndromes (CRS) - Definition, Pathophysiology, and Epidemiology

Identifying and Reducing Risk for Developing CRS

Medical Management

Case Study Discussion Closing Remarks and Evaluation

Pre-program Questions to Consider

What is cardio-renal syndrome?

Which patients are at risk of developing cardio-renal syndrome?

What are treatment strategies for cardio-renal syndrome?

OVERVIEW OF CARDIO-RENAL SYNDROMES

Case PresentationCC:

65-year-old male admitted with 3 weeks of increasing shortness of breath, for consideration of MVR and CABG

HPI49 year h/o type 1 DM, 20 yr of htn, and first MI 21 years

ago. Chronic kidney disease, stage 5, not on dialysis, dx 5 years

ago with nephrotic range proteinuria. Known congestive heart failure with mitral regurgitation. 3 weeks prior to admission he developed increasing

shortness of breath and was unable to walk any distance or climbs stairs. At that time BNP was elevated and he was sent to the emergency room for admission.

Case Presentation

PMHType 1 diabetes diagnosed 1962,MI

1980,Hypertension 1980,Nephrotic syndrome 2005,Diabetic nephropathy 2005 with the first indication of renal failure, Congestive heart failure 2005. Last cardiac cath in 2008 (due to new LBBB)– diffuse 3 VD, no intervention, EF 35 – 45%.

Family history and social history noncontributory No allergiesReview of systems notable only for significant

shortness of breath with no hemoptysis, no chest pain, no lower extremity edema or weakness

Case Presentation

Meds on AdmissionCarvedilol 25 mg BIDQuinapril 20mg dailyAsa 325 dailyCalcitriol 0.5mg dailyInsulin - NPH 20, and 10 regular BIDLipitor 40 mg dailyTekturna HCT (aliskerin)150 mg/25 mg daily

Case Presentation

Admission Exam:Afebrile, BP 120/60, HR reg @60alert and oriented x3 in no significant distressJVP to 15 cmCor: inferolaterally displaced PMI no heave, RRR, +

apical S3, III/VI holosystolic murmur at the apexpulm: Decreased breath sounds at the bases with

adjacent rales, speaking in full sentences, no tachypnea, no accessory muscle use

abdomen soft, nt, nondistended , + liver edgefemoral pulses 2+, trace edema at the ankles

Case Presentation 141 | 115 | 90 --------------------< 230 Ca: 8.6 P: 4.5 Mg: 1.6 [09/08 @ 14:51] 6.6 | 20 | 4.5

WBC: 5.6 / Hb: 10.6 / Hct: 31.2 / Plt: 125

PT: 11.1 / PTT: 28.2 / INR: 1.1 Troponin: 1.06 EKG: NSR @ 84, left bundle branch block, new from ‘08 but

unchanged from previous Echo from < 1 month ago: LV dilated distal anteroseptal wall and

apex akinetic, inferior wall contracts normally, and all other wall hypokinetic, EF 35 -40%, left atrium dilated 4.9 cm,3+ MR (TEE suggested 4+ MR)

Defining CRS Because it has long been recognized that severe cardiac and renal dysfunction rarely

occur in isolation, the concept of cardiorenal syndrome has emerged. But CRS has been very difficult to define because it encompasses many complex physiological, biochemical, and hormonal abnormalities.1

In 2004, the National Heart, Lung, and Blood Institute defined CRS as only one syndrome in which “… therapy to relieve congestive symptoms of heart failure is limited by further worsening renal function (WRF).” 2

However, a reciprocal relationship exists between cardiac and kidney disease --kidney function declines in the presence of cardiac disease, and, conversely, CKD is considered an independent risk factor for developing cardiovascular disease.3

Therefore, definitions have been formulated to also “….stress the complex and bidirectional nature of pathophysiological interactions between the failing heart and kidneys.”4

1. Bock J.S., Gottlieb S.S. Circulation 2010;121:2592-2600.2. NHLBI Working Group. NHLBI web site. http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hg-hd.htm.3. House A.A., et al. Am J Kid Dis 2010;56:759-773.4. Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hg-hd.htm

Defining CRS The Cardiorenal Connection, an extension of Guyton’s hemodynamic model, represents the cyclical nature of CRS.

Guyton’s Hemodynamic Model illustrates the regulation of extracellular volume, cardiac output, and mean arterial pressure through feedback mechanisms between the heart and kidney.3

The Cardiorenal Connection emphasizes these pathophysiologic changes during heart or kidney failure:

- NO-ROS (nitric oxide-reactive oxygen species) imbalance

- sympathetic nervous system activation - renin-angiotensin system activation, and

inflammation. When one of these “connectors” become

deranged, the others do too, leading to heart and kidney dysfunction, and, structural damage. This ongoing cycle results in severe CRS.

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

Defining CRS

There is an urgent need to correctly define CRS in order to improve medical management of a very sick population. Though debate continues over the best definition(s), the following was developed in 2008 at the 7th Acute Dialysis Quality Initiative (ADQI) Consensus Conference on Cardio-Renal syndromes:

“Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other.”

The ADQI also established a classification of CRS subtypes that distinguishes primary organ dysfunction (cardiac vs. renal) and acute vs. chronic timeframe. A patient may exhibit one, several, or all of the subtypes during the course of illness.

Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

CRS Subtypes: Acute Cardiorenal Syndrome Type 1

McCullough P.A. Int J Neph 2010;2011:1-10.

CRS Subtypes: Acute Cardiorenal Syndrome, Type 1

Type 1 is common, with 27-40% of patients hospitalized for ADHF (acute decompensated heart failure) appearing to develop AKI (acute kidney injury).1

The incidence estimates for AKI associated with ADHF and ACS (acute coronary syndrome) have ranged between 24-45% to 9-19%, respectively. The broad ranges are related to varying definitions of WRF, differences in the observed time-at-risk, and the heterogeneity of selected populations being studied.2

The ESCAPE trial fulfills the criteria for acute cardiorenal syndrome (type 1) with a presenting diagnosis of ADHF, and demonstrates the following cardio-

renal interactions2:1. Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.2. Cruz D.N. and Bagshaw S.M. Int J Neph 2010;2011:1-11.

Acute Heart Failure causing AKI

Cardiogenic shock - >70% have AKIAcute anterior wall MIMitral valve papillary muscle rupture

MI, endocarditisAcute aortic regurgitation

EndocarditisAcute decompensation of chronic heart failureFlash pulmonary Edema

Hypertensive emergencyPredominantly preserved LVF/LVH

Predominant RV failure

Cardiorenal Interactions in the ESCAPE Trial

Nohria, A. et al. JACC 2008;51:1268-1274

-The risk of death and death or rehospitalizationat 6 months increased with increasing SCr and decreasingeGFR.-Baseline renal function appeared more predictive of long-term outcomes than WRF during hospitalization.

Characteristics of pts with WRF from ESCAPE trial

No difference in PAC –derived hemodynamic parameters in pts who had improved or worsening RF.

Those with WRF:↑SBP, ↑ prevalence of HTN, ↑suspicion of ascites, ↑use of thiazides, ↑weight loss and rate of weight loss.

RF did not worsen when treatment was PAC directed to lower CVP and PCWPWhereas it did when guided by clinical assessment alone

Testoni et al. Am J Cardiol 2010;106:1763-69Binanay et al. JAMA 2005;294:1625-33

CRS Subtypes: Chronic Cardiorenal Syndrome, Type 2


CRS Subtypes: Chronic Cardiorenal Syndrome, Type 2

Type 2 is common and has been reported in 63% of patients hospitalized with congestive heart failure.4

Of 118,465 admissions in the ADHERE trial, 27.4, 43.5, and 13.1% of patients were found to have mild, moderate, and severe kidney dysfunction at the time of hospital admission, respectively.2

The ADHERE registry used a classification and regression tree (CART) to determine predictors of mortality, and found high BUN to be the best predictor of mortality, with additional risk conferred by low systolic blood pressure, and then even further by high creatinine.2

1. Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.2. Heywood H, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Cardiac Failure 2007;13:422-430.

Journal of Cardiac Failure Vol. 13 No. 6 August 2007

Findings from the ADHERE Database

BUN 43(n=33046)

8.98%(n=647/7202)

SBP 115(n=7150)

15.28%(n=313/2048)

6.41%(n=327/5102)

Cr 2.75(n=2045)

12.42%(n=177/1425)

21.94%(n=136/620)

2.68%(n=673/25122)

SBP 115(n=24933)

5.49%(n=225/4099)

2.14%(n=445/20834)

<<

<<

<<

<<

BUN=blood urea nitrogen, Cr=serum creatinine, SBP-systolic blood pressure

Fonarow GC et al. JAMA 2005;293:572-580..

Case #272 year old woman, who presents for evaluation of

possible MVR and CABG.Flew directly from the Kuwait for opinion.PMH:

1) Ischemic Heart Disease: NSTEMI 2003, 2) HTN on multiple meds, h/o hypertensive emergency (flash

pulmonary edema) in 2/113) HL on atorvastatin4) DM25) Hypothyroidism on synthroid6) Morbid obesity with obesity hypoventilation syndrome on

nighttime O27) CRI (b/l Cr 1.6)

Case # 2Meds:

Candesartan 16 mg daily, Carvedilol 6.25 mg BID, ISMN 60 mg daily, Plavix 75 mg daily, Levothyroxine 50 mcg daily, Norvasc 10 mg daily, Lipitor 20 mg daily, Lasix 40 mg BID, Nexium 40 mg daily, Allopurinol 300 mg daily, ASA 81 mg, Novomix Insulin 70/30, Pregabalin 75 mg daily, Prazosin 2 mg TID

Exam:Gen: morbidly obese, NAD Neck: supple, no JVD, no LADCardiac: diffuse enlarged PMI, 6th IC space, RRR, nl S1/S2, loud

cresc/decresc murmur at RUSB radiating to R neck, HSM at apex, NoS3

Pulm: shallow inspiratory effort, decreased b/l lung basesAbdomen: protuberant, obese, non-tender, +bsExt: no pitting edema, 2+ pulses

Case # 2Initial labs stable : BUN/Creat 70/1.8Lasix held in preparation for cathCardiac cath revealed no change in anatomy from

2007 and only 1+ MR, low filling pressures and RV pressures.

Approx 70% stenosis of the right RA onlyTolerated procedure well, but complained of

abdominal pain afterwards. No evidence of bleeding, and hemodynamics stable for the next 48 hours.

Blood pressure relatively low and meds DC’d over the next few days

Hospital Course:Over the next few days:

Acute renal failure developed BUN/Creat 104/5.48, Na 117, K 6.1, HCO3 16, oliguria but never anuria

Initially fluid status OK, but CHF developedBP low 100/60, never needed pressors, but off ALL

medsJunctional escape rhythm requiriring emergent TPMCVVH initiated, only necessary for 12 hrs.UOP began to increase, creat down to 1.67 over the

next 10 days. Meds resumed.During renal recovery, episode of flash pulm edema

with BP 190/110, required BiPap and IV nitro.

CRS Subtypes:Acute Renocardiac Syndrome, Type 3


CRS Subtypes: Acute Renocardiac Syndrome, Type 3

Due to heterogeneity in the causes and definitions of AKI, as well as variable risk for developing CVD among individuals, and many clinical studies not reporting the occurrence of acute cardiac dysfunction as outcomes, incidence estimates are mostly context and disease-specific.

Patients suffering AKI secondary to contrast were almost twice as likely to suffer downstream adverse events, including cardiovascular events, in the year following contrast exposure.


CRS Subtypes: Chronic Renocardiac SyndromeType 4


Go, et al., 2004

1.01.4

2.0

2.8

3.4

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

≥ 60 45-59 30-44 15-29 < 15

Adju

sted

Haz

ard

Ratio

eGFR

Adjusted hazard ratio for CVD events

- The retrospective study by Go, et al fulfills criteria for chronic renocardiacsyndrome, type 4.- Go found graded increases in the prevalence of CVD and HF, along with higher risk of subsequent cardiac events during follow-up associated with the degreeof decline in eGFR < 60 mL/min/1.73m2.

Go AS, Chertow GM, Fan D, et al. N Engl J Med. 2004 Sep 23;351(13):1296-1305.

CRS Subtypes:Secondary Cardiorenal Syndrome Type 5


IDENTIFYING AND REDUCING RISK FOR DEVELOPING CRS

Shastri S, Sarnak MJ. Cardiovascular Disease and CKD: Core Curriculum 2010. Am J Kidney Dis 2010;56:399-417.

Kidney Failure Is a Rapidly Growing Problem

Num

ber o

f pati

ents

(in

thou

sand

s)

USRDS, 2000

98,953

372,407

661,330

172,667

Prevalence

Incidence

39

Incident Counts and Adjusted Rates, by Primary

Diagnosis

U.S. Renal Data System 2009 ADR

Incident ESRD patients; rates adjusted for age, gender, & race.

Diabetes: The Most Common Diabetes: The Most Common Cause of ESRDCause of ESRD

Primary Diagnosis for Patients Who Start Dialysis

Diabetes50.1%

Hypertension27%

Glomerulonephritis

13%

Other

10%

United States Renal Data System. Annual Data Report. 2000.

No. of patientsProjection95% CI

1984 1988 1992 1996 2000 2004 20080

100

200

300

400

500

600

700

r 2=99.8%

243,524

281,355520,240

No.

of d

ialy

sis

patie

nts

(thou

sand

s)

Stages and Prevalence of CKD (Age ≥ 20 Years)

GFRGFR Prevalence*Prevalence*StageStage DescriptionDescription (mL/min/1.73 m(mL/min/1.73 m22)) n (1000s)n (1000s) %%

1Kidney damage with normal or elevated GFR

≥ 90 5900 3.3

2 Kidney damage with mild decreased GFR 60-89 5300 3.0

3 Moderate decreased GFR 30-59 7600 4.3

4 Severe decreased GFR 15-29 400 0.2

5 Kidney failure <15 (or dialysis) 300 0.1

*Population of 177 million people ≥ 20 yearsAdapted from NHANES III

Stage 5

Stage 4

Stage 3

Stage 2

Stage 1 n=5,900,000

n=5,300,000

n=7,600,000

n=400,000

n=400,000At risk population

Total = 20 millionNHANES III

CKD Patients Are More Likely To Die Than Progress To Kidney Failure

5-Year Mortality Rate

RRT = renal replacement therapy

Keith D, et al. Arch Int Med 2004;164:659-663

14.9%

74.8%

10.2%

16.2%

63.3%

19.5%

10.3%

64.2%

24.3%45.7%

19.9%

27.8%

6.6%

1.0%1.2%

MEDICAL MANAGEMENT

Slow CKD progressionTreat to target BP <130/801

ACEI and/or ARB are first line therapies for hypertension with albuminuria or proteinuriaControl blood sugar in diabetes, target HbA1C <7%Refer to dietitian for food choices appropriate for this patient

Modify all CVD risk factorsControl dyslipidemiaWeight control and smoking cessationAnemia management Control hyperphosphatemia, hyperparathyroidism and vitamin D deficiency

Minimize further kidney injuryAvoid nephrotoxins such as NSAIDs, aminoglycosides, IV and intra-arterial contrast etcAdjust dosages of renally excreted medications; avoid metformin if GFR<60

NKF. KDOQI guidelines.

Challenge of Managing CRS

The treatment of heart failure often depends on large doses of diuretics and afterload reduction in order to optimize preload and afterload.7

As a result of volume depletion, renal function worsens.7

Conversely, treatment with volume to preserve renal function leads to pulmonary and systemic congestion and worsening heart failure.7

Chan EJ, Dellsperger KC. Cardiorenal syndrome: the clinical cardiologists’ perspective. Cardiorenal Med 2011;1:13-22.

Diuretic ResistanceReduced natriuretic response to a given dose of

diureticEscalating doses of loop and non-loop diuretics

at the expense of renal functionOften seen as the response to the “prerenal

state”neurohormonal up-regulation, via AT II, aldosterone

Na retention, vasopressin H2O resorptionrenin release @ macula densa -> direct Na resorption

and intrarenal vasoconstriction -> GFR-> filtered load of Na and H20 -> Kidney respond w/ vasoconstriction @ afferent arterioles -> RBF -> neurohormonal cascade again

CVP, renal venous pressure -> intracapsular pressure - > GFR

Ultrafiltration: UNLOAD Study At 48h, weight loss greater in UF group than

diuretic group At 48h, dyspnea scores similar between

groups At 90 d, 44% reduction in percentage of pts

rehospitalized for HF in UF group compared to diuretic group

No difference in Cr between groups at 48h or at 90 days

Baseline diuretic dose was not doubled in the standard care arm within the first 24 hrs. as mandated by the trial, and so this group may have received less effective treatment, decongestion, and weight loss.

Costanzo, MR et al. J Am Coll Cardiol 2007;49:675.

UNLOAD“Early use of UF may allow more control of the

circulating mass with effective neurohormonal purification and of all the inflammatory mediators” Claudio Ronco. Heart Fail Rev 2010

But…Do we risk putting patients on anticoagulation to achieve

diuresis and natriuresis?Must consider the risk of acute kidney injury with UF.Cost—$14,000 per device and over $900 per filter, which

needs to be replaced every 24hFurther trials may show that the cost-benefit when

taking into account HF hospitalizations, ED visits, etc. favors UF

For now, we use UF as a last resort. No conclusive data to demonstrate improvement in CHF outcomes.

RECOMMENDATION FOR USE OF UF IN HEART FAILURE Class IIa recommendation from the ACC/AHA: Ultrafiltration is

reasonable for patients with refractory congestion not responding to medical therapy. (Level of evidence: B)

If volume overload is confirmed, the dose of loop diuretic should be first increased to ensure that adequate drug levels reach the kidney.

If this is inadequate, a second type of diuretic, usually a thiazide or spironolactone can be added.

A third option to consider is continuous infusion of the loop diuretic. If all diuretic strategies are unsuccessful, UF or another renal

replacement modality may be reasonable.

Consultation with a kidney specialist may be appropriate before selecting any mechanical modality to affect diuresis.

2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation 2009;119:1977-2016.

Management: CRS Type 1 Vasodilators and loop diuretics are

widely recommended in cases of ADHF and CRS type 1. However, loop diuretics predispose to electrolyte imbalances and hypovolemia leading to neurohumoral activation, reduced renal glomerular flow with further rises in serum creatinine.

Vasodilators such as nesiritide may also affect kidney function and even exacerbate kidney injury.

Vasopressin 2 antagonists can improve hyponatremia, but without improvement in survival.

If congestion occurs with low blood pressure, inotropic agents should be considered.

Extracorporeal ultrafiltration may be helpful in ADHF associated with diuretic resistance.

Depending on the cause and setting, left ventricular assist devices as a bridge to transplant or surgery may be appropriate.

Overtreatment with loop diuretics, ACEi, and/or spironolactone may induce AKI.


• Meta-analysis of RCTs to assess risk of worsening renal function with nesiritide– Increase in serum Cr

>0.5mg/dL• 5 RCTs, 1269 pts• Results = Nesiritide

significantly increased risk of worsening renal function compared with non-inotrope based controls and all controls at all infusion rates

A and B = Nesiritide < 0.03 ug/kg/mC and D = Nesiritide < 0.015 ug/kg/mE and F = Nesiritide < 0.06 ug/kg/m

ASCEND-HF

7,000 pts, 300 centersNesiritide vs placebo, with standard of care (including

IV nitro and diuretics) w/in 24hrs of admission.1 – 7 days Rx, ave. 40 hoursNo significant difference in 30 day readmission or

deathOnly 4.7% mortality, 10% total endpoints

Slight ↓in SOB at 6 hrs. and 24 hrs – no statistical sig.NO DECLINE in renal functionConfirmed the safety of nesiritide but no definitive

word on usefulness so far.Need subgroup analysis

O’Connor, et al. N Engl J Med 2011; 365:32-43.

Vasopressin AntagonistsV1 receptors: in vasculature mediates VCV2 receptors: in distal nephron mediates

H2O resorptionAntagonism of V1a rec:

↑CO↓PVR↓MAP↓AVP mediated cardiomyocyte hypertrophy

Antagonism of V2 rec:Aquaresis/free water clearance↓ urine osm↑ serum Na

Lemmens-Gruber, Kamyar, Cell Mol Life Sci 2006;63:1766-79

Vasopressin AntagonistsTolvaptan:

Approved for treating hyponatremia, and is an option not routinely used Initial studies very promising↑ UOP↓ urine osm↓ urine Na concNo change in renal fn or BP↓ furosemide use↓ body weight

BUT…EVEREST trial> 4000 pts and All of above achievedYou see early benefit in dyspnea on day 1 and edema/weight on

day 7, but no benefit on heart failure hospitalization or mortality. The cost for 30 days is close to $6000.

NO overall benefit (need sub-group analyses and more trials)? Timing, ? Length of Rx, ? DoseMost useful in pts with high Copeptin levels? Gheorghiade et al. Circ 2003;107:2690-96

Gheorghiade et al. JAMA 2004;291(16):1963-71Gheorghiade et al. JAMA 2007 (12):1332-43

Management: CRS Type 2 Therapy of CHF with concomitant

renal impairment is not evidence-based, as these patients are usually excluded from CHF trials.

Patients are usually hypervolemic, and more intensive diuretic treatment is needed.

Loop diuretics are preferred, but thiazides may improve diuresis during diuretic resistance.8

Diuretic infusions may be more effective than bolus doses, and can be combined with amiloride, aldosterone antagonists, or metolazone.

Increasing doses of diuretics associated with worse outcomes.

In refractory cases, renal replacement therapy may be needed.

ACEi and ARB initiation may cause deterioration in renal function, which is usually transient and reversible. Patients with CKD or renal artery stenosis are at higher risk and need careful monitoring. Hyperkalemia may occur and dietary restriction of potassium may be needed.

Anemia is often present and correction may improve symptoms.


High CVP: Poor Prognosticator for Worsening Renal Failure in CHF

High CVP on admission and after intense medical therapy was associated with WRF and overall outcome

WRF occurred less when CVP of < 8 achieved

Ability of CVP to stratify risk was independent of HR, PCWP, SBP, CI and SPAP

Baseline CI was actually better in those who developed WRF

“Congestive Kidney Failure”?

Mullins et al. JACC 2009; 53:589-96Damman et al. JACC 2009; 53:582-88

CVP CI

SBP PCWP

High vs low dose IV furosemide From ADHERE registry:

< 160 mg/day of IV furosemide -> hospital mortality, instances of WRF, ICU utilization, and shorter hospitalization then patient's treated with high-dose IV loop diuretics.

Initiation of dialysis occurred less often in low-dose admissions although did not exceed 2% in any cohort

Furosemide in ADHF:Bolus Dose vs Continuous Infusion

8 randomized controlled trials, 254 patientsUrine output greater with continuous infusion

(+271cc/24h, p<0.01)Electrolyte disturbances not significantly

different between the two groups (p=0.5)Less adverse effects (tinnitus, hearing loss) with

continuous infusion (p=0.005)Hospital stay shortened by 3.1d (p<0.0001) and

cardiac mortality reduced (p<0.0001) with continuous infusion based on single study

All-cause mortality reduced based on 2 studies (p<0.0001)

Cochrane Database Syst Rev 2004;1:CD003178..

Management: CRS Type 3

Prevention of contrast nephropathy: - Isotonic fluids - N-acetylcysteine?1

1. Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

Management: CRS Type 4

Cardioprotection for patients with CKD by using ACEi and/or beta blockers, including those on dialysis

Maintenance of fluid and sodium balance in order to prevent volume overload

Correct anemia

Minimize vascular calcification


ACEI/ARB/Renin InhibitorsInclination is to stop them with renal

insufficiency/failureMost troublesome in the setting of

“overdiuresis” or poor renal perfusionelderlyHyperkalemiaIn the setting of contrast agents

Allow for 30% increase in creatinine

ACEI/ARB/Renin InhibitorsReverse vasoconstriction, ↓intraglomerular pressure

and reduce aldosterone mediated sodium retention – therefore should be ideal.

Well established role of renoprotective effects in DM2Most CHF trials are underpowered to assess and/or do

not have enough info on renal function or outcomeMinnesota Heart Study (2000)

2009 - restrospective look at ACE/ARBIf GFR < 15 ml/min, pts were far less likely to get

them (50% vs 65% if GFR > 90)OR of 1 year mortality 0.72 if DC’d on oneOR of 30 day mortality 0.45 if given in hospital

Berger, et al. Am Heart J 2007;153:1064-73

β-Blockers

SNS: β1 – myocardial VC, renin releaseΒ2 – RV vasodilation1 - systemic and RV VC

CKD and CHF overstimulation of SNSStill underutilization w/ CKDCarvedilol – better tolerated due to vasodilating properties

from α blockade, and nonselective blockadeAgain…most large studies excluded pts with significant renal

disease, when used, show ↓in CV events, ↓ in albuminuriaAvoid in decompensated HF, but otherwise push to high

doses

Anemia Prevalence by CKD Stage

69

*NHANES participants aged ≥20 y with anemia as defined by WHO criteria: hemoglobin (Hgb) <12 g/dL for women, and Hgb <13 g/dL for men. USRDS 2004 Annual Data Report. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. Available at: www.usrds.org. Accessed 3/28/05.

Patie

nts W

ith A

nem

ia*

(%)

NHANES IIINHANES 1999-2000

CKD Stage

AJKD Volume 34, Issue 1, 125-134, July 1999

Major Trials of StatinsEarly trials which began to show benefit of statins

Scandinavian Simvastatin Survival Study (4S) supported the use of statins in secondary prevention for cardiovascular disease (Lancet 1994) Pts with elevated LDLs and h/o CAD with LDL reduction from

simvastatin had reduced recurrent cardiovascular eventsThe Heart Protection Study (HPS), which showed

preventative effects of statin use in specific risk groups, such as DM, CAD, other vascular disease, showed reduction in mortality w simvastatin (Lancet 2002)

Most recently the JUPITER trial (NEJM 11/20/08) showed in patients with LDL less than 130 and only elevated CRP, reduction in rates of mi, stroke, or combined endpoint of MI, stroke and death

And many others which examine the role of statin for primary and secondary prevention as well as post MI

Major Statin Trials in CKD?

Many of these trials tend to exclude patients w CKD and transplant patients, despite the fact that ~50% of transplant patients are on statins

Subgroup analysis of the Heart Protection Study and Anglo Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) and Cholesterol and Recurrent Events (CARE) study, did show mortality benefit in patients w mild renal insufficiency

But can this data be applied to CKD and transplant patients for secondary and even primary prevention?

?

The Risks of Calcification

Go Much Deeper than Lumen

Copyright ©2008 American Society of Nephrology

Moe, S. M. et al. J Am Soc Nephrol 2008;19:213-216

Mechanisms of Vascular Calcification

New Strategies for Management

Biomarkers 1

B-type Natriuretic Peptides (BNP and NT-proBNP) Copeptin Fibroblast Growth Factor 23 (FGF – 23) Neutrophil Gelatinase-associated

Lipocalin (NGAL): Cystatin C Kidney Injury Molecule-1 (KIM-1) N-acetyl-B-(D)glucosaminidase Interleukin-18 (IL-18) Bioimpedance Vector Analysis (BIVA) Imaging

Treatments 1,2,3

Furosemide and hypertonic saline (HTS)

Vasopressin antagonists

Adenosine receptor antagonists

Cardiac resynchronization with AICD

Ultrafiltration1. Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

2. House AA, et al. Am J Kid Dis 2010;56:759-773.

3. Chan EJ, Dellsperger KC. Cardiorenal syndrome: the clinical cardiologists’ perspective. Cardiorenal Med 2011;1:13-22.

BNP-guided treatment of CHF

Trials are small and Underpowered

Still not recommended in CHF guidelines

BNP in renal failure

Maisel, et al, ADQI consensus group. Nephrol Dial Transplant 2010. Editorial Review

Cardiac Biomarkers in CRSVan Kimmenade R, et al. JACC 2006;48:1621

• ICON study: NT-pro BNP > 4,647 (mean) and GFR < 60: best predictor of mortality– OR 3.46, accounted for vast

majority of deaths– Those with GFR <60, but ↓NT-

proBNP had 60-day outcomes comparable to those without renal insufficiency

– Those with creat rise: had increase risk if NT-pro BNP levels were above the mean

– Is NT-pBNP better marker of “cardio-renal syndrome”?

Copeptin (CT-proAVP)

Copeptin (C-terminal pro-vasopressin)Stable in serum or plasma, therefore easily

measuredIs it a better marker for mortality and

morbidity in pts with acute HF after AMI?Stronger predictor t of M&M than BNP and

NT-proBNPHigher in pts with decreasing renal fn

Voors, et al. Eur Heart J 2009;30:1187-94Morgenthaler. Cong Heart Fail 2010;16(4) (suppl 1)s37-44

Can levels guide therapy…? VP antagonists

Copeptin in Heart Failure

AVP contributes to LV dysfunction

Aggravates LV wall stress

Stimulates LVHWorsens remodelingStrong correlation

btwn Copeptin levels and mortality

Copeptin & BNP added to risk stratification

Neuhold, et al JACC. 2008;52:26672

Cystatin C

Cysteine protease inhibitorLevels not affected by age, gender, race, diet,

muscle massBetter measure of glomerular function than

creatinineCorrelates well with NT-pro BNP levelsTn T, NT-pro BNP and cysC give complementary

prognostic information in acute HFDetects decline in renal fn within 48 hours

Rise of > 0.3mg/L longer hospitalization, higher in-house mortality, independent predictor of survival during follow-up

Manzano-Fernandez et al. Am J Cardiol 2009;103: 1753-9Linzbach S, et al. Am J Cardiol 2009;103:1128-33

Cystatin C

FINN-AKVA StudyCRS type 1 patients>0.3mg/L rise in cysC

occurred w/in 48 hrs in 16% Extended

hospitalization 3 daysOR 4 for in-house

deathOR 2.8 for 90 day

mortality

Lassus J, et al. Eur Heart J 2010;31:2791-98

CysC >0.1mg/L

CysC >0.3mg/L

CysC > 0.5mg/L

Cystatin C and Creatinine

With 0.2 mg/dL rise in creat and 0.3mg/L rise in cysC, mortality 44.8% at 90d

Cystatin C and NT-pro BNP

Furosemide and HTS

Theory:Offsets the counterproductive neurohormonal up-

regulationtransiently improves hemodynamicspromotes renal Na extraction with accompanied net

water loss and preservation of renal function

Seems counterintuitive, but in a way, it is “giving the body the very sodium it is trying so hard to retain”

Liszowski, Curr Heart Fail Rep. 2010;7:134-39

Furosemide and Hypertonic Saline

↑ natriuresis and diuresisResults maintained over time , when continuing PO

diuretic therapy and low Na (but not restricted) diet

Better survival at 48 months (55 vs 13%)Allows more rapid attainment of dry weightFaster in BNP (↓ BNP maintained with higher Na

diet)Lower LOS and 30 day readmission rate.Improvement in renal fnNo adverse cardiac eventsUS and Brazil w/ ongoing

large studies now

Paterna, et al. Eur. J Heart Fail 2000;2:305-13Paterna et al. Clin Drug Interact; 25:165-174Paterna et al.JACC 2005;45:1887-2003Licata et al. Am Heart J 2003;145;459-66

Adenosine Receptor Antagonists

A1, A2 and A3 receptorsAdo levels are increase in HFAdo activity is mediated by neurohormonal systems, renal

nervous system, and Ado can alter levels of NO and vasodilators

A1 Receptor activation ↓eGFR glomerular arteriolar VC Na reabsorption in prox and distal tubules (TG feedback) ↓ Renin secretion

A2 Receptor ActivationVasodilation↑renal medullar blood flow

Ideal therefore to have A1 Receptor blockade and allow A2 activity ↑ UOP and preservation of eGFR

Nodari. Heart Fail Rev. online 12/7/10Vallon et al.Physiol Rev. 2006;86:901-40Marraccini et al.Cardiovasc Res. 1996;32:949-53Kuan et al.J Cardiovasc Pharmachol.1993;21:822-28

CRT with Impaired Renal FunctionInitial cohort data suggests that pts w/significant

reverse remodeling after CRT showed improved renal fn. and survival

In only 85 pts though…those w/ no significant reverse remodeling had higher baseline eGFRFung, Int J Cardiol 2007;122:10-16

MIRACLE substudy: all groups (eGFR 30–60, 60–90 and > 90) derived

benefit from CRT EF and LV volumesAgain… in LVESV best in patients w/ eGFR > 90,

and worst in GFR 30 – 60. Boerrigter, J Card Failure 2008;14:539-46

CRT with Impaired Renal Function

Feb. 2011 JACC: 490 pts undergoing CRT

CHF pts with mod – severely reduced renal fn (eGFR< 60) as compared to those with normal or mildly reduced renal fn (eGFR > 60), showed worse response to CRT Van Bommel, et al. JACC 211: 57;549-555

CRT with Impaired Renal Function

GFR < 60 had higher mortality than if GRF 60 – 90, or > 90Only 43% in low GFR

group were responderseGFR remained a very

strong predictor of survival after CRT

CRT responders had higher baseline GFR

CRT responders also had preservation of renal fn, nonresponders had slight decline (only a subset of 133 pts).

CRT with Impaired Renal FunctionCan this data help us determine who will

respond to CRT or if CRT is indicated?With or without AICD?If high venous pressures cause renal dysfunction–

then can we prevent renal failure with improvement in LV synchrony? Or…does the high CVP override the benefit? Impaired renal fn is associated with more MR, lower EF Improvement in renal fn is likely due to EF, MR, SBP,

CVPWere “non-responders” actually “responders” as

their renal fn could have declined without CRT?

Integrated Strategies for Both Cardiology and Nephrology

Recognize the cardiorenal syndromeTreat the whole patientTreat for the long-termOptimize heart failure therapy so that renal function is preservedConsider new approaches to diuretic infusion or combination therapy that

may reduce the degree of renal dysfunctionConsider vasodilators for use in the appropriate setting to improve

transrenal blood flow while protecting renal functionConsider newer approaches such as ultrafiltration, vasopressin antagonists

and adenosine receptor blockade for improving volume regulation while preserving renal and cardiac function

Harbir KR, Gupta RS, Singh SR. Challenge of renal protection in acute decompensated heart failure. http://www.apicon2011.org/HTMLPages/12.htm.last accessed November 1, 2011.

http://www.apicon2011.org/HTMLPages/12.htm

Post-program Questions to Consider

What is cardio-renal syndrome?

Which patients are at risk of developing cardio-renal syndrome?

What are treatment strategies for cardio-renal syndrome?

Thank You

Health & Medicine

Cardio renal care-An integated best Practice Approch