CardiorenalSyndrome: Prevention and Management€¦ · [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1 12/1/17 CardiorenalSyndrome: Prevention and Management

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Cardiorenal Syndrome: Prevention and Management

Van N Selby, MDUCSF Advanced Heart Failure ProgramDecember 1, 2017

Disclosures: None

Objectives

§Define cardiorenal syndrome (CRS)§Understand the pathophysiology of CRS§Review current strategies for the prevention and treatment of CRS

Cardiorenal Syndrome

A pathophysiologic disorder of the heart and kidneys

whereby acute or chronic dysfunction in one organ may

induce acute or chronic dysfunction in the other organ

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


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Heart-kidney Interactions

§A bidirectional relationship• The heart is directly dependent on regulation of salt and

water by the kidneys• The kidneys are dependent on blood flow and pressure

generated by the heart

§The effects can be both acute and chronic§Mortality is increased in HF patients with a reduced

glomerular filtration rate (GFR)§Acute or chronic systemic disorders can cause both

cardiac and renal dysfunction

Cardiorenal Syndrome Classification

§Type 1: Acute HF resulting in acute kidney injury

§Type 2: Chronic HF causing progressive kidney disease

§Type 3: Abrupt, primary worsening of kidney function causing acute cardiac dysfunction/HF

§Type 4: Primary CKD contributing to cardiac dysfunction (iecoronary disease, HF, arrhythmia)

§Type 5 (secondary): Systemic disorders that cause both cardiac and renal dysfunction

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

Epidemiology of CRS§30-60% of HF patients have CKD (eGFR < 60 mL/min/1.73 m2)

§ADHERE: Only 9% of patients had normal GFR• 20-30% of patients had a rise in serum creatinine > 0.3 mg/dL

• Risk factors include DM, admission creatinine > 1.5 mg/dL, uncontrolled hypertension

§Renal dysfunction is associated with 2-fold increase in mortality§Type I CRS:

• The rise in serum creatinine usually occurs within 5 days of admission

• ADHF, post-MI, post-cardiac surgery

• Associated with increased LOS, readmissions, and post-discharge mortality

- Smith GL et al, JACC 2006- Heywood JT J Card Fail 2007

Diagnosis of CRS§Usually based on the serum creatinine

• Caution in older, sicker patients

• Most eGFR equations assume the serum creatinine concentration is stable

§ In those with HF and reduced GFR, one must distinguish underlying kidney disease from impaired function related to CRS• Proteinuria

• Active sediment

• Small kidneys on imaging

• None of these can rule out intrinsic kidney disease

§BUN/Cr often used for diagnosis, but should not be used to decide regarding diuretics

§Urine sodium concentration < 25 is more consistent with HF


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Pathophysiology of CRSHemodynamic

⬇systemic perfusion → ⬇ renal blood flow (RBF)Impaired intra-renal autoregulationé central venous pressure (CVP) and intraabdominal

pressure →é renal venous pressure (RVP)

Non-hemodynamicé SNS, RAAS, AVP activation →impaired intra-renal

autoregulationé systemic inflammation →cytokine release and intra-

renal vasculature endothelial dysfunction

GFR Regulation in HF

Cody RJ et al. Kidney International. 1988; 34: 361-367.

34 pts with HF, off meds, multiple hemodynamic and neurohormonal parameters assessed

What accounts for variability in GFR: RBF 69%, FF 25%

CRS Pathophysiology

Damman K et al. Eur Heart J. 2014; 35: 3413-3416.

Hemodynamics and CRS Type I

Mullens W et al. J Am Coll Cardiol. 2009; 53: 589-596.

CVP was a better predictor of low GFR on discharge than CI


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CRS: Glomerular factors

the RIFLE criteria. It is only associated with substantially higher mor-tality rates in the absence of relief of congestion and improvement inHF status. Moresevere formsofAKI (stage2 or3) are rare in acute HFbut if these do occur, prognosis is poor and intensive care manage-ment, including renal replacement therapy is often required.

So, where do we go from here? Specifically, we caution the exten-sion of RIFLE/AKIN/KDIGO AKI definitions to include patientsexperiencing a rise in serum creatinine during successful treatment

of acute decompensated HF, at least in the absence of subjective evi-dence of significant renal injury or failure. In many ways, cardiologistsand nephrologists may be treating two distinct but interacting condi-tions that are simplistically defined by the same biomarker changes.We should also acknowledge that changes in creatinine that occurin HF often have a different cause than AKI described in nephrologyguidelines. Acute kidney injury in patients with renal disease isthe direct consequence of the disease, while in HF the cause of

Figure1 Factors involved in the cause and association with an outcome of changes in renal function in heart failure. (A) Organ-specific factors. Themain determinants of decreased glomerular filtration rate are adecrease in renal blood flowand an increase in central and renal venouspressure. Thelatter can be caused by intravascular congestion, but also by an increase in intra-abdominal pressure. Owing to increased renal venouspressure, renalinterstitial pressure rises, which results a ‘congested kidney’ since the kidney is encapsulated (B and C). Renal artery stenosis is present in !25% ofheart failure patients, which can further compromise renal blood flow, especially in the presence of renin–angiotensin–aldosterone system inhibi-tors. (B)Glomerular factors.Decreased renalbloodflowand lowbloodpressure trigger renal autoregulation, preserving glomerular filtration ratebyincreasing filtration fraction by increased efferent vasoconstriction. The use of renin–angiotensin–aldosterone system-inhibitors inhibits thisprocess,which increases renal blood flow, but leads (in some patients) to a reduction in glomerular filtration rate (pseudo-worsening renal function).Non-steroidal anti-inflammatory drugs inhibit prostaglandin synthesis, thereby impairing prostaglandin associated increase/dependent renal bloodflow. Increased interstitial pressure causes increased pressure in Bowman’s capsule, which directly opposes filtration, in a glomerulus where thefiltration gradient is already low due to a decreased renal blood flow and increased renal venous pressure. Concomitant diseases have direct,but differential effect on glomerular filtration, glomerular integrity and podocyte function, as well as autoregulation. (C ) Nephronic factors. Differenttherapies have different renal effects and exert their action at specific sites as indicated in this diagram. Intravascular volume depletion (in the pres-ence or absence of congestion) can lead to impaired renal perfusion and decreased glomerular filtration rate. The combination of increased inter-stitial pressure, reduced arterial perfusion, concomitant disease and therapies can cause tubular and glomerular injury. Increased renal venouspressure causes increased renal interstitial pressure, resulting in collapsing of renal tubules, which decreases glomerular filtration rate, and eventuallyleads to decreased urine output, sodium retention, and congestion. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptorblocker; FF, filtration fraction; GFR, glomerular filtration rate; MRA, mineralocorticoid receptor antagonist; NSAIDs, non-steroidal anti-inflammatory drugs; RAAS, renin–angiotensin–aldosterone system; RBF, renal blood flow.

K. Damman et al.3414

by guest on October 8, 2015

http://eurheartj.oxfordjournals.org/D

ownloaded from


CRS: Nephron-specific factors


Hemodynamic Profile in CRS Type ICongestion at Rest

LowPerfusionat Rest

• Discordantly ê RBF• Intra-renal microvascular

dysregulation

Warm & Dry Warm & Wet

Cold & Wet

NO

NO YES

YES

Cold & Dry

• Discordantly ê RBF• Impaired intra-renal

autoregulation• Renal v. pressure é

• ê RBF• Impaired intra-renal

autoregulation

• ê RBF• Impaired intra-renal

autoregulation• Renal v. pressure é

Stevenson LW et al. JAMA. 1989; 261: 884-888.

Intra-abdominal Pressure and GFR

Mullens W et al. J Am Coll Cardiol. 2008; 51: 300-306.


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Non-hemodynamic factors in CRS

§Modulation of RAAS

• Angiotensin II promotes renal fibrosis, causes SNS activation

§ Inflammation/oxidative stress§Endothelial dysfunction

§Humoral/cellular immunity

§Anemia

Prevention and treatment of CRS

§Manage volume appropriately

• Diuretics

• Vasopressin antagonists• Inotropes/Dopamine

• Ultrafiltration

§Maintain RBF and FF• Constant plasma refill rate

• Avoid excessive intra-renal vasodilation or vasoconstriction

Diuretic Strategies in CRS

Jentzer JC et al. J Am Coll Cardiol. 2010; 56: 1527-1534.

Diuretic Resistance

Brater DC. N Engl J Med. 1998; 339: 387-395.

“Braking” phenomenon•Decrease in response to diuretic after the first dose givenLong-term tolerance•Tubular hypertrophy to compensate for salt loss

Post-diuretic NaCl retentionDiuretic malabsorption•GI edemaReduced GFRAldosterone antagonism


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Diuretics increase neurohormonal activation

Plas

ma

Reni

n A

ctiv

ity (n

g/m

L/h)

Before Diuretic(n = 12)

After Diuretic(n = 11)

50

10

2.5

0.5

Plas

ma

Ald

oste

rone

(pm

ol/L

)

Before Diuretic(n = 12)

After Diuretic(n = 11)

1000

600

200

100

Mean (95% CI)Mean

(95% CI)

Bayliss J, et al. Br Heart J 1987

Diuretics: DOSE HF

Felker GM et al. N Engl J Med. 2011; 364: 797-805.

Diuretics: DOSE HF

Felker GM et al. N Engl J Med. 2011; 364: 797-805.

Low High p valueDyspnea VAS AUC at 72 hrs 4478 4668 0.041% free from congestion at 72 hrs 11% 18% 0.091Change in weight at 72 hrs -5.3 lbs -8.2 lbs 0.011Net volume loss at 72 hrs 3575 mL 4899 mL <0.001% Treatment failure 37% 40% 0.56% with Cr > 0.3 mg/dL at 72 hrs 14% 23% 0.041Length of stay, days (median) 6 5 0.55

§High dose better efficacy, more worsening Cr§No difference bolus vs. drip

Management of CRS: Tolvaptan§ Inappropriate elevation of arginine vasopressin plays a key role in

mediating water retention

§Tolvaptan is a small molecule antagonist of the V2 receptor

§Compared to furosemide:• Similar effect on urine output• No effect on electrolytes or osmolality

• Preserves renal blood flow• Less neurohormonal activation

§ Improves hemodynamics (RAP, PCWP, CI, SVR)


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Tolvaptan in acute HF: EVEREST

§The EVEREST trial randomized 4133 patients hospitalized for heart failure to tolvaptan vs placebo in addition to standard therapy for HF

§No effect on the co-primary outcomes of all-cause mortality or cardiovascular death or hospitalization for heart failure

Konstam MA et al. JAMA. 2007; 297: 1332-1343.

Change in Global Clinical Status During Hospitalization: EVEREST

Konstam MA et al. JAMA. 2007; 297: 1332-1343.

Treatment of CRS: DopamineP. Varriale and A. Mossavi: Low-dose dopamine during diuresis for CHF 629

2.5 GrouPA Group B Group A GroupB 50 45

8 40 2 7 35 E 30

5 15 G 10 0.5 m 5

0

g 1.5 E

V 2 22;

Group A Group B r GroupA Group B T T h 2.5 T

FIG. 1 Serum blood urea nitrogen (BUN) (mgldl), serum creatinine (mg/dl), calculated corrected creatinine clearance (mlhin), and indexed urinary output (mvkgpn) for Group A and Group B patients. * p = <0.05, + p = NS. = Baseline, = after treatment.

Blood Urea NitrogedCreatinine Ratio output. As a result, an overlap in receptor activation may occur within this lower dosage range. It is problematic, therefore, whether this dose-dependent increase in renal blood flow is exclusively dopaminergic in origin or is due to combined dopaminergic and adrenergic activation without direct mea- surement of cardiac output.”- 29-31

Advocates of low-dose dopamine who favor its putative

In Group A patients, the ratio increased from 17.9 at baseline to 24.5 (NS) after therapy; in Group B patients, the ratio decreased from 24.8 at baseline to 21.5 (NS) after therapy.

Adverse Effects

In Group B patients who received IV dopamine, blood pressure remained unchanged in eight patients and was only slightly elevated in two patients (< 10% of control); heart race declined modestly in seven patients (< 10 beats) and increased slightly in three patients (< 10% of control heart rate). Cardiac arrhythmias were not observed during drug infusion.

Discussion

Evidence from both human and experimental animal studies has demonstrated a direct renal vasodilatation in response to low-dose dopamine (0.5-3 pg/kg/min) that increases renal blood flow, glomerular filtration rate, and urinary output.20, 23-25 A renal vasodilatory response to low-dose dopamine, although to a lesser extent, is also observed in patients with chronic renal impairment.26 The pharmacodynam- ic action of low-dose dopamine responsible for intrarenal vasodilatation and enhanced renal perfusion is mediated predominantly through stimulation of peripheral dopaminergic receptors DA-I and DA-2. DA-I receptors are located postsynaptically on the smooth muscle of the renal vasculature. Activation of DA-2 receptors on presynaptic sympathet- ic nerve terminals, causing reduction of norepinephrine release, may also play a role.20, 27, 28

At a low dose of 2.0 pg/kg/min or slightly above (up to 4.0 pg/kg/min), dopamine may also stimulate B1-adrenergic receptors and augment renal perfusion by an increase in cardiac

benefit on renal function have used this agent to attain renal salvage in critically ill patients with either established acute renal failure or at high risk for developing acute renal failure.l0* 14, 19,32 The role of low-dose dopamine in these situ- ations, however, is not clearly defined and mired in contro- versy. Multiple studies, both experimental and clinical, of the ischemic or toxic kidney have not demonstrated unequivocal- ly the efficacy of dopamine in preserving renal function or have spawned conflicting results.11. l3

In this study, we assessed the role of low-dose dopamine (2 pg/kg/min) as arenal-protective agent when used with vigorous IV diuretic therapy for CHF associated with renal insuffi- ciency (mild to moderate) and without oliguria. Ten patients (Group A) receiving an IV loop diuretic (bumetanide 1 mg bid.) were compared with 10 patients (Group B) randomized to low-dose dopamine infusion (2 pg/kg/min) and a similar diuretic regimen. Vigorous IV diuretic therapy over a period of nearly 5 days resulted in a significant increase in urinary output for both treatment groups (Fig. l), symptomatic relief, and clearance of clinical signs of pulmonary-systematic ede- ma. Group B patients who received low-dose dopamine demonstrated significant improvement of renal function. Serum BUN 48.9 f 10.3 declined to 32.1 f 14.4 mg/dl (p<O.O5), serum creatinine 1.97 & 0.24 fell to 1.49 j, 0.39 mg/dl (p < 0.05), and calculated creatinine clearance 35.6 k 11.6 increased to 48.8 k 12.3 mumin (p < 0.05). On the other hand, those patients who received vigorous IV diuretic therapy alone (Group A) showed a nonsignificant worsening of functional

Varriale P et al. Clin Cardiol. 1997 Jul;20(7):627-30.

Dopamine for CRS I: DAD-HF

Giamouzis G et al. J Card Fail. 2010;16:922-930.


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Dopamine for CRS I: DAD-HF


DAD-HF: Conclusions

§Compared to high dose furosemide, the combination of low dose furosemide and dopamine produced similar diuretic effects

§ Incidence of worsening renal function was lower in the dopamine arm


Dopamine in CRS: ROSE-AF

§360 patients hospitalized for acute HF and renal dysfunction randomized to dopamine 2 mcg/kg/min vs placebo

§Overall, there was no significant difference in the co-primary outcomes of total urine volume and cystatic C at 72 hours

§When the results are stratified by blood pressure and LV ejection fraction:

Chen HH et al. JAMA. 2013; 310: 2533-2543.

Ultrafiltration for AHF

§Removal of isotonic fluid from the venous system

• Maintains physiologic electrolyte balance

• More sodium removal compared to diuretics§Ultrafiltration has now been compared to diuretics in multiple

randomized trials

• Mixed results

• Differing study designs/populations


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Ultrafiltration for Acute HF: CARESS-HF

Bart BA. et al. N Engl J Med. 2012 ;367: 2296-2304.

Ultrafiltration in Acute HF: AVOID HF

Costanzo MR. et al. J Am Coll Cardiol HF. 2016; 4: 95-105.

Adjustable UltrafiltrationAdjustable Loop Diuretics

Ultrafiltration: Conclusions

§A strategy of universal UF for patients with AHF has not been clearly shown to reduce the risk of worsening kidney function or improve outcomes

§Current guidelines give a IIB recommendation for UF:

• May be considered for patients with obvious volume overload to alleviate congestive symptoms and fluid weight

• Ultrafiltration may be considered for patients with refractory congestion not responding to medical therapy.

§Logistics including cost, need for veno-venous access, and need for nursing support are considerations

Yancy CW et al, 2013 ACCF/AHA Heart Failure Guidelines

Plasma Refill Rate

Boyle A. J Card Fail. 2006; 12: 247-249.

§ PRR = ECV – U output§ Monitor with the serum Hct. Keep Hgb/ Hct from rising > 3-5% in 8-

12 hrs

§ PRR = ECV – U output


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Timing of Diuresis

Testani JM. Circulation. 2010; 122: 265-272.

◆ Sustained hemoconcentration (after day 3) is associated with better decongestion and outcomes

Renal dysfunction improves after LVAD

Resolution of renal dysfunction

The circulatory improvement rendered by a VAD is at leastpartially effective in reversing cardiorenal syndrome.Consistent with other reports,34–36 we noted dramaticimprovement in the creatinine and eGFR values within1 month. Although some studies report a gradual decline inGFR during the first 6 to 12 months,37,38 our analysisindicates that, on average, survivors with even moderate orsevere renal dysfunction have stable improvement duringthe first 2 years. These observations are consistent withexperimental studies in which animals supported with long-term continuous-flow devices generally maintained normalend-organ function.39,40 The long-term maintenance of renal

Figure 5 Actuarial survival post-implant, stratified by combi-nations of risk factors. The error bars indicate ! 1 standard error.BIVAD, biventricular assist device; BTT, bridge to transplant; DT,destination therapy; IMACS 1, INTERMACS level 1; LVAD, leftventricular assist device.

Figure 6 Time course of average blood urea nitrogen (BUN)among surviving patients at designated follow-up points, stratifiedby severity of pre-implant renal dysfunction (see Materials andMethods for definitions). The error bars indicate ! 1 standarderror. BIVAD, biventricular assist device; BTT, bridge totransplant; DT, destination therapy; LVAD, left ventricular assistdevice.

Figure 7 Time course of average serum creatinine amongsurviving patients at designated follow-up points, stratified byseverity of pre-implant renal dysfunction (see Materials andMethods for definitions). The error bars indicate ! 1 standarderror. BIVAD, biventricular assist device; BTT, bridge totransplant; DT, destination therapy; LVAD, left ventricular assistdevice.

Table 6 Implants: June 2006–March 2012, Adult PrimaryContinuous Flow Left Ventricular Assist Devices and Biventri-cular Assist Devices, Destination Therapy, and Bridge toTransplant (n ¼ 4,917)

Comparison of riskfactors

Severe renal dysfunction

p-value

o 3 monthspost-implant All others(n ¼ 61) (n ¼ 221)

DemographicsAge, years 60.4 62.2 0.27Body mass index,kg/m2

26.3 24.2 0.02

Clinical statusVentilator, % 21.3 9.0 0.01History of stroke, % 3.5 9.3 0.14INTERMACS level 1, % 41.0 22.6 0.004INTERMACS level 2, % 42.6 44.3 0.81Destinationtherapy, %

39.3 40.3 0.90

Non-cardiac systemsDiabetes, % 37.7 45.7 0.27Creatinine, mg/dl 3.0 2.8 0.29Dialysis, % 47.5 25.3 0.0008Blood urea nitrogen,mg/dL

55.5 56.8 0.78

GFR, mg/dl 23.8 24.4 0.51Right heart dysfunction

RVAD in sameoperation, %

13.1 4.5 0.02

Right atrial pressure,mm Hg

19.7 14.4 0.0007

Bilirubin, mg/dL 3.2 1.7 0.03Ascites, % 14.5 16.6 0.72

Surgical complexitiesHistory of cardiacsurgery, %

45.9 39.4 0.36

Concomitant cardiacsurgery, %

44.3 51.4 0.33

GFR, glomerular filtration rate; INTERMACS, Interagency Registry forMechanically Assisted Circulatory Support; RVAD, right ventricularassist device.

Kirklin et al. Effect of Cardiorenal Syndrome After LVAD Implant 1211

Kirklin JK et al. J Heart Lung Transplant. 2013 Dec;32(12):1205-13.

Resolution of renal dysfunction

The circulatory improvement rendered by a VAD is at leastpartially effective in reversing cardiorenal syndrome.Consistent with other reports,34–36 we noted dramaticimprovement in the creatinine and eGFR values within1 month. Although some studies report a gradual decline inGFR during the first 6 to 12 months,37,38 our analysisindicates that, on average, survivors with even moderate orsevere renal dysfunction have stable improvement duringthe first 2 years. These observations are consistent withexperimental studies in which animals supported with long-term continuous-flow devices generally maintained normalend-organ function.39,40 The long-term maintenance of renal

Figure 5 Actuarial survival post-implant, stratified by combi-nations of risk factors. The error bars indicate ! 1 standard error.BIVAD, biventricular assist device; BTT, bridge to transplant; DT,destination therapy; IMACS 1, INTERMACS level 1; LVAD, leftventricular assist device.

Figure 6 Time course of average blood urea nitrogen (BUN)among surviving patients at designated follow-up points, stratifiedby severity of pre-implant renal dysfunction (see Materials andMethods for definitions). The error bars indicate ! 1 standarderror. BIVAD, biventricular assist device; BTT, bridge totransplant; DT, destination therapy; LVAD, left ventricular assistdevice.

Figure 7 Time course of average serum creatinine amongsurviving patients at designated follow-up points, stratified byseverity of pre-implant renal dysfunction (see Materials andMethods for definitions). The error bars indicate ! 1 standarderror. BIVAD, biventricular assist device; BTT, bridge totransplant; DT, destination therapy; LVAD, left ventricular assistdevice.

Table 6 Implants: June 2006–March 2012, Adult PrimaryContinuous Flow Left Ventricular Assist Devices and Biventri-cular Assist Devices, Destination Therapy, and Bridge toTransplant (n ¼ 4,917)

Comparison of riskfactors

Severe renal dysfunction

p-value

o 3 monthspost-implant All others(n ¼ 61) (n ¼ 221)

DemographicsAge, years 60.4 62.2 0.27Body mass index,kg/m2

26.3 24.2 0.02

Clinical statusVentilator, % 21.3 9.0 0.01History of stroke, % 3.5 9.3 0.14INTERMACS level 1, % 41.0 22.6 0.004INTERMACS level 2, % 42.6 44.3 0.81Destinationtherapy, %

39.3 40.3 0.90

Non-cardiac systemsDiabetes, % 37.7 45.7 0.27Creatinine, mg/dl 3.0 2.8 0.29Dialysis, % 47.5 25.3 0.0008Blood urea nitrogen,mg/dL

55.5 56.8 0.78

GFR, mg/dl 23.8 24.4 0.51Right heart dysfunction

RVAD in sameoperation, %

13.1 4.5 0.02

Right atrial pressure,mm Hg

19.7 14.4 0.0007

Bilirubin, mg/dL 3.2 1.7 0.03Ascites, % 14.5 16.6 0.72

Surgical complexitiesHistory of cardiacsurgery, %

45.9 39.4 0.36

Concomitant cardiacsurgery, %

44.3 51.4 0.33

GFR, glomerular filtration rate; INTERMACS, Interagency Registry forMechanically Assisted Circulatory Support; RVAD, right ventricularassist device.

Kirklin et al. Effect of Cardiorenal Syndrome After LVAD Implant 1211

Conclusions

§Cardiorenal syndrome (CRS) is common among heart failure patients and is associated with worse prognosis

§CRS is multifactorial

• Volume, venous pressures, and intra-abdominal pressures• Cardiac output

• Intra-renal hemodynamics

• Treatment-related mismatch

Conclusions

§Treatment of CRS requires careful management of volume status

• Diuretics (can worsen neurohormonal activation)

• Consider tolvaptan, particularly in hyponatremic patients• Ultrafiltration for those with massive volume overload or

refractory to diuretics

• Aim for slow, sustained hemoconcentration to keep the plasma refill rate constant


12/1/1711

Thank you

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CardiorenalSyndrome: Prevention and Management€¦ · [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 1 12/1/17 CardiorenalSyndrome: Prevention and Management