Cardiorenal Syndrome: Prevention and Management Disclosures: None

Van N Selby, MD UCSF Advanced Program December 1, 2017

Objectives Cardiorenal Syndrome

§Define cardiorenal syndrome (CRS) A pathophysiologic disorder of the heart and kidneys §Understand the pathophysiology of CRS whereby acute or chronic dysfunction in one organ may §Review current strategies for the prevention and induce acute or chronic dysfunction in the other organ treatment of CRS

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

1 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Heart-kidney Interactions Cardiorenal Syndrome Classification

§A bidirectional relationship § Type 1: Acute HF resulting in • The heart is directly dependent on regulation of salt and § Type 2: Chronic HF causing progressive water by the kidneys § Type 3: Abrupt, primary worsening of kidney function causing • The kidneys are dependent on blood flow and pressure acute cardiac dysfunction/HF generated by the heart § Type 4: Primary CKD contributing to cardiac dysfunction (ie §The effects can be both acute and chronic coronary disease, HF, ) §Mortality is increased in HF patients with a reduced § Type 5 (secondary): Systemic disorders that cause both cardiac glomerular filtration rate (GFR) and renal dysfunction §Acute or chronic systemic disorders can cause both cardiac and renal dysfunction

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

Epidemiology of CRS Diagnosis of CRS § Usually based on the serum creatinine § 30-60% of HF patients have CKD (eGFR < 60 mL/min/1.73 m2) • Caution in older, sicker patients § ADHERE: Only 9% of patients had normal GFR • Most eGFR equations assume the serum creatinine concentration is • 20-30% of patients had a rise in serum creatinine > 0.3 mg/dL stable • Risk factors include DM, admission creatinine > 1.5 mg/dL, § In those with HF and reduced GFR, one must distinguish uncontrolled underlying kidney disease from impaired function related to CRS § Renal dysfunction is associated with 2-fold increase in mortality • Proteinuria § Type I CRS: • Active sediment • The rise in serum creatinine usually occurs within 5 days of • Small kidneys on imaging admission • None of these can rule out intrinsic kidney disease • ADHF, post-MI, post-cardiac surgery § BUN/Cr often used for diagnosis, but should not be used to • Associated with increased LOS, readmissions, and post-discharge mortality decide regarding § Urine sodium concentration < 25 is more consistent with HF - Smith GL et al, JACC 2006 - Heywood JT J Card Fail 2007

2 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Pathophysiology of CRS GFR Regulation in HF

Hemodynamic ⬇systemic perfusion → ⬇ renal blood flow (RBF) Impaired intra-renal autoregulation é central venous pressure (CVP) and intraabdominal pressure →é renal venous pressure (RVP) Non-hemodynamic é SNS, RAAS, AVP activation →impaired intra-renal autoregulation é systemic inflammation →cytokine release and intra- renal vasculature endothelial dysfunction 34 pts with HF, off meds, multiple hemodynamic and neurohormonal parameters assessed What accounts for variability in GFR: RBF 69%, FF 25%

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

CRS Pathophysiology Hemodynamics and CRS Type I

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

Damman K et al. Eur Heart J. 2014; 35: 3413-3416. Mullens W et al. J Am Coll Cardiol. 2009; 53: 589-596.

3 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3414 K. Damman et al.

CRS: Nephron-specific factors CRS: Glomerular factors Downloaded from http://eurheartj.oxfordjournals.org/

Figure 1 Factors involved in the cause and association with an outcome of changes in renal function in heart failure. (A) Organ-specific factors. The main determinants of decreased glomerular filtration rate are a decrease in renal blood flowand an increase in central and renal venous pressure. The lattercan be caused by intravascular congestion, but also by an increase in intra-abdominal pressure. Owing to increased renal venous pressure, renal

Damman K et al. Eur Heart J. 2014; 35: 3413-3416. Damman K et al. Eur Heart J. 2014; 35: 3413-3416. by guest on October 8, 2015 interstitial pressure rises, which results a ‘congested kidney’ since the kidney is encapsulated (B and C). is present in 25% of ! heart failure patients, which can further compromise renal blood flow, especially in the presence of renin–angiotensin–aldosterone system inhibi- tors. (B)Glomerular factors. Decreased renalblood flowand lowblood pressuretrigger renal autoregulation, preserving glomerular filtrationrateby increasing filtration fraction by increased efferent vasoconstriction. The use of renin–angiotensin–aldosterone system-inhibitors inhibits this process,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 blood flow. Increased interstitial pressure causes increased pressure in Bowman’s capsule, which directly opposes filtration, in a glomerulus where the filtration 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. Different therapies 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 venous pressure causes increased renal interstitial pressure, resulting in collapsing of renal tubules, which decreases glomerular filtration rate, and eventually leads to decreased urine output, sodium retention, and congestion. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; 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.

the RIFLE criteria. It is only associated with substantially higher mor- of acute decompensated HF, at least in the absence of subjective evi- tality rates in the absence of relief of congestion and improvement in dence of significant renal injury or failure. In many ways, cardiologists HF status. Moresevereforms of AKI (stage2 or 3) arerare in acute HF and nephrologists may be treating two distinct but interacting condi- Hemodynamicbut if these do occur, prognosis Profile is poor and intensive in CRS care manage- Typetions I that are simplisticallyIntra defined by- theabdominal same biomarker changes. Pressure and GFR ment, including renal replacement therapy is often required. We should also acknowledge that changes in creatinine that occur So, where do we go from here? Specifically,Congestion we cautionat Rest the exten- in HF often have a different cause than AKI described in sion of RIFLE/AKIN/KDIGO AKI definitions to include patients guidelines. Acute kidney injury in patients with renal disease is experiencing a rise in serum creatinineNO during successfulYES treatment the direct consequence of the disease, while in HF the cause of Warm & Dry Warm & Wet

• Discordantly ê RBF • Discordantly ê RBF NO • Intra-renal microvascular • Impaired intra-renal Low dysregulation autoregulation Perfusion • Renal v. pressure é at Rest Cold & Dry Cold & Wet

• ê RBF • ê RBF YES • Impaired intra-renal • Impaired intra-renal autoregulation autoregulation • Renal v. pressure é

Stevenson LW et al. JAMA. 1989; 261: 884-888. Mullens W et al. J Am Coll Cardiol. 2008; 51: 300-306.

4 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Non-hemodynamic factors in CRS Prevention and treatment of CRS

§ Modulation of RAAS § Manage volume appropriately • Angiotensin II promotes renal fibrosis, causes SNS activation • Diuretics § Inflammation/oxidative stress • Vasopressin antagonists § Endothelial dysfunction • Inotropes/Dopamine § Humoral/cellular immunity • Ultrafiltration § Anemia § Maintain RBF and FF • Constant plasma refill rate • Avoid excessive intra-renal vasodilation or vasoconstriction

Diuretic Strategies in CRS Resistance

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

Post-diuretic NaCl retention Diuretic malabsorption •GI edema Reduced GFR Aldosterone antagonism

Jentzer JC et al. J Am Coll Cardiol. 2010; 56: 1527-1534. Brater DC. N Engl J Med. 1998; 339: 387-395.

5 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Diuretics increase neurohormonal activation Diuretics: DOSE HF

1000 50 Mean Mean (95% CI) (95% CI) /L) 600 /mL/h) ng pmol 10

2.5 200 Plasma Aldosterone ( Plasma Renin Plasma Activity ( Renin 0.5 100

Before Diuretic After Diuretic Before Diuretic After Diuretic (n = 12) (n = 11) (n = 12) (n = 11)

Bayliss J, et al. Br Heart J 1987 Felker GM et al. N Engl J Med. 2011; 364: 797-805.

Diuretics: DOSE HF Management of CRS: Tolvaptan Low High p value § Inappropriate elevation of arginine vasopressin plays a key role in Dyspnea VAS AUC at 72 hrs 4478 4668 0.041 mediating water retention % free from congestion at 72 hrs 11% 18% 0.091 § Tolvaptan is a small molecule antagonist of the V2 receptor Change in weight at 72 hrs -5.3 lbs -8.2 lbs 0.011 § Compared to furosemide: Net volume loss at 72 hrs 3575 mL 4899 mL <0.001 • Similar effect on urine output % Treatment failure 37% 40% 0.56 • No effect on electrolytes or osmolality % with Cr > 0.3 mg/dL at 72 hrs 14% 23% 0.041 • Preserves renal blood flow Length of stay, days (median) 6 5 0.55 • Less neurohormonal activation § Improves hemodynamics (RAP, PCWP, CI, SVR) §High dose better efficacy, more worsening Cr §No difference bolus vs. drip

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

6 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Tolvaptan in acute HF: EVEREST Change in Global Clinical Status During Hospitalization: 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. Konstam MA et al. JAMA. 2007; 297: 1332-1343.

Treatment of CRS: Dopamine Dopamine for CRS I: DAD-HF P. Varriale and A. Mossavi: Low-dose dopamine during diuresis for CHF 629

Group A GroupB 2.5 GrouPA Group B 50 45 8 40 27 35 E 30 g 1.5 2 22; E 5 15 V G 10 0.5 m5 0

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

Giamouzis G et al. J Card Fail. 2010;16:922-930. Blood UreaVarriale NitrogedCreatinineP et al. Clin Ratio Cardiol. 1997 Jul;20(7):627output.-30. As a result, an overlap in receptor activation may occur within this lower dosage range. It is problematic, therefore, In Group A patients, the ratio increased from 17.9 at base- whether this dose-dependent increase in renal blood flow is line to 24.5 (NS) after therapy; in Group B patients, the ratio exclusively dopaminergic in origin or is due to combined decreased from 24.8 at baseline to 21.5 (NS) after therapy. dopaminergic and adrenergic activation without direct mea- surement of cardiac output.”-29-31 Adverse Effects Advocates of low-dose dopamine who favor its putative benefit on renal function have used this agent to attain renal In Group B patients who received IV dopamine, blood pressure remained unchanged in eight patients and was only salvage in critically ill patients with either established acute renal failure or at high risk for developing acute renal fail- slightly elevated in two patients (< 10% of control); heart race ure.l0*14, 19,32The role of low-dose dopamine in these situ- declined modestly in seven patients (< 10 beats) and increased ations, however, is not clearly defined and mired in contro- slightly in three patients (< 10%of control heart rate). Cardiac versy. Multiple studies, both experimental and clinical, of the were not observed during drug infusion. ischemic or toxic kidney have not demonstrated unequivocal- ly the efficacy of dopamine in preserving renal function or Discussion have spawned conflicting results.11.l3 In this study, we assessed the role of low-dose dopamine (2 Evidence from both human and experimental animal pg/kg/min) as arenal-protective agent when used with vigor- studies has demonstrated a direct renal vasodilatation in re- ous IV diuretic therapy for CHF associated with renal insuffi- sponse7 to low-dose dopamine (0.5-312/1/17 pg/kg/min) that increas- ciency (mild to[ADD moderate) PRESENTATIONand without oliguria. Ten patients TITLE: INSERT TAB > HEADER & es renal blood flow, glomerular filtration rate, and urinary (Group A) receiving an IV loop diuretic (bumetanide 1 mg output.20,23-25 A renal vasodilatory response to low-dose bid.) were comparedFOOTER with 10 patients > (GroupNOTES B) randomized AND HANDOUTS] dopamine, although to a lesser extent, is also observed in pa- to low-dose dopamine infusion (2 pg/kg/min) and a similar tients with chronic renal impairment.26The pharmacodynam- diuretic regimen. Vigorous IV diuretic therapy over a period ic action of low-dose dopamine responsible for intrarenal va- of nearly 5 days resulted in a significant increase in urinary sodilatation and enhanced renal perfusion is mediated output for both treatment groups (Fig. l), symptomaticrelief, predominantly through stimulation of peripheral dopaminer- and clearance of clinical signs of pulmonary-systematic ede- gic receptors DA-I and DA-2. DA-I receptors are located ma. Group B patients who received low-dose dopamine dem- postsynaptically on the smooth muscle of the renal vascula- onstrated significant improvement of renal function. Serum ture. Activation of DA-2 receptors on presynaptic sympathet- BUN 48.9 f 10.3 declined to 32.1 f 14.4 mg/dl (p

§ 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

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

Dopamine in CRS: ROSE-AF Ultrafiltration for AHF

§ 360 patients hospitalized for acute HF and renal dysfunction § Removal of isotonic fluid from the venous system randomized to dopamine 2 mcg/kg/min vs placebo • Maintains physiologic electrolyte balance § Overall, there was no significant difference in the co-primary outcomes of total urine volume and cystatic C at 72 hours • More sodium removal compared to diuretics § When the results are stratified by blood pressure and LV ejection § Ultrafiltration has now been compared to diuretics in multiple fraction: randomized trials • Mixed results • Differing study designs/populations

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

8 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Ultrafiltration in Acute HF: AVOID HF Ultrafiltration for Acute HF: CARESS-HF

Adjustable Ultrafiltration Adjustable Loop Diuretics

Bart BA. et al. N Engl J Med. 2012 ;367: 2296-2304. Costanzo MR. et al. J Am Coll Cardiol HF. 2016; 4: 95-105.

Plasma Refill Rate Ultrafiltration: Conclusions § PRR = ECV – U output § A strategy of universal UF for patients with AHF has not been § Monitor with the serum Hct. Keep Hgb/ Hct from rising > 3-5% in 8- clearly shown to reduce the risk of worsening kidney function or 12 hrs improve outcomes § PRR = ECV – U output § 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 Boyle A. J Card Fail. 2006; 12: 247-249.

9 12/1/17 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] Kirklin et al. Effect of Cardiorenal Syndrome After LVAD Implant 1211 Kirklin et al. Effect of Cardiorenal Syndrome After LVAD Implant 1211 Table 6 Implants: June 2006–March 2012, Adult Primary Continuous Flow Left Ventricular Assist Devices and Biventri- Table 6 Implants: June 2006cular–March Assist 2012, Devices, Adult Destination Primary Therapy, and Bridge to Continuous Flow Left VentricularTransplant Assist (n Devices4,917) and Biventri- ¼ cular Assist Devices, Destination Therapy, and Bridge to Transplant (n 4,917) Severe renal dysfunction ¼ Severe renal dysfunction o 3 months Comparison of risk post-implant All others factors (n 61) (n 221) p-value o 3 months ¼ ¼ Comparison of risk post-implantDemographics All others factors (n Age,61) years (n 221) 60.4p-value 62.2 0.27 ¼ ¼ Demographics Body mass index, 26.3 24.2 0.02 2 Age, years 60.4kg/m 62.2 0.27 Body mass index, 26.3Clinical status 24.2 0.02 kg/m2 Ventilator, % 21.3 9.0 0.01 Figure 6 Time course of average blood urea nitrogen (BUN) Clinical status History of stroke, % 3.5 9.3 0.14 INTERMACS level 1, % 41.0 22.6 0.004 among surviving patients at designated follow-up points, stratified Ventilator, % 21.3 9.0 0.01 INTERMACS level 2, % 42.6 44.3 0.81 by severity of pre-implant renal dysfunction (see Materials and History of stroke, % 3.5 9.3 0.14 Figure 6 Time course of average blood urea nitrogen (BUN) Destination 39.3 40.3 0.90 Methods for definitions). The error bars indicate Ϯ 1 standard INTERMACS level 1, % 41.0 22.6 0.004 among surviving patients at designated follow-up points, stratified therapy, % error. BIVAD, biventricular assist device; BTT, bridge to INTERMACS level 2, % 42.6 44.3 0.81 by severity of pre-implant renal dysfunction (see Materials and Non-cardiac systems transplant; DT, destination therapy; LVAD, left ventricular assist Methods for definitions). The error bars indicate Ϯ 1 standard Destination 39.3Diabetes, % 40.3 37.7 0.90 45.7 0.27 device. error. BIVAD, biventricular assist device; BTT, bridge to therapy, % Creatinine, mg/dl 3.0 2.8 0.29 transplant; DT, destination therapy; LVAD, left ventricular assist Non-cardiac systems Dialysis, % 47.5 25.3 0.0008 device. Resolution of renal dysfunction , % 37.7Blood urea 45.7 nitrogen, 55.5 0.27 56.8 0.78 Creatinine, mg/dl 3.0mg/dL 2.8 0.29 The circulatory improvement rendered by a VAD is at least Dialysis, % 47.5GFR, mg/dl 25.3 23.8 0.0008 24.4Resolution 0.51 of renal dysfunction Blood urea nitrogen, 55.5 56.8 0.78 partially effective in reversing cardiorenal syndrome. Right heart dysfunction – mg/dL Consistent with other reports,34 36 we noted dramatic RVAD in same 13.1 4.5The circulatory 0.02 improvement rendered by a VAD is at least GFR, mg/dl 23.8operation, 24.4% 0.51 improvement in the creatinine and eGFR values within Right heart dysfunction partially effective in reversing cardiorenal syndrome. Right atrial pressure, 19.7 14.4 0.0007 1 month.34 Although–36 some studies report a gradual decline in RVAD in same 13.1mm Hg 4.5 0.02 Consistent with otherGFR reports, during thewefirst noted 6 to dramatic 12 months,37,38 our analysis operation, % Bilirubin, mg/dL 3.2 1.7improvement 0.03 in the creatinineindicates that, and on eGFR average, values survivors within with even moderate or Right atrial pressure, 19.7Ascites, % 14.4 14.5 0.0007 16.61 month. Although 0.72 somesevere studies renal report dysfunction a gradual have decline stable in improvement during 37,38 mm Hg Surgical complexities GFR during the first 6the tofirst 12 2 months, years. Theseour observations analysis are consistent with Bilirubin, mg/dL 3.2History of cardiac 1.745.9 0.03 39.4indicates that, 0.36 on average,experimental survivors studies with even in which moderate animals or supported with long- surgery, % Ascites, % 14.5 16.6 0.72 severe renal dysfunctionterm have continuous- stable improvementflow devices duringgenerally maintained normal Surgical complexities Concomitant cardiac 44.3 51.4the first 2 0.33 years. These observations are39 consistent,40 with surgery, % end-organ function. The long-term maintenance of renal History of cardiac 45.9 39.4 0.36 experimental studies in which animals supported with long- surgery, % fi GFR, glomerular ltration rate; INTERMACS, Interagencyterm continuous- Registry for flow devices generally maintained normal Concomitant cardiac 44.3Mechanically Assisted 51.4 Circulatory 0.33 Support; RVAD, right ventricular 39,40 surgery, % assist device. end-organ function. The long-term maintenance of renal TimingGFR, glomerular of fiDiuresisltration rate; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; RVAD, right ventricular Renal dysfunction improves after LVAD assist device.

Figure 7 Time course of average serum creatinine among ◆ Sustained hemoconcentration (after day 3) is associated with better decongestion and outcomes surviving patients at designated follow-up points, stratified by Figure 5 Actuarial survival post-implant, stratified by combi- severity of pre-implant renal dysfunction (see Materials and fi Testani JM. Circulation. 2010; 122: 265-272.nations of risk factors. The error bars indicateKirklinϮ 1JK standard et al. J Heart error. Lung Transplant.Methods2013 Dec;32(12):1205 for de-13. nitions). The error bars indicate Ϯ 1 standard BIVAD, biventricular assist device; BTT, bridgeFigure to transplant; 7 Time DT, courseerror. of average BIVAD, serum biventricular creatinine assist among device; BTT, bridge to destination therapy; IMACS 1, INTERMACSsurviving level 1; LVAD, patients left at designatedtransplant; follow-up DT, destination points, therapy; stratified LVAD, by left ventricular assist Figure 5 Actuarial survivalventricular post-implant, assist device.stratified by combi- severity of pre-implant renaldevice. dysfunction (see Materials and nations of risk factors. The error bars indicate Ϯ 1 standard error. Methods for definitions). The error bars indicate Ϯ 1 standard BIVAD, biventricular assist device; BTT, bridge to transplant; DT, error. BIVAD, biventricular assist device; BTT, bridge to destination therapy; IMACS 1, INTERMACS level 1; LVAD, left transplant; DT, destination therapy; LVAD, left ventricular assist ventricular assist device. device.

Conclusions Conclusions

§ Cardiorenal syndrome (CRS) is common among heart failure § Treatment of CRS requires careful management of volume status patients and is associated with worse prognosis • Diuretics (can worsen neurohormonal activation) § CRS is multifactorial • Consider tolvaptan, particularly in hyponatremic patients • Volume, venous pressures, and intra-abdominal pressures • Ultrafiltration for those with massive volume overload or • Cardiac output refractory to diuretics • Intra-renal hemodynamics • Aim for slow, sustained hemoconcentration to keep the plasma refill rate constant • Treatment-related mismatch

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