This document provides information about a continuing medical education (CME) activity on cardio-renal syndromes (CRS). It begins with a declaration of disclosure stating the National Kidney Foundation's policy to ensure independence and manage any conflicts of interest among activity planners and faculty. The document then outlines the learning objectives, agenda, and pre-program questions. It also includes an overview of CRS, defining the different subtypes and discussing the bidirectional relationship between cardiac and renal dysfunction. Two case studies are presented to illustrate examples of acute cardiorenal syndrome type 1 and acute renocardiac syndrome type 3.

2. 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.

3. Faculty Disclosures
Refer to handout in participant folder

4. Learning Objectives
Distinguish 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

5. Agenda
Welcome 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

6. 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?

7. OVERVIEW OF CARDIO-RENAL
SYNDROMES

8. Case Presentation
CC:
65-year-old male admitted with 3 weeks of increasing shortness of
breath, for consideration of MVR and CABG
HPI
49 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.

9. Case Presentation
PMH
Type 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 allergies
Review of systems notable only for significant shortness of
breath with no hemoptysis, no chest pain, no lower extremity
edema or weakness

10. Case Presentation
Meds on Admission
Carvedilol 25 mg BID
Quinapril 20mg daily
Asa 325 daily
Calcitriol 0.5mg daily
Insulin - NPH 20, and 10 regular BID
Lipitor 40 mg daily
Tekturna HCT (aliskerin)150 mg/25 mg daily

11. Case Presentation
Admission Exam:
Afebrile, BP 120/60, HR reg @60
alert and oriented x3 in no significant distress
JVP to 15 cm
Cor: inferolaterally displaced PMI no heave, RRR, + apical
S3, III/VI holosystolic murmur at the apex
pulm: Decreased breath sounds at the bases with adjacent
rales, speaking in full sentences, no tachypnea, no accessory
muscle use
abdomen soft, nt, nondistended , + liver edge
femoral pulses 2+, trace edema at the ankles

12. 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)

13. 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.

14. Defining CRSThe 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

15. 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.

16. CRS Subtypes: Acute Cardiorenal Syndrome Type 1
McCullough P.A. Int J Neph 2010;2011:1-10.

17. 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.

18. Acute Heart Failure causing AKI
Cardiogenic shock - >70% have AKI
Acute anterior wall MI
Mitral valve papillary muscle rupture
 MI, endocarditis
Acute aortic regurgitation
 Endocarditis
Acute decompensation of chronic heart failure
Flash pulmonary Edema
Hypertensive emergency
Predominantly preserved LVF/LVH
Predominant RV failure

19. Cardiorenal Interactions in the ESCAPE Trial
Nohria, A. et al. JACC 2008;51:1268-1274
-The risk of death and death or rehospitalization
at 6 months increased with increasing SCr and decreasing
eGFR.
-Baseline renal function appeared more predictive of long-
term outcomes than WRF during hospitalization.

20. 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 PCWP
Whereas it did when guided by clinical assessment alone
Testoni et al. Am J Cardiol 2010;106:1763-69
Binanay et al. JAMA 2005;294:1625-33

21. CRS Subtypes: Chronic Cardiorenal Syndrome, Type 2
McCullough P.A. Int J Neph 2010;2011:1-10.

22. 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.

23. Journal of Cardiac Failure Vol. 13 No. 6 August 2007
Findings from the ADHERE Database

24. ≥≥
≥≥
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..

25. Case #2
72 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 2/11
3) HL on atorvastatin
4) DM2
5) Hypothyroidism on synthroid
6) Morbid obesity with obesity hypoventilation syndrome on
nighttime O2
7) CRI (b/l Cr 1.6)

26. Case # 2
Meds:
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 LAD
Cardiac: 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 bases
Abdomen: protuberant, obese, non-tender, +bs
Ext: no pitting edema, 2+ pulses

27. Case # 2
Initial labs stable : BUN/Creat 70/1.8
Lasix held in preparation for cath
Cardiac 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 only
Tolerated 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

28. 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 developed
BP low 100/60, never needed pressors, but off ALL meds
Junctional escape rhythm requiriring emergent TPM
CVVH 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.

29. CRS Subtypes:Acute Renocardiac Syndrome, Type 3
McCullough P.A. Int J Neph 2010;2011:1-10.

30. 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.
Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

31. CRS Subtypes: Chronic Renocardiac SyndromeType 4
McCullough P.A. Int J Neph 2010;2011:1-10.

32. Go, et al., 2004
1.0
1.4
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
AdjustedHazardRatio
eGFR
Adjusted hazard ratio for CVD events
- The retrospective study by Go, et al fulfills criteria for chronic renocardiac
syndrome, 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 degree
of 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.

34. CRS Subtypes:Secondary Cardiorenal Syndrome Type 5
McCullough P.A. Int J Neph 2010;2011:1-10.

35. IDENTIFYING AND REDUCING RISK FOR
DEVELOPING CRS

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

38. Kidney Failure Is a
Rapidly Growing Problem
Numberofpatients(inthousands)
USRDS, 2000
98,953
372,407
661,330
172,667
Prevalence
Incidence

39. 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.

40. Diabetes: The Most CommonDiabetes: The Most Common
Cause of ESRDCause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Diabetes
50.1%
Hypertension
27%
Glomerulonephritis
13%
Other
10%
United States Renal Data System. Annual Data Report. 2000.
No. of patients
Projection
95% CI
1984 1988 1992 1996 2000 2004 2008
0
100
200
300
400
500
600
700
r2
=99.8%
243,524
281,355
520,240
No.ofdialysispatients(thousands)

41. 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) %%
1
Kidney 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 years
Adapted from NHANES III

42. 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=400,000
At risk population
Total = 20 million
NHANES III

44. 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%

46. MEDICAL MANAGEMENT

49. Slow CKD progression
Treat to target BP <130/801
ACEI and/or ARB are first line therapies for hypertension with albuminuria or
proteinuria
Control blood sugar in diabetes, target HbA1C <7%
Refer to dietitian for food choices appropriate for this patient
Modify all CVD risk factors
Control dyslipidemia
Weight control and smoking cessation
Anemia management
Control hyperphosphatemia, hyperparathyroidism and vitamin D deficiency
Minimize further kidney injury
Avoid nephrotoxins such as NSAIDs, aminoglycosides, IV and intra-arterial
contrast etc
Adjust dosages of renally excreted medications; avoid metformin if GFR<60
NKF. KDOQI guidelines.

50. 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.

51. Diuretic Resistance
Reduced natriuretic response to a given dose of
diuretic
Escalating doses of loop and non-loop diuretics at the
expense of renal function
Often seen as the response to the “prerenal state”
neurohormonal up-regulation, via AT II, aldosterone  Na
retention, ↑ vasopressin  H2O resorption
renin 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

52. 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.

53. 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 24h
Further 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.

54. 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-

55. 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.
Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

56. • 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/m
C and D = Nesiritide < 0.015 ug/kg/m
E and F = Nesiritide < 0.06 ug/kg/m

57. ASCEND-HF
7,000 pts, 300 centers
Nesiritide vs placebo, with standard of care (including IV
nitro and diuretics) w/in 24hrs of admission.
1 – 7 days Rx, ave. 40 hours
No significant difference in 30 day readmission or death
Only 4.7% mortality, 10% total endpoints
Slight ↓in SOB at 6 hrs. and 24 hrs – no statistical sig.
NO DECLINE in renal function
Confirmed 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.

58. Vasopressin Antagonists
V1 receptors: in vasculature mediates VC
V2 receptors: in distal nephron mediates H2O
resorption
Antagonism 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

59. Vasopressin Antagonists
Tolvaptan:
 Approved for treating hyponatremia, and is an option not routinely used
Initial studies very promising
↑ UOP
↓ urine osm
↓ urine Na conc
No change in renal fn or BP
↓ furosemide use
↓ body weight
BUT…EVEREST trial
> 4000 pts and All of above achieved
You 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, ? Dose
Most useful in pts with high
Copeptin levels?
Gheorghiade et al. Circ 2003;107:2690-96
Gheorghiade et al. JAMA 2004;291(16):1963-71
Gheorghiade et al. JAMA 2007 (12):1332-43

60. 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.
Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

61. 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; 53:589-96
Damman et al. JACC 2009; 53:582-88
CVP CI
SBP PCWP

62. 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

63. Furosemide in ADHF:
Bolus Dose vs Continuous Infusion
8 randomized controlled trials, 254 patients
Urine 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..

64. 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.

65. 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
Acute Dialysis Quality Initiative (ADQI) Consensus Group. Eur Heart J 2010;31:703-711.

66. ACEI/ARB/Renin Inhibitors
Inclination is to stop them with renal
insufficiency/failure
Most troublesome in the setting of
“overdiuresis” or poor renal perfusion
elderly
Hyperkalemia
In the setting of contrast agents
Allow for 30% increase in creatinine

67. ACEI/ARB/Renin Inhibitors
Reverse vasoconstriction, intraglomerular pressure↓ and reduce
aldosterone mediated sodium retention – therefore should be
ideal.
Well established role of renoprotective effects in DM2
Most CHF trials are underpowered to assess and/or do not have
enough info on renal function or outcome
Minnesota Heart Study (2000)
2009 - restrospective look at ACE/ARB
If 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 one
OR of 30 day mortality 0.45 if given in hospital
Berger, et al. Am Heart J 2007;153:1064-73

68. β-Blockers
SNS:
β1 – myocardial VC, ↑ renin release
Β2 – RV vasodilation
α1 - systemic and RV VC
CKD and CHF  overstimulation of SNS
Still underutilization w/ CKD
Carvedilol – better tolerated due to vasodilating properties from α
blockade, and nonselective β blockade
Again…most large studies excluded pts with significant renal
disease, when used, show ↓in CV events, ↓ in albuminuria
Avoid in decompensated HF, but otherwise push to high doses

69. 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.
PatientsWithAnemia*(%)
NHANES III
NHANES 1999-2000
CKD Stage

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

71. Major Trials of Statins
Early 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 events
The 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

72. 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?

73. ?

75. The Risks of Calcification
Go Much Deeper than Lumen

78. Copyright ©2008 American Society of Nephrology
Moe, S. M. et al. J Am Soc Nephrol 2008;19:213-216
Mechanisms of Vascular Calcification

81. 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
Ultrafiltration
1. 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.

82. BNP-guided treatment of CHF
Trials are small and
Underpowered
Still not recommended
in CHF guidelines

83. BNP in renal failure
Maisel, et al, ADQI consensus group. Nephrol Dial Transplant 2010. Editorial Review

84. Cardiac Biomarkers
in CRS
Van 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”?

85. Copeptin (CT-proAVP)
Copeptin (C-terminal pro-vasopressin)
Stable in serum or plasma, therefore easily measured
Is 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-
proBNP
Higher in pts with decreasing renal fn
Voors, et al. Eur Heart J 2009;30:1187-94
Morgenthaler. Cong Heart Fail 2010;16(4) (suppl 1)s37-44
Can levels guide therapy…? VP antagonists

86. Copeptin in Heart Failure
AVP contributes to LV
dysfunction
Aggravates LV wall
stress
Stimulates LVH
Worsens remodeling
Strong correlation btwn
Copeptin levels and
mortality
Copeptin & BNP added
to risk stratification Neuhold, et al JACC. 2008;52:26672

87. Cystatin C
Cysteine protease inhibitor
Levels not affected by age, gender, race, diet, muscle mass
Better measure of glomerular function than creatinine
Correlates well with NT-pro BNP levels
Tn T, NT-pro BNP and cysC give complementary
prognostic information in acute HF
Detects 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: 1753-9
Linzbach S, et al. Am J Cardiol 2009;103:1128-33

88. Cystatin C
FINN-AKVA Study
CRS type 1 patients
>0.3mg/L rise in cysC
occurred w/in 48 hrs in
16%
Extended
hospitalization 3 days
OR 4 for in-house death
OR 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

89. Cystatin C and Creatinine
With 0.2 mg/dL rise in creat and 0.3mg/L rise in
cysC, mortality 44.8% at 90d

90. Cystatin C and NT-pro BNP

91. Furosemide and HTS
Theory:
Offsets the counterproductive neurohormonal up-
regulation
transiently improves hemodynamics
promotes 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

92. Furosemide and Hypertonic Saline
↑ natriuresis and diuresis
Results 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 weight
Faster ↓ in BNP ( BNP maintained with higher Na↓
diet)
Lower LOS and 30 day readmission rate.
Improvement in renal fn
No adverse cardiac events
US and Brazil w/ ongoing
large studies now
Paterna, et al. Eur. J Heart Fail 2000;2:305-13
Paterna et al. Clin Drug Interact; 25:165-174
Paterna et al.JACC 2005;45:1887-2003
Licata et al. Am Heart J 2003;145;459-66

93. Adenosine Receptor Antagonists
A1, A2 and A3 receptors
Ado levels are increase in HF
Ado 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 ActivationVasodilation 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 12/7/10
Vallon et al.Physiol Rev. 2006;86:901-40
Marraccini et al.Cardiovasc Res. 1996;32:949-53
Kuan et al.J Cardiovasc Pharmachol.1993;21:822-28

94. CRT with Impaired Renal Function
Initial 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 eGFR
Fung, 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 volumes
Again… ↓ in LVESV best in patients w/ eGFR > 90, and worst
in GFR 30 – 60.
Boerrigter, J Card Failure 2008;14:539-46

95. 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

96. CRT with Impaired Renal Function
GFR < 60 had higher mortality
than if GRF 60 – 90, or > 90
Only 43% in low GFR group
were responders
eGFR 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).

97. CRT with Impaired Renal Function
Can 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,
↓CVP
Were “non-responders” actually “responders” as their
renal fn could have declined without CRT?

98. Integrated Strategies for Both Cardiology
and Nephrology
Recognize the cardiorenal syndrome
Treat the whole patient
Treat for the long-term
Optimize heart failure therapy so that renal function is preserved
Consider new approaches to diuretic infusion or combination therapy that
may reduce the degree of renal dysfunction
Consider vasodilators for use in the appropriate setting to improve
transrenal blood flow while protecting renal function
Consider 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.

99. 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?

100. Thank You