Cardiorenal syndromes and management

1. Cardiorenal syndromes and
management

2. cardiorenal syndromes
cardiorenal syndromes are broadly defined as “disorders
of the heart and kidneys whereby acute
or chronic dysfunction in one organ may induce
acute or chronic dysfunction of the other.”

3. cardiorenal syndromes: burden
 Its bidirectional insult
 Mortality is increased in patients with heart failure (HF) who have a reduced
glomerular filtration rate (GFR).
 mortality increased by approximately 15 percent for every
10 mL/min reduction in eGFR
 Patients CKD have an increased risk of both atherosclerotic cardiovascular disease
and HF
 cardiovascular disease is responsible for up to 50 percent of deaths in patients with
renal failure .
Ronco C, Di Lullo L. Cardiorenal syndrome in Western countries: epidemiology, diagnosis and management
approaches. Kidney Dis (Basel). 2017;2:151–163. doi: 10.1159/000448749

4. cardiorenal syndromes: burden
 The prevalence of moderate to severe kidney impairment (defined as a GFR less
than 60 mL/min per 1.73 m2; normal more than 90 mL/min per 1.73 m2) is
approximately 30 to 60 percent in patients with HF.
 30% patients undergoing treatment for acute or chronic HF frequently develop an
increase in; serum creatinine, which fulfills criteria for type 1 or type 2 CRS .
Ronco C, Di Lullo L. Cardiorenal syndrome in Western
countries: epidemiology, diagnosis and management
approaches. Kidney Dis (Basel). 2017;2:151–163. doi:
10.1159/000448749

5. Classification:
 Type 1 (acute) – Acute HF results in acute kidney injury (previously called acute
renal failure).
 Type 2 – Chronic cardiac dysfunction (eg, chronic HF) causes progressive CKD
(previously called chronic renal failure).
 Type 3 – Abrupt and primary worsening of kidney function due, for example, to
renal ischemia or glomerulonephritis causes acute cardiac dysfunction, which
may be manifested by HF.
 Type 4 – Primary CKD contributes to cardiac dysfunction, which may be
manifested by coronary disease, HF, or arrhythmia.
 Type 5 (secondary) – Acute or chronic systemic disorders (eg, sepsis or
diabetes mellitus) that cause both cardiac and renal dysfunction

6. Patients at risk…
 Pre-existing CKD (30-40%) : twice/thrice the risk
 Diabetes
 High dose diuretics
 Iodinated contrast
 Age
 Anemia
 a prior history of HF,
 and uncontrolled hypertension
(In a retrospective cohort study of 30681 patients with transthoracic echocardiography
and up to 110 months of follow-up, 8% of patients developed at least 1 cardiorenal
syndrome subtype. Of those patients who developed a chronic type of cardiorenal
syndrome, 19% subsequently developed an acute syndrome)

7. Pathophysiology concepts:
 1. neurohumoral adaptations: RAAS activation--nonosmotic release of
antidiuretic hormone (arginine vasopressin), which leads to free water
retention and hyponatremia
 reduced cardiac index is not the primary driver for renal dysfunction in
patients hospitalized for HF(ESCAPE TRIAL ) in fact higher cardiac index was
paradoxically associated with worse eGFR.
 2. reduced renal perfusion :decline in cardiac output of as much as 20
percent due to the reduction in ventricular preload
 3. increased renal venous pressure: increasing intra-abdominal or central
venous pressure venous pressure reduces the GFR.
 4. right ventricular dysfunction:.RV dilatation impairs left ventricular (LV)
filling, and therefore forward output, via a ventricular interdependent effect
(also known as the reverse Bernheim phenomenon) .
 Increased pressure within a distended RV increases LV extramural pressure,
reducing LV transmural pressure for any given intracavitary LV pressure and
inducing leftward interventricular septal bowing.

8. Prognosis:
 CHARM trial : All-cause mortality increased significantly when the baseline
eGFR was below 75 mL/min per 1.73 m2 ,independent of the left ventricular
ejection fraction (LVEF),
 but all-cause mortality increased continuously with reductions in LVEF below
45 percent.
 SOLVD study: showed that early worsening renal function was associated with
increased mortality in the overall population However, in the ACE
inhibitor group, early worsening renal function was not associated with
increased mortality, while in the placebo group, the association with mortality
was strengthened.
 An elevation in blood urea nitrogen (BUN) or blood urea is also associated with
increased mortality in patients with HF

9. HEAAL trial
 studies of renin-angiotensin-aldosterone system (RAAS) inhibition have
similarly demonstrated beneficial effects on long-term outcomes despite
an initial early decline in renal function.
 An analysis of data from the Heart failure End point evaluation of
Angiotensin II Antagonist Losartan (HEAAL) trial found that 150 mg
losartan compared with 50 mg .
 increased risk of acute rise in serum creatinine as well as with greater long-
term reductions in eGFR, but that despite these effects,
 high-dose losartan retained its net clinical benefit and was associated with
reduced risk of death or HF hospitalization
Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a
randomised, double-blind trial.The lancet 2017

11. CRS Type I

12. CRS Type I
 about 25% of patients hospitalized for acute decompensated heart failure
(ADHF)
 a preexistent chronic kidney disease (CKD) is common
 contributes to acute kidney injury (AKI) in 60% of all CRS cases
 AKI : an independent mortality risk factor in ADHF patients
 ADHF--leading to a decreased renal arterial flow and a consequent fall in GFR.
The sympathetic nervous system and renin-angiotensin aldosterone system
(RAAS) activation, chronic inflammatory status and impairment of ROS/NO
production

13. biomarkers
 helpful to differentiate between true kidney injury and pseudoworsening renal function in the
setting of heart failure.
 Cystatin C represents a valid surrogate to test renal function,
 recognized as more predictive of long-term mortality and rehospitalization for ADHF than
serum creatinine or serum BNP.
 cystatin C production is less dependent upon muscle mass and therefore less influenced by
nutritional status .
Other biomarkers:
 KIM-1
 liver type fatty acid-binding protein (L-FABP)
 interleukin-18 (IL-18),
 neutrophil gelatinase-associated lipocalin (NGAL)
 NGAL correlates with renal function markers and adverse cardiovascular outcomes or death in
ADHF patients.

14. CRS Type II

15. CRS Type II
 Chronic disease
 CKD has been observed in 45–63% of chronic heart failure (CHF) patients
Diagnosis:
 creatinine (and eGFR) and urinary protein excretion assay.
 novel kidney biomarkers (cystatin C, NGAL, KIM-1 and N-acetyl-β- D -
glucosaminidase – NAG)
 Kidney ultrasound : the reduction of cortical thickness, corticomedullary
ratio and increased parenchymal echogenicity.
 Echocardiography : high atrial volumes or areas as indices of volume
overload, normal or decreased EF, right chamber dilation and increased
pulmonary arterial pressure, pericardial effusion, and valvular disease
(calcific disease).

16. CRS Type III

17. CRS Type III
 Abrupt and primary worsening of kidney function due, for example, to renal ischemia or
glomerulonephritis ,ATN causes acute cardiac dysfunction, which may be manifested by HF.
 Avoiding or minimizing nephrotoxic medications and procedures is an important strategy to
prevent AKI.
 Antibiotics (aminoglycosides) and contrast medium represent the main nephrotoxic agents
employed in ICUs
 Combination therapy with vancomycin and aminoglycoside or ACE inhibitors ,nonsteroidal
anti-inflammatory drugs and diuretics can lead to renal tubular injury and volume depletion.
 Preventing hypoperfusion is a cornerstone to avoid AKI, and volume depletion should be
corrected. Strict monitoring of fluid balance is fundamental

18. CRS Type IV

19. Type IV CRS
 Type 4 CRS, also defined as chronic renocardiac disease
 characterized by cardiovascular involvement in patients affected by CKD at any
stage.
 It is well established that renal dysfunction is an independent risk factor for
cardiovascular disease with a higher mortality risk for myocardial infection and
sudden death in CKD.
 Almost half of cardiovascular deaths in the end-stage kidney disease population
are related to cardiac arrhythmia or sudden death.
 Chronic inflammation: Genetic risk factors ,Acquired risk factors, Primary
nephropathy ,Diabetes mellitus ,Anemia, Hyperparathyroidism, Chronic
inflammation, Monocyte activation Cytokine release ,

20. Type IV CRS
 Leads to Endothelial dysfunction, Bone remodeling ,Cognitive disorders Acute-phase
proteins, Insulin resistance ,atherogenesis.
 Left ventricular hypertrophy is highly prevalent in patients starting hemodialysis, and
it is accountable for subsequent hospitalizations for heart failure .
 pressure overload leading to left ventricular hypertrophy results from comorbid
conditions such as hypertension and calcific valvular disease particularly prevalent in
hemodialysis patient.

21. CRS Type V

22. Management principles
of CRS

23. Tackle congestion …
 Rapid diuresis --a transient deterioration of estimated GFR, or its surrogate
increase in serum creatinine,
 is not a marker for worse prognosis provided that relief of congestion is
achieved.
 The beneficial effects of drugs targeting the renin–angiotensin–
aldosterone system, despite a sometimes marked elevation of serum
creatinine
 By contrast, deterioration of eGFR with persistence of congestion indicates
a worse prognosis and an increased mortality.
 Hence, decongestion is a major target in AHF.

24. Diuresis
 EVEREST study:An analysis of data from the EVEREST (Efficacy of Vasopressin
Antagonism in heart Failure Outcome Study with Tolvaptan trial demonstrated that
hemoconcentration was associated with greater risk of in hospital worsening renal
function, though renal parameters generally returned to baseline within four weeks
of discharge .
 the timing of hemoconcentration is important.
 hemoconcentration achieved late during the hospitalization was associated with
improved survival while early hemoconcentration was not associated with improved
survival compared with no hemoconcentration.
 Late hemoconcentration was associated with higher average daily loop diuretic
doses and greater weight loss than early hemoconcentration

25. But…Aggressive decongestion, even with WRF
can improve post-discharge survival
Testani et al., Circulation 2010

26. But…Aggressive decongestion, even with WRF
can improve post-discharge survival
Metra et al., Circulation heart Fail 2012

27. Loop diuretic
 of diuretic-induced fluid removal on the GFR (usually estimated from the serum
creatinine) is variable in patients with HF:
 1.an increase in serum creatinine that is presumed due to reduction in renal
perfusion due to a decline in cardiac output induced by the fall in cardiac filling
pressures
 2.no change in serum creatinine that may reflect maintenance of cardiac output
perhaps because they are on the flat part of the Frank-Starling curve where changes
in LV end-diastolic pressure have little or no effect on cardiac performance.
 3.some patients shows: a reduction in serum creatinine mediated perhaps in part
by one or both of the following mechanisms:
o Reductions in intraabdominal and renal venous pressures
o Reduction in right ventricular dilatation, which may improve LV filling and function
via ventricular interdependence (alleviation of the reverse Bernheim phenomenon)

28. CO and LVEDP relations

29. Prevalence of WRF as per CVP,CI,BP,PCWP
Mullens et al., JACC 2009

30. Rapid decongestion is key…
Fallick et al,
Circ Heart Fail 2011

31. Diuretics
Goal: normovolaemia
• Loop diuretics: tailored, assessment volume status
• Agressive treatment of volume overload but
• Avoid hypotension and underfilling
MAP≥65mmHG, or higher in chronic hypertensives
• Intermittent vs. Continuous?
• Monitor weight, Urine output

32. High dose vs low dose…
continuous vs bolus ..
Felker et al, NEJM 2011
Clinical Composite End Point of Death,
Rehospitalization, or Emergency Department Visit.

33. Removal Fluid 3rd space
 • Paracentesis of ascites  Reduces Intra-abdominal pressure  improves
GFR
 Compression therapy of lower extremities  improves Lymphatic drainage
of Interstitial Fluid improves Systemic circulation improves GFR

34. Use of iv therapies in first 48 hours and
in –hospital mortality

35. ROSE-AHF study
 Renal Optimization Strategies Evaluation in Acute Heart Failure study (ROSE-AHF
study ):
 no correlation between worsening renal function (≥20% reduction in eGFR from
baseline to 72 hours) and the tubular injury biomarkers N-acetyl-b-d-glucosaminidase,
NGAL, or KIM1 in patients with acute heart failure undergoing aggressive diuresis.

36. inotropes?
 The role of inotropes in patients with CRS is uncertain
 DAD-HF trial of 60 patients with acute decompensated HF found that the
combination of dopamine 5 mcg/kg/min plus low-
dose furosemide (5mg/h continuous infusion) produced similar urine
output as high-dose furosemide (20 mg/h) with reduced risk of worsening
renal function (defined as rise in serum creatinine of >0.3 mg/dLfrom
baseline to 24 hours; 7 versus 30 percent).
 ROSE trial also tested the hypothesis of whether low-
dose dopamine(2mcg/kg/min) among patients hospitalized with HF and
concomitant renal disease .
 Conclusion: Low-dose dopamine did not enhance decongestion or
improve renal function when added to diuretic therapy.

37. ACEI/ARB
 associated with an improvement in renal function.
 Although a minority of patients have an increase in GFR after initiation of ACE
inhibitor or ARB therapy, most have a moderate reduction in GFR that can often be
ameliorated by reducing the intensity of diuretic therapy
 the risk of adverse events including hyperkalemia and worsening renal function is
higher in CKD patients than in patients without CKD.
 RAAS inhibitors have convincing evidence of benefit on prolonging survival and
reducing morbidity in patients with HFrEF, and both US and European guidelines
give a Class I, Level of Evidence A recommendation for their use.

38. ACEI/ARB
 Physicians who are reluctant to optimize RAAS inhibitor therapy in patients with
cardiorenal syndrome
 concerned primarily about safety, although the perception of risk is often out of
proportion to actual risks.
 in patients with HFrEF, observational studies have repeatedly shown that RAAS
inhibitors are underused, suboptimally dosed, and inadequately monitored.
 These practices are associated with worse outcomes.
 Fears of inducing hyperkalemia or worsening renal function are the primary reasons
cited for underuse or underdosing.
 New potassium binders may enable RAAS inhibitor optimization, as shown with
patiromer (OPAL-HK [A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy
and Safety of Patiromer for the Treatment of Hyperkalemia

39. Nesritide
 ASCEND-HF trial, found no change in risk of worsening renal function with
nesiritide therapy (continuous infusion at 0.01 microg/kg per min with an
optional initial loading dose of 2 microg/kg) .
 Similarly, the Renal Optimization Strategies Evaluation ROSE trial found
that low-dose nesiritide (0.005 mcg/kg/min without bolus for 72 h) did not
enhance decongestion or alter renal function when added to diuretic
therapy.

40. Renal Effects of Levosimendan
 a favorable and sustained effect on renal function in AHF, mediated
primarily through CO and CVP.
 renal arterial vasodilatation and augmented renal blood flow.
LIDO study, Yilmaz et al, by Zemljic and colleagues , the PORTLAND
registry:
 a moderate but significant reduction in serum creatinine compared with
dobutamine.
 Favorable effects on a range of cardiac and vascular echocardiographic
indices, biomarker status (including cystatin C), and New York Heart
Association heart failure grade and duration of hospitalization

41. Renal Effects of Levosimendan
 enhancement of CO promotes improved GFR and diuresis, which leads to
decongestion and a lower CVP.
 by virtue of a reducing and afterload-reducing effect, promotes further
improvement in both cardiac and renal function.
 reduced CVP improves--right ventricular function.
 may have additional renal protective qualities arising from antioxidant,
antiapoptotic, and cytoprotective actions exercised through the opening
of mitochondrial KATP channels and the generation of intrarenal nitrous
oxide.

42. Ultrafiltration
 removal of isotonic fluid from the venous compartment via filtration of plasma
across a semipermeable membrane.
 ultrafiltration is helpful for fluid removal in acute decompensated HF in
patients unresponsive to diuretic therapy
 the available evidence does not establish ultrafiltration as first line therapy for
acute decompensated HF.
 Three randomized trials (UNLOAD, RAPID-CHF, and CARESS-HF) compared
ultrafiltration with diuretic therapy in patients with acute decompensated HF
 RRT is indicated when AKI develops with oligo-anuria

43. Novel Inotropes
 1. Istoroxime: Inotopic( Na+ K+ ATPase inhibitor) and Lusitropic actions
(SERCA 2 stimulator)
 HORIZON AF trial : dose escalation study in HF pts with LVEF <35 % --
shows promise in reducing LVED volumes , PCWP , no
hypotension,tachycardia
 2.Omecamtiv Mecarbil: selective cardiac myosin activator
 ATOMIC-AHF study :increase systolic ejections times, fractional shortning,
LVEF but no overall impact on primary end points and survival.

44. Ultrafiltration
 In UNLOAD and RAPID-CHF, ultrafiltration was associated with a
significantly greater rate of fluid loss than diuretic therapy but no
difference in serum creatinine.
 In CARESS-HF, ultrafiltration was compared with stepped pharmacologic
therapy (including bolus plus high doses of continuous infusion loop
diuretics, addition of thiazide diuretic [metolazone], and selected
intravenous inotrope and/or vasodilator therapy) in patients with
worsening renal function and persistent congestion .
 Although weight loss was similar in ultrafiltration and stepped
pharmacologic therapy groups, ultrafiltration therapy caused an increase in
serum creatinine and a higher rate of adverse events

45. ultrafiltration

46. The effects of tolvaptan therapy on clinical outcomes CRS
 EVEREST Outcome trial,
 Tolvaptan had no effect on the primary end points of all-cause mortality,
mortality or HF hospitalization, or seven-day patient global assessment
compared with placebo .
 significant benefits in a number of secondary end points:
1. an increase in urine output, resulting in reduced dyspnea and edema and
an increase in serum sodium ,clinically insignificant, increase in serum
creatinine .
2. tolvaptan group showed greater early and sustained weight loss.
3. progressively greater improvement in dyspnea scores.

47. Role of Rolophylline ????
Massie et al., NEJM 2010

48. adenosine-1 receptor antagonist
 Adenosine, acting on the adenosine-1 receptor, constricts the afferent
glomerular arteriole, thereby reducing the GFR, and increases tubular
sodium reabsorption
 selective adenosine A1 receptor antagonism can increase GFR and
promote a diuresis , potentially acting synergistically with loop diuretics.
 PROTECT trial, 2033 patients hospitalized with HF and impaired renal
function (mean creatinine clearance 51 mL/min)were randomly assigned to
the rolofylline or to placebo no difference between the groups in
cardiovascular outcomes or in the rate of persistent worsening of renal
function.
 More no seizures and stroke

49. Chen et al, JAMA 2013

50. Treatment of acute heart failure with serelaxin
 dyspnoea relief and
improvement in other
clinical outcomes
 Safe and tolerated well
 no effect on readmission to
hospital.
 no effect on 180-day
mortality

51. Diuretics resistance

52. new conscepts:
 Fibrosis is a common consequence of inflammation- and oxidative
stress–related endothelial dysfunction in aging, hypertension, diabetes
mellitus, obesity, ischemia, and organ injury.
 It is a common feature in heart failure and chronic kidney disease.
 fibrosis may be not only a marker but also the primary driver of
pathophysiology in several cardiorenal syndromes.
 Interstitial fibrosis in the heart, large arteries, and kidneys may play a key
role in the pathophysiology of the cardiorenal syndrome continuum.

53. Fibrosis : as key pathogenetic process
 Myocardial remodeling occurs after cardiac injury
 involves the secretion of extracellular matrix proteins by myofibroblasts to promote
cardiac fibrosis and preserve myocardial structure and function
 this fibrotic state leads to chamber dilatation, cardiomyocyte hypertrophy, apoptosis,
and heart failure.
 tubulointerstitial fibrosis and dysfunction may be generated by the differentiation of
tubular epithelial cells to myofibroblasts toward an epithelial-mesenchymal transition 
the loss of polygonal shape and epithelial markers (eg, E-cadherin) and the acquisition
of a fibroblastic phenotype with enhanced synthesis of extracellular matrix (eg, collagen
I, III, fibronectin).

54.  In a rat model of acute kidney injury induced by bilateral renal ischemia/reperfusion, treatment
with the MRA spironolactone prevented subsequent CKD by avoiding the activation of fibrotic
(including the epithelial-mesenchymal cell transition) and inflammatory pathways.
 Aldosterone may trigger a cascade of mechanisms that typically lead to fibrosis in the heart,
vessels, and kidneys and may reciprocally evolve into a cardiorenal syndrome .
 These results were recently confirmed with the new nonsteroidal MRA finerenone..
 Aldosterone-salt–treated rats present an MR-dependent epithelial-mesenchymal transition and
increased interstitial, glomerular, and vascular fibrosis manifested by kidney hypertrophy,
glomerular hypertrophy, hyperfiltration, albuminuria, and increased sodium and NGAL urine
excretion
 Lattenist L, Lechner SM, Messaoudi S, Le Mercier A, El Moghrabi S, Prince S, Bobadilla NA, Kolkhof P, Jaisser F, Barrera-Chimal J.
Nonsteroidal mineralocorticoid receptor antagonist finerenone protects against acute kidney injury-mediated chronic kidney disease:
role of oxidative stress. Hypertension. 2017;69:870–878. doi: 10.1161/HYPERTENSIONAHA.116.08526

55. Obesity and aldosterone levels
 Obesity is also associated with increased aldosterone concentrations in
humans.
 Abdominal obesity is associated with adverse cardiac and vascular
remodeling, and it may directly impair kidney function through
hyperfiltration, increased glomerular capillary wall tension, and podocyte
stress.
 MR expression is increased in visceral adipose tissue in a preclinical mouse
model of metabolic syndrome and in obese patients.
 A key mechanism that drives the development and progression of kidney
disease in obesity : endothelial dysfunction and associated
tubulointerstitial fibrosis,

56. Ongoing Trials on CRS

57. Ongoing Trials on CRS

58. Ongoing Trials on CRS

59. Ongoing Trials on CRS

61. Take home message ……