This document discusses the relationship between renal disease and cardiovascular illness. Some key points: - The kidneys and heart communicate extensively through hormones and the sympathetic nervous system. Renal dysfunction increases cardiovascular risk. - Risk rises when the estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2. Microalbuminuria also predicts increased CVD risk regardless of diabetes status. - Anemia due to chronic kidney disease is linked to worse heart failure outcomes and increased mortality. Treatment of anemia has risks that may outweigh benefits. - Contrast-induced acute kidney injury is a risk for those with an eGFR <60 undergoing imaging with iodinated contrast

1. Interface Between
Renal Disease and
Cardiovascular Illness
Dr. Sumit Shanker

2. Introduction
 Kidneys receive 20% to 25% of the cardiac output
 Kidney has a central role in electrolyte balance, protein
production and catabolism, and blood pressure regulation
 Communication between the heart and the kidneys
 Sympathetic nervous system
 Renin-angiotensin-aldosterone system
 Antidiuretic hormone
 Endothelin
 Natriuretic peptides
 Obesity contributes to type 2 diabetes mellitus and
hypertension  predispose CKD and CVD

3. CKD and Cardiovascular Risk

5.  With age the eGFR declines from approximately 130 to 60
ml/min/1.73 m2
 Variety of pathobiologic processes appear to begin when the
eGFR drops below 60 ml/min/1.73 m2
 Critical cut point for CI-AKI, restenosis after PCI, recurrent
acute MI, diastolic or systolic heart failure, arrhythmias, and
cardiovascular death
 Serum creatinine is a crude indicator of renal function and
often underestimates renal dysfunction in women and elderly
 eGFR or CrCl calculated by MDRD equation and Cockcroft-Gault
equation provide superior assessment of renal function

6.  Cystatin C also reflects renal filtration function
 Independent of weight and height, muscle mass, age,
or sex
 Less variable than serum creatinine
 Microalbuminuria at any level of egfr indicates CKD
 Random urine albumin-to-creatinine ratio (ACR) of 30 to 300
mg/g
 Microalbuminuria independently predicts CVD for those with
and without diabetes

7. Implications of Anemia Due to CKD
 Anemia due to CKD is present in 20% of patients with
stable coronary disease and 30% to 60% of patients with
heart failure
 Relative deficiency of erythropoietin-alpha
 Normal plasma EPO levels range between 10 and 30 IU/ ml
 During anemic periods  levels may be elevated up to 100
IU/ml
 Increased circulating levels of hepcidin, an inhibitor of the
ferroportin receptor, impair iron absorption and utilization
 Studies of heart failure found anemia to predict mortality
independently

8.  Treatment of anemia with exogenous EPO or darbepoetin alfa
increasing the Hb level from below 10 g/dL to 12 g/dL can improve
left ventricular remodeling, EF, and functional classification and raise
levels of peak oxygen consumption with exercise testing
 EPO can cause three problems:
 (1) Increased platelet activity, thrombin generation, and resultant
increased risk of thrombosis
 (2) Elevated endothelin and asymmetric dimethylarginine which
theoretically reduces nitric oxide availability, and results in
hypertension
 (3) Worsened measures of oxidative stress
 Treatment with ESPs may actually worsen CVD outcomes in CKD
 ESPs should be reserved for the treatment of severe anemia in CKD
with the goal of improving symptoms and avoiding transfusion

9. CONTRAST-INDUCED ACUTE KIDNEY
INJURY
 Iodinated CI-AKI  defined by the Acute Kidney Injury Network
criteria of a 0.3mg/dL or greater rise in serum creatinine from
baseline within 48 hours of intravascular administration
 Occurs in approximately 13% in nondiabetics and 20% of
diabetics undergoing PCI
 CI-AKI leading to dialysis is rare (0.5% to 2.0%)
 Severe CI-AKI is associated with catastrophic outcomes
including a 36% in-hospital mortality rate and a 2-year survival
rate of only 19%
 Transient rises in serum creatinine 
 Longer length of hospital stay, MI, stroke, heart failure, and
rehospitalization

10. Pathophysiology of CI-AKI
 (1) Direct toxicity of iodinated contrast material to nephrons,
 (2) Microshowers of atheroemboli to the kidneys (consequent to
catheter and wire exchanges above the renal arteries)
 (3) Contrast material and atheroemboli induced intrarenal
vasoconstriction of the vasa recta
 Direct toxicity to nephrons with iodinated contrast media appears to
be related to the ionicity and osmolality of the contrast media
 1% of high-risk cases  acute cholesterol embolism syndrome
 acute renal failure
 mesenteric ischemia,
 decreased microcirculation to the extremities
 embolic stroke

12. Prevention of Contrast-Induced
Acute Kidney Injury
 Patients with baseline eGFR < 60 mL/min/1.73 m2, in particular, those
with CKD and diabetes mellitus, should receive preventive measures for
CI-AKI
 Other risk factors
 Hemodynamic instability, use of intra-aortic balloon counterpulsation,
heart failure, older age, and anemia
 CI-AKI prevention:
 (1) hydration and volume expansion
 (2) choice and quantity of contrast material
 (3) pre-, intra-, and postprocedural end-organ protection with
pharmacotherapy
 (4) postprocedural monitoring and expectant care

14.  Hydration with intravenous normal saline or isotonic sodium
bicarbonate is reasonable, starting 3 to 12 hours before the procedure
at 1 to 2 ml/kg/hr
 Patients at risk and able to tolerate the fluid load should receive at
least 300 to 500 ml of intravenous hydration fluid before contrast
 Right-heart catheterization may aid in patients with heart failure
 Postprocedure hydration target is a urine output of 150 ml/hr
 Urinary excretion rates of more than 150 ml/hr should have
intravenous replacement of extra losses
 Normal saline or sodium bicarbonate at 150 ml/hr for at least 6 hours
after the procedure

15.  RCT of iodinated contrast agents have demonstrated the lowest rates of CI-
AKI with nonionic, iso-osmolar iodixanol
 Relative risk of CI-AKI occurring for iodixanol was 0.46 (P = 0.004), compared
with LOCM

16.  Contrast volume should be minimized in any setting, and there is
disagreement about a “safe” contrast limit
 Maximum target volumes of contrast medium should be less than 30
mL for a diagnostic and less than 100 mL for an interventional
procedure
 In staged procedures, more than 10 days should elapse between the
first and second contrast exposures if CI-AKI has occurred with the
first procedure

17.  (1) Loop diuretics or mannitol can worsen CI-AKI if volume
replacement is inadequate for the diuresis that follows
 (2) Low-dose or “renal dose” dopamine or fenoldopam does not
provide protection, given the counterbalancing forces of intrarenal
vasodilation through the dopamine-1 receptor and the
vasoconstricting forces of the dopamine-2, alpha, and beta receptors
 (3) Renal toxic agents including NSAID, aminoglycosides, and
cyclosporine should not be administered in the periprocedural period
 N-acetylcysteine 1200 mg by mouth twice daily the day before and
after the procedure showed no differences in the rates of CI-AKI,
ESRD, or other outcomes

20. CARDIAC SURGERY–ASSOCIATED ACUTE
KIDNEY INJURY
 AKI occurs in approximately 15% of patents after forms of cardiac
surgery with or without use of cardiopulmonary bypass
 Many factors including endogenous/exogenous toxins, metabolic
factors, ischemia and reperfusion, neurohormonal activation,
inflammation, and oxidative stress contribute to renal tubular injury
 In children undergoing cardiac surgery, urine neutrophil gelatinase
associated lipocalin is markedly elevated in those who will go on to
develop AKI
 Other novel cardiac markers
 Urine kidney injury molecule 1, L-type fatty acid binding protein,
alpha-glutathione S-transferase (alpha- GST), pi-GST, and other
proteins that indicate renal tubular cell cycle arrest and apoptosis

21. KIM = kidney injury molecule; L-FABP = L-type fatty acid–binding protein; NGAL
= neutrophil gelatinase–associated lipocalin

22. ACCELERATION OF VASCULAR
CALCIFICATION
 At eGFR below 60 mL/min/1.73 m2, the filtration and elimination of
phosphorus fall and 1,25D3 production decreases  relative hypocalcemia
 Thus subtle degrees of hyperphosphatemia and hypocalcemia increase release
of PTH causing liberation of calcium and phosphorus from bone
 The bone in turn produces greater amounts of FGF-23 which directs the
kidneys to increase the clearance of phosphorus
 This abnormal bone and mineral metabolism markedly increase absolute
values and rates of accumulation of arterial calcium
 No strategies that manipulate calcium-phosphorus balance or treat secondary
hyperparathyroidism significantly influence the progression of coronary
calcification or decrease cardiovascular events in patients with ESRD

23. RENAL DISEASE AND HYPERTENSION
 Sodium retention stimulates increases in systemic and renal arteriolar
pressure in an attempt to force greater degrees of filtration in the
glomerulus
 Glomerular injury activates several pathways that can increase
systemic blood pressure
 Combined CKD and CVD is strict blood pressure control with a target
of less than 130/80 mm Hg
 Sodium restriction, weight reduction of 15% to a target BMI <25 kg/
m2, and exercise for 60 minutes/day most days of the week
 RAAS inhibitors often in combined action with a thiazide type diuretic

24.  Dihydropyridine calcium channel blocker monotherapy should be avoided
because of relative afferent arteriolar dilation increased intraglomerular
pressure and worsen glomerular injury.
 Combinations of multiple RAAS-blocking drugs— ACEi, ARB, direct renin
inhibitor—have not shown superiority to single agents in this class and cause
more complications
 Percutaneous renal artery denervation is undergoing evaluation

25. DIAGNOSIS OF ACS IN PATIENTS WITH
CKD
 Patients with CKD have higher rates of silent ischemia, risk of serious
arrhythmias, heart failure, and other cardiac complications
 In stable outpatients with CKD, 38% and 68% will have a high-
sensitivity cTnI and cardiac troponin T (cTnT) above the 99th
percentile of normal
 Degree of elevation of cTn reflects left ventricular mass and the
severity of renal disease
 cTnI serves best for diagnostic evaluation of patients with CKD or
ESRD experiencing acute chest discomfort, whereas chronic elevations
of cTnT are more common and more prognostic in stable patients
 The skeletal myopathy of CKD can elevate creatine kinase, myoglobin,
and some older-generation cTnI/cTnT assays

26. Renal Dysfunction as a Prognostic Factor
in ACS
 Patients with CKD represent 30.5% of STEMI cases and 42.9% of NSTEMI cases
and CKD is associated with higher rates of in-hospital mortality in a graded
fashion with worsened renal function

27. Reasons for Poor Outcomes after ACS in
Renal Dysfunction
 (1) Excess comorbid conditions associated with CKD and ESRD, in particular,
diabetes mellitus and left ventricular dysfunction
 (2) Therapeutic nihilism
 (3) Toxicity of therapies
 (4) Special biologic and pathophysiologic factors in renal dysfunction that
cause worsened outcomes
 Defects in thrombosis attributable to uremia include excess thrombin
generation and decreased platelet aggregation
 Increased rates of coronary thrombotic events and increased bleeding risks at
the same time

38.  Data support a favorable benefit-to-risk ratio for aspirin, beta-adrenergic
blocking agents (beta blockers), ACE inhibitors, ARBs, aldosterone receptor
antagonists, and statins
 Therapies that require dose adjustment on the basis of CrCl include low-
molecular-weight heparins, bivalirudin and glycoprotein IIb/IIIa antagonists
 SWEDEHEART study reported a benefit to revascularization in ACS in CKD
patient groups with eGFR of 15 mL/min/1.73 m2 or greater

39. CARDIORENAL SYNDROMES
 Cardiorenal syndrome refers to disorders of the heart and
kidneys whereby acute or chronic dysfunction in one organ
may induce acute or chronic dysfunction in the other
 Most common application of the designation cardiorenal
syndrome is in patients with heart failure

41.  CKD, and in particular ESRD, have three key mechanical contributors
to heart failure: pressure overload (related to hypertension), volume
overload, and cardiomyopathy
 20% of patients approaching hemodialysis have pre-existing heart
failure
 CKD influences the blood levels of B-type natriuretic peptide (BNP)
and NT-proBNP
 eGFR is less than 60 mL/min/1.73 m2, higher cut points of 200
pg/mL and 1200 pg/mL should be used in the diagnosis of heart
failure
 ADHF approximately 25% will develop a cardiorenal syndrome during
the hospitalization characterized by a rise in serum creatinine to 0.3
mg/dL or higher and a reduction in urine output

43.  Multiple studies have shown that the predictors of cardiorenal
syndrome (type 1) include baseline egfr, older age, female sex,
increased baseline blood pressure, higher initial natriuretic peptide
levels, and increased central venous pressure
 Type 1 in patients with heart failure rarely occurs in the prehospital
phase
 Loop diuretics, probably by further activating the RAAS and possibly
worsening intrarenal hemodynamics
 Elevated serum creatinine is the most common reason for the use of
positive inotropes or inodilators in hospitalized patients with heart
failure
 Hyponatremia and excess body water are ameliorated slightly with
oral tolvaptan or intravenous conivaptan; however, neither therapy
reduces rehospitalization or mortality

44.  Cardiorenal rescue study in acute decompensated heart failure
(CARRESS-HF) in patients with persistent congestion and renal
dysfunction found no clinical benefits of ultrafiltration over diuretic
therapy
 Retrospective analyses supports the use of an ACE inhibitor or ARB
(not the combination) in patients with ESRD with heart failure
 Frequent outpatient monitoring and avoidance of overly aggressive
diuresis are advised.
 Dialysis patients, despite having volume reduction with mechanical
fluid removal, should have medical therapy with ACE inhibitors or
ARBs, beta blockers, and additional agents for blood pressure control

46. CKD AND VALVULAR HEART DISEASE
 Aggravate mitral annular calcification and aortic valve sclerosis
 80% of patients with ESRD have the murmur of aortic sclerosis
 Bacterial endocarditis may develop in patients with ESRD who have
temporary dialysis access catheters
 Staphylococcus, streptococcus, and enterococcus, in the mitral,
aortic, or tricuspid valves, carries a risk of cerebral embolism of 40%
and a mortality rate of 50% in ESRD
 Valve replacement in ESRD for endocarditis carries a very high
mortality rate
 Tissue or mechanical valve prostheses demonstrate similar survival

47. RENAL FUNCTION AND ARRHYTHMIAS
 Uremia, hyperkalemia, acidosis, and disorders of calcium-phosphorus
balance all link to higher rates of atrial and ventricular arrhythmias
 Concurrent LVH, left ventricular dilation, heart failure, and valvular
disease all contribute
 Dose adjustment required for many antiarrhythmic medications
 ESRD benefit from implantable cardioverter-defibrillators (ICDs)
implantation for secondary prevention
 ESRD may cause elevated defibrillation thresholds and failure of ICDs
and lead to high rates of shock and antitachycardia pacing

50. CONSULTATIVE APPROACH TO SEVERE KIDNEY
DISEASE AND HEMODIALYSIS PATIENTS
 Prevalence of angiographically significant CAD ranges from 25% in
young, nondiabetic hemodialysis patients up to 85% in older patients
with ESRD who have long-standing DM
 Rate of cardiac death in dialysis patients younger than age 45 exceeds
by 100-fold that in the general population
 Third of diabetic renal transplant candidates have one or more lesions
with greater than 75% stenosis
 ESRD patients have substantially more numerous, proximal, and
severe coronary artery lesions, as well as more severe left ventricular
dysfunction
 Hypertension affects 80% of patients with ESRD, and only 30% achieve
adequate control

51. Risk of coronary heart disease death by gradations of CKD
and diabetes; USRDS = US Renal Data Systems

52.  Long-term cardiorenal protection involves two important concepts:
 blood pressure control to a much lower target of a systolic blood
pressure less than 130 mm Hg
 use of an agent that blocks the RAAS
 ACE inhibitors/ARBs can reduce LVH and possibly improve survival
 Beta blockers can serve as both antihypertensive and anti-ischemic
agents
 Improve LVEF and reduce rates of hospitalization, sudden death,
and all-cause mortality
 Achieve these goals without inducing hypotension during dialysis
sessions
 Hypotension during dialysis can worsen clinical and subclinical
ischemia recognized as chest discomfort, shortness of breath, ST-
segment depression on electrocardiography, and elevations of cTn
on blood testing

53.  LDL cholesterol reduction, in most cases with a statin and ezetimibe,
in patients with ESRD is supported by a 17% reduction in major
atherosclerotic events
 In DM blood glucose control to a target glycohemoglobin below 7
mg/dl
 Smoking cessation as another basic reduction manoeuvre
 Chronic administration of antiplatelet agents (aspirin and clopidogrel)
as well as warfarin has been associated with increased risk of death in
ESRD
 Preventive use should be undertaken with caution
 Stable symptomatic CAD  COURAGE trial suggested PCI had no
benefit over optimal medical therapy
 No similar trial data are available for patients with ESRD

54.  In multivessel disease, multiple studies have shown that outcomes
after CABG are superior to those achieved with PCI with DES
 Dialysis dependent patients undergoing CABG
 4.4-fold increased risk of in-hospital death
 3.1 times greater risk of mediastinitis
 2.6-fold increased risk of stroke
 Aggressive approach with medical management for CAD is warranted,
even in the case of subclinical CAD
 A low threshold for diagnostic testing is appropriate in patients with
ESRD

55. EVALUATION AND MANAGEMENT
OF THE RENAL TRANSPLANT RECIPIENT
 Cardiovascular screening is recommended in high-risk CKD patients
before renal transplantation
 DM
 Men >45 years ; Women >55 years
 Previous H/o IHD
 An abnormal ECG
 Left ventricular dysfunction
 Smoker
 Duration of dialysis more than 2 years
 Modality  exercise versus pharmacologic stress and
echocardiographic versus nuclear scintigraphic imaging must be
individualized