The Heart and the Kidney

The Heart and the Kidney

The Heart and the Kidney Jeff Kaufhold, MD, FACP Jan 2016 Summary Case Why this matters Normal Physiology Abnormal Physiology

ARF and CKD staging Renal Syndromes related to the heart Cardiorenal Syndrome Contrast induced acute Kidney Injury Treatment considerations in CRS Objectives 1. Normal physiology of heart and kidney --- 25% of cardiac output goes to the kidneys --- Renin angiotensin - aldosterone cascade regulates blood pressure, and can become pathologic

2. Heart disease can cause acute renal failure by several mechanisms: Contrast injury, cholesterol emboli as a consequence of cardiac cath Impaired output from arrhythmia or MI medication effects from ACE or diuretics 3. Kidney disease has significant negative effects on the heart. Case 56 yo man with CHF admitted with 2 week hx of worsening symptoms. Has DM-2, on metformin, Lisinopril, lasix metolazone and digoxin BP 88/60, P 95 R 20. JVD and S3 present. Edema to mid thigh He is a bit confused, and hands are cold/ clammy. Creatinine 3.1 up from 1.1. sodium 133

CXR shows CHF case In addition to IV diuretics, which of the following is most appropriate management? A. Dobutamine B. IABP C. Milrinone D. Right heart cath Case: Correct answer: A - add dobutamine. This will improve CO Milrinone is excreted by the kidneys and will vasodilate lowering BP IABP would be consideration if he does not respond rapidly to dobutamine

Swan can be helpful to guide therapy, especially if he does not respond as expected. Burden of Atherosclerotic Vascular Disease: CAD, CVD, PVD Prevalence25 million in United States Annual rates Myocardial infarction1.2 million Strokes700,000 CVD mortality931,000 (a death every 30 seconds) Cardiac catheterization1.4 million Percutaneous revascularization1.1 million Surgical revascularization571,000 Annual cost = $250 billion American Heart Association. 2004 Heart and Stroke Statistical Update. At:

Prevalence of Diabetes Among US Adults 2001 1991 No Data <4% 4%-6% Mokdad AH et al. JAMA. 2003;289:76-80. 7%-8% 9%-10% >10%

Framingham Heart Study 30-Year Follow-Up of CVD Events in Patients With Diabetes Risk Ratio Men 10 Women 8 (Ages 35-64) 6 * 4

2 0 Total CVD CHD Cardiac Failure Intermittent Claudication Stroke P<.001 for all values except *P<.05. Wilson PWF, Kannel WB. In: Ruderman N et al, eds. Hyperglycemia, Diabetes and Vascular Disease. 1992. Incidence of Fatal or Nonfatal MI in Patients With and Without Diabetes

P.001 Incidence During 7-Year Follow-Up (%) 50 Nondiabetics with no prior MI Nondiabetics with prior MI 40 Diabetics with no prior MI Diabetics with prior MI 30 P.001 45.0 20.2 18.8

20 10 3.5 0 Events per 100 person years; 7-year follow-up n=1,304 n=69 n=890 n=169

0.5 3.0 3.2 7.8 Haffner SM et al. N Eng J Med. 1998; 339:229-234 Haffner SM et al. N Engl J Med. 1998;339:229-234. Approximate Distribution of Causes of Death in Persons With Diabetes, Based on US Studies 60 50 40 Deaths (%)

30 20 10 0 Heart Disease Cerebrovascular Disease Diabetes Malignant Pneumonia/ All Neoplasms Influenza Other

Based on four cohort studies conducted 1971-1988. Geiss LS et al. Diabetes in America. Bethesda, Md: National Institutes of Health; 1995:233-257. Normal Physiology 25% of cardiac output goes to the kidneys Renin/Angiotensin/Aldosterone cascade regulates blood pressure, and can become pathologic Brain and atrial Natriuretic peptides, along with Aldosterone, regulate volume. Abnormal Physiology Dysregulation of Renin/AT/Aldosterone cascade can lead to vascular and myocardial injury, Malignant Hypertension, Flash Pulmonary Edema.

Alterations in Effective arterial blood volume (EABV) lead to upregulation of angiotensin and aldosterone, ADH New Terminology ARF - RIFLE criteria Risk low uop for 6 hours, creat up 1.5 to 2 times baseline Injury creat up 2 to 3 times baseline, low uop for 12 hours Failure Creat up > 3 times baseline or over 4, anuria Loss of Function Dialysis requiring for > 4 weeks ESRD Dialysis requiring for > 3 months CKD prevalence in world

Populations Country China India Indonesia Pakistan Philipines Vietnam Population CKD est. 1.298.847.624 238.452.952 159.196.336 86.241.697 82.662.800

35.336.295 28.976.185 6.487.322 4.331.076 2.346.281 2.248.914 Assumes 2.72 % incidence CKD Stages Stage 1.

Stage 2. Stage 3. Stage 4. Stage 5. Stage 6. Normal function with known dz GFR 60-80 GFR 30-60 GFR 15-30. GFR less than 15. ESRD on dialysis. US Population with CKD Coresh, Selvin, Stevens. Prevalence of CKD in the US. Impact of renal disease on the heart

Why do patients with acute renal failure die? A. Hyperkalemia/ arrhythmia? B. GI Bleeding? C. Sepsis? D. Fluid overload/ hypoxia? E. Heart attack/ stroke? Impact of renal disease on the heart Why do patients with acute renal failure die? #1 Sepsis # 2 Cardiovascular disease (MI, stroke, CHF) # 3 GI bleeding Impact of renal disease on the

heart Why do patients with Chronic renal failure die? # 1 Cardiovascular disease (MI, stroke, CHF) Sepsis GI bleeding Cardiorenal Syndrome (CRS) Syndrome in which a fairly normal kidney is dysfunctional because of a diseased heart, with the assumption that in the presence of a healthy heart, the kidney would function normally. CRS type 1 Acute CRS Acute heart injury leads to AKI Acute Renal Failure due to cardiogenic shock or reduced cardiac output.

Decreased response to Diuretics Independent marker for initial and 1 year mortality in the face of CHF or MI. Another marker for increased mortality risk in CHF/ CRS is hyponatremia. Renal Syndromes related to Heart Disease ARF Due to contrast, cholesterol emboli Reduced Cardiac Output from MI, arrhythmia Med effects (ACE/ARB/Tekturna) Overdiuresis from diuretics Effects of NSAIDs on the heart and kidneys- NSAID and the heart

In a meta-analysis of 138 randomized trials, COX-2 inhibitors were associated with a significant increase in the risk for myocardial infarction (MI) (risk ratio [RR], 1.86; 95% confidence interval [CI], 1.33-2.59; P =.0003) and vascular events (RR, 1.42; 95% CI, 1.13-1.78; P = .003) compared with placebo. Animal studies suggest that the adverse cardiovascular effects observed with COX-2 inhibitors are due to enhanced endothelial thrombosis (as a result of reduction in prostacyclin synthesis), sodium and water retention, and loss of the protective effects of COX-2 upregulation in the setting of MI, resulting in larger infarction size and thinning of the left ventricular wall in the infarct zone. Timmers L, Sluijter JP, Verlaan CW, et al. Cyclooxygenase-2 inhibition increases mortality, enhances

left ventricular remodeling, and impairs systolic function after myocardial infarction in the pig. Circulation. 2007;115:326-332. CRS Type 2 (chronic CRS) chronic heart failure leads to chronic kidney injury Chronic CHF results in poor flow to kidney and chronic renal dysfunction ESCAPE trial (Evaluation Study of CHF and Pulmonary Catheterization Effectiveness) found that only right heart pressures correlated with renal dysfunction, suggesting that renal vein pressure increases (CVP) lead to renal vascular congestion and loss of function. Renal Syndromes related to Heart Disease Chronic Kidney Disease Due to recurrent injuries from above insults Chronic decrease in renal perfusion from poor

pump function (cardiorenal syndrome) Reduced effective arterial blood volume results in secondary increases in Renin/ AT and Aldosterone, leading to hypervolemia Reduced EABV leads to increased ADH production which causes hyponatremia CRS Type 3 (Acute Renocardiac Syndrome) Abrupt worsening of kidney function leads to acute cardiac dysfunction, from fluid overload, Hyperkalemia, ischemia. Uremia and acidosis lead to depressed cardiac contractility. Angiotensin is a direct endothelial cell toxin and also causes myocardial cell injury. Renal Artery Stenosis is a unique cause of CRS 3. Causes flash pulmonary edema/ severe hypertension Dialysis induced fluid and electrolyte shifts also cause acute cardiac dysfunction, arrhythmia.

CRS Type 4 (Chronic Renocardiac Syndrome) Primary CKD with resultant impact on the heart from HTN, Fluid overload, macroalbuminuria. Leads to ventricular hypertrophy, diastolic dysfunction, marked increased risk of cardiovascular events. Risk is heightened due to the reduced use of ACE, ARB, and contrast dye studies in pts with CKD. CKD pts are much less likely to be treated with these therapies, as well as B-blockers, Aspirin and Plavix. Cumulative probability of a physician visit in the year following CKD diagnosis by physician specialty & dataset Figure 2.10 (Volume 1) Only about 30 %

Patients alive and eligible all of 2008, CKD diagnosis represents date of first CKD claim during 2008, physician claims searched during 12months following that date. Renal Syndromes related to the heart (type 4 CRS) Cardiomyopathy Due to uremia, acidosis (systolic) Chronic hypertension leads to LVH (diastolic and systolic) Diabetes also leads to LVH (diastolic) Fluid overload (diastolic) Can be confused with sleep apnea/ other causes of right heart failure CRS Type 5 (Secondary CRS) Systemic conditions which affect both the heart and the kidney include: Diabetes,

Amyloidosis, Vasculitis, Sepsis, SLE, Sarcoidosis. Treatment of CRS Prevent contrast induced AKI Treatment considerations in diabetics Use of coreg vs other beta blockers Treatment of Hypertension Recognize and Treat OSA Recognize risk factors for CRS Microalbuminuria as marker of vascular disease Use of novel agents Prevalence of comorbidity in NHANES 20012008 participants, by risk factor, expanded

eGFR categories, & method used to estimate GFR Figure 1.5 (Volume 1) NHANES 20012008 participants age 20 & older. Note how HTN is bigger problem as GFR falls Mortality rates in NHANES 1999-2004 participants, by eGFR: MDRD equation Figure 1.11 (Volume 1) NHANES 1999 2004 participants age 20 & older. How to improve CV Morbidity in CKD?

1. Early referral to Nephrology 2. Consider a patient with CKD 4 , 5, and ESRD as having the same risk as a patient who HAS ALREADY HAD THEIR FIRST HEART ATTACK. Beta Blocker Aspirin Statin restart ACE inhibitor or ARB once pt on dialysis To prevent a vessel wall thrombus Hall Thrombus Seen in most teaching hospitals Risk Factors for Contrast Nephropathy Age over 60 Diabetes

Pre-Renal States CHF NSAIDS, ACE Inhibitors, Diuretics Proteinuria Includes, but not limited to Myeloma. Pre-existing Renal Disease Etiology of Contrast induced AKI Two phases of injury: Immediate phase: Contrast load (similar to Gentamicin or Amphotericin) causes intense renal vasoconstriction with immediate oliguria Fluid shifts into vascular space, so patients can go into flash pulmonary edema Can be treated with dialysis Prevented by giving any sodium containing fluid bicarb is not magical

Etiology of Contrast induced AKI Two phases of injury: Delayed/ secondary phase Occurs at the time of the contrast infusion, but creatinine starts climbing 3-7 days after the contrast exposure Due to direct tubular toxicity of the contrast (or gent/ Amphotericin) Due to reactive oxygen radicals Prevented by mucomyst Etiology of Contrast induced AKI Two phases of injury: Delayed/ secondary phase Prevented by mucomyst Mucomyst provides sulfhydryl groups to the Pentose Phosphate shunt, which makes NADP and other free oxygen scavengers

PPS runs concurrently with the Krebs cycle, which is producing ATP and a lot of free oxygen radicals. Risk of CN By Stage of CKD The Kaufhold Nomogram 100 90 80 70 60 Dialysis ARF 50 40 30 20 10

0 Stg 5 < 20 ml/min Stg 4 Stg 3 20 30 30 60 Stg 2 > 60 Incidence of CN

NAOD study 2005 Nationally 4% GVH 2005 GVH 2006 18% 5 DHH 4% Contrast Nephropathy at GVH 2005 %

% CIN 50 50 40 40 30 30 20 20 10 10 0 0 All pts All pts DM DM CHF

CHF Proteinuria Proteinuria CRF CRF Policy / Recommendations Stop ACE/ ARB, NSAIDs, Diuretics day before procedure IVF for everyone NS for low risk pts Bicarb for high risk pts? Urinalysis for all pts/ calculate Creat Clear for all pts. Proteinuria or creat clear < 40 considered High risk.

Mucomyst for High risk pts Limit volume of contrast in High Risk Pts. Consider Nephrology consult if considering Mannitol, Corlepam, or identified as high risk. Contrast Nephropathy GVH 2006 % After Implementation of Policy % CIN 25 25 20 20 15 15 10 5 0

10 5 0 All pts DM CHF Proteinuria CRF Association of Microalbuminuria With CV Events in Patients With Diabetes With Microalbuminura present Microalbuminuria Without microalbuminuria

Microalbuminuria not present 30 25 25 18.6 Percentage (%) 20 15 13.9 9.3 8.5

10 5 2.5 0 MI, Stroke, or CV Death HF Hospitalization Gerstein HC et al. JAMA. 2001;286:421-426 Gerstein HC et al. JAMA. 2001;286:421-426. All-Cause Mortality

Presence of MAU Indicates a Potential Increased Risk for CV Events Urinary Albumin (mg/day) 1,000 900 Macroalbuminuria >300 mg/day Increased CV Risk and Presence of Renal and Vascular Dysfunction 800 700 600 500 400 300 200

100 MAU 30-299 mg/day Increased CV Risk and Vascular Dysfunction 0 Normal Garg JP et al. Vasc Med. 2002;7:35-43. Eknoyan G et al. Am J Kidney Dis. 2003;42:617-622. Treatment Goals for Diabetic Hypertensive Patients Control blood pressure 130/80 mm Hg for most patients 125/75 mm Hg for patients who have proteinuria 1 g/d and renal insufficiency Reduce the risk of end-organ failure

Reduce the risk of CV events MI CV death Delay or prevent the progression to HF JNC 7 Report. JAMA. 2003;289:2560-2572. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. ADA. Diabetes Care. 2003;26(Suppl 1):S33-S49. United Kingdom Prospective Diabetes Study (UKPDS): Results ACEI or BB for BP Control (144/82 vs 154/87 mm Hg) Glucose Control Risk Reduction (%) 0 Any

DiabetesRelated Endpoint 10 20 30 12 (P.0001) DiabetesRelated Death Microvascular Endpoints Any DiabetesRelated Endpoint

DiabetesRelated Death Stroke Microvascular Endpoints 10 (P=.34) 25 (P.01) 25 (P.005) 40

50 UK Prospective Diabetes Study Group 38. BMJ. 1998;317:703-713. UK Prospective Diabetes Study Group 33. Lancet. 1998;352:837-853. 32 (P=.019) 44 (P=.013) 37 (P=.009) UKPDS: Blood Pressure Control Study in Type 2 DiabetesEffect of Intensive BP Lowering on Risk of Micro- and Macrovascular Complications Benefits of 144/82 vs 154/87 0

MI Any DiabetesRelated Endpoint DiabetesRelated Death Retinopathy Renal Failure Stroke Vision Deterioration

HF 10 20 Risk Reduction (%) 21 30 40 50 60 P=.13 24 P=.0046 32

P=.019 34 P=.0038 42 P=.29 44 P=.013 47 P=.0036 56 P=.0043 70 1,148 hypertensive patients with type 2 diabetes were allocated to tight (144/82 mm Hg, n=758) or less tight

(154/87 mm Hg, n=390) and followed for a median of 8.4 years. UKPDS Group. UKPDS 38. BMJ. 1998;317:703-713. MICRO-HOPE: Outcomes in Diabetes Ramiprils Effects Beyond Baseline Therapy Diuretics -blockers Glycemic control medications Relative Risk Reduction (%) Aspirin or other antiplatelets Lipid-lowering agents 0 Composite

Stroke Nonfatal MI CV Death Total Mortality* -5 -10 -15 -20 22% -25

-30 -35 -40 25% ** 33% N=3,577 HOPE Study Investigators. Lancet. 2000;355:253-259. 24% 37% *Secondary

endpoint **P=.0004 P=.0074 P=.01 P=.0001 P=.0004 Physician Concerns About Adding -Blockers in Patients With Diabetes Metabolic Worsening HDL Increased Apo B Negative effects on glucose metabolism Negative effects on renal

blood flow Masked hypoglycemia Bell DS. Endocr Pract. 1999;5:51-53. Tolerability Fatigue Impotence Weight increase Peripheral vasoconstriction (cold extremities) Depression Effect of -Blockers on Insulin Sensitivity in Hypertensive Patients Celiprolol 35%

Carvedilol 13% Dilevalol 10% Pindolol 17% Atenolol 22% Metoprolol Propranolol

21% 33% 40 20 0 % Change Above or Below Baseline Jacob S et al. Am J Hypertens. 1998;11:1258-1265. 20 40 Carvedilol Versus Metoprolol for CHF+diabetes

Deedwania, Am Heart J 2005;149:159 COMET Diabetes Diabetes yes no Overall Carvedilol better 0.50 0.75 Metoprolol better 1.00

1.25 1.50 Albumin:Creatinine Ratio Relative reduction, 16% (Carvedilol vs Metoprolol Tartrate) 95% CI (6, 25) P=.003 4 2.5 Change (%) 0 -4 -8

-12 -16 -14 P=.003 Carvedilol (n=388) P=NS Metoprolol Tartrate (n=542) Bakris GL et al. JAMA. 2004;292:2227-2236. Data on file. GlaxoSmithKline. Cardiovascular Protection as the Therapeutic Target in Diabetes Vasculo-protective/Cardio-protective

Aspirin or clopidogrel ACE inhibitor/ARB -blocker preferably Carvedolol Statin Hemodynamic Blood pressure control Metabolic Blood sugar control Percentage of Adults With Diabetes Who Achieved Recommended Levels of Vascular Risk Factors in NHANES 100 90 NHANES III

80 NHANES IV 70 % 60 50 40 30 20 10 0 Hb A1c 7% Saydah S et al. JAMA. 2004;291:335-342.

BP 130/80 mm Hg TC 200 mg/dL Good Control of All Three High-Risk Hypertensive Patients Require Multiple Agents to Achieve Goal Achieved Systolic BP AASK1 (134 mm Hg) ABCD2,3

(132 mm Hg) ALLHAT4 (135 mm Hg) HOT2,5 (141 mm Hg) IDNT6 (140 mm Hg) RENAAL7 (140 mm Hg) UKPDS2,8

(144 mm Hg) 1 2 3 4 Number of BP Medications Wright JT et al. JAMA. 2002;288:2421-2431. 2Bakris GL. J Clin Hypertens. 1999;1:141-147. 3Estacio RO et al. N Engl J Med. 1998;338:645-652. 4The ALLHAT Officers and Coordinators. JAMA. 2002;288:2981-2997. 5Hansson L et al. Lancet. 1998;351:1755-1762. 6Lewis EJ et al. N Engl J Med. 2001;345:851-860. 7Bakris GL et al. Arch Intern Med. 2003;163:1555-1565. 8UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. 1 What Should Treat patients with diabetes as if they have known CAD Imply?

Same is true for patients with CKD Aspirin (lowers risk of CV events in diabetes) -blocker (lowers risk of MI, stroke, heart failure, and CV mortality in diabetes) ACE inhibitor (lowers risk of MI, stroke, heart failure, and CV mortality in diabetes) Statin (lowers risk of MI, stroke, heart failure, and CV mortality in diabetes regardless of LDL) Smith SC Jr et al. Circulation. 2001;304:1577-1579. Novel Agents for treatment of CHF Neprilysin Inhibitors NEP (neutral endopeptidase) metabolizes ANP and BNP, ( as well as bradykinin.) So inhibitors increase levels of ANP/ BNP and bradykinin Sacubitril or combo of Valsartan/ Sacubitril known as Entresto

Paradigm-HF study showed that pts who tolerated treatment had less readmission for CHF Correction of Anemia in Diabetic CHF Diabetic patients with Hb less than 12.5 g% treated with erythropoetin and IV iron NYHA class improved by 36.8% Dyspnea improved by 69.7% on Visual Analogue Scale EF improved by 7.6% Hospitalizations decreased by 96.6% Silverberg DS et al. Nephrol Dial Transplant. 2003;18:141-146. Obstructive Sleep Apnea, Diabetes, and CHF OSA is more prevalent in both diabetes and CHF Increased sympathetic tone is the common

denominator Increased sympathetic activity increases BP, myocardial stress, and insulin resistance CPAP treatment decreases sympathetic activity and afterload and ANP, and increases LVEF and stroke volume CPAP=continuous positive airway pressure. Somers VKK et al. J Clin Invest. 1995;96:1897-1904. Kaye DM et al. Circulation. 2001;103:2336-2338. Treatment: Digoxin and Diuretics Improve clinical manifestations of HF Improve quality of life for HF patient No effect on mortality

To improve mortality, the remodeling process must at least be halted and, preferably, reversed Guidelines Comparison: Blood Pressure Goals in Hypertensives JNC 7 130/80 mm Hg NKF 130/80 Hg with CKD ADA 125/75 mm Hg* 130/80 mm Hg

*Lower blood pressure levels are recommended for people who have proteinuria >1 g/d and renal insufficiency. JNC 7 Chobanian A et. Al Hypertension 2003. ADA. Diabetes Care. 2002;25(Suppl 1):S33-S49. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Stages of Hypertension Normal < 120 / 80 Prehypertension 120 -139 / 80-89 Stage 1 140-159 / 90-99 Stage 2

> 160 / >100 Treatment of Hypertension Stage 1 or Single agent HCTZ for most pts. B-Blocker for females/ high heart rate. Stage 2 I start with DHP CCB (Nifedipine XL) plus one or both of above. Resistant HTN I look for CLASSES of agents Classes of Antihypertensives Diuretics Rate control agents BBlocker,

Verapamil, Diltiazem ACE/ ARBs Vasodilators Dihydropyridines, Hydralazine, Alpha blockers, Minoxidil Central agents: clonidine, aldomet. Nephrology level htn I tell the pt that well need to control the main route plus the main detours causing the HTN. Average of 3.1 medications to achieve control Rate control (pulse < 78) Diuretic Vasodilator DHP CCB, Hydralazine, Cardura, Minoxidil. ACE / ARB (accept 30% increase in creat if BP responds) Refer to Nephrologist If unable to control on 3 drug regimen

which includes Rate control, diuretic. If you are considering Minoxidil or renal angio. If creatinine climbs more than 30 % or if creatinine is over 2.0. References Ronco, Haapio, House e al. Cardiorenal Syndrome, JACC, Vol 52, No 19, 2008 page 1527-39. New Insights into CV Risk Reduction in the patient with Diabetes. Online. March 6 2005. JNC 7 Report 2003 Eckardt KU, Gillespie IA, Kronenberg F. High cardiovascular event rates occur within the first weeks of starting hemodialysis. Kidney Int. 2015;88:1117-1125. Post Test

Which Treatment has the LEAST impact on progression of renal disease? A. Use of ACE inhibitors B. Referral to a nephrologist C. Use of DHP calcium Channel Blocker D. Control of Diabetes to A1c < 8.0 E. The nature of the underlying renal Disease

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