PULMONARY HYPERTENSION: An Emerging Problem in CKD and Dialysis Patients Gerald Schulman, MD, FASN Vanderbilt University Nashville, Tennessee, USA [email protected]

CLASSIFICATION OF PULMONARY HYPERTENSION 1.1 IDIOPATIC PRIMARY PULMONARY ARTERIAL HYPERTENSION (PAP) 1.2 PAP ASSOCIATED WITH: – – – – –

CONNECTIVE TISSUE DISEASE CONGENITAL HEART DISEASE/PULMONARY HYPERTENSION OF THE NEWBORN PORTAL HYPERTENSION HIV TOXIC DRUGS

2 PULMONARY VENOUS HYPERTENSION – LEFT-SIDED ATRIAL AND VENTRICULAR HEART DISEASE – PULMONARY VENO-OCCLUSIVE DISEASE – EXTRINSIC COMPRESSION OF CENTRAL PULMONARY VEINS

3 PULMONARY HYPERTENSION ASSOCIATED WITH LUNG DISEASE – CYSTIC FIBROSIS/INTERSTITIAL LUNG DISEASE/HIGH ALTITUDE EXPOSURE – COPD – SLEEP DISORDERS

4 PULMONARY HYPERTENSION DUE TO THROMBOEMBOLIC DISEASE – THROMBOTIC DISEASE OF PULMONARY ARTERIES – PE FROM WORLD SYMPOSIUM ON PULMONARY – SARCOIDOSIS AND OTHERS HYPERTENSION

WHO FUNCTIONAL CLASSIFICATION OF PULMONARY HYPERTENSION Class I Patients without limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or syncope.

Class II Patients with slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.

Class III Patients with marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope

Class IV Patients with inability to carry out any physical activity without symptoms. Patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

PULMONARY HYPERTENSION INCIDENCE IN DIALYSIS PATIENTS • HEMODIALYSIS: 40% – 20% OF HEMODALYSIS PATIENTS WITH ARTERIOVENOUS FISTULAS HAVE REDUCED TRICUSPID ANNULUS PLANE SYSTOLIC EXCURSION

• PERITONEAL DIALYSIS: 20% • CHRONIC KIDNEY DISEASE: 20% • HAZARD RISK – ALL-CAUSE MORTALITY, CV MORTALITY AND CV EVENTS ARE 1.85, 2.36 AND 2.27, RESPECTIVELY

FEATURES OF PULMOMARY HYPERTENSION • • • • •

WIDE SPLITTING S2 PULMONARY INSUFFICIENCY ELEVATED JVP EDEMA/ASCITES ECHOCADIOGRAPHIC FEATURES – – – – – –

RIGHT CHAMBER DILATION D-SHAPED RV CHAMBER (FLATTENING OF IV SEPTUM) ABSENT IVC COLLAPSING AND ATRIAL WAVE IVC> 2 cm = RAP> 10 mmHg; < 40% COLLAPSIBILITY RAP > 15 mm Hg ELEVATED Mean PULMONARY ARTERY SYSTOLC PRESSURE • mPAP = 0.61 x SYSTOLIC PULMONARY ARTERY PRESSURE + 2

– ELEVATED SYSTOLIC PULMONARY ARTERY PRESSURE •

sPAP = 4(TRICUSPID REGURGITATION SPEED)2 + RAP

– REDUCED TRICUSPID ANNULUS PLANE SYSTOLIC EXCURSION

PATHOPHYSIOLOGY OF PULMOMARY HYPERTENSION AFTER DI LULLO et al CARDIORENAL MED 2013;96-103

• INCREASED CYTOKINES AND GROWTH FACTORS – FGF, PDGF, TGFBETA, ACE, DECREASED NOS, DECREASED NO(associated with higher hematocrit)

• ABNORMAL SMOOTH MUSCLE PROLIFRTATION AND FIBROSIS • NET RESULT: ARTERIAL MYOINTIMAL PROLIFERATION AND FIBROSIS • THE EFFECT OF THESE PERTUBATIONS AND PRESSURE OVERLOAD LEAD TO WORSENING PULMONARY HYPERTENSION

PATHOPHYSIOLOGY OF PULMONARY HYPERTENSION • ENDOTHELIAL DYSFUNCTION – PROSTAGLANDINS: INBALANCE BETWEEN VASOCOSTRICTION AND VASODILATION – NITRIC OXIDE: LOWER LEVELS PH ASSOCIATED WITH DIMEHHYLARGININE INHIBITING NO PRODUCTION. REDUCED NO SYNTHASE. POTENTIAL EFFECTS OF INCREASED HEMOGLOBLIN LEVELS – ENDOTHELIN: Vascular effects of ET-1. ET-1 is generated in endothelial and smooth muscle cells in response to oxidized LDL, angiotensin II (Ang II), etc. The stimulation of endothelial ETB receptors increases the release of NO, whereas ETA receptors mediate contraction and cell proliferation and migration. ET-1 stimulates interleukin (IL) and tumor necrosis factor-α (TNFα) expression in monocytes, leukocyte adherence, platelet aggregation, and adhesion molecule expression. ET-1 stimulates the production and action of growth factors, DNA and protein synthesis, and cell cycle progression. – INFLAMMATION AND OXIDATIVE STRESS – RIGHT VENTICULAR FAILURE

Vascular effects of ET-1.

Lüscher T F , and Barton M Circulation. 2000;102:24342440 Copyright © American Heart Association, Inc. All rights reserved.

PULMONARY HYPERTENSION BIOMARKERS  PROSTAGLANDINS  ALTERED RATIO OF PROSTACYCLIN TO THROMBOXANE

 NITRIC OXIDE  CONTENT IN EXHALED AIR

 ENDOTHELIN  ELEVATED ET-1/ET-3  LMITED BY THE USE OF ET ANTAGONSITS

 INFLAMMATORY/OXIDATIVE STRESS  CLASS I PAH: ELEVATION IN INTERLEUKINS, TNF, MCP-1, TGFbrta , ISOPROSTANES

 RIGHT VENTRICULAR FAILURE  BNP PREDICTS MORTALITY, DEGREE OF IMPAIRMENT AND RESPONSE TO TREATMENT.

RIGHT VENTRICULAR DYSFUNCTION IN DIALYSIS PATIENTS

DI LULLO ET AL NEPHRON CLIN PRACT 2011; 118:c257-c261

RIGHT VENTRICULAR DYSFUNCTION IN DIALYSIS PATIENTS

RIGHT VENTRICULAT DYSFUNCTION IN DIALYSIS PATIENTS

PULMONARY HYPERTENSION IN HEMODIALYSIS PATIENTS WITHOUT AV ACCESS KIYKIM AA et al RENAL FAILURE 2010; 32:1148-1152

74 PATIENTS WITH CATHETERS, NOT AV ACCESS 51 (68.8%) WITH PULMONARY HYPERTENSION 21 (28.3%) MILD AND 30 (40.5%) MODERATE GROUPS

BEFORE HEMODIALYSIS

AFTER HEMODIALYSIS

CELLULOSE ACETATE PAP

35 mmHg

33 mmHg

POLYSULFONE PAP

36 mmHG

29 mmHg

THE EFFECT OF HEMODIALYSIS ON CARDIAC CONTRACTILITY J CLIN INVEST 71:377-384, 1983

• n = 5 HD PATIENTS UDERGOING ALL STUDIES • CUPROPHANE, ACETATE-BUFFERED DIALYSATE WITH 132 mEq/L SODIUM • 3 MANUVERS – UF ONLY – REGULAR HD – ISOVOLEMIC HD

• PRE/POST HD ECHOCARDIOGRAMS UNDER BASELINE, LOW AND HIGH FILLING PRESSURES (NEGATIVE PRESSURE, TILT)

LV VOLUME: REGULAR DIALYSIS WITH ULTRAFILTRATION 180 160 140 120 100 80

EDV

60 40 20 0 PRE 42 0.61

POST 52 EF(%) 1.04 VCF

STROKE V ESV

LV VOLUME: ULTRAFILTRATION ONLY 180 160 140 120 100 80

EDV

60 40 20 0 PRE 44 0.65

POST 31 EF(%) 0.43 VCF

STROKE V ESV

LV VOLUME: ISOVOLEMIC HEMODIALYSIS 180 160 140 120 100

EDV

80 60 40 20 0 PRE 44 0.64

POST 59 EF(%) 1.26 VCF

STROKE V ESV

LEFT VENTRICULAR FUNCTION CURVES

STROKE VOLUME PRE POST

REGULAR HD +CHANGE IN CONTRACTILITY +STARLING EFFECT

REGULAR

UF ONLY NO CHANGE IN CONTRACTILITY - STARLING EFFECT

ISOVOLEMIC HD +CHANGE IN CONTRACTILITY + STARLING EFFECT

UF ONLY

ISOVOL HD

LEFT VENTRICULAR END DIASTOLIC VOLUME

TRICUSPID REGURGITATION

PEPPER-STUDY (prevalence of precapillary PAH in ESRD) PABST S et al PLoS ONE 2012; 7:e35310

PEPPER-STUDY

PEPPER-STUDY

SLEEP APNEA AND PULMONARY HYPERTENSION

UNIQUE FEATURES OF PULMONARY HYPERTENSION IN DIALYSIS PATIENTS • ANEMIA AND THE HEMODIALYSIS ACCESS – INCREASED RIGHT VENTRICULAR PRELOAD – THE HEMODIALYSIS TREATMENT WITH REDUCTION IN EXTRACELLULAR VOLUME MITIGATES THESE ABNORMALITIES – INCREASING HEMATOCRIT MAY REDUCE NITRIC OXIDE – EPO MAY HAVE BENEFICIAL PELIOTROPHIC EFFECTS AFTER DI LULLO et al CARDIORENAL MED 2013;96-103

MECHANISM OF THE DEVELOPMENT OF PULMONARY HYPERTENSION IN ESRD YIGLA M et al SEMINARS IN DIALYSIS 2006; 19:353-357

ESRD REDUCED NO, INCREASED ET PRODUCTION

PRE HEMODIALYSIS AV ACCESS CREATION

PUMONARY VASOCONSTRICTION NEW OR PREEXIXTING PH

INCREASED CARDIAC OUTPUT HEMODIALYSIS START

WORSENING PH

PAH OUTCOMES

Baseline plasma BNP, ANP, NE, and EPI in patients with PPH according to NYHA functional class. *P