Preventing and Managing CVD Complications in CKD

Richard J, Glassock, MD, MACP

Geffen School of Medicine at UCLA

Orange County Symposium for Cardiovascular Disease Prevention

(Virtual)

October 31, 2020

DISCLOSURES

I have no conflicts of interest to disclose

4

Percentage of NHANES 2013-2016 participants, in the various CKD (eGFR and albuminuria) risk categories

(KDIGO 2012)

2001-2004 2005-2008 2009-2012 2013-2016

Low risk 85.8 85.6 86.5 85.1

Moderately high risk 10.6 10.3 9.7 10.7

High risk 2.4 2.7 2.4 2.7

Very high risk 1.2 1.4 1.4 1.4

13.5 14.2 14.4 14.8

CKD-NHANESPrevalence of CKD Stage 3 by Age Group

(1999-2004)

0%

5%

10%

15%

20%

25%

30%

35%

40%

Prevalence

(%)

20-39 40-59 60-69 70+

Age Group (years)

CAUSES OF CKD(per million population per year

of incident ESKD, 2014)

Diabetes (all Types)- 155 (44%)

Hypertension (?)- 100 (29%)

Glomerulonephritis- 25 (7%)

Polycystic Kidney Disease –10 (3%)

All others- 60 (17%)

TOTAL 350 (100%)

Cardiovascular Disease in CKD/ESKD:Clinical Spectrum

Ischemic (atherosclerotic) Heart Disease (Coronary artery disease), Myocardial Infarction

Left ventricular hypertrophy (and fibrosis)

Congestive Heart Failure (HFrEF/HFpEF)

Arrhythmias (atrial and ventricular fibrillation--Sudden Cardiac Death)

Ischemic and haemorrhagic stroke

Peripheral vascular disease

Vascular calcification (“ossification”)

8

Prevalence of common cardiovascular diseases in patients with or without CKD,

2016

2018 Annual Data ReportVolume 1 CKD, Chapter 4

Reduced GFR (eGFR–creat and CKD Stages) and Age-Standardized Rates of Death, CV Events and Hospitalization

0

5

10

15

20

>60 45-59 30-44 15-29 < 15Ag

e-S

tan

dar

diz

ed R

ates

HOSPITALIZATIONS/10 person-yrs

CV EVENTS/50 person-yrs

ALL CAUSE DEATH/100 person-yrs

Go et al. NEJM 351:1296, 2004

CKD Stage 1 & 2 3 4 5

Albuminuria and ESKD/Mortality Risk

eGFR and HR for All-Cause Mortality according to Age

(Hallan S, et al JAMA , 2012)

CVD is Common in CKD and ESKD

CVD Contributes Greatly to Morbidity and Mortality in CKD

and ESKD

CVD is not Optimally Managed in CKD and ESKD

eGFR and CVDSome Caveats

The risk of CVD in Stage 3A CKD is not greatly increasedunless proteinuria is also present

The risk of CVD increases below an eGFR of about 45-59ml/min/1.73m2 , particularly in males. CV Risk is mainly CHF/Sudden Cardiac Death– not ASCVD- in advanced CKD/ESKD

The risk of mortality (principally CVD) is attenuated by advancing age for all levels of eGFR

RISK STRATIFICATION FOR CVD IN CKD

Risk categories in the eGFR/albuminuria matrix

Older age

Smoking

Obesity and metabolic syndrome

Severity and Characteristics of dyslipidemia

Presence or absence of Diabetes

Blood pressure Control (mainly SBP and ABPM pattern)

Biomarkers (Cystatin C, ACE2 levels)

Coronary artery calcification

Plasma ACE2 and CVD risk(Narula S, et al Lancet 2020; 396:968-976; Anguiano

L, et al Atherosclerosis 2016; 253:135-143)

Increased levels of plasma angiotensin converting enzyme 2 (ACE2) are associated with CVD

Patients with CKD have elevated plasma and the magnitude of ACE2 elevation is associated with increased risk of “silent” ASCVD

ACE2 levels are the highest ranked predictors of CHF, stroke, CAD

PREVENTION OF CVD in CKD

Primary Prevention of CKD

Secondary Prevention of Progression of CKD to advanced stages

Prevention (and management) of CVD in established CKD

PREVENTION OF INCIDENT CKD

Healthy Lifestyle -(No smoking, High Plant Diet [?], Avoiding excess NaCl, Regular Exercise [?])

Maintain Ideal Body Weight-(Avoid Diabetes; mainly T2DM)

Maintain normal blood pressure (?)

Avoid Nephrotoxins- (Aminoglycosides, PPI, chemotherapy, etc, especially as an infant)

Avoid infections -(HIV, HCV, etc)

Have a normal birth weight- (avoid nephropenia)

Choose parents wisely- (genetic disease)

PREVENTION OF PROGRESSION OF CKD to

ADVANCED STAGES

Diet- (Low protein, High Plant foods, NaCl restriction, Supplemental alkali (NaHCO3)

Blood Pressure Control- Targets-

SGLT2 inhibitorsand CKD progression

(Courtesy Christos Argyropoulos; 2020)

Preventative and Management Strategies for CVD in CKD/ESKD

Correction of Dyslipidemia

Reduction of Elevated Blood Pressure

Prevention/Regression of Left Ventricular Hypertrophy

Management of Congestive Heart Failure (HFrEF and HFpEF)

Avoidance of Sudden Cardiac (arrythmogenic) Death

Prevention of Vascular Calcification

Management of Co-morbidity (especially Diabetes, Atrial Fibrillation)

The Study of Heart and Renal Protection (SHARP)

(Baigent C et al. Lancet 377:21`81, 2012)

9270 patients with CKD (3023 dialysis dependent; 6247 not on dialysis) with no prior history of CHD randomized to receive simvastatin (20mg) + ezetimibe (10mg) or a matching placebo

Primary outcome: composite of fatal or non-fatal AMI, ischemic stroke or any arterial revascularization procedure= Major CV events

Follow-up= 4.9 years

SHARP:Outcomes by eGFR:

Major CV events (HR- Sim + E vs Placebo)

00.10.20.3

0.40.50.60.70.80.9

HR

30-59 15-29

SHARP:Outcomes : All- Cause and Cause Specific Mortality:

(HR- Sim + E vs Placebo)

0

0.2

0.4

0.6

0.8

1

1.2

HR

Category

Fatal CHD Ischemic Stroke Non-Vascular All-Cause Mortality

SHARP:Outcomes : Non-Fatal Events:

(HR- Sim + E vs Placebo)

0.65

0.7

0.75

0.8

0.85

HR

Category

Non-Fatal AMI

Ischemic Stroke

Any Coronary Revascularization Procedure

Any Major CV Event

SGLT2 inhibitors and Hospitalization for Heart Failure

(Courtesy of Christos Argyropoulous, MD)

SGLT2 inhibitors and Composite Cardio-Renal Outcomes

(Courtesy of Christos Argyropoulos, MD)

SGLT2 Inhibitors in CKD

CONCLUSIONS- I

CKD is commonly associated with CVD; this association is multi-factorial in origin

CVD is a common cause of morbidity and mortality in CKD

Prevention of CVD in CKD is a three-fold process:

Primary Prevention of CKD

Secondary prevention of Progression of CKD

Prevention and management of CVD in established CKD

CONCLUSIONS- II

In established CKD the main CVD prevention tools are:

Optimal control of BP (target SBP 120-130mmHg; RASi preferred)

Statins for dyslipdemia (except ESKD)

SGLT2 inhibitors (if eGFR >30 ml/min/1.73m2

Diet- mainly NaCl restriction

Glycemic control (in diabetics)

MANY THANKS!!!

32

Percentage of NHANES 2013-2016 participants, in the various CKD (eGFR and albuminuria) risk categories

(KDIGO 2012)Albuminuria categories

Total

A1 A2 A3

Normal to mildly

increased

Moderately

increased

Severely

increased

30

mg/mmol

GFR

cat

ego

rie

s (m

l/m

in/1

.73

m2)

G1 Normal to high ≥90 54.9 4.2 0.5 59.6

G2 Mildly decreased 60-89 30.2 2.9 0.333.5

G3a

Mildly to

moderately

decreased

45-59 3.6 0.8 0.3 4.7

G3bModerately to

severely decreased30-44 1.0 0.4 0.2 1.7

G4 Severely decreased 15-290.13 0.10 0.15 0.37

G5 Kidney failure