Evolving Treatments for Chronic Kidney Disease and ...

Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals

Evolving Treatments for Chronic Kidney Disease

and Complications

Presented as a Live Webinar

Tuesday, June 15, 2021 1:00 p.m. – 2:00 p.m. ET

On‐demand Activity

Recording of live webinar Available after June 22, 2021

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FACULTY

Kelley Doherty Sanzen, Pharm.D., CDOE, PAHM Clinical Pharmacist Specialist Brown Medicine Division of Kidney Disease and Hypertension Providence, Rhode Island

View faculty bio at https://www.ashpadvantage.com/t2d/ckdtx/

WEBINAR INFORMATION

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Evolving Treatments for Chronic Kidney Disease and Complications


Kelley Doherty Sanzen, Pharm.D., CDOE, PAHM

Brown Medicine ‐ Division of Kidney Disease and Hypertension

Providence, Rhode Island

Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals

No one in control of the content of this activity has a

relevant financial relationship (RFR) with an ineligible

company.

As defined by the Standards of Integrity and Independence in Accredited Continuing Education definition of ineligible company. All relevant financial relationships have been mitigated prior to the activity.

Disclosure of Relevant Financial Relationships

© 2021 American Society of Health-System Pharmacists, Inc. All rights reserved. 2


Abbreviations

ACR albumin‐to‐creatinine ratio

ASCVD atherosclerotic cardiovascular disease

BMI body mass index

CHF congestive heart failure

CKD chronic kidney disease

CV cardiovascular

CVD cardiovascular disease

DKD diabetic kidney disease

eGFR estimated glomerular filtration rate

EF ejection fraction

ESKD end‐stage kidney disease

FDA Food and Drug Administration

Fe Iron

GFR glomerular filtration rate

GI gastrointestinal

Hb hemoglobin

HF heart failure

HFrEF heart failure with reduced ejection fraction

HTN hypertension

IV intravenous

MACE major adverse cardiovascular events

MI myocardial infarction

RAAS renin‐angiotensin‐aldosterone system

RBC red blood cell

T1D type 1 diabetes

T2D type 2 diabetes

Learning Objectives

At the conclusion of this activity, participants should be able to

• Describe the disease burden of CKD and its impact on other comorbidities.

• Discuss three complications associated with diabetes and/or kidney dysfunction: heart failure, anemia, and hyperkalemia.

• Summarize current and evolving treatment options for patients with CKD.

• Apply the guideline recommendations for routine screening for CKD in patients with cardiorenal‐metabolic disease.



Disease Burden

Burden of CKD in the U.S.

*Prevalence of CKD in U.S. adults using NHANES 2013‐2016 data. CKD may be overestimated as persistence of albuminuria or creatinine was not accounted for based on KDIGO recommendations.†Based on 2017 data.

KDIGO = Kidney Disease Improving Global Outcomes; NHANES = National Health and Nutrition Examination Survey.

1. Centers for Disease Control. Chronic Kidney Disease in the United States, 2019. https://www.cdc.gov/kidneydisease/pdf/2019_National‐Chronic‐Kidney‐Disease‐Fact‐Sheet.pdf. 2. United States Renal Data System. 2018 Annual Data Report. Volume 1: CKD in the United States. 3. United States Renal Data System. 2019 Annual Data Report. Executive Summary.

Approximately 1 in 7 adults are estimated to

have CKD1,*

In 2016, all‐cause mortality rate for CKD was about 10% in Medicare patients2

Total Medicare expenditure for both CKD

and ESKD3,†

$120 billion



Categories of kidney function and damage

GFR category GFR (mL/min/1.73 m2) Kidney function

G1* ≥90 Normal or high

G2* 60–89 Mildly decreased†

G3a 45–59 Mildly to moderately decreased

G3b 30–44 Moderately to severely decreased

G4 15–29 Severely decreased

G5 <15 Kidney failure

Albuminuria category AER (mg/24 hr) ACR‡ (mg/mmol) ACR‡ (mg/g) Albumin in urine

A1 <30 <3 <30 Normal to mildly increased

A2 30–300 3–30 30–300 Moderately increased†

A3 >300 >30 >300 Severely increased§

CKD is classified based on cause, GFR category, and albuminuria category

eGFR

Albuminuria

*Does not fulfill the criteria for CKD in the absence of evidence of kidney damage; †Relative to young adult level; ‡Approximate equivalent;§Including nephrotic syndrome (albumin excretion usually > 2200 mg/24 hr [UACR > 2220 mg/g; > 220 mg/mmol]).AER = albumin excretion rateKidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1‐150.

Increases in prevalence of CKD risk factors anticipated to increase burden of ESKD

ESKD Incidence and Prevalence per Million Population in the U.S.2

ESKD In

cidence per Million

ESKD Prevalence per Million

500

1000

1500

2000

2500

3000

3500

1980 1990 2000 2010 2020 2030

00

200

400

600

800

1000

Simulated Incidence

ProjectedPrevalence

SimulatedPrevalence

ProjectedIncidence

Hypertension

Diabetes Family History

ASCVD

Obesity

Race and Ethnicity

Age

CKD Risk Factors1

1. Kazancioğlu R. Kidney Intl Suppl. 2013;3(4):368‐371; 2. McCullough KP et al. J Am Soc Nephrol. 2019;30(1):127‐135.



Long‐term progression of kidney disease in patients with T2D

*The UKPDS enrolled patients with newly diagnosed T2D; †Defined as a urinary albumin concentration 50–299 mg/L; ‡Defined as a urinary albumin concentration ≥ 300 mg/L §Defined as urinary albumin concentration ≥ 50 mg/L.

1. Adler A et al. Kidney Int. 2003;63(1):225–32; 2. Retnakaran R et al. Diabetes. 2006;55(6):1832–9.

A substantial proportion of patients with T2D will develop albuminuria and renal impairment

United Kingdom Prospective Diabetes Study (UKPDS)1

5102 patients with T2D*

15 years after diagnosis2

Developed albuminuria§

Developed eGFR < 60 mL/min/1.73 m2

(CKD stage 3–5)

Albuminuria

Normoalbuminuria Microalbuminuria† Macroalbuminuria‡

Progressed from normoalbuminuria to microalbuminuria per year

2%

2.8%Progressed from

microalbuminuria to macroalbuminuria per year

28%

38%

Diabetes is the leading cause of ESKD

37

50

33

4750 50

0

10

20

30

40

50

60

70

80

90

100RRI‐CKD Study

Dialysis Patients

General Population

c

Quality of Life Score

2

Physical Component Scale‡

Mental Component Scale‡

*Data from the International Dialysis Outcomes and Practice Patterns Study (n=2,855); †Data from the Medical Outcomes Study Short Form‐36 manual (n=2,474); ‡Physical and mental component scales consist of physical functioning, physical role, physical pain, general health, vitality, social functioning, emotional role, and mental health.

RRI‐CKD = Renal Research Institute‐Chronic Kidney Disease study; RRT = renal replacement therapy.

1. United States Renal Data System. 2019 Annual data report. Executive summary; 2. Perlman RL et al. Am J Kidney Dis. 2005;45(4):658‐666.

Diabetes47%

Hypertension29%

Glomerulonephritis7%

Cystic kidney3%

Other/unknown14%

†

*

Primary cause of ESKD1

U.S. population, 2017

In U.S. Medicare patients, cost of ESKD in 2017 was 35.9 billion accounting for 7.2% of the overall Medicare spending 1



CV death is more likely than progression to ESKD in patients with CKD

1. Thompson S et al. J Am Soc Nephrol. 2015;26(24):2504–11; 2. Dalrymple L et al. J Gen Intern Med. 2011;26(10):379–85; 3. Matsushita K et al. Lancet Diabetes Endocrinol. 2015;3(7):514‐525.

Leading causes of death in CKD1

• CV events• non‐CV causes (e.g., cancer, infection)

eGFR and ACR are strong predictors of CV mortality

3.8 3.55.4

3.0 2.6

4.80.50.3

1.8

0

2

4

6

8

10

12

14

Rate per 100 person‐years

eGFR (mL/min/1.73 m2)

ESKD, CV mortality, and non‐CV mortality2

< 60 n = 1268

45–59n = 985

< 45n = 283

ESKD CV Mortality Non‐CV Mortality

Cardiovascular Mortality3(n=24,777; 15 studies; 1879 cases)

Full model Base C statistic 0.773

eGFR ‐0.0079 (‐0.0123 to ‐0.0036)

ACR ‐0.0141 (‐0.0193 to ‐0.0088)

eGFR and ACR ‐0.0227 (‐0.0296 to ‐0.0158)

Diabetes ‐0.0025 (‐0.0066 to 0.0016)

Systolic blood pressure ‐0.0064 (‐0.0097 to ‐0.0031)

Total cholesterol ‐0.0005 (‐0.0023 to 0.0013)

HDL cholesterol ‐0.0035 (‐0.0060 to ‐0.0010)

Total and HDL cholesterol ‐0.0040 (‐0.0069 to ‐0.0012)

Smoking ‐0.0058 (‐0.0101 to ‐0.0014)

‐0.04 ‐0.02 0.020

DL is a 50‐year‐old woman with CKD, HTN, T2D. Labs are available to review from 2016 and 2021.

Which of the following factors indicate an increased risk of advancement to higher stages of kidney disease?

a. Increasing blood pressure and decreasing A1C

b. Increasing ACR and decreasing eGFR

c. Increasing BMI and decreasing A1C

d. Decreasing ACR and increasing eGFR

Labs/Vitals 2016 2021

BMI (kg/m2) 26 27

Blood pressure (mmHg) 120/76 124/76

eGFR (mL/min/1.73 m2) 46 32

ACR (mg/g) 66 678

A1C (%) 7.6 7.3



Complications

Complications associated with kidney dysfunction

1. Bello A et al. Kidney Int Suppl. 2017;7(2):122‐129; 2. Miller WL. Circ Heart Fail. 2016;9(8):e002922; 3. Viera AJ et al. Am Fam Physician. 2015;92(6):487‐495; 4. Weiner D et al. Clin J Am Soc Nephrol. 2015;10(8):1444‐1458; 5. Thomas R et al. Prim Care. 2008;25:329‐344.

Sodium & Water Balance1,2

PotassiumBalance3

Elimination of Nitrogenous Wastes1,4

ErythropoietinProduction5

Acid‐baseBalance1

Activation ofVitamin D5

PhosphateElimination5

Hypertension Hyperkalemia Anemia Hypocalcemia

HyperparathyroidismVolume overload

Heartfailure

Uremia Metabolic acidosis

Bone disorders



Hyperglycemia, insulin resistance, hyperinsulinemia

ASCVD

Ischemic cardiomyopathy

Heart Failure

Hypertension

Hypertensive cardiomyopathy

Metabolic disturbances

Disturbed cellular function

Structural alterations

Neurohormonal activation (RAAS)

Diabetic cardiomyopathy

Mechanisms of heart failure in diabetes

Adapted from Low Wang CC et al. Circulation. 2016; 133:2459‐2502.

Patients with cardiorenal disease are at increased risk of hyperkalemia

aHyperkalemia defined as K+ >5.0 mEq/L;1‐3 bNYHA class III or IV and LVEF <35%;2 cHyperkalemia defined as persistent K+ >5.5 mEq/L (or 1 reading of K+ ≥6.0 mEq/L).5

LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; RAASi = renin–angiotensin–aldosterone system inhibitor.

1. Kovesdy CP. Nat Rev Nephrol. 2014;10:653‐662; 2. Vardeny O et al. Circ Heart Fail. 2014;7:573‐579; 3. Nilsson E et al. Int J Cardiol. 2017;245:277‐284; 4. Chomicki J et al. J Am Soc Hypertens. 2014;8:e30. P‐10; 5. Khosla N et al. Am J Nephrol. 2009;30:418‐424.

Advanced Stages of CKD1,a

Up to 40‐50%, especially in patients with diabetes and on RAASi therapy

K+Heart Failure2,a

Up to ~40% in patients with severe HFb on spironolactone 50 mg/day

Diabetes Mellitus3,a

~17% over 3‐year period

Resistant Hypertension4,5,c

Up to ~8‐17% with add‐on MRA therapy

General Population1,a

Incidence and prevalence of hyperkalemia is 2‐3%



51119

239

333

189

326

570

786

0

100

200

300

400

500

600

700

800

900

Incidence of hyperkalemia increases in patients with worsening CKD with or without HF

Note: Hyperkalemia defined as K+ >5.0 mEq/L1,2

1. Thomsen RW et al. Nephrol Dial Transplant. 2018;33:1610‐1620; 2. Thomsen RW et al. J Am Heart Assoc. 2018;7:e008912.

Inciden

ce Rates of Hyp

erkalem

ia

per 1000 Person Years

Population‐based cohort studies linking individual data from hospital, prescription, and laboratory databases from the Danish National Patient Registry in northern Denmark (population 1.8 million) during 2000–2012. Patients with a first‐time diagnosis of CKD (N=157,766) or CKD with HF were identified (N=31,649)1,2

eGFR 45‐59 mL/min/1.73 m2 eGFR 30‐44 mL/min/1.73 m2 eGFR 15‐29 mL/min/1.73 m2 eGFR <15 mL/min/1.73 m2

CKD1

CKD with HF2

n= 108,842 6931 3101 11669839 370731,502 5800

Normal serum K+ range

3.5‐5.0 mEq/L2

Hyperkalemia‐associated mortality is increased in patients with comorbidities

aDifference from control group is significant. bControl group comprised of individuals without known HF, CKD, diabetes, CVD, or HTN.

1. Collins AJ et al. Am J Nephrol. 2017;46:213–221; 2. National Kidney Foundation. What is hyperkalemia? https://www.kidney.org/atoz/content/what‐hyperkalemia (accessed 2021 Mar 17).

HF, CKD, and Diabetesa

CKD (stage 3‐5)a

HFa

Diabetesa

Control groupb

Baseline Serum K+ level (mEq/L)

3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

2.5

Predicted Probab

ility of Mortality

Relationship between serum K+ value and mortality over an 18‐month period1

Analysis of electronic medical record data from multiple U.S. integrated health delivery networks of 911,698 patients (mean age 57.4 years) with 2 serum K+ measurements between 2007 and 20121

All‐cause mortalitywas significantly elevated for every 0.1 mEq/L change in serum K+ <4.0 mEq/L and ≥5.0 mEq/L1



Anemia is a frequent complication of CKD and prevalence increases with disease severity

Note: Anemia was defined as serum hemoglobin ≤12 g/dL in women and ≤13 g/dL in men.1 The presence of anemia in earlier stages of CKD may be due to non‐renal causes (e.g., blood loss, inflammation, nutritional deficits).2

aStages of CKD were defined according to the National Kidney Foundation, with stage 5 as eGFR <15 mL/min/1.73 m2; bEstimated by applying the percentage of U.S. adults with anemia of CKD from the NHANES 2007‐2010 analysis (15.4%),1 to the U.S. CKD population from the Global Burden of Disease Study 2017 (~39 million);3 cWeighted percentage of U.S. adults with anemia of CKD (N=410) who reported being treated for anemia within the previous 3 months. Among these patients, the weighted means were 14.6% for stages 1‐2, 26.4% for stages 3‐4, and 43% for stage 5.

NHANES = National Health and Nutrition Examination Survey.

1. Stauffer ME et al. PLoS One. 2014; doi:10.1371/journal.pone.0084943. 2. Fishbane S et al. Am J Kidney Dis. 2018;71:423‐435; 3. GBD Chronic Kidney Disease Collaboration. Lancet. 2020;395:709‐733.

Patients (Weighted %)

~6millionAmericans were estimated to have anemia of CKD

in 2017b

<23%of patients withanemia of CKD

reported receiving treatment

53.4

50.3

17.4

12.2

8.4

0 10 20 30 40 50 60

CKD stage 5

CKD stage 4

CKD stage 3

CKD stage 2

CKD stage 1

(n=231)

(n=68)

(n=57)

(n=37)

(n=17)

Prevalence of anemia by CKD stage in the U.S.1Cross‐sectional analysis of patients with CKD from NHANES >18 years

of age in 2007–2008 and 2009–2010 (N=2125)a

6.3

4.7

2.4

2.0

1.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

Diabetes + CHF + CKD

CHF + CKD

Diabetes + CKD

CKD

None (Reference)

Relative risk of death

Anemia alone or with comorbidities (including CKD) has been shown to be associated with increased mortality

2‐year risk of death before ESKD in U.S. Medicare patients with anemia and other comorbidities

Analysis of U.S. Renal Data System, 2002

Without anemiaWith anemia

Collins AJ. Adv Stud Med. 2003;3:S194‐S197.

7.3

6.0

3.6

3.7

2.0

0 1 2 3 4 5 6 7 8



Multiple pathophysiological factors in CKD impact erythropoiesis1

Other factors that can contribute to anemia of CKD1‐3

Chronic blood loss Iron deficiencyVitamin B12 or

folic acid deficiency

Shortened RBC survival

Suppression of erythropoiesis

1. Brugnara C et al. In: Brenner and Rector’s the kidney. 10th ed. Philadelphia, PA: Elsevier; 2016:1875‐1911; 2. Lankhorst CE et al. Blood Rev. 2010;24:39‐47; 3. Dev S et al. Hemodial Int. 2017;21(suppl 1):S6‐S20.

Elevated Hepcidin Impaired Oxygen‐SensingInflammation

Treatment Options



Targets for therapeutic intervention in CKD

ProteinuriaIntraglomerular hypertension

Hypoxia

Fluid imbalanceTubulointerstitial

injury

Reduce Kidney Damage1‐3

AnemiaMetabolic acidosis

Electrolyte imbalance

Volume overload Bone disorders

Address CKD Complications4

1. Phan O et al. Eur Cardiol. 2014;9(2): 115‐119; 2. Nangaku M. J Am Soc Nephrol. 2006;17(1):17‐25; 3. Khan Y et al. PLoS One. 2016;11(7):e0159335; 4. Chen T et al. JAMA. 2019;322(13):1294‐1304.

Effective treatment of CKD includes both direct and indirect approaches

Hyperglycemia Hypertension Hypervolemia2

Indirect1

Target risk factors*

Reducing albuminuria

Slowing down eGFR decline

Direct1

Target kidney dysfunction

*This is not an exhaustive list of treatable risk factors.

1. Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1‐150; 2. Bello AK et al. Kidney Int Suppl. 2017;7:122‐129.



Disea

se M

odification

RAASi

Once, twice, or three times daily

ACEi: Block conversion of angiotensin I to angiotensin II

ARB: Inhibit the RAAS by blocking the binding of angiotensin II to its receptor1

See individual product prescribing information for contraindications, warnings and precautions, and side effect profiles

Reduction in glomerular pressure via efferent arteriole vasodilation1

MRAs Once daily Decrease the effect of aldosterone by binding to the mineralocorticoid receptor2

Decrease tubular injury and fibrosis2

SGLT2 inhibitors Once daily Inhibit SGLT‐2 in the proximal convoluted tubule, to prevent reabsorption of glucose and facilitate its excretion in urine3

Reduction in glomerular pressure via afferent arteriole vasodilation4

GLP‐1 receptor agonists

Once daily,Once weekly

Stimulates glucose‐dependent insulin release from pancreatic islet cells to slow gastric emptying, inhibit glucagon release, increase satiety, and increases glucose excretion5

Protective against endothelial injury, oxidative stress, and inflammation6

Treatm

ent of CKD

Complications

Sodium retention and volume overload Sodium restriction, diuretics

Hyperkalemia (non‐life threatening management) Dietary restriction, potassium binders, cation exchange resins, patiromer, sodium zirconium cyclosilicate7

Metabolic acidosis Sodium bicarbonate

Imbalances of calcium and phosphate Phosphate binders, calcimimetics

Anemia Erythropoiesis‐stimulating agents, iron replacement

Summary of therapeutic options: current management of CKD in T2D

ACE‐I = angiotensin converting enzyme‐inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor‐neprilysin inhibitor; GLP‐1 =glucagon‐like peptide‐1; MRA = mineralocorticoid receptor antagonist; RAAS = renin‐angiotensin‐aldosterone system; SGLT2 = sodium‐glucose cotransporter 2; SNS = sympathetic nervous system.

1. Kobori H et al. Curr Pharm Des. 2013;19(17):3033‐3042. 2. Barrera‐Chimal J et al. Kidney Int. 2019;96(2):302‐319. 3. Kalra S. Diabetes Ther. 2014;5(2):355‐366. 4. Skrtić M et al. Diabetologia. 2014;57(12):2599‐2602. 5. Lee YS et al. Metabolism. 2014;63(1):9‐19. 6. Tanaka T et al. Kidney Int. 2014;86(4):701‐711. 7. Kim GH. Electrolyte Blood Press. 2019;17(1):1‐6.

Administration Mechanism of Action Side Effects Pharmacologic Effects

Complication Treatment Options

ACEi or ARB therapy should be used at the highest approved dose that is tolerated in patients with CKD

aThis is a practice point that is used to provide guidance to clinicians when a systematic review was not completed, or was performed, but did not find sufficient evidence to warrant a recommendation. It is not graded for strength or evidence quality; bLevel 1 = “We recommend” and Grade B = moderate quality of evidence.

ACEi = angiotensin‐converting enzyme inhibitor; ARB = angiotensin receptor blocker; KDIGO = Kidney Disease: Improving Global Outcomes.

1. KDIGO Blood Pressure Work Group. Kidney Int Suppl. 2021;99:S1‐S87; 2. KDIGO Diabetes Work Group. Kidney Int Suppl. 2020;98:S1‐S115.

KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD2

• ACEi or ARB is recommended in adults with diabetes, hypertension, and albuminuria, and these medications should be titrated to the highest approved dose that is tolerated (1B)b

KDIGO 2021 Clinical Practice Guideline for The Management of Blood Pressure in CKD1

• ACEi or ARB should be administered using the highest approved dose that is tolerated to achieve the benefits described because the proven benefits were achieved in trials using these dosesa



RAASi therapy is recommended by clinical guidelines for the management of HFrEF

aOr ARB if ACEi is not tolerated/contraindicated; bSacubitril/valsartan; cPatient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma NT‐proBNP ≥600 pg/mL, or if HF hospitalization within the last 12 months, plasma BNP ≥100 pg/mL or plasma NT‐proBNP ≥400 pg/mL) and able to tolerate enalapril 10 mg twice daily.

ACC = American College of Cardiology; ACCF = American College of Cardiology Foundation; ACEi = angiotensin‐converting enzyme inhibitor; AHA = American Heart Association; ARB = angiotensin receptor blocker; ARNi= angiotensin receptor–neprilysin inhibitor; BNP = B‐type natriuretic peptide; ESC = European Society of Cardiology; HFSA = Heart Failure Society of America; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NT‐proBNP = N‐terminal pro‐BNP; NYHA = New York Heart Association; RAASi = renin‐angiotensin‐aldosterone system inhibitor.

1. Ponikowski P et al. Eur Heart J. 2016;37:2129‐2200; 2. Yancy CW et al. J Am Coll Cardiol. 2013;62:e147‐e239; 3. Yancy CW et al. Circulation. 2017;136:e137–e161.

ClassLevel of evidence

Recommendation to reduce morbidity and mortality

I

ACEi: ABeneficial for patients with prior or current symptoms of chronic HFrEF3

MRA: ARecommended in patients with NYHA class II–IV HF and with LVEF ≤35%, unless contraindicated2

MRA: B

Recommended following an acute MI in patients who have LVEF ≤40% who develop symptoms of HF or who have a history of diabetes mellitus, unless contraindicated2

ARB: ARecommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACEitherapies because of cough or angioedema3

ARNi: B–RIn patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or ARB, replacement by an ARNi is recommended3

ClassLevel of evidence

Recommendation to reduce the risk of HF hospitalization and death

I

ACEi: ARecommended, in addition to a β‐blocker, for symptomatic patients with HFrEFa

MRA: ARecommended for patients with HFrEF, who remain symptomatic despite treatment with an ACEia and a β‐blocker

ARB: BRecommended in symptomatic patients with HFrEFunable to tolerate an ACEi (patients should also receive a β‐blocker and an MRA)

ARNib: B

Recommended as a replacement for an ACEiin ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACEi, a β‐blocker, and an MRAc

2016 ESC HF Guidelines12013 ACCF/AHA Guidelines2 and

2017 ACC/AHA/HFSA Focused Update3

ACEi, ARB or ARNi in conjunction with a β‐blocker, and MRA in selected patients, is recommended for patients with chronic HFrEF1‐3

Therapeutic dilemma in managing hyperkalemia while optimizing RAASi therapy

May prevent patients from achieving target

RAASi doses6

HyperkalemiaRAASi Therapy

Leads to RAASi dose reduction or discontinuation and

worse cardiorenal outcomes, including

mortality6

RAASia

improves outcomes

• Reduces CV morbidity and mortality1‐3

• Slows CKD progression4,5

Guidelines recommend optimizing RAASia

therapy1‐5

aACCF/AHA, ACC/AHA/HFSA, and ESC HF guidelines define RAASi therapy as ACEi, ARB, MRA, and ARNi.1‐3 KDIGO 2020 clinical practice guideline for diabetes management in CKD and KDIGO 2021 clinical practice guideline for the management of blood pressure in CKD define RASi therapy as ACEi or ARB.4,5

ACC = American College of Cardiology; ACCF = American College of Cardiology Foundation; ACEi = angiotensin‐converting enzyme inhibitor; AHA = American Heart Association; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor–neprilysin inhibitor; ESC = European Society of Cardiology; HFSA = Heart Failure Society of America; KDIGO = Kidney Disease: Improving Global Outcomes; MRA = mineralocorticoid receptor antagonist; RAASi = renin‐angiotensin‐aldosterone system inhibitor; RASi = renin‐angiotensin system inhibitor.1. Ponikowski P et al. Eur Heart J. 2016;37:2129‐2200; 2. Yancy CW et al. J Am Coll Cardiol. 2013;62:e147‐e239; 3. Yancy CW et al. Circulation. 2017;136:e137–e161; 4. KDIGO Diabetes Work Group. Kidney Int Suppl. 2020;98:S1‐S115; 5. KDIGO Blood Pressure Work Group. Kidney Int Suppl. 2021;99:S1‐S87; 6. Epstein M et al. Am J Manag Care. 2015;21(suppl 11):S212–S220.



Guideline Recommended Management of RAASi Based on Serum K+ (mEq/L)

Don’t Start

MRA1

ACC/AHA/HFSA

ACEi/ARB2

NICE

Use Caution

MRA3

ESC HF

ACEi/ARB1

ACC/AHA/HFSA

Reduce

MRA dose 50%3

ESC HF

Discontinue

ACEi/ARB/MRA3,a

ESC HF

ACEi/ARB2,b

NICE

≥6.0>5.5>5.0

Traditionally guidelines focused on modifying RAASi therapy rather than managing hyperkalemia

aMay require short‐term cessation of K+ retaining agents and RAASi, but this should be minimized and RAASi should be reintroduced as soon as possible while monitoring K+ levels; bIf other drugs known to promote HF have been discontinued.

ACC = American College of Cardiology; ACEi = angiotensin‐converting enzyme inhibitor; AHA = American Heart Association; ARB = angiotensin receptor blocker; ESC = European Society of Cardiology; HFSA = Heart Failure Society of America; MRA = mineralocorticoid receptor antagonist; NICE = National Institute for Health and Care Excellence; RAASi = renin‐angiotensin‐aldosterone system inhibitor.

1. Yancy CW et al. Circulation. 2017;136:e137‐e161; 2. NICE. Chronic kidney disease in adults: assessment and management (CG182). Updated Jan 16, 2015; 3. Ponikowski P et al. Article and web addenda. Eur Heart J. 2016;37:2129‐2200.

Down‐titration or discontinuation of RAASi therapy is associated with doubling of mortality across patient subgroups

Note: RAASi includes ACEi, ARBs, direct renin inhibitors, and select MRAs.

ACEi = angiotensin‐converting enzyme inhibitors; ARB = angiotensin receptor blockers; MRA = mineralocorticoid receptor antagonist; RAASi = renin‐angiotensin‐aldosterone system inhibitor.

Epstein M et al. Am J Manag Care. 2015;21(suppl 11):S212–S220.

(n=43,288 total patients across dose categories)



Mortality by Prior RAASi DoseMaximum dose Down‐titrated dose Discontinued

Retrospective analysis of a U.S. database of electronic health records (Humedica; N>200,000) of patients >5 years of age withvarious comorbidities, with at least 2 serum K+ readings and at least 1 outpatient RAASi prescription from in 2007‐2012

9.8

13.7

5.0

20.3

27.7

10.1

22.4

30.1

13.1

0

5

10

15

20

25

30

35

CKD stages 3‐4 Heart Failure Diabetes

Percent of Patients (%)

Similar mortality rates were observed between those who down‐titrated and those who discontinued treatment



Conventional hyperkalemia treatment options are associated with limitations

aBased on 2 retrospective analyses where primary outcome was a composite of adverse GI events (hospitalization or emergency department visit with intestinal ischemia/thrombosis, GI ulceration/perforation, or resection/ostomy within 30 days of initial SPS prescription in elderly patients4 and hospitalization or death due to intestinal ischemia or thrombosis, GI ulcers and perforation) in adult patients.5

DASH = Dietary Approaches to Stop Hypertension; RAASi = renin‐angiotensin‐aldosterone system inhibitor; SPS = sodium polystyrene sulfonate.

1. Dunn J et al. Am J Manag Care. 2015;21(15 suppl):S307–S315; 2. SPS Suspension prescribing information. CMP Pharma, Inc.; 2018 Mar; 3. Zann V et al. Drug Des Devel Ther. 2017;11:2663–2673; 4. Noel JA et al. JAMA Intern Med. 2019;179:1025‐1033; 5. Laureati P et al. Nephrol Dial Transplant. 2020;35:1518‐1526.

• May be difficult to adhere to

• Limiting K+‐rich foods is associated with constipation

• Contradicts DASH diet; may worsen chronic hypertension

Low‐K+ diet1

• Efficacy depends on residual renal function (until diuresis is present)

• Increased risk of gout and diabetes depending on choice of diuretic

• May produce volume contraction, decreased distal nephron flow, worsening of kidney function, and reduced K+ excretion depending on choice of diuretic

Diuretics1

• Stopping or suboptimal use of renal/cardioprotective RAASi therapy

Discontinuation or dose‐reduction of RAASi

therapy1

• Long‐term efficacy has not been evaluated

• Gastric irritation, anorexia, nausea, vomiting, constipation and occasionally diarrhea may occur

• High risk of hospitalizations or death due to serious GI adverse eventsa

• Hard, gritty texture and unpleasant taste may reduce palatability

Traditional K+ binders(e.g., SPS)1‐5

Emergency/subacute treatments for hyperkalemia1

1. Dunn JD et al. Am J Manag Care. 2015;21(15 suppl):S307‐S315; 2. Panchal AR et al. Part 3: Adult basic and advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020;142(16_suppl_2):S366‐S468; 3. American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005;112(24 suppl):IV1‐203.

Treatment Strategy Mechanism of Action Advantages Limitations

IV calcium (calciumgluconate,1 calcium chloride2,3)

Membrane stabilization • Onset of action in 1–3 minutes

• Efficacy can be monitored with electrocardiogram and dose can be repeated if no changes observed

• Short duration of effect (30‐60 minutes)

• Serum K+ level is unaffected

• Avoid in patients receiving digoxin (risk of digoxin toxicity)

• Risk of hypercalcemia

Insulin and glucose K+ redistribution into the intracellular space

• Onset of action within 30 minutes

• Effect lasts 4–6 hours

• Risk of hypoglycemia

• Does not reduce total body K+ levels

Sodium bicarbonate K+ redistribution into the intracellular space

• Recommended when metabolic acidosis is the cause of hyperkalemia

• No immediate reductions in serum K+; effects may be observed after 4‐6 hours

• Risk of metabolic alkalosis and volume overload

β2‐adrenergic agonists K+ redistribution into the intracellular space

• Onset of action ~30 minutes

• Effect is independent of insulin and aldosterone

• Short duration, inconsistent effect (2‐4 hours)

• Does not reduce total body K+ levels

• Use with caution in ischemic heart disease (risk of tachycardia)

Dialysis(hemodialysis, peritoneal dialysis)

K+ elimination • Onset of action within minutes

• Effects lasting until end of dialysis or longer

• Limitations and complications inherent to each dialysis modality



Available oral potassium‐binding agents to treat hyperkalemiaVariable Sodium Zirconium Cyclosilicate Patiromer Sodium Polystyrene Sulfonate

FDA approval May 2018 October 2015 June 1958

EMA approval March 2018 July 2017 NA

Chemical properties Nonpolymer; nonabsorbedzirconium silicate

Cross‐linked polymer; patiromer sorbitex calcium

Resin/polymer; sodium salt ofpolystyrene sulfonic acid

Sodium content 80 mg/g None ~100 mg/g

Mechanism of action Preferentially captures K+ in exchange for hydrogen and sodium

Exchanges calcium for K+; also binds magnesium

Sodium‐K+ exchange resin/polymer; nonspecifically binds K+, magnesium, and calcium

Onset of action 1 hour 7 hours Hours to days

Dose Initial: 10 g three times daily for up to 48 hoursMaintenance: 10 g once daily (adjust daily dose at weekly intervals in 5‐g increments to obtain the desired serum K+ range)Usual maintenance dose: 5‐15 g once daily

Initial: 8.4 g once daily; increase daily dose as necessary at ≥1‐week intervals in increments of 8.4 g

15 g (4 level teaspoons) 1‐4 times daily

EMA = European Medicines Agency; NA = not applicable.

Palmer BF.Mayo Clin Proc. 2020;95(2):339‐354.

Recent expert consensus documents discuss the management of hyperkalemia using K+ binders in patients with HF

aAngiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, MRA; bHyperkalemia was not defined in the document; cUnknown whether this will improve patient outcomes; dHyperkalemia defined as serum K+ >5.0 mEq/L; eMore data are needed regarding use of such agents in patients with heart failure with reduced ejection fraction, as their use has not been shown to increase GDMT use or have an impact on outcomes in patients.

ACC = American College of Cardiology; ESC = European Society of Cardiology; GDMT = guideline‐directed medical therapy; MRA = mineralocorticoid receptor antagonist; RAASi = renin‐angiotensin‐aldosterone system inhibitor; SZC = sodium zirconium cyclosilicate.

1. Rosano GMC et al. Eur Heart J Cardiovasc Pharmacother. 2018;4:180‐188; 2. Seferovic PM et al. Eur J Heart Fail. 2019;21:1169‐1186; 3. Maddox TM et al. J Am Coll Cardiol. 2021;77(6):772‐810.

2018 ESC Expert Consensus Document on the Management of Hyperkalemia in Patients with CV Disease Treated with RAASi Therapy1

• Patiromer or SZC may be considered in selected patients with HF with or without CKD

– To manage hyperkalemia:b These therapies may enable use of MRAs and other RAASis in more patients and at a higher dosec

– To enable up‐titration of MRA while avoiding hyperkalemia

Consensus Recommendations

2019 ESC HF Clinical Practice Update2

K+ levelOn Target

RAASia DoseRecommendation

4.5 – 5.0 mEq/L No• Initiate/up‐titrate RAASi therapy• Closely monitor K+ levels

>5.0 – ≤6.5 mEq/L

No

• Initiate/maintain treatment with a K+

lowering agent • Optimize RAASi therapy to maximum‐

tolerated doses• Closely monitor K+ levels

Yes• Initiate/maintain treatment with a K+

lowering agent • Closely monitor K+ levels

>6.5 mEq/L Yes or No

• Initiate/maintain treatment with a K+

lowering agent • Discontinue/reduce RAASi therapy• Closely monitor K+

• If hyperkalemiad limits initiation and titration of GDMT, consider treating it with patiromer or SZCe

Suggested Action

2021 ACC Expert Consensus Decision Pathway for Optimization of HF Treatment3



CT is a 68‐year‐old man with T2D and HFrEF. His labs/vitals and medication list are available to review. He has lisinopril on his allergy list due to hyperkalemia.

What is the best option to optimize CT’s medication regimen and decrease mortality risk at this time?

a. Dietary restriction of protein

b. Titrate insulin

c. Add lisinopril 10 mg with labs in 1 week

d. Add dapagliflozin 10 mg with labs in 1 week

Medication List• Aspirin 81 mg daily• Atorvastatin 20 mg daily• Carvedilol 12.5 mg twice daily

• Cholecalciferol 50 mcg daily• Torsemide 20 mg daily• Insulin glargine 34 units at bedtime

• Insulin lispro 4‐8 U pre‐meal

Labs/Vitals• BP 136/88 mmHg• BMI 28 kg/m2

• A1C 7.5%• LVEF 40%• eGFR 28 mL/min/1.73 m2

• ACR 1246 mg/g• Potassium 4.8 mEq/L

Case continuedYou’ve opted to add lisinopril 10 mg to the regimen. A basic metabolic panel is drawn in 1 week.

What changes do you recommend for CT’s regimen?

a. Discontinue lisinopril due to acute kidney injury

b. Recommend dietary K+ restriction

c. Decrease torsemide to 10 mg daily

d. Educate about avoiding high K+ foods, initiate K+ binder, repeat labs in 1 week

Selected Labs/Vitals• eGFR 23 mL/min/1.73 m2

• Potassium 5.3 mEq/L• BP 126/78 mmHg• BMI 28 kg/m2



Disea

se M

odification

RAASi














Treatm

ent of CKD

Complications











Current treatments for anemia of CKD include exogenous supplemental therapies

ESA = erythropoiesis‐stimulating agent.

KDIGO Anemia Work Group. Kidney Int Suppl. 2012;2:279‐335.

Iron Therapy

ESABlood Transfusion



Iron supplementation therapy has limitations

aSystematic review of 104 studies that evaluated GI tolerability of oral iron preparations; GI effects include nausea, vomiting, epigastric discomfort, diarrhea, constipation, and erosive mucosal injury, severity of which can be severe depending on dose used.1

DD‐CKD = dialysis dependent‐chronic kidney disease; KDIGO = Kidney Disease Improving Global Outcomes; NDD‐CKD = non‐dialysis‐dependent chronic kidney disease.

1. Cancelo‐Hidalgo MJ et al. Curr Med Res Opin. 2013;29:291‐303; 2. KDIGO Anemia Work Group. Kidney Int Suppl. 2012;2:279‐335; 3. Macdougall IC et al. Kidney Int. 2016;89:28‐39; 4. Fishbane S et al. Am J Kidney Dis. 2018;71:423‐435; 5. Batchelor EK et al. J Am Soc Nephrol. 2020;31:456‐468; 6. Ferrlecit prescribing information. sanofi‐aventis US LLC; 2020 Dec; 7. Venofer prescribing information. American Regent, Inc.; 2020 Sep; 8. Rostoker G et al. Heliyon. 2019;5:e02045.

IV IronMay be associated with increased risk

of infection, acute reactions, and CV risk 2,5‐7

• Infection has been reported with some IV products6,7

• IV iron may be associated with iron overload/ hemosiderosis and severe acute reactions, including hypotension and dyspnea, as well as anaphylaxis2,8

• Benefit in NDD‐CKD should be weighed against desire to preserve venous access line2

Oral IronGI adverse events1,a and poor

GI absorption4

• Oral iron may not be effective due to poor tolerance and variable absorption2

– Gastrointestinal effects may be severe1,a

– Poor GI absorption associated with use of certain medications (e.g., proton pump inhibitors and calcium‐containing phosphate binders)3

• Generally modestly effective in NDD‐CKD and not effective in DD‐CKD4

High hepcidin, which is associated with chronic inflammation, may limit GI absorption of oral iron contributing to absolute iron deficiency and may also limit use of iron contributing to functional iron deficiency3,5

ESAs were a medical innovation in the management of anemia of CKD

• ESAs reduce the need for RBC transfusion, minimizing the risks of:1

– Transmission of blood‐borne viral diseases

– Volume overload

– Allosensitization that complicates kidney transplantation

– Transfusional hemosiderosis

• Guidelines recommend the use of ESAs and/or iron to avoid transfusion1

Prior to ESAs, iron and transfusions were the primary treatments for anemia2

ESAs, first introduced in 1989, were a breakthrough in the management of anemia of CKD1,2

First available ESA was approved by the FDA3

1989

19901980 2000 2010

ESA = erythropoiesis‐stimulating agent.1. KDIGO Anemia Work Group. Kidney Int Suppl. 2012;2:279‐335; 2. Amgen Inc. Amgen history. https://www.amgen.com/about/amgen‐history/ (accessed 2021 Mar 1).



With higher targets

Targeting higher Hb with ESAs has been associated with increased risk of mortality and CV events

Please note that it is inappropriate to make direct comparisons between the studies as the study design, demographics and other criteria were different.aStudy was terminated early; bSudden death, MI, acute heart failure, stroke, transient ischemic attack, angina pectoris resulting in hospitalization for 24 hours or prolongation of hospitalization, complication of peripheral vascular disease (amputation or necrosis), or cardiac arrhythmia resulting in hospitalization for 24 hours; cSecondary endpoint.CHOIR = Correction of Hemoglobln and Outcomes in Renal Insufficiency; CREATE = Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta; DD = dialysis‐dependent; ESA = erythropoiesis‐stimulating agent; HCT = hematocrit; HD = hemodialysis; HR = hazard ratio; NDD = nondialysis‐dependent; NHCT = Normal Hematocrit Cardiac Trial; RR = risk ratio; TREAT = Trial to Reduce Cardiovascular Events with Aranesp Therapy.

1. Epogen prescribing information. Amgen Inc.; 2018 Jul; 2. Besarab A et al. N Engl J Med. 1998;339:584‐590; 3. Singh A et al. N Engl J Med. 2006;355:2085‐2098; 4. Drüeke T et al. N Engl J Med. 2006;355:2071‐2084;5. Pfeffer M et al. N Engl J Med. 2009;361:2019‐2032; 6. Phrommintikul A et al. Lancet. 2007;369:381‐388.

NHCT1• 1265 patients with DD‐CKD with CHF or ischemic heart disease

• high Hb (14 g/dL) vs.low Hb (10 g/dL)a

• Open‐label, prospective• 1 composite endpoint: Death, non‐fatal MI

• Median follow‐up: 14 months2

RR 1.28 (95% CI 1.06‐1.56)

Increased risk of death/non‐fatal MI

TREAT5• 4038 patients with T2D NDD‐CKD (eGFR 20‐60 mL/min/1.73 m2)

• high Hb (~13 g/dL; ESA) vs. low Hb (9 g/dL; placebo + rescue ESA)

• Randomized, double‐blind, placebo‐controlled

• 1 composite endpoints: (1) Death, MI or hospitalization for MI, stroke, CHF; (2) death or end‐stage renal disease– HR 1.05, 95% CI, 0.94‐1.17

• Median follow‐up: 29.1 months

HR 1.92(95% CI 1.38‐2.68; p<0.001)

Increased risk of fatal or non‐fatal strokec

CHOIR3

• 1432 patients with NDD‐CKD (eGFR 15‐50 mL/min/1.73 m2)

• high Hb (13.5 g/dL) vs. low Hb (11.3 g/dL)a

HR 1.34(95% CI 1.03‐1.74; p=0.03)

• Open‐label, prospective • 1 composite endpoint: Death, MI, hCHF, stroke

• Median follow‐up: 16 months

Increased risk of death/MI/hCHF/stroke

CREATE4• 603 patients with NDD‐stage 3/4 CKD (eGFR 15‐35 mL/min/1.73 m2)

• high Hb (13‐15 g/dL) vs. low Hb (10.5‐11.5 g/dL)

RR 1.48(95% CI 0.87‐2.52)6

• Open‐label, parallel‐group • 1 composite endpoint: CV eventsb

– HR 0.78, 95% CI, 0.53‐1.14• Mean duration: 3 years

Trend of increased mortalityc

Guidelines for ESA therapy

aThe decision to initiate ESA should be individualized based on the rate of fall of Hb concentration, prior response to iron therapy, risk of needing a transfusion, risks related to ESA therapy, and presence of symptoms attributable to anemia.

DD = dialysis dependent; ESA = erythropoietin‐stimulating agent; KDIGO = Kidney Disease Improving Global Outcomes; NDD = non‐dialysis dependent; NKF‐KDOQI = National Kidney Foundation–Kidney Disease Outcomes Quality Initiative.

1. KDIGO Anemia Work Group. Kidney Int Suppl. 2012;2:279–335; 2. Kliger AS et al. Am J Kidney Dis. 2013;62:849‐859.

• No additional comments

• NDD and DD patients:

– Initiate ESA when Hb <10 g/dL

– Upper Hb cutoff of 11 g/dL

• Classify as ESA hyporesponsive when no increase in Hb after ≥2 months of ESA treatment

• Address all correctable causes of anemia prior to initiation of ESA therapy

• Balance the potential benefits of reducing transfusions and anemia symptoms against the potential risks of ESA therapy

• NDD patients: In patients with Hb <10 g/dL , the decision to initiate ESA should be individualizeda

• DD patients: Initiate ESA when Hb 9 g/dL to 10 g/dL

• ESAs should not be used to maintain Hb above 11.5 g/dL (NDD‐CKD or DD‐CKD)

• Classify as ESA hyporesponsive when no increase in Hb after the first month of ESA treatment with appropriate weight‐based dosing

• Suggest avoiding repeated escalation in ESA dose beyond double the initial weight‐based dose

KDIGO1 NKF‐KDOQI2

(Commentary on KDIGO 2012)



RBC transfusion risks and guidelines

ESA = erythropoiesis‐stimulating agent; KDIGO = Kidney Disease Improving Global Outcomes.

1. KDIGO Anemia Work Group. Kidney Int Suppl. 2012;2:279‐335; 2. Brenner N et al. J Nephrol. 2020;33:267‐275; 3. Roger SR. Clin Kidney J. 2017;10(suppl 1):i9‐i15.

Risks of Blood Transfusions

• Infection transmission, immunologic sensitization, hyperkalemia, and volume overload1

• Longer wait time prior to transplantation2

• Higher risk of kidney rejection due to alloimmunization following transplant2

• Iron‐overload, raising concerns of damage to multiple organs, such as the liver and the heart, with chronic RBC transfusion3

• Consider when ESA is ineffective or in patients with high potential for harm from ESA

• Determine need not by a particular Hb threshold, but by presence of anemia symptoms

• Avoid (when possible) to minimize general risks related to its use

• Avoid (when possible) in patients eligible for organ transplantation

KDIGO1

Guidelines for Blood Transfusions

Lower Hb levels are associated with increased morbidity and mortality in patients with NDD‐CKD Stage 3 or 4

Patients treated with erythropoietin‐stimulating agents or blood transfusions before the index hemoglobin were excluded from the analysis.aGFR estimated using MDRD equation; bThe hazard ratios adjusted for significant variables including time‐varying eGFR and Hb in patients with Hb <10.5 g/dL vs. >12.5 g/dL were 5.46 for ESKD, 5.27 for all‐cause mortality, and 2.18 for CV hospitalization (p<0.0001) for all comparisons.

HMO = health maintenance organization; MDRD = Modification of Diet in Renal Disease; NDD = non‐dialysis‐dependent.

Thorp ML et al. Nephrology. 2009;14:240–246.

Risk of death, CV hospitalization, and ESKD in patients with CKD by baseline Hb levelRetrospective cohort study of patients with CKD stage 3 or 4 (eGFR <60 and ≥15 mL/min/1.73 m2)a age ≥20 years from a U.S. HMO database enrolled between January 1997‐December 2004 and followed up to June 30, 2005 (N=5885)

In this population, compared with nonanemic patients (Hb >12.5 g/dL), patients with the lowest Hb (<10.5 g/dL) had an increased risk ofb

Event rates according tobaseline Hb value

Rate per 100 patient‐years

4.02.6

1.3 1.3 1.0

23.4

15.5

9.67.6 7.4

17.0

14.512.6 11.6

10.3

0

5

10

15

20

25

9.4 11.0 11.8 12.3 12.8

Mean Hb (g/dL) per decile

ESRDDeathCV hospitalization

Death

5x

Progression to ESKD

5x

CV Hospitalization

2x



ESA therapy addresses EPO deficiency but not the other factors involved in erythropoiesis1

Note: Figure based on in vitro studies and animal models.aIncreased expressions of DMT1, DCYTB are based on animal models.6

DCYTB = duodenal cytochrome B; DMT1 = divalent metal transporter 1; EPO = erythropoietin; ESA = erythropoiesis‐stimulating agent; HIF = hypoxia‐inducible factor; PH = prolyl hydroxylase.

1. KDIGO. Kidney Int Suppl. 2012;2:279‐335 https://dx.doi.org/10.1038/kisup.2012.35; 2. Pergola PE et al. Presented at: ASN Kidney Week 2020; October 22‐25, 2020; 3. Fishbane S et al. Presented at: ASN Kidney Week 2020; October 22‐25, 2020; 4. Eschbach JW et al. Best Pract Res Clin Haematol. 2005;18(2):347‐61; 5. Provenzano R et al. Am J Kidney Dis. 2016;67:912‐924; 6. del Blazo U et al. J Pharmacol Exp Ther. 2020;374:342–353.

ESA therapy• Exogenously replaces EPO1

• May decrease hepcidin2,3

• Iron therapy is essential to maximize efficacy4

ESA Therapy

Activation of the HIF pathway • Increases endogenous EPO production5

• Decreases hepcidin2,3

• Increases iron availability2,3,6

Erythropoietin5

Kidneys& Liver

Transferrin2,3

Liver

Hepcidin2,3

Liver &Macrophage

DCYTB6a

DMT16a

Duodenum

COORDINATED ERYTHROPOIESIS

HIF PH Inhibitors

HIF‐PH inhibitor

PH

Fe mobilization frombody stores

Fe absorption fromthe GI tract

Fe transport to bone marrow

EndogenousEPO production

ERYTHROPOIESIS

Inflammation contributes to anemia via multiple mechanisms

Multiple pathophysiological factors in CKD impact erythropoiesis

Note: Figures based on in vitro studies and animal models.

EPO = erythropoietin; HIF = hypoxia‐inducible factor; REP = renal erythropoietin‐producing.

Brugnara C et al. In: Brenner and Rector’s the Kidney. 10th ed. Philadelphia, PA: Elsevier; 2016:1875‐1911.

Limits erythroid proliferation and maturation

Serum Iron

Hepcidin

EPO

ANEMIA

Erythropoiesis

Decreases RBC life span

Inflammation

Hepcidin increases in response to inflammation and can contribute to

decreased iron availability

Prior to loss of REP cells, the impaired oxygen‐sensing mechanism in these

cells can result in insufficient endogenous EPO production

ANEMIA

O2HIF

EPORBC

Impaired O2

sensing in REP cells

Inflammation

Hepcidin

Iron Sequestered

Iron Deficiency

Elevated Hepcidin Impaired Oxygen‐SensingInflammation

Iron



HIF‐α HIF‐β

HRE

Nucleus

Target genes transcribed

HIF pathway plays important role in erythropoiesis by directly regulating EPO production and iron metabolism1‐6

Figure based on in vitro studies and animal models.

DCYTB = duodenal cytochrome B; DMT1 = divalent metal transporter 1; EPO = erythropoietin; EPO‐R = erythropoietin receptor; HIF = hypoxia‐inducible factor; HRE = hypoxia response element; TfR = transferrin receptor.

1. Kaelin WG Jr et al. Mol Cell. 2008;30:393‐402; 2. Koury MJ et al. Nat Rev Nephrol. 2015;11:394‐410; 3. Haase VH. Blood Rev. 2013;27:41‐53; 4. Yanatori I et al. Free Radic Biol Med. 2019;133:55‐63; 5. Philpott CC et al. J Biol Chem. 2017;292:12764‐12771; 6. Dautry‐Varsat A et al. Proc Natl Acad Sci U S A. 1983;80:2258‐2262.

Erythropoietin

Kidneys& Liver

Transferrinreceptors

Bone marrow

Transferrin

Liver

Ceruloplasmin

Ferroportin

Liver &Macrophage

FPN

DCYTB

Ferroportin

DMT1

Duodenum

Fe3+

Bone marrow

intracellularsignaling

Nucleus Nucleus

Proerythroblast

Hemoglobin

Erythroblast Reticulocyte Red blood cell

TransferrinTfRINCREASED

Erythropoiesis

INCREASEDEPO production

INCREASEDIron mobilization from

body stores

INCREASEDIron absorption from

the GI tract

INCREASEDIron transport to bone marrow and

iron uptake into erythroblasts

Activation of the HIF pathway decreases hepcidin leading to further increased iron availability1,2

Figure based on in vitro studies and animal models.

DMT1 = divalent metal transporter 1; EPO‐R = erythropoietin receptor; ERFE = erythroferrone; FPN = ferroportin; TfR = transferrin receptor.

1. Koury MJ et al. Nat Rev Nephrol. 2015;11:394‐410; 2. Haase VH. Blood Rev. 2013;27:41‐53.

Bone marrow

INCREASEDErythropoiesis intracellular

signaling

NucleusNucleus

Proerythroblast

Hemoglobin

Erythroblast Reticulocyte Red blood cell

TransferrinTfR

Liver,Duodenum &Macrophage

Reduced hepcidin leadsto increased FPNat the cell surface(i.e., increased transport of iron out of cells andavailability for erythropoiesis)

NucleusFerritin

Fe

Hepatocyte/enterocyte/macrophage

DECREASEDHepcidin production

ERFE

ERFE

ERFE

Fe3+

Fe2+



Phase 3 HIF‐PHI clinical program overview1

Roxadustat Vadadustat Daprodustat

Company AstraZeneca, Astellas, Fibrogen Akebia, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Vifor Pharma

GSK, Kyowa Kirin

Expected U.S. Approval Q3‐Q4 2021 Q1 2022 Q3 2022

Dosing (oral) Three times a week Once daily Once daily or three times a week

CKD Anemia Phase 3 Overview

20 trials total17 trials complete3 trials ongoing

11 trials total9 trials complete 1 trial ongoing1 trial withdrawn

8 trials total3 trials complete5 trials ongoing

Populations Studied (Number of Studies)

DD (10)ID (1)PD (1)NDD (7)DD/NDD (1)

DD (5)ID (1)PD (1)NDD (3)Healthy (1)

DD (4)ID (1)NDD (2)NDD/PD (1)

Cumulative Trial Size* N=9,324 U.S./EU/GlobalN=1,491 China/Japan

N=7,736 U.S./EU/GlobalN=754 Japan

N=1,307 U.S./EU/GlobalN=654 Japan

Population Studied NDD DD NDD DD NDD DD

Trial Size (Global) 5501 DD: 5175ID: 1530

3817 DD: 4243ID: 369

955 DD: 3670ID: 300

*Enrollment included in cumulative trial size for complete and active not recruiting trials only.

DD = dialysis‐dependent; NDD = non‐dialysis‐dependent; GSK = GlaxoSmithKline; HIF‐PHI = hypoxia‐inducible factor prolyl hydroxylase inhibitor; ID = incident dialysis; PD = peritoneal dialysis.

1. Sanghani NS et al. Adv Chronic Kidney Dis. 2019;26(4):253‐266

Disea

se M

odification

RAASi














Treatm

ent of CKD

Complications













Potential effects by which SGLT2 inhibition improves renal outcomes

RAAS = renin‐angiotensin‐aldosterone system; SGLT2 = sodium‐glucose cotransporter 2; SNS = sympathetic nervous system. 1. Heerspink HJL et al. Kidney Int. 2018;94(1):26‐39. 2. Tamargo J. Eur Cardiol. 2019;14(1):23‐32. 3. Shin SJ et al. PLoS One. 2016;11:e0165703. 4. Sano M. J Cardiol. 2018;71(5):471‐476.

Preserved Renal Function2

Protection Against Diabetic

Nephropathy1,2Reduce Glomerular Pressure1

↑Afferent vasoconstric on↓Glomerular hyperfiltra on

Neurohormonal Improvement↓Intrarenal RAAS ac vity3

↓SNS ac vity4

↓Tubular/Glomerular Injury1,2

↓Albuminuria

↓Blood Pressure1

Stabilization of eGFR2

↓Renal Ischemic Injury1

↑Hb/hematocrit2

Inflammation/Fibrosis Reductions1,2

↓Inflammatory markers↓Fibro c markers

Decreased Renal Workload and Hypoxia1,2

↓Solute transport↓Oxygen demand

SGLT2 INHIBITION

O2

CLINICAL EFFECTS

Key renal outcome trials*

*Finerenone not approved by FDA.

ACEi = Angiotensin‐converting‐enzyme inhibitors; ARB = angiotensin receptor blocker; ESC = European Society of Cardiology; hHF = hospitalization for heart failure; MRA = mineralocorticoid receptor antagonist; SGLT2 = sodium‐glucose cotransporter 2; UA = urinary albumin; UACR = urine albumin to creatinine ratio.

1. Perkovic V et al. N Engl J Med. 2019;380:2295‐2306. 2. Study NCT02540993. ClinicalTrials.gov website. 3. Bakris GL et al. Am J Nephrol. 2019;50:333‐344. 4. Heerspink H et al. N Engl J Med. 2020; 383:1436‐1446. 5. Study NCT03594110. ClinicalTrials.gov website.

SGLT2 Inhibitor MRA

CREDENCE1

N = 4401DAPA‐CKD4

N = 4304EMPA‐KIDNEY5

N ~ 6000FIDELIO‐DKD2,3

N = 5734

StatusCompleted

October 2018

Stopped early due to overwhelming efficacy in March 2020 (presented at ESC 2020)

OngoingEst. Completion Date

June 2022

CompletedApril 2020

InterventionCanagliflozin vs. Placebo

≥4 weeks stable on ACEi or ARBDapagliflozin vs. Placebo

≥4 weeks stable on ACEi or ARBEmpagliflozin vs. Placebo

On ACEi or ARBFinerenone vs. Placebo≥4 weeks on ACEi or ARB

Patient Population

• T2D• eGFR ≥30 to <90 mL/min/1.73m2

• UACR >300 to ≤5000 mg/g

• T2D and non‐diabetes• eGFR ≥25 to ≤75 mL/min/1.73m2

• UACR ≥200 to ≤5000 mg/g

• T2D and non‐diabetes• eGFR ≥20 to <45 mL/min/1.73m2

or ≥45 to <90 mL/min/1.73m2 and UACR ≥200 mg/g

• T2D• eGFR ≥25 to <60 mL/min/1.73m2 and UACR ≥ 30 to <300 mg/g and presence of diabetic retinopathy or eGFR ≥25 to <75 mL/min/1.73m2 and UACR ≥300 mg/g

Primary Endpoint

Composite• Doubling of serum creatinine• ESKD• Renal or CV death

Composite• ≥50% sustained eGFR decline• ESKD• Renal or CV death

Composite• Kidney failure• ≥40% sustained eGFR decline• Renal death

Composite• Kidney failure• ≥40% sustained eGFR decline• Renal death

Secondary Endpoints

• CV death or hHF• CV death, MI, or stroke• hHF• Renal composite• CV death• All‐cause death• Composite of CV death, MI, stroke, hHF, or hospitalization for UA

• Renal composite• CV death or hHF• All‐cause death

• CV death or hHF• All‐cause hospitalizations• All‐cause death• Kidney disease progression• CV death• CV death or ESKD

• Stroke or hHF • All‐cause death• All‐cause hospitalizations• ≥57% sustained eGFR decline, kidney failure or renal death

• UACR change from baseline



Importance of Screening and Monitoring

Assessment of kidney function and damage

• Albuminuria ‒ AER ≥ 30 mg/24 hours‒ UACR ≥ 30 mg/g [≥ 3 mg/mmol]

• Urine sediment abnormalities• Electrolyte and other abnormalities due to tubular disorders• Abnormalities detected by histology• Structural abnormalities detected by imaging• History of kidney transplantation

Kidney damage

Kidney function

• Decreased eGFR‒ Calculate from the serum creatinine concentration‒ eGFR <60 mL/min/1.73 m2 (Stage 3a–5)

Diagnosis of CKD requires two abnormal measurements at least 3 months apart

AER = albumin excretion rate; UACR = urine albumin‐to‐creatinine ratio.

Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1–150



KDIGO recommends referral to a nephrologist for advanced CKD

Recommended frequency of monitoring

(number of times per year)by GFR and albuminuria category

Monitoring of CKD should intensify as renalfunction declines

Note: green = low risk (if no other markers of kidney disease, no CKD); yellow = moderately increased risk; orange = high risk; red = very high risk.

KDIGO = Kidney Disease: Improving Global Outcomes; UACR = urine albumin‐to‐creatinine ratio.

Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1–150.

ACR = albumin:creatinine ratio; CKD‐EPI = Chronic Kidney Disease Epidemiology Collaboration; KDIGO = Kidney Disease Improving Global Outcomes; NICE = UK National Institute for Health and Care Excellence.

1. Kidney Disease Improving Global Outcomes CKD Work Group. Kidney Int Suppl 2013;3:1–150; 2. UK National Institute for Health and Care Excellence. NICE clinical guideline CG182, 2014. Chronic kidney disease in adults: assessment and management; 3. American Diabetes Association. Diabetes Care. 2021;44(suppl 1):S151‐S167.

Guidelines recommend routine screening for CKD in patients with cardiorenal‐metabolic disease

• At least once yearly, assess urinary albumin (spot urinary ACR) and eGFR in patients with– T1D with duration of ≥5 years

– T2D

American Diabetes Association3

• Test for CKD using eGFR, creatinine, and ACR in people with‒ Diabetes

‒ Hypertension

‒ Acute kidney injury

‒ CVD (ischemic heart disease, chronic HF, peripheral or cerebral vascular disease)

‒ Structural renal tract disease, recurrent renal calculi or prostatic hypertrophy

‒ Multisystem disease with possible kidney involvement (e.g., systemic lupus erythematosus)

‒ Family history of ESKD or hereditary kidney disease

‒ Opportunistic detection of hematuria

NICE2

• Regular testing of high‐risk groups (including those with diabetes, hypertension, and CVD) can give an early indication of kidney damage

• Public health policies should include screening of these high‐risk populations

KDIGO1



GM is a 56‐year‐old woman with CKD, HTN, T2D (current labs/vitals, medication list shown). Her HTN is well controlled.

According to KDIGO guidelines, what are the recommended test(s) and frequency for assessing GM’s kidney function?

a. eGFR and urinary ACR annually.

b. eGFR and urinary ACR 3 times a year.

c. eGFR 3 times a year; no need to check ACR.

d. eGFR and urinary ACR quarterly.

Labs/Vitals• eGFR 32 mL/min/1.73 m2

• ACR 678 mg/g• A1C 6.8%• BP 124/68 mmHg

Medication List• Aspirin 81 mg daily• Atorvastatin 20 mg daily• Lisinopril 40 mg daily• Amlodipine 10 mg daily• Chlorthalidone 25 mg daily• Glipizide 10 mg twice daily• Metformin 500 mg twice daily• Vitamin D3 50 mcg daily

Key Takeaways



1. Wu B et al. BMJ Open Diabetes Res Care. 2016;4(1):e000154; 2. Szczech LA et al. PLoS One 2014;9(11):e110535; 3. Go AS et al. N Engl J Med. 2004;351(13):1296‐305; 4. United States Renal Data System. 2019 Annual data report. Executive summary; 5. Kidney Disease Improving Global Outcomes CKD Work Group. Kidney Int Suppl 2013;3:1–150; 6. UK National Institute for Health and Care Excellence. NICE clinical guideline CG182, 2014. Chronic kidney disease in adults: assessment and management; 7. American Diabetes Association. Diabetes Care. 2021;44(suppl 1):S151‐S167; 8. Fox CS et al. Lancet. 2012;380(9854):1662–73; 9.Dalrymple L et al. J Gen Intern Med. 2011;26(10):379‐85; 10. Jansson FJ et al. Diabetologia. 2018;61(5):1203‐11; 11. Ragot S et al. Diabetes Care. 2016;39:1259‐66.

Burden of CKD is significant despite current approaches to diagnosis and treatment

KDIGO recommends routine CKD monitoring with increasing frequency as renal function declines5

Engage patients in risk factor reduction, and use multifactorial interventions to tailor treatment regimens to the individual

In patients with T2D, earlier stages (1‐3) of CKD are more common than late stages1

Roughly 10% of patients with CKD and T2D receive a diagnosis2

Progressive deteriorations in renal function increase the risk of adverse outcomes, such as risk of hospitalizations, CV events, death, and healthcare costs3,4

Several guidelines recommend regular screening of patients with increased risk5‐7

Intervene early Preserve renal functionProtect against CV risk, morbidity, and mortality

Lower eGFR and higher albuminuria are independently associated with increased adverse CV outcomes and premature death, which is worse in patients with diabetes8

While CV mortality is more likely than progression to ESKD,9 protecting against renal decline decreases CV risk10,11


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