MANAGEMENT OF ANEMIA,

METABOLIC ACIDOSIS AND

HYPERTENSION IN CKD

JOSEPH V. NALLY, Jr., MDDirector, Center for Chronic Kidney Disease Clinical Professor of Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve UniversityDepartment of Nephrology and Hypertension Glickman Urological & Kidney Institute

CLEVELAND CLINICCleveland, OH, USA

• Grants: NIH/NIDDK and Amgen

• Consultant: Medi Beacon

• Honorarium: ASN

• Off-label usage: None

DISCLOSURE OF FINANCIAL RELATIONSHIPS

OBJECTIVES

Within the context of CKD, understand the pathophysiology and appropriate management of :

– Anemia

– Metabolic acidosis

– Hypertension (HTN)

Anemia of CKD

Anemia Overview

• ESAs– Historical perspective

– Pathophysiology of EPO

– RCT’s

– Hypo-responsiveness to ESA

– Recommendations

• Iron– Pathophysiology—Hepcidin and Ferroportin

– RCT—DRIVE trial

– Recommendations

Erythropoietin Timeline

1980

Androgens, iron therapy

and RBC transfusion

1983

Lin Cloning Epo

1984

Amgen develops Epoetin

alfa

1989

Epoetin alfa available for use in CKD and cancer

2001

Darbepoetin alfa launched

2006

Management of anemia

continues to evolve

Epogen for dialysis patients

Procrit for CKD and cancer patients

Modified Dr. Aja K. Singh

1958-76

Goldwasser experi-ments

2012

Peginesatide approved

+Recalled 2013

Prevalence of Anemia in CKD Patients

Adapted from McClellan et al Curr Med Res Opin. 2004;20:1501-1510.

Normal Erythropoiesis

Hillman RS, et al. Red Cell Manual, 7th ed. Philadelphia, PA: F.A. Davis Company; 1996:chap 1. Papayannopoulou T, et al. In: Hoffman R, et al. eds. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005:chap 20. Brock. Iron Metabolism in Health and Disease. W.B. Saunders Co; 1994

Erythropoietin

Iron dependence

Iron

Pluripotent Burst-Forming Colony-Forming Proerythro- Erythro- Reticulocytes RBCsStem Cell Unit-Erythroid Unit-Erythroid blasts blasts

Cells (BFU-E) Cells (CFU-E)

~ 10-13 days~ 21 days

~1-2 days

EPO dependence

Normal Oxygen Sensing

Adapted from Cell 2001;107:1.

A 68 yr-old WM with DM, HBP, CAD with a prior MI, and a creatinine of 4 mg/dL, has a Hgb of 8.2 g/dL.

What is your goal of correction using erythropoietin?

1) No treatment is needed regardless of symptoms.

2) 13 – 15 g/dL

3) 10 – 11 g/dL

4) 9 – 10 g/dL

TREATMENT OPTIONS - ESAs

• rHuEPO

• Darbepoetin Alfa

• Peginesatide

• C.E.R.A

• PDIs

RECOMBINANT HUMAN EPO

• rHuEPO: human EPO produced in cell culture using recombinant DNA technology

• Marketed as Procrit or Epogen

• Acts on the EPO receptor to stimulate erythropoesis

DARBEPOETIN ALFA

• Darbepoetin is a molecule with 165-amino acids

• Biochemically distinct from rHuEPO:– Contains up to 22 sialic acid molecules (c/w a maximum of 14 for

rHuEPO)

– Contains five N-linked oligosaccharide chains, whereas EPO has only three.

• => Confers a half-life that is 3 times longer than that of EPO

• Binds to the same EPO receptor as rHuEPO (same mechanism) but has a lower receptor affinity

Pivotal CKD Anemia Clinical Trials

• NHCT (1998) Normal Hematocrit Cardiac Trial

• Canadian Cardiac Trial (2005)

• CREATE (Nov 2006) Cardiovascular Risk Reduction by Early Anemia Treatment with epoetin beta

• CHOIR (Nov 2006) Correction of Hemoglobin and Outcomes in Renal Insufficiency

• TREAT (Nov 2009) Trial to Reduce Cardio-vascular Events with Aranesp® Therapy

TARGET HGB

A. DIALYSIS PATIENTS

• Normal Hct Cardiac Trial (NHCT)– 1233 patients on hemodialysis with heart failure or CAD– Baseline Hct 27-33– On EPO– Randomized to achieve/maintain a Hct of 30% or 42%

• Terminated prematurely after 29 months:– Group targeted to normal Ht had a higher mortality that was

approaching statistical significance (7% percent higher)– Rate of access thrombosis in the group targeted to the normal Hgb

was significantly higher

Participants: N=1432; eGFR 15–50 ml/min/1.73 m2; Hb <11 g/dL

Design: SQ Epoetin alfa

High Arm: target 13.5 g/dL

Low Arm: target 11.3 g/dL

Main results: - Study terminated early (futility, safety ?)

- More patients in High Arm had >1 CV event

- No improvement in QoL

- Trend toward faster rate of progression to RRT

CHOIR

Singh AK, et al. N Engl J Med 2006;355:2085.

Correction of Hemoglobin and Outcomes In Renal Insufficiency (CHOIR)

Singh AK, et al. N Engl J Med 2006;355:2085.

Composite endpoint

Death

Achieved Hb

• Low: 11.3 g/dL

• High: 12.6 g/dL

Primary EP:

• Death/HF/MI/CVA

• HR 1.34 (P=.03)

Death

• HR 1.48 (P=.07)

Heart Failure

• HR 1.41 (P=.07)

TARGET HGB

B. NON DIALYSIS CKD PATIENTS

• CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment w Epoetin Beta) trial– 603 pts w CKD (GFR 15-35 mL/min) and anemia on EPO– Randomized to a nl (13-15 g/dL) or subnl (10.5-11.5) Hgb level– Primary endpoint = composite of CV outcomes: SCD, MI, stroke,

TIA…– Targets achieved in both groups

• At three years:– Similar risk of experiencing the primary endpoint– Similar changes in LV mass and rates of progression of CKD– Increased quality of life in the high Hgb group

Dreuke, NEJM, 355:2071, 2006

TREAT Study Design: A Phase III Clinical Trial

Aranesp Group (Target hemoglobin 13.0 g/dL)

Control Group

Study Population

• Hemoglobin 11 g/dL

• GFR 20-60mL/min/1.73 m2

• Type 2 DM

N = 2000

N = 2000

Enrollment 2 years Follow-up period approx 2.5 years

BaselinePrimary Endpoint

• Composite event rate comprising all-cause mortality and CV events

– Myocardial ischemia– Myocardial infarction – Congestive heart failure– Cerebrovascular accident

Secondary Endpoints

• Time to ESRD or all-cause mortality (key 2° endpoint)• Time to

– All-cause mortality– CV mortality – Myocardial ischemia– Myocardial infarction– Cerebrovascular accident– Congestive heart failure– End stage renal disease

• Rate of decline in eGFR relative to baseline • Change in patient reported fatigue

Trial Of Darbepoetin in DM and CKD

• Death or CVasc Dis in 632 Darbe vs. 602 PBO NS

• Death or ESRD in 652 Darbepoetin vs. 618 PBO NS

• Strokes 101 Darbepoetin vs 53 PBO P<.001

• Transfusions 297 Darbepoietin vs. 496 PBO p<.001

• Less fatigue with Darbepoetin

• Increased risk of death secondary to malignancy

Pfeffer, et al. N Engl JMed 2009;361:2019.

- 4038 Pts with DM, CKD not on dialysis, anemia randomized -

“For many persons involved in clinical decision making,

the risk will outweigh the potential benefits.”

Benefits and Risks of ESAs

• Benefits– Reduction in blood transfusions

– Improvement in patient’s quality of life

• Risks– Cardiovascular events

– Hypertension

– Thromboembolism

– Cancer progression

– No benefit in CKD progression

Management of anemia in CKD

• Rule out other causes of anemia – bleeding, nutritional deficiencies.

• Once CKD cause of anemia is established –

–Evaluate for iron deficiency – check TSAT and Ferritin

–Supplement Fe as needed

–Evaluate Hgb response

• If anemia persists consider ESA

• Do Not Over-treat!!! Hgb 10-11 is current goal.

TARGET HGB- KDOQI 2012

• For CKD patients– If Hgb > 10 g/dl => do not give ESA (2D) – If Hgb < 10.0 g/dl => individualized decision based on

risks/benefits (2C)

• For HD patients:– Start ESA when Hgb between 9-10 g/dL (2B) – Do not maintain Hgb levels > 11.5 g/dl (2C)

• In all adult patients, we recommend that ESAs not be used to intentionally increase the Hb concentration above 13 g/dl.

(1B)

USED BY: USED BY:

Distribution of Iron in Adults

Dietary Iron

Muscle (myoglobin)

(300 mg)

Liver parenchyma (1000 mg)

Sloughed mucosal cellsDesquamationMenstruation

Other blood loss(average, 1-2 mg per day)

Iron loss

Storage Iron

Plasma transferrin(3 mg)

Bone marrow

(300 mg)

Circulating erythrocytes

(hemoglobin) (1800 mg)

Reticulo-endothelial

macrophages (600 mg)

24 mg

•Unique homeostasis – no excretory route

“Mammalian iron physiology is complex, but understanding two key proteins- hepcidin and ferroportin- provides insight into the large majority of iron disorders”

Nancy C Andrews. NEJM 2012

Ferroportin Mediated Transport

Nature Reviews 9;72-81.2008

•Combined action of membrane irontransporter and an iron oxidase

Heam is degraded by

heam oxygenase

Hepcidin

Mechanism of action:– Binds to ferroportin (receptor) – inducing internalization and

degradation

• Controls plasma iron levels by:– Regulating GI absorption, release from RES and hepatocyte, and

placental transfer

• Expression is directly, but inversely, related to iron requirements– High requirements- low hepcidin– Low requirements- high hepcidin

• Regulation occurs at the transcription level by:– Iron– Inflammation– Erythropoiesis– Hypoxia

USED BY: USED BY:

Distribution of Iron InflammationDietary

Iron

Plasma transferrin(1-2 mg)

Muscle (myoglobin)

(300 mg)

Bone marrow

(300 mg)

Circulating erythrocytes

(hemoglobin) (1200 mg)

Liver parenchyma (1000 mg)

Reticulo-endothelial

macrophages (800 mg)

Sloughed mucosal cellsDesquamationMenstruation

Other blood loss(average, 1-2 mg per day)

Iron loss

Storage Iron

16-20 mg

Hypo-Responsiveness to ESAs

• Iron deficiency

• Inflammation– Chronic infections

– Failed renal allograft

• Hematological disorders or malignancy

• Hyperparathyroidism

• Nutritional—Folate, vitamin B12, carnitine

• Drugs: ACE/ARB, AL++ overload

• Inadequate dialysis/oxidative stress

Iron Deficiency in Anemia of CKD#1 Cause of Hyporesponsiveness

Fishbane S, et al. Clin J Am Soc Nephrol 2009;4:57.

Anemia of CKDIron Treatment

• Iron — often ineffective by p.o. route

• IV iron — best therapy route in ESRD

–Less rigorously tested in ND-CKD

• Even if KDOQI iron parameters are “on target,” anemia may respond to iron therapy

–“functional iron deficiency”

– iron-restricted erythropoiesis

The Proper Use of Ferritin and TSAT to Guide Decisions on IV Iron Use

CKD 3 and 4

1. A low ferritin (<100 ng/mL) and TSAT (<20) usually indicates absolute iron deficiency.

2. A higher ferritin lacks predictive value. Use clinical judgment on whether to give IV or oral iron.

(TSAT <30 + Ferritin <500)

3. IV iron can raise Hgb, delay or prevent the need for ESA therapy, or lower ESA doses.

Courtesy of Jeff Berns, MD (UpToDate)

A 32‐year‐old Caucasian male with CKD stage 4 due to diabetes mellitus type 1 nephropathy presents for follow‐up of his anemia management.  His Hgb remains at 9.4 gm% despite Darbo 120 µg SQ each week for the last 6 weeks.  He denies any history of bleeding, but he has been hospitalized twice in the past 2 months for severe diabetic foot ulcer which is associated with osteomyelitis requiring ongoing wound care and IV clindamycin.

Pertinent labs:  CBC:    WBC 8400, Hgb 9.4, platelets 212 K, reticulocytes 0.9%. 

TSAT 30%, ferritin 513.  

LDH, folate, B12,  peripheral blood smear are all normal.  Stool hemocult negative.

Question

Which statement is TRUE regarding this patient’s anemia which is hyporesponsive to ESA therapy?

A.The primary cause of the hyporesponsiveness to ESA therapy is overt iron deficiency.B.The chronic inflammation  associated with his osteomyelitis has produced a deficiency in H1Fα resulting in anemia resistant to ESA therapy.C.The resistant anemia is likely due to clindamycin‐induced hemolysis.D.The chronic inflammation with his osteomyelitis upregulates hepcidin which alters effective iron utilization which prevents successful incorporation of iron into Hgb.E.The anemia is likely due to pure red cell aplasia induced by the vehicle in the ESA product.

PlasmaFe-Tf

Spleen

Bone marrow

RBC

Liver

Role of inflammation and hepcidin in anemia of CKD

Duodenum

Modified from Zaritsky et al.

ASN 2008

Erythropoiesis in CKDCauses of Hyporesponsiveness

Kalantar-Zadeh K, et al. Adv Chronic Kid Dis 2009:16:143.

A Schematic of the Study Procedures of DRIVE and DRIVE-II

• Major inclusion criteria: Hb 11 g/dL, TSAT 25%, Ferritin 500-1200 ng/mL, Epoetin dose ≥ 22,500 IU/week, and 125 mg/week IV iron in any of the 4 weeks preceding enrollment

• Major exclusion criteria: active infection, recent blood loss, recent inpatient hospitalization

Kapoian T, et al. JASN 2008;19:372-9.

DRIVE Trial: Use of Ferritin to Guide IV Iron Use

• 47% responded to IV iron with >2 g/dL increase in Hgb

• Ferritin of 500 to 1200 ng/mL had no predictive value

• Withholding IV iron leads to iron-restricted eythropoiesis as seen by steadily falling reticuloycte Hgb content 9CHr)

Coyne DW et al. JASN 2007;18:975-84.

DRIVE II The Proper Use of Ferritin and TSAT to Guide Decisions on IV Iron Use

CKD 3 and 4

1. A low ferritin (<100 ng/mL) and TSAT (<20) usually indicates absolute iron deficiency.

2. A higher ferritin lacks predictive value. Use clinical judgment on whether to give IV or oral iron.

(TSAT <30 + Ferritin <500)

3. IV iron can raise Hgb, delay or prevent the need for ESA therapy, or lower ESA doses.

Patients on Dialysis

1. A low ferritin (< 200 ng/mL) and TSAT (<20) usually indicates absolute iron deficiency.

2. A higher ferritin lacks predictive value. Use clinical judgment on whether to give IV iron.

(TSAT <30 + Ferritin <500)

3. IV iron can raise Hgb and lower ESA doses and cost.

Courtesy of Jeff Berns, MD (UpToDate)

METABOLIC ACIDOSIS

1. Edema

2. Worsening of Hypertension

3. Slowing the progression of CKD

4. Improved patient survival

Q: In stage 4 CKD patients with Metabolic Acidosis, therapy with Sodium Bicarbonate is most likely to result in which of the following?

Metabolic acidosis in CKD

• Onset: GFR < 25 – 30 mL/min/1.73 m2

• Hyperchloremic phase

• High anion gap phase

• Multiple metabolic (catabolic) effects– Protein wasting– Bone lysis– SNS over-activity

• Recent issues:– CKD progression– Mortality

Serum bicarbonate levels and the progression of kidney disease: A cohort study (n=5422)

CONCLUSIONS: Low serum bicarbonate level is associated with progression of kidney disease independent of baseline eGFR and other clinical, demographic, and socioeconomic factors. Prospective studies are needed to confirm this relationship and evaluate the efficacy of alkali supplements for slowing progression.

Shah SN, et al. Am J Kidney Dis 2009;54:270.

Risk for progression of CKD

Shah SN, et al. Am J Kidney Dis 2009;54:270.

Metabolic Acidosis in CKDBicarbonate Trial Primary End Points

de Brito-Ashurst et al. J Am Soc Nephrol 2009;20(9):2075.

Metabolic Acidosis in CKDBicarbonate Trial (N=134)

de Brito-Ashurst, et al. J Am Soc Nephrol 2009;20:2075.

>23HCO3

20

No difference

Edema

Worsening BP

Hospitalization

Daily Oral NaHCO3 Preserves GFR in Early Hypertensive Nephropathy

• NaHCO3 and Na Citrate slow GFR decline in severe CKD.

• Prospective, blind, controlled trial of PBO vs. NaCl vs. NaHCO3 (0.5 mEq/kg/D) daily for 5 years

• 40 pts/arm 48%M 63%AA eGFR 75 cc/min

• Equal HBP control w ACE inhibition

Mahajan A, Simoni J, Sheether SJ, et al. Kidney Int 2010;8:303.

At 5 yrs NaHCO3 group had less loss of GFR by slope P creatinine, cystatin C, eGFR, less albuminuria – lower U endothelin levels.

A 52‐year‐old African American male is seen in follow‐up of CKD stage 4 with eGFR of 26 ml/min/1.73 m2 attributable to diabetic nephropathy.  Blood pressure is well‐controlled on ACE inhibitor therapy, but he has metabolic acidosis with serum bicarbonate of 18 mEq/L.

You prescribe Na+HCO3 therapy with the intent to treat his metabolic acidosis, reduce metabolic bone disease, and slow the progression of his CKD.

Question:The most likely explanation for how alkali therapy slows the progression of CKD is:

A. Increased systemic BP with increased renal blood flow

B. Improved glomerular hemodynamics with efferent arteriolar vasodilatation

C. Reduced tubular‐interstitial damage by limiting inflammatory urinary biomarkers such as ET and TGF‐β

D. Improved ultrafiltration coefficient (Kf) of glomerular hemodynamics

Metabolic Acidosis in CKDCitrate Attenuates ET-1 & NAG

Study initiation: GFR 33 mL/min/1.73 m2

– Citrate ↓ rate of GFR decline by 24-mo– Wt + 0.8 kg in Citrate Group

Phisitkul, et al. Kidney Int 2010;77:617.

0 mo 6 mo 30 mo

10

5

20

15

UN

AG●

V (

U /

g C

r)

– Citrate (N=29) + Citrate (N=30)Phisitkul S, et al. Kidney Int 2010; 77(7):617.

UalbV UTFGβV

Metabolic Acidosis in CKD

Mechanisms linking acidosis and CKD

Simon EE, Hamm LL. Kidney Int 2010;77:567.

CKD

Metabolic acidosis

Kidney NH4+ Kidney H+

Complement activation Endothelin

Interstitial fibrosisETA ETB

receptors receptors

Kidney injury Proximal and distal H+ secretion

SUMMARY: Metabolic Acidosis in CKD

• Aggravates bone disease, protein/muscle wasting, and CKD progression

• Target HCO3 is > 23 mEq/L

• Treatment does not worsen BP control

• Treatment may reduce CKD progression rate

1. 30%

2. 50%

3. 70%

4. 90%

Q: What is the prevalence of HTN in Stage 3B CKD?

1. Increased vasoconstriction due to enhanced RAAS

2. Increased Volume Expansion due to impaired pressure

natriuresis.

3. Increased total peripheral resistance from a stimulated SNS

4. Increased Sodium reabsorption from increased A II effects

5. All of the above

Q: What is the pathophysiological mechanism of the HTN associated with CKD?

Prevalence of HTN with reduced GFR

Overall No. (%) Prevalence of HTN

eGFR (ml/min/1.73 m2):

<30 671 (19) 617 (92)

30-39 848 (23) 772 (91)

40-49 969 (27) 853 (88)

50 – 59 723 (20) 593 (82)

> 60 401 (11) 269 (67)

n = 3612 n (%)

Muntner. Am J Kidney Dis 2009;55:441.

VasoconstrictorsNa reabsorption

Peripheral resistanceVolume expansion

Angiotensin IIEndothelinSympathetic NervesNOS inhibitorsDecreased PGsDigoxin- like factors

Angiotensin IISympathetic nervesNOS inhibitorsImpaired pressure natriuresis Glomerular surface areaDecreased PGs

Pathophysiologic basis of treatment of hypertensive kidney disease

HYPERTENSIONDiuretic Vasodilator

CKD and Hypertension (HTN)

• HTN is common (80+% in CKD stages 3-4)

• Both salt retention and increased peripheral resistance contribute

• BP accelerates decline in renal function

• BP exacerbates proteinuria

• ACE inhibitors and angiotensin receptor blockers (ARB) preferred agents in many cases, especially with proteinuria

Pharmacologic Treatment

KDOQI blood pressure guidelines for CKD. Am J Kidney Dis 2004 May Suppl.

Goal BP and Initial Therapy in CKD or Diabetes to Reduce CV Risk or Slow Nephropathy Progression

* Indicates use with diuretic

GroupGoal BP (mmHg) 

Initial Therapy

ADA (2012) <130/80  ACE Inhibitor/ARB*

KDOQI (NKF) (2007)  <130/80  ACE Inhibitor/ARB

ESH (2007+ 2009) <130/80  ACE Inhibitor/ARB*

KDOQI (NKF) (2004)  <130/80  ACE Inhibitor/ARB*

JNC 7 (2003) <130/80  ACE Inhibitor/ARB*

Am. Diabetes Assoc  (2003)  <130/80  ACE Inhibitor/ARB*

Canadian HTN  Soc. (2002)  <130/80  ACE Inhibitor/ARB*

Am. Diabetes Assoc  (2002)  <130/80 ACE Inhibitor/ARB*

Natl. Kidney Foundation (2000) <130/80  ACE Inhibitor*

British HTN Soc. (1999)  <140/80 ACE Inhibitor

WHO/ISH (1999) <130/85 ACE Inhibitor

JNC VI (1997) <130/85 ACE Inhibitor

There are NO Randomized Trials on BP level in

Diabetic Nephropathy

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Years of follow up

50

45

40

35

30

25

20

15

10

5

0

Placebo 202 184 173 161 142 99 75 45 22 Captopril 207 199 190 180 167 120 82 50 24

Captopril(n = 25)

Placebo(n = 43)

P = 0.007

Cumulative % Patients with Primary End Point: Doubling of Baseline Serum Creatinine

Adapted from Lewis EJ, at al. N Engl J Med 1993;329(20):1456.

48% risk reduction

BP~ 134/82

64

RENAAL Primary Components

ESRD or Death

P (+ CT)L (+ CT)

Months

% w

ith e

vent

0 12 24 36 480

10

20

30

40

50

751 714 625 375 69762 715 610 347 42

751 692 583 329 525252525252762 689 554 295 363636363636P (+ CT)

L (+ CT)

762 715 610 347 424242424242751 714 625 375 696969696969

P (+ CT)L (+ CT)

Doubling of Serum Creatinine

Months

% w

ith e

vent

p=0.006Risk Reduction: 25%

0 12 24 36 480

10

20

30

P

L

P

L

p=0.010Risk Reduction: 20%

ESRD

Months

% w

ith e

vent

0 12 24 36 480

10

20

30p=0.002Risk Reduction: 28%

P

L

Blood Pressure Targets in Chronic Kidney Disease: Proteinuria as an Effect Modifier

• 3 RCTs (8 reports) with a total of 2272 participants (ALL NON-DIABETIC CKD)

– MDRD (Modification of Diet in Renal Disease) Study

– AASK (African American Study of Kidney Disease and Hypertension) Trial

– REIN-2 (Ramipril Efficacy in Nephropathy 2) trial

• 2- to 4-year trial follow-up

Upadhyay A, et al. Annals Intern Med 3/2011

Proportion of patients with end-stage renal disease in each study arm REIN-2

Ruggenenti P, et.al. Lancet 365 (9463):939-946, 2005.

% w

ith E

vent

s

Composite Clinical Events: Declining GFR Event,ESRD or Death by BP Goal

Low vs. Usual:RR=2%, (p=0.85)

RR=Risk Reduction

Low (Achieved: 127/77)Usual BP ((Achieved: 140/85)

0

5

10

15

20

25

30

35

40

Follow-Up Time (Months)0 6 12 18 24 30 36 42 48 54 60

Wright JT Jr, et.al. JAMA, 2002

AASK Trial KDIGO BP Guidelines 2012-BLOOD PRESSURE MANAGEMENT IN CKD WITHOUT DIABETES

• We recommend that non‐diabetic adults with CKD and urine 

albumin excretion <30 mg/24 h whose office BP is consistently 

>140/90mm Hg be treated with BP‐lowering drugs to maintain BP 

consistently ≤140/90 mm Hg. 

• GRADE 1B

• We suggest that non‐diabetic adults with CKD and albuminuria 

between 30 to 300 mg/24 h whose office BP is consistently 

>130/80 mm Hg be treated with BP‐lowering drugs to maintain a 

BP consistently ≤130/80 mm Hg. 

• GRADE 2D

Kidney Int Suppl 2012

KDIGO BP Guidelines 2012-BLOOD PRESSURE MANAGEMENT IN CKD WITHOUT DIABETES

• We suggest that non‐diabetic adults with CKD and urine albumin excretion>300 mg/24 h whose office BP is consistently >130/80 mm Hg  be treated with BP‐lowering drugs to maintain a BP that is consistently ≤130/80 mmHg.

GRADE 2C

• We suggest that an ARB or ACE‐I be used as first‐line therapy in non‐diabetic adults with CKD and with urine albumin excretion of 30 to 300 mg/24 h in whom treatment with BP‐lowering drugs is indicated. 

• GRADE 2D

Kidney Int Suppl 2012

KDIGO BP Guidelines 2012BLOOD PRESSURE MANAGEMENT IN CKD WITH DIABETES AND ALBUMINURIA

•Adults with diabetes and CKD with <30 mg/24 h albuminuria whose office BP is consistently >140/90 mm Hg be treated with BP‐lowering drugs to maintain a BP consistently ≤140/90 mm Hg. 

GRADE‐(1B)

•An ARB or ACE inhibitor should be used as first‐line therapy in adults with CKD and diabetes with albuminuria >300 mg/24 h in whom treatment with BP‐lowering drugs is indicated.

GRADE‐ (1B)

•Adults with diabetic CKD with albuminuria >30 mg/24 h  whose office BP is consistently >130/80 mm Hg should be treated with BP‐lowering drugs to maintain a BP ≤130/80 mm Hg.

GRADE ‐(2D)

Kidney Int 2012 (Dec. Supplement)

ANGIOTENSIN I

ANGIOTENSIN II

Angiotensin Converting

Enzyme

Renin

AT1 Receptor

RENIN INHIBITORS

ACE INHIBITORS

AII ANTAGONISTS

ANGIOTENSINOGEN

•t-PA

•Cathepsin G

•Tonin•CAGE

•Cathepsin G

•Chymase

Aldosterone

ALDOSTERONE ANTAGONISTS

The delicate balance

Hyperfiltration

Ischemia

Is there evidence-based medicine (EBM) for lower than <120/80 BP target?

Is there EMB for combination therapy?

No:

• COOPERATE RCT retracted

• ON-TARGET – no benefit, risk.

• ALTitude Trial stopped Nov. 2011

• VA Nephron D

No: ACCORD, AASK

ACEi + ARB ?

ACEi + DRI ?

Systolic Blood Pressure in ACCORD Trial

73N  Engl J Med 2010;362:1575‐85

Kaplan-Meier Analyses of Selected Outcomes

74N  Engl J Med 2010;362:1575‐85

Trials of Intensive BP Lowering

ACCORD SPRINT

Patients Diabetics Non-Diabetics

Intervention Glycemic, Lipids,BP

BP

Number 4,733 9,500

Targets SBP < 120 mm Hg vs < 140 mm Hg

Duration (years) 5 7-8

Primary Outcome Measure

MI, Stroke, CV Death

JNC 2013

In patients with CKD (GFR or ACR)• Target BP <140/90

• Preferred agents: ACE, ARB

• Strength of Recc’d---Expert Opinion

JAMA Dec 2013

Well,… we slogged through it!