How To Achieve Blood Pressure Target in Chronic Kidney

Disease : The Benefit of Candesartan Across

Cardiovascular Renal Continuum

dr. Nyoman Paramita Ayu, SpPD, K-GH, FINASIM

Division of Nephrology
Department of Internal Medicine, Faculty of Medicine
Udayana University / Prof dr IGNG Ngoerah Hospital, Denpasar Bali
Disclaimer
• This event is a non-promotional event, sponsored by WELESTA
which may contains off label information.
• During this event, data may refer to medicines or indications that
may not be approved in Indonesia. They are presented in the spirit
of education and the right of the scientific and medical community
to be fully informed concerning scientific and medical progress. The
information should under no circumstances be regarded as a
recommendation for use of the medicine or indication.
Background
Background

IRR 2018
ETIOLOGY OF CKD
5D
Hypertension and CKD

cause or effect
Pathophysiology
RAA SYSTEM

Ruilope L. Vascular Health and Risk Management · February 2007

• Cheriyan J et al. Hypertension. Oxford. 2010
• Gareth Beevers et al. Pathophysiology of hypertension. ABC of Hypertension, Sixth Edition. 2015
 ChronicKIDNEY
CHRONIC Kidney Disease
DISEASE
Pathophysiology
• The pathogenesis of hypertension
in CKD is complex and involves
many factors.

• There are an increasing number of

factors that are implicated in the
blood pressure regulation in CKD

• Huan Y, et al. Pathophysiology of Hypertension in Chronic Kidney

Disease. Elsevier. 2015
Pathogenesis Chronic Kidney Disease

• The increase in blood pressure

results from four basic
interrelated mechanisms by which
blood pressure is regulated:
• Sodium and fluid retention,
• RAAS hyperactivation,
• Sympathetic nervous system
hyperactivation,
• Vascular endothelial
dysfunction.
• Drug  ESA, NSAIDs,
Calcineurin inhibitors

• Townsend R. Pathophysiology of Hypertension CKD. Elsevier. 2020

• Huan Y, et al. Pathophysiology of Hypertension CKD. Elsevier. 2015
How to
achieve Diet
control
blood
pressure in Drug
CKD

Dialysis
Diet

• William JE et al. Comprehensive Clinical Nephtology Sixth Ed. 2019

• Indonesian Society of Hypertension. Konsensus Penatalaksanaan Hipertensi. 2021
6.5 Statement on Sodium
Guideline 3: Protein and Energy Intake
3.0 Statements on Protein Amount

Protein Restriction, CKD Patients Not on Dialysis and Without Diabetes

3.0.1 In adults with CKD 3-5 who are metabolically stable, we recommend,
under close clinical supervision, protein restriction with or without keto
acid analogs, to reduce risk for end-stage kidney disease (ESKD)/death (1A)
and improve quality of life (QoL) (2C):
• a low-protein diet providing 0.55–0.60 g dietary protein/kg body
weight/day, or
• a very low-protein diet providing 0.28–0.43 g dietary protein/kg body
weight/day with additional keto acid/amino acid analogs to meet protein
requirements (0.55–0.60 g/kg body weight/day)
Guideline 3: Protein and Energy Intake
Protein Restriction, CKD Patients Not on Dialysis and With Diabetes
3.0.2 In the adult with CKD 3-5 and who has diabetes, it is reasonable to prescribe, under close
clinical supervision, a dietary protein intake of 0.6-0.8 g/kg body weight per day to maintain a
stable nutritional status and optimize glycemic control (OPINION).

3.1 Statement on Energy Intake

3.1.1 In adults with CKD 1-5D (1C) or post-transplantation (OPINION) who are metabolically
stable, we recommend prescribing an energy intake of 25-35 kcal/kg body weight per day
based on age, sex, level of physical activity, body composition, weight status goals, CKD
stage, and concurrent illness or presence of inflammation to maintain normal nutritional
status.
Why Dietary Protein Restriction ?
- Decrease load on remaining nephrons (preserve renal function)
- Improve proteinuris /albuminuriua
- Additive effect of ACE inhibitors
- Ameliorate Uremic Syndrome (delay initiation of dialysis)
- Improve metabolic profile
- Improve insulin resistance, acidosis and oxidative stress
- Lack of serious objective reasons for not recommending
Potential Pathways of Protein Restriction Diet and RAAS Blockler in Kidney
Disease Progression

Kalantar-Zadeh, N ENGL J MED 377;18 , Nov 2017 Kalantar-Zadeh K, et al. Chronic kidney disease, Vol 398 August 28, 2021

Am J Kidney Dis. 2019 Feb; 73(2): 248-257

Compared the effect of very low protein diet (VLPD) supplemented with
ketoanalogs of essential amino acids (0.35 g/kg/day), low protein diet
(LPD, 0.60 g/kg/ day), and free diet (FD) on BP in patients with CKD
stages 4 and 5
After 6 months follow up:
• protein intake was lower in VLPD than LPD and FD (0.540.11, 0.780.10, and 1.040.21 g/kg/day,
respectively; P<0.0001).

• BP diminished only in VLPD, from 14319/8410 to 12816/787 mm Hg (P<0.0001), despite reduction of

antihypertensive drugs (from 2.61.1 to 1.81.2;P<0.001).

• Urinary urea excretion directly correlated with urinary sodium excretion, which diminished in VLPD
(from 18132 to 13136 mEq/day; P<0.001).

• At multiple regression analysis, BP results independently related to urinary sodium excretion (P =

0.023) and VLPD prescription (P= 0.003)
Drug

• William JE et al. Comprehensive Clinical Nephtology Sixth Ed. 2019

• Indonesian Society of Hypertension. Konsensus Penatalaksanaan Hipertensi. 2021
Comorbidities BP to start Drug of choise Target BP Target LDL
and therapy
complications

CAD 140/90 RAS blocker, <130/80 < 55 mg/dL

B Blocker with (<140/90 in
or without CCBs elderly)
HF 140/90 RAS blocker, <130/80 but < 70 mg/dL
mineralocorti >120/70
coid receptor
antagonist

Previous stroke 140/90 RAS blocker, 130/80 < 70 mg/dL

CCBs, diuretics (<140/90 in
elderly)

CKD 140/90 RAS inhibitor <130/80 < 70 mg/dL

(<140/90 in
elderly)
Diabetes 140/90 RAS inhibitor <130/80 < 70 mg/dL
and CCB and/or (<140/90 in
thiazide like elderly)
diuretic
BLOOD PRESSURE MANAGEMENT IN PATIENTS WITH CKD,
WITH OR WITHOUT DIABETES, NOT RECEIVING DIALYSIS
 ARBs
CANDESARTAN
ARBs are not equal
Candesartan has the highest
insurmountability and longest dissociation
time from AT1 receptor compared to other
ARB molecules.

1. Cernes R, Mashavi M, Zimlichman R. Differential clinical profile of candesartan compared to other angiotensin receptor blockers. Vasc Health Risk Manag. 2011;7:749-59. doi: 10.2147/VHRM.S22591
2. I. van Liefde, G. Vauquelin. Sartan- AT receptor interactions: evidence for insurmountable antagonism and inverse agonism. Molecular and Cellular Endocrinology, Elsevier, 2009, 302 (2), pp.237. ff10.1016/j.mce.2008.06.006
CARDIOVASCULAR RENAL CONTINUUM
ARB (candesartan) plays an important
role, related to AT1 blocker mechanism Candesartan

Candesartan

Candesartan
Candesartan

Candesartan

Ruilope L. Vascular Health and Risk Management · February 2007

Patients received candesartan (8 mg, once daily) monotherapy
for 12 weeks. All patients receiving anti-hypertensive medication
were switched to candesartan, with all other anti-hypertensive
medications withdrawn. At the end of the run-in period, baseline
evaluations were performed and only patients with SBP 130 mm
Hg and/or DBP 80 mm Hg were used in the next phase of the
study.
BP Reduction Albumin Excretion Reduction

There was no significant difference in BP between

the two groups throughout the study period.
Furthermore, there was no significant difference in
the reduction in BP between the up-titration The reduction was much greater in the up- titration
(△SBP/△DBP -11.0/ -0.8 mm Hg; mean BP -3.1 mm group (41.5±14.3%) than in the combination group
Hg) and combinaion (△SBP/ △DBP -8.7/-1.6 mm (9.2±37.6%; P<0.0001)
Hg; mean BP -2.3 mm Hg; NS) groups.
BP Reduction

Albumin Excretion Reduction

Dialysis

• William JE et al. Comprehensive Clinical Nephtology Sixth Ed. 2019

• Indonesian Society of Hypertension. Konsensus Penatalaksanaan Hipertensi. 2021
 CHRONIC KIDNEY DISEASE

Dialysis
• Decrease volume overload
• Remove uremic toxin
• Correction of acid base and
electrolyte imbalance
• Achievement of individual
patient’s dry weight

• Huan Y, et al. Pathophysiology of Hypertension in Chronic Kidney

Disease. Elsevier. 2015
Dialysis patient’s dry weight

Sinha and Agarwal proposed a definition that combines subjective and objective measurements.
According to this definition, dry-weight is defined as the lowest tolerated post dialysis weight
achieved via gradual change in postdialysis weight at which there are minimal signs or symptoms
of hypovolemia or hypervolemia. (Sinha AD, Agarwal R. Semin Dial, 2009)

• No or minimal patient’s complaint

• No or minimal peripheral oedema
• Good nutrition and good appetite
• Controlled blood pressure (no hyper or
hypotension event intra and
interdialytic) Adequate Dialysis
• Good control of anemia
• Patient not dependent on dialysis
• No itch
 Hemodialysis
Advantages • Maximum ultrafiltration and
solute clearance
• Rapid correction of
electrolyte
• Bed side vascular access
• Relative easy for patient
Disadvantages • Hemodynamic instability
• Rapid fluid and solute shift
• Complex equipment
• Need to travel to center
dialysis 3 times per week
• Risk of bacteremia
• Difficult in small infants
Peritoneal Dialysis
• Better hemodynamic stability
• Better preservation of RRF
• No need anticoagulant
• Less blood loss
• Low risk infection transmission
(hep and hep C)
• Suitable for senior age and
pediatric patients
• Protein loss in dialysate fluid
• Inadequate ultrafiltration or solute
clearance; depend on type of
peritoneum
• Risk of peritonitis
• Risk of hernia, pericatheter leak
and other mechanical
complication
CASE 1

Male 52 yo, initially referred for due to uncontrol DM and

hypertension. He’s taking 2 kind of OAD, ARBs. His BMI is 32 kg/m 2,
average blood pressure 160/90 mmHg. Last laboratory result : Hb 11
g/dL, BUN 67 mg/dL, Creatinine 3.2 mg/dL, eGFR 21.1 mL/min/1.73
m2, uric acid 8,5 mg/dL, ACR urine 800 mg, A1C 9 %
 Diet
Low salt (sodium < 2 g/day)
Low protein 0.6 - 0.8 g/kg body weight / day
Energy 25-35 kcal/kg body weight/day
Low purin
Fluid control

Physical exercise
Drug
• Consider change to insulin (target HbA1C < 6.5 - < 8 %)
• Antihypertension : increase dose of ARB (candesartan) (observation of
potassium level) or combination with CCB, combine with Beta-blocker if
there is specific condition (target BP 120-130/70-79 mmHg)
• Control lipid profile
• Anti platelet
Case 2

Female 60 yo, referred because she has swollen on both leg, feel weak, nausea, vomit,
decrease of appetite and itch. She had DM and hypertension for 10 years but not
routine control and take medicine. Currently she’s taking short acting insulin 6 IU (not
every pre meal), captopril 25 mg bid, HCT 25 od morning and amlodipine 10 mg od.

Physical examination : look weak and pale, BP 170/100 mmHg, Pulse 88 x/mnt, anemic
on eyes, oedema on both lower extremity.

Laboratory : Hb 8 g/dL, proteinuria +3, glucosuria +1, BUN 98 mg/dL, Screatinine 7

mg/dL, eGFR 5,8 mL/min/1.73 m2 Albumin 2.8 mg/dL, natrium 122 mg/dL, potassium
5,7 mg/dL
Diet
Low salt (sodium < 2 g/day)
Low protein 0.8 g/kg body weight/day, in dialysis 1-1,2 g/kg body weight/day
Energy 25-30 kcal/kg body weight/day
Low potassium
Fluid control
Drug
Insulin (adjust glycemic target)
Antihypertension : combination ARB with CCB, increase dose, combine with
Beta-blocker if there is specific condition
(in dialysis patient target BP 130-139/80-89 mmHg)

Start dialysis
Access dialysis : Right access, right patients, right time and right reason
Achieving patient’s individual dry weight

Physical exercise
In stable condition
 Summary
• Chronic Kidney Disease interacts with hypertension on many levels. There
is a bidirectional relationship between the two diseases
• Controlling hypertension in those with CKD not only slows progression of
renal damage but reduces the risk of cardiovascular disease
• Achieving blood pressure (BP) control in CKD may be difficult, often
requiring a combination of antihypertensive medications as well as lifestyle
modification and dialysis
• ARB (candesartan) has more effects beyond than only lowering blood
pressure
• Managing BP and volume in dialysis requires an individualized approach
with integration of numerous clinical, dialysis treatment, and patient factors
Criteria of Hypertension and
CKD
 ISH 2020

ESC/ESH 2018

InaSH 2021
Keto-Acids: Mechanism of action
• The keto- and hydroxy-analogues are transaminated to the
corresponding EAA by taking nitrogen from NEAA, thereby
decreasing the formation of urea by re-using the amino group
• Additional nutrient source
 Enables protein-energy status to be maintained with VLPD
• Decrease metabolic waste products
 Improved uremic symptoms, improved GFR loss
• Improved Metabolic Profile
• Acidosis
• Inflammatory response, Insulin Resistance, MBD
Dietary Protein Intake, MHD and PD Patients
Without Diabetes
3.0.3 In adults with CKD 5D on MHD
(1C) or PD (OPINION) who are
metabolically stable, we recommend
prescribing a dietary protein intake of 1.0-
1.2 g/kg body weight per day to maintain a
stable nutritional status. 3.1 Statement on Energy Intake
3.1.1 In adults with CKD 1-5D (1C) or posttransplantation
Dietary Protein Intake, Maintenance (OPINION) who are metabolically stable, we
Hemodialysis and Peritoneal Dialysis Patients recommend prescribing an energy intake of 25-35
With Diabetes kcal/kg body weight per day based on age, sex,
3.0.4 In adults with CKD 5D and who have level of physical activity, body composition, weight
diabetes, it is reasonable to prescribe a status goals, CKD stage, and concurrent illness or
dietary protein intake of 1.0-1.2 g/kg body presence of inflammation to maintain normal
weight per day to maintain a stable nutritional status.
nutritional status. For patients at risk of
hyper- and/or hypoglycemia, higher levels
of dietary protein intake may need to be
considered to maintain glycemic control
(OPINION).
BLOOD PRESSURE MANAGEMENT IN PATIENTS WITH CKD,
WITH OR WITHOUT DIABETES, NOT RECEIVING DIALYSIS
CASE 1

Male 52 yo, initially referred for due to uncontrol DM and hypertension. He’s taking metformin 850 mg
bid, glimepiride 2 mg od, valsartan 80 mg od. His BMI is 32 kg/m2 ,average blood pressure 160/90 mmHg.
Last laboratory result : Hb 11 g/dL, BUN 67 mg/dL, Creatinine 2,8 mg/dL, eGFR 24,8 mL/min/1.73 m 2, uric
acid 8,5 mg/dL, ACR urine 500 mg, A1C 9 %
Case 2

Female 60 yo, referred because she has swollen on both leg, feel weak, nausea, vomit, decrease of appetite
and itch. She had DM and hypertension for 10 years but not routine control and take medicine. Currently
she’s taking short acting insulin 6 IU (not every pre meal), captopril 25 mg bid, HCT 25 od morning and
amlodipine 10 mg od.

Physical examination : look weak and pale, BP 170/100 mmHg, Pulse 88 x/mnt, anemic on eyes, oedema on
both lower extremity.

Laboratory : Hb 8 g/dL, proteinuria +3, glucosuria +1, BUN 98 mg/dL, Screatinine 7 mg/dL, eGFR 5,8
mL/min/1.73 m2 Albumin 2.8 mg/dL, natrium 122 mg/dL, potassium 5,7 mg/dL
CKD Staging

• KDIGO. Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. 2021
 Hemodialysis

Dialysis
Renal
Replacement
Therapy
Peritoneal Dialysis
Kidney
Transplantation
 Cardiovascular continuum: ARB plays an important role, related to AT1
blocker mechanism

AT1-receptor blockade in the cardiovascular continuum

European Heart Journal Supplements, Volume 6, Issue suppl_H, December 2004, Pages h3-h9, https://doi.org/10.1093/eurheartj/6.suppl_h.h3
Intraglomerular Effect

Effects of dietary protein and sodium intake and pharmacological therapies on afferent and efferent arteriolar tone,
intraglomerular pressure, and glomerular structures and functions
Kalantar-Zadeh K, et al. Chronic kidney disease, Vol 398 August 28, 2021
 Trophy
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