Diuretic Resistance

& Role of Agent Options : When Loop is Inadequat

Mochammad Thaha
MNHU & PODIN
Malang
2021

M.Thaha
 EPIDEMIOLOGY
& PATOPHYSIOLOGY

M.Thaha
 What is diuretic resistance ?

The general definition refers to the failure to achieve

effective congestion relief despite appropriate or escalating
doses of diuretics

(Maaten et al, 2015)

(Jardim et al., 2018)
M.Thaha
 CARDIORENAL SYNDROME
➔HF pts have high prevalence of comorbid cardiovascular
condition such as CKD (40 – 50 %)
➔ADHERE ➔ >30% pts with acute decomp HF have acute
or chronic renal insuffiency. In another study, only 17 %
pts with HF have normal GFR
➔Reduced congestion might worsen renal function (WRF)

➔ CKD is powerful independent risk factor ➔ CVD

• USA > 60% CKD patients have CVD (degree of CVD
correlates closely with CKD severity)
➔ Compared to pts with normal kidney function, pts with
at least moderately reduced kidney function
➔ 3 fold higher risk of HF
➔ 10-30 fold higher risk of mortality
AKI can also contribute to the progression of CVD ➔
increase mortality by 5-7 fold

M.Thaha Nature Reviews Nephrology 12, 610–623 (2016) doi:10.1038/nrneph.2016.113 Published online 30 August 2016
 Change in body weight
at discharge based on ADHF
National Registry database

Amir Kazory. Cardiorenal Syndrome: Ultrafiltration Therapy for Heart Failure—Trials and Tribulations
M.Thaha
 Diuretic dose and long-term outcomes in elderly
patients with heart failure after
hospitalization – Increased Mortality

Relationship between furosemide dose and survival rate after discharge

[Study 4,406 heart failure patients 65 years or older were followed
overview] up for 5 years,\ and the relationship between mortality and The high dose of furosemide
hospitalization rate due to heart disease and renal
dysfunction was examined.
becomes the predictive
Those dose of furosemide was divided into low-dose group factor of death and clinical
(1~59mg/day), mid-dose group (60~119mg/day) and high- event cases in relation to
dose group (120mg//day or more).
deterioration of prognosis

━━ Low-dose
━━ Mid-dose
━━ High-dose
Survival rate (%)

Higher dose of furosemide

led to deterioration of
prognosis

Days after discharge

Abdel-Qadir, H.M. et al.: Am. Heart J., 160(2), 264-271, 2010
M.Thaha
 3 KEY PATHOPHYSIOLOGICAL
OF CARDIO—RENAL INTERACTION

Ultimately, lack of Transrenal Perfusion Pressure (TPP) will activate the NEUROHORMONAL ACTIVITY

Schefold JC, Filippatos G, Hasenfuss G, Anker SD, von Haehling S. Heart failure and kidney dysfunction: epidemiology, mechanisms and
Thaha management. Nat Rev Nephrol. 2016; 12:610-623
M.Thaha
 EXCESSIVE NEUROHORMONAL ACTIVATION, RELEASE OF
VASOCONSTRICTING & SODIUM/WATER RETAINING
FACTORS & ACTIVATION OF THE SNS ARE THE HALLMARK
OF CRS

“THEURAPEUTIC STRATEGIES IN CRS ARE DIRECTED TO DECREASE

FLUID OVERLOAD AND VENOUS CONGESTION WHILE MAINTAINING OR
IMPROVING KIDNEY FUNCTION, NOT WORSENING RENAL FAILURE
(WRF)”

Verbrugge FH, Mullens W, Tang W. Management of cardio-renal syndrome and diuretic resistance. Curr Treat
Options Cardio Med. (2016)

M.Thaha
 DIURETICS
MODE OF ACTIONS AND ISSUES

M.Thaha
 Diuretic Options for Decongestions

Sites & Mode of action of diuretics

M.Thaha (Mullens et al., 2019)
 Suggestion regarding speed, dilution,
access administration…..

Loop diuretics should not be administered IV as a rapid "push“,

the following approach seems reasonable:
• 20 to 40 mg over 5 minutes (1.2.5)
• 60 to 120 mg over 20 minutes (3.6.20)
• 160 to 200 mg over 40 to 50 minutes (4 mg/min)

Bolus IV furosemide doses of 160 to 200 mg occasionally cause

transient tinnitus. This effect can be minimized by giving the dose
more slowly. Ototoxicity is most common when high doses of a
loop diuretic are given rapidly at rates for furosemide above 4
mg/min

Usual Infusion Concentrations for Adult IV infusion: 1 mg/mL or 2 mg/mL or

undiluted as 10 mg/mL . No data for particular access in intravenous use.

M.Thaha Brater and Ellison, 2019

 Intermittent bolus or Continuous infusion?

IV Bolus Continuous
infusion

• Prone to tinnitus, hearing loss. • Continuous infusion should be preceded by

• Non significantly higher rates of a loading dose, which assures the prompt
ventricular tachycardia and achievement of a steady-state of plasma
myocardial infarction loop diuretic concentration
• A continuous infusion should only be used
• Could lead more unfavorable
in patients who are first responsive to
hemodynamics bolus loop diuretic therapy
• Thus, in patients who fail to respond to the
maximal bolus doses, continuous infusion
will be ineffective

Continuous infusion was associated with a significantly lower rate of ototoxicity,

defined as hearing loss or tinnitus (relative risk 0.06, 95% CI 0.01-0.44)

M.Thaha Brater and Ellison, 2019

 LOOP DIURETIC DOSING

• Diuretics have a dose-response curve and

the effect only begins once the diuretic
level reaches a therapeutic threshold
within the renal tubular lumen
• Diuretic doses below threshold are
ineffective, so a higher effective single
loop diuretic dose is needed rather than
administering an inadequate dose more
frequently

M.Thaha (Ellison and Felker, 2017)

 How the subsequent dose should be given?

• Subsequent dosing is determined by

the diuretic response
• IV onset of diuresis is within 30
minutes with peak diuresis usually at
1-2 hours
• If there is little or no response to the
initial dose, the dose should be
doubled at two-hour intervals, as
needed, up to the maximum
recommended doses

M.Thaha (Brater and Ellison, 2019;Ellison and Felker, 2017)

 How should I start for loop diuretic?

The initial dose of IV loop diuretic should be approximately 2 or 2.5

times the patient's total maintenance daily oral dose

Maximum effective dose: defined as the dose that achieves the

maximal peak rate of sodium excretion. This dose differs in patients
with heart failure, cirrhosis, nephrotic syndrome, and reduced GFR

Dose that is above the maximum effective dose may be an effective

strategy to enhance total natriuresis, and in order to avoid toxicity
the administered dose should not exceed the Maximum
recommended daily dose
M.Thaha
 How and when effectiveness should be measured?

M.Thaha
 2017 AHA Recommendations of Heart Failure
with PRESERVED EF

2016 ESC Recommendations of Heart Failure with Reduced EF

M.Thaha
 2017 KDIGO Recommendations
of the treatments of AKI

M.Thaha
 The DOSE Trial
Diuretic Optimization Strategies Evaluation

M.Thaha N Engl J Med. 2011 Mar 3;364(9):797-805.

 Max Effective dose in Cardiorenal Syndrome

• eGFR > 30, Maximum Effective Dose, 80

mg IV
• eGFR < 30, Maximum Effective Dose, 200
mg IV
• Oliguric AKI, Maximum Effective Dose, up
to 500 mg IV

M.Thaha Brater and Ellison, 2019

 WHAT ABOUT LOOP DIURETICS
& ITS RESISTANCE

M.Thaha
 Loop Diuretics

Furosemide
▪ Blocks the TAL Na/K/2Cl pump
▪ Better Efficacy in patients with reduced
GFR
▪ Better Bioavailability
▪ Primary Choice
▪ PG, less Neurohormonal, Fena >, less
rebound, switch oral, etc
▪ No current guideline dosing

Cautions: Chronic use -> cellular hypertrophy -> increased Na reabsorption -> Failure of diuresis

l-Qadir et al: Diuretics Dose and Long term Outcomes in Patients with Acute Decompensated Heart Failure.
M.Thaha American Heart Journal 160 (2), 265-271, 2010
 EXCESSIVE NEUROHORMONAL ACTIVATION, RELEASE OF
VASOCONSTRICTING & SODIUM/WATER RETAINING
FACTORS & ACTIVATION OF THE SNS ARE THE HALLMARK
OF CRS

“THEURAPEUTIC STRATEGIES IN CRS ARE DIRECTED TO DECREASE

FLUID OVERLOAD AND VENOUS CONGESTION WHILE MAINTAINING OR
IMPROVING KIDNEY FUNCTION, NOT WORSENING RENAL FAILURE
(WRF)”

Verbrugge FH, Mullens W, Tang W. Management of cardio-renal syndrome and diuretic resistance. Curr Treat
Options Cardio Med. (2016)

M.Thaha
 Neurohormonal Activity

Adenosine
Nijst P, Verbrugge FH, Grieten L, et al. The pathophysiological role of interstitial sodium in heart failure. J Am Coll Cardiol. 2015;65:378-388.
.
M.Thaha
 What is Braking Phenomenon?

• is an appropriate
homeostatic response
that prevents excessive
volume depletion during
continued diuretic
therapy
• Decreased response to the
action of a diuretic that
results from increased
sodium reabsorption in
other nephron segments

M.Thaha (Maaten et al, 2015;Ellison and Felker, 2017)

 Causes and Mechanisms
of Developing Resistance
to Diuretics
Causes of resistance to
Mechanism
diuretic drugs in HF
1. Noncompliant patient Lack of drug administration,
increased
Na, inadequate diuretic dose
2. Low intestinal absorption Abdominal venous
congestion
3. Low tubular secretion Low CO, chronic renal failure
4. Simultaneous drugs: Inhibiting sodium cleansing
NSAID and vasodilatatory PG
synthesis
5. Diuretic tolerance and Distal tubules hypertrophy
increase of Na
reabsorption
6. Neurohormonal Prolonged treatment with
(short term) diuretic drugs, heart
failure

M.Thaha Romanian Journal of Cardiology | Vol. 22, No. 2, 2012

 Studi Okabe
301 ADHF in 537
days & WRF

M.Thaha Okabe et al, 2014

 DIURETIC RESISTANCE,
WHAT ARE THE ALTERNATIVE SOLUTIONS?

M.Thaha
 Efforts in treating diuretic Resistant

M.Thaha Maaten et al, 2015

 2nd line agent for decongestion
(combination diuretic therapy)

Combination of two or more diuretics from different classes may produce an additive or
synergistic mechanism of action and diuretic response, and can be an effective approach in
resistant cases

Without Hypokalemia:
• add metolazone (5 to 10 mg once daily initially, increased to a maximum dose of 20 mg
once daily), hydrochlorothiazide (25 to 50 mg twice daily initially, increased to a
maximum dose of 200 mg per day) is same effective.
• hydrochlorothiazide is given orally in patients treated with an IV loop diuretic, the
thiazide diuretic should precede the loop diuretic by 2-5 hours, since the peak effect of
the thiazide is 4-6 hours after ingestion

With Hypokalemia:
• add a potassium-sparing diuretic first (eg, amiloride or a mineralocorticoid receptor
antagonist). Potassium-sparing diuretics, such as mineralocorticoid receptor
antagonists and amiloride, can help limit potassium wasting, although data
demonstrating their efficacy in reducing extracellular fluid volume are limited
• ESC recommended the dose of spironolactone is 25 to 50 mg once daily.

M.Thaha
Brater and Ellison, 2019
 Unproven Strategies that We Should not use

Dopamine

Addition of low dose dopamine on 360 ADHF patients in the large randomized
ROSE-HF trial. The addition of low-dose dopamine did not significantly increase
urine volume or improve decongestion compared with placebo, although it did
increase the incidence of arrhythmias (7% in the dopamine group vs 1% in the
placebo group, P<0.001)

Albumin

Co-administration of albumin and furosemide, Data in Heart Failure are lacking.

It is possible that infusion of furosemide or other loop diuretics plus albumin
would be effective in patients with refractory edema and severe
hypoalbuminemia (<2.0)

M.Thaha Brater and Ellison, 2019

 RESPONDING TO INADEQUATE DIURESIS

Jentzer JC, Chawla LS, et al. A clinical approach to the acute cardiorenal syndrome. Crit Care Clin. 2015; 31: 658-703
M.Thaha
 When should we initiate UF?

Ultrafiltration in patients
with heart failure appears
to be indicated primarily
when dialytic treatment is
indicated in patients with
combined heart failure &
kidney failure.

M.Thaha Ponikowski et al., 2016 ; Brater and Ellison, 2019

 AQUARETICS,
DOES IT REALLY SOLVE THE PROBLEMS ?

M.Thaha
 ROLE OF AVP ANTAGONIS

• DISTAL TUBULE SODIUM

BLOCKAGE (-)

• EFFECTIVE FREE WATER REMOVAL

• LESS NEUROHORMONAL
ACTIVATION

• PRESERVATION OF RBF, LVEF

• BREAK UP OF THE VICIOUS CYCLE
OF CARDIO-RENAL CONNECTION

Tamaki, 2017
M.Thaha
 Vasopressin Regulation
of Water Reabsorption from Renal Tubular Cells

Collecting Duct Cell

Collecting duct
Vasa recta

ATP
GTP AQP2 Exocytic
(Gs) Insertion
cAMP

PKA

Recycling Endocytic
vesicle Retrieval

Basolateral membrane Luminal membrane

M.Thaha Mayinger et al. Exp Clin Endocrinol Diab 1999;107:157-65.

 Incidences of worsening renal function in
tolvaptan group and furosemide group

Method : Randomized controlled trial

enrolled 52 consecutive hospitalized
patients with ADHF. The patients were
assigned alternately to either the TLV
group (TLV plus conventional treatment, n TLV Group FRM Group

FRM starting dose (mg/day) 20.00± 0.00 38.46±6.13

= 26) or the FRM group (increasing the
FRM total dose (mg) 124.2±66.3 299.6±201.1
dose of FRM, n = 26). TLV was Tolvaptan (mg/day) 8.37± 2.44 0
administered within
Serum creatinine (mg/dl) 1.282± 0.814 1.000± 0.401
24 h from admission.
eGFR (ml/min) 44.84± 16.74 51.95± 18.28
CCr (ml/min) 43.00± 18.34 46.86± 22.66
M.Thaha
 Early administration of tolvaptan preserves
renal function in elderly patients with acute
decompesated heart failure
The incidence of worsening renal function (A) Incidence of persistent worsening renal
(WRF) within 7 days from admission was function (p-WRF). The persistent-WRF rate
was significantly lower in the tolvaptan (TLV)
significantly lower in the TLV group compared to the furosemide (FRM) groups.

C) Incidence of late-onset worsening renal

function (late-WRF). The late-WRF rate was
significantly lower in the tolvaptan (TLV)
compared to the furosemide (FRM) groups.

57.7%
(n = 15)
26.9%
(n = 7)

Conclusion : Early administration of TLV,

compared to increased FRM dosage,
reduces the incidence of WRF and
significantly effective on renal protection in
elderly patients with ADHF.

Kimura, J Cardiol. 2015 Dec 11

M.Thaha
 60 pts; renal effect & neurohormonal in ADHF, 30 Fur 40 mg iv vs TLV 7.5 mg/hari ; WRF & rasio BUN/SK sig lower in TLV group

M.Thaha Jujo et al, 2016

M.Thaha
 Tamaki, 50 pts EF > 45%, WRF risk tolv (26) vs fur (24) in 24/48 hrs & FeUN renal perfusion lower in TLV (-)
M.Thaha Tamaki et al, 2017
 TAKE HOME MESSAGES

DIURETIC RESISTANCE IS A WORST CASE SCENARIO FOR CHF PTS

MORTALITY IS CLEARLY WORSENED BY THE PRESENCE OF WRF
MANAGEMENT OF DR IS A MAJOR MEDICAL CHALLENGE :
EARLY DIAGNOSIS & TREATMENT MIGHT IMPROVE SURVIVAL
LOOP DIURETICS AS A GOOD, BAD, AN UGLY OPTION
PROMISING NEW THERAPIES E.G – AVP ANTAGONIST, ETC
INTERDISCIPLINARY CARE TEAMS SHOULD INCLUDE THE EARLY
INVOLVEMENT OF BOTH CARDIOLOGISTS AND NEPHROLOGISTS

M.Thaha