diuretics in ckd

DIURETICS IN CKD

DM SEMINAR22/12/10Vishal Golay

Diuretics

Agents which promote the formation of urine by the kidney

Greek "dia-", thoroughly + "ourein", to urinate

= to urinate thoroughly.

ALLHAT trial (JAMA. 2002;288:2981-2997)randomized, double-blind, active-

controlled clinical trialFebruary 1994 through March

2002.Inclusion:

◦33357 participants ◦55 years or older with hypertension ◦at least 1 other CHD risk factor◦623 North American centers.

ALLHAT trialIntervention: Randomised to receive

◦ chlorthalidone, 12.5 to 25 mg/d (n=15255); ◦ amlodipine, 2.5 to 10 mg/d (n=9048); ◦ lisinopril, 10 to 40 mg/d (n=9054)

Doxazosin arm was prematurely terminatedFollow-up of approximately 4 to 8 years.Primary outcome: combined fatal CHD or

nonfatal MI Secondary outcomes: all cause mortality,

stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease).

ALLHAT trial-ResultsPrimary end points: no differenceAll cause mortality: no differenceFive-year systolic blood pressures were

significantly higher in the amlodipine (P=.03) and lisinopril (P.001) groups compared with chlorthalidone

Amlodipine vs chlorthalidone: secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine

Lisinopril vs chlorthalidone : lisinopril had higher 6-year rates of combined CVD

ALLHAT trial

Conclusion: “Thiazide-type diuretics are superior

in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.”

Fallout: JNC 7 hypertension guidelines

recommended that thiazides should be the first line antihypertensive

Hypertension in CKD

50% to 75% of individuals with GFR 60 mL/min/1.73 m2 (CKD Stages 3-5) have hypertension.

Central role of kidney in BP homeostasis: Guyton’s Hypothesis

AJKD, Vol 32, No 5, Suppl 3 (November), 1998: pp S120-S141

Mechanism of Na retention in CKD

Decreased

filtered load of

Na

Increased compens

atory retention in tubules

Sodium and fluid overload

Patients with CKD have a 10 to 30% increase in extracellular and blood volume, even in the absence of overt edema Am J Med 72: 536–550, 1982

Diuretics as Antihypertensives in CKD

Decreased tubular Na absorption

Increased Na

excretion

Reverses ECF

expansion

Lowering BP

Facilitates responses to other Antihypertensives

Salt Restriction

Classes of DiureticsLoop DiureticsThiazide and thiazide like diureticsK-sparing diuretics

◦Aldosterone antagonists◦ENaC blockers

Carbonic Anhydrase InhibitorsOsmotic DiureticsMisc. Agents(DA agonists, A1

receptor antagonists, vaptans)

Mechanisms of action of diuretics

Diuretics used in CKD

Loop diureticsBumetanide and torsemide have

better oral bioavailability than furosemide —› doubling oral dose of furosemide

Vd inversely varies with albumin concentration

50% furosemide metabolized by kidney(glucuronidation)

Torsemide and bumetanide metabolized exclusively in liver

Loop diureticsDuration of action:

torsemide >furosemide>bumetanide

In CKD: ◦t½ of furosemide is prolonged:

accumulates leading to toxicity,◦Fe of unchanged drug increases: greater

natriuresis◦Renal clearance of active LD decreased

in prop to CCl

Loop diureticsIn CKD:

◦Competition for luminal transport with other OA (eg urate)

◦Metabolic acidosis decreases tubular secretion

◦Hypoalbuminemia: increases metabolism in S1 segment and decreases tubular secretion in S2 segment of PT

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Thiazide and thiazide like diuretics?Class effect as antihypertensives

Decreases Ca excretion

Decreases urate clearance

Impairs maximal urinary dilution but not maximal concentration, along with increases AQP2 expression, makes hyponatremia 12 times more common than loop diuretics.

Thiazide and thiazide like diureticsIn CKD:

◦Poor diuretics when CCl <30ml/min◦Indapamide and bendroflumethiazide

are metabolized in the liver: limits accumulation in renal failure

◦Metolazone found to have synergistic action with loop diuretics in very low GFR even where other thiazides are not very effective

Potassium Sparing DiureticsAmiloride and triamterine are

organic cationsAR antagonists are competitive

antagonistsThese drugs produce only

modest natriuresisMore effective than furosemide in

cirrhotic ascites

Potassium Sparing DiureticsIn CKD:

◦Not very useful as primary drugs◦Can be of adjunctive use in resistant

hypertension◦Hyperkalemia is a dreaded complication◦May reduce proteinuria in CKD (?retards

disease progression) Kidney Int. 2006

Dec;70(12):2116-23.

◦Has role in preventing cardiac remodeling

Misc. diureticsOsmotic Diuretics:

◦have been tried in ARF◦In CKD-can cause expansion of ECV,

hemodilution, MA, can ppt ARF in high doses

CAI:◦Development of life threatening MA

limits use in CKD

Adverse effects of diuretics

Diuretic drug dosing in CKD

Diuretic Resistance in CKDHigh dietary intake of sodium (i.e.

Urinary Na >100mmol/day)

Pharmacokinetics:Decreased deliveryDecreased secretion in PT by

OAT-1Intratubular binding of secreted

diuretic to filtered albumin.

Diuretic Resistance in CKD

Pharmacodynamics:

Reduced number of functioning nephrons and decreased Na filtered load

Diuretic Braking phenomenon

Braking PhenomenonPostdiuretic fluid and Na retention

Compensation by Na retaining hormones/ upregulation of ion transporters along the TALH/ Structural and functional changes in the distal nephron segments

Co-administration with thiazide-supraadditive (sequential duiretic blockade)

Braking PhenomenonClinical implications of this

phenomenon:◦Salt retention should always be

advised in all patients who are on diuretics

◦Addition of a second diuretic increases natriuresis

◦Use of a long acting drug /more frequent /iv administration has more effect

◦Diuretic therapy should not be stopped abruptly unless Na intake is curtailed

J Nephrol 6: 118–123, 1993

Rationale for combination therapy

Newer agentsAdenosine type I receptor antagonists:

◦Disrupts TGF and GTF and thus decreases proximal resorption and increases GFR

◦Used in diuretic resistant CHF◦Use in CKD is equivocal

Vasopressin Antagonists:◦Vaptans(conivaptan, tolvaptan, lixivaptan)◦Allows free water loss without natriuresis◦Predominantly used to treat

eu/hypervolemic hyponatremia

KDOQI GUIDELINE 12: USE OF DIURETICS IN CKD

12.1 Most patients with CKD should be treated with a diuretic (A).

12.1.a Thiazide diuretics given once daily are recommended in patients with GFR ≥30 mL/min/1.73 m2 (CKD Stages 1-3) (A);

12.1.b Loop diuretics given once or twice daily are recommended in patients with GFR <30 mL/min/1.73 m2 (CKD Stages 4-5) (A);

KDOQI GUIDELINE 12: USE OF DIURETICS IN CKD

12.1.c Loop diuretics given once or twice daily, in combination with thiazide diuretics, can be used for patients with ECF volume expansion and edema (A).

12.1.d Potassium-sparing diuretics should be used with caution:◦ 12.1.d.i In patients with GFR <30

mL/min/1.73 m2 (CKD Stages 4-5) (A);◦ 12.1.d.ii In patients receiving concomitant

therapy with ACE inhibitors or ARBs (A);◦ 12.1.d.iii In patients with additional risk

factors for hyperkalemia (A).

KDOQI GUIDELINE 12: USE OF DIURETICS IN CKD

12.2 Patients treated with diuretics should be monitored for:◦ 12.2.a Volume depletion, manifest by

hypotension or decreased GFR (A);

◦ 12.2.b Hypokalemia and other electrolyte abnormalities (A).

◦ 12.2.c The interval for monitoring depends on baseline values for blood pressure, GFR and serum potassium concentration

12.3 Long-acting diuretics and combinations of diuretics with other antihypertensive agents should be considered to increase patient adherence (B).

KDOQI GUIDELINE 12: USE OF DIURETICS IN CKD

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