diuretics in ckd
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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