1. DIURETICS IN CKD
DM SEMINAR
22/12/10
Vishal Golay

2. Diuretics
 Agents which promote the formation of
urine by the kidney
 Greek "dia-", thoroughly +
"ourein", to urinate
= to urinate thoroughly.

3. ALLHAT trial (JAMA. 2002;288:2981-
2997)
 randomized, double-blind, active-
controlled clinical trial
 February 1994 through March 2002.
 Inclusion:
◦ 33357 participants
◦ 55 years or older with hypertension
◦ at least 1 other CHD risk factor
◦ 623 North American centers.

4. ALLHAT trial
 Intervention: 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 terminated
 Follow-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).

5. ALLHAT trial-Results
 Primary end points: no difference
 All cause mortality: no difference
 Five-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

6. 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

7. 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

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

9. Mechanism of Na retention in
CKD
Decreased filtered
load of Na
Sodium
and fluid
overload
Increased
compensatory
retention in tubules
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

10. Diuretics as Antihypertensives in
CKD
Facilitates responses to other
Antihypertensives
Decreased Increased Reverses
Lowering
tubular Na Na ECF
BP
absorption excretion expansion
Salt Restriction

11. Classes of Diuretics
 Loop Diuretics
 Thiazide and thiazide like diuretics
 K-sparing diuretics
◦ Aldosterone antagonists
◦ ENaC blockers
 Carbonic Anhydrase Inhibitors
 Osmotic Diuretics
 Misc. Agents(DA agonists, A1
receptor antagonists, vaptans)

12. Mechanisms of action of
diuretics

13. Diuretics used in CKD

14. Loop diuretics
 Bumetanide 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

15. Loop diuretics
 Duration 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

16. Loop diuretics
 In 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

17. •
% of filtered Na+ load excreted
17

18. 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.

19. Thiazide and thiazide like
diuretics
 In 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

20. Potassium Sparing Diuretics
 Amiloride and triamterine are organic
cations
 AR antagonists are competitive
antagonists
 These drugs produce only modest
natriuresis
 More effective than furosemide in
cirrhotic ascites

21. Potassium Sparing Diuretics
 In 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

22. Misc. diuretics
 Osmotic 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

23. Adverse effects of diuretics

24. Diuretic drug dosing in CKD

25. Diuretic Resistance in CKD
 Highdietary intake of sodium (i.e.
Urinary Na >100mmol/day)
Pharmacokinetics:
 Decreased delivery
 Decreased secretion in PT by OAT-1
 Intratubular binding of secreted
diuretic to filtered albumin.

26. Diuretic Resistance in CKD
Pharmacodynamics:
 Reduced number of functioning
nephrons and decreased Na filtered
load
 Diuretic Braking phenomenon

27. Braking Phenomenon
 Postdiuretic 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

28. Braking Phenomenon
 Clinical 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

29. J Nephrol 6: 118–123, 1993

30. Rationale for combination
therapy

31. Newer agents
 Adenosine 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

32. 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);

33. 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).

34. 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).

35. KDOQI GUIDELINE 12: USE OF
DIURETICS IN CKD

36. THANK YOU