Diuretics are commonly used to treat hypertension in patients with chronic kidney disease (CKD). The ALLHAT trial found thiazide-type diuretics were superior to other antihypertensives in preventing cardiovascular disease and were less expensive. In CKD, loop diuretics are recommended for patients with a GFR <30 mL/min, while thiazide diuretics can be used for those with a GFR ≥30 mL/min. Combination diuretic therapy may be needed to overcome diuretic resistance seen in CKD. Close monitoring is required due to risks of electrolyte abnormalities and dehydration.

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