Diuretics in CKD


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  • Guytons hypothesis; all mechanisms are one way or the other linked to decreasing the filtered load of Na which causes a secondary increase in SVR and hypertension
  • 91-99% bound to albumin
  • Met acidosis causesdepolarisation of memb potential of PT cells which decreases OA transport.
  • Na decreases intracellularly, increases Na-Ca exchange in the basolateralDecreasedClintracellularly, increase abs of Ca via TRPV5Increased prox abs of Ca due to Ecv depletionLoop causes Ca loss due to decrease lumen positivityUratecl is dec due to ECV depletion and competition for tubular uptake: loop initially causes increase excretion due to decrease abs initially from prox but later causes decreased clearance due to volume depletion
  • ARF ppt by vasoconstriction,
  • Decreased delivery is due to decreased blood flow (renal perfusion) and wider Vd due to hypoalbuminemiaDecreased secretion is due to competition due to metabolic acidosis and accumulated organic anions(urates)
  • To overcome this compensation loop Diu must be administered continuouslyCell hypertrophy of the DCT and CD in presence of aldosterone, increased no of thiazide sensitive co-transporters in the apical membrane and Na-K ATPase in basolateral
  • Caffeine and theophylline causes diuresis
  • Diuretics in CKD

    1. 1. DIURETICS IN CKD DM SEMINAR 22/12/10 Vishal Golay
    2. 2. Diuretics Agents which promote the formation of urine by the kidney Greek "dia-", thoroughly + "ourein", to urinate = to urinate thoroughly.
    3. 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. 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. 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. 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. 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. 8. AJKD, Vol 32, No 5, Suppl 3 (November), 1998: pp S120-S141
    9. 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 inextracellular and blood volume, even in the absence ofovert edema Am J Med 72: 536–550, 1982
    10. 10. Diuretics as Antihypertensives in CKDFacilitates responses to otherAntihypertensives Decreased Increased Reverses Lowering tubular Na Na ECF BP absorption excretion expansion Salt Restriction
    11. 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. 12. Mechanisms of action ofdiuretics
    13. 13. Diuretics used in CKD
    14. 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. 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. 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. 17. • % of filtered Na+ load excreted17
    18. 18. Thiazide and thiazide likediuretics ?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. 19. Thiazide and thiazide likediuretics 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. 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. 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. 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. 23. Adverse effects of diuretics
    24. 24. Diuretic drug dosing in CKD
    25. 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. 26. Diuretic Resistance in CKDPharmacodynamics: Reduced number of functioning nephrons and decreased Na filtered load Diuretic Braking phenomenon
    27. 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. 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. 29. J Nephrol 6: 118–123, 1993
    30. 30. Rationale for combinationtherapy
    31. 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. 32. KDOQI GUIDELINE 12: USE OF DIURETICSIN 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. 33. KDOQI GUIDELINE 12: USE OFDIURETICS 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. 34. KDOQI GUIDELINE 12: USE OFDIURETICS 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).
    36. 36. THANK YOU