Diuretic use in renal disease

PRESENTOR : K. VENKATARAMANAN MODERATOR: PROF. DR. SHAM SUNDER

Introduction
Diuretics are mainly used in patients with chronic kidney disease (CKD) for
Treatment of edema To assist in reducing blood pressure and To aid in lowering serum levels of K+ in patients with hyperkalemia (a secondary feature of their action)

Nat. Rev. Nephrol. 2012;8:100109

Introduction
Loop diuretics are the most commonly used diuretics in patients with CKD Understanding of their pharmacology (pharmacokinetics and pharmacodynamics) is important for their efficient use

Nat. Rev. Nephrol. 2012;8:100109

Introduction
Many questions exist about the use of diuretics in such patients Some of the most frequent questions include:
When should a thiazide-type diuretic be converted to a loop diuretic during progression of renal failure; Are all loop diuretics equipotent and how best is combination diuretic therapy employed; Do diuretics accelerate the loss of renal function in CKD;
Nat. Rev. Nephrol. 2012;8:100109

Introduction
Some of the most frequent questions.. include:
Can loop diuretics be safely and effectively used in patients on hemodialysis; What are the most worrisome adverse events with diuretic therapy in patients with CKD; and How are diuretics used in patients who are allergic to sulfonamide?

We shall discuss above points..

Nat. Rev. Nephrol. 2012;8:100109

Diuretic usage pattern

Diuretics
Remain a mainstay in the treatment of hypertension and extracellular fluid volume overload in the presence of renal insufficiency and/or the nephrotic syndrome
For example, ~84% of patients in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study required
diuretic therapy (among other antihypertensive medications) to achieve the BP goal of <140/90 mmHg

Nat. Rev. Nephrol. 2012;8:100109

Diuretic usage pattern

Diuretics
In the group of patients treated with amlodipine, the frequency of diuretic use was as follows:
Thiazide-type (33.9%), loop (72.5%), K -sparing (7.8%) and combination (8.1%);
+

diuretics were by far the most common add-on therapies, with some patients receiving >1 diuretic

Can be presumed that diuretic usage followed a standard-of-care pattern for the components of diabetic nephropathy
Ann. Intern. Med. 2003;138:542549

Clinical pharmacology of diuretics

The site of action for all diuretics (with the exception of spironolactone) is in the luminal space Glomerular filtration has a minor role in diuretic entry into the urinary compartment, largely because all diuretics are bound to protein Diuretics are then delivered to their luminal site of action by organic anion transporters that are expressed in the straight segment of the proximal tubule
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Pharmacodynamics
Determining the threshold dose for diuretic effect is clinically important, particularly in patients with renal failure
In so doing, doses can be tailored to the individual needs of a patient and excessive diuretic dosing can be avoided

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Pharmacodynamics
A reduction in the GFR, and thus the filtered load of extracellular fluid and Na+, limits the maximum achievable response to any diuretic and is a
particularly relevant consideration in patients with renal failure

However,
although a reduced GFR limits the effect of a diuretic in patients with CKD, adaptive increases in fluid delivery from the proximal tubule, together with transporter overexpression (both in the loop of Henle and the distal tubule), preserves diuretic response even in patients with very advanced CKD
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Pharmacodynamics
Patients with a GFR of ~15 ml/min/1.73 m2 secrete only 1020% of the amount of loop diuretic that is secreted into tubular fluid in similarly dosed patients with a normal GFR
Thus, in patients with advanced CKD, an increased diuretic dose must be given to ensure delivery of tubular fluid sufficient to elicit a diuretic response
In so doing, the response is then similar to what is observed in healthy volunteers, unless patients with CKD have a tendency to retain Na+, as might be the case if the patient also has heart failure or the nephrotic syndrome

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Pharmacodynamics
CKD: what is the ceiling dose that can (or should) be given?
In severe CKD, studies have shown that the maximal natriuretic response (~20% of the filtered Na+ load) is achieved. Doses in excess of these will not result in an incremental natriuretic response

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MAXIMUM EFFECTIVE DOSE

In nephrotic syndrome with a relatively normal glomerular filtration rate 120 mg of furosemide, 3 mg of bumetanide, or 50 mg of torsemide. In moderate chronic kidney disease 80 mg of furosemide, 2 to 3 mg of bumetanide, or 20 to 50 mg of torsemide. In severe chronic kidney disease 200 mg of furosemide, 8 to 10 mg of bumetanide, or 50 to 100 mg of torsemide. In oliguric acute kidney injury These doses may be adjusted upward to as much as 500 mg of intravenous furosemide .

Pharmacodynamics
CKD: what is the ceiling dose that can (or should) be given?
Normal doseresponse relationship for loop diuretics, as might be present in patients with CKD who do not have edema, can be unfavorably distorted by a number of clinical conditions, ranging from volume depletion to the presence of heart failure or the nephrotic syndrome (disease state alterations), and by various drug therapies, such as NSAIDs
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Tolerance of loop diuretics

physiologic adaptations (also termed braking phenomenon) soon develop that preclude continued volume loss with successive doses (rightward shift of the dose response curve).

 In patients without edema, this adaptation develops within days . In patients with edema, this process might take somewhat longer to fully activate, enabling a greater net weight loss.

 A reduction in extracellular fluid volume and neurohumoral activation are important factors in the origin of Na+ retention after administration of a diuretic, which can be ascribed to an increase in both proximal and distal tubular Na+ absorption.

 Structural hypertrophy in the distal nephron These nephron adaptations -Na+ retention can persist for up to 2 weeks after discontinuation of a loop diuretic. initiation of thiazide therapy can reverse the structural adaptations produced by loop diuretics

MANAGEMENT OF REFRACTORY EDEMA

Exclude high salt intake Decreased loop diuretic secretion
- Maximum effective dose - Application to refractory edema -Continuous infusion - Posture - Infusion with albumin

Enhanced tubular sodium reabsorption

- Thiazide plus loop diuretics - Use of dopamine

Ultrafiltration

Diuretics - CKD
A loop diuretic is generally the diuretic of choice in patients with renal insufficiency Although a thiazide-type diuretic will initiate diuresis in patients with mild renal insufficiency, the response in patients with a GFR of <50 ml/min/1.73 m2 is less than that seen with a loop diuretic.
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Diuretics - CKD
The thiazide-type diuretics metolazone and chlortalidone
Not more potent than other diuretics Both long-acting and heavily compartmentalized in red blood cells
These pharmacokinetic features lead to a low-level diuresis being sustained for a lengthier period of time than with other thiazides and Enable the occasional successful use of either compound in patients with CKD
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Hypertension in CKD
Diuretics are useful in the management of most patients with CKD and hypertension Limited information from controlled trials exists to guide diuretic dosing to control blood pressure in patients with stages 4 or 5 CKD;
thus, such dosing is empiric and frequently determined by the elimination of edema (if present) and less so by control of blood pressure (Table 1)
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Hypertension in CKD
The major outcomes data in patients with stage 3 CKD and hypertension comes from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in which the
thiazide-type diuretic chlortalidone was compared with the ACE inhibitor lisinopril and the calciumchannel blocker amlodipine
Chlortalidone was superior to both amlodipine and lisinopril in preventing heart failure, independent of the level of renal function
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Hypertension in CKD
Loop diuretics, given once or twice daily, are recommended in patients with stages 4 or 5 CKD
This regime of loop diuretics, in combination with thiazide diuretics, can be used for patients with considerable extracellular fluid volume expansion and edema

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Hypertension in CKD
K+-sparing diuretics, such as spironolactone and eplerenone, are
Used more regularly than previously in the CKD population on the basis of their
Blood pressure-reducing ability and Prominent antiproteinuric effect
The package labels for both spironolactone and eplerenone specifically state that these drugs should not to be used in patients with mild to moderate renal insufficiency
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Hypertension in CKD
However, use (or not) of an ARA in patients with CKD is not merely a function of the level of renal function; rather, it should take into account the probability of clinically relevant hyperkalemia developing
Hyperkalemia attributable to an ARA is connected with several factors, including dose, patient predisposition to hyperkalemia (as in the case of renal failure), dietary intake of K+ and/or volume-depleting illnesses that result in a decline in renal function
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The nephrotic syndrome

The nephrotic syndrome often presents as a diuretic-resistant state. pharmacokinetics and pharmacodynamics of loop diuretics -blunting of the effects of diuretics

 Delivery of loop diuretics is impaired in patients with hypoalbuminemia. decreased renal secretion of a loop diuretic in patients with the nephrotic syndrome relates to the movement of these drugs from the intravascular to the interstitial compartment. diuretic metabolism increases with an increased rate of glucuronidation, which is specific to furosemide.

 Diuretics can bind to albumin in the tubular fluid, which decreases the amount of unbound, active drug that is available albumin are >4 g/l, as much as 65% of the diuretic that reaches the tubular fluid is bound to albumin.

 diminished natriuretic response to a loop diuretic excessive Na+ reabsorption occurs in proximal and/or more distal nephron activated reninangiotensin system with high circulating levels of angiotensin II and high concentrations of aldosterone.

 reduce the degree of proteinuria -ACE inhibitors, ARBs, ARAs and/or statin restricting the intake of salt and water. chance that renal function can decline if the rate of diuresis exceeds, specially in patients receiving moderate to high doses of an ACE inhibitor or an ARB.

Combination diuretic therapy

The use of diuretic combination therapies in patients who are resistant to diuretics is predicated on the ability of diuretics of different classes to affect sequential nephron blockade, which generates an additive natriuretic response
Although all permutations of diuretic combinations have been tried, a thiazide and a loop diuretic with or without a K+-sparing diuretic is the most commonly used combination in clinical practice

Nat. Rev. Nephrol. 2012;8:100109

Combination diuretic therapy

The metolazonefurosemide combination is particularly useful when a large volume removal is needed, as might be the case in patients with CKD and the nephrotic syndrome

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End-stage renal disease

Fluid intake in some dialysis patients is inordinately high, which results in considerable interdialytic weight gain
Such patients are candidates for loop diuretic therapy if sufficient residual renal function exists to enable a meaningful diuretic effect If loop diuretic therapy is contemplated in patients on hemodialysis, large doses or combination therapy is needed to achieve the desired effect
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End-stage renal disease

The Dialysis Outcomes and Practice Pattern Study (DOPPS) examined practice patterns for the use of diuretic therapy in 16,420 patients on hemodialysis
In this prospective observational study, overall use of loop diuretics ranged from 9.2% in the US to 21.3% in Europe, whereas use within 90 days of dialysis initiation ranged from 25.0% (US) to 47.6% (Japan)
Use of diuretics was associated with a reduced interdialytic weight gain and a lower probability of developing hyperkalemia (levels of K+ >6.0 mmol/l) than was not receiving a diuretic
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End-stage renal disease

Patients with residual renal function (defined as a daily urine output of 200 cm3) on diuretic therapy were almost two times more likely to retain residual renal function after 1 year in the study than were patients not receiving diuretics.

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Dialytic removal
Hemodialysis and hemofiltration do not influence the pharmacokinetics of loop diuretics
As a result of the high plasma protein binding, which is common to all diuretics, <10% of a loop diuretic that is in the body is eliminated by dialysis
Therefore, patients with ESRD can be given diuretics without undue concern that the diuretic will be removed during dialysis or that dosing will be required after dialysis.
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Diuretic-related adverse events

Diuretic-related electrolyte adverse events are readily picked up with periodic blood testing, which simplifies management of the abnormality
Six well-established electrolyte adverse events that arise from diuretic use in patients with CKD
Hyponatremia, hypokalemia, hyperkalemia, hyperuricemia, hypercalcemia and hypocalcemia

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Hyponatremia
Hyponatremia is an uncommon but potentially serious complication of diuretic therapy in patients with CKD. Hyponatremia is more likely with thiazide diuretics than with loop diuretics. Loop diuretics- maximal osmotic gradient can not be achieved. thiazide-type diuretics -maintain the innate concentrating capacity of the kidney

 mild asymptomatic hyponatremia (typically levels of Na+ of 125135 mmol/l) as a result of diuretic therapy, including
withholding the diuretic restricting free water intake and/or correcting hypokalemia if present.

 When a thiazide-type diuretic is associated with hyponatremia, substituting a loop diuretic. vasopressin receptor antagonists have become available for the management of patients with hyponatremia.
conivaptan, lixivaptan and tolvaptan, all improve renal water handling and correct hyponatremia in conditions associated with water retention.

Hypokalemia
occurs variably in patients who are treated with loop and/or thiazide diuretics. mechanisms that contribute
increased flow-dependent distal K+ secretion (more often observed when Na+ intake is high); a fall in distal tubule luminal Cl concentration; metabolic alkalosis; and secondary hyperaldosteronism.

 Na+ intake needs to be restricted whether or not CKD is present lowest possible diuretic dose and restricting Na+ intake. K+ supplements and/or K+-sparing compounds can be used (even in patients with CKD). K+-sparing drugs are available- reduce the activity of the reninangiotensin system such as ACE inhibitors, ARBs or direct renin inhibitors, and K+sparing diuretics.

Hyperkalemia
K+-sparing diuretics
reduced GFR (especially the elderly), K+ supplements or salt substitutes (K+ at 60 mmol/15 ml), patients on an ACE inhibitor, ARB or an NSAID, or predispose to hyperkalemia such as metabolic acidosis, hyporeninemic hypoaldosteronism, administration of trimethoprim/sulfamethoxazole, or heparin therapy. U-shaped relationship between serum levels of K+ and mortality has been observed,

Hyperuricemia
35% with the use of thiazide diuretics. Decreased clearance of urate might be associated with increased reabsorption
secondary to a reduction in the extracellular fluid volume competition for tubular secretion,

Diuretic-related adverse events

Diuretic-related allergic reactions Ototoxicity
furosemide is infused should not exceed 4 mg/min and serum concentrations <40 g /ml concomitant aminoglycoside therapy

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Conclusions
Diuretics are mainstays of therapy in patients with CKD, as they can treat edema as well as facilitate reductions in blood pressure Understanding the determinants of the dose response relationship for diuretics is important to their efficient use

The rate and extent of diuretic absorption has some involvement in the sought-after natriuretic response

Conclusions
Diuretics can be given alone and in combination, with the latter sometimes proving effective if diuretic resistance exists Also, diuretics can be used in patients with ESRD who have residual renal function and therein decrease the fluid pull during dialysis runs

Conclusions
Many adverse events exist with diuretics that are either physiological or non-physiological in nature; however, despite the potential for adverse events with these compounds, they remain
Vital components of the treatment plan for the majority of patients with CKD