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Ascites in the chronic renal failure patient with cirrhosis

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1 Ascites in the chronic renal failure patient with cirrhosis
Dr.Rajeev Jayadevan MD (Vellore), DNB (Medicine), MRCP(UK), American Board Certification in Medicine American Board Certification in Gastroenterology Senior Consultant Gastroenterologist Sunrise Hospital

2 Acknowledgements Dr. Jayant Thomas Mathew MD, DM Consultant Nephrologist, Amala Medical College Dr. Sooraj Y.S. MD, DNB (Nephrology) Consultant Nephrologist, Sunrise Hospital Dr. Abi Abraham MD, DM Consultant Nephrologist, Lakeshore Hospital

3 Outline Refresh our basic physiology about ascites and discuss what is pertinent here Practical aspects of treating a patient with CRF and CLD who has ascites

4

5 Ascites in CLD: some basic science
A major issue here is that kidneys retain Na and H2O excessively. Why? When kidneys of cirrhotic or heart failure patients were transplanted, they stopped retaining Na and H2O. This meant that the signal for Na/H2O retention came from outside the kidney.

6 What triggered Na/H2O retention?
Could it be low total blood volume? No, because when measured, these patients had normal or, even increased blood volume! Could it be low cardiac output? No, because, pregnancy has high output, but the kidneys still retain Na and H2O!

7 Who, then, tells the kidneys to retain Na/H2O?
Unloading of high-pressure baroceptors (blue circles) in the left ventricle, carotid sinus, and aortic arch generates afferent signals (black) that stimulate cardioregulatory centers in the brain, resulting in the activation of efferent pathways in the sympathetic nervous system (green). The sympathetic nervous system seems to be the primary integrator of the neurohumoral vasoconstrictor response to arterial underfilling. Activation of renal sympathetic nerves stimulates the release of renin and angiotensin II, thereby activating the renin-angiotensin-aldosterone system (RAAS). Concomitantly, sympathetic stimulation of the supraoptic and paraventricular nuclei in the hypothalamus results in the nonosmotic release of arginine vasopressin (AVP). Sympathetic activation also causes peripheral and renal vasoconstriction, as does angiotensin II. Angiotensin II constricts blood vessels and stimulates the release of aldosterone from the adrenal gland, and it also increases tubular sodium reabsorption and causes remodeling of cardiac myocytes. Aldosterone may also have direct cardiac effects on fibrosis, in addition to increasing the reabsorption of sodium and the secretion of potassium and hydrogen ions in the collecting duct. The blue lines designate circulating hormones. Reprinted from reference 2 (Schrier RW, Abraham WT: Hormones and hemodynamics in heart failure. N Engl J Med 341: 577–585, 1999

8 “Arterial underfilling.”
Can be from : Decreased cardiac output Arterial vasodilatation

9 Effective vs. Total blood volume
Estimates of blood volume distribution indicate that 85% of blood circulates on the low-pressure, venous side of the circulation, whereas an estimated 15% of blood is circulating in the high-pressure, arterial circulation. Schrier, J Am Soc Nephrol 18: 2028–2031, 2007

10 How does cirrhosis lead to arterial underfilling?

11 Vaso- constrictor systems not turned on

12

13 How to treat nephrogenic ascites
Patient with ascites, CLD and CRF. Question: Is the ascites from the liver or the kidney?

14 How to differentiate cirrhotic vs. uremic ascites
Transudate Low protein High SAAG > 1.1 Creatinine < 5 Slow reaccumulation Exudate High protein Low SAAG Creatinine > 5 Rapid reaccumulation

15 HRS Hypovolemia-induced Parenchymal Drug-induced

16 Ascites in CKD + CLD. Why is treatment difficult?
Management difficult as: Symptoms overlap Creatinine value unreliable due to CLD Diuretics don’t work as easily as in CLD: “Diuretic Resistance” PREVALENCE OF ASCITES IN CHRONIC KIDNEY DISEASE The incidence of ascites in advanced chronic kidney disease (CKD) varies, but tends to fall between 0.7% and 20%.22 The prevalence of CKD along with hepatic cirrhosis and ascites is not precisely established, but there is a clear increase in the frequency of the occurrence of this association due to the growing prevalence of both diseases. Chronic liver disease frequently progresses along with renal disorders that lead to CKD, even reaching levels requiring dialysis treatment.23 The optimal time for commencing dialysis in these patients is difficult to determine, since they share symptoms such as anorexia and weight loss, among others, which could be due to both uraemia and liver disease. Additionally, the over-estimation of renal glomerular filtration rates leads the physician to attribute the symptoms to the liver disease more than to uraemia.24

17 Diuretics and the nephron
Diuretics may be classified according to their chemical structure, their mechanism and site of action within the nephron, and their diuretic potency. Those agents with primary action in the proximal nephron include the carbonic anhydrase inhibitors, e.g. acetazolamide, a sulfonamide derivative. Other drugs containing the sulfonamido grouping, e.g. furosemide, chlorothiazide and metolazone, also have secondary effects on the proximal nephron. Those drugs which have their major pharmacologic activity within the ascending limb of the loop of Henle, inhibiting the sodium/potassium/2 chloride electroneutral transport system, include the sulfonamide agents furosemide, bumetanide, piretanide and torasemide, and the phenoxyacetic acid derivative, ethacrynic acid. In the early portion of the distal convoluted tubule, sodium chloride reabsorption is impaired by the thiazide group, indapamide and metolazone, as their primary site of action. In the late reaches of the distal convolution and in the collecting duct, agents that inhibit the exchange of sodium for that of hydrogen and potassium have their major sites of activity. These agents, spironolactone, amiloride and triamterene, differ not only chemically but in their mechanisms of action. Diuretics may also be grouped according to potency. The loop of Henle agents are the most powerful, causing the excretion of 20-25% of filtered sodium load. The thiazide group and metolazone are moderately potent, resulting in the excretion of 5-8% of filtered sodium, and the 'potassium-sparing' drugs are only mildly potent, causing the excretion of only 2-3% of filtered sodium. 13 a. Carboanhydrase inhibitors (eg, acetazolamide) act on the carboanhydrase (CA) in the brush borders and inside the cells of the proximal tubules. Inhibition of the metallo-enzyme reduces the conversion of filtered bicarbonate to carbon dioxide. As a result, there is a high concentration of bicarbonate and sodium in the tubular fluid of the proximal tubules. Up to half of the bicarbonate normally reabsorbed is eliminated in the urine causing a high urine flow and a metabolic acidosis. Thus, these inhibitors are diuretics. They are mainly used in the treatment of open-angle glaucoma (ie, an intraocular pressure above 22 mmHg). Acetazolamide promotes the outflow of the aqueous humour and probably diminishes its isosmotic secretion. 13 b. Loop diuretics (bumetanide and furosemide, torasemide) inhibit primarily the reabsorption of NaCl in the thick ascending limb of Henle by blocking the luminal Na+-K+-2Cl--symporter. The reabsorption of NaCl, K+ and divalent cations is reduced, and also the medullary hypertonicity is decreased. Hereby, the distal system receives a much higher rate of NaCl, water in isotonic fluid, and K+. The overall result is an increased excretion of NaCl, water, K+ and divalent cations. The patient’s plasma- [K+] should be checked regularly.  13 c. Thiazide diuretics (bendroflurazide, hydrochlorothiazide) act on the early part of the distal tubule by inhibiting the (Na+- Cl-)-symporter. They increase K+ excretion by increased tubular flow rate. Thiazide and many other diuretics are secreted in the proximal tubules. This secretion inhibits the secretion of uric acid, so thiazide is contraindicated by gout.   13 d. Potassium-sparing diuretics (eg, amiloride) inhibit Na+-reabsorption by inhibition of sensitive Na+-channels in the principal cells of the distal tubules and collecting ducts. Hereby, they reduce the negative charge in the lumen and thus the K+-secretion. Amiloride causes natriuresis and reduces urinary H+- and K+-excretion  13 e. Aldosterone-antagonists (eg, spironolactone) compete with aldosterone for receptor sites on principal cells. As aldosterone promotes Na+-reabsorption and H+/ K+ -secretion, aldosterone-antagonists cause a natriuresis and reduce urinary H+ - and K+ -excretion. Aldosterone-antagonists are weak potassium-sparing diuretics, mainly used to reduce K+ -excretion caused by thiazide or loop diuretics. 13 f. Angiotensin-converting-enzyme (ACE)-inhibitors (captopril, enapril and lisinopril) reversibly inhibit the production of angiotensin II, reduce systemic blood pressure, renal vascular resistance and K+ -secretion. ACE-inhibitors promote NaCl and water excretion. ACE-inhibitors increase RBF without much increase in GFR, because of a decrease in both afferent and efferent arteriolar resistance. The development of diabetic nephropathy can be markedly delayed by early reduction of blood pressure with ACE-inhibitors and by careful diabetic management. 13 g. Osmotically active diuretics are substances such as mannitol and dextrans. These substances retard the normal passive reabsorption of water in the proximal tubules. Osmotic therapy with mannitol is used in the treatment of cerebral oedema. Mannitol is a hexahydric alcohol related to mannose and an isomer of sorbitol. Mannitol passes freely through the glomerular barrier and has hardly any reabsorption in the renal tubules. Its presence in the tubular fluid increases flow according to the concentration of osmotically active particles, which inhibit reabsorption of water. The high flow of tubular fluid means that the excretion of Na+ is great - despite the rather low Na+ concentration. Mannitol may help to flush out tubular debris in shock with acute renal failure, but the results are controversial.  Dextrans (ie, polysaccharides) have a powerful osmotic and diuretic effect. - The larger, molecules (macrodex) are seldom used as volume expanders during shock because of allergic reactions. 

18 Mechanisms of diuretic resistance in CRF
1. Reduced basal level of fractional Na reabsorption 2. Enhanced NaCl reabsorption in downstream segments: DCT hypertrophy: beyond the reach of Furosemide 3. Reduced delivery of diuretic to the kidney. Diuretics are secreted by the organic anion transporters (OATS), in the PCT, these get inhibited by Acidosis. 4. Hypoalbuminemia decreases delivery of Furosemide and also increases its metabolism to glucuronide Loop diuretics are firmly bound to serum proteins; they reach the tubular lumen predominantly by active secretion and not by glomerular filtration or passive diffusion. In renal insufficiency secretion of furosemide and other loop diuretics is reduced because of accumulation of endogenic organic anions competing with loop diuretics for the receptor sites of the organic anion transporter.2 Higher doses are required to overcome this competitive inhibition and to obtain therapeutic urinary concentrations in heart failure patients with renal impairment. The bioavailability of loop diuretics is unaltered in CHF, but peak urinary concentrations are reduced and tend to occur later, resulting in a less powerful diuretic effect.2 This is a second pharmacokinetic mechanism that interferes with a satisfactory diuresis.

19 Hypertrophy of distal tubule
Exposure to loop diuretic DCT Taller cells Larger rounded nuclei Taller lateral cell processes

20 Na Due to prolonged action of Loop diuretic in the Loop of Henle, more Na gets absorbed by a hypertrophied DCT

21 Loop diuretic resistance: Curve shifts to the right
EFFECT DOSE

22 NEPHROTIC SYNDROME = ALBUMIN IN LUMEN
Luminal action

23 Measures to combat diuretic resistance in CRF
Restriction of fluid intake 1.5 L daily Maintain Sodium intake of 2 g daily Use of escalating doses of loop diuretics up to established ceiling levels. Judicious use of a second diuretic acting at a downstream site , but watch for ADR Reducing renal proteinuria in nephrotic syndrome using ACEI or ARB Assess compliance with salt restriction and medicine intake. If necessary, measure the amount of salt and diuretic in the urine. Discontinue NSAIDs. Adjust the dose of the diuretic in patients with renal impairment. Switch to intravenous administration to overcome problems associated with impaired absorption. As it avoids postdiuretic salt retention, a continuous intravenous infusion of a loop diuretic may succeed where other treatments have failed. Combine loop diuretics with other diuretics, preferably a thiazide diuretic. J Am Soc Nephrol 13: 798–805, 2002

24 Diuretic resistance: How to test?
If < 50 mmol urine sodium in 8 hours after Lasix 80 mg IV: Resistant. HEPATOLOGY, Vol. 49, No. 6, 2009

25 Choice of loop diuretic:
LASIX vs. TORASEMIDE Preferred Better bioavailability Predictable outcome OD dosing Does better than Lasix in the 6-24 hr interval 20mg as good as 80 mg Lasix

26 Choice of diuretic- 2 Spironolactone Be cautious
Monitor K more closely Patients already on ACEI or ARB, chance of spike in K

27 Less effective, however.
What if gynaecomastia? Try Amiloride mg/d. Less effective, however.

28 Second-line agents Triamterene, HCTZ, Metolazone ( mg OD) are second-line agents used to treat ascites.

29 Choice of Fluids Be careful with saline: pulmonary edema
Albumin/ Plasma are OK: they stay in the intravascular space

30 Protein in diet: how much?
In CKD not on dialysis: very conservative g/kg/day If on dialysis: can give more: 1.2 g /kg/day

31 Dialysis patient: what day to tap?
Tap on non-dialysis days Heparin can cause bleed otherwise

32 Dialysis patient with ascites: how to tap:
Large-volume paracentesis with IV Albumin replacement at 8 g Albumin per liter of ascitic fluid removed

33 FFP or Platelets before a tap…..?? No.
Routine tests of coagulation do not reflect actual bleeding risk in patients with cirrhosis. These patients regularly have normal global coagulation because of a balanced deficiency of procoagulants and anticoagulants. AASLD guideline HEPATOLOGY, June 2009

34 Do not send CA-125 in patients with ascites
Patients with ascites should not have serum tested for CA-125. It will be elevated due to pressure on mesothelial cells

35 CKD + Cirrhosis : What dialysis: HD or PD? Peritoneal dialysis:
Less hemodynamic instability Less bleed risk Less Hepatitis B/C risk No published increased risk of peritoneal sepsis although theoretical risk from cirrhosis (Same rates of sepsis for CKD patients on PD, regardless of presence of cirrhosis) 40% more expensive

36 Reinfusion of ascitic fluid into the dialysis machine: PRECEED
2 HD patients with CLD and refractory ascites: quick improvement, well-tolerated

37 TIPS: any role? Patients with parenchymal renal disease, especially those on dialysis, may not respond as well to TIPS as those with functional renal insufficiency. Michl P, Gulberg V, Bilzer M, Waggershauser T, Reiser M, Gerbes AL. Transjugular intrahepatic portosystemic shunt for cirrhosis and ascites: effects in patients with organic or functional renal failure. Scand J Gastroenterol 2000;35:

38 Main points: Ascites in CKD and CLD.
Rule out other causes of ascites Diuretic resistance occurs in CKD Furosemide or Torasemide mainstay Use Spironolactone with caution Be liberal with IV albumin Avoid IV fluids like saline Work closely with the nephrologist

39 Systemic arterial vasodilation causes arterial underfilling with resultant neurohumoral activation
and renal sodium and water retention. In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. Reprinted from Schrier,7 with permission. In sodium- and water-retaining disorders that occur secondary to systemic arterial vasodilation, the compensatory hemodynamic response is an increase in cardiac output that occurs secondary to the reduced cardiac afterload. In both circumstances of arterial underfilling in edematous disorders, whether as a result of a decrease in cardiac output or arterial vasodilation, the neurohumoral axis is stimulated and renal sodium and water retention occurs as a compensatory mechanism to maintain arterial perfusion. This includes activation of the sympathetic system and the renin-angiotensin-aldosterone system (RAAS) as well as nonosmotic vasopressin release (Figure 1). Reversal of sodium retention with mineralocorticoid antagonist has been shown in cardiac failure11 and cirrhosis. 12 Similarly, oral active, nonpeptide vasopressin V2 receptor antagonists have been shown to correct hyponatremia in cardiac failure and cirrhosis. 13 In some circumstances, a decrease in both cardiac output and arterial vasodilation may be involved in arterial underfilling. Such is the case when primary arterial vasodilation occurs in cirrhosis or sepsis, because an accompanying increase in circulating TNF- decreases myocardial contractibility. 14 With the primacy of the integrity of the arterial circulation in renal sodium and water regulation, sensitive arterial receptors that respond to arterial under-With the primacy of the integrity of receptors that respond to arterial under- A Low output cardiac failure, Pericardial tamponade, Constrictive pericarditis Non-osmotic vasopression stimulation Stimulation of sympathetic nervous system Activation of ventricular and arterial receptors Activation of the Renin-angiolensinaidosterone system Extracellular fluid volume Oncotic pressure and/or Capillary permeability CARDIAC OUTPUT RENAL WATER RETENTION SYSTEMIC AND RENAL ARTERIAL VASCULAR RESISTANCE MAINTENANCE OF ARTERIAL CIRCULATORY INTEGRITY RENAL SODIUM B SYSTEMIC ARTERIAL VASODILATION CARDIAC OUTPUT WATER SODIUM AVP stimulation SNS Activation of RAAS Activation of arterial baroreceptors High-output cardiac failure Sepsis Cirrhosis Arteriovenous fistula Pregnancy Arterial vasodilators SYSTEMIC ARTERIAL VASCULAR AND RENAL RESISTANCE Figure 1. Clinical conditions in which a decrease in cardiac output (A) and systemic arterial vasodilation (B) causes arterial underfilling with resultant neurohumoral activation transport by the proximal tubule epithelium. Reprinted from Schrier,7 with permission. SCIENCE IN RENAL MEDICINE J Am Soc Nephrol 18: 2028–2031, 2007 Edema and Arterial Underfilling 2029 filling must exist. In this regard, there are sensitive stretch receptors in the carotid artery, aortic arch, and the glomerular afferent arteriole that respond to a decrease in arterial pressure. Because of the importance of arterial perfusion, the compensatory responses to arterial underfilling occur rapidly. With arterial underfilling, as a result of a decrease in cardiac output, arterial vasodilation, or both, a decrease in glossopharyngeal and vagal tone from the carotid and aortic receptors leads to a rapid increase in sympathetic activity with associated activation of the RAAS and nonosmotic release of vasopressin. The resultant increase in systemic vascular resistance and renal sodium and water retention attenuates the arterial underfilling and associated diminished arterial perfusion. There are low-pressure receptors in the cardiac atria that suppress vasopressin release, decrease renal vascular resistance, and increase sodium and water excretion in response to an increased transmural atrial pressure.15 In cardiac failure, however, atrial pressure rises, yet sodium and water retention occurs. This suggests that activation of the arterial stretch receptors in cardiac failure predominate over any atrial pressure receptor reflex in cardiac failure. An increase in the ventricular synthesis of brain natriuretic hormone (BNP) and thus circulatory BNP concentrations also occurs in cardiac failure and may attenuate the degree of renal sodium and water retention.16 BNP may decrease the edema formation in cardiac failure by both suppressing the RAAS and inhibiting tubular sodium reabsorption. Of further interest is the renal sodium and water retention that occurs with diastolic dysfunction in the presence of normal cardiac output, as assessed by ejection fraction.17 Although a decrease in stroke volume and diminished arterial pressure have been shown to release the tonic inhibition from the carotid and aortic baroreceptors on the sympathetic outflow from the central nervous system, this should not be a reflex pathway for sodium and water retention in patients with diastolic dysfunction and a normal cardiac output. There are, however, ventricular receptors that may be involved with sodium and water retention in patients with diastolic dysfunction.18 Similar reflexes may be involved in right ventricular failure that occurs with pulmonary hypertension in association with renal sodium and water retention. This possibility, however, is in need of investigation. Monitoring arterial underfilling in edematous patients by measuring the hormones that are associated with activation of the neurohumoral axis is obviously neither timely nor cost-effective in the clinical setting. However, in edematous patients who are on a normal sodium intake and in the absence of diuretics, a low fractional excretion of sodium indicates clinically important arterial underfilling and should initiate a search for an associated decrease in cardiac output and/or systemic arterial vasodilation, which are potentially reversible. A unifying pathway for body fluid volume regulation by the kidney should be applicable in both health and disease. In healthy pregnancy, systemic arterial vasodilation and a decrease in BP occur in the first trimester in association with a compensatory rise in cardiac output.19,20 As expected for a state of arterial underfilling, activation of the RAAS occurs early in normal pregnancy. Renal sodium and water retention is also a feature of normal pregnancy as is expansion of total blood volume. A decrease in plasma osmolality, stimulation of thirst, and persistent nonosmotic vasopressin release are other features of normal pregnancy. In contrast to disease states such as cardiac failure and cirrhosis, pregnancy, is associated with an increase in GFR and renal blood flow. The systemic and renal arterial vasodilation in pregnancy seems to involve nitric oxide. Estrogen upregulates endothelial nitric oxide synthase in pregnancy, and inhibitors of nitric oxide synthesis normalize the systemic and renal hemodynamics in rat pregnancy.21 On the background of this unifying mechanism of body fluid volume regulation by the kidney, the clinical use of the term “decreased effective blood volume” can be considered outdated and be replaced by “arterial underfilling.” However, if the use of the term persists in clinical medicine, then it should be “decreased effective arterial blood volume.”

40 Treatment of hepatorenal syndrome
Albumin infusion plus administration of vasoactive drugs such as octreotide and midodrine should be considered in the treatment of type I hepatorenal syndrome. (Class IIa, Level B) HEPATOLOGY, June 2009

41 Major criteria for the diagnosis of hepatorenal syndrome
Cirrhosis with ascites Serum creatinine >1.5 mg/dL No improvement with diuretic withdrawal or IV albumin Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal kidney disease U/A or USG No improvement of serum creatinine (decrease to a level of 1.5 mg/dL or less) after at least 2 days with diuretic withdrawal and volume expansion with albumin (The recommended dose of albumin is 1 g/kg body weight/day )

42

43 “decreased effective arterial
Dr. Robert W. Schrier “decreased effective blood volume” can be considered outdated and be replaced by “arterial underfilling.” or “decreased effective arterial blood volume.”

44 Sympathetic atrophy In the late stages of portal hypertension.
Decreases the vascular tone of the mesenteric tree, allowing an increased activity of vasodilatory mediators

45 Does Fluid retention lead to ascites?
Not necessarily. Many patients with fluid retention have no ascites. Fluid retention per se seen in patients with nephrogenic ascites is unlikely to account solely for ascites formation.

46 Diuretics and the nephron
13 a. Carboanhydrase inhibitors (eg, acetazolamide) act on the carboanhydrase (CA) in the brush borders and inside the cells of the proximal tubules. Inhibition of the metallo-enzyme reduces the conversion of filtered bicarbonate to carbon dioxide. As a result, there is a high concentration of bicarbonate and sodium in the tubular fluid of the proximal tubules. Up to half of the bicarbonate normally reabsorbed is eliminated in the urine causing a high urine flow and a metabolic acidosis. Thus, these inhibitors are diuretics. They are mainly used in the treatment of open-angle glaucoma (ie, an intraocular pressure above 22 mmHg). Acetazolamide promotes the outflow of the aqueous humour and probably diminishes its isosmotic secretion. 13 b. Loop diuretics (bumetanide and furosemide) inhibit primarily the reabsorption of NaCl in the thick ascending limb of Henle by blocking the luminal Na+-K+-2Cl--symporter. The reabsorption of NaCl, K+ and divalent cations is reduced, and also the medullary hypertonicity is decreased. Hereby, the distal system receives a much higher rate of NaCl, water in isotonic fluid, and K+. The overall result is an increased excretion of NaCl, water, K+ and divalent cations. The patient’s plasma- [K+] should be checked regularly.  13 c. Thiazide diuretics (bendroflurazide, hydrochlorothiazide) act on the early part of the distal tubule by inhibiting the (Na+- Cl-)-symporter. They increase K+ excretion by increased tubular flow rate. Thiazide and many other diuretics are secreted in the proximal tubules. This secretion inhibits the secretion of uric acid, so thiazide is contraindicated by gout.   13 d. Potassium-sparing diuretics (eg, amiloride) inhibit Na+-reabsorption by inhibition of sensitive Na+-channels in the principal cells of the distal tubules and collecting ducts. Hereby, they reduce the negative charge in the lumen and thus the K+-secretion. Amiloride causes natriuresis and reduces urinary H+- and K+-excretion  13 e. Aldosterone-antagonists (eg, spironolactone) compete with aldosterone for receptor sites on principal cells. As aldosterone promotes Na+-reabsorption and H+/ K+ -secretion, aldosterone-antagonists cause a natriuresis and reduce urinary H+ - and K+ -excretion. Aldosterone-antagonists are weak potassium-sparing diuretics, mainly used to reduce K+ -excretion caused by thiazide or loop diuretics. 13 f. Angiotensin-converting-enzyme (ACE)-inhibitors (captopril, enapril and lisinopril) reversibly inhibit the production of angiotensin II, reduce systemic blood pressure, renal vascular resistance and K+ -secretion. ACE-inhibitors promote NaCl and water excretion. ACE-inhibitors increase RBF without much increase in GFR, because of a decrease in both afferent and efferent arteriolar resistance. The development of diabetic nephropathy can be markedly delayed by early reduction of blood pressure with ACE-inhibitors and by careful diabetic management. 13 g. Osmotically active diuretics are substances such as mannitol and dextrans. These substances retard the normal passive reabsorption of water in the proximal tubules. Osmotic therapy with mannitol is used in the treatment of cerebral oedema. Mannitol is a hexahydric alcohol related to mannose and an isomer of sorbitol. Mannitol passes freely through the glomerular barrier and has hardly any reabsorption in the renal tubules. Its presence in the tubular fluid increases flow according to the concentration of osmotically active particles, which inhibit reabsorption of water. The high flow of tubular fluid means that the excretion of Na+ is great - despite the rather low Na+ concentration. Mannitol may help to flush out tubular debris in shock with acute renal failure, but the results are controversial.  Dextrans (ie, polysaccharides) have a powerful osmotic and diuretic effect. - The larger, molecules (macrodex) are seldom used as volume expanders during shock because of allergic reactions. 

47 Diuretics and the nephron
13 a. Carboanhydrase inhibitors (eg, acetazolamide) act on the carboanhydrase (CA) in the brush borders and inside the cells of the proximal tubules. Inhibition of the metallo-enzyme reduces the conversion of filtered bicarbonate to carbon dioxide. As a result, there is a high concentration of bicarbonate and sodium in the tubular fluid of the proximal tubules. Up to half of the bicarbonate normally reabsorbed is eliminated in the urine causing a high urine flow and a metabolic acidosis. Thus, these inhibitors are diuretics. They are mainly used in the treatment of open-angle glaucoma (ie, an intraocular pressure above 22 mmHg). Acetazolamide promotes the outflow of the aqueous humour and probably diminishes its isosmotic secretion. 13 b. Loop diuretics (bumetanide and furosemide) inhibit primarily the reabsorption of NaCl in the thick ascending limb of Henle by blocking the luminal Na+-K+-2Cl--symporter. The reabsorption of NaCl, K+ and divalent cations is reduced, and also the medullary hypertonicity is decreased. Hereby, the distal system receives a much higher rate of NaCl, water in isotonic fluid, and K+. The overall result is an increased excretion of NaCl, water, K+ and divalent cations. The patient’s plasma- [K+] should be checked regularly.  13 c. Thiazide diuretics (bendroflurazide, hydrochlorothiazide) act on the early part of the distal tubule by inhibiting the (Na+- Cl-)-symporter. They increase K+ excretion by increased tubular flow rate. Thiazide and many other diuretics are secreted in the proximal tubules. This secretion inhibits the secretion of uric acid, so thiazide is contraindicated by gout.   13 d. Potassium-sparing diuretics (eg, amiloride) inhibit Na+-reabsorption by inhibition of sensitive Na+-channels in the principal cells of the distal tubules and collecting ducts. Hereby, they reduce the negative charge in the lumen and thus the K+-secretion. Amiloride causes natriuresis and reduces urinary H+- and K+-excretion  13 e. Aldosterone-antagonists (eg, spironolactone) compete with aldosterone for receptor sites on principal cells. As aldosterone promotes Na+-reabsorption and H+/ K+ -secretion, aldosterone-antagonists cause a natriuresis and reduce urinary H+ - and K+ -excretion. Aldosterone-antagonists are weak potassium-sparing diuretics, mainly used to reduce K+ -excretion caused by thiazide or loop diuretics. 13 f. Angiotensin-converting-enzyme (ACE)-inhibitors (captopril, enapril and lisinopril) reversibly inhibit the production of angiotensin II, reduce systemic blood pressure, renal vascular resistance and K+ -secretion. ACE-inhibitors promote NaCl and water excretion. ACE-inhibitors increase RBF without much increase in GFR, because of a decrease in both afferent and efferent arteriolar resistance. The development of diabetic nephropathy can be markedly delayed by early reduction of blood pressure with ACE-inhibitors and by careful diabetic management. 13 g. Osmotically active diuretics are substances such as mannitol and dextrans. These substances retard the normal passive reabsorption of water in the proximal tubules. Osmotic therapy with mannitol is used in the treatment of cerebral oedema. Mannitol is a hexahydric alcohol related to mannose and an isomer of sorbitol. Mannitol passes freely through the glomerular barrier and has hardly any reabsorption in the renal tubules. Its presence in the tubular fluid increases flow according to the concentration of osmotically active particles, which inhibit reabsorption of water. The high flow of tubular fluid means that the excretion of Na+ is great - despite the rather low Na+ concentration. Mannitol may help to flush out tubular debris in shock with acute renal failure, but the results are controversial.  Dextrans (ie, polysaccharides) have a powerful osmotic and diuretic effect. - The larger, molecules (macrodex) are seldom used as volume expanders during shock because of allergic reactions. 

48 Diuretic resistance: How to test?
8 hour urine excretion of 50 mmol after 80 mg of IV Lasix confirms diuretic sensitivity.

49 Nephrogenic ascites Nephrogenic ascites is defined as clinically evident chronic ascites, occurring in patients with ESRD without other clear cause . Its pathogenesis remains unknown, has limited treatment options and is associated with a grave prognosis. J. Am. Soc. Nephrol. 1994; 5: )

50 Epidemiology Nephrogenic ascites has marked center-to-center variability in incidence (0.7 to 20%) A wide age range of onset ( 1 1 to 71 yr; mean, 42 yr) Male sex (male : female = 2: 1 )

51 How long before ascites develops?
Ascites accumulation can occur as early as 18 months before or as late as 69 months after the initiation of hemodialysis

52 Possible pathogenesis of nephrogenic ascites
Elevated Hepatic Venous Hydrostatic Pressure Volume Overload Increased Peritoneal Membrane Permeability Secondary to Uremic toxins Prior exposure to dialysis solutions Renin-angiotensin activation Circulating immune complexes deposit on peritonal membrane Hemosiderosis Impaired Lymphatic Drainage

53 How to treat (purely) nephrogenic ascites

54 Mechanisms of diuretic resistance in CRF
1. Reduced basal level of fractional Na reabsorption 2. Enhanced NaCl reabsorption in downstream segments: DCT hypertrophy: beyond the reach of Furosemide 3. Reduced delivery of diuretic to the kidney. Diuretics are actively secreted by the organic anion transporters (OATS), in the PCT, these get inhibited by Acidosis and competition from organic anions. 4. Hypoalbuminemia decreases delivery as loop diuretics are protein-bound of Furosemide and also increases its metabolism to glucuronide

55 Mechanisms of diuretic resistance in CRF
1. Reduced basal level of fractional Na reabsorption 2. Enhanced NaCl reabsorption in downstream segments: DCT hypertrophy: beyond the reach of Furosemide 3. Reduced delivery of diuretic to the kidney. Diuretics are secreted by the organic anion transporters (OATS), in the PCT, these get inhibited by Acidosis. 4. Hypoalbuminemia decreases delivery of Furosemide and also increases its metabolism to glucuronide 5. Post-diuretic salt retention Strict salt restriction or split dosing can help overcome retention.

56 Spironolactone Stops the Na- retaining action of Aldosterone on renal collecting tubules May use singly (sequentially) or in combination with Furosemide Use with great caution in renal failure

57 How to titrate weight loss?
There is no limit to the daily weight loss of patients who have massive edema. Once the edema has resolved, 0.5 kg is probably a reasonable daily maximum. Encephalopathy, Na < 120 mmol/L despite fluid restriction, or serum creatinine > 2.0 mg/dL should lead to reassessment of diuretic regime.

58 Antibiotic use in SBP: choice and dose
1) Patients with ascitic fluid PMN counts >250 cells/mm3 should receive empiric antibiotic therapy, Cefotaxime 2 g IV Q 8H. (Class I, Level A) 2) Oral Ofloxacin 400 mg bd considered a substitute for intravenous cefotaxime in inpatients without complications

59 Antibiotic use in ascites of CLD
Oral Norfloxacin 400 mg daily to be considered long-term Watch for adrenal insufficiency in severe sepsis In patients with cirrhosis and ascites but no gastrointestinal bleeding, long-term use of norfloxacin (or trimethoprim/sulfamethasoxazole) can be justified if the ascitic fluid protein <1.5 g/dL and at least one of the following is present: serum creatinine >1.2 mg/dL, blood urea nitrogen >25 mg/dL, serum sodium <130 mEq/L or Child-Pugh >9 points with bilirubin >3 mg/dL. (Class I, Level B) N Engl J Med 2009;361:

60 Dialysis patient developing ascites: when to tap?
If dyspnea or severe distention

61 How to counter diuretic resistance

62 Strategies in nephrotic syndrome

63 Dosing….the 100:40 ratio (Spironolactone:Furosemide)
The doses of both can be increased simultaneously every 3-5 days (maintaining the ratio). This ratio maintains K+ levels if normal kidneys Maximum doses are 400 mg/day and 160 mg/day

64 Ceiling doses of loop diuretics

65 Exudative ascites (Serum Albumin - Ascites Albumin <1.1 gm/dl)
Sarcoidosis Lymphatic obstruction: a. Intestinal lymphangiectasia, b. Lymphoma Pseudomyxoma peritonei Struma oovarii Amyloidosis Prior abdominal trauma with ruptured lymphatics Hemodialysis CRF related ascites Neoplastic diseases involving the peritoneum: Peritoneal carcinomatosis, Lymphomatous disorders Tuberculous peritonitis Pancreatitis Post surgery talc or starch powder peritonitis Transected lymphatics following portal caval shunt surgery Myxedema

66 Transudative ascites (SAAG >1.1 gm/dl)
Nephrotic syndrome Meig's ovarian tumor syndrome Constrictive pericarditis Inferior vena cava obstruction Viral hepatitis with submassive or massive hepatic necrosis Liver cirrhosis Congestive heart failure Hepatic vein obstruction (Budd Chiari syndrome) a. Assoc. with tumors (hepatoma, hypernephroma, pancreatic Ca) b. Assoc. with hematologic disorders (myeloproliferative disease, polycythemia vera, myeloid metaplasia c. Due to infections

67 Uremic encephalopathy
Can precipitate due to volume shift at paracentesis Avoid by using albumin cover

68 Dialysis patient with ascites: greater bleeding risk
Platelet dysfunction Heparin

69 Diuretic resistance: How to test?
A random “spot” urine sodium concentration that is greater than the potassium concentration correlates with a 24-hour sodium excretion greater than 78 mmol/day with approximately 90% accuracy. Stiehm AJ, Mendler MH, Runyon BA. Detection of diuretic-resistance or diuretic-sensitivity by the spot urine Na/K ratio in 729 specimens from cirrhotics with ascites: approximately 90% accuracy as compared to 24-hr urine Na excretion . HEPATOLOGY 2002;36:222A.


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