Diuretics and Kidney Dieases overview for medicalstudents.pptx

Overview about Diuretics

1. Diuretics and Kidney Diseases A diuretic is a substance that increases the rate of urine volume output Most diuretics increase the urinary excretion of solutes, especially sodium and chloride which causes natriuresis (increased sodium output ), in turn causing diuresis (increased water output). Increased water excretion occurs secondary to inhibition of tubular sodium reabsorption because sodium remaining in the tubules acts osmotically to decrease water reabsorption. The most common clinical use of diuretics is to reduce extracellular fluid volume, especially in diseases associated with edema and in hypertension. The many diuretics available for clinical use have different mechanisms of action and, therefore, inhibit tubular reabsorption at different sites along the renal nephron .

2. Classes of Diuretics, Their Mechanisms of Action, and Tubular Sites of Action Class of Diuretic (examples) Mechanism of Action Tubular Site of Action Osmotic diuretics ( mannitol ) Inhibit water and solute reabsorption by increasing osmolarity of tubular fluid Mainly proximal tubules Loop diuretics (furosemide, bumetanide ) Inhibit Na +, K+, Cl - co-transport in luminal membrane Thick ascending loop of Henle Thiazide diuretics ( hydrochloro thiazide, chlorthalidone ) Inhibit Na+, Cl - co-transport in luminal membrane Early distal tubules Carbonic anhydrase inhibitors (acetazolamide) Inhibit H+ secretion and HCO3- reabsorption, which reduces Na+ reabsorption Mainly proximal tubules Aldosterone antagonists (spironolactone, eplerenone ) Inhibit action of aldosterone on tubular receptor, decrease Na+ reabsorption, decrease K+ secretion Collecting tubules Sodium channel blockers (triamterene, amiloride ) Block entry of Na+ into Na+ channels of luminal membrane, decrease Na+ reabsorption, decrease K+ secretion Collecting tubules Classes of Diuretics, Their Mechanisms of Action, and Tubular Sites of Action

3. Osmotic Diuretics Decrease Water Reabsorption by Increasing Osmotic Pressure of Tubular Fluid Injection of substances into the blood stream that are filtered by the glomerular capillaries but are not easily reabsorbed by the renal tubules, such as urea, mannitol , and sucrose, causes a marked increase in the concentration of osmotically active molecules in the tubules. The osmotic pressure of these solutes then reduces water reabsorption , flushing large amounts of tubular fluid into the urine . Large volumes of urine are also formed in certain diseases associated with excess solutes that fail to be reabsorbed from the tubular fluid, For example, when blood glucose concentration rises to high levels in diabetes mellitus, the increased filtered load of glucose into the tubules exceeds their capacity to reabsorb glucose (above 250 mg/dl ). The excess glucose remains in the tubules, acts as an osmotic diuretic , and increases urine flow rate. That’s why one of the hallmarks of uncontrolled diabetes mellitus is polyuria (frequent urination), which is balanced by a high level of fluid intake (polydipsia ) secondary to dehydration, increased extracellular fluid osmolarity , and activation of the thirst mechanism. 

4. Loop Diuretics (Decrease Sodium-Chloride-Potassium Reabsorption in the Thick Ascending Loop of Henle ) Furosemide, ethacrynic acid, and bumetanide are among the most powerful of the clinically used diuretics that decrease reabsorption in the thick ascending limb of the loop of Henle by blocking the 1- sodium , 2- chloride , 1- potassium co-transporter located in the luminal membrane of the epithelial cells. Loop diuretics increase urine output of sodium, chloride, potassium , and other electrolytes , as well as water, for two reasons: ( 1) they greatly increase the quantities of solutes delivered to the distal parts of the nephrons, and these solutes act as osmotic agents to prevent water reabsorption ; and ( 2) they disrupt the countercurrent multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium , thereby decreasing the osmolarity of the medullary interstitial fluid.

5. Thiazide Diuretics (Inhibit s odium c hloride r eabsorption in the e arly d istal tubule ) Thiazides such as chlorothiazide , act mainly on the early distal tubules to block the sodium-chloride co-transporter in the luminal membrane of the tubular cells, causing a maximum of 5% to 10% of the glomerular filtrate to pass into the urine, which is about the same amount of sodium normally reabsorbed by the distal tubules.  Carbonic Anhydrase (Inhibitors Block Sodium Bicarbonate Reabsorption.) Acetazolamide inhibits the enzyme carbonic anhydrase, which is critical for reabsorption of bicarbonate (HCO3- ) in the renal tubules. Carbonic anhydrase is especially abundant in the proximal tubule, the primary site of action of carbonic anhydrase inhibitors. Some carbonic anhydrase is also present in other tubular cells, such as in the intercalated cells of the collecting tubule. Because hydrogen ion (H+) secretion and HCO3-reabsorption in the proximal tubules are coupled to sodium reabsorption through the sodium-hydrogen ion counter-transport mechanism in the luminal membrane, decreasing HCO3- reabsorption also reduces sodium reabsorption . The blockage of sodium and HCO3- reabsorption from the tubular fluid causes these ions to remain in the tubules and act as an osmotic diuretic.

6. Mineralocorticoid Receptor Antagonists (Decrease s odium reabsorption f rom and potassium s ecretion i nto the c ollecting t ubules ) Spironolactone and eplerenone are mineralocorticoid receptor antagonists that compete with aldosterone for receptor-binding sites in the collecting tubule and collecting duct epithelial cells and, therefore, can decrease the reabsorption of sodium and secretion of potassium in these tubular segments. As a result, sodium remains in the tubules and acts as an osmotic diuretic, causing increased excretion of water, as well as sodium . Mineralocorticoid receptor antagonists also block the effect of aldosterone (to promote potassium secretion in the tubules), they decrease the excretion of potassium cause movement of potassium from the cells to the extracellular fluid . This movement causes extracellular fluid potassium concentration to increase excessively . For this reason, they are referred to as potassium-sparing diuretics .

7. . Sodium Channel Blockers (Decrease sodium r eabsorption in the c ollecting t ubules ) Amiloride and triamterene inhibit sodium reabsorption and potassium secretion in the collecting tubules, similar to the effects of spironolactone. However, at the cellular level, these drugs act directly to block the entry of sodium into the sodium channels of the luminal membrane of the collecting tubule epithelial cells causing decreased activity of the sodium-potassium–adenosine triphosphatase pump (Na+-K+ ATPase pump). This reduces the transport of potassium into the cells and ultimately decreases the secretion of potassium into the tubular fluid. For this reason , the sodium channel blockers are also potassium-sparing diuretics and decrease the urinary excretion rate of potassium.

8. KIDNEY DISEASES Kidney diseases can be grouped into two categories: Acute kidney injury (AKI ), in which there is an abrupt loss of kidney function within a few days. Acute renal failure refers to severe acute kidney injury, in which the kidneys may abruptly stop working entirely or almost entirely, necessitating renal replacement therapy such as dialysis. In some cases , patients with AKI may eventually recover to nearly normal kidney function. Chronic kidney disease (CKD), in which there is progressive loss of function of more and more nephrons that gradually decreases overall kidney function . Kidney diseases can affect kidney blood vessels , glomeruli, tubules, renal interstitium , and parts of the urinary tract outside the kidney, including the ureters and bladder.

9. ACUTE KIDNEY INJURY The causes of AKI are often divided into three main categories: AKI resulting from decreased blood supply to the kidneys . This is often referred to as prerenal AKI to reflect an abnormality originating outside the kidneys. For example, as a consequence of heart failure causing reduced cardiac output and low blood pressure or conditions associated with diminished blood volume and low blood pressure, such as severe hemorrhage . Intrarenal AKI resulting from abnormalities within the kidney itself, including those that affect the blood vessels, glomeruli, or tubules . Postrenal AKI , resulting from obstruction of the urinary collecting system. The most common causes of obstruction of the urinary tract outside the kidney are kidney stones, caused by precipitation of calcium, urate , or cystine .

10. PRE-RENAL ACUTE KIDNEY INJURY CAUSED BY DECREASED BLOOD FLOW TO THE KIDNEY K idneys normally receive about 20% to 25% of the cardiac output to provide enough plasma for the high rates of glomerular filtration needed for effective regulation of body fluid volumes and solute concentrations . Decreased renal blood flow leads to decreased GFR and decreased urine output of water and solutes causing oliguria. This causes accumulation of water and solutes in the body fluids. If renal blood flow is markedly reduced, total cessation of urine output can occur, a condition referred to as anuria Causes of Pre-renal Acute Kidney Injury Intravascular Volume Depletion Hemorrhage (e.g., trauma, surgery, postpartum, gastrointestinal ) Diarrhea or vomiting Burns

11. Cardiac Failure Myocardial infarction Valvular damage Peripheral vasodilation and resultant hypotension Anaphylactic shock Anesthesia Sepsis , severe infections Primary renal hemodynamic abnormalities Renal artery stenosis, embolism, or thrombosis of renal artery or vein INTRARENAL ACUTE KIDNEY INJURY CAUSED BY ABNORMALITIES IN THE KIDNEY Refers to abnormalities that originate in the kidney and abruptly diminish urine output and are further divided into the following:

12. Conditions that injure the glomerular capillaries or other small renal vessels; Conditions that damage the renal tubular epithelium ; C onditions that cause damage to the renal interstitium . This type of classification is based on the primary site of injury, but because the renal vasculature and tubular system are functionally interdependent , damage to the renal blood vessels can lead to tubular damage , and primary tubular damage can lead to damage of the renal blood vessels. Causes of Intra-renal Acute Kidney Injury: Small vessel and/or glomerular injury Vasculitis ( polyarteritis nodosa ) Cholesterol emboli Malignant hypertension Acute glomerulonephritis

13. Tubular epithelial injury (tubular necrosis) Acute tubular necrosis due to ischemia Acute tubular necrosis due to toxins (e.g., heavy metals, ethylene glycol, insecticides, poison mushrooms, carbon tetrachloride) Renal interstitial injury Acute pyelonephritis Acute allergic interstitial nephritis Acute Kidney Injury Caused by Glomerulonephritis Acute glomerulonephritis is a type of intrarenal AKI usually caused by an abnormal immune reaction that damages the glomeruli, usually occurring 1 to 3 weeks after an infection elsewhere in the body, often caused by certain types of group A beta streptococci. It can be secondary to a streptococcal sore throat, streptococcal tonsillitis , or even streptococcal infection of the skin. A s antibodies develop against the streptococcal antigen, the antibodies and antigen react to form an insoluble immune complex that becomes entrapped in the glomeruli attracting large numbers of white blood cells which also become entrapped in the glomeruli causing inflammation .

14. Tubular Necrosis as a Cause of Acute Kidney Injury This refers to destruction of epithelial cells in the tubules mostly due to: Severe ischemia and inadequate supply of oxygen and nutrients to the tubular epithelial cells; This can result from circulatory shock or other disturbances that severely impair the blood supply to the kidneys. If the ischemia is severe enough, damage or destruction of the epithelial cells can occur, causing tubular cells to slough off and plug many of the nephrons so that there is no urine output from the blocked nephrons; the affected nephrons often fail to excrete urine, even when renal blood flow is restored to normal P oisons, toxins , or medications that destroy the tubular epithelial cells; for example carbon tetrachloride , heavy metals (e.g., mercury and lead), various insecticides and some medications (e.g., tetracyclines ). These substances have specific toxic actions on the renal tubular epithelial cells, causing death of many of them. As a result, the epithelial cells slough away from the basement membrane and plug the tubules.

15. POSTRENAL ACUTE KIDNEY INJURY CAUSED BY ABNORMALITIES OF THE LOWER URINARY TRACT Abnormalities in the lower urinary tract can block or partially block urine flow and lead to AKI , even when the kidneys’ blood supply and other functions are initially normal. If the urine output of only one kidney is diminished, no major change in body fluid composition will occur because the contralateral kidney can increase its urine output sufficiently to maintain relatively normal levels of extracellular electrolytes and solutes, as well as normal extracellular fluid volume. Normal kidney function can be restored if the basic cause of the problem is corrected within a few hours . However, chronic obstruction of the urinary tract that lasts for several days or weeks can lead to irreversible kidney damage. Some of the causes of postrenal AKI include the following: B ilateral obstruction of the ureters or renal pelvises caused by large stones or blood clots. Bladder obstruction; and Obstruction of the urethra.  

16. PHYSIOLOGICAL EFFECTS OF ACUTE KIDNEY INJURY Edema: The major physiological effect of AKI is the retention of water , waste products of metabolism, and electrolytes in the blood and extracellular fluid which can lead to water and salt overload, which, in turn, can lead to edema and hypertension. Hyperkalemia: Excessive retention of potassium, however, is often a more serious threat to patients with AKI because hyperkalemia above 8 mEq /L (only twice normal) can be fatal. Metabolic acidosis : Because the kidneys are also unable to excrete sufficient hydrogen ions, patients with AKI may experience metabolic acidosis, which in itself can be lethal or can aggravate the hyperkalemia. Anuria: In most severe cases of AKI, complete anuria occurs. The patient will die in 8 to 14 days unless kidney function is restored or unless an artificial kidney is used to rid of the excessive retained water, electrolytes, and waste products of metabolism.

17. CHRONIC KIDNEY DISEASE CKD refers to the presence of kidney damage or decreased kidney function that persists for at least 3 months. CKD is often associated with progressive and irreversible loss of large numbers of functioning nephrons. Serious clinical symptoms usually do not occur until the number of functional nephrons falls to at least 70% to 75 % below normal . Causes of Chronic Kidney Disease Metabolic Disorders ( e.g Diabetes mellitus, Obesity, Amyloidosis) Hypertension Renal Vascular Disorders (Atherosclerosis, Nephrosclerosis -hypertension) Immunological Disorders (Glomerulonephritis, Polyarteritis nodosa , Lupus erythematosus ) Infections like Pyelonephritis, Tuberculosis Primary Tubular Disorders due to Nephrotoxins (analgesics, heavy metals ) Urinary Tract Obstruction (Renal calculi, Hypertrophy of prostate, Urethral constriction) Congenital Disorders like Polycystic disease, Congenital absence of kidney tissue (renal hypoplasia)

18. VICIOUS CYCLE OF CHRONIC KIDNEY DISEASE LEADING TO END-STAGE RENAL DISEASE

19. Common Causes of End-Stage Renal Disease (ESRD) Cause Total No. of Patients With ESRD (%) Diabetes mellitus 45 Hypertension 27 Glomerulonephritis 8 Polycystic kidney disease 2 Other, unknown 18 INJURY TO RENAL BLOOD VESSELS AS A CAUSE OF CHRONIC KIDNEY DISEASE The most common vascular lesions that can lead to renal ischemia and death of kidney tissue are: Atherosclerosis of the larger renal arteries, with progressive sclerotic constriction of the vessels. It frequently affects one kidney, causing unilateral diminished kidney function F ibromuscular hyperplasia of one or more of the large arteries, which also causes occlusion of the vessels. Nephrosclerosis , caused by sclerotic lesions of the smaller arteries, arterioles, and glomeruli most common form of kidney disease in people above 60 years. There is progressive thickening of the vessel wall that eventually constricts the vessels and, in some cases , they get occluded.

20. INJURY TO THE GLOMERULI AS A CAUSE OF CHRONIC KIDNEY DISEASE—GLOMERULONEPHRITIS Chronic glomerulonephritis can be caused by several diseases that cause inflammation and damage to the glomerular capillary loops of the kidneys. It is a slowly progressive disease that often leads to irreversible renal failure. It may be a primary kidney disease, following acute glomerulonephritis , or it may be secondary to a systemic disease, such as systemic lupus erythematosus . Accumulation of antigen-antibody complex in the glomerular membranes causes inflammation , progressive thickening of the membranes, and eventual invasion of the glomeruli by fibrous tissue . In the final stages of the disease, many glomeruli are replaced by fibrous tissue and are unable to filter fluid.

21. INJURY TO THE RENAL INTERSTITIUM AS A CAUSE OF CHRONIC KIDNEY DISEASE—INTERSTITIAL NEPHRITIS I nterstitial nephritis refers to Primary or secondary disease of the renal interstitium . It can result from vascular, glomerular, or tubular damage that destroys individual nephrons, or it can involve primary damage to the renal interstitium by poisons, drugs , and bacterial infections. Renal interstitial injury caused by bacterial infection is called pyelonephritis and is usually caused by Escherichia coli , which originate from fecal contamination of the urinary tract. These bacteria reach the kidneys either by way of the blood stream or, more commonly , by ascension from the lower urinary tract via the ureters to the kidneys, due to; The inability of the bladder to empty completely, leaving residual urine in the bladder; O bstruction of urine outflow, impairing ability to flush bacteria from the bladder, the bacteria multiply, and the bladder becomes inflamed , a condition termed cystitis. Urine is propelled up one or both of the ureters during micturition due to a condition called vesicoureteral reflux

22. NEPHROTIC SYNDROME—EXCRETION OF PROTEIN IN THE URINE Is characterized by the loss of large quantities of plasma proteins into the urine. In some cases, this syndrome occurs without evidence of other major abnormalities of kidney function, but it is usually associated with some degree of CKD. The cause of the protein loss in the urine is usually increased permeability of the glomerular membrane . Therefore , any disease that increases the permeability of this membrane can cause N ephrotic syndrome. Such diseases include the following: chronic glomerulonephritis , which affects primarily the glomeruli and often causes greatly increased permeability of the glomerular membrane; amyloidosis , which results from deposition of an abnormal proteinoid substance in the walls of the blood vessels and seriously damages the basement membrane of the glomeruli; minimal-change nephrotic syndrome

23. NEPHRON FUNCTION IN CHRONIC KIDNEY DISEASE Loss of functional nephrons requires surviving n ephrons to excrete more water and solutes. Isosthenuria - inability of the k idney to concentrate or dilute the urine . The effect of the rapid rate of tubular flow that occurs in the remaining nephrons of diseased kidneys is that the renal tubules lose their ability to concentrate or dilute the urine fully, mainly because of the following: The rapid flow of tubular fluid through the collecting ducts prevents adequate water reabsorption; The rapid flow through both the loop of Henle and collecting ducts prevents the countercurrent mechanism from operating effectively to concentrate the medullary interstitial fluid solutes. Therefore, as more nephrons are destroyed, the maximum concentrating ability of the kidney declines .

24. ‘ Effects of Renal Failure on the Body Fluids- Uremia The effect of CKD on the body fluids depends on the following: water and food intake ; and the degree of impairment of renal function. Assuming that a person with complete renal failure continues to ingest the same amounts of water and food, the concentrations of different substances in the extracellular fluid would change. Important effects include: G eneralized edema resulting from water and salt retention; A cidosis resulting from failure of the kidneys to rid the body of normal acidic products; High concentration of the nonprotein nitrogens (Azotemia): especially urea, creatinine, and uric acid- resulting from failure of the body to excrete the metabolic end products of proteins ; High concentrations of other substances excreted by the kidney, including phenols, sulfates, phosphates , potassium , and guanidine bases . This total condition is called uremia because of the high concentration of urea in the body fluids.

25. Other effects: Anaemia due to decreased erythropoietin hormone secretion Osteomalacia caused by decreased p roduction of active Vitamin D and by phosphate retention by the kidneys Hypertension c aused by increased r enal s ecretion of renin . Specific Renal Tubular Disorders Renal Hypophosphatemia- Failure of the k idneys to reabsorb phosphate. Renal Tubular Acidosis- Reduced tubular s ecretion of hydrogen ions. Nephrogenic Diabetes Insipidus - Failure of the kidneys to respond to a ntidiuretic hormone. Fanconi Syndrome- generalized r eabsorptive defect of the renal tubules. Bartter Syndrome- decreased s odium , chloride , and potassium reabsorption in the loops of Henle . Gitelman Syndrome- decreased sodium c hloride reabsorption in the distal t ubules .

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