Diuretics and Kidney Diseases Lecture Outline PDF

Diuretics and Kidney Diseases Lecture Outline I. Diuretics and their mechanisms of action II. Kidney diseases III. Acute kidney injury IV. Chronic kidney disease is often associated with irreversible loss of functional nephrons 1 Diuretics and Kidney Disease Lecture Objectives 1. Know the genera...

Diuretics and Kidney Diseases Lecture Outline I. Diuretics and their mechanisms of action II. Kidney diseases III. Acute kidney injury IV. Chronic kidney disease is often associated with irreversible loss of functional nephrons 1 Diuretics and Kidney Disease Lecture Objectives 1. Know the general mechanism of action of each diuretic 2. Know definitions related to kidney diseases including oliguria, anuria, azotemia, uremia, and renal failure 3. Explain the difference in tests of glomerular filtration and renal tubular function 4. Compare the three categories of causes of AKI (prerenal, intrarenal, and postrenal) 5. Explain perioperative renal protective measures for at-risk patients 6. Explain how the kidney loses its ability to concentrate urine 7. List five indications for dialysis 8. Explain why patients with ESRD are at increased risk of developing pulmonary edema, ischemia, and acidosis 9. List anesthesia considerations for CKD/ESRD patients including fluid therapy, ventilation, and succinylcholine 10. Know the hormones produced by the kidney that explain pathophysiology related to CKD 2 References Assigned reading from your text: Hall Chapter 32 3 Diuretics 4 Diuretics • “Diuretics” increase urine volume, but most that are used clinically reduce Na+ reabsorption as their main action, and this increases excretion of Na+ and other electrolytes. • “Osmotic diuretics” are substances (e.g., mannitol) not easily reabsorbed by renal tubules; they reduce water reabsorption and this increases urine volume and excretion of electrolytes. • Diuresis and natriuresis is transient after diuretic treatment Carbonic Anhydrase Inhibitors Block HCO3− Reabsorption ❑ Carbonic anhydrase inhibitors • Produce a weak diuresis by dramatically reducing HCO3reabsorption in the PT • Used for glaucoma- not diuresis • Prophylaxis for altitude sickness: • Multiple MOAs • Acetazolamide decreases HCO3- reabsorption • Response to hypoxia (of altitude) is hyperventilation and respiratory alkalosis • May also prevent cerebral edema induced by altitude Acetazolamide X X Metabolic acidosis ↑HCO3− excretion Loop Diuretics Used to treat: •Volume overload • Acute – pulmonary edema • Chronic- cirrhosis Associated with: • Reduced urine concentrating ability • Potassium loss (hypokalemia) • Powerful - large amounts of Na, K, Mg, etc. excreted Thiazide Diuretics Used to treat: • Hypertension • Heart failure • Edema • Renal stones (nephrolithiasis) Mineralocorticoid Receptor Antagonists, Na + Channel Blockers Used to treat: • Aldosterone-related endocrine disorders • “Resistant” hypertension • Heart failure • Hypertension (Na+ channel blockers) • MR antagonists can cause hyperkalemia Kidney Disease 10 Kidney Diseases ❑ • • • Altered kidney function- Kidney Failure Failure of the kidneys to perform their excretory functions to maintain homeostasis When filtrations slows- urine production declines Further decline involves retention of water, ions, wastes ❑ • • • • • Definitions Normal output 800 ml-2L/24 hr Oliguria- urine output < 0.5 ml/kg/hr- a common perioperative finding Anuria- lack of urine output Azotemia- elevated blood urea nitrogen or creatinine Renal failure is azotemia + oliguria or anuria ❑ Renal disease can be categorized by either the site of the lesion or by the nature of factors that have led to the disease (tubulointerstitial versus immunologic) Kidney Injury, Disease, and Failure ❑ • • • Acute kidney injury (AKI) or Acute renal failure (ARF) Usually asymptomatic- detected by biochemical monitoring (labwork) Reversible if treated correctly Kidney function abruptly decreases (GFR declines) over days to weeks may recover • Most common cause of AKI/ARF is perioperatively is renal ischemia ❑ Chronic kidney disease (CKD) or chronic renal failure (CRF) • Impaired renal function persists for more than 3 months • Progressive and irreversible loss of functioning nephrons – symptoms appear when 75% of nephrons lost or when GFR drops below 60 ml/min/1.73 m 2 for 3 months. • Damage is irreversible- can be slowed or perhaps arrested with effective treatment Most common cause of perioperative AKI is renal ischemia Pathophysiology FIGURE 16-5 Pathophysiology of ischemiainduced acute kidney injury. • Mild or uncomplicated medullary hypoxia results in tubuloglomerular reflex adjustments that restore medullary oxygen sufficiency at the price of diminished renal function. • However, in the event of extreme renal medullary hypoxia or when associated with complicating factors such as those indicated in the figure, full-blown acute kidney injury develops. • Whether acute kidney injury is reversible or irreversible depends on a balance of reparative and complicating factors. NSAIDS 13 Kidney Injury, Disease, and ESRD ❑ Progression of Disease – Acute Kidney Injury (AKI) – Elevated BUN, creatinine and oliguria (<30 mL/hr); may be reversible – Chronic renal disease (CKD, Renal insufficiency) – End stage renal disease (ESRD) – <10–15% of GFR – Dialysis required to replace the function of the kidneys – ASA physical status classification – These patients have severe systemic disease – May be a constant threat to life Tests Used for Evaluation of Renal Function Glomerular Function Measured by GFR Renal Tubular Function Measured by Concentrating Ability • BUN 10-20 mg/dL • FENA 1% (-3% Na+ intake) • Serum creatinine .0.7-1.5 mg/dL • Urine osmolality 65-1400 mOsm/L • Cr Clearance 110-150 mL/min • Urine sodium % 130-260 mEq/day • Urine specific gravity 1.003-1.030 15 Chronic Renal Disease and Plasma Concentrations of Solutes ❑ Patterns of solute concentrations in renal failure A- Creatinine, urea • Correlates with clinical indicators of renal function correlate with NPN • Creatinine clearance • BUN B- Phosphate and H+ C- Na and Cl maintained due to decreased tubular reabsorption Plasma Creatinine Can Be Used to Estimate Changes in GFR ❑ Tests of Glomerular Filtration ❑ Plasma creatinine: • Proportional to muscle mass • Undergoes filtration- not reabsorption • Predictable changes in GFR • Late change • Creatinine clearance • Most accurate method for assessing overall renal function since • BUN • Urea is the primary metabolite of protein metabolism • Undergoes filtration and reabsorption • Many nonrenal variables response for elevations of BUN and creatinine - including bleeding Acute Kidney Injury 18 Susceptibility of the Kidney to ARF in Specific Regions ❑ Hemodynamic Factors regulating blood flow have profound effects on the kidney: ❑ GFR-a primary determinant of renal function- depends on renal blood flow ❑ Kidney is susceptible to hypoxic (ischemic) injury ❑ Prerenal azotemia (elevated BUN without tubular necrosis) is directly related to decreased GFR ❑ Renal medulla is a low oxygen tension environment which makes it susceptible to ischemic injury – Pre-renal ARF can cause Intra-renal ARF – Without treatment, prerenal azotemia may progress to acute tubular necrosis (ATN) ❑ Glomerulus is the initial filter of blood entering the kidney: this is a prominent site of injury related to the immune complex deposition and complement fixation 19 Categories of Causes of Acute Kidney Injury (AKI) • Prerenal AKI—caused by decreased blood flow to kidneys (~50–55% of ARI) • Intrarenal AKI—caused by abnormalities within the kidneys (~35–40% of ARI) • Postrenal AKI—caused by obstruction in the lower urinary tract (~ 5% of ARI) • Hypoperfusion • Due to hemodynamic factors • Loss of blood/volume • Hypotension • Myocardial ischemia • Renal artery stenosis • Vasoconstrictors/NSAIDS Prerenal Renal • Parenchymal • Acute Tubular Necrosis • Inflammatory diseases • Ischemia from Prerenal ARF • Obstruction • Renal calculi • Blood clots • Prostatic hypertrophy • Bladder cancer Postrenal GFR Depends on Renal Blood Flow Vander’s Human Physiology Figure 14-9 Control of GFR by constriction or dilation of afferent (AA) or efferent (EA) arterioles. • Constriction of the afferent arteriole (a) or dilation of the efferent arterioles ( c) reduces PGC, thus decreasing GFR. • Constriction of the efferent arteriole, (b) or dilation of the afferent arteriole (d) increases PGC thus increasing GFR. 21 Pre-Renal ARF Causes ❑ Causes • Altered renal hemodynamics – Low cardiac output state: positive pressure ventilation, poor heart function, renal artery stenosis • Systemic vasodilation – Sepsis, anti-hypertensives, anaphylaxis and anesthesia • Renal vasoconstriction – Catecholamines, hypercalcemia, amphotericin B • Impairment of renal autoregulation – NSAIDS- inhibit PGE2 and PGI – ACE inhibitors & ARBS both vasodilate the efferent arteriole • Hypovolemia – Hemorrhaged, GI loss, renal loss such as diuretics, extravascular sequestration, dehydration ❑ Pathophysiology of hypovolemia occurs when RBF drops below 25% normal for a prolonged period 22 Medications that Contribute to Pre-Renal ARF ❑ NSAIDS- inhibit PGE2 and PGI ❑ ACE inhibitors & ARBS both vasodilate the efferent arteriole • ACE inhibitors interfere with production of angiotensin II and efferent vasoconstriction • Angiotensin II receptor blockers- prevent angiotensin II from stimulating vasoconstriction in systemic and efferent arterioles 23 Sites of Intra-Renal (Intrinsic) ARF ❑ Parenchymal damage can occur at multiple sites: (examples given) • glomerular capillaries, peritubular capillaries, or vasa recta • epithelia of renal tubules • interstitial tissues (eg mesangium) Glomerular Injury Can Be Acute or Chronic ❑ Glomerulonephritis- result of abnormal immune reaction that damages glomeruli • Many glomeruli blocked by inflammation- others permeable enough to let RBCs leak through • May return to normal or progress to complete CKD ❑ Inflammatory process: • Primary inflammation of glomeruli on a chronic basis• eg Strep A antigen-antibody complexes entrapped in glomerulus with proliferation in the mesangium • Secondary inflammation is a disease outside the kidney causes resultant inflammation of glomeruli • Antigen-antibody complex deposits, accumulates, membrane thickens, replaced by connective tissue • Loss of functional glomerular tissue causes a loss of GFR ❑ Glomerulonephritis (glomerular injury) can be further divided clinical presentation (Image next slide) • Nephrotic disorders- profound proteinuria but no evidence of a cellular inflammatory reaction • Immune complexes damage foot processes and the selective nature of the glomerular filter • Nephritic disorders-proteinuria with red and white blood cells in the urine • Immune complexes deposit in subendothelial location or in the glomerular basement membrane or mesangium • Subendothelial deposits may be phagocytized and recover is possible OR greater destruction could occur 25 Glomerulonephritis Pathophysiology Figure 16–4 Anatomy of a normal glomerular capillary is shown on the left. Note the fenestrated endothelium (EN), glomerular basement membrane (GBM), and the epithelium with its foot processes (EP). The mesangium is composed of mesangial cells (MC) surrounded by extracellular matrix (MM) in direct contact with the endothelium. Ultrafiltration occurs across the glomerular wall and through channels in the mesangial matrix into the urinary space (US). Typical localization of immune deposits and other pathologic changes is depicted on the right. (1) Uniform subepithelial deposits as in membranous nephropathy. (2) Large, irregular subepithelial deposits or “humps” seen in acute postinfectious glomerulonephritis. (3) Subendothelial deposits as in diffuse proliferative lupus glomerulonephritis. (4) Mesangial deposits characteristic of immunoglobulin A nephropathy. (5) Antibody binding to the glomerular basement membrane (as in Goodpasture syndrome) does not produce visible deposits, but a smooth linear pattern is seen on immunofluorescence. (6) Effacement of the epithelial foot processes is common in all forms of glomerular injury with proteinuria. 26 Intra-Renal ARF Causes ❑ Acute Tubular Necrosis- Nephrotoxic chemical toxins and medications contribute to acute tubular necrosis (ATN) • Kidney injury by intra-renal vasoconstriction - IV radiocontrast dye • Antibiotics that accumulate in tubular cells- aminoglycosides (gentamicin) • Endogenous nephrotoxins- myoglobin, hemoglobin • Exogenous nephrotoxins- heavy metals and ethylene glycol (antifreeze) ❑ Interstitial nephritis • Inflammation of interstitium (tissue outside the renal tubules) • Caused by poisons, drugs and bacterial infections - Allergic reactions and immune complexes - Long-term use of NSAIDS - Chronic bacterial infections- eg E.coli 27 Post-Renal ARF ❑ Causes • Obstruction to urine flow out of excretory tract – Ureters or anywhere along the tract from the neck of bladder to the urethral meatus • Bladder neck obstruction- most commonly is benign prostatic hyperplasia (BPH) • Ureteric obstruction – Calculi (kidney stones) – Blood clots – Common problem with obstruction • Causes a buildup of hydrostatic back pressure on the kidney • Increased back pressure decreases GFR • Resultant effect is azotemia 28 At-Risk Patients ❑ At risk perioperative patients include: • Pre-existing renal disease • Prolonged renal hypoperfusion- CHF, sepsis, advanced age • High risk surgery- with procedures associated with significant physiological trespass eg cardiac and vascular surgeries. ❑ Renal protection includes adequate hydration and maintenance of RBF for patients at risk of developing AKI ❑ Correct management of patients with renal insufficiency is critical- especially during involved surgeries • Goal is to avoid further injury ❑ Goal for ESRD patients is to maintain homeostasis- prevent systemic insults AKI and Anesthesia ❑ Normal occurrences during general and regional anesthesia include reversible decreases in: • RBF • GFR • Urinary flow • Sodium excretion ❑ Risk of renal insults minimized when intravascular volume and normal BP maintained ❑ Surgery and anesthesia responsible for postoperative fluid retention via ADH in response to: • Positive end-expiratory pressure • Positive pressure ventilation • Hypotension • Volume depletion 30 Chronic Kidney Disease 31 Chronic Kidney Disease or CHD (Guyton: Chronic Kidney Failure) ❑ Most Common Causes Account for 75% of All Adult Cases 1. Diabetes Mellitus* 2. Hypertension* 3. Glomerulonephritis *Obesity is the Major Risk Factor for both 32 Types of Renal Vascular Injury and CKD ❑ Atherosclerosis of renal arteries- usually one is more affected than the other (renal stenosis) • Fatty deposits in walls of vessels leads to constriction of lumina and occlusion resulting in reduced blood flow to the kidney ❑ Fibromuscular hyperplasia • Addition of smooth muscle cells to muscular layer of larger intrarenal arteries- occludes affected arterioles ❑ Nephrosclerosis • Deposition of fat and connective tissue in walls of radial arteries and afferent arterioles occludes blood supply • Benign nephrosclerosis is a function of aging- 10% decrease in functional nephrons for each decade after 40 yo 33 Chronic Kidney Disease Stages- Do Not Memorize Stage 1. Slight kidney damage with normal or relatively high GFR (≥90 mL/min/1.73 m 2) Stage 2. Mild reduction in GFR (60–89 mL/min/1.73 m 2) with kidney damage Stage 3. Moderate reduction in GFR (30–59 mL/min/1.73 m 2) Stage 4. Severe reduction in GFR (15–29 mL/min/1.73 m 2); Preparation for renal replacement therapy Requires dialysis or kidney transplant Stage 5. Established kidney failure (GFR <15 mL/min/1.73 m 2 Requires dialysis or kidney transplant Progressive Nature of Chronic Kidney Disease ❑ Adaptation through Hypertrophy • A slowly developing vicious cycle • Increase in size of remaining functional nephrons including their glomeruli • Hypertrophy of remaining nephrons accompanied by increased arterial pressure • Allows kidneys to excrete normal amounts of solute and water with as little as 25% kidney function/ mass • Long-term adaptations lead to further damage of remaining normal nephrons and glomeruli due to increased stretch and hydrostatic pressure imposed on remaining glomeruli • Adaptations further damage remaining nephrons and lead to ESRD Inability of Kidney to Concentrate Urine ❑ Kidney diseases diminishes nephrons ability to concentrate (most important) and dilute urine • As nephron loss progresses, remaining nephrons have a higher than normal flow rate • Rapid flow rate through remaining nephrons decreases water reabsorption • Rapid flow washes out the counter current osmotic multiplier system • Isosthenuria occurs- Specific gravity of urine becomes similar to GFR • Occurs from the combination of: • Reduced concentrating ability and • Medullary interstitium washout Uremia ❑ A syndrome of systemic disease characterized by high levels of urea in the ECF • Urea= 50% of total NPN substances that contribute to azotemia • Urea concentration measured by BUN • Effect of kidney shutdown at ESRD on body fluids depends on • Food and water intake • Degree of CKD • The pathogenesis of clinical uremia r/t: • Retained products normally excreted by the kidneys (wastes, K+, etc) • Normal products such as hormones now present in increased amounts • Loss of normal products of the kidney (erythropoietin) • Degree of severity related to: • Diet- Salt and water retention • Degree of nephron involvement Physiological Effects of Kidney Failure Decreased kidney function (loss of GFR) leads to: ❑ Uremia • Progressive elevation of BUN, serum creatinine and other toxins • Azotemia – elevated non-protein nitrogen • Uremia increases risk of bleeding- uremic frost on skin ❑ Life-threatening electrolyte, volume, and acid-base abnormalities • Hyperkalemia is a serious abnormality- HD if K+ >6 mEq/L • Can give succinylcholine if K+ normal (after HD) • Water retention/Edema • High risk of pulmonary edema • Metabolic acidosis • Loss of HCO3+ with • Decreased excretion acids • Reason to use controlled ventilation • Avoids hypercarbia and increased K+ECF Anemia and CKD ❑ Anemia • Erythropoietin (EPO) stimulates red bone marrow to increase production of RBCs under conditions of hypoxia • EPO is produced by interstitial cells associated with peritubular capillaries • Loss of nephrons results in decreased synthesis of EPO ❑ Increased vulnerability to ischemia: • Lower RBC= lower O2 carrying capacity (RBCs) 39 Metabolic Acidosis in Renal Patients ❑ Etiology or acidosis in renal patients: • Loss of nephrons impairs kidney’s ability to: • Excrete acid (ammonium) and generate base (ammonia) in CKD • If GFR above 20 ml/min- only moderate acidosis develops • Acidosis can be treated with oral sodium bicarbonate by mouth daily ❑ These patients are highly susceptible to acidosis in the event of: • Increased acid load (ketoacidosis, lactic acidosis, hyperchloremic acidosis, respiratory acidosis) • Or bicarbonate loss (diarrhea) • Pre-existing acidosis is a reason to use controlled ventilation instead of spontaneous • Avoid respiratory acidosis that can occur with ineffective respiration after sedation • Avoids hypercarbia and increased K+ECF ❑ Body is hyper-responsive to rapid onset metabolic acidosis (acute)may be associated with profound hypotension, arrhythmias, and death • Acidosis associated with alterations in transcellular ion pumps • Result is vasodilation and diminished myocardial performance and arrhythmias 40 Osteomalacia ❑ Osteomalacia of CKD related to loss of ability to produce active Vit D3 • Lack of nephrons causes a lack of active Vit D3 in the blood • Active VitD 3 is required by the small intestine for the absorption of Ca++ in the blood • Hypocalcemia occurs in CKD • Bone becomes weakened and soft due to lack of Ca++ deposition into bone matrix 41 Cardiovascular and Hematologic Abnormalities ❑ • • • Heart failure and pulmonary edema can develop due to salt and volume overload HTN is common Hyperreninemia- failing kidney overproduces renin- also elevates systemic BP Pericarditis can develop from the irritation and inflammation of the pericardium by uremic toxins • Dialysis has decreased this complication in developed countries • Increased incidence of CV disease in CKD population ❑ • • • Hematologic abnormalities Abnormalities in RBC, WBC, and clotting parameters Treatment with erythropoietin analogues improves their hematocrit Prone to bruising, decreased clotting, and increased incidence of spontaneous hemorrhage • GI, cerebrovascular (including hemorrhagic strokes and subdural hematomas) Uremic toxins of uremia linked to leukocyte suppression and increased susceptibility to infections • 42 Other Systems Involved in CKD ❑ • • • • Neuromuscular abnormalities Range from mild sleep disorders to impaired concentration, judgement, seizures, and coma Neuromuscular irritability includes cramps, twitching, seizures Peripheral neuropathy a common finding- restless legs syndrome and neuropathic pain Autonomic neuropathy may cause gastroparesis ❑ GI abnormalities • Anorexia, hiccups, nausea, vomiting- usually improve with dialysis ❑ Endocrine abnormalities • Low estrogen, testosterone common • Insulin degradation decreases- stabilizing effect if diabetic ❑ • • • • Dermatologic abnormalities Display pallor- anemia Ecchymoses and hematomas from coagulopathy Pruritis and excoriations as a result of Ca++ deposits Uremic frost- evaporation of sweat high in urea leaves a residue 43 Treatment of Kidney Failure With Dialysis ❑ Dialysis ❑ Indications: • • • • • Volume overload Hyperkalemia Severe metabolic acidosis Symptomatic uremia Overdose with a drug cleared by dialysis ❑ Considerations: • • • • Hemodialysis is more efficient than PD Hemodialysis causes more fluid shifts than PD Emergent dialysis is an indication for central access Hypotension most common event related to dialysis • Not ideal immediately pre-op Anesthesia and CKD ❑ Patients with ESRD at risk of pulmonary edema and CHF • ECF overload from Na+ retention • Increased cardiac demand from a combination of anemia and HTN • Smaller bags of IVF (250-500 ml instead of 1000ml) ❑ • • • Exaggerated hemodynamic effects due to: Antihypertensive medications – esp ACE Inhibitors, ARBs Attenuated SNS tone Intravascular volume depletion if recently dialyzed ❑ Succinylcholine • Safe in renal patients with a normal K+ • If K+ > 5.5 mEq, succinylcholine may cause a dangerous increase in K+ • Normally causes an increase of 0.5-1.0 mEq/L (~10-15 minutes) 45 Perioperative Fluid Management in Renal Dysfunction ❑ Management • Maintain perfusion- eg MAP > 65 mmHg • Absence of renal function narrows the margin of safety between insufficient and excessive fluid administration • 500 ml bolus balanced salt solution to restore volume • Use caution with LR and K+-containing fluids • Vasopressors often needed- may be useful to maintain GFR and UOP • Autonomic neuropathy common finding ❑ Increased morbidity and mortality with: • IVF- increased risk of renal morbidity with hydroxyethyl starch (Voluven) • Large volume of 0.9% NaCl may cause hyperchloremic metabolic acidosis • Lactic acidosis worse than iatrogenic hyperchloremic acidosis ❑ Intraoperative urine output not predictive of postoperative renal insufficiency • 0.5 ml/kg/hr urine output is reasonable • Most likely cause of oliguria is an inadequate circulating fluid volume • Administering diuretic may further compromise renal function and increase morbidity and mortality 46 Exam 4 Review Questions 1. Erythropoietin is secreted by which of the following? A. B. C. D. Cells of the distal tubules Juxtaglomerular cells Cells in the peritubular capillary bed Cells of the macula densa 2. During normal antidiuresis, when vasopressin is high, urea is deposited in the medullary interstitium. What happens to urea in CKD? A. B. C. D. Kidneys excrete more urea than normal There is lower production of urea than normal Urea isn’t removed from blood by glomerular filtration There is no change in urea handling by the kidney in chronic kidney disease 3. Which of the following may have a beneficial effect in a patient with CKD? A. B. C. D. Water retention and intravascular volume Insulin clearance by the kidneys Change in clotting ability O2-carrying capacity 4. What is a main cause of intrarenal acute renal failure? A. B. C. D. Kidney stones Blood clots Benign hypertrophy of the prostate Pre-renal failure 47