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Sara Gordon Therapeutics Study Session 11/20/2016 [email protected] Normal Kidney Physiology Functions: Regulation of water, inorganic ion balance, and acid-base balance Removal of waste products – urea, uric acid, creatinine Removal of foreign chemicals Gluconeogenesis Production of hormones/enzymes – erythropoietin, renin, 1,25-dihydroxyvitamin D Nephron is the functional unit of the kidney, each kidney contains ~1 million nephrons Each nephron contains a renal corpuscle and renal tubule Renal corpuscle = glomerulus + Bowman’s capsule Each glomerulus is supplied blood by the afferent arteriole as blood flows through the glomerulus ~20% is filtered into Bowman’s capsule (glomerular filtrate) and the remaining blood exits via efferent arteriole o The remaining ~80% of blood that goes to the efferent arteriole travels through the peritubular capillaries to supply blood to the tubule Renal tubule = continuation of Bowman’s capsule; composed of proximal tubule, loop of Henle, descending and ascending limb, distal convoluted tubule, collecting duct The glomerular filtrate flows through the renal tubule where its concentration is altered by movement of substances from the tubule to peritubular capillaries and vice versa o Tubular reabsorption: movement from tubular lumen plasma o Tubular secretion: movement from plasma tubular lumen Why is SCr used to indicate GFR changes? o In a normal person, SCr ~1 and remains stable because the amount of creatinine excreted is equal to the amount of creatinine produced o If suddenly a patient is not filtering SCr appropriately, will see increase in SCr Acute Kidney Injury (AKI) Clinical syndrome generally defined by an abrupt reduction in kidney function as evidenced by changes in serum creatinine, blood urea nitrogen (BUN), and urine output Consequences of AKI can be serious, therefore early recognition along with supportive therapy is the focus of management as there is no therapy that directly reverses the injury Patients at risk, such as those with history of chronic kidney disease (CKD), need to have their hemodynamic status monitored closely and their exposure to nephrotoxins minimized Management goals include maintenance of blood pressure, fluid, and electrolyte homeostasis. Additional therapies designed to eliminate or minimized the insult that precipitated AKI include discontinuation of the nephrotoxic drug, aggressive hydration, maintenance of renal perfusion, and renal replacement therapy Definitions/Classification No universal definition Often characterized as an increase in serum creatinine (SCr) >0.5 mg/dL or more than 50% from baseline and generally measure of urine production Urine output classifications: o Anuric: <50mL/day o Oliguric: 50-450 mL/day o Nonoliguric: >450 mL/day Acute Kidney Injury Network defines AKI as > 0.3 mg/dL increase over 48 hours or urine output <0.5 mL/kg/hr for 6 hours or more RIFLE: SCr increase to 1.5-fold or GFR decrease >25% from baseline or urine output <0.5 mL/kg/hr for 6 hours or more KDIGO: SCr >/= 0.3 mg/dL or 1.5-1.9 times from baseline or urine output <0.5 mL/kg/hr for 6-12 hours Prerenal Acute Kidney Injury Results from hypoperfusion of the renal parenchyma, with or without systemic arterial hypotension Hypoperfusion with systemic hypotension can be caused by either a decline in the intravascular volume or the effective circulating blood volume o Decline in intravascular volume can result from hemorrhage, excessive GI losses (severe vomiting or diarrhea), dehydration, excessive burns, and diuretic therapy o Effective circulating blood volume may be reduced in conditions associated with decreased cardiac output and systemic vasodilation (sepsis) Hypoperfusion without systemic hypotension usually occurs with bilateral renal artery occlusion (or unilateral occlusion if the patient only has one kidney) Patients with a mild reduction in effective circulating blood volume or volume depletion are generally able to maintain a normal GFR by activating compensatory mechanisms: o Stimulation of the sympathetic nervous and the renin-angiotensin-aldosterone system and release antidiuretic hormone to reverse hypotension Vasoconstriction and stimulation of thirst o Afferent arteriole dilation mediated by intrarenal production of vasodilatory prostaglandins, kinins, and nitric oxide o Efferent arteriole constriction medicated by angiotensin II Drugs such as NSAIDs and ACEI/ARBs can alter afferent and efferent arteriole tone and place patients at higher risk of prerenal AKI o (think of the kidneys as selfish organs – when they have decreased perfusion, they’ll do whatever they can to make sure they get increased blood flow) If renal hypoperfusion is promptly corrected, prerenal AKI can be reversed and renal function will return to baseline. Prolonged prerenal AKI can cause direct injury to the renal parenchyma and lead to the development of ischemic ATN Treatment of prerenal AKI: optimize renal perfusion Fluids – composition of replacement fluids should be targeted to the type of fluid loss o Blood loss packed red blood cells o Plasma loss from burns and pancreatitis Isotonic crystalloid and/or colloid o Vasopressors (norepinephrine, phenylephrine, vasopressin) are recommended in patients with signs and symptoms of hypoperfusion and persistent hypotension despite adequate fluid resuscitation (septic shock) o Optimization of cardiac function may require inotropic agents, preload- and afterload-reducing agents, antiarrhythmic drugs, and mechanical aids such as an intraaortic balloon pump Intrinsic Acute Kidney Injury Results from direct damage to the kidney and is categorized based on the injured structures within the kidney o Can be further classified based on location of damage Renal Vasculature Damage (rare) Atheroemboli developed during vascular procedures that cause atheroma dislodgement such as angioplasty and aortic manipulations or thromboemboli from dislodgement of a thrombus can cause occlusion of the larger renal vessels Smaller vessels can become obstructed, however the development of significant AKI is unlikely o Small vessels are susceptible to inflammatory processes that lead to microvascular damage and vessel dysfunction Glomerular Damage Proteinuria (urine protein excretion >3.5 g/day/1.73m2) +/- a decline in GFR is hallmark sign of glomerular damage o Major cause is uncontrolled diabetes Tubular Damage (Acute Tubular Necrosis) Caused by renal ischemia (often an extension of prerenal state) or result of exposure to direct tubule toxins (endogenous toxins include myoglobin, hemoglobin, uric acid; exogenous toxins (include contrast agents, drugs – aminoglycosides, ampho B) Tubules located within the medulla of the kidney are at increased risk for ischemic injury due to metabolic activity and therefore high oxygen requirements Progression: o Ischemic injury causes tubular epithelial cell necrosis or apoptosis and is followed by an extension phase with continued hypoxia and an inflammatory response involving the nearby interstitium o Damage to the epithelial cells results in glomerular filtrate leaking back into the interstitium and reabsorbed back into systemic circulation o Additionally, urine flow is blocked by damaged epithelial cells and cellular debris o Results in decreased urine-concentrating ability, decreased urine output, and decreased GFR. Continued tubular damage kills more and more cells and propagates the inflammatory response o When the toxin/ischemia resolves tubule cells are regenerated and a notable diuresis will ensue. If the injury is extremely severe or prolonged, cortical necrosis may occur and tubule cell growth may be limited Interstitial Damage Renal interstitium can become severely inflamed and edematous, which can lead to acute interstitial nephritis (AIN) o Can be caused by drugs, infections, and possibly autoimmune idiopathic diseases Caused by an immune response If AIN is promptly identified and the offending agent removed, patients will regain normal kidney function within several weeks If left unrecognized, persistent renal dysfunction due to interstitial fibrosis and tubular atrophy may develop Postrenal AKI Results from an obstruction of urine flow downstream from the kidney Must involve both kidneys to produce clinically significant AKI Bladder outlet obstruction is often the result of a prostatic process (BPH, cancer, infection) which produces a physical impingement on the urethra and prevents the passage of urine Wherever the obstruction is located, urine will accumulate in the renal structures above the obstruction, resulting in increased pressure Treatment Remove offending agent Loop diuretics (furosemide, torsemide, bumetanide) may be used for fluid overloaded patients at risk for AKI o Clinical studies have found that loops do not reduce the incidence of AKI nor improve patient outcomes o KDIGO guidelines recommend limiting their use to fluid overloaded patients and avoiding their use for the sole purpose of prevention or treatment of AKI Vasodilators: o Low-dose dopamine (1-5 mcg/kg/min) did not prevent AKI, need for dialysis, or mortality compared with placebo therefore, KDIGO guidelines do not support the use of low-dose dopamine for prevention or treatment of noncardiogenic AKI o Fenoldopam is a selective dopamine A1 receptor agonist that increases renal blood flow, natriuresis, and diuresis without systemic alpha or beta adrenergic stimulation Some studies have demonstrated decreased mortality and need for RRT while others did not find any benefit. KDIGO does not recommend fenoldopam for the prevention and treatment of AKI Renal Replacement Therapy (RRT) o Intermittently or continuously o Optimal mode of hemodialysis is unclear and varies depending on the patient o Indications for renal replacement therapy: A: acid-base abnormalities E: electrolyte abnormalities I: intoxications O: fluid overload U: uremia Electrolyte Abnormalities o Hypernatremia Limit sodium intake Be aware of drugs that contain sodium – IV metronidazole, amipicillin, piperacillin o Hyperkalemia Life-threatening cardiac arrhythmias o Hyperphosphatemia o Hypermagnesemia Patient Cases: Case 1 AW is a 71 y/o CM with PMH HFrEF (EF 25%), HTN, CAD, and osteoarthritis. His home medications include furosemide 40 mg daily, enalapril 5mg daily, metoprolol XL 100mg daily, digoxin 0.125mg daily, atorvastatin 40mg daily, and naproxen 550mg BID He presents today with lower leg 3+ pitting edema, pulmonary crackles, and an S3 heart sound. Las month his BUN and SCr were 23 and 1.2, respectively. You recheck his labs and significant lab findings include Na 140, BUN 56, SCr 1.5 What type of AKI does AW likely have? Prerenal o His heart failure puts him at risk because his diminished cardiac output can result in decreased effective circulating volume which impairs renal perfusion His body has likely tried to compensate by stimulating afferent arteriole vasodilation, however this action is prostaglandin dependent. Since he is also taking an NSAID (naproxen) this is limiting prostaglandin production through the inhibition of COX-1 and COX-2, thereby negating compensatory vasodilation How should AW’s prerenal AKI be treated? Optimize HF regimen to improve cardiac output D/c naproxen and change to acetaminophen for OA pain Case 2 HH is a 43 y/o WM being treated for gram-negative septic shock. For the past 3 days HH has been in the MICU intubated because of hypotension, respiratory failure, and altered mental status. Current medications: Norepinephrine 18 mcg/min, pancuronium 0.02 mg/kg every 3 hours, famotidine 20 mg IV Q12h, lorazepam IV 2 mg/hr, ceftriaxone 2g daily, and gentamicin 140 mg IV Q8h Labs: Admission (6 days ago) Today BUN 13 67 SCr 0.9 5.4 WBC 23.5 16.7 During the past 2 days, HH’s urine output has steadily declined, and today it is 700mL/24 hours Serum gentamicin concentration obtained revealed a trough of 9.1 (goal <2) What are likely sources of HH’s AKI? Septic shock – requiring norepinephrine (prerenal) Aminoglycoside administration with supratherapuetic trough (acute tubular necrosis) Risk factors for aminoglycoside nephrotoxicity in general: o Elderly, underlying renal disease, dehydration, hypotension and septic shock o Gentamicin > tobramycin > amikacin, therapy >3 days, multiple daily dosing, trough >2 Case 3 TC is a 48 y/o AAM who presented to the ED complaining of sharp flank pain radiating to the groin, gross hematuria, and dysuria. He states he has had these symptoms for ~4 hours and are similar to previously experienced episodes of calcium nephrolithiasis. His BUN and SCr are 34 and 1.5, respectively, which is increased from his baseline of 15 and 0.9. A urine sample was obtained and it was determined that TC passed a kidney stone. On questioning he admits to not drinking as much water and his urine volume has been markedly lower than usual What type of AKI does TC have? Post-renal due to the obstruction that kidney stones produce Admits to having reduced fluid intake What common drugs cause crystal-induced AKI? Acyclovir, methotrexate, sulfonamides, triamterene o Insoluble in urine and crystallize in the distal tubule o Patients should be counseled to take with plenty of water