Download T2 - 11-20

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