Acute Kidney Injury - Pharmacotherapy

1. Acute Kidney injury (AKI)

2.  AKI: defined as rapid decrease in kidney function
shown by changes in Serum creatinine, BUN and urine
output.
Definition:

3. RIFLE Category Scr and GFR
b
Criteria Urine Output Criteria
Risk Scr increase to 1.5-fold or GFR decrease >25% from baseline <0.5 mL/kg/h for ≥6 hours
Injury Scr increase to twofold or GFR decrease >50% from baseline <0.5 mL/kg/h for ≥12 hours
Failure Scr increase to threefold or GFR decrease >75% from
baseline, or Scr ≥4 mg/dL (≥354 μmol/L) with an acute
increase of at least 0.5 mg/dL (44 μmol/L)
Anuria for ≥12 hours
Loss Complete loss of function (RRT) for >4 weeks
ESKD RRT >3 months
AKIN Criteria Scr Criteria Urine Output Criteria
Stage 1 Scr increase ≥0.3 mg/dL (≥27 μmol/L) or 1.5- to 2-fold from
baseline
<0.5 mL/kg/h for ≥6 hours
Stage 2 Scr increase >2- to 3-fold from baseline <0.5 mL/kg/h for ≥12 hours
Stage 3 Scr increase >3-fold from baseline, or Scr ≥4 mg/dL (≥354
μmol/L) with an acute increase of at least 0.5 mg/dL (≥44
μmol/L), or need for RRT
<0.3 mL/kg/h for ≥24 hours or anuria
for ≥12 hours
KDIGO Criteria Scr Criteria Urine Output Criteria
Stage 1 Scr increase ≥0.3 mg/dL (≥27 μmol/L) or 1.5-1.9 times from
baseline
<0.5 mL/kg/h for 6-12 hours
Stage 2 Scr increase 2-2.9 times from baseline <0.5 mL/kg/h for ≥12 hours
Stage 3 Scr increase three times from baseline, or Scr ≥4 mg/dL
(≥354 μmol/L), or need for RRT, or eGFR
c
<35 mL/min/1.73
m
2
(<0.34 mL/s/m
2
) in patients <18 years
Anuria for ≥12 hours
Staging systems:

4.  Risk factors ass/ with AKI: CKD, DM, heart or liver dz,
albuminuria, major surgery, Acute decompensated heart
failure, sepsis, Hotn, volume depletion, medications, advanced
age, male, African American race.
 AKI TYPES:
 Prerenal which results from decreases renal perfusion in the
setting of the undamaged parenchymal tissue.
 Intrinsic which is the result of structural damage to the kidney
( tubule from ischemic or toxic insult)
 Postrenal which is caused by obstruction of urine flow
downstream from the kidney.
Epidemiology & Etiology:

5. Etiology:

6. • Blood flows through afferent arteriole to the glomerulus
and exit through efferent arteriole.
• blood flow or renal perfusion prerenal reduction in
renal function so kidney compensate by vasodilating
afferent arteriole and vasoconstricting the efferent
arteriole.
• Some drugs may interfere with this process.

7. Clinical
presentation
Urinary
output
Sudden wt
gain
Severe
abdominal
of flank
pain

8.  Healthcare professional should start with a thorough
review of pt medical records and focus on chronic
conditions, drugs taken, lab tests, and surgery.
Patient Assessment:

9. Hints:
Type of Urinary Evaluation Presence of Suggestive of
Urinalysis Leukocyte esterases Pyelonephritis
Nitrites Pyelonephritis
Protein
Mild (<0.5 g/day) Tubular damage
Moderate (0.5-3 g/day) Glomerulonephritis, pyelonephritis, tubular damage
Large (>3 g/day) Glomerulonephritis, nephrotic syndrome
Hemoglobin Glomerulonephritis, pyelonephritis, renal infarction, renal tumors, kidney stones
Myoglobin Rhabdomyolysis-associated tubular necrosis
Urobilinogen Hemolysis-associated tubular necrosis
Urine sediment Microorganisms Pyelonephritis
Cells Red blood cells Glomerulonephritis, pyelonephritis, renal infarction, papillary necrosis, renal
tumors, kidney stones
White blood cells Pyelonephritis, interstitial nephritis
Eosinophils Drug-induced interstitial nephritis, renal transplant rejection
Epithelial cells Tubular necrosis
Casts Granular casts Tubular necrosis
Hyaline casts Prerenal azotemia
White blood cell casts Pyelonephritis, interstitial nephritis
Red blood cell casts Glomerulonephritis, renal infarct, lupus nephritis, vasculitis
Crystals Urate Postrenal obstruction
Calcium phosphate Postrenal obstruction

10. Laboratory Test Prerenal AKI Intrinsic AKI Postrenal AKI
Urine sediment Hyaline casts, may be
normal
Granular casts, cellular
debris
Cellular debris
Urinary RBC None 2–4+ Variable
Urinary WBC None 2–4+ 1+
Urine Na (mEq/L or
mmol/L)
<20 >40 >40
FENa (%) <1 >2 Variable
Urine/serum osmolality >1.5 <1.3 <1.5
Urine/Scr >40:1 <20:1 <20:1
BUN/Scr (urea/Scr, SI) >20 (>100) ~15 (~60) ~15 (~60)
Urine specific gravity >1.018 <1.012 Variable
Diagnostic parameters for
differentiating causes of AKI:

11.  FENa=
𝐸𝑥𝑐𝑟𝑒𝑡𝑒𝑑 𝑁𝑎
𝑓𝑖𝑙𝑡𝑒𝑟𝑒𝑑 𝑁𝑎
𝑋100 =
𝑈𝑣𝑜𝑙𝑥𝑈𝑁𝑎
𝐺𝐹𝑅𝑥𝑆
𝑁𝑎
X100
 -> GFR=
𝑈𝑣𝑜𝑙𝑋𝑈𝑐𝑟
𝑆𝑐𝑟𝑋𝑡
 FENa=
𝑈𝑁𝑎𝑋𝑆𝑐𝑟𝑋100
𝑈𝑐𝑟𝑋𝑆𝑁𝑎
 Used to differentiate causes of AKI. A low urinary sodium
concentration (≤ 20 mEq/L [mmol/L]) and low FENa (≤1%) in
a patient with oliguria suggest that there is stimulation of
the sodium-retentive mechanisms in the kidney and that
tubular function is intact prerenal azotemia.
 The inability to concentrate urine results in a high
FENa (greater than 2%), suggesting tubular damage as the
primary cause of the intrinsic AKI.
Fractional excretion of Sodium
(FENa):

12.  Goals of prevention: to screen and identify pts at risk,
monitor high-risk pts until the risk subsides and
implement prevention strategies when appropriate.
 Outpts. should be educated to have fluid intake (2l/d)
to avoid dehydration esp if they receive nephrotoxic
medication.
 Inpts. Adequate hydration, standardized
hemodynamic support in critically ill and avoid
nephrotoxic drugs
Prevention of AKI:

13. Drug Indication
Recommended for
Prevention
Recommended for
Treatment
Comments
ANP AKI No (2C) No (2B)
Diuretics AKI No (1B) No (2C) Acceptable if managing
concurrent fluid
overload
Dopamine (1-3
μg/kg/min)
AKI No (1A) No (1A)
Fenoldopam AKI
CI-AKI
No (2C)
No (1B)
No (2C)
Isotonic saline IV AKI
CI-AKI
Yes (2B)
Yes (1A)
Yes (2B) For AKI: recommended
in the absence of
hemorrhagic shock
NAC AKI
CI-AKI
No (2D)
Yes (2D)
For CI-AKI: give in
combination with
isotonic saline
RRT AKI
CI-AKI
No (2C) Yes (NG)
Sodium bicarbonate IV CI-AKI Yes (1A)
Theophylline CI-AKI No (2C)
Vasopressors AKI Yes (1C) Yes (1C) Recommended in
combination with fluids
in vasomotor shock
KDIGO Recommendations for
Prevention and Treatment of AKI:

14.  HYDRATION
 Both isotonic crystalloids and colloid-containing solutions can
replace intravascular volume.
 hyperoncotic hydroxyethyl starch have been associated with
renal dysfunction and should generally be avoided in patients at
risk for AKI.
 Albumin appears to be safe for the kidneys; however, it is more
costly and does not provide better patient outcomes compared
with isotonic saline.
 As a result, KDIGO guidelines recommend isotonic crystalloids
over colloids for intravascular volume expansion in patients at
risk for AKI
Nonpharmacological therapy:

15.  Ascorbic acid (3 g orally preprocedure and 2 g orally twice
daily for two doses postprocedure) and N-
acetylcysteine (600–1200 mg orally every 12 hours for 2–3
days [first two doses precontrast]) are antioxidant options
for prevention of CIN. Study results with these two agents
are inconsistent.
 Current KDIGO guidelines suggest that moderate control
of blood glucose to levels of 110 to 149 mg/dL
with insulin therapy is appropriate to prevent hyper- and
hypoglycemia in critically ill patients with AKI.
Pharmacological therapy:

16.  Goals of Treatment: Short-term goals include minimizing
the degree of insult to the kidney, reducing extrarenal
complications, and expediting recovery of renal function.
Restoration of renal function to pre-AKI baseline is the
ultimate goal.
 Supportive care goals include maintenance of adequate
cardiac output and blood pressure to optimize tissue
perfusion while restoring renal function to pre-AKI
baseline.
 Discontinue medications associated with diminished renal
blood flow. Initiate appropriate fluid and electrolyte
management. Avoid use of nephrotoxins. Optimize
nutritional status.
Treatment of AKI:

17.  The principal of fluid therapy is to maintain or restore
effective intravascular volume to assure adequate tissue
perfusion.
 crystalloids such as isotonic saline or balanced solutions
are preferred.
 patient should be monitored for body weight changes,
fluid intake and urine output, pulmonary and peripheral
edema, blood pressure and serum electrolytes. Urine
output ≥ 0.5 mL/kg/h is generally targeted during the initial
fluid resuscitation phase
1) Hydration:

18.  Hypernatremia, fluid retention and hyperkalemia!!!
Also phosphorus and Mg.
 All these require monitoring.
 The KDIGO guidelines currently recommend a caloric
intake goal of 20 to 30 kcal/kg/day
Electrolyte Management:
Nutritional Considerations:

19.  loop diuretics are frequently used for the
management of fluid overload in patients with AKI.
 Diuretic resistance is a relatively common problem in
patients with AKI.
 One effective technique to overcome diuretic
resistance is to administer loop diuretics via
continuous infusion instead of intermittent boluses.
(and less S.E)
 Initial loading dose is given prior to infusion.
Diuretics:

20. Causes of Diuretic Resistance Potential Therapeutic Solutions
Excessive sodium intake (sources may be
dietary, IV fluids, and drugs)
Remove sodium from nutritional sources and
medications
Inadequate diuretic dose or inappropriate
regimen
Increase dose, use continuous infusion or
combination therapy
Reduced oral bioavailability (usually furosemide) Use parenteral therapy, switch to oral torsemide
or bumetanide
Nephrotic syndrome (loop diuretic protein
binding in tubule lumen)
Increase dose, switch diuretics, use combination
therapy
Reduced renal blood flow
Drugs (NSAIDs, ACEIs, vasodilators) Discontinue these drugs if possible
Hypotension Intravascular volume expansion and/or
vasopressors
Intravascular depletion Intravascular volume expansion
Increased sodium resorption
Nephron adaptation to chronic diuretic
therapy
Combination diuretic therapy, sodium restriction
NSAID use Discontinue NSAID
Heart failure Treat heart failure, increase diuretic dose, switch
to better-absorbed loop diuretic
Cirrhosis Paracentesis
Acute tubular necrosis Increase diuretic dose, diuretic combination
therapy
Causes of diuretic resistance:

21.  Drug therapy optimization in AKI is a challenge.
Confounding variables include residual drug clearance,
fluid accumulation, and use of RRTs.
 Volume of distribution for water-soluble drugs is
significantly increased due to edema. Use of dosing
guidelines for CKD does not reflect the clearance and
volume of distribution in critically ill patients with AKI.
 Patients with AKI may have a higher residual nonrenal
clearance than those with CKD with similar creatinine
clearances; this complicates drug-therapy individualization,
especially with RRTs.
Drug dosing considerations in AKI:

22.  In AKI cases, drug response is impaired due to the
processes that exist in AKI, that’s why individualized
pharmacotherapeutic regimens and frequent
assessment is required to optimize patient outcomes.
(Dose adjustment)
Personalized Pharmacotherapy

23. Parameter Frequency
Fluid intake & output Every shift
Patient weight Daily
Hemodynamics (blood pressure, heart rate,
mean arterial pressure, etc.)
Every shift
Blood chemistries
Sodium, potassium, chloride,
bicarbonate, calcium, phosphate,
magnesium
Daily
Blood urea nitrogen/serum creatinine Daily
Drugs and their dosing regimens Daily
Nutritional regimen Daily
Blood glucose Daily (minimum)
Serum concentration data for drugs After regimen changes and after renal
replacement therapy has been instituted
Times of administered doses Daily
Doses relative to administration of renal
replacement therapy
Daily
Urinalysis
Calculate measured creatinine clearance Every time measured urine collection
performed
Calculate fractional excretion of sodium Every time measured urine collection
performed
Plans for renal replacement Daily
Evaluation of therapeutic outcomes: