pharmacotherapy for pharmacy

1. Acute kidney Injury
(AKI)
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2. Contents
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 Introduction
 Definition
 Epidemiology
 Etiology
 Pathophysiology
 Clinical Presentation and diagnosis
 Prevention of AKI
 Treatment
 Diuretic resistance
 Evaluation of therapeutic outcomes

3. Objectives
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 Upon completion of the chapter, the students
will be able to:
 Assess a patient’s kidney function based on
clinical presentation, laboratory results, and
urinary indices.
 Identify pharmacotherapeutic outcomes and
endpoints of therapy in a patient with acute
kidney injury (AKI).
 Apply knowledge of the pathophysiology of AKI
to the development of a treatment plan.

4. Objectives
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 Design a diuretic regimen to treat volume
overload in AKI.
 Develop strategies to minimize the occurrence
of drug and radiocontrast-induced AKI.
 Monitor and evaluate the safety and efficacy
of the therapeutic plan.

5. Brain storming question
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 What is the function of KIDNEY?

6. Introduction
 Functions of kidney
 Excretory Function
 Filtration, secretion, and reabsorption processes
 Regulate volume of blood, electrolyte content and
acid base balance
 Endocrine function
 secretion of renin, erythropoietin
 production and metabolism of prostaglandins and
kinins
 Metabolic function
 the activation of vitamin D3
 metabolism of insulin, steroids, and xenobiotics
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7. 7
Fig one: Structures of the nephron

8. Definition
 Acute kidney Injury(AKI) is characterized
clinically by an abrupt decrease in renal function
over a period of hours to days resulting in:
 the accumulation of nitrogenous waste products
(azotemia)
 the inability to maintain and regulate fluid,
electrolyte, and acid–base balance
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9. Table one: RIFLE Classification
Schemes for Acute Kidney Failure
(AKF)
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RIFLE by Acute Dialysis Quality Initiation (ADQI)

10. Table two: AKIN* Classification
Schemes for Acute Kidney Injury
(AKI)
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* AKIN – Acute Kidney Injury Network

11. KDIGO* – AKI Definition
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 AKI is defined as any of the following:
 Increase in SCr by ≥ 0.3 mg/dl (≥ 26.5 μmol/l)
within 48 hours; or
 Increase in SCr to ≥ 1.5 times baseline, which
is known or presumed to have occurred within
the prior 7 days; or
 Urine volume <0.5 ml/kg/h for 6 hours
 *KDIGO - Kidney Disease Improving Global
Outcomes

12. Table three: AKI is staged for severity
according to the following criteria
(KIDGO)
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13. Epidemiology
 Approximately 5% to 7% of all hospitalized
patients develop AKI
 AKI is 5 to 10 times more prevalent in the hospital
setting than in the community setting
 About 5% to 20% of critically ill patients develop
AKI
 30% to 40% of survivors progress to chronic
kidney disease (CKD)
 Mortality generally exceeds 5% for patients in
general wards to 50% for ICU patients
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14. Table four: Incidence and
Outcomes of Acute Kidney Injury
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15. Etiology
 (a) prerenal AKI: results from decreased renal
perfusion in the setting of undamaged
parenchymal tissue
 (b) intrinsic AKI: the result of structural damage
to the kidney, most commonly the tubule from
an ischemic or toxic insult,
 (c) postrenal AKI: caused by obstruction of
urine flow downstream from the kidney
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16. Fig two: Physiologic classification of AKI
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17. Pathophysiology- Prerenal AKI
 Prerenal AKI is characterized by reduced blood
delivery to the kidney
 Cause:
 intravascular volume depletion (hemorrhage,
dehydration, extensive burns or GI fluid losses)
 reduced effective circulating blood volume
(reduced cardiac output, sepsis)
 Hypotensive events (e.g., shock or medication-
related hypotension)
 renovascular obstruction or vasoconstriction
(renal artery stenosis, hepatorenal syndrome)
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18. Pathophysiology- Prerenal AKI
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 With a mild to moderate decrease in renal blood
flow, intraglomerular pressure is maintained by:
 Stimulation of the sympathetic nervous and
the RAAS and release antidiuretic hormone
 dilation of afferent arterioles & constriction of
efferent arterioles
 redistribution of renal blood flow to the
oxygen-sensitive renal medulla

19. Pathophysiology- Prerenal AKI
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 If, however, the decreased renal perfusion is
severe or prolonged,
 these compensatory mechanisms may be
overwhelmed, and prerenal AKI will be
clinically evident.
 Sustained prerenal conditions can result,
however, in glomerular ischemia causing acute
tubular necrosis (ATN)
 Drugs may cause a functional AKI when they
interfere with these autoregulatory mechanisms

20. 20
Fig three: Drugs that alter renal hemodynamics by causing
afferent arteriole vasoconstriction or efferent arteriole

21. Pathophysiology- Intrinsic AKI
 Intrinsic AKI results from direct damage to the
kidney
 Categorized on the basis of the injured
structures within the kidney:
 Tubules
 The renal vasculature
 Glomeruli
 Interstitium
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22. Pathophysiology- Intrinsic AKI
 Tubular Damage
 Approximately 85% caused by ATN
50% are a result of renal ischemia, often arising
from an extended prerenal state (hypotension,
vasoconstriction)
35% are the result of exposure to direct tubule
toxins,
endogenous (myoglobin, hemoglobin, or uric
acid)
exogenous (contrast agents, aminoglycoside
antibiotics, penicillins, sulfonamides etc)
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23. Pathophysiology- Intrinsic AKI
 The clinical evolution of ATN is characterized by
three distinct phases:
 Initiation
 Maintenance
 recovery
 The hallmarks of the initiation phase are:
 Ischemic injury
 GFR reduction
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24. Pathophysiology- Intrinsic AKI
 Ischemic injury causes tubular epithelial cell
necrosis or apoptosis an extension phase
(continued hypoxia and an inflammatory response -
involving the nearby interstitium)
 The loss of epithelial cells between the filtrate and
the interstitium results in:
 denudation of basement membrane
 inability of the basement membrane to
appropriately regulate fluid and electrolyte
transfer
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25. Pathophysiology- Intrinsic AKI
 As a result,
 the glomerular filtrate starts leaking back into
the interstitium and is reabsorbed into the
systemic circulation.
 urine flow is obstructed by accumulation of
sloughed epithelial cells, cellular debris, and
formation of casts
 The onset of ATN can occur over hours to days
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26. Pathophysiology- Intrinsic AKI
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 Regardless of the etiology; tubular injury, back
leakage, and obstruction
 lead to a loss in the ability to concentrate urine,
decreased urine output, and, ultimately, GFR
 Continued kidney hypoxia or toxin exposure after
the original insult
 kill more cells and propagates the inflammatory
response
 extend the injury and delay the recovery process
 damage and kill the tubular epithelial cells in the
corticomedullary junction

27. Pathophysiology- Intrinsic AKI
 When the toxin or ischemia is removed,
 a maintenance phase ensues and may last
anywhere from a few weeks to several months
 The maintenance phase is eventually followed by
a recovery phase,
 during which new tubule cells are regenerated
 The recovery phase is associated with a notable
diuresis,
 which requires prompt attention to maintain fluid
balance, or a secondary prerenal injury may
occur.
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28. Pathophysiology- Intrinsic
AKI
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 Renal Vasculature Damage
 Occlusion of the larger renal vessels resulting
in AKI is not common but can occur
if large atheroemboli or thromboemboli
occlude renal arteries
 Smaller vessels can also be obstructed by
atheroemboli or thromboemboli,
the damage is limited to the vessels
involved,
the development of significant AKI is
unlikely

29. Pathophysiology- Intrinsic
AKI
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These vessels are susceptible to
inflammatory processes that lead to:
microvascular damage
vessel dysfunction when the renal capillaries
are affected
 Neutrophils invade the vessel wall, causing
damage that can include:
 thrombus formation, tissue infarction, and
collagen deposition within the vessel
structure

30. Pathophysiology- Intrinsic
AKI
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 Diffuse renal vasculitis can be mild or severe,
with severe forms promoting concomitant
ischemic ATN.
 The Scr is usually elevated when the lesions
are diffuse; thus, the area of damage is large.

31. Pathophysiology- Intrinsic
AKI
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 Glomerular Damage
 Account 5%
 Similar damage observed in the renal
vasculature by the same mechanisms can
occur
in addition to severe inflammatory processes
specific to the glomerulus

32. Pathophysiology- Intrinsic AKI
 Interstitial Damage
 If the renal interstitium becomes severely inflamed
and edematous,
 it can lead to development of acute interstitial
nephritis (AIN).
 AIN may be caused by drugs, infections, and,
rarely, autoimmune idiopathic diseases.
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33. Pathophysiology- Intrinsic AKI
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 Acute interstitial injury is characterized by:
 lesions comprised of monocytes, eosinophils,
macrophages, B cells, or T cells,
clearly identifying an immunologic response as
the injurious process affecting the interstitium.
 If symptoms of AIN remain unrecognized, and the
exposure to the causative agent continues,
 persistent renal dysfunction associated with
interstitial fibrosis and tubular atrophy may
develop

34. Pathophysiology - Postrenal AKI
 Postrenal AKI
 accounts for less than 5% of all cases of AKI
 occurs as the result of obstruction at any level
within the urinary collection system from the
renal tubule to the urethra
 Cause:
Bladder outlet obstruction
Prostatic hypertrophy, infection, cancer
Improperly placed bladder catheter
Anticholinergic medication
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35. Pathophysiology - Postrenal AKI
 Ureteral
 Cancer with abdominal mass
 Retroperitoneal fibrosis
 Nephrolithiasis
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36. Pathophysiology - Postrenal
AKI
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 Renal pelvis or tubules
 Nephrolithiasis
Oxalate
Indinavir
Sulfonamides
Acyclovir
Uric acid
 Extremely elevated uric acid concentrations
from chemotherapy-induced tumor lysis
syndrome

37. Pathophysiology - Postrenal AKI
 At the location of the obstruction, urine will
accumulate in the renal structures above the
obstruction and cause increased pressure
upstream.
 The ureters, renal pelvis, and calyces all
expand, and the net result is a decline in GFR.
 If renal vasoconstriction ensues, a further
decrement in GFR will be observed.
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38. ARF
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Fig four: Classification of acute kidney injury (AKI) based on

39. Clinical course (1)
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 The oliguric phase
 occurs over 1 to 2 days
 is characterized by a progressive decrease in
urine production
 last from days to several weeks
Urine production of
<500 mL/day is termed oliguria
<50 mL/day Is termed anuria
>500 mL/day of urine output- Nonoliguric
renal failure

40. Clinical course (2)
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 Diuretic phase
 a period of increased urine production occurs
over several days
 Result from
in part, a return to normal GFR before
tubular reabsorptive capacity has fully
recovered
the elevated osmotic load from uremic toxins
the increased fluid volume retained during
the oliguric phase

41. Clinical course (3)
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 The recovery phase
 occurs over several weeks to months, depending
on the severity of the patient’s ARF
 signals
the return to the patient’s baseline kidney
function,
normalization of urine production
the return of the diluting and concentrating
abilities of the kidneys.

42. Clinical Presentation and
diagnosis
 Symptom & sign
 Change in urinary habits (e.g., decreased
urine output or urine discoloration)
 Sudden weight gain
 Severe abdominal or flank pain
 Severe headache
 Nausea, vomiting, diarrhea,
 Edema
 Fever
 Colored or foamy urine
 In volume-depleted patients, orthostatic
hypotension
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43. Clinical Presentation and
diagnosis
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 Physical Examination Findings
 Increased blood pressure
 Jugular venous distention (JVD)
 Pulmonary edema
 Rales
 Hypotension or orthostatic hypotension (prerenal
AKI)
 Rash (intrinsic AKI due to acute interstitial
nephritis)
 Bladder distention (postrenal bladder outlet
obstruction)

44. Clinical Presentation and
diagnosis
 Laboratory Tests
 Elevations in the serum potassium, BUN,
Creatinine, and phosphorous, or a reduction in
calcium and the pH (acidosis), may be present.
 An increased serum white blood cell count may be
present in those with sepsis-associated ARI, and
eosinophilia suggests acute interstitial nephritis.
 Urine microscopy can reveal cells, casts, or
crystals that help distinguish among the possible
etiologies and/or severities of ARI
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45. Clinical Presentation and
diagnosis
 An elevated urine specific gravity suggests
prerenal ARI, as the tubules are concentrating
the urine.
 Urine chemistry also indicates the presence of
protein, which suggests glomerular injury, and
blood, which can result from damage to virtually
any kidney structure.
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46. Clinical Presentation and
diagnosis
 Other Diagnostic Tests
 Urinary catheterization
 Renal ultrasonography or cystoscopy may be
needed to rule out obstruction
 Computed tomography
 Magnetic resonance imaging
 Renal angiography
 Retrograde pyelography
 Renal biopsy is rarely used, and is reserved
for difficult diagnoses.
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47. Table five: Diagnostic Parameters for
Differentiating Causes of Acute Kidney
Injury
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48. Fractional excretion of sodium
(FENa)
 The FE Na+ is a measurement of how actively
the kidney is reabsorbing sodium
 The FE Na+ is calculated as:
 FE Na+ = (UNa × PCr ) /(UCr× PNa) x 100%
 where UNa = urine sodium, PCr= plasma
creatinine, UCr= urine creatinine, and PNa=
plasma sodium.
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49. Table six: Urinary Findings as a
guide to the Etiology of AKI
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50. Table six: Urinary Findings as a
guide to the Etiology of AKI
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51. Table seven: Advantages and
Disadvantages of Novel Clinical
Biomarkers of AKI
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52. Prevention of AKI
 Desired outcome
 The goals of AKI prevention are to
 (a) screen and identify patients at risk,
 (b) monitor high-risk patients until the risk has
subsided,
 (c) implement prevention strategies when
appropriate
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53. Nonpharmacologic Therapies
 Prevention of Radiocontrast dyes induced
nephrotoxicity
1. Hydration
 Normal saline infusion (1 mL/kg/h for 12 hours before and
12 hours after the procedure).
 MOA: diluting the contrast media, preventing renal
vasoconstriction that contributes to hypoxia and
ischemia, and minimizing tubular obstruction
 Sodium bicarbonate regimen is 154 mEq/L (154 mmol/L)
infused at 3 mL/kg/h for 1 hour before the procedure and
at 1 mL/kg/h for 6 hours after the procedure.
 MOA: reduce the formation of oxygen free radicals by
alkalinizing renal tubular fluid
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54. Nonpharmacologic Therapies
 2. Renal Replacement Therapy
 Prophylactic administration of RRT (such as
hemodialysis and peritoneal Dialysis) to patients
who are at high risk of AKI
N.B. KDIGO guidelines do not currently
recommend RRT for prevention of CIN
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55. Pharmacologic Therapies
 1. Loop Diuretics, theoretical advantages:
 decreased risk of tubular obstruction 20 to an
increased urine flow and flushing out of debris;
 increased urine output that may be beneficial in
itself
 decreased risk of ischemic injury as the result of
inhibition of the sodium/potassium chloride
cotransporter and thus a reduction in oxygen
demand
 enhanced renal blood flow due to increased
availability of renal prostaglandins
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56. Pharmacologic Therapies
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 But, they neither reduce the incidence of AKI nor
improve patient outcomes, (mortality, need for RRT,
and renal recovery
2. Vasodilator Therapy
 a. Dopamine
 IV dopamine (1 to 3 mcg/kg/min) increase renal blood
flow, induce natriuresis and diuresis
 controlled studies have found that low-dose
dopamine did not prevent AKI, need for dialysis, or
mortality compared with placebo
 KDIGO guidelines do not support the use of low dose
dopamine

57. Pharmacologic Therapies
 b. Fenoldopam mesylate
 a selective dopamine A-1 receptor agonist that
increases renal blood flow, natriuresis, and
diueresis
 current KDIGO guidelines do not recommend its use
(Due to a lack of large multicenter trials as well as risk of
hypotension)
 c. Natriuretic Peptides
 atrial natriuretic peptide (ANP) and brain
natriuretic peptide (BNP)
mediate vasodilation, diuresis, and natriuresis
 current KDIGO guidelines do not recommend its use
(Due to the need for further research on appropriate
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58. Pharmacologic Therapies
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3. Antioxidants
 a. Ascorbic Acid
 alleviate oxidative stress caused by CIN-
associated ischemia reperfusion injury.
 3 g orally before the procedure, then 2 g orally
twice daily for two doses after the procedure
 current KDIGO guidelines do not recommend
its use (clinical studies have reported
inconsistent results)

59. Pharmacologic Therapies
 b. N-Acetylcysteine (NAC)
 antioxidant that has been widely studied in the
prevention of CIN in patients with renal
insufficiency
 600 to 1,200 mg orally every 12 hours for 2 to
3 days, with the first two doses administered
prior to contrast exposure
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60. Pharmacologic Therapies
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 4. Insulin
 current KDIGO guidelines suggest using
insulin therapy to target plasma glucose of
110 to 149 mg/dL (6.1 to 8.3 mmol/L)
 5. Adenosine Receptor Antagonists
(theophylline)
 KDIGO guidelines suggest against using
theophylline for prevention of CIN (Due to the
risk of adverse effects as well as a relatively
small benefit)

61. Treatment of AKI
 Desired Outcomes
 Short-term goals include:
minimizing the degree of insult to the kidney,
reducing extrarenal complications
Expediting(facilitating) the patient's recovery
of renal function.
 The ultimate goal is to have the patient's renal
function restored to his or her pre-AKI
baseline.
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62. General Approach to
Treatment
 Prerenal sources of AKI should be managed with
hemodynamic support and volume replacement.
 If the cause is immune related, as may be the
case with interstitial nephritis or
glomerulonephritis, appropriate
immunosuppressive therapy must be promptly
initiated
 Postrenal therapy focuses on removing the
cause of the obstruction.
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63. General Approach to
Treatment
 Supportive care is the mainstay of AKI
management regardless of etiology
 RRT may be necessary to maintain fluid and
electrolyte balance while removing
accumulating waste products.
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64. Nonpharmacologic
 Initial modalities to reverse or minimize prerenal
AKI include
 eliminating medications associated with
diminished renal blood flow
 improving cardiac output
 removing a prerenal obstruction
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65. Nonpharmacologic
 For dehydration - appropriate fluid replacement
therapy
 Moderately volume-depleted patients
Oral rehydration fluids
If IV fluid is required, isotonic normal saline is
the replacement fluid of choice
initiated with 250 to 500 mL of normal
saline over 15 to 30 minutes
1 to 2 L is usually adequate
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66. Nonpharmacologic
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 Patients with diabetic ketoacidosis or a
hyperosmolar hyperglycemic state often have a
10% to 15% total-body water deficit, and more
aggressive fluid replacement is necessary.

67. Nonpharmacologic
 Up to 10 L may be required in the septic
patient during the first 24 hours, because of
the profound increase in vascular capacitance
and fluid leakage into the extravascular,
interstitial space
 Patients with anuria or oliguria
 Slower rehydration, such as 250 mL boluses
or 100 mL/h infusions of normal saline(reduce
the risk for pulmonary edema)
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68. Nonpharmacologic
 Dehydration resulting from severe diarrhea is
often accompanied by metabolic acidosis
caused by bicarbonate losses.
 5% dextrose with 0.45% sodium chloride
(NaCl) plus 50 mEq (50 mmol) of sodium
bicarbonate per liter, administered as bolus
 followed by a brisk continuous infusion (200
mL/h) until rehydration is complete, acidosis
corrected, and diarrhea resolved
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69. Nonpharmacologic
 If the prerenal AKI is a result of blood loss or is
complicated by symptomatic anemia
 red blood cell transfusion to a hematocrit no
higher than 30% is the treatment of choice.
 Albumin - limited to individuals with severe
hypoalbuminemia (e.g., liver disease and
nephritic syndrome) who are resistant to
crystalloid therapy.
 Severe hypoalbuminemia-associated third
spacing that complicates fluid management, and
albumin may be useful in this setting.
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70. Nonpharmacologic
 The most common interventions of intrinsic or
post obstructive AKI involve fluid and electrolyte
management.
 Supportive care goals for the hospitalized
patient with any type of AKI include:
 maintenance of adequate cardiac output
 blood pressure to allow adequate tissue
perfusion
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71. Nonpharmacologic
 Renal Replacement Therapies (RRT)
 Intermittent Hemodialysis(IHD)
 Continuous Renal Replacement Therapies
continuous venovenous hemofiltration
(CVVH)
continuous venovenous hemodialysis
(CVVHD)
Continuous venovenous hemodiafiltration
(CVVHDF)
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72. 72
Fig Five: Continuous renal replacement therapy (CRRT)
variants

73. Table Eight: Common Indications
for
Renal Replacement Therapy
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74. Pharmacologic
 Once the kidney has been damaged by an
acute insult initial therapies should be directed:
 to prevent further insults to the kidney, thereby
minimizing extension of the injury.
 The time to recovery from AKI is determined
from the most recent insult to the kidney, not the
first insult.
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75. Pharmacologic
 If sepsis is present, antibiotic therapy regimens
should be adjusted:
 for decreased renal elimination
 the potential for increased elimination if the
agent is removed by hemodialysis
 the ability to treat the infection to prevent
further damage to the kidney.
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76. Pharmacologic
 To date, no pharmacologic approach to reverse the
decline or accelerate the recovery of renal function
has been proven to be clinically useful.
 Frusemide
reserved for fluid-overloaded patients who make
adequate urine in response to diuretics to merit
their use
lower cost, availability in oral and parenteral
forms, and reasonable safety and efficacy
profiles
initial furosemide doses, which should not
76

77. 77
Fig six : Algorithm for treatment of extracellular fluid

78. 78
Fig Six : Algorithm for treatment of extracellular fluid

79. Pharmacologic
 Mannitol,
 an osmotic diuretic
 can only be given parenterally
 A typical starting dose is mannitol (20%) 12.5 to 25 g
infused intravenously over 3 to 5 minutes.
 It has little nonrenal clearance
 so when given to anuric or oliguric patients,
mannitol will remain in the patient, potentially
causing a hyperosmolar state.
 Additionally, mannitol may cause AKI itself,
 so monitor carefully by measuring urine output and
serum electrolytes and osmolality.
79

80. Diuretic resistance
 The inability to respond to administered diuretics
is common in AKI
 Diuretic resistance may occur simply
because of
 excessive sodium intake overrides the ability
of the diuretics to eliminate sodium.
 Reduced number of functioning nephrons on
which the diuretic may exert its action.
 Glomerulonephritis, are associated with heavy
proteinuria.
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81. Diuretic resistance
 Intraluminal loop diuretics cannot exert their
effect in the loop of Henle because they are
extensively bound to proteins present in the
urine.
 Reduced bioavailability of oral furosemide
because of intestinal edema, often associated
with high preload states, which further reduces
oral furosemide absorption.
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82. Diuretic resistance
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 An effective technique to overcome diuretic
resistance is:
to administer loop diuretics via continuous
infusions instead of intermittent boluses
Increase frequency of administration
Combine with other diuretics

83. Table Nine: Common Causes of Diuretic
Resistance in Patients with AKI
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84. Table Nine: Common Causes of
Diuretic Resistance in Patients with
AKI
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85. Diuretic resistance
 Metolazone, unlike other thiazides, produces
effective diuresis at a GFR <20 mL/min (0.33 mL/s).
 This combination of metolazone and a loop
diuretic has been used successfully in the
management of fluid overload in patients with
heart failure, cirrhosis, and nephrotic syndrome.
 Despite a lack of supporting evidence, oral
metolazone at a dose of 5 mg is commonly
administered 30 minutes prior to an IV loop diuretic
to allow time for absorption.
85

86. 86
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Table Ten :Key Monitoring Parameters for Patients
with Established Acute Renal Injury