Presentation Title

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Dr. Ahmed A. Elberry, MBBCH, MSc, MDAssociate Professor of Clinical PharmacyFaculty of pharmacy,KAU

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New concept of teaching: not to teach & give information but to teach how to get information2

3aelberry.kau.edu.safilesother- Dyslipidemia- Hypertension- HF- IHD- Arrhythmia- Thrombosis & DVT- Shock- Stroke

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Acute Kidney Injury (AKI)Ahmed A. Elberry,MBBCH, MSc, MDAssociate Professor of Clinical Pharmacy,Faculty of Pharmacy, KAU10

Kidney functions11

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AKI Abrupt decrease in renal function over a period of hours to days, resulting in the accumulation of nitrogenous waste products (azotemia).

ARF should now be restricted to patients who have AKI and need renal replacement therapy.

Definition & staging has been modified in 2004, 2007 & 2012

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13Reversible in most cases

ADQI, AKIN & KDIGO definitions of AKIDefinition of decrease in renal function- in SCr of 0.5 mg/dL or more or- in SCr 1.5-fold from baseline or- UO < 0.5 mL/kg/h for >6 h or - GFR > 25%- in SCr of 0.3 mg/dL or more or- in SCr 1.5-fold from baseline or- UO < 0.5 mL/kg/h for >6 h- in SCr of 0.3 mg/dL or more within 48 h or- in SCr 1.5-fold from baseline within the last 7 days or- UO < 0.5 mL/kg/h for >6 h

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ADQI group (2004): AKIN (2007): KDIGO (2012):Definition of AKIAbrupt (1-7 days) in renal function from base lineAbrupt (within 48 h) in renal function from base lineAbrupt (hours-days) in renal function from base line

Acute Dialysis Quality Initiative - Acute Kidney Injury Network - Kidney Disease Improving Global OutcomesNormal cr level: 0.7-1.4 mg/dl14

ADQI, AKIN & KDIGO staging of AKIKDIGO criteriaSCr criteriaUO criteriaStatge 1As AKINAs AKIN

Stage 2As AKINAs AKINStage 3As AKINOReGFR < 35 mL/min. in patients < 18 yearsAs AKIN

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RIFLE categorySCr & GFR criteriaUO criteriaRSCrincreased 1.5-2 times baseline orGFR decreased >25%UO < 0.5 mL/kg/h >6 hISCr increased 2-3 times baseline orGFR decreased >50%UO < 0.5 mL/kg/h >12 hFSCr increased >3 times baseline orGFR decreased 75% orSCr 4 mg/dL with acute rise 0.5 mg/DlUO < 0.3 mL/kg/h 24 horanuria >12 h

LPersistent failure: complete loss of kidney function >4 wk (requiring RRT)EComplete loss of kidney function >3 mo (requiring RRT)

AKIN criteriaSCr criteriaUO criteriaStage 1SCrincreased 1.5-2 times baseline OrSCr increased >0.3 mg/dLAs RIFLE (R)

Stage 2SCr increased 2-3 times baselineAs RIFLE (I)Stage 3SCr increased >3 times baseline OrSCr 4 mg/dL with acute rise 0.5 mg/dL OrNeed RRTAs RIFLE (F)

AKIN& KDIGO deleted GFRNormal UO: 0.5-1 ml/kg/h in infant up to 215

Epidemiology

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Community-Acquired AKIHospital-Acquired AKIICU-Acquired AKI

IncidenceLow ( human ergosterol

Bind with ergosterol & cholesterolAmphotericin binds to the lipids in these vehicles with an affinitybetween that for fungal ergosterol and that for human cholesterol. The lipid vehicle then serves as an amphotericin reservoir,reducing nonspecific binding to human cell membranes.Ambisome, Amphotec, Abelcet

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Aminoglycosides Incidence: The most common drug causing nephrotoxicity10% and 25% of patients receiving a therapeuticneomycin> gentamicin = tobramycin = amikacin = netilmicin> streptomycin

Mechanism:ATN: 5% of filtered drug is actively reabsorbed by the PCT cells formation of myeloid bodies tubular cells swell and burst, releasing aminoglycoside & lysosomal enzymes into the tubule lumen further tubular destruction

Extended-interval aminoglycoside dosing (One large daily dose)AdvantagesConc. Dependent killing activityPostantibiotic effect observed with aminoglycoside while minimizing time-dependent toxicity

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These agents are polycationic bind to the negatively charged brush-border cells within the tubule lumen. Once attached, these agents undergo pinocytosis and 29

Risk Factors for Developing Aminoglycoside NephrotoxicityPatient factors:ElderlyUnderlying renal diseaseDehydrationHypotension & shockHepatorenal syndrome

Aminoglycoside factorsAminoglycoside choice: gentamicin > tobramycin > amikacinTherapy >3 daysMultiple daily dosingSerum trough >2 mg/LRecent aminoglycoside therapy

Concomitant therapy Amphotericin BContrast mediaCisplatinumCyclosporineFoscarnetFurosemideVancomycin

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Type of aminoglycosideToo long tttToo much 2 daily dose or moreTrough level more than 2Taken before30

Pathophysiology Pass in 3 phases:Initial phaseMaintenance phaseRecovery phase

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Initial phaseUO: (50% normal & 50% oliguria or anuria)Oliguria : UO 400 mL/day . Anuria: UO < 100 mL/day. Fluid overloadNitrogenous waste products accumulate in the blood due to impaired glomerular filtration & concentrating capacity (Azotemia) - SCr., sulfate, phosphate, & organic acid levels rapidly.

**Hyponatremia: dilutional hyponatremia.Hyperkalemia: Due to metabolic acidosis. Hyperphosphatemia due to phosphate excretion hypocalcemia S& S of hypocalcemia (generally not seen in AKI ??? But seen in CKD)

Metabolic acidosis32

All as expected EXCEPT Na - it is dilutional so dont increase Na in diet despite it is decreased32

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Maintenance phaseDiuretic phase: UO >500 mL/day ?? after several days of oliguria. This diuretic response may not be seen in non-oliguric patients

Azotemia & associated laboratory findings may persist until UO reaches 1000 -2000 mL/day.

The maintenance phase carries a risk of fluid & electrolyte abnormalities, GI bleeding, infection, & respiratory failure.Recovery phase Renal function gradually returns to normal (in 2 weeks; however, may continue for a year). 34

It is not normal but more than normal (diuretic phase) as the anatomy returned bot not the physiology (function)34

Clinical manifestations:Non-specific: usually & Diagnosed accidently

Symptomatic: in some patientsUO or anuria: from 20-500 mL/day. Complete anuria is rare.S&S of hypervolemia (headache, confusion, blurred vision, N,V, HTN, edema)S& S of hypovolemia may be in diuretic phase & if the cause is prerenal

S&S of hyperkalemia, (resulting from metabolic acidosis & potassium excretion):HyperphosphatemiaHyponatremia.

Uremia caused by excessive nitrogenous waste retentionMetabolic acidosis

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accidently by an abnormal blood test

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Clinical manifestations (contin.)Signs & symptoms of hyperkalemia: ???

Hyponatremia Loss of concentration, impaired consciousness, confusion, lethargy, convulsions weakness

Metabolic acidosis is evidenced by: CNS: lethargy & coma. CVS: hypotension, pulmonary edema, ventricular fibrillation.Respiration: Kussmauls respiration (compensatory hyperventillation)GIT: N, VSkin: warm & flushed (VD)Muscles: twitches & weakness

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4C

Muscle cramps & paresthesia followed by weaknessUrine abnormalities (oliguria or anuria)Respiratory distressDecreased cardiac contractility & hypotensionECG changes with potential cardiac arrestReflex abnormalities (hype or hyporeflexia)

HYPERVINTILLATIO to git rid of CO2 and acids

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Clinical manifestations (contin.)Hyperphosphatemia hypocalcemia: Confusion & convulsions.Arrhythmia & HypotensionTetany & crampsStridor, spasm & soft tissue calcification.

Uremia: A,N,VAstrexis (flapping tremors)Bleeding & PericarditisConfusion, convulsions, comaDeath

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Hypocalcemia: CATSHyponatremia: 4C

Hypocalcemia is rare as acidosis increase the ionised free Ca (note that when u treat hypocalemia, tetany occur)37

Clinical manifestations (contin.)NB.:If the cause is prerenal Manifestations of Intravascular volume depletion: Hypotension, orthostatic hypotension, Dehydration, dry mm

If the cause is postrenal suprapubic or flank mass, costovertebral angle tenderness, bladder distention.

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Diagnostic testsConventional markers in Urine & blood with calculation of CLcr, RFI, FENa

Novel biomarkers

Radiographic

Renal biopsy

ECG

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Any investigation:1- to prove the condition2- to assess the condition3- to investigate for the cause40

Urine analysisPrerenal Renal 1- Urine-specific gravity> 1018< 10122- Urine osmolality.> 1.5< 1.53- Urinary sediment (Casts)Hyaline casts Epithelial or granular casts: in ATNWBCs (eosinophilic) casts: AINRBCs casts: AGN4- Urinary Cr levels Ucr Ucr 5- Urinary NaLow 40 mEq/L6- FENaLow < 1% High > 2%7- Renal failure index (RFI): The ratio of UNa to the Ucr -to- Scr. ratio. < 1> 2 (EXCEPT AGN < 1)NB.: In post renal it is also > 2

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Normal sp gravity: 1015-1025Normally: proximal tubule reabsorbs 99% of filtered Na. Urinary Na may be high in prerenal if receiving DIURETICS

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CLcr

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Blood Chemistry BUN SCr. (rapid increase >1 mg/dL/d) in Hb & Hct ( in cases of dehydration).Abnormal serum electrolytes.Hyperkalemia: Serum K above 5 mEq/LHyperphosphatemia: Serum phosphate above 2.6 mEq/L (4.8 mg/dL)Hypocalcemia: Serum Ca below 4 mEq/L (8.5 mg/dL). (serum Ca level must be correlated with the serum albumin level. Each rise or fall of 1 g/dL of serum albumin beyond its normal range is responsible for a corresponding increase or decrease in serum calcium of approximately 0.8 mg/dL.)Hyponatremia: Serum Na below 135 mEq/L

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Novel biomarkersCystatin C: cysteine proteinase, released into the plasma by all nucleated cells in the body , then freely filtered by the glomeruli. It does not undergo any secretion or reabsorption, but is completely metabolized by PCT. Thus, a in GFR or tubular function cystatin C in plasma & urine conc.

NGAL (neutrophil gelatinaseassociated lipocalin ):Present on cell surfaces of neutrophils, freely filtered & reabsorbed in PCT. Thus it increases in urine in tubular injury

IL18: proinflammatory that in urine in ATNKIM-1: biomarker that is in urine in ATN

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Radiography & renal biopsyRadiographic findingsUS may detect urinary tract obstruction.X- Ray may reveal urinary tract calculi.Radionuclide scan may reveal:slow radionuclide uptake, suggesting ATN.CT scan provide better visualization of obstruction.

Renal biopsy: when other test results are inconclusive.

45ECGEvidence of hyperkalemia: tall, peaked T waves; widening QRS; prolonged PR interval, decreased amplitude & disappearing P waves; ventricular fibrillation & cardiac arrest.

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Prevention of AKIAvoid dehydrationAvoid nephrotoxic drugs

Adequate hydration with isotonic solutionNa bicarb

Look for STOP (sepsis & hypotension, Toxins, Obstruction, Parenchymal kidney disease)

NB.: No role of the following despite theoretical benefits:DopamineFenoldopamLoop diureticsNACVit C47

ACCORDING TO KDIGO47

Treatment objectivesPreventing further renal damage: through correcting reversible causes

Prevention of complications & alleviation of symptoms through correction of body chemistry alteration & electrolyte imbalance (may need dialysis).

Facilitate renal recovery through correction & maintenance of fluid & electrolyte balance.48

a. Discontinue nephrotoxic drugs; gastric lavage, & dialysis.b. Treat underlying infection.c. Remove any urinary tract obstructions.

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Conservative Fluid managementFluid intake should match fluid losses (500-1000 mL/day). But avoid overload (HTN & HF)Patient should be weighed daily to determine fluid volume status.

Dietary measures(1) High-calorie, low-protein diet(2) Na If edema or HTN .(3) K (Fruits, vegetables, & salt substitutes containing K).50

High-calorie, low-protein diet renal workload by decreasing production of end products of protein catabolism that the kidneys cannot excrete50

Hyperkalemia Calcium chloride or calcium gluconateSodium bicarbonateSodium polystyrene sulfonate (SPS) (Kayexalate)

Regular insulin with dextrose

Dialysis51

ACIDS

ACIDS: acidosis correction, calcium, insulin + glucose, dialysis, SPSCalcium chloride or calcium gluconateReplaces & maintains body Ca, counteracts the cardiac effects of hyperkalemia.Sodium bicarbonaterestores bicarb. that the renal tubules cannot reabsorb & increases arterial pH. shift of K into cells serum K conc.Regular insulin with dextrosecauses an intracellular shift of K. The combination of insulin with dextrose deposits potassium with glycogen in the liver, reducing the serum potassium.Sodium polystyrene sulfonate (SPS) (Kayexalate)K-removing resin that exchanges Na ions for K ions in the intestine (1 g of SPS exchanges 0.5 to 1 mEq/L of potassium).Dialysis51

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Hyperphosphatemia (contin.)Calcium carbonate, acetate, citrate:IV calcium: first-line therapy for severe life-threatening hyperphosphatemia.Oral: bind dietary phosphorus in the GIT.

Aluminum hydroxide (AlternaGel)Binds phosphate in the intestine (Onset of action is 6-12 hrs.)Orally as a tablet or 3-4 times daily with meals.SE: constipation& anorexia osteomalacia fatal neurological symptoms (in dialysis patients (Dialysis encephalopathy))

53Magnesium hydroxide, carbonate:Not preferred as it is needed in high dose that may cause severe diarrhea & hypermagnesemia (muscle weakness, cardiac depression, CNS depression)

Calcium citrate is a calcium salt with a phosphatebinding capacity similar to that of calcium carbonate; however,because it also increases aluminum absorption from the GI tract, its use is not recommended in patients with kidney disease.

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Hyperphosphatemia (contin.)Sevelamer hydrochloride (Renagel) or carbonate (Renvela): binds dietary phosphorus in the GIT.In addition it decreases LDL levelSevelamer hydrochloride may increase incidence of acidosis, while carbonate may increase the bicarb level.

Lanthanum carbonate (Fosrenol): It dissociates into a trivalent cation with similar binding capacity as aluminum salts. Supplied as chewable tab. & excreted in bile

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Take home quizNew phosphate binders other than sevelamer & lanthum??????

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Hypocalcemia IV Calcium gluconateOral calcium salts. Calcium carbonate, chloride, gluconate, or lactate in mild hypocalcemia 56Hyponatremia Moderate or asymptomatic hyponatremia: fluid restriction.severe hyponatremia (serum Na < 120 mEq/L): 3% - 5% NaCl slow IV inf. Metabolic acidosis Na bicarb. may be given if the arterial pH is < 7.35

In hyponatremia: (Normal serum sodium level actual serum sodium level) total body water(ii) Typically, 400 mL or less is administered.

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Fluid overload & edemaDiuretics (Mannitol or loop diuretic ) & dopamine may be given to fluid volume excess & edema.

Treatment should be initiated as soon as possible after oliguria begins.

NB.: Avoid Thiazides because they are ineffective when CLcr is less than 25 mL/min, they may worsen AKI.57

Loop diuretics:Mechanism of action. Inhibit NaCl reabsorption at the loop of Henle, water excretion

Onset & duration of action Onset: orally (1 hr); IV (several minutes) Duration of action: orally (is 6 - 8 hrs); IV (2- 3 hrs).58

Oral furosemide therapy should be avoided because gut edema may limit its bioavailability.58

Types of loop diuretics:FurosemideBumetanideTorsemide Ethacrynic a. The most commonly used,

Used IV in AKI. The usual initial dose is 1.0 - 1.5 mg/kg. If the 1st dose does not produce UO of 10-15 mL within 30 mins, a dose of 2 - 3 mg/kg is given; if the desired response still does not occur, a dose of 3-6 mg/kg is given 30 mins after the 2nd dose.If unresponsive or allergic to furosemide.IV or IM in the ttt of AKI, 0.5-1.0 mg/day; up to 20 mg/day. A 2nd or 3rd dose may be given at intervals of 2-3 hrs.

Orally, 0.5-2 mg/day, repeat up to 2 times, if needed, every 2 - 3 hrs.If unresponsive to or allergic to furosemide. IV, 20 mg, & may be increased by doubling up to 200 mg; 10-20 mg of torsemide = 40 mg of furosemide = 1 mg bumetanide.

Better OBA compared to other loop diuretics; but, it is more expensive.Less commonly used because ototoxicity. given to patients who are allergic to sulfa. It may be given IV (slowly for several minutes) 50-100 mg.

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SE & monitoring of loop diureticsHpokalemia , Hyponatremia , Hypomagnesemia, Hypochloremic alkalosis (monitor electrolytes) Hyper uricemia , Hyper glycemia (monitor glu in DM), Hyper lipidemia , Hyper sensitivity

Decrease calcium, Deafness (esp with rapid IV), Dehydration (monitor BP), Disturbance of GIT

Drug interaction: Aminoglycoside potentiate the ototoxicity of loop diuretic.NSAIDs antagonize the diuretic response.Ethacrynic acid potentiate warfarin anticoagulants.

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Ethacrynic acid is highly bound to pp

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Mannitol Mechanism of action. the osmotic pressure in Blood hypervolemia RBF & GFR Glomerular filtrate urine flow. Used to prevent AKI in high-risk patients, such as those undergoing surgery.

Onset of action: 15-30 mins. Duration of action is 3-4 hrs.

Administration and dosage. is available in solutions ranging from 5% - 25%. Initial dose (12.5- 25.0 g) IV; the maximum daily dose is 100 g.61

Mannitol (contin.)SE. & MONITORING:A. Hypervolemia & hyponatremia:due to osmotic effect in Bl.V. This effect can lead to water intoxication: complicate HF & pulmonary edema. Headache, confusion, blurred vision, nausea, & vomiting.

B. Dehydration, Hyperkalemia, & HypernatremiaExcessive use of mannitol can lead to severe dehydration, hypernatremia & hyperkalemia. (monitor electrolytes)

CI:anuria, pulmonary edema or congestion, intracranial hemorrhage.

severe dehydration, 62

As water is extracted from cells, intracellular K+ concentration rises, leading to cellular losses and hyperkalemia62

Diuretic resistance in AKICauses of Diuretic ResistancePotential Therapeutic Solutions1- Na intake (dietary, IV fluids, drugs)Remove Na from diet & medications2- Inadequate diuretic dose or inappropriate regimen dose, use continuous infusion or combination 3- Reduced OBA (usually furosemide)Use parenteral therapy; Switch to oral torsemide or bumetanide4- Nephrotic syndrome (loop diuretic protein binding in tubule lumen) dose, switch diuretics, use combination therapy5- Reduced renal blood flowDrugs (NSAIDs, ACEIs, vasodilators)HypotensionIntravascular depletionDiscontinue these drugs if possibleIntravascular volume expansion and/or vasopressorsIntravascular volume expansion6- sodium resorptionNephron adaptation to chronic diuretic therapyNSAID useHeart failure

CirrhosisCombination diuretic therapy, sodium restrictionDiscontinue NSAIDTreat HF, diuretic dose, switch to better-absorbed loop diureticParacentesis7- ATN dose of diuretic, diuretic combination therapy;

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Metolazone is used in combination with loop63

Continuous infusions Vs intermittent boluses. Dosing of continuous inf.: Initial loading dose is given (equivalent to furosemide 4080 mg) prior to the initiation of a continuous infusion at 10 - 20 mg/h of furosemide or its equivalent

Advantage of continuous inf.:Less incidence of diuretic resistanceLess incidence of SE as ototoxicity & myalgia64

RRTIndications:Anuria, Acute fluid overload (acute pulmonary edema)

Metabolic Acidosis ( less than 7.2) severe hyperkalemia, BUN level above 100 mg/dL.65

PrognosisMortality rate: varies according to the cause (increase in intrinsic causes) The % increases in:multi-organ failure, (70%). over 60 years age.

Cause of Death: Death resulting from uremia and hyperkalaemia are very uncommon. The major causes of death are septicemia & intercurrent acute vascular events (as MI & stroke).

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High circulating levels of uraemic toxins that occur in AKI result in general debility. These, together with the significant number of invasive procedures such as bladder catheterisation and intravascular cannulation which are necessary in the management of AKI, leave such patients prone to infection and septicaemia. 66

NB.: Pseudorenal Kidney Injury in BUN or the SCr without in GFR due to: Cross-reactivity with the assay used to measure the BUN or SCr Drugs inhibiting the secretion of Cr (eg. Clavulanic acid, cephalexin, cephradin)

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in UO without real in GFR due to:Inaccurate method of measurementObesity 67

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GOOD LUCK

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