RENAL FAILURE 1. 2 ACUTE RENAL FAILURE Acute renal failure (ARF) Community-acquired Acute renal...

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NEPHROLOGY RENAL FAILURE 1

Transcript of RENAL FAILURE 1. 2 ACUTE RENAL FAILURE Acute renal failure (ARF) Community-acquired Acute renal...

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NEPHROLOGYRENAL FAILURE

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ACUTE RENAL FAILURE

Acute renal failure (ARF)Community-acquired Acute renal failureHospital-acquired Acute renal failureICU-acquired Acute renal failureMultifocal insult to kidney

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ACUTE RENAL FAILURE

Acute renal failure (ARF)

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Polycystic kidney disease

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Acute renal failure (ARF)• ARF or AKI is an acute decrease in

kidney function (GFR) over hours

associated with an accumulation of

nitrogen waste products and

(usually) volume.

ACUTE RENAL FAILURE

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ARF

Dec. of ≥ 25% in GFR

Inc. in SCr ≥ 0.5 mg/dl (in patient with normal renal

function )

Inc. in SCr ≥ 1 mg/dl (in patient with chronic kidney

disease)

Urine output less than 0.5 mL/kg/hour for more than 6

hours.

*Fluid overload

* Acid-base abnormalities

Inc. in BUN out of proportion to increases in the SCr.

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Urine output Classification:

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-better outcomes -easier to

manage

*Anuric < 50/24 hr

*Oliguric 50-500 mL / 24hrs

*Nonliguric > 500 mL / 24 hr

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ACUTE RENAL FAILURE

Community-acquired Acute renal failure

Hospital-acquired Acute renal failure

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2- Community-acquired Acute renal failure• Low incidence (<1%) and high survival rate of 70%-95%.• Single insult to the kidney• Reversible

3- hospital-acquired Acute renal failure• Moderate incidence(2%-5%)• Moderate survival rate 30%-50%.• Single or multifocal insults to the kidney.• Reversible.

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ACUTE RENAL FAILURE

ICU-acquired Acute renal failure

Multifocal insult to kidney

2007 American college of clinical pharmacy (ACCP)

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4- ICU-acquired Acute renal failure• High incidence (6%-23%)• Low survival (10%-30%)

5-Multifocal insult to kidneyPoorly reversible

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ACUTE RENAL FAILURE

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Estimating glomerular filtration rate

Formula for the Cockcroft-Gault

equation: Estimated creatinine clearance, or GFR =

[(140-Age) * Mass (in kg)] / [72 * Serum creatinine (in mg/dL)]

x 0.85 if female

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Cockcroft-Gault equation Difficult because commonly used

equations (Cockcroft-Gault and MDRD) are not appropriate

Use in stable SCr Brater and Jeliffe are probably more

accurate than the Cockcroft-Gault in ARF

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Estimating glomerular filtration rate in ARF-cont’d

GFR Calculator for Children

Schwartz Formula

GFR (mL/min/1.73 m2) = k (Height) / Serum Creatinine

k = Constant o k = 0.33 in Preemie Infants o k = 0.45 in Term infants to 1 year old o k = 0.55 in Children to 13 years o k = 0.65 in Adolescent males (Not females because of the presumed increase in male muscle mass. The constant remains .55 for females.)

Height in cm Serum Creatinine in mg/dl

LOINC® Technical Brief

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Estimating glomerular filtration rate in ARF-cont’d

Brater and Jeliffe equations more accurate than Cockroft-Gault equations but have not been vigorously validated in the literature. MDRD is not appropriate in ARF.

2007 American college of clinical pharmacy (ACCP)

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B-Jelliffe (mL/min/1.73 m 2)

Ess (males) = IBW x (29.3 -[0.203 x (age)])Ess (females) = IBW x (25.1 -[0.175 x (age)])

Esscorr = Ess x [1.035 - 0.0377(Scr)]      Scr  = If serum creatinine values are RISING, enter the most

RECENT SCR.  If SCR values are declining enter the AVERAGE VALUE between the two SCR values.

E = Esscorr - [4 x IBW x (Scr2-Scr1)] /  (Time difference in days)         

Scr2= latest serum creatinine.   Scr1= earlier serum creatinine.

CrCl (ml/min/1.73 M2) = E / (14.4 x Scr)

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A-Brater(mL/min/70 kg)

• CrCl =[293-2.03(age)] x [1.35-0.01685(SCr1+SCr2)] + 49(SCr1+SCr2) * 0.86 if F

(SCr1+SCr2) (SCr1+SCr2) ∆t day

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RISK FACTORS

Preexisting CKD (eGFR less than 60 mL/minute/1 .73m2)

Volume depletion—Vomiting, diarrhea, poor fluid intake, fever, diuretic use

Effective volume depletion – CHF, liver disease with ascites

Obstruction of the urinary tract

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RISK FACTORS

Use of nephrotoxic medications Intravenous radiographic contrast Aminoglycosides, amphotericin NSAIDs and COX-2 inhibitors ACEIs and ARBs Cyclosporine and tacrolimus

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RISK FACTORS ACUTE RENAL FAILURE

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NONMODIFIABLE

GENETICS

DIABETES

HYPERTENSION

AGE

INFECTION /SEPSIS

CANCER

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CLASSIFCATION OF ARF

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Pre-renal (functional) Renal (structural) Post-renal (obstruction)

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CLASSIFCATION OF ARF

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Pre-renal (functional)

Prerenal AKI Initially, the kidney is undamaged Characterized by hypoperfusion to the kidney Systemic hypoperfusion: Hemorrhage,

volume depletion, drugs, CHF Isolated kidney hypoperfusion: Renal artery

stenosis, emboli Urinalysis will initially be normal (no

sediment) but concentrated. Physical examination: Hypotension, volume

depletion

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Renal (structural)

Kidney is damaged. Damage can be linked to structure involved: Small blood vessels, glomeruli, renal tubules, and interstitium

Most common cause is ATN and others AIN, vasculitis, and acute glomerulonephritis

Urinalysis will reflect damage Urine generally not concentrated Physical examination: Normotensive,

euvolemic, or hypervolemic; check for signs of allergic reactions or embolic phenomenon

History: Identifiable insult, drug use, infections

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Post-renal (obstruction)

Kidney is initially undamaged Bladder outlet obstruction is the most common Lower urinary tract obstruction may be caused by

calculi Ureteric obstructions cause by clots or intraluminal

obstructions Extrarenal compression cause postrenal disease Increased intraluminal pressure upstream of the

obstruction will result in damage if obstruction is not relieved

PE: Distended bladder, enlarged prostate History: Trauma, benign prostatic hypertrophy,

cancers

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Prevention of AKI

Avoid nephrotoxic drugs when possible. Ensure adequate hydration. Patient education

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Treatment and Management of Established AKI

Prerenal azotemia: Correct primary hemodynamics Normal saline if volume depleted Pressure management if needed Blood products if needed

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Postrenal azotemia

Relieve obstruction. Early diagnosis is important. Consult urology and/or radiology

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Intrinsic:

No specific therapy universally effective Eliminate the causative hemodynamic

abnormality or toxin. Avoid additional insults. Fluid and electrolyte management.

Prevent volume depletion or overload and electrolyte imbalance

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Medications used in AKI

Fenoldopam and Atrial natriuretic peptide : May reduce need for renal replacement therapy (RRT) and in-hospital mortality

Loop diuretics: Consider loop diuretics for patients who are

Oliguric , euvolemic or hypervolemic. Diuretic does not reduce mortality or improve

renal recovery but may assist in fluid/ electrolyte management.

Given intravenously at relatively high doses Low-dose dopamine. Ineffective. Avoid

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Dialysis (RRT)

Renal replacement therapy—Indications BUN greater than 100 Volume overload unresponsive to

diuretics Uremia or encephalopathy Life-threatening electrolyte imbalance e.

Refractory acidosis

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Prevention of ARF Avoid nephrotoxic drugs.

Hydration : 0.9% NACL.

Pt. education

*Tight glycemic control 80-110 mg/dl using

insulin

(reduce ARF by 41%) Also reduce infection,

days on mechanical ventilation and ICU

length of stay.

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A-Fluid management- Maintain renal perfusion & production of urine

- Diuretic therapy: (consider of Pt. who are oliguric and euvolemic, or

hypervolemic)

B. Loop diuretic: bumetanide-furosemide-torsemide –ethacrynic acid

Parenteral therapy Furosemide intermittent therapy:40-80 mg IV q 6-8

hrs Furosemide continous inf.: 40-80 mg IV bolus, then

10- 20 mg /hr Other diuretics: Thiazide - Metolazone -

Mannitol

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Treatment and management of Established ARF

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Acidosis

1) Restrict dietary protein (< 0.5 g/kg/day of high quality protein

2) Sodium bicarbonate to maintain bicarbonate (HCO3 ) > 15 meq /L and arterial P 7.2

3) Dialysis

Electrolyte and nutrition abnormalities

ACUTE RENAL FAILURE

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Treatment and management of Established ARF

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Renal Damage

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DRUG-INDUCED KIDNEY DAMAGE

Drugs are responsible for kidney damage through many mechanisms

Evaluate potential drug-induced nephropathy based on the period of ingestion, patient risk factors, and the propensity of the suspected agent to cause kidney damage

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Renal Damage

Idiosyncratic reaction: not predictable Predictable reactions : High dose Risk factors Epidemiology Kidney at risk Pseudo drug – induced nephropathy

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Predictable reactions – based PK and Pt. risk factors

-Hypoperfusion/ischemia -Inflammation -Direct cellular damage

Risk factors -Prior history of CKD -Increased age

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ACUTE RENAL FAILURE

Cont’d

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Renal Damage

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Epidemiology

7% of all drug toxicities 18%–27% of AKI in hospitals 1%–5% of NSAID users in community Most implicated medications: Aminoglycosides NSAIDs, ACEIs Contrast dye Amphotericin

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Why kidney at risk

High exposure to toxin: Kidney receives 20%–25% cardiac output

High intrarenal drug metabolism Tubular transport processes Concentration of solutes (i.e., toxins) in

tubules High-energy requirements of tubule

epithelial cells Urine acidification

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Pseudo drug- induced nephropathy

Drugs that inhibit Cr tubular secretion: Triamterene; cimetidine

Drugs that increase BUN: Corticosteroids; tetracycline

Drugs that interfere with Cr assay: Cefoxitin and other cephalosporins

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Acute Tubular Necrosis

Most common drug-induced kidney disease in the inpatient setting

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1-Aminoglycoside nephrotoxicity (1.7 % - 58 % )

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Pathogenesis

-Proximal tubule damage (obstruction of the lumen)-Cationic charge of drug bind to tubular epithelial cells and uptake into those cells-Accumulation of phospholipids & toxicity

Presentation

-↑ CRs & ↓ GFR after 6-10 days of therapy- Non-oliguric RF- Wasting of K+ and Mg 2+

Acute Tubular Necrosis(ATN)

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1-Aminoglycoside nephrotoxicity

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ACUTE RENAL FAILURE

Risk factors

•Relating to dosing (accumulation, prolonged therapy, high conc.>2mg/L•Concurrent use of other nephrotoxins•Pt. pre-existing renal insufficiency (age-poor nutrition-shock- gram negative bact )•Liver disease-↓Albumin, obstructive jaundice, dehydration•↓K+ - ↓Mg 2+

Prevention

-Avoid in high risk Pt.-Adequate hydration-↓ the total cumulative aminoglycoside dose-Avoid other nephrotoxins-Use of extended interval (once daily) dosing.

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE

2. Radiographic contrast media nephrotoxicity (IV contrast)

• 3rd leading cause of inpatient ARF • 2 % - 50 % (incidence)• * Hospital mortality rate 34 %

Radiographic contrast media nephrotoxicity Consists of •Iso-osmolar (300 mOsm/kg)•low-osmolar (780–800 mOsm/kg)•high-osmolar (more than 1000 mOsm/kg) agents• Also categorized as ionic versus nonionic

Acute Tubular Necrosis(ATN)

2007 American college of clinical pharmacy (ACCP)

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ACUTE RENAL FAILURE

Pathogenesis

•Direct tubule toxicity due to reactive oxygen species•Renal ischemia•Hyperosmolar contrast >900 mOsmo/Kg→ osmotic diuresis → dehydration )•Hypotension•Renal vasoconstriction

Presentation

-Transient osmotic diuresis followed by tubular proteinuria-↑SCr & peak after 2-5 days-50 % of Pt. Oliguria & some will require dialysis

2. Radiographic contrast media nephrotoxicity (IV contrast)

Acute Tubular Necrosis(ATN)

2007 American college of clinical pharmacy (ACCP)

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ACUTE RENAL FAILURE

Risk factors

•Diabetes mellitus, Pre existing kidney disease•Volume depletion•Age older than 75 years•Anemia •Conditions with decreased blood flow to the kidney (e.g., CHF)•Hypotension•Other nephrotoxins•Large doses of contrast (more than 140 mL)

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE

Prevention

•Hydration: IV NS•Begin 6–12 hours before procedure.•Maintain urine output greater than 150 mL/hour•Discontinue nephrotoxic agents. Avoid diuretics.•Use low-osmolar or iso-osmolar contrast agents in patients at risk

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE

Prevention contrast-induced nephropathy

Non Emergency (elective)

(A) NS or ( NaHCo3 in 5% Dex. ) *Before Procedure 1-3 mL/kg/hr for 6-12 hrs *After Procedure 1 mL/kg/hr

(B) Acetylcysteine *Before Procedure 600 mg orally 2 time/day for 2dosese *After Procedure 600 mg orally 2 time/day for 2dosese

2-Radiographic contrast media nephrotoxicity (IV contrast)

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE

Prevention contrast-induced nephropathy

Emergency procedures

NaHCO3 in 5% Dex. ) 145mEq/L (unless alkalosis; then give NS)IV 3 mL/kg/hr 1hr before to procedure Continue fluids 1mL/kg/hr for 6 hr (NaHCO3)Continue fluids 1mL/kg/hr for 12 hr (NS)Ascorbic acid *Before procedure 3 g *After procedure 2 g 2 times/day for

2 doses

2-Radiographic contrast media nephrotoxicity (IV contrast)

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE

Pathogenesis

•Tubule cellular damage•Eventual loss of GFR &impaired distal tubular function

Presentation

•SCr peaks 10-12 days after starting therapy•↓ Renal magnesium (sever with CNS symptoms)•Hypokalemia and hypocalcemia•Irreversible kidney damage

3-Cisplatin and Carboplatin nephrotoxicity •6 % - 13 % with appropriate dosing and administration

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE

Risk factors

*Multiple courses of cisplatin * Pt. age *Dehydration*Concurrent nephrotoxins *Renal irradiation*Alcohol abuse

Prevention

•Avoid concurrent nephrotoxins•Low dose and dec. frequency of administration •Aggressive IV hydration 1-4 liters within 24 hrs of high dose of cisplatin or carboplatin•Amifostine (cisplatin chelating agent)

3-Cisplatin and Carboplatin nephrotoxicity 6 % - 13 % with appropriate dosing and administration

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE

Pathogenesis

* Direct proximal & distal tubular toxicity→ ↑ tubular permeability and necrosis with arterial vasoconstriction and ischemic injury*↑Tubular permeability →↑ cellular energy vasoconstriction leads to ↓ oxygen delivery

Direct proximal and distal tubular toxicityArterial vasoconstriction

Presentation

•loss of tubular function lead to electrolyte wasting(K , Na and Mg)•↑SCr & ↓GFR (↓ renal blood flow from vasoconstriction)

4-Amphotericin B nephrotoxicity (80% with cumulative doses of ≥ 4 g)

Acute Tubular Necrosis(ATN)

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Risk factors

•Existing renal dysfunction •High dose•Diuretic use •Volume depletion •Concomitant nephrotoxins •Rapid infusion

Prevention•Avoid other nephrotoxins (cyclosporine) •Limit total cumulative dose•IV hydration (1 L/day) 0.9% NaCL prior to each dose

4-Amphotericin B nephrotoxicity (80% with cumulative doses of ≥ 4 g)

Acute Tubular Necrosis(ATN)

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ACUTE RENAL FAILURE 57

Results from a decrease in intraglomerular pressure through the vasoconstriction of afferent arterioles or the vasodilation of

efferent arterioles

Hemodynamically –mediated renal failure

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Decrease in intraglomerular pressure:

A. From vasoconstriction of afferent arterioles

B. From vasodilatation of efferent arterioles

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ACEI ARBS

NSAID

CYCLOSPORIN TACROLIMUS

Hemodynamically –mediated renal failure – Cont’d

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1. ACE-inhibitor & ARBS

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ACUTE RENAL FAILURE Hemodynamically –mediated renal failure – Cont’d

Pathogenesis

*Angiotensin II’s effects of vasoconstriction of the efferent arteriole are reduced with ACE inhibitor or ARB therapy *leads to a decrease in glomerular hydrostatic pressure and cause decrease in GFR

Presentation

Reduction in GFRSCr rise by up to 30 %(A)Usually occurs within 2-5 days(B)Usually stabilize in 2-3 weeks(C)Increases > 30% may be

detrimental(D)Usually reversible upon drug

discontinuation

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1. ACE-inhibitor & ARBS-Cont’d

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ACUTE RENAL FAILURE Hemodynamically –mediated renal failure – Cont’d

Risk factors

•RF for toxicity: •Pt. with bilateral (unilateral with a solitary kidney) renal artery stenosis•Decreased effective renal blood flow (CHF, cirrhosis)•Pre-existing kidney disease and volume depletion

Prevention

*Initial therapy with low doses of short-acting drugs and gradually titrate upward*Switch to long-acting drug once tolerance is established*Monitor renal function and SCr level frequently(daily for inpatient) Weekly for outpatient*Avoid use of concomitant diuretics if possible during initiation of therapy.

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2.NSAIDS Incidence: estimates indicate that 500,000 to 2.5 million people develop NSAID-induced nephrotoxicity annually in the united

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Pathogenesis

*Vasodilatory prostaglandins help maintain glomerular hydrostatic pressure via afferent arteriolar dilation, especially in time of ↓ renal blood flow*Administration of an NSAID in the setting of decreased renal perfusion reduces this compensatory mechanism by ↓ the production of prostaglandins

Presentation

*Can occur with days of starting therapy*Pt. generally have low urine volume and sodium and an increase in BUN, SCr, K, edema, and weight.

Hemodynamically –mediated renal failure – Cont’d

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2.NSAIDS-Cont’d

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ACUTE RENAL FAILURE Hemodynamically –mediated renal failure – Cont’d

Risk factors

•*Pre-existing renal disease, system lupus erythematosus (SLE)•Pt. with high plasma renin activity (e.g. CHF, hepatic disease), diuretic therapy, artherosclerotic disease, and the elderly

Prevention

*Use therapies other than NSAIDs when appropriate *Sulindac is a potent NSAID that may affect renal prostaglandin synthesis to a lesser extent than other NSAIDs.*Question the utility of COX-2 specific inhibitors; have not been found to prevent renal dysfunction and increase cardiovascular complications.*If NSAID-induced ARF is suspected, discontinue drug and give supportive care. Recovery is usually rapid.

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63

ACUTE RENAL FAILURE Hemodynamically –mediated renal failure – Cont’d

3.CYCLOSPORINE AND TACROLIMUS

•The 5-year risk of developing CKD after transplantation of a non-renal organ ranges from 7% to 21%.•The occurrence of kidney failure in the transplant patient population has a 4-fold increased risk of death.

2007 American college of clinical pharmacy (ACCP)

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i

64

ACUTE RENAL FAILURE Hemodynamically –mediated renal failure – Cont’d

3.CYCLOSPORINE AND TACROLIMUSPathogenesi

s *Results from a dose-related hemodynamic mechanism*Causes vasoconstriction of afferent arterioles through possible ↑↑↑activity of various vasoconstrictors (thromboxane A2, endothelin, sympathetic nerveous system) or ↓activity of vasodilators (nitric oxide, prostacyclin)*↑vasoconstriction from angiotension II may also contribute*Effects usually resolve with dose reduction.

Presentation

*Can occur within days of starting therapy*SCr rises and GFR ↓↓*Pt. often have HTN ↑K and ↓ Mg*Biopsy is often needed for renal transplant pt. to distinguish this from acute allograft rejection

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65

ACUTE RENAL FAILURE Hemodynamically –mediated renal failure – Cont’d

3.CYCLOSPORINE AND TACROLIMUS

Risk factors

*Increased age, high initial cyclosporine dose, renal graft rejection, hypotension, infection, and concomitant nephrotoxins

Preventio

n

*Monitor serum cyclosporine and tacrolimus levels closely*Use lower doses in combination with other non-nephrotoxic immunosuppressant *Calcium channel blockers may help antagonize the vasoconstrictor effects of cyclosporine by dilating afferent arterioles.

2007 American college of clinical pharmacy (ACCP)

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Tubulointerstitial Disease

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Tubulointerstitial Disease

Involve the renal tubules and surrounding interstitial area.

Can be acute or chronic in onset : Acute onset generally involves interstitial

inflammatory cell infiltrates, rapid loss of renal function, and systemic symptoms (i. e. fever, rash) .

b . Chronic onset shows interstitial fibrosis, show decline in renal function, and no systemic symptoms.

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1-Acute Allergic Interstitial Nephritis

Cause for up to 3 % of all cases of ARF Results from an allergic hypersensitivity

reaction that affects the interstitium of the kidney .

Idiosyncratic reaction, so no risk factors are necessary

Various drugs can cause this type of renal failure .

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1-Acute Allergic Interstitial Nephritis

Penicillins : Classic presentation of AIN Signs/ sysmptoms occur about 1-2 weeks

after initiation of therapy and include fever, maculopapular rash, eosinophilia, pyuria, hematuria and proteinuria. Eosinophiluria may to also be present .

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1-Acute Allergic Interstitial Nephritis

NSAIDs: Onset is much more delayed typically

occurring around 6 months into therapy Usually occurs in elderly patients on

chronic NSAID therapy Patients usually do not have systemic

symptoms .

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1-Acute Allergic Interstitial Nephritis

Renal biopsy may be needed to confirm diagnosis

Treatment includes stopping the offending drug and possibly initiating steroid therapy

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Chronic interstitial nephritis : Often progressive and irreversible Lithium . i . Toxicity results from a dose-related

decrease in response to antidiuretic hormone

ii . ARF from lithium usually occurs during acute lithium intoxication

Patients become dehydrated secondary to nephrogenic diabetes insipidus.

There is also direct damage to the proximal and distal tubules

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Lithium

Risks include elevated serum levels and repeated episodes of ARF from lithium toxicity

Prevention is accomplished by maintaining lowest serum lithium levels possible, avoiding dehydration and monitoring renal function closely

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Chronic interstitial nephritis :

Cyclosporine : Presents later into therapy (about 6- 12

months) than hemodynamically mediated toxicity

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3-Papillary necrosis :

Form of chronic interstitial nephritis affecting the renal papillae, causing necrosis of the collecting ducts.

Results from the long-term use of analgesics . "Classic" example was with products that

contained phenacetin. Evolves slowly over years Affects women more than men . Difficult to diagnose and much controversy

still remains regarding risk, prevention, and cause.

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Obstructive Nephropathy

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Obsrtuctive Nephropathy :

Results from obstruction of the flow of urine after glomerular filtratioin.

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Renal tubular obstruction Caused by intratubular precipitation of tissue

degradation products or precipitation drugs or their metabolites .

Tissue degradation products: Uric acid intratubular precipitation after tumor

lysis following chemotherapy Drug-induced rhabdemolysis to intratubular

precipitation of myoglobin Results in rapid decline in renal function with

resultant oliguric or anuric renal failure

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Renal tubular obstruction Drug precipitation : Sulfonamides, methotrexate, acyclovir,

ascorbic acid Can be diagnosed by observing needle-like

crystals in leukocytes found on urinalysis . Prevention includes pretreatment hydration,

maintaining high urinary volume, and alkalinization of the urine

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Extrarenal urinary tract obstruction :

BPH can be worsened by anticholinergic drugs

Bladder outlet or ureteral obstruction from fibrosis following cyclophophamide for hemorrhagic cystitis

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4 . Nephrolithiasis :

Usually does not affect GFR, so does not have classis signs/symptoms of nephrotoxicity

Few drugs contribute to the formation of kidney stones: triamterene, sulfadiazine, indinaver, and ephedrine derivatives

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Glomerular Disease

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Glomerular Disease Proteinuria is the hallmark sign of glomerular

injury and may occur with or without a decrease in GFR.

A few distinct drugs can cause glomerular injury .

Heroin : Can be caused by direct toxicity or toxicity from additives or infection from injection.

Parenteral gold: results from immune complex formation along glomerular capillary loops .

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Common Neprotoxins and site of injury :

Tubular epithelial cell damage Tubulointerstitial disease :Acute tubular necrosis Acute allergic interstitial nephritis Aminoglycoside antibiotics Penicillins Radiographic contrast media Ciprofloxacin Cisplatin/ carboplatin Nonstreroidal ani-inflammatory drugs Amphotericin BOsmotic nephrosis Omeprazole Mannitol Furosemide Dextrin Chronic interstitial nephritis Intravenous immunoglobulin CyclosporineHemodynamic ally-mediated Lithiumrenal failure Aristolochic acid Angiotensin-converting Papillary necrosis enzyme inhibitors Combined phenacetin, aspirin, Angiotensin II receptor and caffeine analgesicsantagonists Nonsteroidal anti-inflammatory drugs

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Obstructive nephropathy Renal vasculitis, thrombosis, and

Intratubular obstruction Cholesterol embolic

Acyclovir Vasculitis and thrombosis

Sulfadiazine Hydralazine

Indinavir Propylthiouracil

Foscarnet Allopurinol

Methotrexate penicillamine

Extrarenal obstruction Gemcitabine

Tricyclic antidepressant Mitomycin C

Indinavir Methamphetamines

Nephrolithiasis Cholesterol emboli

Triamterene Warfarin

Indinaver Thrombolytic agents

Glomerular Disease Pseudo –renal failure

Gold Corticosteroids

NSAIDs Trimethoprim

Pamidronate Cimetidine

Common Neprotoxins and site of injury :

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CHRONIC KIDNEY DISEASE (CKD)

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CHRONIC KIDNEY DISEASE (CKD):

Background : Kidney disease is in underreported and

undertreated in the United States. In 1984, there were fewer than 100.000 persons with end-stage kidney disease requiring. In 2004, there were about 472.000 patients with ESRD ( 335.000 on maintenance dialysis).

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CHRONIC KIDNEY DISEASE (CKD):

The number of persons with earlier stages of kidney disease has increased

It is estimated that 10.9 % of adults in the United States have CKD

The National Kidney Foundation Kidney Disease Outcome Quality Initiative Advisory Board recommends a definition of CKD and staging guidelines

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CHRONIC KIDNEY DISEASE (CKD)

Definition : Kidney damage for > 3 months, as

defined by structural or functional abnormality of the kidney, with or without decreased GFR, manifested by either pathologic abnormalities; or markers of kidney damage, including abnormalities in the composition of blood or urine, or abnormalities in imaging tests

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CHRONIC KIDNEY DISEASE (CKD)

Definition : GFR < 60 mL/minute/1.73 m2 for > 3

months, with or without kidney damage

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CHRONIC KIDNEY DISEASE (CKD)

Stages of CKD :

Stage 1 kidney damage with normal or increased GFR (GFR= 90 mL/ minute/ 1.73 m2).

Stage 2 kidney damage with mild decrease in GFR (GFR=60- 89 mg/ minute/ 1.73 m2) .

Stage 3 moderate decrease in GFR (GFR 30- 59 mL/ minute/ 1.73 m2).

Stage 4 severe decrease in GFR (GFR 15- 29 Ml/ minute/ 1.73 m2).

Stage 5 kidney failure (GFR< 15 mL/minute/ 1.73 m2 or on dialysis).

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CHRONIC KIDNEY DISEASE (CKD)

Etiology : Diabetes (40% of new cased of ESRD in USA) b . Hypertension (25 % of new cases) Glomerulonephritis (10 %) . Others : urinary tract disease, polycystic

kidney disease, lupus, analgesic nephropathy, unknown

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CHRONIC KIDNEY DISEASE (CKD)

Risk Factors for kidney disease :

Susceptibility :advanced age, reduced kidney mass and low birth weight, racial/ ethnic minority, family history, low income or education, systemic inflammation, dyslipidemia.

Initiation : diabetes, hypertension, autoimmune disease, polycystic kidney diseases drug toxicity.

Progressing : hyperglycemia, elevated blood pressure, proteinuria, smoking

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CHRONIC KIDNEY DISEASE (CKD)

Albuminuria/ proteinuria : Marker of kidney damage and

cardiovascular (CV) risk factor. Definitions : Normal albumin excretion < 30 mg/24

hours Microalbuminuria 30- 300 mg/ 24 hours Macroalbuminuria (overt proteinuria) >300

mg/24 hours Nephrotic range proteinuria > 3 g/24

hours.

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CHRONIC KIDNEY DISEASE (CKD)

Assessment for Proteinuria : Spot urine : untimed sample is adequate for

adults and children (screening test) First morning urine specimen preferred Urine dipstick Confirm positive dipstick tests (+ 1 or

greater) with quantitative tests (albumin: creatinine ratio)

Proteinuria is confirmed by 2 or more quantitative tests (1-2 weeks apart) .

Monitor proteinuria with quantitative tests

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CHRONIC KIDNEY DISEASE (CKD)

Factors that can interfere with testing for abluminuria/ proteinuria :

Fluid balance : dehydration (+) fluild overload (-) Hematuria (+) Exercise (+) Urine proteins other than albumin (-) Drugs that increase urine PH>6 (+)

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CHRONIC KIDNEY DISEASE (CKD)

Assessment of Renal Function (GFR) : Measurement of GFR : Inulin, iothalamate and others not routinely used Measurement of CrCl via a urine collection Reserve for vegetarians, patients with low

muscle mass, amputation, dietary assessment and documentation of need to start dialysis .

In most cases, equations will overestimate renal function because cretonne levels will be low in patients with very low muscle mass. Urine collection will give a better estimate in these patients .

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CHRONIC KIDNEY DISEASE (CKD)

Assessment of Renal Function (GFR) : Serum creatinine: Avoid use as sole assessment of renal

function Dependent no age, sex, weight, muscle

mass

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CHRONIC KIDNEY DISEASE (CKD)

Calculated using Cockcroft and Gault (mL/min CrCl) – overestimates GFR .

(140- age) x ideal body weight (IBW)/ (SCr x 72) x (0.85 if female)

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CHRONIC KIDNEY DISEASE (CKD)

Estimated GFR using Modification of Diet in Renal Disease (MDRD) study data

Estimated GFR (mL/minute/ 1.73 m2) in patients with known CKD (<90 mL/minute) .

GFR (mL/minute/1.73 m2)= 186 x SCr -1.154 x Age -0.203 (0.742 if female) x (.21 if African – American) .

MDRD formulae are not validated in all population groups (validated in Caucasian/ African- American, men and women). Not studied in diabetes, pediatrics, elderly, or obese.

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CHRONIC KIDNEY DISEASE (CKD)

Children : Schwartz – Estimates creatinine clearance

(mL/minute) 0.55 x body length (in cm) /SCr . Counahan- Barratt – Estimates GFR

(mL/minute/ 1.73 m2). 0.43 x body length (in cm) /SCr .

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CHRONIC KIDNEY DISEASE (CKD)

Diabetic NephropathyPathogenesis : Hypertension (systemic and

intraglomerular) Glycosylation of glomerular proteins Genetic links Diagnosis : Long history of diabetes mellitus (DM) Proteinuria Retinopathy (suggests microvascular

disease).

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Diabetic Nephropathy Monitoring : Type I : Begin annual monitoring for

microalbuminuria 5 years for diagnosis Type II : Begin annual monitoring immediately

(don’t know long they’ve had DM)

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Diabetic Nephropathy Management/ Slowing Progression : Aggressive BP management : Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure (JNC) VII goal is < 130/80.

ACE inhibitors and ARBs are preferred, Drugs should be used with microalbuminuria even if patient is normo-tensive .

Calcium channel blockers are second line to ACE/ARBs. Data emerging for combined therapy

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Diabetic Nephropathy

Intensive Blood Glucose Control : Glycosylated Hb <7 % Protein Restriction – not good data in

diabetes. Patients should avoid high-protein diets

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CHRONIC KIDNEY DISEASE (CKD)

Non –diabetic Nephropathy : Manage hypertension . If proteinuric use ACE, ARB

Minimize protein in diet a . Controversial. May slow progression

based on Modification of Diet in Disease (MDRD) study but may also impair nutrition .

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CHRONIC KIDNEY DISEASE (CKD)

Other guidelines to slow progression:

Manage hyperlipidemia. follow NCEP guidelines

Goal LDL <100 Statins are first line Stop smoking

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RENAL REPLACEMENT THERAPY :

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RENAL REPLACEMENT THERAPY

Indications for Renal Replacement Therapy :

A – acidosis (not responsive to bicarbonate) . E – electrolyte abnormality (hyperkalemia;

hyperphosphatemia) . I – intoxication (boric acid; ethylene glycol;

lithium; methanol; Phenobarbital; salicylate; theophylline) .

O – fluid overload (symptomatic(pulmonary edema)).

U – uremia (pericarditis and weight loss) .

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RENAL REPLACEMENT THERAPY

Two Primary modes of dialysis . Hemodialysis – most common modality. Peritoneal Dialysis.

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RENAL REPLACEMENT THERAPY

Hemodialysis (Intermittent for ESRD) .

Access :a . Atreriovenous fistula Natural, formed by anastomosis of artery and

vein . Lowest incidence of infection and thrombosis,

lowest cost, longest survival . Takes weeks/ months to “mature”.

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RENAL REPLACEMENT THERAPY

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RENAL REPLACEMENT THERAPY

Hemodialysis (Intermittent for ESRD) .

Arteriovenous graft : Synthetic (polytetrafluoroethylene, or PFTE) Often used in patients with vascular disease

Catheters : Commonly used if permanent access is not

available Problems include high infection and

thrombosis rates. Low blood flows lead to inadequate dialysis

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RENAL REPLACEMENT THERAPY

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RENAL REPLACEMENT THERAPY

HemodialysisDialysis Membranes : High flux and High Efficiency : Large pores. Can remove some drugs that

were impermeable to standard membranes (vancomycin).

Large amounts of fluid removal (utrafiltrate).

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RENAL REPLACEMENT THERAPY

HemodialysisAdequacy :a . Kt/ v – unities parameter. K = clearance,

t=time on dialysis, and V is volume of distribution of urea. Kidney Disease Outcomes Quality Initiative (KDOQI) set goal of > 1.2 .

b . URR: urea reduction ration. URR=BUN post/BUN pre x 100% Goal 65 % .

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HemodialysisCommon complications of

hemodialysis :Intradialytic : Hypotension – Primarily related to fluid

removal. Common in elderly and diabetics . Treatment: Limit fluid gains between

sessions, give normal or hypertonic saline, midodrine.

Less well studied agents includes include fludrocortisones, selective serotonin reuptake inhibitors (SSRIs) .

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HemodialysisCommon complications of

hemodialysis :Intradialytic : Cramps – Vitamin E or Quinine

(controversial due to adverse effect profile) Nausea/ vomiting Headache/ chest pain/ back pain

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HemodialysisCommon complications of

hemodialysis :Intradialytic :Vascular access complications : Most

common – with catheters . Infection : Staphylococcus aureus. Need to

treat aggressively. May need pull catheter. Thrombosis: Suspected with low blood flows.

Oral antiplatelets for prevention not used due to lack of efficacy.

Can treat with alteplase I mg per lumen

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RENAL REPLACEMENT THERAPY

Factors That Affect Efficiency of Hemodialysis:

Type of dialyzer used (changes in membrane surface area and pore size)

Length of therapy Dialysis flow rate Blood flow rate Development of polarized protein layer

on the filter surface

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RENAL REPLACEMENT THERAPY

Continuous Hemodialysis for Acute Renal Failure:

CAVH/CVVH. Removes fluid and solutes by dialysis. CAVH differs from CVVH in that the “VV’ access requires an in-line pump. Used primarily when fluid removal is most important .

CVVHD/CAVDH. dialysate which flows in countercurrent to blood flow. Fluid and solute removal greater with this procedures. Used when there is a need for fluid removal and better solute clearance.

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RENAL REPLACEMENT THERAPY

Peritoneal Dialysis : Dialysis fluid may be instilled onto peritoneum (fill), allowed

to dwell for specified amount of time, and then drained . Solutes and fluids diffuse across peritoneal membrane. PD is usually not used to treat acute renal failure in adults.Peritonitis: Infection of peritoneal cavity, diabetic and elderly patients

have a higher infection rate, a major cause of PD failure. Treatment Most common Gram +ve organisms include S.aureus,

S.epidermis, Streptococci . most common Gram –ve organisms include E.coli and P.aeruginosa.

Empiric treatment should cover both Gram +ve & -ve bacteria. Adjust as needed.

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RENAL REPLACEMENT THERAPY

Types of peritoneal dialysis: CAPD. Classic, requires mechanical

process, can be interruptive to daytime routine.

Automated PD (APD). Many variants but continuous cycling PD (CCPD) most common. Patients undergo multiple exchanged during sleep via a cycling machine. Minimize potential contamination. Lowest incidence of peritonitis.

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Complications Of Chronic Kidney Disease

Anemia In CKD , anemia is generally treated with Hgb<11 g/dl. Several factors are

responsible for; decreased erythropoietin production (most important), shorter lifespan of RBCs, blood loss during dialysis, iron deficiency, anemia of chronic disease, renal osteodystrophy.

Prevalence : a . 67% of persons beginning dialysis have had a reported hematocrit <30 % . Signs and symptoms . a . Symptoms of anemia of CKD are similar to anemia associated with causes .

Anemia work –up : i . Hb/Hct . ii . MCV (mean corpuscular volume) . iii . Reticulocyte count . iv . Iron Studies . Transferrin saturation (total iron/ total iron binding capacity) – assesses iron . Ferretin – measures stored iron . v . Stool guaiac .

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AnemiaTreatment :

Erythropoietin receptor agonists Goal is to achieve target Hb 11 mg/dl . Most recent KDOQI

guidelines warn against intentional increasing HgB< 13 g/dL.

Epotein – a :

Binds to and activates erythropoietin receptor . May be administered SQ (subcutaneously), IV, or IP

(intraperitoneal). Initial dose 80- 120 units/kg/ week SQ divided into 2-3

doses/ week . Initial dose 120- 180 units/ kg/ week IV divided into 2-3

doses/ week . Higher doses are required for once a week dosing than for 2-

3 doses/ week/ dosing .

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AnemiaDarbepoetin-a Bind to and activates erythropoietin receptor

. May be administered SQ or IV . Initial dose 0.45 mcg/ kg weekly; typically 40

mcg . Dose adjustment is based on Hgb response. Adjustment parameters are the same for

epotein-a or darbepoetin-a . Dosage adjustments upward should not be

made more frequently than every 4 weeks .

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AnemiaMonitoring for effect : Both epoetin-a and darbepoeitn-a require

similar monitoring parameters. Monitor Hb initially every 1-2 weeks then

2-4 weeks when stable. Monitor BP as it may rise (treat as

necessary) . Iron stores . Ferretin : HD target is 200- 500, PD/CKD

target is 100- 500 . TSAT target is > 20 % (upper limit of 50%

removed from recent guidelines .

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AnemiaCommon causes of inadequate response to erythropoietin

therapy. Iron deficiency is the most common cause of EPO

resistance. Increased use of intravenous iron products has reduced the problem, however .

Other causes in patients with adequate stores (First three most common) :

Infection/ inflammation. Chronic blood loss. osteitis fibrosa. Aluminum toxicity . Hemoglobinopathies. Foliate or vitamin B12 Deficiency. Multiple myeloma. Malnutrition. Hemolysis. Vitamin C deficiency.

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Anemia Iron therapy : Most patients with CKD and receiving

erythropoietin therapy require parenteral iron therapy to meet needs (increased requirements, decreased oral absorption) .

Most adults require 1 g or more of elemental iron stores.

Iron stores usually replete several weeks . For adult dialysis patients, an empiric 100 mg dose

is usually given and equations are rarely used. Monitor transferrin saturation and Ferretin as

noted during erythropoietin therapy ) .

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Commercial Iron PreparationsIron Therapy

Iron Dextran Ferric Gluconate Iron Sucrose

Replacement therapy %TSAT< 20% and ferritin < 100- 200 mg/dL

IVP: 100 m IV 3 times/ week during HD for 10 doses (1 gram).

IVPB: 500- 1000 mg in 250 mL NSS infused over at least I hour (option for non hemodialysis patients)

125 mg IV 3 times/ week during HD for 8 doses (1 gram)

100 mg IV 3 times/ during HD for 10 doses (1 gram)

For non-dialysis CKD 200 mg IV X 5 doses

Maintenance therapy (iron stores in goal)

25- 100 mg/week IV X 10 Week

31.25- 125 mg/ week IV X 10 weeks

25- 100 mg/week IV x 10 weeks

Iron overload % TSAT > 50% and/ or ferritin> 500

Hold therapy Hold therapy Hold therapy

Initial test dose Yes. 25 mg one-time test dose

No No

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Oral iron products Available in the United States :

FerrousSulfate

Ferrous Gluconate

Ferrous Fumarate

PolysaccharideIron complex

Strength 300- 325 mg 325 mg 325 mg 150 mg

Elemental iron/ tablet

65 mg 38 mg 106 mg 150 mg

Usual dose 1 tablet PO TID 2 tablet PO TID 1 tablet PO BID 2 tablets/ day PO

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Renal Osteodystrophy And Secondary Hyperparathyroidism

Pathophysiology: Calcium and phosphorous homeostasis is complex; it involves the interplay of hormones affecting the bone, gastrointestinal tract, the kidneys and parathyroid hormone (PTH).

Process may begin as early as GFR 60 mL/minute. Most important force behind the process is hyperphosphatemia!

Nephron loss : decreased production of 1,25 dihydroxyvitamin D3 and phosphate retention .

Increased Phosphorous levels : Inhibition of activation of vitamin D, reducing

absorption of calcium in the gut . Decrease levels of ionized (free calcium) . Direct stimulation of PTH secretion .

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Renal Osteodystrophy And Secondary Hyperparathyroidism Elevated PTH Levels : Decreased reabsorption of phosphorus and

increased reabsorptin of calcium in proximal tube – this renal adaptive mechanism is lost as GFR falls below 30 mL/minute .

Important : calcium in not well absorbed through the gut at this point, and calcium levels are maintained by increased bone reabsorption via elevated PTH .

Unabated calcium loss from the bone results in renal osteodystrophy.

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Renal Osteodystrophy And Secondary Hyperparathyroidism

Prevalence : Major cause of morbidity and mortality in

patients undergoing dialysis. Is now aggressively treated with dietary

phosphate restriction, phosphate binders, and vitamin D analogs .

Signs and symptoms : Insidious onset : patients may complain of

fatigue, musculoskeletal and gastrointestinal complaints; calcification may be visible on x-ray; bone pain and fractures can occur if progression is left untreated .

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Renal Osteodystrophy And Secondary Hyperparathyroidism

Laboratory abnormalities : Phosphorus . Corrected calcium . Intact parathyroid hormone .

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Renal Osteodystrophy And Secondary HyperparathyroidismTreatment : Goals of therapy

KDOQI Guidelines for Calcium, Phosphorus, Ca x PO 4 product, and Parathyroid Hormone in CKD Stages 3-5

CKD Stage 3 CKD Stage 4 CKD Stage 5

Calcium (mg/Dl)* Normal Normal 8.4- 9.5

Phosphorus (mg/dL) 2.7- 4.6 2.7- 4.6 3.5- 5.5

Ca x PO4 product < 55 < 55 < 55

Parathyroid Hormone (pg/ Ml)

35- 70 70- 110 150- 300

* Use Corrected calcium = serum Ca+ (0.8 x (normal albumin – patient albumin)).

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Renal Osteodystrophy And Secondary Hyperparathyroidism

Treatment : Nondrug therapy : Dietary phosphorus restriction 800- 120

mg/day. Dialysis removes various amounts of

phosphorus depending on treatment modalities .

CAPD can remove – 300 mg/day . Conventional HD can remove 500- 700 mg/day

. High-flux HD can remove – 900 mg/day .

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Renal Osteodystrophy And Secondary Hyperparathyroidism

Drug therapy : 1- Phosphate binders : take with meals to bind

phosphorus in the gut; products from different groups are used together for additive effect .

a- Calcium – containing phosphate binders (calcium carbonate, calcium acetate) .

Considered initial binder of choice; relatively inexpensive. Also treat hypocalcaemia, which sometimes occurs in

patients with CKD . Calcium carbonate can also decrease metabolic acidosis . Use may be limited by development of hypocalcaemia . Total elemental calcium per day = 2000 mg/day( 1500-

mg binder; 500 – mg diet) .

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Renal Osteodystrophy And Secondary Hyperparathyroidism

b- Aluminum- containing phosphate binders (aluminum hydroxide, aluminum carbonate, sucralfate) .

Effectively lower phosphorus levels . Avoid. Not used as frequently due to aluminum toxicity

(adynamic bone disease, encephalopathy, and erythropoietin resistance) .

Deferoxamine chelation therapy may be required for aluminum toxicity .

c-Sevelamer : a nonabsorbable phosphate binder : Effectively binds phosphorus . Consider if calcium – phosphorus factor > 55 mg2/ dL2. Decreases LDL cholesterol and increases HDL cholesterol . Hypocalcaemia may occur if sevelamer is sole phosphate

binder.

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Renal Osteodystrophy And Secondary Hyperparathyroidism

d- Lanthanum carbonate : As effective as aluminum in phosphate

binding capability. Tasteless, chewable wafer . Consider if calcium x phosphorus product

>55 mg2/ dL2.

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Renal Osteodystrophy And Secondary Hyperparathyroidism

2-Vitamin D analogs: suppress PTH synthesis and reduce PTH concentrations ; therapy is limited by resultant hypocalcaemia, hyperphosphatemia and elevated calcium- phosphorus product; pulse therapy is preferred over daily therapy .

products include: calcitriol , Paricalcitol , Doxercalciferol

a-Calcitriol is the pharmacologically active from of 1,2 hydroxyvitamin D3, FDA label- approved for the management of hypocalcemia, and the prevention and treatment of secondary hyperparathyroidism .

Oral and parenteral formulations . Does not require hepatic or renal activation . Low-dose daily oral therapy reduces hypocalcemia, but

does not reduce PTH levels significantly .

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Renal Osteodystrophy And Secondary Hyperparathyroidism

b- Paricalcitol : vitamin D analog; FDA label-approved for the treatment and prevention of secondary hyperparathyroidism .

Parenteral and oral formulation . Does not require hepatic or renal activation . Less incidence of hypocalcaemia (decreased mobilization of

calcium from the bone and decreased absorption as frequent as every 2 weeks .

Dose adjustment as frequent as every 2 weeks . c-Doxercalciferol: vitamin D analog; FDA label-approved for the

treatment and prevention of secondary hyperparathyroidism . Parenteral and oral formulation . Pro-drug, requires hepatic activation; may have more

physiologic levels . Less incidence of hypocalcaemia (decreased mobilization of

calcium from bone and decreased absorption of calcium from gut.

Dose adjustments at 4-8 week intervals .

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Renal Osteodystrophy And Secondary Hyperparathyroidism

3- Cinacalcet HCL : attaches to calcium receptor on parathyroid gland, resulting in negative feedback suppression of PTH secretion .

Initial dose is 30 mg irrespective of patient PTH level . Monitor serum calcium every 1-2 weeks (risk of

hypocalcaemia ≈ 5%); do not start therapy if serum Ca < 8.4 mg/dL .

Can be used in patients irrespective of phosphate binder (important) or vitamin D analog use .

Caution in patients with seizure disorder (hypocalcaemia may exacerbate).

Adverse effects are nausea (30 %) and diarrhea (20 %) . CYP 2D6 metabolism: dose reductions in drugs with narrow

therapeutic indexes may be required (flecainide, tricyclic antidepressants, thioridazine) .

Ketoconazole increases cinacalcet concentrations up to 2-fold.

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY :

Dosages of many drugs will require adjustment to prevent toxicity in patients with CKD; adjustment strategies will vary depending on whether patient is receiving renal replacement therapy or not, and the type of renal replacement therapy

Pharmacokinetic Principles Can Guide Therapy Adjustments :

Absorption : a . Oral absorption can be decreased . Nausea and vomiting . Increased gastric PH (uremia) . Edema . Physical binding of drugs to phosphate binders .

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY :

Distribution : Changes in concentrations of highly protein bound and highly

water soluble drugs change as extracellular fluid status changes. Acidic and neutral protein bound drugs are displaced by toxin

build-up. Other mechanisms include conformational changes of plasma protein site .

Phenytoin is a classic example . Hypoalbuminemia correction . Conc. adjusted= Conc. measured / {(0.2 x measured albumin)+

0.1)} Renal failure adjustment . Conc .adjusted = Conc. measured / (0.1 x measured albumin)+

0.1). Patients will have lower total concentrations despite having

adequate free concentrations . Dosage adjustment of phenytoin not needed, just a different

approach to evaluating to evaluating level

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY :

Metabolism : Variable changes can occur with uremia . Metabolites can accumulate . Excretion : Decreased . Pharmacodynamic Changes Can Also

Occur . Patients with CKD can be more sensitive

to benzodiazepines. 

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY :

General Recommendations :Approach : Patient history and clinical data . Estimate CrCl (Joliffe or Brater in ARF;

Cockroft-Gault in stable renal function ) . Identify medications that require

modification

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Dose Adjustments in Decreased Renal Function

Agent Dose Adjustment

Antibiotics Almost all antibiotics will require dosage dosage adjustment (exceptions: cloxacillin, clindamycin, linezolid, metronidazole, macrolides )

Cardiac medications Atenolol,ACEIs, digoxin, nadolol, sotalol; avoid potassium- sparing diuretics if CrCl < 30 ml / min

Lipid-lowering therapy Clofibrate, fenofibrate, statins

Narcotics Codeine, avoid meperidine; other drugs may also accumulate .

Antipsychotic/ antiepileptic agents Chloral hydrate, gabapentin, lithium,paroxetine,primidone,topiramate,trazodone,vigabatrin

Hypoglycemic agents Acarbose, chloropropamide, glyburide, glipizide insulins, metformin.

Antiretrovirals Individualize therapy: monitor CD4 counts, viral load and adverse effects (agents requiring dose adjustment: lamivudine, adefovir, didanosine, stavudine, tenofovir, zalcitabine, zidovudine).

Miscellaneous Allopurinol, colchicines, H2-receptor antagonists, ketorlac, terbutaline

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY :

Calculate drug individualized for patient . Published data . Rowland – Tozer estimate . Q = 1 ( fe (1- KF) ) . Q = kinetic parameter or drug adjustment factor . Fe = fraction of drug renally excreted unchanged . Kf= ratio of patients CrCl to normal (120 mL/minutes) . Monitor patient (e.g., renal function; clinical parameters)

and drug concentration (if applicable) . Revise regimen as appropriate . Drug Dosing in Hemodialysis : Dosing changes in hemodialysis patients may be necessary

of accumulation due o kidney failure and/or because the procedure may remove drug from the circulation .

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY :

Drug-related factors affecting drug removal during dialysis :

Molecular weight- with high flux membranes larger molecules (like vancomycin) can be removed .

Water soluble – non soluble drugs not likely removed .

Protein binding – Because albumin cannot pass through membrane, neither can protein-bound drugs.

Volume of distribution – Drugs with small volume of distribution (Vd) (<1L/Kg) are available in central circulation for removal. Large Vd's can't be removed (digoxins, tricyclic antidepressants) .

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DOSAGE ADJUSTMENTA IN RENAL INSUFFICIENCY :

Procedure-related factors affecting drug removal :

Type of dialyzer- High flux widely used now .

Blood flow rate; increased rate will increase deliver and maintain gradient across membrane .

Duration of dialysis session . Dilaysate flow rate; high rate of flow will

increase removal by maintaining gradient across membrane .