lecture 14 - aki

Acute Kidney Injury

Warren Kupin M.D., FACP

Professor of Medicine

Co-Director Transplant Nephrology

University of Miami / Jackson Memorial Hospital

Diagnosis of Renal Disease

Acute Chronic

Acute Renal Failure (ARF) Chronic Renal Failure (CRF)

Acute Kidney Chronic Kidney Injury (AKI) Disease (CKD)


Acute Kidney Chronic Kidney Injury (AKI) Disease (CKD)

Change in Serum Creatinine Decrease in GFR (days to weeks) (>3 months)

or Change in GFR

Definitions

• Acute Kidney Injury (AKI)– Rapid deterioration in renal function resulting

in the accumulation of nitrogenous waste (BUN-Azotemia)• Days to weeks in development (< 3 months)

– Inability of the kidney to regulate electrolyte, acid-base and/or water homeostasis

– Factors not included in the definition• No specific level of

–BUN–Potassium

• Clinical signs or symptoms

Renal Disease : Definitions

• Chronic Kidney Disease (CKD)– An irreversible loss of renal function (nephron

number) that may or may not lead to End Stage Renal Disease (ESRD)

– Duration of kidney failure > 3 months• End Stage Renal Disease (ESRD)

– Irreversible renal failure of a magnitude that requires renal replacement therapy• GFR (glomerular filtration rate) – Creatinine

Clearance < 10 cc/min

Definitions

• Oliguria– < 400 cc of urine output in 24 hours

• Non- Oliguric– > 400 cc of urine output in 24 hours

• Anuric– < 100 cc of urine output in 24 hours

All the above adjectives are used to describe types of AKI – Oliguric AKI / Non- Oliguric AKI /Anuric AKI

Abbreviations/Definitions to Remember

• AKI

• CKD

• ESRD

Assessment of Renal Function (GFR)Glomerular Filtration rate

• Serum creatinine– Indirect predictor of GFR

• 24 hour Creatinine clearance – Measured GFR

• Mathematical Formulas– Calculated GFR

• Cockroft and Gault formula• MDRD

• Iothalamate clearance – Measured GFR

• nuclear radiology study

Serum Creatinine

• End product of muscle metabolism – Cyclic anhydride of creatine

(nonenzymatic)• Creatine is synthesized in the liver and

stored in muscle (CPK)–Also ingested orally and localized to

muscle• Renal excretion of Creatinine

– GFR - filtration– Tubular secretion

50%

50%

Creatine Creatinine

CPKCreatine phosphokinase

Energy source for muscles

Acute Renal Failure : Determination of GFR by the Serum Creatinine

• Secretion of creatinine– Proximal tubule– Organic cation secretory pathway– Accounts for 15% of urinary creatinine in

normal patients• Increased secretion in renal disease

–Accounts for 35-50% of urinary creatinine–Overestimates true function sinced the

blood level of creatinine will be lower than it really should be at any given GFR

Range of Creatinine Values in the Population

0

10

20

30

40

50

60

< 0.7 0.7 - 0.8 0.9 - 1.0 1.1 - 1.2 1.3 - 1.4 1.5 - 1.6 1.7 - 1.8 1.9 - 2.0

Male Female

The normal creatinine level is relative to muscle massWomen < 1.2 mg/dlMen < 1.5 mg/dl(represents 2 SD above the mean)

0.95 1.15

Acute Kidney Injury

• The accuracy of the serum creatinine measurement is variable so that an absolute change of 0.5 mg/dl is needed to be confident that a real change in renal function has occurred

Cr – baseline Cr – New levelMale 1.2 1.7 AKIFemale 0.9 1.4 AKIAny sex 2.4 2.9 AKI

on Chronic

Exceptions

• Rare cases where the baseline creatinine is very low and a rise of 0.5 mg/dl will not increase the creatinine above the critical levels of –1.2 mg/dl for a woman –1.5 mg/dl for a man

Exceptions

– Cirrhosis• Minimal protein intake with severe malnutrition• Liver failure with impaired creatine production

– Pregnancy• Volume expansion and an increase in GFR

– Extremes of age/nutrition – pediatric / elderly

– Baseline or “normal” creatinine in these conditions is < 0.6 mg/dl

– Patients can be in AKI in all these circumstances with serum creatinines of 1.1 mg/dl

The creatinine level is not an effective indicator of the degree of renal failure

The greatest loss of renal function occurs between a creatinine of 1 - 2 mg/dl

Creatinine is a poor predictor of GFR

12

6

The change in serum creatinine with kidney failure is exponential – not linear

Creatinine Loss of GFR

1 2 50%

2 3 17%

3 4 8%

4 5 5%

34

33

Determination of Renal Function

• It is essential that you use the range of normal values for the serum creatinine only as a relative guide

• You must use the clinical characteristics and underlying medical disease state (not cause of kidney disease) of each patient to determine what the normal range of creatinine for that patient should be

Assessment of Renal Function

• Serum creatinine• Creatinine clearance• Cockroft and Gault formula• Iothalamate clearance

Measurement of Renal Function

• 24 hour Creatinine Clearance– Overestimates true kidney function by 15% in

normal patients and by > 30% in patients with kidney failure• Creatinine is filtered but also secreted by

the tubules• Accuracy of 24 hour urine collections is not

proven–Retained urine in bladder–Timing errors of collection

24 Hour Creatinine Clearance

• Requires– Complete 24 hour urine collection

• Not morning to evening ! – Simultaneous measurement of

• Urine creatinine• Serum creatinine

• Clearance formula– (urine concentration) * (urine volume)

Plasma concentrationU V P

=


• Clearance formula– (urine concentration) * (urine volume)

Plasma concentration

• Example– 24 hour urine

• Urine Creatinine 140 mg/dl• Urine volume 1000 ml

– Plasma creatinine 1.0 mg/dldl = 100 cc


• Clearance formula– (140 mg/dl) * (1000 ml)

1.0 mg/dl

• Example– 24 hour urine

• Urine Creatinine 140 mg/dl• Urine volume 1000 ml

– Plasma creatinine 1.0 mg/dldl = 100 cc


• Clearance formula– (140 mg/dl) * (1000 ml)

1.0 mg/dl

– (140 mg/100 ml) * (1000 ml)

1.0 mg/100 ml

= (1400 * 100 ml ) / 1 = 140,000 ml / 24 hours

= 140 L / 24 hoursCr Cl is always expressed as ml/min


• How many minutes in a day ?? 1440 !!!

Therefore :

140,000 ml / 24 hours = 140,000/1440 minutes = 97 ml/min

That is the creatinine clearance !

Normal Cr Cl = 90 – 130 ml /min

Creatinine Clearance

• The most common mistake is to forget to include the minutes per day in the calculation

• The creatinine clearance is routinely expressed as

• ml / min

• A Cr Cl change of > 20 cc/min is an indication to evaluate for AKI


Acute Kidney Injury (AKI)

Serum Creatinine change of > 0.5 mg/dl Or

Change in GFR > 20 cc/min

(days to weeks, < 3 months)

Assessment of Renal Function

• Serum creatinine• Creatinine clearance• Formulas• Iothalamate clearance

Measurement of Renal Function

• Cockroft and Gault Formula– (140-age)*wgt (Kg) / (72 * cr)– Multiply by .85 for women

• Does not require any urine collection• Takes into consideration the importance of

– Age– Weight (muscle mass)– Sex (muscle mass)

Examples

• Cockcroft and Gault for creatinine = 2.0– Male 70 kg– Age 30– = (140-30)*70/(72 * 2.0) = 53 cc/min– Female = 53 * 0.85 = 45 ml/min

– Male 70 kg– Age 70– = (140-70)*70/(72*2.0) = 34 cc/min– Female = 34 * 0.85 = 29 ml/min

Calculated GFR

• MDRD formula–Study called Modification of Diet in Renal

Disease–During the analysis a mathematical formula

was derived that accurately predicts the GFR– It is now the standard used by most

laboratories• 186 * cr (mg/dl)-1.154 * age -.203 * 1.212 (if black)

* .742 (if female)

Acute Renal Failure

• Caveat –All creatinine values are not the same ! –The same creatinine level will mean

different degrees of renal function based on• Age • Sex• Weight

Calculation of Kidney Function

• For the same creatinine value –Renal function will be better (higher

creatinine clearance)• Men > women• Young age > older age

Age Sex Weight(kg) Diagnosis Creatinine

25 M 70 Diabetes 1.2

25 F 70 Hypertension 1.2

75 M 65 Diabetes 1.2

75 F 65 Polycystic Kidney 1.2

75 F 60 Focal Sclerosis 1.2 Lowest GFR

Best GFR

Blood Urea Nitrogen (BUN)

• Directly related to protein intake–Byproduct of metabolism

• Exists in a constant ratio with the creatinine level–BUN/Cr = 10-15:1

• Not directly toxic to the body–Reflects the simultaneous accumulation of

other nitrogenous compounds that may result in the clinical sequela of uremia

Elevations of BUN (Azotemia)with Normal Renal Function

• Corticosteroids

• GI bleeding

• Catabolism

• Increased protein intake

The BUN can not be used independently as a marker for kidney function

Approach to the Patient with Renal Failure

Questions

• Is it real ?

• Is it acute or chronic ?

• If acute – where is the lesion ?

Spurious Elevations of Serum Creatinine with Normal Renal Function

• Interference with the assay– Jaffe reaction (colorimetric)– Enzymatic – Alkaline Picrate

• Impaired tubular secretion

• Increased creatinine production


Impaired tubular secretion• Trimethoprim (Antibiotic)

–Bactrim (Trimethoprim and Sulfamethoxazole)

–15 – 35% increase in serum creatinine• Cimetidine (Tagamet) – H2 antagonist

–20% increase in serum creatinine–Not seen with proton pump inhibitors (PPI)


Increased Production

• Rhabdomyolysis

– Release of creatine from damaged muscle membrane

– Conversion of creatine peripherally to creatinine

– Etiologies

• Trauma

• Statins (HMG CoA reductase inhibitors)

• Seizures

• Increased intake

– Cooked meat

CheckCPK level


• Clinical clues

–Normal level of BUN

–BUN / Cr ratio decreases < 10:1

• Normal ratio 10 –15:1

–Normal urine output

–No obvious hemodynamic or toxic insult


Questions

• Is it real ?



Differentiating Acute Kidney Injuryand Chronic Kidney Disease

Acute• Renal size > 10 cm• Normal echogenicity• Absent osteodystrophy• Granular casts or bland

sediment on urinalysis

Chronic • Renal size < 9 cm• Increased echogenicity• Renal osteodystrophy• Waxy casts

Factors that do not correlate with ARF or CRF• Calcium

• Phosphorous• Anemia• Acidosis


Questions

• Is it real ?



AKI Workup

Determine the site of the lesion• Categories of AKI

–Pre-renal • Inadequate perfusion of the kidney

–Renal• Specific damage to the kidney

–Post renal• Obstruction to urinary flow with

preserved perfusion

Acute Tubular Necrosis

Pre-renal

ATN

Interstitial Nephritis

Glomerulonephritis

Vascular

Renal

Post - Renal

Acute Kidney Injury

Outpatient Acute Kidney Injury : Etiologies

10%

14%

10%

66%

Pre-renal azotemia

Obstructive Uropathy

Acute GN

Acute InterstitialNephritis

Majority of Outpatient AKI is Pre-renal Azotemia

Etiology of Acute Kidney Injury in the Hospital

48%

11%

22%

9%

5% 5%

Interstitial NephritisPre-Renal AzotemiaATNObstructionAcute on ChronicGlomerulonephritis

Majority of inpatient AKI is Renal - ATN

80 200

GFR

or RBF

Pre Renal Azotemia : Renal Autoregulation

Systolic Blood Pressure

Renal Autoregulation

• The ability of the kidney to maintain adequate blood flow and GFR through a wide range of systemic blood pressures

• A complex interaction of multiple enzyme / cytokine systems–Renin-angiotensin–Prostaglandin–Neurohumoral–Endothelial


Hypovolemia

Activation of Carotid and Cardiac Baroreceptors

Increased Neurohumoral ResponsesNorepinephrineAngiotensin II

ADHEndothelin

Activation of MyogenicResponse

Normal Glomerulus and Tubules

Normal Glomerular Capillary

Filtration Pores in the Basement Membrane

Normal Glomerular Capillary

Filtration Pores in the Basement Membrane

Capillary Lumen

Bowman’s Space

UltrafiltrateUltrafiltrate

Urine Flow into Bowman’s Space

High Pressure

PGE2Increased efferent arteriolar constrictionAngiotensin II

Increased afferent arteriolar vasodilationPGE2NOPGI2

Autoregulation

Autoregulation

Prostaglandins Renin

Angiotensin I

Angiotensin II Aldosterone

Importance of Prostaglandins

Juxtaglomerular Cells

Adrenal

Macula Densa

ARF Workup

Categories of ARF– Pre-renal

• Inadequate perfusion of the kidney– Renal

• Specific physical damage to the kidney– Post renal

• Obstruction to urinary flow with preserved perfusion and lack of direct nephrotoxic damage

Pre – Renal Azotemia

• A state of underperfusion of the kidneys• Normal response of the kidney to

underperfusion–Reabsorb sodium and water

• Expand intravascular volume• Increased sodium reabsorption occurs

–Proximal tubule (80%)–TALH (20%)–DCT (< 5%)

Pre – Renal AzotemiaDecreased Effective Circulating Volume

• Absolute volume depletion

• Relative volume depletion

• Impaired cardiac output

• Impaired renal autoregulation

Pre-renal Azotemia : Absolute Volume Depletion

• Gastrointestinal– Diarrhea– Vomiting

• Hemorrhage• Sweating• Renal

– Diuresis• Osmotic• Diuretics

– Salt-wasting• Burns

Pre-renal Azotemia : Relative Volume Depletion

3rd spacing (interstitial space)• Hypoalbuminemia

–Nephrotic syndrome–Liver disease–Malnutrition

• Pancreatitis• Sepsis 1st space – intravascular

2nd space - intracellular

Pre-renal Azotemia : Cardiac/ Pulmonary Dysfunction

A form of Relative Volume Depletion• Cardiomyopathy• Valvular disease• Myocardial infarction• Tamponade• Pulmonary Hypertension• Renal Artery Stenosis

Low Cardiac Output states

Pre-renal Azotemia : Abnormal Autoregulation

• Blockade of Angiotensin activity–ACEI (angiotensin converting enzyme

inhibitors)–AII receptor blockers (ARBS)

• Prostaglandin inhibitors–NSAIDs (nonsteroidal anti-

inflammatory drugs) • Inhibit the enzyme cyclooxygenase

Non-Steroidal Anti-inflammatory Agents (NSAIDS)

• Prostaglandins–A group of lipid compounds –Derived from essential fatty acids

• Originally isolated from the prostate (seminal fluid) – 1935

–Found in all tissues and organs• Autocrine (self stimulatory)• Paracrine (locally active)

Prostaglandins

Cell Membrane Phospholipids

Arachidonic Acid

Prostaglandins

Phospholipase A

Cyclooxygenase (COX)

Drug Categories that Disrupt Renal Autoregulation

• NSAID– Ibuprofen

• Motrin• Alleve

– Naprosyn– Toradol– Vioxx– Celebrex

• ACEI– Captopril– Ramipril– Zestril– Lisinopril– Enalapril

• ARB– Losartan– Irbesartan– Candesartan– Olmesartan

Cellular Arachidonic Acid

PGG2 + PGH2

PGI2 PGE2 TXA2

Prostacyclin Thromboxane

PGF2a(Leukotriene)

Cyclooxygenase

VasodilationRenin production

Arachidonic Acid PGF2a

Vasoconstriction

NSAIDs

80 200

GFR

or RBF



80 100 200

GFR

or RBF

Disruption of Renal Autoregulation


NSAID

Normal Normal

Shift to the right

Impaired Autoregulation : ACEI / ARB

Absent or Blocked AII

80 100 200

GFR

or RBF

Disruption of Renal Autoregulation


ACEI/ARB

Normal Normal

Shift to the right

Drug Categories that Disrupt Renal Autoregulation

• NSAID– Ibuprofen

• Motrin• Alleve

– Naprosyn– Toradol– Vioxx– Celebrex

• ACEI– Captopril– Ramipril– Zestril– Lisinopril– Enalapril

• ARB– Losartan– Irbesartan– Candesartan– Olmesartan

NSAIDS ACEI/ARB

Afferent ArteriolarConstriction

Efferent ArteriolarVasodilation

DecreasedIntraglomerular

Pressure

AKI : Impaired Renal Autoregulation

• Patients at highest risk include – CHF– Cirrhosis– Nephrotic– Renovascular disease-renal artery stenosis (bilateral)

• Use of ACEI or ARB in these patients requires very careful and frequent monitoring

• NSAIDS are completely prohibited in these patients• A normal individual with euvolemia is at no risk from

NSAID or ACEI/ARB

Unilateral Renal Artery Stenosis and ACEI/ARB

Aorta

Lower Extremity

R Renal Artery L Renal Artery

Efferent Arteriole

Efferent Arteriole

GlomerulusGlomerulus

ACEI/ARB

PGE2 / NO

Renal Artery Stenosis and ACEI/ARB

• ACEI/ARB in Unilateral renal artery stenosis– Lose function of the kidney on the affected

(ipsilateral) side – Contralateral side kidney will increase blood flow

and hypertrophy• Renal function will stay at almost 80-90% of

normal

Bilateral Renal Artery Stenosis and ACEI/ARB

Aorta

Lower Extremity

R Renal Artery L Renal Artery

Efferent Arteriole

Efferent Arteriole

GlomerulusGlomerulus ACEI/ARB ACEI/ARB

Renal Artery Stenosis and ACEI/ARB

• ACEI/ARB in Bilateral renal artery stenosis–Lose function of both kidneys –No perfusion pressure–Marked decrease in urine output –Acute Kidney Injury

• ACEI/ARB are contraindicated in the presence of bilateral renal stenosis

AKI Secondary to ACEI/ ARB

• ACEI / ARB are highly recommended by JNC (Joint National Commission) for patients with CKD

• The benefit of these agents in preserving renal function exceeds any potential risk of AKI–Renal artery stenosis is excluded by

clinical and radiologic studies• ACEI/ARB are reno-protective !

What Have We Learned So Far ?

• Definitions of AKI/CKD/ESRD• Calculation of renal function

– Creatinine– Creatinine Clearance– Cockcroft and Gault formula– MDRD

• Classification of ARF• Normal Physiology of renal perfusion• Examples of Pre-renal azotemia

P re-ren al

A T N

In terstitia l N ep h r itis

G lom eru lon ep h r itis

V ascu lar

R en a l

P ost - R en a l

A cu te R en a l F a ilu re

Etiology of Acute Kidney Injury in the Hospital

48%

11%

22%

9%

5% 5%

Interstitial NephritisPre-Renal AzotemiaATNObstructionAcute on ChronicGlomerulonephritis

Intrinsic AKI

ATNAcute Tubular Necrosis

Ischemic(60%)

Toxic(40%)

Outer medulla

Inner Medulla

Cortex

Cortex has a much higher oxygen delivery and oxygen content than the medulla

The outer medulla operates in a delicate balance as it consumesalmost all of the oxygen delivered

Blood Flow Rate and Oxygen Consumption of Different Organs

Blood Flow Rateml/min/100g

O2 consumption/O2

delivery

Hepatic 58 18%

Brain 54 34%

Heart 84 65%

Kidney 420 8%

Outer medulla 190 79%

Muscle 2.7 34%

Geography of the Kidney

Outer medulla

Inner Medulla

Cortex Proximal Tubules – Pars Recta Pars ConvolutaDistal Tubules

Proximal Tubules-Pars RectaTALH – Thick Ascending Limb of Henle

Thin Descending limb of the loop of HenleThin Ascending limb of the loop of HenleCollecting Duct

Pars Recta

Pars Convoluta

AKI – Site of Injury

• Ischemic–Outer Medulla

• Proximal tubule–Pars recta

• TALH (major site)• Toxic

–Proximal tubule (pars convoluta) >> Distal tubule

AKI - ATN

• Prolonged Pre-renal azotemia can lead to ATN– Due to the high oxygen requirements for sodium

absorption cellular ischemia will result if impaired delivery of blood remains prolonged• Breakdown of cell membrane• Entry of calcium and efflux of intracellular

contents–Cell death–Sloughing of the renal tubular cell in the

urine

Intrinsic AKI

Pre-Renal Azotemia

ATN

Prolonged Hypotension/ Shock/ Hypoperfusion of the Kidneys

Renal Origin : AKI

ATN (85%)

Ischemic(50%)

Toxic(35%)

ATN : Toxins

• Increased risk secondary to – High delivery of blood flow

• 25% cardiac output– Concentration in the medulla and interstitium

through the countercurrent mechanism– Organic transporters

• Proximal tubule– Local metabolism to toxic compounds


• Common clinical cause– Radiology Material

• IV Contrast – iodinated compound (radiology) that is directly toxic to the proximal tubule

• Extreme care must be taken when using these agents in patients with CKD


• Heme pigments – Released from damaged muscle cells (Rhabdomyolysis) or damaged red cells (hemolysis) leading to toxicity of the proximal tubule

• Light chains – Kappa >> Lambda light chains from overflow proteinuria as a result of a hematopoietic malignancy (myeloma) –proximal tubule damage

AKI : Diagnosis

• Pre-renal azotemia is rapidly reversible• ATN will require 2 –3 weeks for recovery and

possible temporary or permanent dialysis• Diagnostic Workup

–Check volume status of the patient–Rule out obstruction–Urinary electrolytes–Urinalysis

Clinical Examination – Fluid Status

• Volume Overload– DOE (Dyspnea on exertion)– PND (paroxysmal nocturnal dyspnea)– Orthopnea– JVD (jugular venous distension) – Rales– LE (lower extremity) edema– Ascites– Peri-orbital edema– HTN (Systolic > 140 mmHg))– S4 gallop

Examination – Fluid Status

Volume Depletion• Clinical exam

– Poor skin turgor– Dry mucosa : axillae / oral cavity / vaginal- groin– Orthostatic hypotension

• Decreased systolic (>20 mmHg) and diastolic BP (>10 mmHg) with upright position

• Increased heart rate (> 100 bpm)– Absent edema– Absent JVD

Radiologic Diagnosis of AKI

• Obstruction accounts for 10% of cases of AKI• Imaging techniques

– Ultrasound• Preferred modality

– MRI • No Gadolinium

– In renal failure may lead to an irreversible systemic inflammatory condition with diffuse organ fibrosis (Nephrogenic systemic fibrosis)

– CAT scan • No IV contrast (nephrotoxic)


Questions

• Is it real ?



Renal Ultrasound

• Purpose – Compare the echo texture of the kidneys to the

liver– Kidneys are normally less echogenic than the

liver due to the presence of glomeruli and tubules – A clear differentiation is usually seen due to the

difference in density of the tubules between the cortex and the medulla of the kidneys• Corticomedullary differentiation

Renal Ultrasound

• AKI– No change in echogenicity– No loss of the corticomedullary differentiation

• CKD– Increased echogenicity of the kidneys

• Increased fibrosis of the cortex– Decreased size – loss of the corticomedullary differentiation

Cortico-Medullary Differentiation in a Normal Kidney

Renal artery

Renal vein

Ureter

Renal capsule Cortex

Medullary pyramids

Minor Calyx

Kidney Anatomy

Medulla

Sinus

Major Calyx

Normal Kidney

Liver

Diaphragm

Sinus

Cortex

Anterior

Posterior

Superior Inferior

9 – 12 cm in length

Normal vs. CKD

Small / echogenicNormal

Laboratory Evaluation of AKI

• Urine Na• FENA (Fractional Excretion of Sodium)• FEUREA (Fractional Excretion of Urea)• BUN/Cr ratio• Urine Specific Gravity• Urinary Sediment

AKI – Urine Sodium

• In pre-renal azotemia the kidney is underperfused and will make every effort to restore the intravascular volume– Sodium and water reabsorption (sympathetic

nervous system)• Proximal tubule • TALH• Distal tubule

– Water reabsorption (ADH production)• Collecting Duct

AKI – Urine Sodium

• Urine sodium concentration will be markedly reduced in pre-renal azotemia – Random urine sodium

• < 20 meq/L –Intense sodium avidity

• In ATN the tubules are physically damaged so sodium can not be retained adequately– Random urine sodium

• > 40 meq/L• No attempt at sodium retention

Fractional Excretion of Sodium (FENA)

• Compares the clearance of sodium to the clearance of creatinine and is expressed as a percentage (%) !

• In a sodium avid state the proximal tubule will absorb as much sodium as possible– At the same time creatinine will continue to be

secreted – Therefore the clearance of sodium will decrease

while the clearance of creatinine does not decrease to the same degree

– As a ratio, the clearance of sodium / clearance of creatinine will decrease


• Calculation– Simultaneous

• Urine sodium• Urine creatinine• Serum sodium• Serum creatinine

– Formula• (Una / Pna) / (Ucr / Pcr) * 100

–< 1% = sodium retention i.e. pre-renal azotemia

–> 2% = sodium diuresis i.e. ATN

No volume used in the calculation since it is the same in the numerator and denominator and cancels itself out


• Interpretation problems– Diuretics

• Will result in an elevated FENA if they are effectively causing a diuresis

– Therefore• An elevated FENA is not meaningful during

diuretic therapy• Need to stop diuretics 48 hours or more for

the effect to wear off– However

• A low FENA is absolutely important during diuretic therapy

• Indicates ineffective diuresis

BUN / Creatinine Ratio

• Clinical tool to provide an indirect marker for volume status in the setting of renal failure

• Normal BUN/Cr ratio = 10-15 : 1– BUN = 10 mg/dl / Creatinine = 1.0 mg/dl – In volume depletion the BUN will increase to a greater

extent than the creatinine secondary to obligate creatinine secretion in the proximal tubule and BUN reabsorption• BUN/Cr ratio will increase > 20 : 1

–BUN = 50 mg/dl / Creatinine = 2.0 mg/dl• Ratio = 25

BUN / Creatinine Ratio

• Established Renal Failure (Acute intrinsic / Obstruction or Chronic)– BUN and Creatinine will increase to the same proportion

since the tubules are damaged to the same extent as the glomeruli preventing creatinine secretion

– BUN = 50 mg/dl / Creatinine 5.0 mg/dl = 10– Interpretation

• In the presence of an elevated creatinine– BUN/Cr ratio > 20 : 1 = volume depletion (Pre-

renal azotemia)– BUN / Cr ratio = 10-15:1 = intrinsic renal failure

(renal or post renal )

Fractional Excretion of Urea = FEurea

Urea is a nitrogenous compound derived from protein metabolism

BUN = Blood urea nitrogen An indirect measurement of the amount of urea by detecting only the 2 nitrogens within the molecule

http://en.wikipedia.org/wiki/File:Urea.png

Fractional Excretion of Urea

• BUN (a derivative of Urea) is absorbed passively in the proximal tubule with water

• Patients with volume depletion will increase the absorption of BUN (Urea)

• Creatinine will be absorbed also but it then gets secreted in the tubule

Therefore– The fractional excretion of BUN (urea) compared

to creatinine will DECREASE

Fractional Excretion of Urea

–Formula• (Uurea nitrogen / PBUN) / (Ucr / Pcr) * 100

–< 35% = Pre Renal azotemia–> 50% = Intrinsic AKI (ATN)

–This formula is especially useful in patients on diuretics which will increase the FENA and mask Pre-Renal Azotemia• Diuretics do not affect BUN absorption

Example

• Patient on furosemide (loop diuretic) comes in feeling weak and tired. He was working in the hot sun for hours in his yard.

BP 100/60 P 120

Oral mucosa – dry

Axillae – dry

Skin turgor – poor

Example

• Laboratory– Random urine sodium 50 meq/l– Random urine urea nitrogen 120 mg/dl– Random urine creatinine 30 mg/dl

– Serum creatinine 2.1 mg/dl– Serum BUN 45 mg/dl– Serum sodium 142 meq/l

Example

• Interpretation– Urine Na = 50 meq/l suggests ATN– FENA = 2.3% suggests ATN– BUN/Cr = 22:1 suggests Pre-renal

BUT the patient is on a loop diuretic

FEurea = 18% suggests Pre-Renal

This patient will respond to fluid replacement !

Urine Specific Gravity

• Used as a marker for urinary concentration• Reflects the removal of water from the urine by the

action of ADH on the collecting tubules• Definition

– The “weight” of urine compared to water– Water is given a specific gravity value of 1.000

• Nothing can be less than that number– Correlates with the osmole concentration of urine

• For every 30 mosm/L increase in the urine the specific gravity increases by 0.001


• Example

Osmolality Specific Gravity

0 1.000

90 1.003

180 1.006

300 1.010 (Isosthenuria)

450 1.015

600 1.020Concentrated

Urine

DiluteUrine


• Isosthenuria– Urine that is neither concentrated nor diluted – The same osmolality as plasma

• Concentrated urine– Increased ADH

• Urine Osmolality > 450-500• Specific Gravity > 1.015

– Damaged tubules will not respond to ADH and the urine is usually Isosthenuric • Specific Gravity = 1.010

Laboratory Evaluation of ARF

Pre- renal Azotemia

ATN

Urine Sodium < 20 > 40

Urine Osmolality

> 500 280

Specific gravity > 1.015 1.010

FENA < 1% > 2%

BUN/Cr > 20:1 10-15:1


Questions

• Is it real ?



Urinalysis : ATN

• Renal tubular cells• Granular casts

• “Muddy brown” casts• Renal tubular cell casts

Casts are made of Tamm-Horsfall glycoprotein – derived from the ascending limb

of the loop of Henle

Hyaline Casts

Normal constituentsNot indicative of renal disease

Granular Casts

Indicative of acute tubular damageNot a normal constituentNot present in Pre-renal azotemia

Granular Casts-ATN

Granular Casts - ATN

Waxy Casts

Indicative of CKD

Red Blood Cell Casts

Indicative of Acute Glomerulonephritis

White Blood Cell Cast

Indicative of Pyelonephritis

White Blood Cell and Red Blood Cells

Laboratory Evaluation of AKI

Pre- renal Azotemia

ATN CKD CKD+ AKI

RBCs ------ ----- ------ -----

WBCs ------ ----- ------ ------

RBC cast ------ ----- ------ ------

Waxy Cast ------- ------ +++ +++

Granular cast ------ +++ ------ +++

Differentiating Acute and Chronic Kidney Injury

• Remember – Pts with CKD can develop AKI– Example

• Diabetic with CKD –baseline creatinine 2.5 mg/dl

• Develops dehydration and the creatinine increases to 4.6

• Urinalysis clue–Granular casts AND waxy casts

Management of AKI

• HTN control• Anemia control• Dietary modification• Calcium and Phosphorous balance• Acid Base Balance• Potassium control

Management of AKI – Potassium

• Impaired potassium secretion (distal tubule) is a natural accompaniment of all forms of AKI

• Potassium dietary restriction should be initiated early • Factors predisposing to increased potassium

– Catabolism– GI bleed– Constipation– K sparing drugs

• ACEI / AII blockers• Bactrim• NSAIDs

Drug Induced Hyperkalemia

prostaglandins

Renin

Angiotensin I


Hyperkalemia

ACE

NSAID

Drug Induced Hyperkalemia : ACEI

prostaglandins

Renin

Angiotensin I


Hyperkalemia

ACE

Drug Induced Hyperkalemia

prostaglandins

Renin

Angiotensin I


Hyperkalemia

ACE

ARB

Hyperkalemia

Peaked T waves

Loss of p wave (Sinus node failure)

Widening of QRS (slow conduction)

Sine wave pattern (cardiac arrest)

K+ and the Cell membrane

-90mVResting Membrane Potential

Threshold Potential

Spontaneous Depolarization

Action Potential

-60mV

Normal K+ level

Nernst Equation : Resting Membrane Potential (RMP)

RMP =

-61 log K intracellularK extracellular

Hyperkalemia causes the RMP to become less negative

Hypokalemia causes the RMP to become more negative

Hyperkalemia and the Action Potential


Threshold Potential


Action Potential

-60mVHyperkalemia : New RMP

Normal K+ level

Hyperkalemia and the Action Potential


Threshold Potential


Action Potential

-60mVHyperkalemia : RMP

Inability to repolarize since RMP is above the Threshold Potential

Normal K+ level

Ca+2 and the Cell membrane


Threshold Potential


Action Potential

-60mV

Normal K+ level

Normal Ca2+ level

Increased Ca2+ level New Threshold Potential

Calcium in the Treatment of Hyperkalemia


Threshold Potential

Action Potential

-60mVHyperkalemia : RMP

Inability to repolarize since RMP is above the Threshold Potential

Normal K+ level

New Threshold PotentialAfter IV Calcium

repolarization

Remember This !

• Potassium affects the resting membrane potential RMP) of the cell– Hyperkalemia makes the RMP less negative

and results in spontaneous depolarization but prevents repolarization

• Calcium affects the threshold potential of the cell– Increased calcium will make the threshold

potential less negative making it harder for the cell to depolarize

RMP = -60*Log Ki/Ke

AKI : Hyperkalemia

• Treatment of Symptomatic Hyperkalemia – EKG Changes–Antagonize membrane effects

•Calcium–Redistribute K+ from extracellular to

intracellular environment• Insulin•beta -2 receptor stimulation

Increase Na-K ATPase pump stimulation

AKI : Hyperkalemia

–Remove K+ from the body•Exchange resin – Kayexalate

–Exchanges a K+ for a Na+ in the colon

•Dialysis–Bicarbonate therapy only if severe

acidosis is present

Indications for Dialysis in ARF

• Uncontrolled Hyperkalemia• Intractable Fluid overload• Uremia• Pericarditis• Intractable Metabolic acidosis

ATN : Treatment

• No proven benefit of any treatment in enhancing recovery –Dopamine–Diuretics – Lasix

• All treatment at present is supportive to allow time for tubular regeneration

Phases of AKI

• Initiating Phase–Time of exposure to hemodynamic or toxic

insult• Oliguric Phase

–Period of oliguria (67%) • Urine volume < 400 cc/day

Duration of AKI at this point : 10 –14 days

Phases of AKI

• Diuretic phase– Increasing urine output (non-oliguric)–No change in renal function

• Recovery phase–May last 3 – 12 months before full

functional recovery occurs• Acid base / Water homeostasis

Outcome of ATN

Complete recovery

15%

Partial recovery

30%

Dialysis dependent

5%

Death50%

Cause of Death in AKI

3530

10

20

5

0

10

20

30

40

50

Pneumonia GramNegative

Sepsis

GI Bleed Cardiac Hyperkalemia

%

Check list Approach to AKI

1. Document with repeat values for BUN and Cr

2. Assess for spurious increases in BUN and Cr

3. Look at BUN/Cr ratio

4. Evaluate hemodynamic status

5. Look for nephrotoxin exposure

6. Examine the urinary sediment and urinary indices- FENA, Urine Na, Specific gravity

7. Order radiologic evaluation of the kidneys

8. Follow course of electrolytes / volume status / nutrition on a daily basis

9. Watch the potassium level !

What I Really Want You to Know :

• Understand – FENA/FEUREA– Creatinine clearance – MDRD / Cockcroft and Gault

• How to interpret – BUN/Cr ratio– Urine Na / FENA/FEUREA– Urine specific gravity– Urinalysis sediment

• Renal Autoregulation– The curve– The effects of Angiotensin II and prostaglandins

What I Really Want You to Know :

• Where and why ATN occurs in the kidney

• Factors that influence interpretation of the serum creatinine

• Natural history of ATN

• Causes of, clinical effects and treatment of hyperkalemia

lecture 14 - aki

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