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Therapeutics I Test 2
Nyman - Measures of Kidney Function
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01/27/2013
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Term

Measures of Kidney Function

Today (Her schpeel)

 Definition

*Emphasize that exam questions can come from readings and that lecture is not intended to be a summary of the reading. 

•Introduction to nephrology module
•Background information
–Functions of the kidney
•Determining kidney function
–Creatinine as a marker of kidney function
–Measured creatinine clearance and glomerular filtration rate
–Estimates of creatinine clearance and glomerular filtration rate
•Guideline recommendations
•Dosing drugs in kidney disease
–Pro/Con grid
•Clinical scenarios
– Class discussion
•Role of the urinalysis, imaging studies 
Term

Measures of Kidney Function

Objectives

(10)

 Definition

•Memorize the CG equation and list the variables in the MDRD and CKD-EPI equations
•Describe variables that affect the accuracy of these equations
•List guideline recommendations regarding measures of kidney function
•Calculate:
–Estimated creatinine clearance (eCrCl) using the Cockcroft-Gault equation (CG)
–Estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations 
•Compare and contrast CG, MDRD, CKD-EPI, and a timed creatinine clearance
•Create a pro/con grid for the CG, MDRD and CKD-EPI equations for drug dosing
•Given a clinical scenario, recommend an appropriate method of determining a patient’s kidney function
•Describe the components of the urinalysis and state what an abnormal result might mean
Term

The Nephron: Functions

Excretory Functions

(5)

 Definition

•Eliminates water
•Regulates electrolytes
•Regulates acid/base
•Eliminates waste products
•Eliminates drugs, toxins
Term

The Nephron: Functions

Endocrine Functions

(3)

 Definition

–Erythropoietin (Low 02 delivery to kidneys- incr RBCs)
–Renin
–Prostaglandins and kinins
Term

The Nephron: Functions

Metabolic Functions

(3)

 Definition

–Activation of vitamin D
–Gluconeogenesis
–Metabolism of insulin and other endogenous/drug substances
Term

Measures of Kidney Function

Glomerular Filtration Rate (GFR)

(5)

 Definition

•Best overall index of kidney function
•Amount of plasma filtered by the kidney
•Units = mL/min or mL/min/1.73m2
•Normal GFR for young adults = 125ml/min
•As GFR declines, generally so do other functions of kidney
Term

Measures of Kidney Function

Ideal Marker for GFR

(6)

 Definition

•Freely filtered by the glomerulus
•Not reabsorbed or secreted in the tubules
•Not metabolized by the kidney
•Clinically nothing meets this criteria (too cumbersome)
•Instead rely on less ideal markers
 - SCr (secreted by tubules = not idela
Term

Measures of Kidney Function

Measures of GFR

(5)

 Definition

•Inulin
•Radiolabeled (99mTc-DTPA, 51Cr-EDTA,  125I-iothalmate)
•Non-radiolabeled (iothalmate, iohexol)
•Complex requirements for use
•Not commonly used clinically
Term

Measures of Kidney Function

Serum Creatinine (SCr)

(6)

 Definition

•Derived from metabolism of creatine in the muscle and from dietary meat intake
•Released into blood at relatively constant rate
•Commonly used as a marker of kidney function
–Freely filtered by glomerulus
–Also secreted by the tubules
•Factors affecting SCr
 
Term

Measures of Kidney Function

Creatinine Assay Standardization

(5)

 Definition

•Previously, inter-laboratory variation (3mg/dL) in serum creatinine concentrations reported
•Effort to standardize all assays to ONE national standard
–Called IDMS or isotope-dilution mass-spectrometry assay
•All labs should be reporting standardized SCr
–On average, 0.12 mg/dL decrease in SCr for labs after standardization
Term

Quantifying Kidney Function

Direct Measure

(2)

 Definition

–CrCl
–GFR (difficult to measure directly)
Term

Quantifying Kidney Function

Estimates of Kidney Function: CrCl

(3)

 Definition

•Cockcroft-Gault (most common for adults)
•Schwartz (pediatric)
•Others
Term

Quantifying Kidney Function

Estimates of Kidney Function: GFR

(5)

 Definition

•MDRD
•CKD-EPI
•CKD-EPI cystatin C (Instead of Cr)
•CKD-EPI creatinine-cystatin C

Crystatin is newest guidelin but not used clinically yet
Term

Direct Measures of Kidney Function

(5)

CRclv vs. GFR

 Definition

•CrCl versus GFR
–CrCl is similar to GFR, but not equivalent
(esp w/ decline in kidney function [actually diverge])
•Why? (urine collection over time)
–Creatinine is secreted by the tubules
–As kidney function declines, the contribution of creatinine secretion to overall CrCl will proportionally increase, increasing the difference between CrCl and GFR
Term

Estimates of Kidney Function

(7)

 Definition

•eCrCl
–Cockcroft-Gault
•eGFR
–MDRD
–CKD-EPI
–2012 CKD-EPI cystatin C
–2012 CKD-EPI creatinine-cystatin C
Term

Estimates of Kidney Function

Crystatin C

(5)

 Definition

•Protein produced by all nucleated cells
•Filtered by the glomerulus
–Metabolized by tubules
•Cystatin C-based eGFR is more predictive of adverse clinical outcomes than SCr-based eGFR
–Impact on patient care to be determined
Term

Measures of Kidney Function

KDIGO Guideline Recommendations

(6)

 Definition

•To determine kidney function for diagnosing kidney disease in adults:
–Use an eGFR equation rather than relying on SCr alone
–CKD-EPI
•Use additional tests for confirmatory testing when eGFR based on serum creatinine is less accurate, such as
–eGFR equation based on cystatin C
–Clearance measurement
Term

Measures of Kidney Function

KDIGO Recommendations

(2)

 Definition

•Laboratories should report eGFR when SCr is reported
•For children, use Schwartz equation
Term

Measures of Kidney Function

KDIGO Recommendations

Pediatrics

(8)

 Definition

•Normal GFR varies based on age
•Schwartz Equations (or CKiD)
–eGFR (mL/min/1.73m2) = k x [Height in cm/SCr]
•k=0.413
•Ages 1-16 years
•Developed for use with standardized SCr
–eGFR (mL/min/1.73m2) = 70.69 x (SCysC)-0.931
•Ages 1-16
Term

Measures of Kidney Function

Cockroft-Gault Controversies

(11)

 Definition

•Which weight?
–Total body weight (TBW) Highest, (historically used)
•Used in CG paper
–Ideal body weight (IBW)
•Men IBW (kg) = 50 + 2.3 x [# inches over 5 feet]
–Adjusted body weight (ABW)
•ABW (kg) = IBW + 0.4* (TBW – IBW)
•*Some reports of using 0.3 as correction factor
–Lean body weight (LBW)
–No body weight
-- Muscle mass determined by weight
Term

Survey of 200 nephrology and critical care pharmacists
Which Weight Do You Use in CG Eqtn? 

 Definition
  • Actual body weight - 1%
  • Ideal Body Weight - 22%
  • Some Other Body weight (i.e adjusted) - 23%
  • Combination of above depending on obesity - 47%
Term

Measures of Kidney Function

Cockroft-Gault Controversies: Which Weight?

(6)

 Definition

–Consider the clinical situation
–If TBW > 30% above IBW, many pharmacists use IBW (or ABW)
–Some use IBW whenever TBW > IBW
–In very obese patients, LBW may be best
–As a quick reference, simplified equation may yield reasonable results
-- Will overestimate Kidney function, dont use IBW if pts TBW is less than IBW
Term

Measures of Kidney Function

Cockroft-Gault Controversies: To Round or Not to Round

(6)

 Definition

–Elderly patients with low muscle mass and SCr < 1.0 mg/dL
•Low SCr due to low muscle mass and not due to great kidney function
•Some practitioners round up to 1.0 mg/dL
–Very limited data to support this practice
•One study showing worse performance of CG
•Introduction of a variable amount of error in CG calculation
Term

Measures of Kidney Function

MDRD/CKD-EPI: Controversies

(8)

 Definition

•Limited data in elderly
–MDRD
•Population where equation derived: age 18-70
•Limited data indicates that MDRD may overestimate kidney function in the very elderly
–CKD-EPI population
•Mean age 47
•13% with age > 65
•4% with age > 70
Term

Measures of Kidney Function

EQTNs Give Estimations, Not Truth

(3)

 Definition

•Percentage of estimates within 30% of measured GFR
–Cockcroft-Gault = 69%
–MDRD = 83%
•
Term

Measures of Kidney Function

When Creatinine Based EQTNs May Be Inaccurate

(8)

 Definition

•Extremes of body size
•Severe malnutrition or obesity
•Severe liver disease
•Skeletal muscle disease
•Paraplegia or quadriplegia
•Vegetarian diet
•SCr not at steady state
•Pregnancy
Term

Measures of Kidney Function

When Cystatin C EQTNs May Be Inaccurate

(5)

 Definition

•Cystatin C not at steady state
•Race/ethnicity other than US or European black and white
•Hyperthyroidism
•Administration of corticosteroids
•Possibly diabetes and obesity
Term

Measures of Kidney Function

If Estimating EQTNs are Inaccurate: Options

(2)

 Definition

–Obtain measured CrCl
–Make decisions based on a risk:benefit assessment of the clinical scenario
Term

Measures of Kidney Function

Drug Dosing: National Kidney Disease Education Program

(estimations)

(2)

 Definition

–eCrCl
–eGFR
Term

Measures of Kidney Function

Urinalysis

(6)

 Definition

•pH (NL 4.5 – 8.0)
•Specific gravity (NL 1.003 – 1.030): indicates concentrating ability of the kidneys
•Glucose (NL 0): In uncontrolled diabetes, may spill into urine
•Ketones (NL 0): Present in ketoacidosis or starvation
•Nitrite (NL 0): Many gram negative bacteria convert nitrate to nitrite so presence may mean infection
•Leukocyte esterase (NL 0): Comes from WBCs, so presence may mean infection
Term

Measures of Kidney Function

Urinalysis

Blood

 Definition

•Blood (NL 0): If present without RBCs, may mean hemolysis or rhabdomyolysis
Term

Measures of Kidney Function

Urinalysis

Protein

(3)

 Definition

•Protein (NL 0): Reported as trace to 4+ or by concentration [1+ = 30 mg/dL, 2+ = 100 mg/dL, etc].
–If present, often means proteinuria, which is indicative of glomerular disease 
–Microalbumin-specific dipsticks are available for screening for microalbuminuria (30-300 mg/d albumin excretion)
•
Term

Measures of Kidney Function

Urinalysis

Uribilinogen,RBCs, WBCs, Casts, Crystals

(5)

 Definition

•Urobilinogen (NL 0.2-1.0): Pigment produced from metabolism of bilirubin.  High levels may indicate liver disease or hemolytic anemia
•Red blood cells (RBCs) (NL <2-3/HPF): Indicates trauma to kidneys, ureters, bladder, or urethra
•White blood cells (WBCs) (NL 0 or trace): Indicates inflammation or infection in kidneys, ureters, bladder, or urethra
•Casts (NL 0): Several types. Cylindrical proteins indicative of a wide variety of kidney disease.
•Crystals
Term

Other Abnormalities in Kidney Disease

(9)

 Definition

•Urinary output (UOP)
–Anuria: < 50 mL/day of urine output
–Oliguria: 50-500 mL/day of urine output
•Edema
•Electrolytes
–Potassium, magnesium, phosphate
•Acid/base status
•Nitrogen (BUN)
•Creatinine
Term

Measures of Kidney Function

Procedures

KUB

(3)

 Definition

•KUB: plain x-ray of kidneys, ureters, bladder
–Allows clinician to check kidney size
–May be able to visualize renal stones
 
Term

Measures of Kidney Function

Procedures

Renal Ultrasound

(7)

 Definition
  • Renal ultrasound: Uses sound waves to generate a 2-d image
  • Able to determine size of; 
    • kidneys, 
    • echogenicity (eval for chronic versus acute kidney disease), 
    • visualize hydronephrosis 
    • and cysts present in the kidney
  • Also used sometimes to guide biopsy
Term

Measures of Kidney Function

Procedures

Doppler Ultrasound

 Definition
•Doppler ultrasound of the renal arteries: Determine velocity of flow through renal arteries to evaluate for renal artery stenosis
Term

Measures of Kidney Function

Procedures

Radionuclide Scan: Renal Scan

 Definition

•Radionuclide scan (renal scan): particularly useful in assessing renal perfusion and whether the outflow tract is intact
Term

Measures of Kidney Function

Procedures

Computed Tomography (CT)

(5)

 Definition

•Computed tomography (CT): Cross-sectional anatomic imaging technique based on x-ray data
–Gives greater contrast resolution than conventional radiography
–Often used to evaluate obstructive uropathy, malignancy, and infections of the kidney
–IV contrast dye often administered to enhance imaging
•Can cause acute kidney injury, so must be used judiciously
Term

Measures of Kidney Function

Procedures

Magnetic Resonance Imaging (MRI)

(4)

 Definition

•Magnetic resonance imaging (MRI): Uses magnet and radiofrequency pulses to generate an image
–Can be used to evaluate for obstruction, malignancy, and renovascular lesions
–MRA (magnetic resonance angiography, where gadolinium is typically administered to visualize the arteries) can be used to evaluate renal vasculature and renal artery stenosis
•Gadolinium has been associated with a very serious condition called nephrogenic systemic fibrosis (NSF) in patients with severe kidney disease, so generally not used when GFR< 30
Term

Measures of Kidney Function

Procedures

Biopsy

(2)

 Definition

•Biopsy: Useful in making definitive diagnosis as to cause of kidney disease
–Risk of bleeding
Term

Factors affecting SCr

(8x3)

 Definition
  • Older Age
    • Decrease SCr
    • Age related decrease in muscle mass
  • Female Sex
    • Decrease SCr
    • Gender related lower avg muscle mass
  • African American
    • Increase SCr
    • Higher avg muscle mass than caucasins
  • Restriction of Dietary protein
    • Decrease SCr
    • Decrease in creatinine generation
  • Ingestion of cooked meat
    • Increase SCr
    • Increase in creatinine (transient) may be blunted by increase in GFR
  • Muscular
    • Increase SCr
    • More muscle mass
  • Malnutrition/wasting/amputation
    • Decrease SCr
    • Decreases SCr
  • obesity
    • No Change
    • Excess weight is not muscle
Term
If mona and David both have an SCr of 1.2 who has better kidney function
 Definition
  • David
  • Normal SCr is 0.5 -1.2
  • Higher Scr = lower kidney function
  • Consider production and elimination
  • If david makes more but has the same SCr he must have better kidney function to eliminate
Term
Shaq vs. Spike Lee, Both have SCr of 1.2 who has better function
 Definition
  • Shaq
  • More muscle mass so he creates more creatinine
  • will need to eliminate well to have same SCr
Term

C-G controversy

Weight

 Definition
  • –Total body weight (TBW)
    •Used in CG paper
    –Ideal body weight (IBW)
    •Men IBW (kg) = 50 + 2.3 x [# inches over 5 feet]
    –Adjusted body weight (ABW)
    •ABW (kg) = IBW + 0.4* (TBW – IBW)
    •*Some reports of using 0.3 as correction factor
    –Lean body weight (LBW)
    –No body weight
Term

Estimating Kindey function in morbid obesity

Study

(12)

 Definition
  • Design
    • Compared mCrCl as determined by 24-hour urine collection to estimations obtained using equations (MDRD4, CG using actual, ideal, adjusted, fat-free, and lean body weight, Salazar-Corcoran)
  • Participants
    • BMI ≥ 40, age 18-75, stable SCr, admitted to hospita
    • N = 54, mean mCrCl = 110 mL/min, 31% BMI ≥ 50
  • Results
    • Cockcroft-Gault equation using lean body weight and fat-free weight showed greatest accuracy
    • LBW(male) = (9270 x weight)/(6680 + 216 x BMI)
    • LBW(female) = (9270 x weight)/(8780 + 244 x BMI)
    • Fat-free weight calculated using bioelectric  

           impedence analysis

  • Conclusion
    • CG using LBW may provide best estimate of kidney function in patients with BMI > 40

 
Term

Weight terms in CG eqtn study

(15)

 Definition
  • Design
    • Meta-analysis of studies comparing measured CrCl (mCrCL) with estimated CrCl using Cockcroft-Gault
  • Inclusion
    • Used 24 hour urine collections to determine mCrCl
    • Study data reported in usable format
    • N = 13 studies
  • Results
    • TBW overestimated mCrCl (+16 mL/min) [N=1128]
    • IBW underestimated mCrCl (-5 mL/min) [N=1174]
    • No body weight (+ remove 72 from denominator) was no different than mCrCl (+0.4 mL/min) [N=153]
    • ABW using 0.3 or 0.4 correction factor not statistically different from mCrCl
      • 0.3 correction factor: +5 mL/min [N=121]
      • 0.4 correction factor: +20 mL/min [N=76]
  • Conclusion
    • Eliminating the body weight term may provide reasonable estimate of kidney function

 
Term

Rounding in C-G 

Study

(11)

 Definition
  • Design
    • Meta-analysis of studies comparing measured CrCl (mCrCL) with estimated CrCl using Cockcroft-Gault
  • Inclusion
    • Used 24 hour urine collections to determine mCrCl
    • Study data reported in usable format
    • N = 13 studies
  • Results
    • TBW + rounding up SCr was similar to mCrCl (+3.5 mL/min) [N=52]
    • IBW + rounding underestimated mCrCl (-30 mL/min) [N=121]
  • Conclusion
    • Rounding up SCr cannot be recommended

 
Term

MDRD vs CG for drug Dosing

study

(16)

 Definition
  • Design
    • Compared drug dosing recommendations for 13 drugs eliminated by the kidneys based on mGFR (iothalmate), MDRD eGFR, and Cockcroft-Gault eCrCl using IBW (CGIBW) and ABW (CGABW)
  • Participants
    • N=5504 from 6 research studies and 4 clinical population
    • Average age 47 years, mean BMI 28 kg/m2
  • Results
    • Percentage of time equations resulted in same drug dosing:
    • CGABW and MDRD  89%
      • MDRD resulted in lower drug doses in 9% of cases
    • CGIBW and MDRD 88%
      • MDRD resulted in higher drug doses in 10% of cases
    • More likely to have differences between MDRD and CG equations in drugs with higher numbers of dosing breakpoints
  • Conclusions
    • CG and MDRD equations result in different dosing recommendations 11-12% of the time
    • MDRD appears to provide an estimate between that of CGABW and CGIBW
    • IBW is most conservative (lowest estimate)
    • MDRD falls btwn CG-/W-ABW & CG- w/-IBW

 
Term

Cockroft-Gault

Pro

 Definition
  • Convenience (do in head)
  • Been used for decades (tried and true)
  • Weight Variable
  • Dosing guidelines based on CrCl for most drugs
    • Best arg for its use
Term

Cockroft-Gault

Con

 Definition
  • Less accurate than eGFR
  • Not for use with standardized Scr
  • Which weight variable to use?
Term

MDRD 

Pro

 Definition
  • Use w/ standardized Scr
  • More accurate estimate of GFR than CG
  • Developed in more diverse pt population
    • (although CG used in practice in all pt pops)
  • Automated reporting
Term

MDRD 

Con

 Definition
  • Less clinical experience
    • Pharnacists = conservative in practice
  • Limited data in elderly
  • Not validated for drug dosing
  • Convert to units of mL/min
  • People who are very large or small
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