9/22/2016

Drug Use in Renal Failure:

Assessment of Renal Function
Jamie Benken, PharmD, BCPS
September 26, 2016
jjosep9@uic.edu

Objectives
Understand basic renal physiology and the role of the
kidney in maintaining homeostasis

Discuss the available methods to evaluate proteinuria and

the role of tests such as ultrasound and biopsy in renal
function evaluation

Compare and contrast various methods to estimate and

measure creatinine clearance (CrCl) and glomerular
filtration rate (GFR)

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Kidney: Excretory Function

Most important contribution of kidney to body
homeostasis: excretion

Nephron = functional unit of the kidney (Each kidney = 1 to

1.3 million nephrons)
Glomerular filtration
Tubular secretion
Reabsorption

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Excretion: Glomerular Filtration

Water, small molecular weight ions/molecules passively

diffuse across glomerular capillary membrane Bowman

capsule proximal tubule

Proteins and protein-bound compounds mostly too large to

be filtered

Amount of solute filtered related to:

Glomerular filtration rate
Extent of plasma protein binding

Excretion: Secretion
ACTIVE transport from renal circulation into tubular lumen,

mainly in proximal tubule

Renal clearance via secretion can be > GFR (1000 ml/min)

Several anionic and cationic transport systems for wide

range of endogenous and exogenous substances
Not mutually exclusive

Efflux proteins i.e. p-glycoprotein contribute to renal

elimination of many drugs

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Excretion: Reabsorption
Water and solutes: reabsorbed throughout nephron
Most drugs: reabsorbed in distal tubule and collecting duct
Urine flow rate affects reabsorption
Physicochemical characteristics affect reabsorption
Highly ionized molecules wont be reabsorbed unless
urine pH changes and they become unionized

Kidney: Excretory Function

FILTRATION

SECRETION

REABSORPTION
EXCRETION

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Nephron Function Video

http://www.youtube.com/watch?v=hiNEShg6JTI

CKD Progression: Pathophysiology

Reduced # appropriately functioning nephrons
Unaffected nephrons compensate (hyperfunction)
Single-nephron GFR increases
Whole-kidney GFR remains close to normal until extensive
injury

CKD patients relatively asymptomatic until disease

progresses
NKF recommends routine monitoring of kidney function
indices in those with CKD or at increased risk for CKD

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Qualitative & Semi-quantitative

Indices of Kidney Function
Serum creatinine (SCr)
to estimate GFR
Blood Urea Nitrogen (BUN)
Also elevated in other non-renal conditions i.e. high
protein intake

Renal ultrasound
Serum electrolytes
Na, K, Cl, CO2
Urinalysis
Albumin: Cr or Prot:Scr in spot urine, 24h protein collection

PROTEINURIA

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Urine Protein or Albumin

Principal marker of kidney damage
Characterizes severity of CKD and monitors disease
progression/regression

Most protein not excreted into urine, too big to be

filtered by glomerulus

Detecting Protein in the Urine:

Semi-quantitative
Urine dipstick tests
Semi-quantitative
Grades proteinuria as 1+, 2+, etc
False positives and false negatives possible
False positives: concentrated urine sample may be reported as a 3+
proteinuria

False negatives: protein may be undetected until excretion gets to high level
Other reasons for falsely elevated protein in the urine on a spot check:
Exercise within past 24 hours
Urinary tract infection
Congestive heart failure
Marked hyperglycemia
Pregnancy
Marked HTN
Hematuria

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Detecting Protein in the Urine:

Quantitative
Normal

24-hr
collection

Spot Protein :
Cr

Spot Albumin :
Cr

< 300 mg/day

protein

< 200 mg/g

< 30 mcg/mg

n/a

30 299
mcg/mg

> 200 mg/g

> 300 mcg/mg

often reported as
<0.2 mg/mg

< 30 mg
albumin
Microalbuminuria

Clinical
proteinuria

30 300
mg/day
albumin
> 300 mg/day
albumin or
protein

often reported as >

0.2 mg/mg

Qualitative Diagnostic Procedures

To evaluate etiology of the kidney disease
Renal ultrasound
Can detect structural abnormalities such as obstruction
Biopsy
To facilitate diagnosis when clinical, laboratory, and

imaging findings are inconclusive

To evaluate renal parenchymal disease
Complications include perirenal hematoma (caution in
those with bleeding risk)

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Measuring and Estimating

Kidney Function ( CrCl and GFR)

MEASUREMENT OF KIDNEY
FUNCTION
GFR (glomerular filtration rate)
GOLD standard quantitative index of kidney function
Early detection, staging, and monitoring of patients with
CKD

Creatinine clearance (CrCl)

Estimation of GFR
Important for drug dose adjustment in patients with
renal impairment

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MEASUREMENT OF GFR
GFR
Volume of plasma filtered across glomerulus per unit
time

Normal GFR levels

127 20 ml/min/1.73m2 in healthy men
118 20 ml/min/1.73m2 in healthy women
CKD
GFR < 60 ml/min/1.73m2 x 3 months
Cannot be directly measured

Measurement of glomerular
filtration rate (GFR)
Clearance methods of solutes to estimate GFR
Markers must be FREELY filtered, NOT secreted, NOT
reabsorbed, NOT metabolized

Exogenous compounds: inulin, iothalamate, iohexol,

radioisotopes
Special administration and detection technique
More accurate measure of GFR

Endogenous compounds: creatinine

Less technical
More variable results

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Measurement of GFR- EXOGENOUS compounds

Inulin

Low availability, high cost, assay

variability, sample prep

Iothalamate

Iodine-containing radiocontrast
dye; iodine allergy

Iohexol

Iodine-containing radiocontrast
dye; iodine allergy

Radiolabeled markers

125I-iothalamate, 99mTc-DPTA

Determines individual
contribution of each kidney to
total renal function

These compounds are selected as they are mainly eliminated through

glomerular filtration. They are minimally secreted, reabsorbed, or
metabolized in the kidney. They are minimally protein bound and have
minimal non-renal clearance.

Serum Creatinine: endogenous marker

THE IMPERFECT MARKER
Most widely used indirect measure of GFR
Metabolic product of creatine and phosphocreatine, both found
almost exclusively in muscle

Production is related to age, gender, race, muscle mass

Small, does not bind to plasma proteins, and is freely filtered by
the glomerulus

Cr undergoes variable tubular secretion

Results in overestimation of kidney function
As renal function declines, tubular secretion of SCr increases
Medications can inhibit tubular secretion
trimethoprim, dronedarone, H2 blockers

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Creatinine-based estimations of
GFR
Cockcroft and Gault (CG)
Modification of Diet in Renal Disease (MDRD)
Both equations use SCr in combination with age, gender
(CG uses weight, MDRD includes race)
in order to address limitations of SCr as a marker in
estimating renal function

These are the equations used in the electronic medical

record at University of Illinois Hospital

Equation History for CrCl and GFR

Cockcroft-Gault Equation 1976
Jelliffe 1973 does not require height/weight, normalized to BSA
CrCl(mL/min1.73m 2 )=9816[(Age20)/20 ]
SCr
CrCl is multiplied by 0.9 for female patients

Salazar-Corcoran 1988 better than CG(using ABW) or Jelliffe for

obese, phased out by using CG with 40% adjBW
CrCl(men)=(137Age)(0.285Weight(kg))+(12.1Height(m)2 )

51SCr
CrCl(women)=(146Age)(0.287Weight(kg))+(9.74Height(m)2)
60SCr

MDRD-6 1999 updated to MDRD-4

CKD-EPI 2009

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Estimation of CrCl
Cockcroft-Gault equation to calculate CrCl
Study population: 249 caucasian male patients with
and without CKD

Variables: SCr, Age, and Weight (actual body weight =

ABW*)

Men: CrCl = (140-age) ABW / (SCr x 72)

Women: CrCl x 0.85
*Original equation calls for actual body weight however
different weights often substituted i.e. IBW, adjusted BW
Most commonly used equation to determine drug dosages in patients
with impaired kidney function MEMORIZE!

Which weight to use in CockcroftGault equation?

Original CG study used actual body weight (ABW) but suggests a

correction factor to be used for obese

SCr production based on lean body mass/muscle mass rather than
total body mass

IBW often used for CG equation in automated electronic medical

record CrCl calculations
IBW male = 50 kg + 2.3 kg for each inch over 5 feet
IBW female = 45.5 kg + 2.3 kg for each inch over 5 feet

Actual BW? IBW? Adjusted BW?

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Which weight to use in

Cockcroft-Gault equation?
Impact of various body weights and SCr on the bias and

accuracy of the Cockcroft-Gault equation Pharmacotherapy

2012
Retrospective analysis, n = 3678 pts with stable renal fxn
24h urine collection vs. CG equation with different weights
Underweight, normal weight, overweight, obese, morbidly
obese
Underweight (BMI <18.5): use actual BW
Normal weight (BMI 18.5-24.9): use IBW
Overweight/obese/morbid obese (BMI >25): least biased and
most accurate to use adjusted body weight with factor of 0.4
Adjusted BW = IBW + 0.4 (actual BW IBW)

SPECIAL POPULATIONS CG equation

Liver disease
SCr from reduced muscle mass
and many other factors
Cockroft-gault tends to
overestimate measured 24-hr
CrCl
Renal transplant, HIV
Cockroft-gault tends to
overestimate measured 24-hr
CrCl
Pregnancy
Cockroft-Gault correlates well
with measured 24-hr CrCl
Unstable renal function:
Special equations exist to
SCr not at steady state
estimate CrCl however their
Normal renal fxn: increased SCr
accuracy and precision not
> 50% over a day
established
CKD: increased SCr > 30% or by >
1mg/dl over 1-2 days

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SPECIAL POPULATIONS- CG equation

Children
Schwartz equation:
CrCl (ml/min/1.73m2) = [length
(cm) x k]/SCr
K= variable that changes
according to age

Estimation of CrCl more

dependent on childs age and
length than on weight

Elderly

muscle mass = SCr

Cockroft-Gault may be used to
estimate CrCl
Rounding SCr up to 1 NOT
recommended at this time

Estimation of GFR
Modification of Diet in Renal Disease Study (MDRD)
Study population: 1,628 men and women with CKD
GFR was measured by renal clearance of 125I-iothalamate
MDRD6 equation for estimated GFR found to correlate with

measured GFR better than measured CrCl or CrCl estimated by

Cockcroft-Gault

Modified 4-variable equation = MDRD4 = similar GFR results to

MDRD 6

Variables: SCr, Age, Gender, and Race

Less accurate with patients with GFR > 60 ml/min/1.73m2
Use with caution in children, elderly, pregnant women,

critically ill
Recommended by National Kidney Foundation for estimating GFR in
patient with CKD

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Equations for Estimation of Creatinine Clearance and GFR

Cockroft and
Gault

Men: CrCl = (140-age) ABW / (SCr x 72)

Women: CrCl x 0.85
ABW = actual body weight
Substitute ABW with IBW or 40% adjBW PRN

MDRD6

GFR = 170 x (SCr)-0.999 x [age]-0.176 x [0.762 if

patient is female] x [1.180 if patient is black] x
[SUN]-0.170 x [Alb]0.318
SUN= serum urea concentration

MDRD4

GFR = 186 x (SCr)-1.154 x [age] -0.203 x [0.742 if

patient is female] x [1.210 if patient is black]
Available online at www.kidney.org/gfr

Limitations of Any SCr-based

Estimate
Cockcroft-Gault, MDRD-6, and MDRD-4 all use SCr
Use of SCr as a filtration marker
Production affected by age, gender, race, muscle mass
Undergoes variable tubular secretion
Affected by unusual dietary habits

Populations not included in Cockroft-Gault and MDRD studies:

pregnant, obese, vegetarian, amputees, liver disease, transplant,

HIV, children, elderly, unstable renal function

Cockcroft-Gault study population: with and without CKD

MDRD study population: CKD population only How best to
estimate renal function in non-CKD population?

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CKD-EPI
Many additional equations under investigation
CKD-EPI (Chronic Kidney Disease Epidemiology
Collaboration)
N = 8524
Predominantly Caucasian and AA
With and without CKD, included DM and SOT

GFR < 60 m/min: AS accurate as MDRD

GFR > 60 ml/min: possibly MORE accurate than MDRD,
further studies required?

IDMS-SCr Assay
To standardize SCr across institutions, IDMS SCr assay used in
most centers to measure Scr

5% to 20% under-estimation of SCr with this assay

(overestimates GFR)

Cockroft-Gault equation: Scr-IDMS is converted to SCr-old and

plugged into equation
CrIDMS=0.989*Crold-0.05

MDRD-IDMS equation recommended to be used with IDMS-SCr

assay to account for this variation
= 175 x (SCr)-1.154 x [age] -0.203 x [0.742 if patient is female] x
[1.210 if patient is black]

CKD-EPI already set to use IDMS-SCr

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Application of renal function estimation

equations for drug dosing
MDRD equations estimate GFR better than CockcroftGault Should we use GFR estimated by MDRD for
drug dosing?

As drug dosing is usually studied according to CrCl

(estimated by Cockcroft-Gault), eGFR by MDRD is NOT

recommended to be used for renal dose adjustments

Should we be using eGFR by MDRD to guide renal dose

adjustments?
Requires further study and paradigm shift in how we
conduct pharmacokinetic studies

Application of renal function estimation

equations for drug dosing
Estimated CrCl using Cockcroft-Gault equation
Most commonly used approach in renal drug dosing
Plug in appropriate weight
Using other equations to estimate renal function (eGFR)
CrCl vs. GFR
eGFR expressed ml/min/1.73m2 therefore extremes

from average BSA need to be considered when drug

dosing or estimating GFR
Most FDA-approved package inserts contain CockcroftGault CrCl-guided dosing

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Application of renal function estimation

equations for drug dosing
Automated estimated GFRs reported in the
clinical setting
Substitute eGFR for CrCl for renal dose
adjustments?
Package inserts often contain CrCl-based
dosing algorithms

Renal and Metabolic

Tests for Patient AB
BUN

19 mg/dl

SCr

0.9 mg/dl

BUN/SCr

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ratio
Potential dosing errors and toxicity
Especially in narrow therapeutic index CrCl
drugs

Estimated

Further studies needed to assess

GFR
relationship between eGFR and a drugs
pharmacokinetics and pharmacodynamics

105 ml/min
112
ml/min/1.73
m2

Summary of CrCl and GFR

GFR
Gold standard quantitative index of kidney function
Can be indirectly measured with exogenous and endogenous
compounds

Estimated with Cockcroft-Gault (CrCl), MDRD-6, MDRD-4, CKD-EPI

equations

MDRD-4 commonly used to stage CKD

CKD-EPI more accurate in non-CKD (GFR > 60ml/min) but not
widely implemented yet

CrCl calculated by Cockcroft-Gault commonly used for drug

dosing

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References
Pharmacotherapy - A Pathophysiologic Approach, 8th ed., JT Dipiro et al., eds., McGraw Hill,
New York, 2011.

Barrett K.E., Boitano S, Barman S.M., Brooks H.L. (2012). Chapter 37. Renal Function &

Micturition. In Barrett K.E., Boitano S, Barman S.M., Brooks H.L. (Eds), Ganong's Review of
Medical Physiology, 24e.

Lam A.Q., Seifter J.L. (2012). Chapter 57. Assessment and Evaluation of the Renal Patient. In

McKean S.C., Ross J.J., Dressler D.D., Brotman D.J., Ginsberg J.S. (Eds), Principles and Practice of
Hospital Medicine.

Modification of Diet in Renal Disease Study Group. 1: Ann Intern Med. 1999 Mar 16;130(6):461-70
.

Winter M, Guhr K, Berg G. Impact of various body weights and serum creatinine concentrations

on the bias and accuracy of the cockroft-gault equation. Pharmacotherapy. 2012 Jul;32(7):604-12

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron.
1976;16(1):31-41.

Jelliffe RW. Letter: Creatinine clearance: bedside estimate. Ann Intern Med. 1973;79(4):604-5
Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese
patients from estimated fat-free body mass. Am J Med. 1988;84(6):1053-60.

Drug Use in Renal Failure:

Assessment of Renal Function
Jamie Benken, PharmD, BCPS
September 26, 2016
jjosep9@uic.edu

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