Measuring Glomerular Filtration
Rate (GFR) in ICU
Daljit K Hothi
Great Ormond Street Hospital, London
What is GFR?
▪ GFR is the volume of fluid filtered from the glomerular
capillaries into the Bowman’s capsule per unit time
….the cumulative performance of all functioning nephrons
….the most reliable marker of functioning renal mass
▪ GFR influenced by age, sex, BSA
▪ GFR also varies by a number of other variables
▪ time of day, protein intake, pregnancy, extracellular fluid status, blood
pressure extremes, use of anti-hypertensives
Why is Assessment of GFR Important?
Diagnosis
▪ Detection of Acute kidney Injury
▪ Change in level of GFR: improvement and deterioration
▪ Challenging
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in extremes of body size
In neonates
severe malnutrition (cirrhosis)
high or low creatinine intake
grossly abnormal muscles mass
Definition and Staging of Acute Kidney Disease
AKI Classification
▪ AKI staged by cause and severity of abnormal kidney measures.
Example: Pediatric modified RIFLE AKI classification system (pRIFLE)
URINE OUTPUT?
▪ No benefit using 1-h vs 6-h urine output in diagnosing AKI
▪ 32% increase in the incidence of AKI with urine output criterion [Macedo
et al. 2011]
Why is Assessment of GFR Important?
Prognosis
▪ Critically ill children with pRIFLE I or pRIFLE F (>50% decrease
in est Crt clearance) at increased risk of persistent AKI of >48
hours and exhibit higher mortality rates
▪ Percentage fluid overload at the time of RRT initiation in
children with AKI is independently associated with mortality
Why is Assessment of GFR Important?
Guiding Therapy
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Dosing and monitoring for medication
Determining safety of diagnostic tests/procedures
Referral to nephrologists
Placement of dialysis access
GFR
▪ GFR cannot be measured directly.
▪ Most common method is based on the concept of clearance
▪ The renal clearance of substance x (Cx) is calculated as:
CX = UXV/PX
V is the urine flow rate (ml/min)
UX is urine concentration of substance x
PX is the plasma concentration of substance x
▪ If the substance is freely permeable across the glomerular capillary
and is not synthesized, transported, or metabolized by the kidney,
CX is equal to GFR
Children –Specific Considerations
▪ Significant developmental changes influence measurement of GFR
▪ All nephrons are terminally differentiated at birth, only the
juxtamedullary glomeruli are used at birth.
▪ Continuous recruitment of additional glomeruli until 18–24 months
of age
▪ Growth spurts [1st year of life & puberty] and rapid increase of
muscle mass have significant impact on measuring GFR
▪ GFR by renal clearance: practically challenging in children not toilet
trained or incomplete bladder emptying
Measured GFR
▪ Clearance measured with plasma or urinary methods record renal
clearance of endogenous or exogenous substances
▪ Ideal substance: freely filtered at the glomeruli, neither secreted
reabsorbed by the renal tubules
▪ Renal clearance of inulin is the gold standard in children and adults
▪ Inulin is not protein bound, freely filtered by the glomerulus and not
secreted, metabolized, or reabsorbed by the renal tubules
▪ However need for continuous infusion, multiple blood and urine
samples makes it difficult, time consuming
▪ Alternatives exogenous markers: 51Cr EDTA, 99mTc-DTPA
radioisotopes, iohexol
▪ In children owing to expense, time, requirement for multiple blood
samples mGFR only reserved for situations where accuracy
essential
Estimated GFR
▪ Estimates GFR without need for urine collection
▪ Uses endogenous markers
▪ The National Kidney Foundation guidelines recommend the use of
serum marker-based prediction equations for eGFR as opposed to
serum markers alone
eGFR Creatinine
• Derived from creatine and phosphocreatine in muscle
• Freely filtered, not reabsorbed or metabolised but significant
proximal tubular secretion which increases with lower GFR
– Proximal tubular creatinine secretion equates to 10–20% of the
excreted load
– Can reach up to 50% when GFR is reduced, resulting in overestimation
of GFR
• Age and muscle mass dependency of serum creatinine creates
difficulties measuring GFR challenges in children with co-morbidities:
– spina bifida
– neuromuscular disease
– anorexia nervosa
– liver cirrhosis
eGFR Creatinine in PICU
CHALLENGES….
• Positive fluid balance and volume of distribution dilutes sCr
concentrations and delays diagnosis
• Rapidly fluctuating renal hemodynamics
• Plasma creatinine is not in a steady state
• Inhibition of secretion by the renal tubule
– For example trimethoprim
• Interference with extrarenal elimination by gut bacteria
– Broad spectrum antibiotics
• Errors common with standardized assays due to interference
from substances such as ketones
Creatinine Based Prediction Equations
▪ In children Schwartz formula most commonly used clinically
▪ eGFR = k x L/Scr
L is height in cms
Scr is serum creatinine in mg/dl
k is an empirical constant
▪ Cockroft-Gault equation gives an appropriate estimate of creatinine
clearance in children >12 yrs of age
▪ Modification of Diet in Renal Disease (MDRD) formula used in adults.
More accurate than Cockroft-Gault equation but grossly inaccurate in
children and underestimates GFR …..resulting in false positive diagnosis
of CKD
▪ The CKD-Epidemiology Collaboration equation performs better than
MDRD especially at GFR above 60 mL/min per 1.73 m2
eGFR Cystatin C
• A non-glycosylated protein produced by all nucleated cells
• Cystatin C freely filtered, reabsorbed and completely metabolized in
tubular cells
• However cystatin C is catabolized and almost completely
reabsorbed by renal proximal tubular cells, it cannot be used to
measure GFR, only offers estimation of GFR
• More stable rate of production & less influenced by race and
ethnicity than eGFRcr
• Serum cystatin C levels are also influenced by non GFR determinants
– uncontrolled thyroid disease, corticosteroid use, age, sex, adipose tissue
• Meta-analysis of 46 studies, in adults & children: the reciprocal
value of CysC closely related to GFR with higher area under the
curve (0.93 vs 0.84) Dharnidharka VR 2002
Levey et al. Jama 2015
eGFR in Children
CKiD Study
▪ eGFR using demographic variables and endogenous biochemical
markers of renal function including creatinine, cystatin C, and blood
urea nitrogen (BUN)
eGFR = 39.1 x [height (m2)/Scr(mg/dl)]0.516
x [1.8/cystatin C (mg/L)]0.294 x [30/BUN (mg/dl)]0.169
x [1.099male] x [height (m)/1.4]0.188
▪ This equation shows the highest accuracy and correlation and the
narrowest 95% limits of agreement with measured GFR
▪ More precise eGFR with combined cystatin C and creatinine
demographic-based formulas
Schwartz et al C JASN 2009
In AKI…..
• eGFRcr can be improved by incorporating data on creatinine
generation and fluid balance
• In adults the Jelliffe's equation accounts for fluctuations in
serum creatinine over time in AKI
• Modified Jelliffe's equation also takes into account the
variations in fluid balance
In AKI…..
• Cystatin C has 1/3 the volume of distribution of creatinine &
reaches a new steady state 3 x faster than creatinine
• An increase in plasma cystatin C precedes plasma creatinine
• Subtle decrements in GFR are more readily detected by changes in
serum cystatin C than by serum creatinine partly due to the shorter
half-life of cystatin C.
• The affect of acute illnesses on cystatin C production rate in
unknown
• Although a standardized reference material is now available,
considerable variation remains among cystatin C assays
• More costly than serum creatinine measurements
Alternative Markers
• Several biomarkers proposed
• Still experimental
Aminoglycoside Clearance
• Aminoglycosides clearance can provide an estimation of renal
function
• In ICU gentamycin and tobramycin clearance was compared with
standard MDRD and CG formulae along with serum cystatin C
• Gentamycin clearance performed the best, being within 10% of
the value on 44% of occasions and within 20% on 78% of
occasions.
• Gentamycin clearance better estimate of creatinine clearance
than the 24-h urine estimate [TE Jones et al. 2009]
MicroRNAs
• In humans 700 -1000 miRNAs estimated
• Implicated in several physiological events as well pathologic
processes
• Most studies have measured miRNA in tissue, therefore
cumbersome to measure in clinical practice
Magnetic resonance imaging
• Measure GFR through dynamic
imaging of uptake of contrast
agent using a two-compartment
model
• Gadolinium based exogenous
filtration markers
• Quick….direct measurement of
GFR 4 min following injection of
gadolinium
• Risk of systemic nephrogenic
fibrosis in renal impairment
Ratiometric Approach
• Use two-photon microscopy to monitor the ratio in renal capillaries
of a filterable and a nonfilterable fluorescent marker following
simultaneous intravenous injection of both [Yu et al.]
• This technique is promising for use in critically ill patients with varying
GFR, but validation required
Renal Angina…
Alternative Approach: Goldstein et al
• Proactive approach versus reaction
• Predict AKI prior to its development
• Allowing for earlier intervention
Step 1: Identify Children at risk of AKI
Epidemiology of AKI in
children has changed from
primary kidney disease to
diseases in which the
kidneys are affected as a
result of another systemic
disease or its treatment
Step 2: Renal Angina Syndrome
• In AKI no characteristic syndrome that prompts concern
and investigation
• Alerts…..
– small changes in serum creatinine/estimated creatinine
clearance
– increasing degrees of fluid overload
Conclusion
• Several biomarkers to screen and diagnose kidney disease
• Each has its limitations….all at best only provide an ESTIMATION
• Most commonly use eGFRcrt
• Cystatin C promising alternative but widespread use not yet
recommended due to incomplete understanding of non-GFR
factors affecting serum concentration, higher costs and incomplete
standardization of assays
• Practically eGFR show the direction and magnitude of kidney
function changes and rarely inhibit clinical decision making
• New biomarkers …but none validated to make clinical decisions
• If accuracy required…need to measure clearance