GFR estimation The key to assess

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					 GFR estimation: the key to
assessment of kidney disease
          Dr Graham Jones
  Department of Chemical Pathology
    St Vincent’s Hospital, Sydney


                               RCPA / AACB 2007 - GFR
         Functions of the Kidney
• Homeostatic / waste removal
  – water
  – hydrogen ions (pH)
  – sodium
  – potassium
  – calcium
  – phosphate
  – magnesium
  – nitrogen
  Kidney damage: abnormalities of these factors
                                          RCPA / AACB 2007 - GFR
                 Homeostasis
• For a person in steady state: input = output

• Urine volume = water intake (food + drink)
                    - fecal, sweat, respiratory
                           losses
• Sodium excretion = sodium intake – fecal and
                         sweat losses




                                         RCPA / AACB 2007 - GFR
    Other Functions of the Kidney
• Endocrine
  – 1-Hydroxylation of vitamin D
  – Erythropoietin production
  – Renin production
• Metabolic
  – Glycogen storage (minor role)
• Drug removal
  Kidney Damage: hypocalcaemia, anaemia
     Impaired drug removal
  Plus: acute phase changes
                                     RCPA / AACB 2007 - GFR
                         CKD Symptoms




Tietz Textbook of Clinical Chemistry: Renal Function and Nitrogen Metabolites
                                                                         RCPA / AACB 2007 - GFR
             “Renal Failure”
• Chronic
  – CKD: Chronic Kidney Disease
• Acute
  – ARF: Acute Renal Failure
  – AKI: Acute Kidney Injury
• Acute Classification
  – Pre-renal
  – Renal
  – Post-renal
                                  RCPA / AACB 2007 - GFR
             The CKD problem
• Clinically silent in the early stages
• Cost of renal disease can be extreme to health
  care service
• Effects of renal disease can be extreme on patient
• Treatments now available to slow progression

• Need an “early warning” system for CKD



                                        RCPA / AACB 2007 - GFR
          Diseases of the Kidney
•   Diabetes
•   Hypertension
•   Atherosclerosis           All global renal
•   Glomerular diseases       diseases affect
•   Toxins                  glomerular filtration
                                rate (GFR)
    – Gentamicin
    – NSAIDS
    – Compound analgesics
• Inherited diseases
• Tubular disorders                       RCPA / AACB 2007 - GFR
K/DOQI (USA)   RCPA / AACB 2007 - GFR
               What is GFR?
• Glomerular Filtration Rate is the volume of fluid
  passing through the glomerulus in a given period of
  time.
• Influenced by renal perfusion pressure, renal
  vascular resistance, glomerular damage, post-
  glomerular resistance.
• “Normal Range” approx 90 - 150 mL/min
  – Approx 170 L per day
• A larger healthy person has a higher GFR
  – Can be reported as 90 - 150 mL/min/1.73m2
• Values fall with increasing age
                                         RCPA / AACB 2007 - GFR
  Other reasons for estimating the
               GFR
• Monitoring progression of CKD
• GFR estimates are used for drug dosing decisions
  – Dosing of renally excreted drugs
  – Avoiding nephrotoxic drugs
• Risk factor for cardiovascular disease mortality
• Renal involvement in systemic diseases, such as
  diabetes mellitus or SLE



                                        RCPA / AACB 2007 - GFR
      How do we measure GFR?
• Ideal marker of GFR:
  – Constantly produced
  – Freely filtered at the glomerulus
  – Neither resorbed or secreted in the tubules
  – Not lost to the body in any other way

 • Inulin is the prototype GFR marker
    – Sugar of MW 5,000
    – Requires constant inulin infusion
    – Not used in practice
                                           RCPA / AACB 2007 - GFR
         Measurement of GFR
• Cr51-EDTA, I125-iothalamate, Tc99-DTPA, iohexol
• Intravenous injection of substrate
• Measure concentrations in blood and or urine at
  various time points
• Calculate clearance as estimate of GFR
• Time consuming
• Expensive
• Radioactive material
• Significant Between-laboratory variation (5-20%)
• “Gold standard” not very golden
                                       RCPA / AACB 2007 - GFR
               Estimate of GFR
•   Measured GFR
•   Serum creatinine
•   Creatinine clearance
•   Formulae based on serum creatinine
  – Cockcroft and Gault
  – MDRD
                      All based on measurements
• Other
                        of serum creatinine
  – Eg Cystatin C


                                         RCPA / AACB 2007 - GFR
      Marker of GFR (creatinine)
• Constant production 
• Freely filtered at the glomerulus 
• No tubular secretion or resorption
  – Some tubular secretion X
• No extra-renal metabolism 
• No extra-renal loss
  – Some GIT loss X
• Loss of creatinine through avenues other than
  glomerular filtration means Creatinine Clearance
  is slightly higher than the GFR
                                        RCPA / AACB 2007 - GFR
         Serum Creatinine Alone
• Default / Historical position
• Only marker universally available
  – Only marker for screening (case finding)
• Concentration reflects rate of production as well as
  rate of removal
• Relationship to rate of removal is not linear
  – “rectangular hyperbola”
• Requires doctor to take multiple (non-linear)
  factors into account

                                          RCPA / AACB 2007 - GFR
                                 S.creatinine approx. = 1/GFR
Serum Creatinine (mg/dL)




                           GFR
                                                    RCPA / AACB 2007 - GFR
            Cockroft and Gault
• Developed in 1976 from 249 people (96%
  male)
  – Subsequently validated in at least 58 studies
• A measure of creatinine clearance
• Estimate urine creatinine based on age, weight
  and sex of patient.
• False elevation of serum creatinine assays (in
  1976) gave lower results, serendipitously
  approximating the GFR
• Newer (better) creatinine assays give falsely
  elevated GFR estimates (approx 15%)
                                            RCPA / AACB 2007 - GFR
   Cockcroft and Gault - questions
• Should we correct for “new” creatinine
  measurements (decrease results by 15%)
• Should we use ideal body weight (estimated from
  height)
  – If so, when




                                       RCPA / AACB 2007 - GFR
           Creatinine Clearance
• Measurement of clearance of creatinine using:
  – Serum creatinine concentration
  – Timed urine collection (often 24 hours)
  – Urine creatinine concentration
  – Urine Volume
  – Clearance = Ucreat x Uvol / Screat x 24 hours
• Timed urine samples notoriously difficult



                                          RCPA / AACB 2007 - GFR
              GFR Assessment
•   Measured GFR
•   Serum creatinine
•   Creatinine Clearance
•   Cockcroft and Gault



• or one of over 40 other formulae using serum
  creatinine


                                       RCPA / AACB 2007 - GFR
                 MDRD* Formula
•   Levey et al Ann Intern Med 130:461-470, 1999
•   Approx 1070 in training set and 558 validation set
•   New formula developed for GFR
•   More accurate and precise than other formulae
• *Modification of Diet in Renal Disease




                                              RCPA / AACB 2007 - GFR
               MDRD – Notes:
• Not good for people with normal renal function
  – Few normals in training set
  – Low creatinine measurement less good
• Results reported as mL/min/1.73 m2 BSA
  – Good for grading renal failure
  – Effect on drug dosing?
• “Abbreviated” MDRD only requires age, sex and
  race (African-American or not)

                                        RCPA / AACB 2007 - GFR
      KHA, RCPA, AACB Proposal:
• Report estimated GFR with MDRD with all
  creatinine requests for patients over 18
• Results >60 mL/min/1.73m2 reported as “>60
  mL/min/1.73m2”
    – to be extended to 90 mL/min/1.73m2
•   Accuracy approximately +/- 30%
•   Recommended in USA (www.nkdep.nih.gov)
•   Recommended in UK (MDRD or C&G)
•   Law in France (C&G)

                                           RCPA / AACB 2007 - GFR
  www.nkdep.nih.gov



www.kidney.org/
PROFESSIONALS/kdoqi



  www.kdigo.org

  www.kidney.org.au

            RCPA / AACB 2007 - GFR
                Limitations
• Not a sensitive test for renal failure
   – Serum creatinine best for early detection
     and monitoring patients
• Delayed response in severe acute renal failure
  (as with serum creatinine)
• Wrong in dialysis patients
• Drug dosing issues not well addressed
• Interpretation in the elderly
• Interpretation in different racial groups

                                      RCPA / AACB 2007 - GFR
              Actual Outcomes
• Almost universal uptake of eGFR reporting
• Near complete standardisation of units
  – umol/L and mL/min
• Increase in referrals to nephrologists
  – Initial spike
  – Settled to approx. 30% increase
  – 85% of referrals were appropriate
  – Referrals were undertreated
     • Professor David Johnston (Queensland)
• Awareness of reduced GFR increased
                                               RCPA / AACB 2007 - GFR
                    Meeting 2
•   December 2006
•   Issues
•   The “175” equation for IDMS-aligned assays
•   Reporting up to 90 mL/min/1.73m2
•   Age-related decision points
•   Drug Dosing
•   Racial differences



                                        RCPA / AACB 2007 - GFR
                   The Future
• Better detection and management of CKD
• Better relationship with clinical colleagues
  – Started on urine albumin and protein
  – Starting on LFT and uric acid
• Recognition of role of laboratory
  – Recognising and solving metrological issues
  – Effector organ for clinical guidelines
• Better co-operation between laboratories for the
  benefit of doctors and patients

                                           RCPA / AACB 2007 - GFR
                    References
• Assessing Kidney Function - Measured and Estimated
  Glomerular Filtration Rate
   – Stevens LA et al. NEJM 2006;354:2473-83.
• Automated Reporting of Glomerular Filtration Rate - Just
  what the doctor ordered.
   – Levey AS et al. Clin Chem 2006;52:2188-93
• Australasian Creatinine Consensus Working Group.
  Chronic Kidney Disease and Automatic Reporting of
  eGFR. A position statement.
   – Med J Aust. 2005;183:138-141

                                              RCPA / AACB 2007 - GFR

				
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