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					                     East Kent Hospitals
                                 NHS Trust




Kidney Function Testing - 1


                   Dr Edmund Lamb

                   ACB National
 Ucr x V           Training Course,
 Pcr x T
                   September 2007
                            East Kent Hospitals
                                        NHS Trust




            Overview
Part one
• Classification of CKD
• GFR
• Creatinine and eGFR

Part two
• Cystatin C
• Proteinuria/albuminuria
                              East Kent Hospitals
                                          NHS Trust




What won’t be covered
   •   Urea
   •   Urinary pH
   •   Urinary osmolality
   •   Fractional bicarbonate
       excretion
   •   Ammonium chloride loading
       test
   •   Water deprivation test
   •   „Stone screens‟
   •   …etc
                                           East Kent Hospitals
                                                       NHS Trust




   Why do we care about GFR?
• GFR best overall index of kidney function
• Total kidney GFR = sum individual nephron GFR
• Decreasing GFR seen in all forms of progressive
  kidney disease
• Easily understood that kidney acts as a „filter‟
• Continuous scale, „Know your number!‟
• Stages of CKD defined in terms of GFR
• Renal NSF recommends eGFR on all serum
  creatinine requests
                                     East Kent Hospitals
                                                 NHS Trust


Filtration takes place at the
         glomerulus



                                                     17 mm Hg




            100 uL/day/nephron        200 L UF/day
            200 L/day = 140 mL/min
                                                                      East Kent Hospitals
                                                                                  NHS Trust



                        CKD classification
               (NKF-K/DOQI 2002, KDIGO 2005)
Stage                GFR                Management                              Prevalencea

1                    >90                Slow progression,                       3.3%
                                        CVD risk reduction
2, mild              60-89              Estimate progression,                   3.0%
                                        manage hypertension
3, moderate          30-59              Manage complications                    4.3%
                                        (anaemia, LVH, 2o hyperPTH,
                                        hyperlipidaemia)
4, severe            15-29              Prepare for RRT                         0.2%
5, failure           <15                RRT , if appropriate                    0.2%

                                                                                11.0%

a NHANES     III, Coresh et al, AJKD 2003;41:1-12
                                                      East Kent Hospitals
                                                                  NHS Trust




   Renal NSF. Part Two: Chronic Kidney Disease,
     Acute Renal Failure and End of Life Care


Quality requirements
1.    Early detection of CKD
         eGFR
         Protein:creatinine ratios
         NICE guidance on diabetes (type 1 & 2)
         NICE guidance on hypertension
2.    Minimising progression/managing complications
         Integrate with CHD/Diabetes NSFs
         NICE guidance on anaemia (jn progress)
3.    Identify ARF
4.    Palliative care
                                                               East Kent Hospitals
                                                                           NHS Trust



          Renal NSF. Part Two: Chronic Kidney Disease,
            Acute Renal Failure and End of Life Care

                              “Local health organisations can work with pathology services
                                and networks to develop protocols for measuring kidney
                               function by serum creatinine concentration together with a
                               formula-based estimation of GFR, calculated and reported
Quality requirements             automatically by all clinical biochemistry laboratories”
1.    Early detection of CKD
         eGFR
         Protein:creatinine ratios
         NICE guidance on diabetes (type 1 & 2)
         NICE guidance on hypertension
2.    Minimising progression/managing complications
         Integrate with CHD/Diabetes NSFs
         NICE guidance on anaemia (jn progress)
3.    Identify ARF
4.    Palliative care
                East Kent Hospitals
                            NHS Trust




Why detect CKD early?
                                                                              East Kent Hospitals

        Increased risk in CKD                                                             NHS Trust




          Age-standardised rate of death
                                   cardiovascular
         Age-standardised rate of hospitalizations events
          from100 person-y) 100 person-y)
          (per any cause (per
         (per 100 person-y)
         160
          40
          16                                                                            36.60
                                                                                        144.61
                                                                                        14.14
          35
         140
          14
                                                                      11.36
          30
         120
          12
          25
         100
          10                                                          21.80
                                                                      86.75
          20
          80
           8
          15
          60
           6                                         11.29
                                                     45.26
                                                     4.79
          10
          40
           4
                       13.54        17.22
                                    3.65
          20
           5
           2            2.11
                        0.76        1.08
           0
                        ≥60       45–59       30–44            15–29              <15
                                    Estimated GFR (ml/min/1.73 m2
                                    Estimated GFR (mL/min/1.73 m2))
No. of events        73,108
                    366,757
                     25,803    106,543
                                34,690
                                11,569      18,580
                                            49,177
                                             7802             8809
                                                             20,581
                                                              4408        11,593
                                                                           3824
                                                                           1842

                                                                       Go et al NEJM 2004; 351: 1296-1305
                                             East Kent Hospitals


       Why detect CKD early? – (1)
                                                         NHS Trust




             complications
• Better manage CVD risk: increased awareness leading to -
      improved RAAS blockade in hypertensives with
      proteinuria
      earlier treatment of anaemia
      less development of LVH
• Better manage other complications -
      metabolic bone disease
      acidosis
      nutritional advice
      diabetic control
• Avoidance of nephrotoxic drugs
• Suggestion that 45 mL/min/1.73 m2 better threshold (3A/3B)
                                             East Kent Hospitals
                                                         NHS Trust




  Why detect CKD early? – (2) RRT
• Late referral (i.e. < 3 months before RRT required) of
  patients with CKD requiring RRT is common (approx 1/3)
• Late referral commoner in older, female, socially deprived,
  sicker patients
• Late referral associated with poor prognosis (even after
  adjusting for above) – 3 x risk of death in first months of
  dialysis
• Due to dialysis preparation (better access), pre-emptive
  transplantation, avoiding uraemic complications (e.g.
  hyperkalaemia, pulmonary oedema)
East Kent Hospitals
            NHS Trust
                                                                East Kent Hospitals
                                                                            NHS Trust




A questionable test
BY Margaret McCartney, Published: March 3rd 2007

         You take your car to the garage. The windscreen wiper isn’t working
   properly. Nor is the rear light. It’s minor stuff so you expect a quick turnaround
   and an affordable bill. You are told, however, that there is a problem with the
   exhaust. It is failing and there is nothing much you can do about it. The mechanic
   can offer no odds about how likely the exhaust is to fail but he does offer you
   some expensive equipment that may or may not help. You’ll need to let your
   insurance company know either way and you’ll need to come to terms with a
   large chunk of uncertainty either way about the car’s future driving potential…..
         This is not a perfect analogy but it is an approximation of the kinds of
   dilemmas being caused by the “eGFR" test. You may or may not have heard of
   eGFR, or know that it stands for ESTIMATED GLOMERULAR FILTRATION
   RATE. But if you’re on blood pressure medication and have had a blood test
   recently, you are likely to have had it measured.
         The eGFR……..
                                       East Kent Hospitals
                                                   NHS Trust




What are the risks of eGFR reporting?

• Misclassification of CKD due to
  imprecision/inaccuracy
• Use of MDRD formula in inappropriate
  patient/ethnic group
• Identifying non-disease (e.g. in older people)
• Directing health-care resources to the wrong people
• Clinician didn‟t want to know eGFR!
            East Kent Hospitals
                        NHS Trust




How do we assess
     GFR?
                                             East Kent Hospitals
                                                         NHS Trust




                    Clearance
Traditionally, GFR assessed using concept of „clearance‟
Clearance = USV/PST

When substance S has: stable concentration in plasma,
 physiologically inert, freely filtered, not secreted,
 synthesised, reabsorbed nor metabolised by kidney

then clearance = GFR
                                       East Kent Hospitals
                                                   NHS Trust




Gold standard - Inulin
• Fructose polymer (Mr 5,000 Da)
• Gold standard is a constant infusion, urinary clearance
  method
• Requires urine collection and infusion
• (Single bolus methods can be used)
• Time-consuming & inconvenient for patient
• Exogenous compound
• Extra-renal clearance 0.083 mL/min/kg
• Expensive and difficult to measure
                                    East Kent Hospitals
                                                NHS Trust




Single bolus technique
                                    Distribution
                                    phase
    Log
    conc.                  k
            Co

             Time after injection


            GFR = k x Co
                                           East Kent Hospitals
                                                       NHS Trust




     Other exogenous markers
• 51Cr-ethylenediaminetetraacetic acid (EDTA)
• 99mTc-diethylenetriaminepentaacetic acid (DTPA)
• 125I-iothalamate
• Iohexol (Niculescu-Duvaz et al, Kidney Int 2006)

• All have relative advantages and disadvantages
• All give reasonable agreement with gold standard
• 51Cr-EDTA preferred „silver standard‟ method in UK
Iohexol - outpatient         East Kent Hospitals
                                         NHS Trust




    procedure
               Non-radioisotopic
               HPLC or capillary
               electrophoresis
               R2=0.96




               (Niculescu-Duvaz et al, Kidney
               Int 2006)
                                       East Kent Hospitals
                                                   NHS Trust




          Endogenous markers
No need for injection
Single blood sample (+/- urine) required

•   Creatinine clearance
•   Serum creatinine
•   Calculated clearances (estimated GFR, eGFR)
•   Cystatin C
                                         East Kent Hospitals
                                                     NHS Trust




           Creatinine clearance
•   First used in 1937 (Popper and Mandel)
•   Problems of timed collection
•   Tubular secretion (exceeds GFR by 10-100%)
•   Day-to-day CV 25%
•   “Health resources are wasted by the routine
    measurement of creatinine clearance; it should be
    abandoned” - Payne 1986
                                                East Kent Hospitals
                                                            NHS Trust




    Serum creatinine (Mr 113 Da)
• Creatine stored in muscle cells, where it is precursor of
  phosphocreatine; a high energy storage compound
• ~2%/day spontaneously breaks down to creatinine
• Clearance predominantly renal
• Therefore, blood conc. reflects renal function
• Most widely used test of renal function
• In east Kent, 450,000 tests/y/600,000 popn.
• Equates to 45 million creatinine assays/y in UK
                                            East Kent Hospitals
                                                        NHS Trust


             Serum creatinine is inversely
                   related to GFR

                 GFR=k/serum




                               creatinine
creatinine




                               1/Serum
                 creatinine
Serum




                 GFR                        GFR
            East Kent Hospitals
                        NHS Trust




Why isn’t serum
creatinine good
   enough?
                                                            East Kent Hospitals
                                                                        NHS Trust




     Serum creatinine - problems
Non-renal influences:
• gender, ethnicity and age
• nutrition/diet
• drugs (e.g. cimetidine)
• muscle mass

Clinical utility
• Poor sensitivity for CKD
• Not useful in ARF
• Muscle wasting disorders

Analytical problems:
• Non-specificity (protein, ketones, ascorbic acid) (pseudo-chromogens)
• Spectral interferences (icterus/lipaemia/haemolysis)
• No international standardization
                           East Kent Hospitals
                                       NHS Trust




SCr 110 umol/L   SCr 110 umol/L
GFR 40 mL/min    GFR 120 mL/min
                                                        East Kent Hospitals
                                                                    NHS Trust

Serum creatinine - sensitivity for kidney disease



Plasma
creatinine                     Stage of
(umol/L)
                               kidney disease


              5     4      3        2
                                                                  Reference
                                                                  Range



                  Glomerular Filtration Rate (ml/min)
                                             East Kent Hospitals
                                                         NHS Trust




                Estimated GFR
Equations based on serum creatinine but taking into account
  non-renal influences improve its relationship with GFR

“GFR should be estimated from prediction equations that
  take into account serum creatinine and some or all of age,
  gender, race and body size…….In adults, either
  Cockcroft & Gault or MDRD equations are useful”


NKF-KDOQI 2002
                                                            East Kent Hospitals
                                                                        NHS Trust




     Serum creatinine - problems
Non-renal influences:
• gender, ethnicity and age
• nutrition/diet
• drugs (e.g. cimetidine)
• muscle mass

Clinical utility
• Poor sensitivity for CKD
• Not useful in ARF
• Muscle wasting disorders

Analytical problems:
• Non-specificity (protein, ketones, ascorbic acid) (pseudo-chromogens)
• Spectral interferences (icterus/lipaemia/haemolysis)
• No international standardization
                                       East Kent Hospitals
                                                   NHS Trust




                Why eGFR?
• GFR is the best overall index of kidney function
• Gold-standard GFR techniques are not practical
  for the entire CKD population
• Estimates of GFR are better/more practical than
  creatinine clearance
• Estimates of GFR are more sensitive for CKD
  than creatinine alone
                                                                   East Kent Hospitals
                                                                               NHS Trust




            GFR prediction equations
Cockcroft & Gault, 1976
(140 - age) x weight/0.814 x serum creatinine (x 0.85 if female)

Original MDRD (6-v), 1999
170 x [serum creatinine x 0.011312]-0.999 x age-0.176 x (0.762 if female) x (1.180 if
   black) x (serum urea x 2.801)-0.170 x (serum albumin x 0.1)+0.318

Abbreviated MDRD (4-v), 2000
186 x [serum creatinine x 0.011312]-1.154 x age-0.203 x (1.212 if black) x (0.742 if F)

ID-MS traceable MDRD (4-v), 2005
175 x [serum creatinine x 0.011312]-1.154 x age-0.203 x (1.212 if black) x (0.742 if F)
                                     East Kent Hospitals
                                                 NHS Trust




Cockcroft & Gault (1976)

                                                 R2 0.48
  R2 0.69




            Coresh et al, AASK study 1998
                                     East Kent Hospitals
                                                 NHS Trust




           The MDRD Study
• Modification of Diet in Renal Disease Study
• 1628 patients with CKD
• (1070 equation development, 558 testing)
• Reference GFR – 125I-iothalamate clearance
• Creatinine – kinetic Jaffe on Beckman Astra CX3
  (Cleveland Clinic Foundation)
• Stepwise regression approach
                        East Kent Hospitals
                                    NHS Trust




MDRD formula (6-v)



R2 0.84                  R2 0.90
Bias 19.8%               Bias -11.5%



     Levey et al 1999
                                             East Kent Hospitals
                                                         NHS Trust




          MDRD formula (2000)
Abbreviated MDRD (4-v)
186 x [serum creatinine (umol/L) x 0.011312]-1.154 x age-
  0.203 x (1.212 if black) x (0.742 if F)



Published in abstract form only
No requirement for urea and albumin (or weight)
Little loss of accuracy R2 = 0.89, bias -12.1%
90% of subjects within 30% of true GFR
                                               East Kent Hospitals
                                                           NHS Trust



    ID-MS traceable MDRD formula
                (2005)
186 x [serum creatinine x 0.011312]-1.154 x age-0.203 x (1.212 if
  black) x (0.742 if F)

Becomes:

175 x [serum creatinine x 0.011312]-1.154 x age-0.203 x (1.212 if
  black) x (0.742 if F)


                         Levey et al 2006
                                                                East Kent Hospitals
                                                                            NHS Trust




                    C&G vs MDRD
               Lewis et al 2001             African-Americans
               Vervoort et al 2002          Type 1 diabetes
               Bostom et al 2002            CKD patients
               Lin et al 2003               Healthy donors
               Rodrigo et al 2003           Transplant recipients
               Pierrat et al 2003           Children >12 y
               Van den Noortgate et al 2003 „Old old‟
               Lamb et al 2003              Older people
               Rule et al 2004              Healthy donors
               Poggio et al 2005            CKD patients
               Poggio et al 2005            Kidney donors
               Froissart et al 2005         European CKD

               • Reviewed in Ann Clin Biochem September 2005

4v-MDRD offers practical advantages & is more accurate & precise
                      for stage 3-5 CKD
                                   East Kent Hospitals
                                               NHS Trust


         National/International
          Recommendations
• NKF – now favour 4v MDRD
• NKDEP – 4v MDRD
• ERA EBPG – any method validated against BSA-
  corrected GFR
• KDIGO - method validated against a gold-
  standard measure of GFR
• Kidney Health Australia – 4v MDRD
• UK CKD guidelines/DoH – 4v MDRD
                                                                     East Kent Hospitals
                                                                                 NHS Trust


          DoH eGFR Guidance
•    Implement eGFR nationally on 1st April 2006
•    Use IDMS traceable MDRD equation
•    Report in all adults (not children)
•    Screen high risk groups (e.g. diabetes, vascular disease, heart failure,
     hypertension, urinary tract obstruction, …etc.)
•    If eGFR exceeds 89 then report as >90
•    Use UKNEQAS factors to improve consistency

•    Communicate with users that:
a)   GFR 60-89≠CKD unless other evidence
b)   x1.212 for African-Caribbean‟s
c)   not valid in ARF, pregnancy, oedema, muscle wasting, amputees,
     malnourished
                                              East Kent Hospitals
                                                          NHS Trust


      Why April 1st 2006?
• Quality and Outcomes Framework 2006-7
 ChKD 1    Register of patients with CKD 6 points
 ChKD 2    % with BP recording                6 points
 ChKD 3    % with BP<140/85                   11 points
 ChKD 4    % on ACEI/ARB                      4 points

        Context: >600 points in QOF, only 27 for CKD
        Approx £250/point for practice of 10,000
        Therefore £6,700 for CKD
        QOF may = 40% of practice income
               East Kent Hospitals
                           NHS Trust




       eGFR –
 jumping the gun or
just what the doctor
      ordered?
                                              East Kent Hospitals
    Issues and questions                                  NHS Trust




• Accuracy
• Precision and level of GFR
• Sample type – fasting/random
• Does it work on older people?
• What about South Asians and Chinese?
• What about type 2 diabetes?
• What about monitoring rate of decline?
• Drug dosage – absolute or relative clearance?
• Should we correct for BSA? Du Bois or Haycock formula?
• Is 1.73 m2 still appropriate? Does it matter (e.g. 1.0 m2 for
  LVMI)?
• Outcomes – BSA corrected versus uncorrected GFR
• Etc…
                              East Kent Hospitals
                                          NHS Trust




Issues and questions
• Accuracy/standardization
• Precision and level of GFR
• Sample type – fasting/random
• Does it work on older people?
• What about South Asians and
  Chinese?
• What about type 2 diabetes?
                                        East Kent Hospitals
                                                    NHS Trust




    Serum creatinine - measurement
•    Jaffe methods
•    Enzymatic methods
•    HPLC
•    ID-MS – reference method

    Review of the sedimentation
    process which is caused in normal
    urine by picric acid and a new
    reaction of creatinine
    By M. Jaffe (Submitted to the
    editor on 26th June 1886)
                                          East Kent Hospitals
                                                      NHS Trust




3% use enzymatic assay + 13% dry-slide enzymatic
                                                                                                  East Kent Hospitals
                                                                                                              NHS Trust




UKNEQAS survey: accuracy against ID-MS
                               60
                                                            All methods
                               55                           OCD (J&J) slides [1JJ]
                               50                           Abbott reagents [11AB]
% Method Bias from MS Target




                               45                           Bayer reagents [11TE]
                               40                           Beckman reagents [11BK]

                               35                           Olympus reagents [11OL]
                                                            Roche Integra reagents [11RO]
                               30
                                                            Roche Modular reagents [11BO]
                               25
                                                            In-house reagents [14OO]
                               20                           Olympus reagents [14OL]
                               15                           Synermed reagents [14SR]
                               10                           ILab reagents [6IL]

                                5
                                0
                                -5
                               -10
                               -15
                                     0   100   200   300    400       500       600         700      800       900
                                                     Mass Spec Creatinine (umol/L)
                                    East Kent Hospitals
                                                NHS Trust




 Accuracy – possible solutions

• Align all assays to MDRD lab (Beckman Astra
  CX3)
• International standardization
• Harmonise equations for assays (UKNEQAS
  approach)
                                    East Kent Hospitals
                                                NHS Trust




  International standardization

“Serum creatinine assays should be
  calibrated using an international standard”



               NKF-KDOQI 2002
                                                   East Kent Hospitals
                                                               NHS Trust




International standardization




   Reference measurement system for creatinine, Panteghini et al 2006
                                   East Kent Hospitals
                                               NHS Trust



Harmonisation approaches
SRM 967           Assay specific
NKDEP/IFCC        adjustments


Standardization


 Creatinine       MDRD
 result                            eGFR
                  equation

Specificity


  Enzymatic,
  IDMS assays
                                               East Kent Hospitals
                                                           NHS Trust




 UKNEQAS ‘adjustment’ factors
• Allow alignment of       Method      Intercept Slope
  all major assays for
  use in ID-MS             Abbott      13.21         0.940
  traceable MDRD
  formula                  Bayer       17.78         0.927
• E.g. for Abbott:         Beckman     5.92          0.994
  175 x [((serum
  creatinine –             Olympus     16.14         0.955
  13.21)/0.940) x
  0.011312]-1.154 x age-   Roche (I)   2.03          0.988
  0.203 x (1.212 if
  black) x (0.742 if F)    Enzymatic -0.26           1.011
           May 2006
                                East Kent Hospitals
     40 y old white female,                 NHS Trust


   true creatinine 81 umol/L,
‘true’ eGFR 67 mL/min/1.73 m2


                                   as reported by
                                   labs
                                   CV 8.5%,
                                   eGFR 63.1




                                     what could be
                                     achieved with
                                     slope adjustors
                                     CV 6.0%,
                                     eGFR 64.6
                                East Kent Hospitals
                                            NHS Trust




    Issues and questions
•   Accuracy/Standardization
•   Precision and level of GFR
•   Sample type – fasting/random
•   Does it work on older people?
•   What does it mean in older people?
•   What about South Asians and Chinese?
•   What about type 2 diabetes?
Scatter increases as GFR                East Kent Hospitals
                                                    NHS Trust



approaches physiological levels




                                  Froissart et al 2005
                         East Kent Hospitals
                                     NHS Trust


Equation Performance




                       M. Mafham (Unpublished) 2005
                       University of Oxford,
                       Clinical Trials Support Unit
                                                    East Kent Hospitals
                                                                NHS Trust




         MDRD and level of GFR
                       CKD                   ‘healthy’
Rule et al 2004        -6.2%                 -29%
Poggio et al 2005      -0.5 mL/min/1.73 m2 - 9.0 mL/min/1.73 m2

Froissart et al 2005   1.3 mL/min/1.73 m2    -3.3 mL/min/1.73 m2


   •NKDEP/KHA – don’t report if >60 mL/min/1.73 m2
   •Scottish Renal Registry – don’t report if >60 mL/min/1.73 m2
   •UK CKD – don’t report if >90 mL/min/1.73 m2
                               East Kent Hospitals
                                           NHS Trust




    Issues and questions

•   Accuracy/Standardization
•   Precision and level of GFR
•   Sample type – fasting/random
•   Does it work on older people?
•   What does it mean in older people?
•   What about South Asians and Chinese?
•   What about type 2 diabetes?
                                       East Kent Hospitals
                                                   NHS Trust




          Creatinine and diet
• Physiologically, protein intake increases GFR
• Cooking meat converts creatine to creatinine
• Readily absorbed and causes increased serum
  creatinine (effect persists for hours)
• Reported in BMJ and Lancet letters late
  1970‟s/early 1980‟s
• Effect on eGFR largely ignored – no
  recommendation re: sample type
                                                  East Kent Hospitals

Effect on serum creatinine
                                                              NHS Trust




n=32               Median serum creatinine (Jaffe, umol/L)

                   Preprandial      1 to 2 h pp     3 to 4 h pp

Meat               80.5             101.0*          99.0*

Non meat           89.5             88.5            86.5

*p<0.001, enzymatic and ID-MS methods showed same trend
Cystatin C was unaffected by meat intake
                                                  Preiss et al 2007
                                           East Kent Hospitals
                                                       NHS Trust



            Effect on eGFR
                 Median eGFR (Jaffe, mL/min/1.73 m2)

                 Preprandial   1-2 h pp    3-4 h pp

Meat             84.0          59.5*       64.0*

Non meat         76.5          77.5**      80.0**


*p<0.001, **p<0.01

                                          Preiss et al 2007
                                East Kent Hospitals
                                            NHS Trust




    Issues and questions

•   Accuracy/standardization
•   Precision and level of GFR
•   Sample type – fasting/random
•   Does it work on older people?
•   What about South Asians and Chinese?
•   What about type 2 diabetes?
                                         East Kent Hospitals
                                                     NHS Trust




      MDRD in older people (1)
Whilst approx. 10% of population overall have
 CKD, in over 70 y age group >25% have GFR
 <60 mL/min/1.73 m2

A. Is this an artificial problem induced by the
  MDRD equation?
B. Does it reflect normal ageing?
                                          East Kent Hospitals
                                                      NHS Trust




      MDRD in older people (2)
• 46 older people, mean age 80, range 69-92 years
• Mean 51Cr EDTA 55 (range 24-100) mL/min/1.73
  m2
• Creatinine results recalibrated to give Beckman
  Astra CX3 equivalent data
• eGFR calculated with 4v-MDRD
• Mean bias vs. EDTA -2.0 (95% CI -18 to 14)
  mL/min/1.73 m2 (not significant)
                                        Lamb et al 2007
                                East Kent Hospitals
                                            NHS Trust




    Issues and questions
•   Accuracy/standardization
•   Precision and level of GFR
•   Sample type – fasting/random
•   Does it work on older people?
•   What about South Asians and Chinese?
•   What about type 2 diabetes?
                                                  East Kent Hospitals
                                                              NHS Trust


                  Chinese
• 684 participants (mean GFR 55+35)
• 99mTc-DTPA reference GFR
• Creatinine calibrated to Beckman Astra CX3
• MDRD underestimates true GFR at normal function and
  overestimates GFR at low levels
• 58% within 30% of true GFR
• 175 x [serum creat. x 0.011312]-1.234 x age-0.179 x (0.79 if F)
• Approx. 80% within 30% of true GFR


                     Zuo et al 2005                Ma et al 2006
                                            East Kent Hospitals
                                                        NHS Trust




           Other Asian studies
• Pakistani individuals but reference method was
  creatinine clearance. Jafar et al. 2005

• Japanese-Americans but reference method was creatinine
  clearance, Gerchman et al. Diabetes Res Clin Pract. 2006
                                East Kent Hospitals
                                            NHS Trust




    Issues and questions
•   Accuracy/standardization
•   Precision and level of GFR
•   Sample type – fasting/random
•   Does it work on older people?
•   What about South Asians and Chinese?
•   What about type 2 diabetes?
                                             East Kent Hospitals
                                                         NHS Trust


            Type 2 diabetes
• MDRD better than C&G for identifying stage 3 and 4
  CKD
                                  Rigalleau et al 2005

• Neither MDRD nor C&G accurate in stage 1 or 2 CKD:
  underestimate GFR and rate of change in GFR
                                  Rossing et al 2006
• MDRD and C&G underestimate GFR in stage 1 CKD
  but can be used to monitor patients in stage 2-3 CKD

                                   Fontsere et al 2006
                               East Kent Hospitals
                                           NHS Trust




  How robust is eGFR?
• Better than creatinine clearance
• As robust as the underlying serum
  creatinine measurement….
• But highlights age and gender related
  influences
• eGFR is improving recognition of CKD

• But, there are problems…
                                       East Kent Hospitals
                                                   NHS Trust




           Remaining issues
Need to:
• be more prescriptive about sample (fasting, delay)
• improve methodology (? enzymatic assays,
  international standardization – NIST SRM 967)
• better define CKD and identify progressors
• better understand natural history of CKD
  (especially wrt older people)
                                          East Kent Hospitals
                                                      NHS Trust




   Where do we go from here?
• Debate has been started in laboratory and nephrology
  community
• Attention re-focused on creatinine measurement
• Manufacturer‟s likely to move towards ID-MS alignment
  with an international creatinine standard
• Validation of MDRD equation being expanded and
  limitations better understood
• Many areas remain controversial
• Better markers of GFR still needed
                                         East Kent Hospitals
                                                     NHS Trust




                 Serum urea
• Poor indicator of GFR
• Affected by extra-renal factors (high-protein diet,
  increased protein catabolism, GI haemorrhage,
  liver disease, dehydration)
• Main use is in conjunction with creatinine (ratio)
• Many laboratories have abandoned „U & E‟s‟
                                          East Kent Hospitals
            Hierarchy of GFR tests                    NHS Trust




                             Inaccurate    Relatively
• Urea                                     practical
• 24 hr CCr
• Creatinine
• Cystatin C
• eGFR
• 3 hr CCr with Cimetidine
•   99mTc-DTPA

•   125I-iothalamate

• Iohexol
•   51Chromium-EDTA
                                          Impractical for
• Inulin                      Accurate    widespread use
      East Kent Hospitals
                  NHS Trust




End
                                       East Kent Hospitals
                                                   NHS Trust




   56 y white male, pool 123
Distribution 8, May 2006   Distribution 16, Feb 2007




 CV 5.6%, eGFR 58               CV 4.9%, eGFR 59
                                         East Kent Hospitals
                                                     NHS Trust


  Has the eGFR UK NEQAS been a
            success?
• Appears to have been early and widespread
  participation and uptake of factors in laboratories
• Between lab. CVs for eGFR respectable
• UK NEQAS have undertaken to provide support
  (factors) for new methods and on-going periodic
  adjustment/checks of existing factors
• Ultimate aim is to improve creatinine
  measurement
                                                                    East Kent Hospitals
                                                                                NHS Trust



       CKD prevalence: calibration &
          population estimates
Stage GFR                   Prevalencea Prevalenceb Prevalencec

1        >90                3.3%                -                  -
2        60-89              3.0%                -                  -
3        30-59              4.3%                5.43%              9.19%
4        15-29              0.2%                0.22%              0.35%
5        <15                0.2%                0.05%              0.05%


a NHANES III, Coresh et al, AJKD 2003;41:1-12
b NEOERICA, n=162,000, crude data, Stevens et al Kidney Int 2007
c NEOERICA, n=162,000, after calibration, Stevens et al Kidney Int 2007

				
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