Mätning av renalt inulin-clearance = sanningen

Transkript

1 Vad är GFR? Den glomerulära filtrationshastigheten, GFR, är den volym primärurin som produceras per tidsenhet, motsvarande den plasmavolym som filtrerats under samma tid.

2 Mätning av renalt inulin-clearance = sanningen

3 Vad är sanning? Absolut sanning finns bara i himlen eller i Platons idévärld. Vad är då den högsta vetenskapliga sanning som kan uppnås på jorden?

4 Vad är jordisk sanning? Alla artiklar som publicerats i ämnet samlas in och genomläses av specialister inom sanningsområdet. Därefter väljs de bästa artiklarna ut enligt en kvalitets-skala och specialisterna bedömer om det finns möjlighet att dra slutsatser och graderar slutsatsernas styrka enligt: Det finns starkt vetenskapligt underlag ( ) för att... Det finns måttligt starkt vetenskapligt underlag ( ) för att... Det finns begränsat vetenskapligt underlag ( ) för att... Det finns otillräckligt vetenskapligt underlag ( ) för att bedöma om...

5 Olika metoder att mäta GFR jämförda med renalt inulinclearance

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9 During a total of eight articles on cystatin C as a GFR-marker were published, but only by the Lund group, possibly due to their use of a slow, manual method, enzymeamplified single radial immunodiffusion, for analysis.

10 Kyhse-Andersen J, Schmidt C, Nordin G, Andersson B, Nilsson- Ehle P, Lindström V, Grubb A. Serum cystatin C, determined by a rapid, automated particle-enhanced turbidimetric method is a better marker than serum creatinine for glomerular filtration rate Clin Chem 40: , (1994)

11 PubMed search February 2012 for cystatin C AND (renal OR glomerular) generated 1513 hits Google search for cystatin C February 2012: hits

12 40 Å 30 Å 5 Å

13 Advantages of cystatin C as a GFR-marker Demonstrates the early, potentially reversible, decrease of GFR in the creatinine-blind area Independent of diet No tubular secretion Low influence by muscle mass, gender and race (African American) Independent of age for children and adults above 1 year Demonstrates the decrease of GFR in old persons Mirrors the diurnal GFR variation Elucidates filtration quality and life expectancy

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17 GFR-markers for patients with muscle atrophy Non-parametric ROC plots for serum cystatin C (solid line) AUC = and serum creatinine (dotted line) AUC = AUC = 0.50 equals the diagnostic efficiency of tossing a coin

18 Disadvantages of cystatin C as a GFR-marker High doses of corticosteroids increase significantly the P-Cystatin C level (but not low doses e.g. ointments, inhalation) Hyperthyreosis moderately increases the P-Cystatin C level (and decreases the P-Creatinine level due to increased tubular secretion) The cost of analysing P-Cystatin C is higher than that of analysing P-Creatinine (prices in Lund 2011: 2 versus 1 Euro)

19 GFR-prediction equations Relative GFR in ml/min/1.73m 2 Creatinine-based for adults: MDRDIDMS-traceable: egfr = 175 x (creatinine/88.4) x age x (if female) x (if African American) Cystatin C-based for adults and children: egfr = 85 x cystatin C -1.68

20 Creatinine-based egfr equations MDRD : x [S- creat ( mol/l)/88.4] x age x (if female) x (if African American) or e x ln(creat) x ln(age) (if female) (if African American) Only for adults Schwartz: 0.55 x height (cm) x [P- creat ( mol/l)/88.4] -1 Only for children Counahan Barratt : 0.43 x height (cm) x [P- creat ( mol/l)/88.4] -1 Only for children Lund-Malmö : e x creat x ln(age) x age (if female) For children and adults

21 Age-related GFR-predictions at a constant creatinine level of 80 micromol/l for 3 prediction equations

22 Reasons for the multitude of GFR prediction equations A Use of different calibrators B Use of different methods with varying doseresponse curves C Use of different mathematical models D Use of different study populations

23 Reduction of the multitude of GFR prediction equations A Use of different calibrators - Use verified international calibrators B Use of different methods with varying dose-response curves - Use international calibrators and commutability studies to equalize all methods C Use of different mathematical models - Use improved mathematical models D Use of different study populations - Identify the most important types of population

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26 The cystatin C international calibrator, ERM-DA471/IFCC, was released June 2010

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32 Ongoing calibration work 4049 samples from patients with known GFR (iohexol clearance) years of age 472 children below 18 years of age 1022 above 70 years of age 1943 with GFR > 60 ml/min/1.75 sqm Use of four different commutable methods adjusted to the international calibrator for cystatin C (ERM-DA471/IFCC): Gentian, Siemens, Dako, Sentinel (Abbott)

33 Aims of ongoing calibration work To arrive at method-independent cystatin C-based GFR prediction equations To compare prediction equations for GFR above and below 60 ml/min/1.75sqm. Do we need separate equations? To compare cystatin C-based GFR prediction equations for adults and children. Do we need separate equations? To determine diagnostic performance at different GFR levels

34 P30%-värdet för en GFR-prediktions-ekvation anger det procenttal av alla estimeringar som faller inom +/- 30% av det uppmätta GFR (med invasiv Gold Standard clearancemetod). De bästa kreatinin- och cystatin C- baserade ekvationerna når P30%-värden på 85-90%. Ekvationer baserade på både cystatin C- och kreatinin-baserade ekvationer når P30%-värden på 90-95%.

35 Suggestion for optimal diagnostic use of egfr Run both cystatin C and creatinine and calculate egfr (cystatin C) and egfr (creatinine) at the initial patient contact. If they agree: GFR is correct, no invasive clearance determination is required. If they do not agree: Try to find a biomedical explanation (low muscle mass, high dose of glucocorticoid). If an obvious explanation is found no invasive clearance determination is required. The non-affected egfr is used. P/S-Creatinine can be used to follow a correct egfr as defined above. If the two egfrs do not agree and no obvious explanation for the difference can be found: An invasive clearance determination is justified (iohexol clearance). Site: egfr.se

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41 egfr-verktyg och information /

42 It is more dangerous to have a reduced egfr (cystatin C) than a reduced egfr (creatinine), because you have a higher risk to die or develop end-stage renal disease. Why?

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44 It has been suggested that the inreased risk of having a reduced egfr (cystatin C) compared to that of having a reduced egfr (creatinine) is due to that not only reduced GFR, but also inflammation, increase the cystatin C level. This suggestion is based upon that some large cohort studies have shown a significant correlation between cystatin C and CRP levels.

45 Elective surgery to obtain elfin ears

46 Does systemic inflammation influence cystatin C? 20 persons with normal levels of CRP, SAA, orosomucoid and haptoglobin were subjected to elective surgery and the levels of these inflammatory markers and cystatin C and creatinine followed for 7 consecutive postoperative days Grubb et al. Scand J Clin Lab Invest 71: (2011)

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48 N o r m a l

49 I n d i s e a s e?

50 I n d i s e a s e!

51 No passage Passage

52 Functional glomerular pore size

53 GFR/filtration quality regulated levels of LMW-proteins/peptides Glucagon 3.5 kda Insulin 6 kda 2 -microglobulin 11 kda ProBNP 12 kda IL1-17 kda TNF- 17 kda FGF-2 18 kda Growth Hormone 22 kda Light Ig-chains 23 kda TGF- 25 kda IL-6 26 kda

54 Cystatin C, kreatinin och liv och död och obehag egfr används för att kunna: 1.Följa utvecklingen av njursjukdomar 2.Dosera läkemedel och kontrastmedel 3.Förutsäga utveckling av förvärrad njursjukdom (dialys, transplantation), behov av sjukhusvård och annat lidande 4.Förutsäga död