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Tools for calculating

ROBUST CYSTATIN C- AND CREATININE-BASED ESTIMATES OF RELATIVE GFR

and

ABSOLUTE GFR FROM RELATIVE GFR

as well as for diagnosing

SHRUNKEN PORE SYNDROME

Introduction

To be able to correctly evaluate the kidney function of a patient, and to correctly dose a medicine or a contrast agent mainly excreted via the kidneys, knowledge of the glomerular filtration rate (GFR) of the patient is required. GFR might be determined using invasive procedures, e.g., by measuring the renal clearance of inulin, 51Cr-EDTA or iothalamate, or the plasma clearance of iohexol or 51Cr-EDTA1,2. Such procedures are expensive, slow and not completely free of risks for the patient. Therefore, cystatin C- or creatinine-based estimating equations for GFR have been suggested with the result being designated as eGFRcystatin C or eGFRcreatinine, respectively. This site suggests a simple strategy to obtain the best estimation of GFR by use of equations based upon cystatin C- or creatinine-assays adjusted to international calibrators2-8. The strategy also allows diagnosis of shrunken pore syndrome with its high morbidity and mortality9-13 due to that the filtration of 5-40 kDa molecules at this condition is reduced compared to that of small molecules, like water and creatinine, and the concomitant accumulation of atherosclerosis-promoting proteins13. Specifically, the use of the cystatin C-based CAPA-6 and the creatinine-based LM-Rev7,8-equations are recommended. The mean of the two estimated GFR-values is generally the best estimate for adults and the reliability of this estimate can be tested by comparison of the two estimates3-5. For children, the best estimate is obtained from the cystatin C-based estimating equation alone6.

Calculating robust estimates of relative GFR

The level of cystatin C in plasma/serum is relatively independent of body composition and simple cystatin C-based equations for GFR, containing only the cystatin C-concentration and the age of the patient as parameters, are therefore useful for both children and adults6,9.

The creatinine level in plasma/serum is, in addition to GFR, strongly influenced by a person´s muscle mass. Knowledge of the age and sex of a person allows calculation of the mean muscle mass of a person of that age and sex and is therefore used in addition to the creatinine level to generate creatinine-based estimating equations for GFR3,7,8.

For most adult patient populations, the mean of the two GFR estimates, (eGFRcystatin C + eGFRcreatinine)/2, is the best estimate and its reliability can be tested by comparison of the two separate estimates3-5. For children, the best estimate is obtained from the cystatin C-based estimating equation6.

Optimal evaluation of results

If, for an adult, the GFR estimated by the cystatin C-based equation agrees with that estimated by the creatinine-based equation, no invasive determination of GFR is required and the GFR-estimate representing the mean of the two estimates, (eGFRcystatin C + eGFRcreatinine)/2, should be used. The closer the agreement between eGFRcystatin C and eGFRcreatinine,the more reliable is the mean value as a GFR estimate and if the eGFRcystatin C/eGFRcreatinine>-ratio is between 0.8 and 1.20 the mean value is generally reliable.

If the GFR estimates obtained by the cystatin C- and creatinine-based equations do not agree, e.g., if the eGFRcystatin C/eGFRcreatinine-ratiois outside the interval 0.8 - 1.20, a clinical evaluation of the patient has to be performed.

If the muscle mass of the patient deviates considerably from that of his/her age and sex category (e.g., because of paralysis, immobility, anorexia or excessive bodybuilding) or if the patient recently ingested boiled meat or a medicine affecting the tubular excretion of creatinine, a GFR-estimate based solely upon cystatin C should be used14-18.

If the patient is treated with large amounts of glucocorticoids his/her synthesis of cystatin C is significantly increased and in this case a GFR-estimatebased solely upon creatinine (+age and sex) should be used19.

For adult patients who do not belong to any of the above-mentioned categories, an invasive determination of GFR might be required. In hyperthyroidism the cystatin C level will increase and the creatinin level decrease without corresponding changes in GFR20.

The tools of this site for estimation of GFR are based upon the cystatin C-based equation of reference 6 (the CAPA-equation)and the creatinine-based equation of references 7 and 8 (the LM-Rev-equation).

Diagnosing shrunken pore syndrome

If eGFRcystatin C is less than 70% of eGFRcreatinine, i.e.the eGFRcystatin C/eGFRcreatinine-ratio is < 0.70,and no non-renal factors influence the estimates, the patient suffers from shrunkenpore syndrome with strong increase in morbidity and mortality, inter aliadue to cardiovascular manifestations9-13. The increase in morbidity and mortalityis inversly proportional to the eGFRcystatin C/eGFRcreatinine-ratiostarting at a ratio of 0.8021. It should be emphasized that it has not yetbeen established that the shrunken pore syndrome exists in children younger than18 years.

Calculating absolute GFR from relative GFR

To study the kidney function of a person, the "relative glomerular filtration rate" (relative GFR), which has the unit "mL·min-1·(1.73m2)-1", sometimes written as "mL/min/1.73 sqm", is often used.

The relative GFR of a person is thus normalized to a certain body surface area, which allows the use of virtually the same reference values for males and females, adults and children. The relative GFR of a person is accordingly also independent of his/her actual body surface area. The relative GFR is suitable for assessing and monitoring the kidney function of a patient. But if you want to correctly dose a medicine or a contrast agent mainly excreted via the kidneys, knowledge of the absolute GFR (mL/min) of the patient is required. The estimating equations accounted for above provide estimates of the relative GFR (tab ”Relative GFR”). The tab ”Absolute GFR”can be used to easily calculate the absolute GFR (mL/min) of a person from his relative GFR (mL · min-1·(1.73 m2)-1), weight and height. The DuBois and DuBois formula is thereby used to estimate body surface area22.

  1. Soveri I, Berg U, Björk J, Elinder CG, Grubb A, Mejare I, Sterner G, Bäck SE onbehalf of the SBU review group. Measuring GFR: A Systematic Review. Am J Kidney Dis 2014; 64: 411-424.
  2. SBU. Methods to estimate and measure renal function (glomerular filtration rate). Asystematic review. Stockholm: Swedish Council on Health Technology Assessment(SBU); 2012. SBU report no 214.
  3. Grubb A. Non-invasive estimation of glomerular filtration rate (GFR). The Lund model: Simultaneous use of cystatin C- and creatinine-based GFR-prediction equations, clinical data and an internal quality check. Scand J Clin Lab Invest, 2010; 70: 65 - 70
  4. Nyman U, Grubb A, Sterner G, Björk J: Different equations to combine creatinine and cystatin C to predict GFR. Arithmetic mean of existing equations performs as well as complex combinations. Scand J Clin Lab Invest 2009; 69: 619-627.
  5. Grubb A, Nyman U, Björk, J: Improved estimation of glomerular filtration rate (GFR) by comparison of eGFRcystatin C and eGFRcreatinine. Scand J Clin Lab Invest 2012; 72: 73-77.
  6. Grubb A, Horio M, Hansson LO, Björk J, Nyman U, Flodin M, Larssson A, Bökenkamp A, Yasuda Y, Blufpand H, Lindström V, Zegers I, Althaus H, Blirup-Jensen S, Itoh Y, Sjöström P, Nordin G, Christensson A, Klima H, Sunde K, Hjort-Christensen P, Armbruster D, Ferrero C: Generation of a new cystatin C-based estimating equation for glomerular filtration rate using seven assays standardized to the international calibrator. Clin Chem 2014; 60: 974-986. + unpublished observations
  7. Björk J, Grubb A, Sterner G, Nyman U: Revised equations for estimating glomerular filtration rate based on the Lund-Malmö study cohort. Scand J Clin Lab Invest 2011; 71: 232-239.
  8. Nyman U, Grubb A, Larsson A, Hansson L-O, Flodin M, Nordin G, Lindström V, Björk J: The revised Lund-Malmö GFR estimating equation outperforms MDRD and CKD-EPI across GFR, age and BMI intervals in a large Swedish population. Clin Chem Lab Med 2014; 52: 815-824.
  9. Grubb A. Cystatin C is indispensable for evaluation of kidney disease. eJIFCC 2017; 28: 269-276.
  10. Grubb A, Lindström V, Jonsson M, Bäck SE, Åhlund T, Rippe B, Christensson A. Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: “Shrunken pore syndrome”. Scand J Clin Lab Invest 2015; 75: 333-340.
  11. Dardashti A, Nozohoor S, Grubb A, Bjursten H. Shrunken Pore Syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting. Scand J Clin Lab Invest 2016; 76:74-81.
  12. Purde MT, Nock S, Risch L, Medina Escobar P, Greb- hardt C, Nydegger UE, Stanga Z, Risch M. The cystatin C/ creatinine ratio, a marker of glomerular filtration quality: associated factors, reference intervals, and prediction of morbidity and mortality in healthy seniors. Transl Res 2016; 169: 80–90.
  13. Sällman-Almén M, Björk J, Nyman U, Lindström V, Jonsson M, Abrahamson M, Schiller Vestergren AL, Lindhe Ö, Franklin G, Christensson A, Grubb A. Shrunken pore syndrome is associated with increased levels of atherosclerosis-promoting proteins. Kidney Int Rep 2019; 4: 67-79.
  14. Thomassen SA, Johannesen IL, Erlandsen EJ, Abrahamsen J, Randers E. Serum cystatin C as a marker of the renal function in patients with spinal cord injury. Spinal Cord 2002; 40:524-8.
  15. Viollet L, Gailey S, Thornton DJ, Friedman NR, Flanigan KM, Mahan JD, Mendell JR. Utility of cystatin C to monitor renal function in Duchenne muscular dystrophy. Muscle Nerve 2009;40:438–42.
  16. Preiss DJ, Godber IM, Lamb EJ, Dalton RN, Gunn IR. The influence of a cooked-meat meal on estimated glomerular filtration rate. Ann Clin Biochem 2007;44:35– 42.
  17. Tangri N, Stevens LA, Schmid CH, Zhang YL, Beck GJ, Greene T, Coresh J, Levey AS. Changes in dietary protein intake has no effect on serum cystatin C levels independent of the glomerular filtration rate. Kidney Int 2011;79:471–7.
  18. Blackwood WS, Maudgal DP, Pickard RG, Lawrence D, Northfield TC. Cimetidine in duodenal ulcer. Controlled trial. Lancet 1976;2:174–6.
  19. Risch L, Herklotz R, Blumberg A, Huber AR. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem 2001; 47:2055-2059.
  20. Karawajczyk M, Ramklint M, Larsson A. Reduced cystatin C-estimated GFR and increased creatinine-estimated GFR in comparison with iohexol-estimated GFR in a hyperthyroid patient: A case report. J Med Case Reports 2008; 2:66.
  21. Herou E, Dardashti A, Nozohoor S, Zindovic I, Ederoth P, Grubb A, Bjursten H. The mortality increase in cardiac surgery patients associated with shrunken pore syndrome correlates with the eGFRcystatin C/eGFRcreatinine-Ratio. Scand J Clin Lab Invest 2019; Epub ahead of print.
  22. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Medicine. 1916; 17:863-871.

Calculating robust estimates of relative GFR

µmol/L mg/dL

Unknown Man Woman


CAPA/LM-Rev-ratio <0.70 means shrunken pore syndrome



Calculating absolute GFR from relative GFR

a mL/min/1.73 m2