Optimum Re 2015 Charlotte A. Lee, M.D., FLIM, DBIM EVALUATING RENAL FUNCTION

Tests available:  BUN  Serum Creatinine  Urine Creatinine  Creatinine clearance  Glomerular filtration rate  Cystatin

Why not BUN alone?  State of hydration  Diet  Blood in gut  Liver function (urea production occurs in the liver)  Multiple meds, including ASA, antibiotics, thiazides  Age

Why not creatinine alone?  Used instead of GFR by some carriers  Not disease-specific but reliable marker of renal insufficiency  Influenced by specimen integrity  Influenced by age (muscle atrophy) and gender (muscle mass)  Does not rise until at least 50% of the functioning nephrons are destroyed.

What Constitutes CKD? GFR mL/min/1.73m 2 for 3 months or more = early kidney disease GFR 3 months = CKD *SI expressed in mL/sec

reatinine Clearance vs. GFR C reatinine Clearance vs. GFR  Creatinine clearance approximates GFR but overestimates it due to the fact that creatinine is secreted by the proximal tubule as well as filtered by the glomerulus. Creatinine clearance can be measured from serum creatinine and creatinine excretion or estimated from serum creatinine using estimating equations

Creatinine Clearance(eGFR ) Cockroft-Gault Method: (140-age) x weight (kg) P cr x 72 X 0.85 (for women)

Creatinine Clearance (eGFR) MDRD (Modification of Diet in Renal Disease) 4 variables: eGFR = 186 x Cr s x Age ( X 1.21 if Black ) ( X if Female )

CKD-EPI 2009 Chronic Kidney Disease Epidemiology Collaboration Variables: serum creatinine, age, gender, race As accurate as MDRD at GFR<60ml/min/1.73m 2 More accurate than MDRD at GFR >60

MAYO CLINIC QUADRATIC (MCQ) EQUATION GFR = exp ( (5.249/serum creatinine) –(2.114/serum creatinine 2 ) × age – (if female)) If serum creatinine is <71 μmol/L, it is replaced by 71 μmol/L.4

Mandatory in UK for labs to calculate the eGFR Anticipated that the MDRD formula would be used for patients with renal disease and not for screening persons with no prior history of renal disease (e.g., insurance population) No accompanying clinical evaluation in insurance screening for many Thoughts on eGFR

Thoughts on eGFR(cont’d) Some laboratories report an actual GFR only if it is <60ml/min/1.73m 2 Many individuals aged over 65 who have an eGFR <60 (particularly females) do not actually have CKD Unnecessary referrals for evaluation for CKD

eGFR—Not meant for Everyone! Not as reliable in:  Younger than 18  Older than 70  Pregnant  Very overweight  Very muscular  Very thin and lean  Concomitant serious illness

Rule of Thumb: All estimating equations are less accurate for persons with normal or mildly impaired kidney function Lin J, Knight EL, Hogan ML, Singh AK. A comparison of prediction equations for estimating glomerular filtration rate in adults without kidney disease. Journal of the American Society of Nephrology. 2003;14(10):2573–2580.

Sample eGFRs 63-year-old woman– Creatinine = 1.82 mg/dL: eGFR if African American = 34 mL/min/1.73 m 2 eGFR if non-African American = 28 mL/min/1.73 m 2 62-year-old man—Creatinine = 1.35 mg/dL: eGFR if African American = ≥ 60 mL/min/1.73 m 2 eGFR if non-African American = 54 mL/min/1.73 m 2 55-year-old man—Creatinine = 1.07 mg/dL: eGFR if African American = ≥ 60 mL/min/1.73 m 2 eGFR if non-African American = ≥ 60 mL/min/1.73 m 2

Cystatin C—What is it?  A 13 kD, non-glycosylated, basic protein that is produced by all nucleated cells  Freely filtered by the glomerulus and then reabsorbed and catabolized by the tubular epithelial cells, with only small amounts excreted in the urine.

Cystatin C (cont’d)  Urinary clearance cannot be measured, which makes it difficult to study factors affecting its clearance and generation.  Cystatin C appears to be less variable and less affected by age and sex than serum creatinine; however, some studies have reported increased cystatin C levels associated with higher levels of C- reactive protein or body mass index (BMI), hyperthyroidism, and steroid use.

Serum creatinine vs. Cystatin C  Variable statements re. whether Cystatin C or creatinine/creatinine clearance is more sensitive for renal function  Overall, felt to be equally as effective as creatinine in making this determination

Is Cystatin C a more accurate filtration marker than creatinine?  Some studies show that serum levels of cystatin C estimate GFR better than serum creatinine alone. 1  Recent studies have clearly demonstrated that cystatin C is a better predictor of adverse events in the elderly, including mortality, heart failure, bone loss, peripheral arterial disease, and cognitive impairment, than either serum creatinine or estimated GFR. 2,3

Perhaps because cystatin C is a better filtration marker than creatinine, particularly in the elderly. Alternative explanation is that factors other than GFR that affect serum levels of creatinine and cystatin C differentially confound the relationships between these measures and outcomes. Why ?

Should you use Cystatin C?

Highly Recommended:

References 1. Madero M, Sarnak MJ, Stevens LA. Serum cystatin C as a marker of glomerular filtration rate. Curr Opin Neph Hypertens. 2006;15(6): Sarnak MJ, Katz R, Stehman-Breen CO, et al. Cystatin C concentration as a risk factor for heart failure in older adults. Ann Intern Med. 2005;142(7): Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005;352(20):