Seung Hyeok Han, MD, PhD Department of Internal Medicine Yonsei University College of Medicine

Seung Hyeok Han, MD, PhD Department of Internal Medicine Yonsei University College of Medicine

Age and Kidney Weight renal weight and thickening of the vascular intima Platt et al. Gerentology 1999;45:243-253

Aging and Number of Glomeruli Number of glomeruli Kidney has about 600,000 to 1,200,000 glomeruli with a progressiv e decrease of 30-50% in number after age of 40 Platt et al. Gerentology 1999;45:243-253

Age Dependent Changes of the Normal Kidney Glomeruli become sclerotic- secondary to changes in renal blood flow that occur with age. - decreased cardiac output - fibroelastic hyperplasia of arterioles and small arteries Glomerular filtration rate (GFR) is reduced with aging. Platt et al. Gerentology 1999;45:243-253

JCI 1949

Decline in Kidney Function with Age Stevens et al. NEJM 2006;354:2473-2483

Issues in Elderly People (1) Atherosclerosis (2) Hypertension/left ventricular dysfunction (3) Glucose intolerance/diabetes mellitus (4) Obesity (5) Heart failure (6) Undetected renal disease (7) Smoking (8) Disabling diseases

Relationship between GFR and S-Cr

Assessment of Kidney Function

Assessment of Kidney Function Chemical analysis of urine Serum urea Serum creatinine Serum cystatin C Timed urine collections (Creatinine clearance) Exogenous markers Inulin clearance Iothalamate clearance Iohexol Radiolabeled markers

The Perfect Marker Endogenous Freely filtered Not secreted or reabsorbed Inexpensive to measure Not impacted by non-renal influences Such a marker does not exist!

Gold Standard Methods for GFR Measurement Inulin test - Freely filtered at the glomerulus - Neither secreted, reabsorbed, synthesized, nor metabolized by the kidney - Expensive, difficult to assay, requires a continuous IV infusion, multiple blood samples, and bladder catheterization Alternative filtration markers - iothalamate - iohexol - DTPA or EDTA All these tests have limitation in their application in clinical practice.

Too complicated!!!

Assessment of Kidney Function Calculated GFR approximations - CrCl by Cockcroft Gault formula - egfr by MDRD formula - egfr by CKD EPI formula

Serum Creatinine Assay Alkaline picrate methods - Jaffe method (classic) - Compensated (modified) Jaffe method Enzymatic methods High-performance liquid chromatography Isotope dilution mass spectrometry (IDMS) Gas chromatography Liquid chromatography

Jaffe Method (Alkaline Picrate Method) Non-creatinine chromogens in the serum sample - Can be detected as up to 20% of the color reaction (Urine does not contain non-creatinine chromogens) - Can overestimate s-cr and underestimate ClCr May be a problem within the normal reference range of s-cr Enzymatic Jaffe method - Also reports a s-cr value higher than actual (positive bias) thereby underestimating ClCr most significantly within the upper range of normal for creatinine values values that define early-onset CKD.

Limitations with S-Cr Values Compensatory hypertrophy - May not initially lead to a reduction in GFR or a rise in the s-cr Variations in Cr secretion - An initial decline in GFR may lead to only a slight increase (0.1 to 0.2 mg/dl) in the s-cr because of an increase in proximal tubular Cr secretion. - ex) True GFR of 60-80 ml/min may indicate SCr < 1.0 mg/dl (potentially underestimates early stage of CKD) Variation in Cr production - Dietary intake, muscle mass, amputations, etc.

S-Cr Levels and GFR

S-Cr Levels and Sex

Changes in Cr Excretion, s-cr, and ClCr in Healthy Individuals at Different Ages

Problems with Using Plasma Cr & Formulae Formulae only apply in steady state. Not good for ARF Plasma creatinine can increase following protein loads. - Goulash effect. 80% rise in creatinine after 300g of cooked beef. - Less variability in early morning creatinine Strenuous exercise may increase creatinine by 14% Muscle mass more difficult to predict in oedematous patients and late pregnancy Patients with muscle wasting Patients with liver disease Drugs inhibiting tubular secretion can raise creatinine conc. (cimetidine, trimethoprim) Post Grad Med J 1988;64:204-208

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 difficult and inaccurate

Two Major Errors with ClCr Incomplete urine collection - daily creatinine excretion < 50 years of age; 20 to 25 mg/kg of LBW in men 15 to 20 mg/kg of LBW in women. 50 to 90 years of age; a progressive 50% decline in creatinine excretion (to about 10 mg/kg in men), due primarily to a fall in muscle mass Increasing creatinine secretion - Due to enhanced Cr secretion as GFR falls - Potentially overestimates GFR (CKD 4-5)

Example Ccr = 2200 mg/1440 min = 126 ml/min 1.2 mg/dl x dl/100 ml Ccr = 1000 mg/1440 min = 57 ml/min 1.2 mg/dl x dl/100 ml How can you interpret? - an incomplete urine collection? - a decrease in muscle mass or diet?

Cockcroft and Gault Equation CrCl CrCl (ml/min) = (140 age) x wt x (0.85 if female) 72 x Scr (mg/dl) Systematically overestimates the GFR because of tubular secretion of creatinine. Nephron 1976;16:31-41

Limitations Bias in estimating GFR varies markedly. Tends to overestimate measured GFR (especially at low GFR) Less accurate at extremes of age, patients with variations in dietary intake or muscle mass, pregnancy, obesity and drugs (eg. cimetidine, trimethoprime) Curr Opin Nehrol Hypertens 2006; 15: 643-647 Clin Chem Lab Med 2006;44: 1295-1302

The MDRD Equation egfr Ann Int Med 1999;130:461-470

Limitations Less accurate when GFR > 60mL/min/1.73m2 Less accurate in obese, older, hospitalized or Asian patients Not well studied in age> 75, pregnancy, amputees, extreme body size, muscle mass or nutritional status. Complicated equation Ann Int Med 1999;130:461-470

The CKD-EPI Equation egfr

Limitations Unlikely to work well in all populations- limited to whites and black Few patients had high GFRs. Incomplete data on DM, immunosuppressive agents, and measures of muscles mass Very complicated equation

Limitations of All Equations Use of scr as a filtration marker Decreased accuracy in - Higher levels of GFR - Extremes of age - Extremes of body size These equations are used for stable renal function (not accurate in acutely changing renal function).

Cystatin C Cysteine proteinase inhibitor C (MW13000) Constant production rate by all nucleated cells Freely filtered at glomerulus Not reabsorbed, but metabolized in the tubules limit the use of cystatin C to directly measure clearance No known extra-renal excretion routes Correlation of 1/[cystatin C] (r=0.81) with Cr-EDTA clearance is better than 1/[Plasma Creatinine] (r=0.51)

Cystatin C Less unaffected by gender, age, or muscle mass, but its higher levels may be associated with male gender, greater height and weight, and higher lean body mass Increase sharply with age Affected by hyper- and hypothyroidism Correlated with markers of inflammation (CRP), body size (in particular fat mass), and diabetes Affected by steroid use, therefore limiting its use in transplant recipients.

Cystatin C More closely correlated with the GFR than the serum Cr concentration More sensitive in identifying mild reductions in kidney function than serum Cr Equation based on cystatin-c - may be more accurate in populations with lower Cr production such as the elderly, children, renal transplant recipients, or patients with cirrhosis.

Cystatin C versus Creatinine in Determining Risk Based on Kidney Function Shlipak et al. NEJM 2013

Cockcorft- Gault MDRD CKD-EPI Cystatic C- based Eq Inulin Clearance Few studies have been done regarding which equation is better in elderly people.

(N = 50) rs = -0.72, p<0.0001

Cr Cystatin C

Mildly Decreased GFR in the Elderly are Not at Any Increased Risk of Death Risk for death by GFR after stratification by age group O Hare et al, JASN 2006

HRs for All-Cause and Cardiovascular Mortality

egfr Decline

Mildly Decreased GFR in the Elderly are Less Likely than Younger Patients to Progress to ESRD O Hare et al, JASN 2007

Case A 55-year male visited our hospital for the evaluation of kidney function. His son was preparing for kidney transplantation due to ESRD. - No history of DM or hypertension - Bwt, 66 kg; Ht, 169.0 cm; BP 126/75 mmhg - Serum Cr: 1.10 mg/dl - egfr (MDRD): 69 ml/min per 1.73 m 2 A urologist raised a concern about low egfr as a kidney donor. Is this man acceptable for kidney transplantation?

- Urinalysis: pro (-), RBC (-) - Random urine PCR and ACR: 0.17 mg/mg and 6.2 mg/g - egfr (CKD-EPI): 75 ml/min per 1.73 m 2 - Cystatin C: 0.86 mg/dl (reference range: 0.65 ~ 1.10) - egfr (Cystatin-based): 109 ml/min per 1.73 m 2

Case A 82-year male underwent ICU care due to cerebral hemorrhage. In the mean time, he was treated with CRRT due to sepsisinduced AKI. His kidney function was quite recovered from AKI and he continued supportive care at the general wards. - history of DM for 30 years - underwent CABG 5 years ago - Bwt, 52 kg; Ht, 170.0 cm; BP 130/80 mmhg - Serum Cr: 1.50 mg/dl egfr (MDRD): 45 ml/min per 1.73 m 2 - Cystatin C: 2.5 mg/l egfr (cystatin-c): 25 ml/min per 1.73 m 2 How can you interpret this discrepancy?

Changes in the Lower Urinary System The changes of bladder wall - The elastic tissue becomes tough and the bladder becomes less stretchy. - The bladder cannot hold as much urine as before. - The bladder muscles weaken. The urethra can become blocked. - In women, this can be due to weakened muscles that cause the bladder or vagina to fall out of position (prolapse). - In men, the urethra can become blocked by an enlarged prostate gland.

Summary and Conclusion Aging kidney is unavoidable. - Aging should come along with a decrease in the number of glomeruli and decline in kidney function. The elderly people are vulnerable to kidney injury because of many comorbidities and frailty accompanied by the aging process. No tests can precisely evaluate kidney function in the elderly given the intrinsic problem of creatinine-based assessment. Much careful attention should be paid to preserve kidney function in the elderly.

Thank you for your attention!