Stephen R. Ash, MD, FACP IU Health Arnett Lafayette, Indiana 2017 Predicting the Progress of Chronic Kidney Disease; Combining eGFR and Proteinuria LMEF PRESENTATION Stephen R. Ash, MD, FACP IU Health Arnett Lafayette, Indiana 2017

A bucket analogy to explain the concept of kidney clearance Water Inflow 100 ml/min, output flow begins through hole

Outflow rate from bucket soon “magically” equals inflow Pressure increases, output flow increases until = input

Add generation of a chemical marker Rice generation 1 piece (1mg)/min

Marker concentration equilibrates so generation = excretion Rice generation 1 piece (1mg)/min Clearance Rate = Amount removed/minute = Cb Generation rate = Cb Outflow rate   If Cb = 1 mg/100 ml, then Clearance = 1 mg/min 1 mg/100 ml = 100 ml/min = outflow rate Cl = N/Cb

What happens if outflow rate decreases 50%? What if the outflow hole becomes smaller? Outflow rate decreases 50% Inflow rate also is decreased so bucket doesn’t overflow

Cb increases until output again equals generation of marker; clearance shows the new outflow rate Rice generation stays the same, so concentration doubles Clearance Rate = Amount removed/minute = 2*Cb Generation rate = 2* Cb = 50 ml/min

The kidney can generate its own inflow fluid, like screens in this model Add a screen downstream through which the rice can’t penetrate, and fluid can be returned to the bucket Since the rice doesn’t penetrate the screen, it is concentrated in the outflow fluid. Clearance = generation rate Cb = bucket outflow rate (even if this flow isn’t seen) Kidney then generates its own inflow fluid Roller pump

Kidney creatinine clearance follows same mathematics Generation rate of creatinine marker approx. 1 mg/min Glomerular filtration rate (GFR) approx= 100 ml/min = Creatinine Clearance = generation rate Cb   99% of fluid reabsorbed, without creatinine Cb approx. = 1 mg/100ml plasma Urine excretion of creatinine approx. = 1 mg/min GFR (calculated, unseen) = 1 mg/min 1 mg/100ml = 100 ml/min

GFR determined by creatinine clearance (CrCl) Generated by muscle metabolism of creatine and dietary meat Creatinine generation is fairly constant day-to-day, 20-25 mg/kg/day (LBW) in men, 15-20 mg/kg/day in women (LBW) Creatinine daily excretion decreases 50% from age 50 to 90. Creatinine is filtered by glomerulus and not absorbed, but 10-20% of creatinine in urine is secreted by normal kidneys, making creatinine clearance overestimate GFR. Percentage of creatinine secreted to urine increases with progression of CKD.

To measure CrCl by 24 hour urine Measure volume (V), urine creatinine concentration (Ucr) Measure serum creatinine (SCr) UCr x V = N = Excretion rate GFR = [UCr x V]/SCr Normalize by BSA, GFR/1.73M2

Formulas for Estimation of GFR: prediction of creatinine generation using age, weight, sex, race, nutrition Cockcroft-Gault (ml/min, developed using older creat assays): CrCl =(1 or 0.85)*(140 - Age) SCr * LBW/72 Need to adjust for BSA Still calculated because drug dosing based on this formula

2. MDRD 170 x SCr [-0.999] x Age[-0.176] x BUN [-0.170] x Alb [+0.318] x (0.762 if female) x (1.18 if black) Abbreviated MDRD: 175 * SCr-1.154 * Age-0.203 * (0.742 if female) x (1.21 if black) Both are mL/min/1.73 m2

3. CKD-EPI 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if Black] mL/min/1.73 m2 SCr (standardized serum creatinine) = mg/dL κ = 0.7 (females) or 0.9 (males) α = -0.329 (females) or -0.411 (males) min = indicates the minimum of SCr/κ or 1 max = indicates the maximum of SCr/κ or 1 age = years

MDRD and CKD-EPI both are somewhat imprecise, but… Both expressed as ml/min/1.73 M2 Neither need urine tests In new forms, neither needs albumin or BUN Both require age, sex, race data from outside the lab

Aging Decreases Kidney Function

Causes/Results of aging in the kidney

Therapies and factors of aging kidneys

Decline in CrCl with Age

So, if progressive loss of clearance is part of aging, how do we determine which patients have risk for ESRD? Patients with proteinuria (urine albumin/creatinine ratio determines micro or macro) Patients with rapid or sudden progression Patients with systemic diseases

KDOQI gave us the classification of severity of kidney disease, in 2002

Number of patients with CKD 3 were astounding

So they added albuminuria grade in 2012

Studies confirmed that risk of ESRD increased with degree of proteinuria HR

Best approach-combine eGFR and proteinuria for prediction Referral based on current stages 3 to 4 CKD (eGFR 15 to 59 ml/min per 1.73 m2) would include 4.7% of the general population and identify 69.4% of all individuals progressing to ESRD. Referral based on our classification system would include 1.4% of the general population without losing predictive power (i.e., it would detect 65.6% of all individuals progressing to ESRD).

More papers confirm value of proteinuria measurement

And, other studies as well…

Prediction is very helpful…

Albuminuria has cardiac as well as renal risks

Summary of four main points… The kidney’s efficiency in removing toxins is measured as “clearance” Creatinine clearance can be estimated from a single blood test and some patient data Aging affects the kidney almost uniformly, and creatinine clearance decreases with age To determine which patients are at risk of serious kidney problems, estimate creatinine clearance and measure proteinuria.

Thank you.