Early detection of CKD CKD: Its out there somewhere

The Problem Chronic Kidney Disease is an epidemic worldwide Growth 6-8% per annum of dialysis patients Accumulating data re: possibility of delaying the progression of kidney disease, using multiple drug and behaviour intervention therapies. Under-recognition at earlier stages of kidney dysfunction persists Late referral Lost opportunities for improved patient outcomes  

Known CKD <1% of population Unrecognised CKD 10% of population

CKD Patients Are More Likely to Die than to Progress to ESRD 5 year follow-up This study demonstrates that death was a far more common outcome than dialysis in all stages of CKD. Key Talking Points Keith and colleagues set out to understand the natural history of CKD with regard to progression to renal replacement therapy (RRT) (dialysis or transplant) and death in a representative patient population. In 1996, 27,998 patients with estimated GFRs (eGFRs) <90 mL/min/1.73 m2 on 2 separate measurements were identified from computerized medical records. These patients were followed until either RRT, death, or disenrollment from the health plan, or until June 30, 2001. Among the adverse outcomes for CKD patients, death is more common than RRT at any CKD stage. The data showed that the rate of RRT over the 5-year observation period was 1.1%, 1.3%, and 19.9%, respectively, for the K/DOQI™ stages 2, 3, and 4. However, the mortality rate was 19.5%, 24.3%, and 45.7%, respectively. Significantly, ~46% of stage 4 CKD patients died and did not end up on RRT. Keith and colleagues suggest that efforts to reduce mortality in this population should be focused on treatment and prevention of coronary artery disease, congestive heart failure, diabetes, and anemia of CKD. Reference Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164:659-663. Transition to Next Slide These data suggest there should be increased predialysis management of CKD. N=27998 Keith, et al, Arch Int Med; 2004; 164:659-663

The Patient with early stage CKD is 5 to 10 times more likely to die from a cardiovascular event than progress to ESRD. Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, Collins AJ. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005; 16:489-95.

So what do we do ?

CKD: An Overall Health Approach Complications Normal Increased risk Damage GFR Kidney failure DEATH Screening for CKD risk factors CKD risk factor reduction, screening for CKD Diagnosis and treatment, treat comorbid conditions, slow progression Estimate progression, treat complications, prepare for replacement Replacement by dialysis and transplant

Defining “CKD” Kidney damage for ≥ 3 months, defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either Pathologic abnormalities, or Markers of kidney damage, such as abnormalities of the blood or urine, or in imaging tests. GFR < 60 mL/min/1.73 m2 for ≥ 3 months with or without kidney damage. Introduction The NKF defines CKD according to the presence or absence of kidney damage and level of kidney function. Key Talking Points Chronic kidney disease is defined as structural or functional abnormalities of the kidneys for 3 months, as manifested by either GFR <60 mL/min/1.73 m2, with or without kidney damage Kidney damage, with or without decreased glomerular filtration rate (GFR), defined by Pathologic abnormalities or Markers of kidney damage: blood or urine abnormalities or imaging tests Proteinuria is a reflection of kidney injury and refers to increased urinary excretion of albumin, other specific proteins, or total protein.1 GFR is widely accepted as the best overall index of kidney function in health and disease.1,2 Normal GFR varies according to age, sex, and body size; in young adults it is approximately 120 to 130 mL/min/1.73 m2 and declines with age. A decrease in GFR precedes the onset of kidney failure; therefore, a persistently reduced GFR is a specific indication of CKD.2 References 1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266. 2. National Kidney Foundation—Kidney Learning System: frequently asked questions. Available at: http://www.kidney.org/kls/professionals/faq.cfm#1. Accessed June 27, 2005.

Defining “Kidney Damage” Markers of Kidney Damage? Proteinuria Microalbuminuria Hematuria (especially when seen with proteinuria) Isolated hematuria has a long differential: infection, stone, malignancy, etc. Casts (especially with cellular elements)

Stages of CKD by GFR Stage Description GFR 1 Kidney damage with (mL/min/1.73m2) * 1 Kidney damage with normal or  GFR >90 2 Mild  GFR 60-89 3 Moderate  GFR 30-59 4 Severe  GFR 15-29 5 Kidney failure <15 or Dialysis Clinical practice guidelines 2000 New nomenclature and staging was designed to improve communication for clinical care, research initiatives and public awareness/education Make the note that GFR (mL/min/1,73m2) can be approximated to percentage of kidney function * It is helpful to think of GFR (mL/min/1.72m2) as an approximation of % Kidney function

NKF-K/DOQI Stages of “CKD” Description GFR (mL/min/1.73m2) 1 Kidney damage with normal or  GFR > 90 2 Mild  GFR 60-89 3 Moderate  GFR 30-59 4 Severe  GFR 15-29 5 Kidney Failure < 15 or dialysis Primary Care Focus is here!

Measurement of Kidney Function

What Tests Are Available? Direct GFR measurement Inulin clearance Radionuclides Iohexol clearance 3 hr CrCl with Cimetidine Prediction equations Cystatin C 24 hr urine CrCl Serum creatinine Accurate Inaccurate

Gold Standards Inulin clearance Radionuclides Tedious, time consuming & unavailable Radionuclides 125Iodine-iothalamate, technetium DTPA, 51Chromium-EDTA clearance Time consuming and expensive Research, accurate drug dosing

Chronic Kidney Disease In 1999, the NKF approved a proposal for K/DOQI, Kidney Disease Outcomes Quality Initiative (an evolution of the DOQI (Dialysis Outcomes Quality Initiative). The purpose was to develop clinical practice guidelines for the spectrum of kidney diseases. In February 2002, Clinical Practice Guidelines for Chronic Kidney Disease (CKD): Evaluation, Classification, and Stratification were published. Find the KDOQI guidelines at http://www.kidney.org/professionals/KDOQI/

Guideline 1. Definition and Stages of Chronic Kidney Disease Adverse outcomes of CKD can often be prevented or delayed through early detection and treatment. Earlier stages of CKD can be detected through routine laboratory measurements. The presence of CKD should be established, based on presence of kidney damage and level of kidney function (glomerular filtration rate [GFR]), irrespective of diagnosis. Among patients with CKD, the stage of disease should be assigned based on the level of kidney function, irrespective of diagnosis, according to the K/DOQI CKD classification

Who should we screen?

How should we screen?

Serum Creatinine, CrCl, and eGFR--Nothing is Perfect! Serum Creatinine alone CAN NOT be used to accurately assess level of kidney function. S. creatinine is a function of production (muscle mass) and excretion (both GFR and tubular secretion). Age, sex, and lean body mass have to be taken into account. Estimations of eGFR (MDRD equation) and CrCl (Cockcroft-Gault equation) were NOT developed in subjects with normal renal function or normal health.

Factors Affecting Serum Creatinine Concentration Increase Decrease Kidney Disease Ketoacidosis Ingestion of cooked meat Drugs: Trimethoprim Cimetidine Flucytosine Some cephalosporins Reduced Muscle Mass Malnutrition

Serum Creatinine: Problems Non-renal influences Gender, ethnicity, age and muscle mass Nutrition/diet Drugs (e.g. cimetidine) Clinical utility Poor sensitivity for CKD Not useful in ARF Muscle wasting disorders and amputees Analytical problems Non-specificity (protein, ketones, ascorbic acid) No international standardization Spectral interferences (icterus/lipaemia/haemolysis)

Serum Creatinine Hides Early Renal Damage 600 400 Serum creatinine (µmol/L) 200 2 3 4 5 CKD stage Proportion misdiagnosis 35 70 105 140 GFR (mL/min/1.73m2) Reproduction from the late David Newman

Introduction of eGFR Will facilitate early recognition of CKD Will result in increased awareness of advanced CKD previously not recognised as such

Effects of age on eGFR The “normal” eGFR is age-related In normal “healthy” individuals, the eGFR will fall by one percent for every year after 40 years of age An 80 year old man will have an expected eGFR of 50-60 ml/min Not all patients with reduced eGFR need active management

Which individuals with abnormal eGFR should we to worry about? Those with very poor function for age Those with deteriorating function Those who may have reversible/treatable cause (unexplained proteinuria/haematuria) Those with functional consequences of CKD (anaemia, renal bone disease, persistent hyperkalaemia)

GFR normally decreases with age! Remember…. GFR normally decreases with age!

Cockcroft-Gault Equation to Predict GFR Developed to predict creatinine clearance, thus an overestimate of GFR Prediction based on age, gender, creatinine and ideal body weight ClCr (cc/min) = [140-age] x IBW/72 x SCr x [0.85 if female] Used almost universally as the basis for drug dosing!

MDRD Equation to Predict GFR Prediction based on age, gender, race and serum creatinine. Developed to follow GFR as part of the Modification of Diet in Renal Disease (MDRD) study. Validated. GFR/1.73m2 = 186 x [Pcr]-1.154 x [age]-0.203 x [0.742 if female] x [1.212 if AfAm] Get it at http://www.kidney.org/professionals/KDOQI/gfr.cfm

TA-DA! (Your on-line link to the MDRD GFR calculator) http://www.kidney.org/professionals/KDOQI/gfr.cfm

Cockcroft-Gault vs. MDRD The MDRD equation estimates GFR. eGFR is given per 1.73m2 BSA The Cockcroft-Gault equation estimates CrCl. CrCl is best used for drug dosing decisions--drug dosing is usually indexed to CrCl.

Comparing the Cockcroft-Gault and MDRD: Do these patients have the same level of renal function? 20 year old AfAm Washington Redskins tackle, weighing 144 kg with a SCr 1.2 mg/dl? ClCr=[140-20][144]/72 x [1.2] =200 cc/min MDRD GFR Value:99 mL/min/1.73 m2 93 year old Caucasian female nursing home resident, weighing 44 kg with a SCr 1.2 mg/dl. ClCr = [140-93][44]/72 x [1.2] x 0.85 = 20 cc/min MDRD GFR Value:45 mL/min/1.73 m2

Patient meets definition of Chronic Kidney Disease? YES NO Determine Stage of CKD Determine underlying cause Identify risk factors for progression Identify comorbidites Risk Factor Reduction

Tools for Determining the Cause of Chronic Kidney Disease CKD is often silent. Assessment relies on laboratory testing and imaging. A Good History! ROS, existence of chronic diseases (DM, HTN, CHF, cirrhosis), medication review, accurate PMH and FH of kidney disease. Helpful Physical Examination! BP, evidence of co-morbid conditions and complications of CKD.

A Simple Laboratory Evaluation!

Simplified Classification of CKD by Diagnosis Diabetic Kidney Disease Nondiabetic Kidney Disease Glomerular disease autoimmune, sytemic infections, drugs, neoplasia, idiopathic Vascular disease ischemic renal disease, hypertensive nephrosclerosis, microangiopathy Tubulointerstitial disease UTO, stones, UTI, drug toxicity Cystic disease Post-Transplant

Differential Diagnosis of Chronic Kidney Disease Everyone deserves a diagnosis! This is especially true for Stage 1 or 2 CKD! When in doubt, consult a nephrologist! Initial evaluation will guide further diagnostics, decisions about renal biopsy and often decisions about treatment and prognosis.

(There’s a lot you can do!) So Now What Do You Do? (There’s a lot you can do!)

Measuring Proteinuria—Get into the right spot! When you get to this point, Don’t continue to get microalbumin!

Glomerular Filtration Rate Sum of all nephron filtration rates Best index of overall function Reduction implies a problem Translatable concept Equates to percentage Kidney function

GFR Prediction Equations Cockcroft-Gault formula Ccr (ml/min) = 1.23 x (140-age) x weight/Pcr (x 0.85 if female) MDRD Study equation GFR (ml/min/1.73 m2) = 186 x [(Pcr)/88.4]-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if African American) Cockcroft & Gault. Nephron 1976; 16: 31-41 Levey AS, et al. Ann Intern Med 1999;130: 461-70

MDRD equation vs serum creatinine 220 200 180 160 140 120 100 80 220 200 180 160 140 120 100 80 Males Females sCr (µmol/L) 79.4% sCr (µmol/L) 98.4% 27.7% 81% 30 40 50 60 30 40 50 60 eGFR (ml/min/1.73m2) eGFR (ml/min/1.73m2) Middleton et al 2004

Scatter Increases as GFR Approaches Physiological Levels Froissart et al JASN 2005;16:763-773

MDRD Formula: validation

CKD: A Typical GP Practice of 10000 5 6 15 4 60 Stage of Kidney Disease 30 (GFR) 380 3 60 2 460 90 1