OUTLINE OUTLINE. KDIGO Modification (2006) Chronic Kidney Disease (CKD): Classification-(NKF-K/DOQI-2002)

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1 Changes in Serum Creatinine: Pitfalls in Evaluating Patients for Chronic Kidney Disease (CKD) Richard J. Glassock, MD, MACP Emeritus Professor- The Geffen School of Medicine at UCLA 5 rd Raymond Kay Internal Medicine Symposium Palm Springs, CA November, 9 OUTLINE Definitions of CKD Estimation of GFR by formulas Application of Definitions to the Role of proteinuria (albuminuria) in diagnosis and prognosis of CKD in the elderly Conclusions and OUTLINE Definitions of CKD Estimation of GFR by formulas Application of Definitions to the Role of proteinuria (albuminuria) in diagnosis's and prognosis in the elderly Conclusions and Chronic Kidney Disease (CKD): Classification-(NKF-K/DOQI-) Stage Kidney egfr Damage (ml/min/.7m ) NA -59 NA NA <5 (or dialysis) (calculated from serum creatinine level by the abbreviated MDRD equation; NA= not applicable: findings must persist for months) KDIGO Modification (6) Suffix T added to Stages - if recipient of a renal transplant Suffix D added to Stage 5 if receiving Dialysis Question #: An Woman with a low egfr A 75 year old widow is seen by her general internist for a pre-operative evaluation connected with a planned left hip replacement for debilitating osteoarthritis and necrosis of the femoral head. Other than impaired vision from cataracts she feels well. There is no personal or family history of kidney disease. She takes an occasional NSAID for pain, and regular ergocalciferol and calcium supplements.

2 Question # Her physical examination reveals a thin (weight= 5 kg, height.6m), but otherwise healthy appearing elderly woman with a blood pressure of /78mmHg. There is no edema or JV distension. No abdominal bruits. Pulses are full and intact. Pain on pressure over the left hip is found. Question # Laboratory studies reveal a serum creatinine of.5mg/dl (a calculated egfr= 5ml/min/.7m according to the report). Hemoglobin is.6gms/dl, serum albumin is.g/dl, the blood sugar (fasting) is 9mg/dL,and serum cholesterol is 85mg/dL. All other biochemical studies are also normal. A urinalysis is negative for protein and blood An EKG and chest X-Ray are normal Question # Based on an egfr of 5ml/min/,7 m the patient is told she has Chronic Kidney Disease (CKD), Stage. Which ONE of the following would you recommend now? A. Perform metabolic investigations, including a,5 and 5-hydroxy Vitamin D level, parathyroid hormone B. Order an abdominal ultrasound and CT scan C. Refer to a Nephrologist for further evaluation of CKD D. Reassure her that she can undergo her planned hip surgery as scheduled E. Cancel her scheduled hip surgery Question # The correct answer is D The patient has normal egfr for her age and gender and does not have CKD CKD-NHANES Prevalence of CKD (KDOQI)Stage by Age (999-) Prevalence (%) % 5% % 5% % 5% % 5% % Age Group (years) CKD-NHANES: Characteristics of the Staged Populations using KDOQI () Stages and (8% of Total) % had abnormal albuminuria (by definition)-88% had microalbuminuria and % had macroalbuminuria Stage (59% of Total) 67% had no abnormal proteinuria (not needed for definition) Stage (.8% of Total) % had no abnormal proteinuria Total Stage - (% of total) M/F ratio =.7 87% had no abnormal proteinuria

3 Chronic Kidney Disease (CKD): UK (NICE) Classification Stage and - Same as KDOQI Stage - Divided into parts: > Stage A (egfr= -59ml/min/.7m) > Stage B (egfr= -9ml/min/.7m) > Stages A/B designated as proteinuria + (p+, UAE=>5mg/d; UACR= >.5) or negative (p-, UAE= <5mg/d; UACR= <.5)) Stage - Same as KDOQI Stage 5- Same as KDOQI (Eight Stages total) Chronic Kidney Disease (CKD): Kaiser-Permanente Definition (Rutkoski et al AJKD 5:s86-s99, 9) Stage and - macroalbuminuria only; egfr criteria same as KDOQI Stage - egfr threshold= egfr + age/ <85ml/min/.7m but >ml/min/.7 m Stage - same as KDOQI Stage 5- Same as KDOQI CKD Prevalence by Modified and Standard KDOQI Criteria (Rutkowski, et al AJKD, 9; Coresh, et al JAMA, 8).%.%.% 8.% 6.%.%.%.% Stage Stage Stage Stage Stage 5 Stages -5 Chronic Kidney Disease (CKD): Winearls-Glassock Classification (Winearls C, Glassock R. KI- 75:9, 9) Stage - Collapses KDOQI Stage and into single stage and eliminates microalbuminuria; egfr > 5 th percentile for age and gender; evidence of renal disease (urinalysis, imaging/biopsy) Stage - egfr < 5 th percentile fro age and gender but >ml/min/.7m; same as Stage above Stage - egfr 5-ml/min/.7m (irrespective of age or gender) Stage - egfr <5ml/min/.7m (not on RRT) Stage 5- Dialysis dependent DEFINITIONS OF CKD Confused? Clarity may come from an International Consensus Conference to be Held in London, UK under the auspices of KDIGO on October -5, 9 OUTLINE Definitions of CKD Estimation of GFR by formulas Application of Definitions to the Role of proteinuria (albuminuria) in diagnosis's and prognosis in the elderly Conclusions and

4 egfr (MDRD) vs mgfr (Cin) (Botev, et al, 9) Precision and Bias: egfr (MDRD) vs mgfr (Cin) (Botev R, et al CJASN :899-96, 9) 7% 6% 5% egfr % Relative % Bias/ % Precision % % -% -% <5 mgfr (ml/min/.7m) Bias (% mean difference) Precision (% one SD of mean) Classifications of CKD According to mgfr (C edta )and egfr (MDRD) (Froissart, et al. JASN, 5) (95 subjects; 995 with CKD/6 normal donors) mgfr > Stage 67% 6%.5% Stage % 6% % Stage.6% % 78% Stage.% % Stage 5 Original KDOQI +egfr (MDRS) schema overestimates prevalence of CKD (especially in older women) 5-9 <5 7%.% 79% %.% 65% NO EPIDEMIC OF CKD! OUTLINE Definitions of CKD Estimation of GFR by formulas Application of Definitions to the Role of proteinuria (albuminuria) in diagnosis's and prognosis in the elderly Conclusions and Question #- A Frail elderly lady in the ICU A 66 year old woman with uro-sepsis following a liver transplant. She is small (weight Kg), malnourished and frail. Scr=.8mg/dL egfr (MDRD)=.ml/min/.7m eccr (C-G)=.ml/min

5 Question # Which ONE of the following statements MOST accurately describes the true (actual) GFR in this patient? A. The egfr (MDRD) and eccr (C-G) accurately reflect her actual GFR B. Her actual GFR is greater than either the egfr (MDRD) or the eccr (C-G) predict C. Her actual GFR is less than either the egfr (MDRD) or eccr (C-G) predict D. The egfr (MDRD) is a more accurate estimation of the actual GFR E. The eccr (C-G) is a more accurate estimation of the actual GFR Question # The correctt answer is C A hour urine collection was performed to quantify the endogenous creatinine clearance The value was.6ml/min eccr (C-G)/endogenous Ccr=. egfr (MDRD)/endogenous Ccr=.5 (See Freedberg Kidney Int 766:9, 9) Question # GFR (Cin) According to Age- (Wesson, LG, 98) Muscle wasting (sarcopenia) markedly reduced creatinine generation, leading to overestimation of Ccr (and GFR) by both egfr (MDRD) and eccr (C-G) formulas (which rely on Scr, age, gender (and weight) only. The same thing will happen in pure vegetarians and the opposite will happen in highly muscular in individuals 6 CKD: egfr in Healthy Caucasians by Gender Males 6 Females x X = chromium EDTA clearance X = MDRD egfr 95% CIs egfr (ml/min/.7m) Age (years) egfr (ml/min/.7m) th Percentile 5 th Percentile 5 th Percentile Age (years) x x (Nijmegen Biomedical Study, 8) The case of Prof K single kidney and CKD 5

6 Percentile Charts: Useful for Following Progression of CKD Microalbuminuria: Prevalence (PREVEND, ) (N=,69) Patients who move down the percentile values (e.g. from 75th to 5th to 5 th ) have progressive disease, even if they remain in the same KDOQI stage Patients who remain in the same percentile do not have progressive disease, even if they move to higher KDOQI stages Prevalence of Microalbuminuria 8% 6% % % % 8% 6% % % % Age (years) Males Females UACR with Aging Albuminuria: Gender associated changes with Aging (Verhave JC, et al AJKD :6, ) Lean body mass (LBM; muscle mass) decreases steadily after about age years in normal subjects (around Kg/decade) Urinary creatinine excretion is tightly correlated with LBM At constant urinary albumin excretion rate, the urinary albumin to creatinine ratio increases with aging Ratio of 6 Prevalence 5 [Old (7-75 y) to Young (8- y)] Males Females UAE (- mg/d) UACR - mg/gm UACR (M=7-9mg/gm;F =5-5mg/gm) egfr does not Correlate with UAE (Cirillo M, et al. Gubbio Population Study. Arch Intern Med 68:67, 8) OUTLINE Definitions of CKD Estimation of GFR by formulas Application of Definitions to the Role of proteinuria (albuminuria) in diagnosis's and prognosis in the elderly Conclusions and 6

7 Question # In order to properly utilize egfr or Albuminuria to diagnose CKD one should adjust for the effects of gender and normal aging A 68 year old woman is discovered to have Stage CKD (by KDOQI-CKD Classification Criteria) following routine outpatient serum creatinine test. She is a non-smoker, has no diabetes and has no family history of heart disease Laboratory Tests: FBS- mg/dl, Total Cholesterol 7mg/dL, Uric acid.mg/dl, egfr (MDRD) 55ml/min/.7m, urinalysis negative protein/blood by dipstick, urinary albumin/creatinine ratio= 7mg/gm creatinine Question # Which ONE of the following best characterizes her risk for a subsequent cardiovascular (CV) event compared to a similar patient with an egfr (MDRD) >6ml/min/.7m? A. She is at increased risk for a fatal/non-fatal CV event over the next 5- years B. She is at decreased risk for a fatal/non-fatal CV event over the next 5- years C. Her risk for a fatal/non-fatal CV event is neither decreased or increased Question # The Correct answer is C- In the absence of proteinuria (albuminuria) a low GFR (in the normal range for her age and gender) does not constitute a significant CV risk factor egfr and Albuminuria in Prediction of ESRD and CVD Albuminuria is a better predictor of risk of ESRD and CVD events than egfr Non-albuminuric Stage CKD (Stage A, p-) uncommonly progresses to ESRD and has a low relative risk of CVD in subjects over 65 years of age Hazard Ratios for ESRD by egfr and Urinary Albumin/Creatinine Ratio (Hallan S, et al JASN April, 9) 5 5 Hazard Ratio 5 ( years) 5 5 > egfr (ml/min/.7m) Normoalbuminuria Microalbuminruia Macroalbuminuria 7

8 Change in egfr over time in CKD (Halbesma N, et al, PREVEND. JASN 7:58-59, 6) All-Cause Mortality and Proteinuria (At same egfr strata) Taiwan Health Management Institution Study; Lancet 8 6 Change in egfr (ml/min/.7m) over years Hazard Ratio 5 egfr <5th percentile (% albuminuria) Hematuria (5% albuminuria) Macroalbuminuria (5% egfr < 5th percentile) egfr (ml/min/.7m Normal Proteinuria Minimal Proteinuria Overt Proteinuria CVD and CKD: Cross-Classification of egfr and Microalbuminuria: Effect on CV Event Risk (Foster MC, et al Arch Intern Med 67:86-9, 7) CKD Stage Risk of Cardiovascular Disease (Brantsma AH, et al and PREVEND. NDT, 8) (n= with CKD) CV Events (Hazard Ratio after adjustment for comorbidity-95% CI) Microalbuminuria Absent Present egfr Not Reduced.. (ref) (.8-.8) Reduced.9.6 (.6-.) (.-.5) (<6ml/min/.7m in males; <59ml/min/.7m in females) Hazard Ratio for CV Events (no CKD=.) Stage Stage Stage (All) Stage (UAE Stage (UAE <mg/d) >mg/d) CKD Stage PREVEND egfr MDRD vs CVD events (Van der Velde M, et al PREVEND-ASN 8) PREVEND egfr (CyC), Ccr (Age > 6 years): Kidney Center UMCG 8 HR 6 <6 Age < 6 yrs 9-6 >9 <6 Age > 6 yrs 9-6 >9 MA+ Kidney Center UMCG,5,5 HR,5,5 <6 egfr CysC 9-6 >9 MA-,5,5 HR,5 MA+,5 MA- Creatinine clearance <6 9-6 >9 8 HR 6 MA+ MA- MA- MA+ 8

9 egfr and Diagnosis of CKD: An Illustration A 5 year old man with an egfr of 55 ml/min/.7m is 5% below the median for his age and -5 ml/min/.7m below the 5th percentile for age and gender A 75 year old man with an egfr of 55ml/min/.7m is % below the median for his age and +5 ml/min/.7m above the 5th percentile for age and gender WHICH ONE HAS SIGNIFiCANT CKD? Question # Patient A a 5 year old man with an egfr of 55 ml/min/.7m (p-) is 5% below the median for his age and -5 ml/min/.7m below the 5th percentile for age and gender Patient B- a 75 year old man with an egfr of 55 ml/min/.7m (p-) is % below the median for his age and +5 ml/min/.7m above the 5th percentile for age and gender Question # Which ONE of the patients described has significant CKD? A. Patient A only B. Patient B only C. Patient A and B D. Neither Patient A or B OUTLINE Definitions of CKD Estimation of GFR by formulas Application of Definitions to the Role of proteinuria (albuminuria) in diagnosis's and prognosis in the elderly Conclusions and CONCLUSIONS Use of egfr alone to diagnose CKD leads to many false positives particularly in elderly females No clear rationale for separating Stage and in KDOQI and NICE Albuminuria is a much stronger risk factor than egfr in predicting outcome (ESRD and CVD), but values must be adjusted for age and gender RECOMMENDATIONS New and uniform criteria, with adjustment for effects of age and gender, for diagnosing CKD are needed Assessment of Albuminuria (UACR, second morning void), adjusted for gender and age, should be used for early detection of high risk subjects (at any age) and for prediction ESRD and CVD risk. Prospective trials are needed to assess the cost-effectiveness of detection (screening) strategies based on albuminuria 9

10 PROPOSED NEW DEFINITIONS OF CKD BASES ON egfr and UACR CRITERIA THANK YOU CKD-- No CKD- unless imaging, urinalysis or biopsy abnormal- Low Risk of CVD/ESRD CKD-- Possible CKD- depends on Age <65 y, imaging, urinalysis or pathology abnormal- Moderate Risk of CVD/ESRD - Definite CKD- without need for abnormal imaging, urinalysis or pathology- High Risk of CVD/ESRD A Grid For Diagnosis and Prognosis Of Chronic Kidney Disease (CKD) A Grid For Diagnosis and Prognosis (CVD-RR) Of Chronic Kidney Disease (CKD) A A A A A A G (9+) G (6-89) G a (5-59) G b (-) G (5-9) G 5 (<5) (<mg/gm) CKD- CKD- CKD-/ CKD- CKD- (-mg/gm) CKD-/ CKD- CKD- CKD- (>mg/gm) G (9+) G (6-89) G a (5-59) G b (-) G (5-9) G 5 (<5) (<mg/gm) > (-mg/gm) > (>mg/gm) > Classification of CKD: The Future? Refinement of a G (egfr)-a (Albuminuria) stratification (8 cells) Sub-stratification by Age (< or > 65 years) and Gender (M/F) Relative and Absolute Risks of All-Cause mortality, CVD mortality, ESRD, Progressive CKD by G-A Stage Risk Scoring by G-A Stage, modified by Age and Gender (Low, Medium, High) Example 5 year old man with Autosomal Dominant Polycystic Kidney Disease; egfr 6ml/min/.7m, UACR 5mg/gm, bilaterally enlarged Cystic kidneys by ultrasound CKD--G A ; RR=- for CVD; ADPKD