Is CKD prevalence of 10-13% in Europe, US and China a realistic number or is there overdiagnosis of CKD? Marc E De Broe.

Is CKD prevalence of 10-13% in Europe, US and China a realistic number or is there overdiagnosis of CKD? Marc E De Broe November 2016

An example of partnership Maremar Maladies rénales au Maroc

CKD IN MOROCCO: Early detection and intervention project Kidney damage : proteinuria, hematuria, sediment imaging Confirmation of proteinuria, hematuria ; chronicity of egfr GFR (ml/min/1.73m 2 ) CKD Kidney damage with normal or increased GFR Kidney damage with mildly decreased GFR +90 CKD1 60-89 CKD2 Moderately decreased GFR 30-59 CKD3 Severely decreased GFR 15-29 CKD4 Kidney failure <15 (or dialysis) CKD5 The National Kidney Foundation Kidney Quality Outcomes Initiative (KDOQI) KDIGO (2012)Chronic Kidney Disease (CKD) Classification System

CKD IN MOROCCO: Early detection and intervention project Prevalence of CKD stages 1 through 4 in Norway and the USA No confirmed albuminuria; no chronicity of egfr decrease Hallan SI et al: JASN 17: 2275-2284, 2006

Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000 Calculated false +proteinuria (based on a small sample 50%), no chronicity of decreased egfr Coresh J et al: JASN 16: 180-188, 2005

CKD IN MOROCCO: Early detection and intervention project All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan No confirmed albuminuria; no egfr chronicity Wen CP et al: Lancet 371: 2173 82, 2008

CKD IN MOROCCO: Early detection and intervention project Prevalence of chronic kidney disease in China: a cross-sectional survey No confirmed albuminuria; no egfr chronicity Albuminuria was defined as a urinary albumin:creatinine ratio > 30 mg/g creatinine. CKD was defined as egfr <60 ml/min per 1.73 m 2 or albuminuria. All prevalences are adjusted for synthesised weights. egfr= estimated glomerular filtration rate. CKD: chronic kidney disease. Zhang L et al: Lancet 379: 815 822, 2012

CKD IN MOROCCO: Early detection and intervention project Prevalence of CKD in different studies around the world according to the KDOQI staging guidelines. CKD 1 and 2 GFR <90, GFR 90-60 ml/min 1.73m2 AND albuminuria CKD 3-4-5 GFR < 60, 30, 15 ml/min 1.73m2 1988-1994 1999-2000 Number US adults 8.8% 9.4% 19,000,000 JASN 2005 Norway JASN 2006 10.2% 510,000 Taiwan 11.9% 200,000 Wen, Lancet 2008 (11.3 12.5) Mainland China 10.2% 140,000,000 Zeng, Lancet 2012 (10.2 11.3) Maremar 2.9 % 150,000 manus (2015)

MAREMAR: Four main objectives To estimate the prevalence of CKD, hypertension obesitas,diabetes in a representative randomized sample of the adult population of Morocco (26 70 years of age) To identify subjects at risk to develop CKD, To identify health related habits associated with an increased risk to develop CKD, To establish an intervention program for a follow-up period of 5 years.

Measurements: estimated Glomerular Filtration Rate (egfr) using the MDRD equation (Modification of Diet in Renal Disease) serum creatinine (Scr) using a methodology traceable to the Scr reference system (NIST) (GC-IDMS). Quality control /monthly,in case of hemolysis a new sample was analysed. Chronicity (3m.) microproteinuria (mpr) using the Hemocue method and nephelometry (quaility control), dipstick =+ +/macroproteinuria (MPR) using dipstick (=++ or more) on two morning midstream urine samples over 2-3 weeks fasting glycemia NIST= National Institute of Standards and Technology IDMS= isotope dilution mass spectrometry transport system from H.C. to lab within hours

SAMPLE SIZE CALCULATION,STRATIFIED RANDOM SAMPLE Based on this sample size, (10.000, 9%of adult population of the 2 towns) we expect to recruit: between 200 and 800 CKD patients (2-8% of screened population) with signs of renal impairment, needing further clinical investigations and appropriate treatment (28) between 2000 and 3000 patients (20-30% of screened population) with pathological findings (hypertension, diabetes and/or microalbuminuria) at risk to develop CKD, to whom a preventive treatment for 5 years (based on a prevalence of 20% hypertension and 6% diabetes in Morocco with or without microalbuminuria (29) ) will be offered. between 1000 and 2000 subjects (10-20% of screened population) with two or more health related habits increasing the risk for the development of renal impairment, that will be invited for a new screening after 1, 3 and 5 years (29, 33-37)) With a total sample size of 10 000 participants, the 95% confidence interval for the observed prevalence of CKD will be lower than 1%. This means that, even with a CKD prevalence of e.g. 7,5%, we will be able to state with 95% confidence that the real prevalence will be not lower than 7% and not higher than 8%.

Sampling KHEMISSET EL JADIDA 105 088 144 440 Population 46 553 67 309 26 70 years Sampling Voters list 5 000 5 000 Recruitment Stratified random sample (9% of eligible people) Period of six months

Sampling Stratified randomized sample, voters list 1000 participants / centre in total 10 health centers, (HC) = 10,000 subjects 5 health centers of screening/city in two cities (40 subjects/week x25 weeks = 1000 /health center ) Age Sex M 25-40 y N N 40-55 y N N 55-70 y N N F

VOTERS LIST First list(1999) obtained after one year (2008) of negotiations was useless. Missing,wrong adressess Second updated list was given after the elections of 2009 Second list turned out to be usefull

Organization, training & monitoring 19 official meetings 10 education meetings, workshops and training sessions 38 local visits 88 people involved at different levels

Screening 1 st visit (Investigations) Dipstick Albuminuria 3X sitting Glycemia Creatininemia Understanding is essential

Screening 2 nd visit (1 week) Confirmation of pathological findings Dipstick > + Microalbuminuria > 20mg/l SAP>140 mmhg and/or DAP> 90 mmhg

How to perform a midstream urine sample illitaration rate: 30% Dirk De Weerdt

CKD IN MOROCCO: Early detection and intervention project Recruitment: response rates at first visit Response rates during the different phases of the Maremar recruitment procedure Total number : n= 10524

Prevalence of hypertension (SAP 140 mmhg and/or DAP 90 mmhg) 26-40 years 7.2% 41-55 years 20.3% 56-70 years 39.2% All 16.7% 0 10 20 30 40 Correction: based on the demographic structure of the population Hypertension confirmed in 1003/1458 cases %

Prevalence of obesity (BMI 30 kg/m²) 26-40 years 18.3% 41-55 years 28.1% 56-70 years 25.9% All 23.2% 0 5 10 15 20 25 30 %

Prevalence of obesity markers BMI >30 W-H ratio > 1 M, 0,85 F Waist > 104 M, 80 F 1, 2 or 3 11,3 36,4 24,2 4,6 53,5 29,7 6,3 58,1 32,9 16 72,6 45,1 0 10 20 30 40 50 60 70 80 Male Female All Health outcomes : no difference between men and woman

Prevalence of hyperglycemia 1.26g/l Mean glycemia was 1.13 g/l (SD 0.49). 26-40 years 6.3% 41-55 years 18.2% 56-70 years 27.4% All 13.8% 0 5 10 15 20 25 30 Corrected prevalence of glycemia between 1.00-1.25 g/l was 30.3% %

CKD IN MOROCCO: Early detection and intervention project egfr (MDRD) in the adult population of Morocco: Percentiles within the gender and age categories

CKD IN MOROCCO: Early detection and intervention project egfr(mdrd) in the adult population of Morocco: Gaussian distribution of three age categories 0.3% 0% 0.3% 13.7% 85.8% 0.2% 0.1% 0.9% 28.5% 70.2% 0.4% 0.4% 5.8% 42.1% 51.2%

CKD IN MOROCCO: Early detection and intervention project

CKD IN MOROCCO: Early detection and intervention project KDOQI-classification based on egfr and proteinuria (confirmed dipstick investigation) prot.:negative CKD1-5 = 4.2% study population CKD1: 0.7% CKD2: 0.7% CKD3: 2.2% CKD4-5: 0.5%

CKD IN MOROCCO: Early detection and intervention project KDIGO-classification based on egfr, proteinuria and hematuria (confirmed dipstick investigation) CKD1-5 = 7.4% study population

CKD IN MOROCCO: Early detection and intervention project egfr age (MDRD formula) KDIGO 3-4-5 Kidney International May 2016 M Ben Gharby et al

CKD IN MOROCCO: Early detection and intervention project egfr age: MDRD formula MAREMAR Moroccan adult male population Dutch adult male population males P95 P75 P50 P25 P05 Kidney Int 2007

CKD IN MOROCCO: Early detection and intervention project egfr age: MDRD formula Japanese adult male population MAREMAR Moroccan adult male population Arab-Berber population: egfr = 175 x s(c) -1.154 x [Age] -0.203 x [0.742 if female] x [1.212 if black] Japanese population: Baba M 2015 Plus One egfr = 194 scr 1.094 Age-0.287 (if female 0.739)

Life expectancy according to chronic kidney disease stages egfr proteinuria Gansevoort RT et al: Lancet 2013; 382: 339 52

Mortality risk in elderly swedish women with CKD (KDIGO definition) Observed Hazard Ratio (HR-and 95% CI) in women age 75-85 years (egfr >60 ml/min/1.73m 2 as reference) according to egfr estimating formulas fully adjusted for co-morbidity CKD 3A CKD 3B-5 CKD-EPI= 1.4 (1.0-1.99) MDRD= 1.3 (0.9-1.8) Lund-Malmo= 1.1 (0.7-1.5) BIS1= 1.1 (0.8-1.4) Cockcroft-Gault= 1.3 (1.0-1.7) none= p<0.05 CKD-EPI= 3.5 (2.1-9.8) MDRD= 3.4 (2.1-5.6) Lund-Malmo= 3.2 (2.0-5.0) BIS1=3.1 (2.0-5.0) Cockcroft-Gault=2.2 (1.3-2.9) all p=<0.007 Malmgrem L, et al. Nephron 2015; 136:245-255

CKD IN MOROCCO: Early detection and intervention project Prevalence of CKD in different studies around the world according to the KDOQI staging guidelines. CKD 1 and 2 GFR <90, GFR 90-60 ml/min 1.73m2 AND albuminuria CKD 3-4-5 GFR < 60, 30, 15 ml/min 1.73m2 1988-1994 1999-2000 Number US adults 8.8% 9.4% 19,000,000 JASN 2005 Norway JASN 2006 10.2% 510,000 Taiwan 11.9% 200,000 Wen, Lancet 2008 (11.3 12.5) Mainland China 10.2% 140,000,000 Zeng, Lancet 2012 (10.2 11.3) Maremar 2.9-5.1 150,000 manus (2015)

CKD IN MOROCCO: Early detection and intervention project Demography and CRF population pyramids Morocco Belgium Prevalence of CRF egfr< 60 ml/min/1.73m 2 56-70y 6.6% 41-55y 1.3% 26-40y 0.5% 1.6% 4.7% Reasons for Overdiagnosis

CKD IN MOROCCO: Early detection and intervention project Low prevalence of CKD in Maremar The 2 nd reason is overdiagnosing : single investigation of proteinuria. Most published reports, dealing with epidemiology of CKD, confirmation of the proteinuria was not performed ( good quality??). False positivity of urine analysis dipstick + 67.5% Malaysia KI 2013 : 57% dipstick ++/+++ 28.7% The chronicity criterion was never used mainly because follow-up data on serum Many factors can influence protein/albumin excretion such as obesity, age, gender, distant inflammation, high blood pressure, remote infection and drug use (Rosuvastatine) creatinine were not collected 3th reason is the lack of confirmation of chronicity of decreased egfr (CKD 3A : 32.2% false positives, CKD3B : 7.4% false positives) (NDT 30; supl.4 ;2015) Equation problem?

CKD IN MOROCCO: Early detection and intervention project 3th reason is the lack of confirmation of chronicity of decreased egfr (CKD 3A : 32.2% false positives, CKD3B : 7.4% false positives) The chronicity criterion was never used mainly because follow-up data on serum creatinine were not collected Bruck c et al NDT 2015 The prevalence of CKD might have been SLIGHTLY overestilated using single creatinine and albuminuria measurements Bruck C et al JASN 27; 2015 )

CKD Prevalence Varies across the European General Population The prevalence of CKD might have been slightly overestimated using single creatinineand albuminuria measurements. However, this will not have influenced the variation of CKD prevalence across studies, as all estimations will be equally affected. page 2143 right side K Brück et al JASN 2016, 27, pg 2135 The chronicity criterion was never used mainly because follow-up data on serum creatinine were not collected K Brück et al, NDT 30; 2015

CKD IN MOROCCO: Early detection and intervention project Chronicity of egfr measurement False positives: CKD 3A: 32.2% CKD 3B: 7.4% Clear improvement of accuracy

False positive rates for single determinations of egfr in diagnosis of CKD A population-based study of the inhabitants of Tromso, Norway (n=58,000) 38,241 screened: - 6863 had an MDRD egfr of 30-59 ml/min/1.73m 2 (17.9%) - median age= 75 years egfr repeated after 3 months: - 88 had egfr <30 ml/min/1.73m 2-2175 had egfr >60 ml/min/1.73 m2 False positive rate for diagnosis of CKD (Stages 3-5) = 31.7% Eriksen B and Ingebretsen O, Kidney Int 2006; 69:375-382

Inker La et al CJASN 2016 Lifetime Risk of Stage 3 5 CKD in a Community-Based Sample in Iceland Estimates are lower than reported using single estimtates of egfr Condition 4 only one measurment of egfr Condition 1,2,3 at least two determinations of egfr

A false positive result was found in 67.2% of the subjects with mild proteinuria (+) decreasing substantially to 28.7% in subjects with overt (++/++++) proteinuria. mild or overt proteinuria at first visit: n= 513 4.9% of study population confirmed mild or overt proteinuria: n= 206 1.9% of study population Chronicity of egfr: The vast majority (75%) of false positives found in the subjects with CKD3A ; 32.2% had an egfr exceeding 60ml/min/1.72m 2. 90% of studies do not evaluatetd chronicity

CKD IN MOROCCO: Early detection and intervention project Assessment of CKD CKD assessment based on egfr 1 egfr,+ unconfirmed proteinuria/hematuria (most studies) with proteinuria with proteinuria and/or hematuria 7.0% 14.0% 2 egfr + confirmed proteinuria (some studies) 4.2% 7.4% 3 Chronicity egfr + conf. proteinuria/hematuria (KDIGO 2013) MAREMAR 3.9% 6.7% 3+ correction for total populations 2.9% 5.1% Mild or overt proteinuria at first visit (n=513): 4.9% of study population A false positive result was found in 67.2% of the subjects with mild proteinuria (+) and decreased substantially to 28.7% in subjects with overt (++/++++) proteinuria. mild or overt proteinuria at first visit: confirmed mild or overt proteinuria: n= 513 4.9% of study population n= 206 1.9% of study population Chronicity of egfr: The vast majority (75%) of false positives found in the subjects with CKD3A ; 32.2% had an egfr exceeding 60ml/min/1.72m 2.

Under/Over estimation of CKD Demography Confirm proteinuria 3-4 weeks Chronicity egfr < 60 5 months < 60 MDRD EPI formula and others, clearly under or above 3 th % line

51.2% CKD3A have egfr > P03, no proteinuria, no hematuria, no chronic kidney disease (CKD) 77 71

CKD IN MOROCCO: Early detection and intervention project CONCLUSION Lack of confirmation of proteinuria and no demonstration of chronicity of a decreased egfr are the main reasons for the inflation ( up to 60%or more) of the CKD prevalence in published reports. The choice of arbitrary single thresholds of egfr for classifying CKD 3 to 5 inevitably leads to substantial over-diagnosis (false positives) of CKD3 in the subjects 50 years of age or more, particularly in those without proteinuria, hematuria, or hypertension. It also leads to under-diagnosis (false negatives) of CKD in younger individuals without proteinuria,with an egfr above 60 ml/min/1.73 m2 and below the third percentile of their age/sex category who can t be classified by the current KDIGO guidelines.. Kidn. Intern. Mohammed Ben Gharbi et al May 2016

CKD IN MOROCCO: Early detection and intervention project Subjects aged 50 years of age or more with an egfr between 60-45ml/min/1.73m2 without proteinuria, hematuria and hypertension can t be considered as CKD3A. The use of a third percentile egfr level as cutoff, based on age-/sex-specific reference values of egfr, allows the detection of these false positives and negatives. The physiological aging process of the kidney, along with a decrease in renal function, is rather comparable across populations of different races. There is urgent need for quality prevalence studies of CKD confirming the relative low prevalence observed in Maremar, stopping the inflation of CKD based on very weak data Kidn. Intern. Mohammed Ben Gharbi et al May 2016

Who is who Steering Committee - A. Belghiti Alaoui - R. Bayahia - M. Benghanem Gharbi - A. Bitane - M. De Broe - E. El Haroudi - O. Elmenzhi - B. Ramdani - S.S. Youssef Docters, nurses, administrative personnel of the health centers Scientific Committee - M. De Broe - M. Benghanem Gharbi - M. Arrayhani - R. Bayahia - A. Belghiti Alaoui - N. Benahadi - S.S. El Khayat - O. Elmenzhi - M. Elseviers - B. Ramdani - E. Trabelssi - M. Zamd

Mohammed Ben Gharbi, Monique Elseviers, Mohammed Zamd

CKD IN MOROCCO: Early detection and intervention project Pieter Bruegel (Antwerpen 1525-1569) The Blind leading the Blind

Inker La et al CJASN 2016 Lifetime Risk of Stage 3 5 CKD in a Community-Based Sample in Iceland Estimates are lower than reported using single estimtates of egfr Condition 4 only one measurment of egfr Condition 1,2,3 at least two determinations of egfr