Did the KDOKI–CKD Classification Corresponds to the Clinical ...

The National Kidney Foundation –KDIGO guidelines ( 2002-2013 KI Supl 3)Chronic Kidney Disease (CKD) Classification System

CKD1

CKD2

CKD3

CKD4

CKD5

Kidney dammage : proteinuria, hematuria, sediment….imaging

Chronic kidney disease awareness, prevalence, and

trends among U.S. adults, 1999 to 2000

Coresh J et al: JASN 16: 180-188, 2005

Hallan S J Jasn , 17 , 2275 , 2006

All-cause mortality attributable to chronic kidney

disease:a prospective cohort study based on 462 293

adults in Taiwan

Wen CP et al: Lancet 371: 2173–82, 2008

Prevalence of chronic kidney disease in China:

a cross-sectional survey

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 KDIGO 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% 19,000,000JASN 2005

Taiwan 11.9% 2,000,000Wen,.. Lancet 2008 (11.3 – 12.5)

Mainland China 10.8% 140,000,000Zhang,.. Lancet 2012 (10.2 – 11.3)

Maremar 2.9-5.1% 750,000( 2014) manus (2015)

Single eGFR and no confirmed proteinuria exept Maremar

ESTIMATED PREVALENCE 3-42 (%)

20

McCullough et al N.D.T. 2012

An example of partnership

Maremar

“Maladies rénales au Maroc””

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

• microproteinuria (mPR) mild,using the Hemocue method and

nephelometry (quaility control), dipstick = > +

• macroproteinuria (MPR) overt, 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 systemfrom H.C. to lab within hours

KDIGO guidelines

http://www.nist.gov/


Time schedule

• Jan – May 2008: discussion of the protocol (Ben Gharbi, M Elseviers, M DE Broe)

• June – Aug 2008: negotiation of the contract

• October 2008:

• ethical committee: approval of protocol

• official approval of the release of voters by Min. of Internal affairs,

Pasha of Khemmisset

• order for dipsticks, BP measurement, devices (Hemocue…)

• hardware – software

• 28 November 2008: Meeting in Marrakech of Internal Steering Committee

• Mid December 2008: training sessions of health care personnel

• January 2009: Pilot study in Khemisset

• February 2009: Start of the study in Khemisset

• May 2009: Start of the study in El JadidaVoters list

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

26 – 70 years

Stratified random sample (9% of eligible people)

Sampling

5 000

46 553 67 309

5 000

Recruitment

Voters list

Period of six months

Sampling

5 health centers of screening/city in two cities

(40 subjects/week x25 weeks = 1000 /health center )

Stratified randomized

sample , voters list

1000 participants / centre

in total 10 health centers,

(HC) = 10,000 subjects

Sex

Age

M F

25-40 y N N

40-55 y N N

55-70 y N N

VOTERS LIST

• First list obtained after one year of negotiations was useless.(1999)

• Missing,wrong adressess

• Second updated list was given after the elections of 2009

• Second list turned out to be usefull

Centre de Santé Khemisset

Organization, training & monitoring

• 19 official meetings

• 10 education meetings, workshops and training sessions

• 38 local visits

• 88 people involved at different levels

Screening1st visit (Investigations)

Dipstick

Albuminuria

Glycemia

Creatininemia3X sitting

Understanding is essential

Screening2nd visit (1 week)

Confirmation of pathological findings

Dipstick > +

Microalbuminuria > 20mg/l

SAP>140 mmHg and/or DAP> 90 mmHg

illitaration rate: 30%

How to perform a midstream urine sample

Dirk De Weerdt


Recruitment: response rates

Response rates during the different phases of the Maremar recruitment procedure

Total number : n= 10524

at first visit

Recruitment

KHEMISSET EL JADIDA

Age KHEMISSET EL JADIDA Total26 – 40 years 1 832 1 674 3 50641 – 55 years 1 910 1 779 3 68956 – 70 years 1 725 1 604 3 329Total 5 467 5 507 10 524

07 December 2009 to 16 June 2010 17 May 2010 to 18 March 2011

Prevalence of hypertension(SAP ≥ 140 mmHg and/or DAP ≥ 90 mmHg)

16.7%

39.2%

20.3%

7.2%

0 10 20 30 40

All

56 - 70 years

41 - 55 years

26 - 40 years

%

Correction: based on the demographic structure of the populationHypertension confirmed in 1003/1458 cases

9

18,5

27,7

18,2

1,7

5,6

12,8

6,6

0,31,5

5,8

2,44,1

10,4

21,8

11,9

0

5

10

15

20

25

30

Stage I Stage II Stage III Systolic

26-40 years

41-55 years

56-70 years

All

Prevalence of hypertension stages by age (%)

Prevalence of obesity (BMI ≥ 30 kg/m²)

23.2%

25.9%

28.1%

18.3%

0 5 10 15 20 25 30

All

56 - 70 years

41 - 55 years

26 - 40 years

%

45,1

32,9

29,7

24,2

72,6

58,1

53,5

36,4

16

6,3

4,6

11,3

0 10 20 30 40 50 60 70 801, 2

or 3W

aist >

104

M, 8

0 FW

-H ra

tio >

1 M

, 0,8

5 F

BMI >

30

Male

Female

All

Prevalence of obesity markers

Health outcomes : no difference between men and woman

Prevalence of hyperglycemia ≥ 1.26g/l

13.8%

27.4%

18.2%

6.3%

0 5 10 15 20 25 30

All

56 - 70 years

41 - 55 years

26 - 40 years

%

Mean glycemia was 1.13 g/l (SD 0.49).

Corrected prevalence of glycemia between 1.00-1.25 g/l was 30.3%

Prevalences observed in the study population ,total group(n=10524), males (5122) , females (5402).


eGFR(MDRD) in the adult population of Morocco:

Gaussian distribution of three age categories

85.8% 13.7% 0.3% 0.3% 0%

70.2% 28.5% 0.9% 0.2% 0.1%

51.2% 42.1% 5.8% 0.4% 0.4%


eGFR (MDRD) in the adult population of Morocco:

Percentiles within the gender and age categories


dipstick + = 67.2%; dipstick +/++ = 28.6% FALSE POSITIVE RESULTSfever, exercice, smoking,obesity,medication (Rosuvastatin),diet

KDIGO classification of eGFR and confirmed proteiniuria (mild, overt)


KDIGO-classification based on eGFR, proteinuria and

hematuria (confirmed dipstick investigation)

Changes in excretion of creatinine, plasma creatinine and creatinine clearance in healthy individuals at different ages

Stewart Cameron J & Macias-Nunez JF: 'Renal function in the elderly'in: Oxford Textbook of Clinical Nephrology, Oxford Med Publ 1998, pp 78-91

Percentiles of estimated GFR by age

Coresh et al: JASN 2005 : 16 , 180

eGFR-MDRD for men

Wetzels et al Kidney Int 2007 , 72, 632-637

Fall of GFR with age

Ferrari P. et al., NDT ; 2009 24, 1828

Interpretation of creatinine clearance

Elseviers MM, M E De Broe et al:. Lancet 1: 457,1987

N =12.000


CKD 1-2: n=153Total group eGFR >60: n=4971

CKD 1-2: n=260Total group eGFR >60: n=5269

eGFR – age (MDRD formula)

Overdiagnosed


Unclassifiable KDIGO, “underdiagosed”

CKD 3, 4, 5,4 ,5

CKD1=44.9CKD2=52.8CKD3=60.3CKD4=60.6CKD5=49.2

AGE

Dutch population

Arab-Berber population

Wetzels et al Kidn InternWetzels et al Kidn. Intern 2007

Maremar manuscript submitted august 2015

Prevalence of CKD in different studies around the world according to the

KDIGO 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% 19,000,000JASN 2005

Taiwan 11.9% 2,000,000Wen,.. Lancet 2008 (11.3 – 12.5)

Mainland China 10.8% 140,000,000Zhang,.. Lancet 2012 (10.2 – 11.3)

Maremar 2.9-5.1% 750,000( 2014) manus (2015)

Single eGFR and no confirmed proteinuria exept Maremar


Belgium

Demography and CRF

Morocco

Prevalence of CRFeGFR< 60 ml/min/1.73m2

56-70y 6.6%

41-55y 1.3%

26-40y 0.5%

4.7%

population pyramids

1.6%


Low prevalence of CKD in Maremar

The second reason is the “overdiagnosing” due to investigation of proteinuria limited to the first screening time. Indeed in most published reports, dealing with epidemiology of CKD, confirmation of the proteinuria was not performed even in the those considered as of good quality

False positivity of urine analysis dipstick + 67;5%dipstick ++/+++ 28.7%

Many factors can influence protein/albumin excretion such as obesity, age, gender, distant inflammation, high blood pressure, remote infection and drug use (Rosuvastatine)

The third reason of “overdiagnosis” is : the MDRD equation has been demonstrated to systematically under-estimate to a certain extend renal function in healthy individuals

Proteinuria Dipstick Analysis• Confirmed False Positives

• First visit => + n= 513 (4.9%) 206 (1.9%)

• mild n= 408 (3.9% ) 139 (1.6%) 67.2%

• overt n= 105 (1.0%) 67 (0.3%) 28.7%

• False positive results using dipstick proteinuria : 59,8% in our study

population , mainly mild proteinuria

• Many factors however can influence protein/albumin excretion such as

obesity, age, gender, distant inflammation, high blood pressure, remote

infection and drug use (Rosuvastatin), excercise.

• Hooi LS, Ong LM, Ahmad G, Bavanandan S, Ahmad NA, Naidu BM. A population-based study

measuring the prevalence of chronic kidney disease among adults in West Malaysia. Kidney Int.

2013;84(5):1034-40. [PMID: 23760287] doi: 10.1038/ki.2013.220 :55% false + )• Qaseem A, Wilt TJ, Cooke M, Denberg TD. The paucity of evidence supporting screening for

stages 1-3 CKD in asymptomatic patients with or without risk factors. Clin J Am SocNephrol.

2014;9(11):1993-5. [PMID: 25237074] doi: 10.2215/CJN.02940314


McCullough et al N.D.T. 2012

Summary of the prevalence of CKD reported in high quality

studies (%; 95% CI)

nine best studies

Chronicity of eGFR measurement

False positives:CKD 3A: 32.2%CKD 3B: 7.4%

Clear improvement of accuracy


Assessment of CKD

CKD assessment based on eGFR

with proteinuria with proteinuria

and/or hematuria

1 eGFR ,+ unconfirmed proteinuria/hematuria 7.0% 14.0%

2 eGFR + confirmed proteinuria 4.2% 7.4%

3 Chronicity eGFR + conf. proteinuria/hematuria

(KDIGO 2013)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: n= 513 4.9% of study populationconfirmed 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/1.72m2.


Prevalence of CKD stages 1 to 4 as mean and

SD of 6 studies according to the KDOQI criteria

Prevalence rate of stage 3 is many times more common than CKD 4/5, suggesting that stage 3 CKD is not simply a stage in the evolution of CKD. It’s a stage that seldom progresses to kidney failure.

KDOQI CKD in our study: 6.6% corrected : 5.1%without hematuria : 3.9% corrected : 2.9%

LIMITATIONS of CKD DEFINITION in KDOQ - KDIGO

• Single absolute eGFR criterion unadjusted for normal decline in GFR

with age ,sex , leads to high prevalence of “false positive CKD and false

negatives “whenever used for diagnosis and treatment

• eGFR 60 -45 ml/mi/1.73m2 without proteinuria are not at greater risk of

CVD compared with eGFR greater than 60 ml/min and proteinuria

• Majority of living related or non related donors will be excluded ( are in

the US) when <60 ml/min is used as criterion of CKD

• Association of decreased and declining e GFR and increased risk of

CVD is steeper and more robust when eGFR is less than 45ml/min

(CKD 3b) and is GREATLY magnified by the presence of

PROTEINURIA

• In stage 3 of CKD representing almost 40-55% of the CKD population

the number that will PROGRESS to ESRD is estimated (measured) at

only 0.15 –0.2 % per year over 10-25 years. The vast majority of

these patients are younger that 60 years of age

Measures to Define Chronic Kidney Disease (CKD)

• A higher absolute risk and lower relative MORTALITY

risk in older versus younger adults with SIMILAR

levels of eGFR means that survival is generally more

limited at older ages and varies less as a funtion of

eGFR. O’Hare 2013

• FALSE NEGATIVES and FALSE POSITIVES

• Young and middle –aged adults with an eGFR of 60-74

ml/min/1.73m2 but WITHOUT proteinuria and whose life

expectancy is probably substantially shorter than those with

higher levels of eGFR , will NOT meet the criteria for CKD ,

whereas a large number of older adults with eGFR levels slightly

below 60ml/min/1.73m2 and no proteinuria , whose life

expectancy is probably similar to those with higher levels of

eGFR , WILL meet the criteria.

• O’Hare JAMA April 2013

REVISION of the CKD 3 definition in the KDOQI guidelines

• We favor to include the presence of kidney dammage as

manifested from an elevated albuminuria in stage CKD3 .

• Stage 1 and 2 CKD subjects with elevated albuminuria with a

fairly normal eGFR have a WORSE prognosis than the present

CKD3 subjects without elevated albuminuria.

• P De Jong ,R Gansevoort NDT, 23; 1092; 2008

• The risk of developing a CV event was NOT increased in subjects with

stage 3CKD without increasd albuminuria . In stage 3CKD subjects with

albuminuria was the CV risk elevated. P De Jong ,R Gansevoort NDT, 23; 1092; 2008

•

• For a given level of kidney function older adults have a clearly LOWER

risk of ESRD compared with younger adults

• M Tamura , W Winkelmayer JAMA June 2012 vol 307,

CONCLUSIONSMaremar demonstates that the choice of an arbritrary single threshold of eGFR for classifying CKD3-5 inevitably leads to “over-diagnosis “( false positives) of CKD in the elderly, particularly in those without proteinuria ,hematuria , hypertension. It also leads to “under-diagnosis” (false negatives ) of CKD in younger individuals with an eGFR above 60ml/min/1.73m2 and below the 3th percentile of their age and gender category

The use of a 3th percentile eGFR level as cut –off based on age and gender specific reference values of eGFR of the Moroccan population allows the detection of these false positives and negatives.

Lack of confirmation of increased proteinuria and absence of demonstration of ‘chronicity’ of

the decreased eGFR found at inclusion are the main reasons for the important inflation of the prevalence of CKD in the literature

Maremar demonstrates that the combination of population screening encompassing four different major health problems in the same screening procedure, using the correct methodologies and procedures, combined with a prevention and follow up program results in a clinically and scientifically relevant program.

Mohammed Ben Gharbi, Monique Elseviers, Mohammed Zamd

Pieter Bruegel (Antwerpen 1525-1569) The Blind leading the Blind

McCullough et al N.D.T. 27; 1812 ; 2012

MAREMAR : O O O, Proteinuria , confirmedHematuria , confirmed

MaReMar Baseline results, update December 2014

2014

Prevalences

Corrected prevalence according to the Moroccan population distribution:

x 0.78 (41-55y) and x 0,29 (56-70y)

Hypertension: confirmed BPsyst>140 or BPdiast>90

Diabetes: fasting glycemia>1,25

Obesitas: BMI>30

Proteinuria and Hematuria: confirmed dipstick analysis >= one cross positive

In case only confirmed proteinuria is taken into account KDOQI CKD : 3.0%

Observed

prevalence

Corrected

prevalence

26-40y 41-55y 56-70y

n=10524 n=3506 n=3689 n=3329

Hypertension 21,9% 7,2% 20,3% 39,2% 16,7%

Diabetes 16,8% 6,2% 17,8% 26,7% 13,4%

Obesitas 24,2% 18,3% 28,2% 25,9% 23,2%

KDOQI CKD 6,6% 3,0% 5,3% 12,0% 5,1%

eGFR<60 2,7% 0,5% 1,3% 6,6% 1.6%

Proteinuria 1,6% 0,9% 1,2% 2,7% 1,3%

Hematuria 3,4% 1,9% 3,3% 5,2% 2,4%

Observed prevalence

according to age

MDRD 4 variable equation for estimating eGFR from gender, age, ethnicity and plasma creatinine

MDRD equation:[1] Estimated GFR (ml/min/1.73m2) = 186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black)

http://www.patient.co.uk/doctor/estimated-glomerular-filtration-rate-gfr-calculator

https://mail.ua.ac.be/owa/redir.aspx?C=wGbKuZ-m50-UFRJVdlZx5KCJx_g_RtII-dwm5B6mEsHc7LGbVbqaedILeAqV5idp8haAncE_gRI.&URL=http%3a%2f%2fwww.patient.co.uk%2fdoctor%2festimated-glomerular-filtration-rate-gfr-calculator%23ref-1


CKD: Etiologies

The progression of chronic kidney disease: A 10-year population-based study

of the effects of genderand age

BO Eriksen and OC Ingebretsen Kidn Intern 2006; 69 ; 375 .

• The different prognoses of CKD stage 3 in identifiable subgroups make it

difficult to establish guidelines with a general approach to these patients.

• A patient with stable GFR may need more attention to an increased risk of

• cardiovascular disease, whereas patients with progressiev disease must also

be prepared for RRT.

• The present National Kidney Foundation Kidney Disease Outcomes

• Quality Initiative guidelines do not incorporate different approaches to

subgroups of the CKD population, presumably because the evidence base

has been lacking.This should be changed.

• Proteinuria is known to be associated with progressive disease.

• Although included in the definition of stages 1 and 2, definitions of the more

advanced stages have been made without taking proteinuria into account.

This needs to be reconsidered.

Using a single threshold GFR value, in the absence of any additional information such as urinary protein concentration, for the definition of CKD (Chronic Kidney Disease) is creating a huge number of false positives which among the “’Western “ populations goes up to 50% and according to recent papers even higher.

This leads to excessive futile use of health care resources.This puts a wrong label of a serious disease on individuals who will never consult a nephrologist or be treated by renal replacement techiques and will die of CV diseases.

Such a uncorrect CKD label has many untoward and undesirable effects , such as unnecessary anxiety , unneeded additional investigations and loss of insurabillity

It creates a non-negligible number of false negatives at younger ages. Younger individuals who are in urgent need to be seen by a nephrologist. We all known how silent a renal disease may progress and early detection is of paramount importance..


“Reduced/ impaired kidney function “ would be established by the finding of an eGFR less than fifth (or less) percentile for healty individuals of similar age, gender, and ancestry without proteinuria/hematuria.

CKD has the same definition plus the presence of dipstick positivity or increased ACR and or “renal” hematuria



with age ,sex , leads to high prevalence of “false “ positive CKD and

false negatives whenever used for diagnosis and treatment

• eGFR 60 -45 ml/mi/1.73m2 without proteinuria are not at greater risk of

CVD compared with eGFR greater than 60 ml/min and proteinuria


the US) when <60 ml/min is used as criterion of CKD




PROTEINURIA





SCREEN or NOT to SCREEN the GENERAL ADULT POPULATION

• Maremar found 16.7 hypertension; 13.4% diabetes type 2; 23.3% of obesitas and 5.1% of KDOQI CKD in the general adult population (25-70 years of age) in Morocco .More than 50% of the subjects were unaware of their diseases

• Subjects with one of these diseases or CKD stage were followed up and appropriate treatment was installed if necessary

• The results of Maremar have been implemented in the teaching program of the faculties of medicine in the country at master and post graduate level .

• At institutional level the Maremar model (kidney, hypertension, diabetes, CV diseases screening ) is planned to be implemented in the “centres de santé “ throughout the country.

• Screening of the adult population in Morocco within the frame of the methodology used in Maremar was highly relevant

CONCLUSIONS

MAREMAR is a prevalence study of hypertension, diabetes,obesitas KDIGO

CKD of a randomized ,stratified , representative sample of the adult

population of Morocco.

The relative low level of KDIGO CKD prevalence in Morocco has to do with the

structure of the population pyramid and the fact that, in contrast with our

study, almost all prevalence studies have NOT confirmed proteinuria-

hematuria and NOT proven the chronicity of the CKD stage (false positives)

The CKD3a group without proteinuria ( 30% of CKD population) should be

renamed ‘impaired kidney function’(IKF) and NOT CKD . Dose adaptation in

prescribing nephrotoxic drug.

CONCLUSIONS

eGFR percentiles within gender- age categories, and NOT a SINGLE threshold GFR value, should be used. Improved accuracy and much less false+ and -

Screening for hypertension , diabetes, obesitas, and KDIGO CKD linked to a diagnostic –therapeutic follow up and implementation into the CV of the medical schools, makes screening of the adult population highly relevant.

There is a need for other quality studies on the prevalence of CKD using the appropriate methodologies and confirmation of the findings in time according to the KDIGO guidelines (confirmation of proteinuria. , hematuria…. , chronicity of CKD)

Urinary analysis

Blood analysis & drugs

Analyzers

Equipment & software

Printing

Workload

Meetings & Training

NB: not included expertise, workload, supervision and travel costs

of principal investigators who are involved on a voluntary basis.

Financial aspects Phase of recruitment and screening

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

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

Who is who

Docters, nurses , administrative personnel of the health centers

Sarlingyi, Burma

Maremar poster ASN 2012 eGFR

Whether early identification and treatment of subjectswith “reduced” levels of GFR within the normal range for their age/gender, but without any other manifestations of kidney disease, will reduce the subsequent risk of cardiovascular events or progression to end-stage-renal disease is

currently unproven

Screening for CKD with eGFR. Doubts and DangersRichard J. Glassock and Christopher WinearlsClin J Am Soc Nephrol 3: 1563–1568, 2008

Gansevoort et al 2012 Lancet

MaReMar Baseline results, February 2012

Renal failure

Khemisset El Jadida

numbers corrected %

age 26-40 0,2% 1,0% 19/3487 19/3487 0,5%

age 41-55 1,3% 1.2% 47/3678 37/2869 1,3%

age 56-70 5,9% 7.4% 220/3320 64/963 6,6%

TOTAL 2,4% 3.1% 286/10485 120/7319 1.6%

TOTAL

RENAL FAILURE (GFR<60)

Correction: based on the demographic structure of the adult population (25-70years)

n= 29.608.009 , 50.1% female

Age 41-55: correction factor 0.78 (size of this population is only 78% of group 1)


(magic KDOQI number)

Definition of CKD

One or more of the following symptoms: - eGFR (MDRD) < 60 ml/min/1.73 m² , (confirmed)- Macroalbuminuria ≥ 200 mg/L, (confirmed)- Diabetes type I with microalbuminuria between

20-199 mg/L (confirmed)- Dipstick investigation showing more than one

cross positive (after confirmation) for proteins or blood. (confirmed)

Conclusion

• MaReMar generated, for the first time in Morocco, quantitative and scientifically correct information on the prevalence of CKD Hypertension, Obesitas, Diabetes, Risk Habits

• This information is highly relevant for future national health strategies.

z

Ishani et al JASN 2006, 17, 1444-1452

prot ++/+++

prot +

eGFR <60ml/mn

eGFR 60-75 ml/m



with age ,sex ,will lead to high prevalence of “false “ positive CKD

whenever used for diagnosis and treatment

• eGFR below 60 ml/min without proteinuria are not at greater risk of CVD

compared with eGFR greater than 60 ml/min


the US) when <60 ml/min is udsed as criterion of CKD




PROTEINURIA





ISN GO Clinical Research & Prevention - Awarded Projects

(KHDC Program)

Maremar

EGIPT-CKD

Enugu

Maiduguri

Kwazulu-Natal

Durban

Maputo

Cape town

Blantyre

Cairo

Ile-Ife

Kumasi

Kilimanjaro

Johannesburg


Renal function:

DOQi and dipstick positive

GFRdoqi

90 plus 60-89 30-59 15-29 15 min Total

% % % % % %

albumine no albuminuria 68,84 27,41 2,00 0,13 0,22 98,60

macroalbuminuria 0,53 0,49 0,24 0,05 0,09 1,40

Total 69,38 27,90 2,24 0,18 0,31 100,00

number 7274 2925 235 19 32 10 485

GFRdoqi and macroalbuminuria (confirmed dipstick >= ++)


Pre-diabetes and diabetes

Khemisset El Jadida

numbers corrected %

age 26-40 20,9% 33,5% 939/3490 939/3490 26,9%

age 41-55 30,2% 36,0% 1214/3679 947/2870 33,0%

age 56-70 33,6% 35,7% 1149/3320 333/963 34,6%

TOTAL 28,2% 35,1% 3302/10489 2219/7323 30,3%

Khemisset El Jadida

numbers corrected %

age 26-40 5,9% 6,8% 221/3490 221/3490 6,3%

age 41-55 16,4% 20,1% 669/3679 522/2870 18,2%

age 56-70 23,8% 31,2% 909/3320 264/963 27,4%

TOTAL 15,2% 19,2% 1799/10489 1007/7323 13,8%

PREDIABETES (glycemie 1-1.24)

TOTAL

TOTAL

DIABETES (glycemie>1.25)

Correction: based on the demographic structure of the population



Obesitas: use of different criteriaTOTAL Male Female

age 26-40 18.3% 8,8% 27,4%

age 41-55 28,2% 13,3% 41,4%

age 56-70 25,9% 11,6% 40,4%

TOTAL 24.2% 11,3% 36,4%

age 26-40 20,8% 2,5% 38,3%

age 41-55 30,5% 3,9% 54,3%

age 56-70 38,2% 7,5% 69,1%

TOTAL 29,7% 4,6% 53,5%

age 26-40 22,8% 3,6% 41,1%

age 41-55 36,5% 6,6% 63,3%

age 56-70 39,5% 8,9% 70,3%

TOTAL 32,9% 6,3% 58,1%

OBESITAS waist-hip ratio (>1 male, >0,85 female)

OBESITAS waist (>104 male, >88 female)

OBESITAS BMI >30

SCREEN or NOT to SCREEN the GENERAL ADULT POPULATION

• Maremar found 16.7 hypertension, 13.4% diabetes type 2, 23.3% of

obesitas and 5.1% of KDOQI CKD in the general adult population (25-70

years of age) in Morocco .More than 50% of the subjects were unaware

of their diseases

• Subjects with one of these diseases or CKD stage were followed up and

appropriate treatment was installed if necessary

• The results of Maremar have been implemented in the teaching program

of the faculties of medicine in the country at master and post graduate

level .

• At institutional level the Maremar model (kidney, hypertension, diabetes,

CV diseases screening ) is planned to be implemented in the “centres

de santé “ throughout the country.

• Screening of the adult population in Morocco within the frame of the

methodology used in Maremar was highly relevant

Screening for CKD with eGFR. Doubts and Dangers

Richard J. Glassock and Christopher Winearls

Clin J Am Soc Nephrol 3: 1563–1568, 2008

• Whether early identification and treatment of subjects

• with “reduced” levels of GFR within the normal range

for their age/gender, but without any other

manifestations of kidney disease, will reduce the

subsequent risk of cardiovascular events or

progression to end-stage-renal disease is

• currently unproven

MaReMar Baseline results, revision Augustus 2014

Tabel Hematuria

HematuriaDipstick:

FirstInvestigation

N=10 430

ConfirmedHematuriaN=10 430

0 9509 (91,2%)

+ 593 (5,7%) 216 (2,0%)

++ 245 (2,3%) 123 (1,2%)

+++ 83 (0,8%) 20 (0,2%)

Hematuria>= +

921 (8,8%) 359 (3,4%)


Clinical Outcome according to age

Agen=10 524

Renal failure (1)%

Diabetes(2)%

Hypertension(3)%

Obesitas(4)%

26-40 0,6% 6,2% 7,2% 34,8%

41-55 1,3% 17,8% 20,3% 48,5%

56-70 6,6% 26,7% 39,2% 52,1%

Total 2,7% 16,8% 21,9% 45,1%

(1) Renal failure=GFR<60mg/min/1,73m2

(2) Diabetes= Glycemia >125 mg/L

(3) Hypertension=confirmed blood pressure systolic >140 mmHg

or diastolic >90 mmHg

(4) Obesitas = BMI >30


Renal Failure

GFRdoqi

90 plus 60-89 30-59 <30 Total

% % % % %

albumine no proteinuria (n=10088) 98,90 97,60 86,80 66,70 98,40

mild proteinuria (n=101) 0,80 1,60 6,80 7,80 1,00

overt proteinuria (n=63) 0,30 0,80 6,40 25,50 0,60

Total 69,6 27,7 2,2 0,5 100,00

number 7131 2842 228 51 10252

GFRdoqi and proteinuria (confirmed dipstick investigation)

Nieuwe figuur aangevraagd (zoals screen 83)

op basis van deze algemene cijfers


Hypertension and proteinuria

No hypertension:

0,8% mild and 0,3% overt proteinuria (confirmed)

Hypertension:

1,6% mild and 1,7% overt proteinuria (confirmed)

MaReMar Baseline results, update Maart 2015

Age and gender per CKD class

CKD n %

age

mean (SD)

Gender

% M/F

NO CKD 9788 93,4 46,9 (11,9) 49-51

90 plus 245 2,3 48,6 (11,4) 36-64

60-89 168 1,6 55,3 (10,0) 39-61

45-59 178 1,7 60,7 (7,5) 49-51

30-44 55 ,5 60,2 (10,2) 60-40

15-29 19 ,2 60,8 (6,7) 53-47

min 15 32 ,3 49,2 (11,3) 66-34

total 10485 100,0 47,5 (12,0) 49-51

Follow-up CKD3 subjects KhemissetJanuary 2010 – January 2014

Comparison Hemocue - Nephelometry (UZA)

University of Antwerp, Laboratory of Pathophysiology

2. Sample size calculation

In November 2004, the population of the two towns, was as follows:El Jadida: Total : 144,440 inhabitants ; 26-70 years old: 67,309 Khemisset: Total 105,088 inhabitants ; 26-70 years old: 46,553

A total of 113,862 subjects are eligible to participate in the screening program.

Recruitment will be performed in a period of 6 months based on the assumption that 8 subjects will be screened per working day in each of the 5 health care area’s per town, making a total of 40 subjects per area per week. Recruitment during 25 weeks will result in 1000 subjects per area multiplied by 5 area’s in each town giving a total sample size of 2x 5000 (10,000)participants (approximately 9% of the eligible population). Sampling will take into account that a non-response rate between 20 and 40% can be expected.


eGFR – age (MDRD formula)

Recrutement

Mohammed Ben Gharbi, Monique Elseviers, Mohammed Zamd

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

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

Who is who

Table 2: Prevalences according to age categories and adult population of Morocco.

Observed

prevalence

Observed prevalence according to age Corrected prevalence according to the Moroccan

population

26-40y 41-55y 56-70y

n=10,524 n=3506 n=3689 n=3329 95% CI

Hypertension 21.9% 7.2% 20.3% 39.2% 16.7% 16.0-17.4

Diabetes 16.8% 6.2% 17.8% 26.7% 13.4% 12.8-14.1

Obesitas 24.2% 18.3% 28.2% 25.9% 23.2% 22.4-24.0

CKD 6.7% 3.0% 5.3% 12.0% 5.1% 4.7-5.5

eGFR<60 2.7% 0.5% 1.3% 6.6% 1.6% 1.4-1.8

Proteinuria 1.6% 0.9% 1.2% 2.7% 1.3% 1.1-1.5

Hematuria 3.4% 1.9% 3.3% 5.2% 2.4% 2.1-2.7

Corrected prevalence according to the Moroccan population distribution: x 0.78 (41-55y) and x 0,29 (56-70y)

Hypertension: confirmed BP syst>140 mmHg or BPdiast>90mmHG

Diabetes: glycemia>1,25g/l

Obesitas: BMI>30

Proteinuria and hematuria: confirmed => one cross positive


CONCLUSIONSMaremar demonstates that the choice of an arbritrary single threshold of eGFR for classifying CKD3-5 inevitably leads to “over-diagnosis “( false positives) of CKD in the elderly, particularly in those without proteinuria ,hematuria , hypertension. It also leads to “under-diagnosis” (false negatives ) of CKD in younger individuals with an eGFR above 60ml/min/1.73m2 and below the 3th percentile of their age and gender category

The use of a 3th percentile eGFR level as cut –off based on age and gender specific reference values of eGFR of the Moroccan population allows the detection of these false positives and negatives.Lack of confirmation of increased proteinuria and absence of demonstration of ‘chronicity’ of the decreased eGFR found at inclusion are the main reasons for the important inflation of the prevalence of CKD in the literature

Maremar demonstrates that the combination of population screening encompassing four different major health problems in the same screening procedure, using the correct methodologies and procedures, combined with a prevention and follow up program results in a clinically and scientifically relevant program.


KDIGO-classification based on eGFR, proteinuria

and hematuria (confirmed dipstick investigation)

Did the KDOKI–CKD Classification Corresponds to the Clinical ...

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