Why overestimate or underestimate chronic kidney disease when correct estimation is possible?

doi: 10.1093/ndt/gfw267

Full Review

Why overestimate or underestimate chronic kidney disease when correct estimation is possible?

Marc E. De Broe ¹ , Mohamed Benghanem Gharbi ² , Mohamed Zamd ² and Monique Elseviers ³

1

Laboratory of Pathophysiology, University of Antwerp, Wilrijk, Belgium,

Faculty of Medicine and Pharmacy, University Hassan II, Casablanca, Morocco and

Department of Biostatistics, Center for Research and Innovation in Care, University of Antwerp, Wilrijk, Belgium

Correspondence and offprint requests to: Marc E. De Broe; E-mail: [email protected]

A B S T R AC T

There is no doubt that the introduction of the Kidney Disease:

Improving Global Outcomes (KDIGO) guidelines 14 years ago, and their subsequent updates, have substantially contributed to the early detection of different stages of chronic kidney disease (CKD). Several recent studies from different parts of the world mention a CKD prevalence of 8 – 13%. However, some editorials and reviews have begun to describe the weaknesses of a substan- tial number of studies. Maremar (maladies rénales chroniques au Maroc) is a recently published prevalence study of CKD, hyper- tension, diabetes and obesity in a randomized, representative and high response rate (85%) sample of the adult population of Mo- rocco that strictly applied the KDIGO guidelines. When adjusted to the actual adult population of Morocco (2015), a rather low prevalence of CKD (2.9%) was found. Several reasons for this low prevalence were identi fi ed; the tagine-like population pyra- mid of the Maremar population was a factor, but even more im- portant were the con fi rmation of proteinuria found at fi rst screening and the proof of chronicity of decreased estimated glomerular fi ltration rate (eGFR), eliminating false positive results.

In addition, it was found that when an arbitrary single threshold of eGFR (<60 mL/min/1.73 m

) was used to classify CKD stages 3, 4 and 5, it lead to substantial ‘ overdiagnosis ’ (false positives) in the elderly (>55 years of age), particularly in those without protein- uria, haematuria or hypertension. It also resulted in a signi fi cant

‘ underdiagnosis ’ (false negatives) in younger individuals with an eGFR >60 mL/min/1.73 m

and below the third percentile of their age-/gender-category. The use of the third percentile eGFR level as a cut-off, based on age-gender-speci fi c reference values of eGFR, allows the detection of these false positives and negatives. There is an urgent need for additional quality studies of the prevalence of CKD using the recent KDIGO guidelines in the correct way, to

avoid overestimation of the true disease state of CKD by ≥50%

with potentially dramatic consequences.

Keywords: false positives and negatives, eGFR percentile lines, CKD prevalence, single threshold for CKD

INTRODUCTIO N

Since the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines were introduced in 2002, followed by sev- eral updated editions with the most recent published in 2012 [1], chronic kidney disease (CKD) has become an item of great interest, reflected in the impressive number of prevalence studies that have been published. These criteria define CKD as a combination of estimated glomerular filtration rate (eGFR) be- tween 90–120 mL/min/1.73 m

and 60–90 mL/min/1.73 m

, respectively, and proteinuria, haematuria or any other measur- able sign of kidney damage for CKD stages 1 and 2 and eGFR of

<60 mL/min/1.73 m

for CKD stages 3–5. It is important to note that the KDIGO guidelines repeatedly specify that these abnormalities in eGFR and ‘signs of kidney damage’ must be confirmed in order to demonstrate the chronicity of the process.

Recently [2], the global prevalence and absolute burden of CKD in 2010 was estimated by pooling data from population- based studies. These studies (n = 33) reported the gender and age- specific prevalence of CKD in representative population samples.

The age-standardized global prevalence of CKD stages 1–5 in adults ≥20 years of age was 10.4% in men [95% confidence inter- val (CI) 9.3–11.9] and 11.8% in women (95% CI 11.2–12.6). This global prevalence was 8.6% in men (95% CI 7.3–9.8) and 9.6% in women (95% CI 7.7–11.1) in high-income countries and 10.6% in men (95% CI 9.4–13.1) and 12.5% in women (95% CI 11.8–14.0) in low- and middle-income countries.

Nephrol Dial Transplant (2017) 32: ii136–ii141

A recent study [3] estimated CKD prevalence in the general European adult population and investigated international vari- ation in CKD prevalence by age, sex and the presence of diabetes, hypertension and obesity. Data from 19 general population stud- ies from 13 European countries were collected. CKD stages 1 – 5 were de fi ned as eGFR <60 mL/min/1.73 m

, as calculated by the Chronic Kidney Disease Epidemiology Collaboration equa- tion, and or albuminuria >30 mg/g, while CKD stages 3 – 5 were de fi ned as eGFR <60 mL/min/1.73 m

. CKD prevalence was age- and sex-standardized to the population of the 27 member states of the European Union.

The adjusted CKD stages 1 – 5 prevalence varied between 3.31%

(95% CI 3.30 – 3.33) in Norway and 17.3% (95% CI 16.5 – 18.1) in northeast Germany. Except for Norway, all other countries had a prevalence of >7%. The adjusted prevalence of CKD stages 3 – 5 var- ied between 1.0% (95% CI 0.7 – 1.3) in central Italy and 5.9% (95%

CI 5.2 – 6.6) in northeast Germany. The variation in CKD preva- lence strati fi ed by diabetes, hypertension and obesity status fol- lowed the same pattern as the overall prevalence.

An explanation for this important variation in prevalence was not found nor proposed. It is worth noting that in this com- prehensive study analyzing 19 of the best epidemiological stud- ies available, the chronicity criterion of decreased eGFR at fi rst screening was never used, because follow-up data on serum cre- atinine were not collected. Based on these data, it is not surpris- ing that, in a recent discussion at the European parliament, a representative of the International Renal Society declared that

‘… today [2013] one in 10 Europeans suffers from some degree of CKD and experts predict a further increase over the next decade ’ . However, McCullough et al. [4] and several editorials, comments and short reviews by Glassock [5, 6], Inker et al. [7]

and Mills et al. [2] have described the methodological weak- nesses of a substantial number of studies and the irrationality of using a single arbitrary set point, i.e. the diagnosis of CKD whenever eGFR is <60 mL/min/1.73 m

and sustained for

≥ 3 months, even in the absence of any corroborating evidence of kidney damage such as proteinuria, haematuria, abnormal imaging or renal pathology.

More recently, Maremar, an epidemiological study of CKD based on a randomized (recent voters list) representative sample (n = 10 524) of the adult population of Morocco and properly ap- plying the KDIGO guidelines, i.e. con fi rmation of proteinuria found at fi rst screening and demonstration of chronicity of de- creased eGFR at least 3 months after the fi rst screening, found an adjusted prevalence of only 2.9% (5.1% when haematuria was added to the analysis). The adjusted prevalence of subjects with eGFR <60 mL/min/1.73 m

was 1.6%, a low percentage when compared with most other analogous studies [8]. These prevalence numbers are among the very lowest in the world com- pared with recent reports summarizing the best-quality preva- lence studies of CKD to date [2, 3, 7, 9 – 14].

W H Y IS C K D P R E VA L E N C E I N T H E A D U LT POP UL ATI ON O F MOROC CO SO LOW ?

Maremar had an 85% response rate, and a relatively short recruitment/screening period (9 – 11 months), minimizing

potential serum creatinine assay problems by using an im- proved Jaffe method (isotope-dilution mass spectrometry) with a standard traceable to the serum creatinine reference sys- tem (National Institute of Standards and Technology) [15].

There seem to be three reasons to explain the high participa- tion in the study: the visit of a well-trained nurse explaining the aims of the study in detail, the personal bene fi t that the partici- pants could expect from their participation (follow-up and free medication for 5 years) and the provision of a simple booklet to visually explain the different steps of the study. The latter was included because the rate of illiteracy in the Moroccan popula- tion is as high as 30% in rural communities. The question is whether this low prevalence is related to the particular charac- teristics of the Arab Berber population investigated or to par- ticular methodological aspects used in this study compared with most other prevalence studies.

One of the most important reasons for ‘ overdiagnosing ’ /

‘ overestimating ’ CKD, observed in almost all studies, is the limi- tation of the investigation of proteinuria to a one-off event [2, 16]. The methodology used in the Maremar study was validated dipstick analysis of fresh, morning midstream urine samples, clearly explained with diagrams in the booklet used to intro- duce the study to the potential participants [17]. It is a cheap, easy-to-use and highly reproducible method when performed properly on a fresh, morning midstream urine sample [17].

However, many factors in fl uence protein excretion, such as obesity, age, sex, distant in fl ammation, high blood pressure, in- fection and drug use (such as rosuvastatin) [5], resulting in wide fl uctuations and hence false positivity of proteinuria. Initially, we decided to use the HemoCue Albumn 201 system (Radio- meter Benelux BV) and the dipstick (Combiscreen 7 Sys Plus;

Alere, Waltham, MA, USA). An excellent correlation of r = 0.932 was obtained between the HemoCue test system and a nephelo- metry assay when 128 urine samples from the study population were analyzed in a range of proteinuria of 0 – 250 mg/L. Once the screening started in the two cities, El Jadida and Khemisset, after a pilot study and training of collaborators in the different manip- ulations, we were rapidly faced with important differences in the weekly online monitoring report between the health centers (n = 5/city) in microalbuminuria results obtained by the Hemo- Cue system. By visiting the centres, we were able to identify a technical problem (small air bubbles) during the immersion of the microcuvette in the urine sample by some of the collabora- tors. Although training was resumed, we could not completely eliminate the incorrect use of the HemoCue device. We decided not to use the results already collected and limited the analysis of proteinuria to the dipstick methodology.

The dipstick analysis at the fi rst visit resulted in proteinuria being detected in 513 subjects (4.9%): mild (+) in 408 (79.5%) and overt (>+) in 105 (20.5%). Of these 513, a second dipstick investigation was performed 1 – 2 weeks later in 384 subjects, in- cluding 69.3% of subjects with mild proteinuria and all subjects with overt proteinuria. The prevalence of con fi rmed protein- uria was 206 (1.9%): mild in 139 cases and overt in 67 (36++, 25+++, 6++++). A false positive result was found in 67.5% of subjects with mild proteinuria (dipstick +) and decreased sub- stantially to 28.7% in overt proteinuria (dipstick ++ to +++).

It is interesting to note that only 14.4% (3A, 10.6%; 3B,

FUL L REVIEW

30.9%) of the subjects with CKD3A and 3B had proteinuria.

Even in subjects with CKD4/5, proteinuria was found in only 43.1% of the subjects.

These observations, and those of others [14, 18], indicate the necessity to con fi rm proteinuria within a reasonable period of time (2 – 3 weeks), as de fi ned by the KDIGO guidelines, before classifying someone as CKD stage 1 or 2, to prevent substantial overestimation ( particularly at low values of proteinuria) in cases of single screening only or the extrapolation of false positivity out of a very small sample of the population being studied [14, 18].

A second important reason for the overestimation of CKD is the absence of demonstration of chronicity of decreased eGFR in many [16], if not all, studies. Of the subjects initially categor- ized as stage 3 CKD, 25 – 30% no longer fall into this category when repeated measurements are obtained over a subsequent time period (minimum 3 months) [19] (32% in our CKD3A cases). The Maremar study, and those of Eriksen and Ingebret- sen [19] and Inker et al. [7], demonstrate that proving the chronicity of the initial decreased eGFR, i.e. repeating the eGFR measurement after at least 3 months and ideally longer, is of the utmost importance.

In a recent systematic review [16], considerable variation in methods for sampling the general population and the assess- ment of kidney function across studies reporting CKD preva- lence was found. The review mentions that, in all studies reviewed, proof of chronicity of decreased eGFR was lacking, as was the absence of con fi rmation of proteinuria in most stud- ies. The chronicity criterion was never used, mainly because follow-up data on serum creatinine were not collected.

In their recent work, Brück et al. [3] state that the prevalence of CKD that they recorded across the European general popu- lation might have been slightly overestimated using single cre- atinine and albuminuria measurements. Taking into account the Maremar results and those of others [7, 14, 18, 19], indicat- ing false positivity of moderate proteinuria of 60% and that 25 – 32% of the subjects initially categorized as stage 3 CKD no long- er fall into this category when repeated measurements of eGFR are obtained over a subsequent time period (minimum 3 months), substantial overestimation of CKD is indicated when prevalence studies do not include con fi rmation of pro- teinuria and proof of chronicity of decreased eGFR, as is the case in the majority of such studies [3]. When the results of the Maremar study were recalculated using the ‘ classical ’ ap- proach applied in the majority of prevalence studies (single urine sample screening for proteinuria and no demonstration of chronicity of decreased eGFR), a CKD prevalence of 7.0 was found (Table 1). By progressively introducing the

KDIGO 4.2 guidelines (Table 1), a prevalence of 3.9% was found, which dropped to 2.9% when corrected for the total population. As indicated in Table 1, the introduction of screen- ing for haematuria clearly increased the prevalence of CKD.

A third reason why CKD prevalence may be estimated as

>10% is the structure of the studied population pyramid, play- ing an important role in the fi nal result of age-adjusted CKD prevalence. The fact that the population pyramid in Morocco is tagine-like (i.e. broad based with a small top), in contrast to the constrictive population pyramids that have a broad domed aspect used in most CKD prevalence studies, results in a lower percentage of individuals >60 years of age, hence a lower per- centage of CKD3, which is by far the most prevalent CKD stage associated with ageing.

A fi nal reason for this could be the Modi fi cation of Diet in Renal Disease (MDRD) study equation systematically under- estimating true renal function in healthy individuals and im- precision at higher levels of GFR [20, 21].

U S E OF A S I N G L E C UT - O F F VA L U E FO R E G F R R E S U LTS IN OV E R D I A G N O S I S A N D U N D E R D I A G N O S I S

The eGFR distribution of the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles (P) within the sex and age categories (n = 10 524) of the adult population of Morocco is shown in Figure 1.

The ‘ normal ’ decline in eGFR of the study population is 0.75 mL/min/1.73 m

/year, which is comparable with other studies using the same MDRD 4 formula [22]. The changes in renal function (eGFR, MDRD 4 formula) in the three age classes (26 – 40, 41 – 55 and 56 – 70 years) are distributed in a Gaussian way, with a shift of the curve to the left in the ageing population indicating that this is a manifestation of a fundamental physio- logical process such as ageing.

When eGFR and con fi rmed proteinuria were taken into ac- count, the CKD1 and 2 KDIGO classes represented 17.8 and 17.2%, respectively, of the total CKD population (n = 442) of the study.

In Figure 2, some relevant data of subjects with CKD stages 3 – 5 with and without proteinuria and haematuria are shown.

CKD3 represented the most prevalent stage: 52.5% (3A, 40.2%; 3B, 12.3%), whereas CKD4 and 5 represented 4.4 and 7.2% of the total CKD population, respectively. The majority of the subjects with CKD3A (79.2%) and 3B (58.1%) had no proteinuria or haematuria, whereas 45% of subjects with CKD5 had no proteinuria nor haematuria.

Table 1. Assessment of CKD based on eGFR, proteinuria and haematuria using Maremar data

Proteinuria Proteinuria and/or haematuria

1. Single eGFR + unconfirmed proteinuria/haematuria (as in most studies) 7.0% 14.0%

2. Single eGFR + confirmed proteinuria/haematuria (as in some studies) 4.2% 7.4%

3. Chronicity (repeated) eGFR + confirmed proteinuria/haematuria (according to KDIGO 2012) (as in this study) 3.9% 6.7%

4. 3 + correction for total population 2.9% 5.1%

Mild to overt proteinuria at first visit (n = 513): 4.9% of study population.

Con fi rmed mild to overt proteinuria (n = 206): 1.9% of study population.

False positive result: 67.2% mild proteinuria, 28.7% overt proteinuria.

Repeating eGFR after 3 months = 32% of false positives.

FUL L REVIEW

F I G U R E 1 : The eGFR distribution, using the MDRD formula showing the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentiles (P) within the sex and age categories (study population n = 10 524). The ‘ normal ’ decline in eGFR of the study population is 0.75 mL/min/1.73 m

/year (reprinted with permission from ref. 8).

FIGURE 2: Some subjects in the CKD3A and a few in the CKD3B group (red backdrop) have no proteinuria/haematuria and an eGFR still above the 3th percentile of the eGFR distribution of their age and sex categories (see figure 1). They have to be considered as false positives (50% of the men and 51% of the women in this red backdrop). In the green backdrop are shown individuals having a low to very low eGFR for their age and sex (below the third percentile) no proteinuria/haematuria (97%). They have to be considered as false negatives since they do not meet the criteria for CKD1 or 2. See text for further explanation (Adapted from ref. 8).

FUL L REVIEW

Half of the subjects with CKD3A, males and females, had an eGFR above the third percentile for their age, were ≥ 55 years old, many of them have no proteinuria or haematuria and most had no hypertension. Hence, their risk of developing pro- gressive renal failure necessitating renal replacement therapy is comparable with subjects of their age category with higher eGFRs. They have to be considered as false positives for being classi fi ed as CKD3A.

Indeed, it has been shown [23] that CKD3, and particularly CKD3A, patients have no additional risk of mortality when compared with similarly aged individuals with an eGFR >60 mL/min/1.73 m

after adjustment for age, race, sex and co- morbidities [24]. Life expectancy of subjects with CKD3A was found to be comparable to that of CKD stage 1 and 2 subjects [25]. The Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study and others [23, 26] have demonstrated that there is very little increased risk of cardiovascular disease, either deaths or events, in stage CKD3A patients in the absence of proteinuria when compared with those with an eGFR >60 mL/min/1.73 m

without proteinuria. De Jong and Gansevoort [27] proposed that there is a need to improve the de fi nition of stage 3 CKD. Con fi rmed proteinuria should be included in stage 3 before a subject is labelled as CKD3.

In contrast to the overdiagnosis of CKD, ‘ underdiagnosis ’ (false negatives) has received much less attention. In the Mare- mar study, 130 subjects (57 males and 73 females, 1.2% of the study population) with unclassi fi able CKD stage were observed.

Indeed, they had an eGFR >60 mL/min/1.73 m

, and the vast majority had no proteinuria (97%), hence they did not have CKD stage 1 or 2 according the KDIGO classi fi cation. However, they had a low eGFR for their age: below the third percentile for their age and sex categories (Figure 2). O ’ Hare notes that young and middle-aged adults with an eGFR of 60 – 74 mL/min/1.73 m

but without proteinuria, whose life expectancy is probably sub- stantially shorter than those with higher levels of eGFR, do not meet the criteria for CKD, whereas a large number of older adults with eGFR levels slightly <60 mL/min/1.73 m

and no protein- uria, whose life expectancy is probably similar to those with high- er levels of eGFR, are classi fi ed as CKD3A [26]. Malgrem et al.

[28] could not observe a statistical difference in the mortality risk, fully adjusted for comorbidity, of women 75 – 85 years of age with CKD3A compared with individuals in the same age range with eGFR >60 mL/min/1.73 m

, using fi ve different for- mulas to calculate eGFR, fully adjusted for comorbidity.

Glassock and Winearls [29] and Elseviers et al. [30] have claimed that the use of a ‘ cut-off ’ of eGFR of <60 mL/min/

1.73 m

without any correction for age or gender, and without any consideration of concomitant albuminuria, may misclassify as many as 30 – 50% of elderly subjects as having stage 3 CKD, thus in fl ating CKD prevalence estimates. A substantial revision of the Kidney Disease Outcomes Quality Initiative (and KDIGO) guidelines for staging stage 1 – 4 CKD needs to take into account the gender-speci fi c ‘ normal ’ decline in eGFR with ageing, using percentile rather than absolute eGFR thresholds [29].

A number of age- and sex-speci fi c percentile lines of eGFR (most using MDRD formulas) or measured GFR have been published [22, 30 – 33]. It is notable that the 60 mL/min/1.73 m

value line in the Maremar study hits the third to fi fth percentile

lines between 50 – 60 years of age in men, and at slightly younger age in women, as is the case with comparable studies performed in The Netherlands [22] and Japan [33, 34], indicating that the physiological ageing process of the kidney, along with a de- crease in renal function [35], is comparable across populations of different races.

Such inaccurate labelling in middle-aged and older indivi- duals has several undesirable effects, such as unnecessary anx- iety, unnecessary additional investigations and, in some cases, loss of insurability [6].

These age- and gender-speci fi c percentile charts should be made available in primary care, not only to aid the selection of patients requiring referral, but also to track the progress of patients diagnosed with CKD to trigger referral when a stage requiring specialist input is reached or unpredicted deterior- ation is observed.

In their systematic literature survey of CKD prevalence stud- ies, Bruck et al. [16] conclude that the lack of comparability of prevalence studies is possibly due to methodological differ- ences, and not differences in investigating different popula- tions. We hope that our results will contribute to providing recommendations to help optimize both the design and report- ing of future CKD prevalence studies, which will enhance the comparability of study results. Such recommendations are sum- marized in Table 2.

CON C LU SI ON

The lack of con fi rmation of proteinuria and no demonstration of ‘ chronicity ’ of decreased eGFR are the main reasons for the

Table 2. Recommendations for comparison of CKD prevalence results

• Sampling:

○

Frame, design, randomization, representative sample

• Sample size calculation

• Recruitment:

○

Methodology taking into account illiteracy

• Response rate at different stages of recruitment, keep recruitment time as short as possible

• Online data collection

• Methodology:

○

IDMS calibration for creatinine

• Proteinuria:

○

Nephelometry

○

Dipstick

• Confirmation of proteinuria over a period of 2 weeks to 1 month

• Chronicity of eGFR decrease <60 mL/min/1.73 m

after ≥3 months, define CKD stages properly and avoid false positives

• Automatic blood pressure monitoring in sitting position, right arm on a desk, three measurements at 15-s intervals

• Body mass index, hip and waist circumference

• Data reporting unadjusted and adjusted (total adult population) CKD

• Prevalence and 95% CI

• Stratification by age groups and/or disease (diabetes, hypertension, obesity)

Adapted from Bruck et al. [16].

FUL L REVIEW

in fl ation (100% or more) of CKD prevalence in published re- ports. The choice of arbitrary single thresholds of eGFR for clas- sifying CKD stages 3 – 5 inevitably leads to substantial over-diagnosis (false positives) of CKD3 in patients who are

≥ 50 years of age, particularly in those without proteinuria, haematuria or hypertension. It also leads to underdiagnosis (false negatives) of CKD in younger individuals without pro- teinuria, with an eGFR >60 mL/min/1.73 m

and below the third percentile of their age/sex category, who cannot be classi- fi ed by the current KDIGO guidelines. Subjects ≥ 50 years of age with an eGFR between 45 and 60 mL/min/1.73 m

without proteinuria, haematuria and hypertension should not be con- sidered as CKD3A. The use of a third percentile eGFR level as a cut-off, based on age-/sex-speci fi c reference values of eGFR, allows the detection of these false positives and negatives.

The physiological ageing process of the kidney, along with a de- crease in renal function, is comparable across populations of different races. There is an urgent need for quality prevalence studies of CKD to con fi rm the relatively low prevalence ob- served in the Maremar study.

AC K N OW L E D G E M E N T

To conduct this study, the authors had the support of a great team, the MAREMAR team. A list with their names and affilia- tions was published as supplemental data in Kidney Inter- national, ref #8. In addition, once again we have to thank Dirk De Weerdt for his excellent drawings. Thanks also to Erik Snelders for his sustained outstanding help.

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Received for publication: 2.6.2016; Accepted in revised form: 4.6.2016

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