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Articles

Measures of chronic kidney disease and risk of incident


peripheral artery disease: a collaborative meta-analysis of
individual participant data
Kunihiro Matsushita, Shoshana H Ballew, Josef Coresh, Hisatomi Arima, Johan rnlv, Massimo Cirillo, Natalie Ebert, Jade S Hiramoto, Heejin Kimm,
Michael G Shlipak, Frank L J Visseren, Ron T Gansevoort, Csaba P Kovesdy, Varda Shalev, Mark Woodward, Florian Kronenberg, for the Chronic Kidney
Disease Prognosis Consortium*

Summary
Background Some evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery Lancet Diabetes Endocrinol 2017
disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease Published Online
(estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease. July 14, 2017
http://dx.doi.org/10.1016/
S2213-8587(17)30183-3
Methods In this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis
See Online/Comment
Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and http://dx.doi.org/10.1016/
albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic S2213-8587(17)30256-5
kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral *Members listed at end of paper
artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations Johns Hopkins Bloomberg
of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of School of Public Health,
peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent Baltimore, MD, USA
(K Matsushita MD,
claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics. S H Ballew PhD, Prof J Coresh MD,
Prof M Woodward PhD);
Findings We analysed 817084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. Department of Preventive
18261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 74 years Medicine and Public Health,
Faculty of Medicine, Fukuoka
[IQR 5789], range 20158 years across cohorts). Both chronic kidney disease measures were independently University, Fukuoka, Japan
associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 173 m, adjusted (Prof H Arima MD); Division of
hazard ratios (HRs) for incident study-specific peripheral artery disease was 122 (95% CI 114130) at an eGFR of Family Medicine and Primary
45 mL/min per 173 m and 206 (170248) at an eGFR of 15 mL/min per 173 m. Compared with an ACR of 5 mg/g, Care, Department of
Neurobiology, Care Science and
the adjusted HR for incident study-specific peripheral artery disease was 150 (141159) at an ACR of 30 mg/g Society, Karolinska Institutet,
and 228 (212244) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 368 (95% CI Huddinge, Sweden
300452) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 576 [490677] (Prof J rnlv MD); School of
Health and Social Studies,
for incident peripheral artery disease and 1061 [5701977] for amputation in eGFR <30 mL/min per 173 m plus
Dalarna University, Falun,
ACR 300 mg/g or dipstick proteinuria 2+ or higher vs eGFR 90 mL/min per 173 m plus ACR <10 mg/g or dipstick Sweden (Prof J rnlv); Scuola
proteinuria negative). Both eGFR and ACR significantly improved peripheral artery disease risk discrimination beyond Medica Salernitana, University
traditional predictors, with a substantial improvement prediction of amputation with ACR (difference in c-statistic 0058, of Salerno, Italy
(Prof M Cirillo MD); Charit
95% CI 00450070). Patterns were consistent across clinical subgroups.
University Medicine, Institute
of Public Health, Berlin,
Interpretation Even mild-to-moderate chronic kidney disease conferred increased risk of incident peripheral artery Germany (N Ebert MD); Division
disease, with a strong association between albuminuria and amputation. Clinical attention should be paid to the of Vascular and Endovascular
Surgery, Department of
development of peripheral artery disease symptoms and signs in people with any stage of chronic kidney disease.
Surgery, University of California
San Francisco, San Francisco,
Funding American Heart Association, US National Kidney Foundation, and US National Institute of Diabetes and CA, USA (J S Hiramoto MD);
Digestive and Kidney Diseases. Institute for Health Promotion,
Department of Epidemiology
and Health Promotion,
Introduction Several previous studies have been done to investigate Graduate School of Public
Lower-extremity peripheral artery disease affects the association of mild and moderate stages of chronic Health, Yonsei University, Seoul,
810 million adults in the USA1 and more than 200 million kidney disease with peripheral artery disease.714 However, South Korea (Prof H Kimm PhD);
San Francisco VA Medical
adults around the world.2 Its prevalence increased by most of these studies were cross-sectional710 or Center, San Francisco, USA
24% globally in the past decade.2 Peripheral artery disease investigated either, but not both, of the two kidney (Prof M G Shlipak MD);
increases the risk of adverse clinical outcomes3,4 and impairs measures (estimated glomerular filtration rate [eGFR] or University of California,
lower-extremity function.5 It is especially important for albuminuria) used to define and stage chronic kidney San Francisco, USA
(Prof M G Shlipak); Department
people on haemodialysis and its incidence (about 400 per disease.912 This limited evidence might have contributed of Vascular Medicine, University
1000 patient-years) is much higher than the incidence of to chronic kidney disease not being included among the Medical Center Utrecht,
coronary heart disease and stroke (about 100150 per risk factors for peripheral artery disease in the Utrecht, Netherlands
1000 patient-years each) in this clinical population.6 2016 guidelines on peripheral artery disease from the (Prof F L J Visseren MD);

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Articles

Department of Nephrology,
University Medical Center Research in context
Groningen, University of
Groningen, Groningen, Evidence before this study mild-to-moderate chronic kidney disease (when either of eGFR
Netherlands Lower-extremity peripheral artery disease is an important 3059 mL/min per 173 m or urine albumin-to-creatinine ratio
(Prof R T Gansevoort MD); complication for patients on haemodialysis, and its incidence is 30299 mg/g is present) conferred 154-times higher risk of
Memphis Veterans Affairs
Medical Center, Memphis, TN,
much higher than that for coronary heart disease and stroke in peripheral artery disease beyond traditional risk factors.
USA (Prof C P Kovesdy MD); this clinical population. No formal systematic review was Accordingly, both kidney measures improved the prediction of
University of Tennessee Health undertaken; KM searched PubMed for papers published to June peripheral artery disease risk beyond traditional risk factors,
Science Center, Memphis, TN, 30, 2016, and co-authors provided feedback on relevant articles. with more evident improvements with albuminuria than with
USA (Prof C P Kovesdy); Maccabi
Institute for Research and
For low-severity stages of chronic kidney disease, several eGFR. Albuminuria was particularly strongly associated with the
Innovation, Maccabi previous studies have investigated the risk for peripheral artery risk of leg amputation and substantially improved its risk
Healthcare Services, Faculty of disease, but most of them were cross-sectional or investigated prediction.
Medicine, Tel Aviv University, either (but not both) of the two kidney measures used to define
Tel Aviv, Israel Implications of all the available evidence
(Prof V Shalev MD); The George
and stage chronic kidney disease: estimated glomerular
Our results suggest that individuals with chronic kidney
Institute for Global Health, filtration rate (eGFR) or albuminuria. This limited evidence
disease, even at mild-to-moderate stages, might warrant
University of Sydney, Sydney, might have contributed to 2016 guidelines on peripheral artery
NSW, Australia clinical attention to leg signs and symptoms of peripheral
disease from the American Heart Association and the American
(Prof M Woodward); The George artery disease. Annual foot care is currently recommended in
Institute for Global Health, College of Cardiology not including chronic kidney disease
patients with diabetes, but adherence to this recommendation
University of Oxford, Oxford, among the risk factors for peripheral artery disease.
UK (Prof M Woodward); and
is low. Thus, as the first step to improve this low adherence,
Division of Genetic Added value of this study people with both diabetes and chronic kidney disease
Epidemiology, Department of In this individual-level data meta-analysis, with 18261 incident (particularly when albuminuria is present) might be a
Medical Genetics, Molecular peripheral artery disease cases from 08 million participants reasonable target for strong encouragement of regular foot
and Clinical Pharmacology,
Medical University of
from 21 cohorts, we examined the prospective and care. Assessment of kidney function and albuminuria is already
Innsbruck, Innsbruck, Austria independent associations of eGFR and albuminuria with future recommended in patients with diabetes or hypertension. As
(Prof F Kronenberg MD) risk of peripheral artery disease. Our results showed that both such, in these clinical populations, the chronic kidney disease
Correspondence to: albuminuria and reduced eGFR were independently associated measures should be readily available to classify the risk of
Prof Josef Coresh, with future risk of peripheral artery disease. Even peripheral artery disease.
Department of Epidemiology,
Johns Hopkins Bloomberg
School of Public Health,
Baltimore, MD 21287, USA
American Heart Association (AHA) and the American whereas other cohorts in the CKD-PC did not. This study
ckdpc@jhmi.edu
College of Cardiology (ACC).15 was approved for use of de-identified data by the
We aimed to quantify the independent and joint institutional review board at the Johns Hopkins
associations of eGFR and albuminuria with future risk of Bloomberg School of Public Health (Baltimore, MD,
peripheral artery disease using data from eligible cohorts USA), and the need for informed consent was waived.
in the Chronic Kidney Disease Prognosis Consortium Cohorts with baseline measurements of eGFR and
(CKD-PC).16 These rich data also allowed us to assess albuminuria, at least 1000 participants (this criterion not
improvement of prediction of peripheral artery disease applied to cohorts exclusively enrolling patients with
with these measures of chronic kidney disease and to chronic kidney disease), and at least 50 peripheral artery
investigate several different definitions of peripheral artery disease events were eligible for inclusion. We obtained
disease such as leg amputation and revascularisation. individual level data from most cohorts but used a
distributed data analysis model to include the three cohorts
Methods that were unable, for logistic or legal reasons, to send
Study design and data sources individual level data. We sent out tailored code to
Details of the CKD-PC are described elsewhere.16,17 Briefly, individuals responsible for the cohort database to run on
the CKD-PC is an international consortium established to their individual participant data and then send us matrices
provide evidence that can improve prevention and with descriptive data and -coefficients to be able to meta-
management of chronic kidney disease and currently analyse across all cohorts. Transfer of individual participant
consists of more than 70 prospective cohorts, including data or standardised analysis of outputs for meta-analysis
participants from 40 countries or regions with data for took place between July 1, 2015, and Jan 31, 2017, with
eGFR, albuminuria, and clinical outcomes. The present baseline measurements done between 1972 and 2014.
study is a collaborative meta-analysis including data from
nine general population cohorts, eight cohorts of patients Procedures
at high risk of cardiovascular disease (such as patients We primarily estimated GFR using the Chronic Kidney
with diabetes), and four cohorts exclusively enrolling Disease Epidemiology Collaboration (CKD-EPI) creatinine-
patients with chronic kidney disease. These prospective based equation,18 because serum creatinine is the most
studies had data on incident peripheral artery disease, widely used filtration marker in clinical practice.19 However,

2 www.thelancet.com/diabetes-endocrinology Published online July 14, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30183-3


Articles

as a secondary analysis, we analysed eGFR using the We excluded any patient with missing values for eGFR,
CKD-EPI cystatin-C equation in six studies with relevant albuminuria, or traditional cardiovascular risk factors at
data because cystatin-C-based eGFR has shown a stronger baseline.18 However, we included a few studies that
association with clinical outcomes than creatinine-based systematically did not record data for some traditional
eGFR.20 For measurement of albuminuria, we preferred to risk factors (appendix pp 67). All estimates were
use urine albumin-to-creatinine ratio (ACR), as obtained within each cohort first and then meta-analysed
recommended by chronic kidney disease guidelines,21 by a fixed-effects model, with the number of events in
but we also accepted semiquantitative assessment of each cohort as weights, to have consistent weights
proteinuria with a dipstick test.16 between the analysis of risk relation and risk prediction.18,27
We defined the following factors in the AHA/ACC We did meta-analyses for peripheral artery disease
Pooled Cohort Equations22 as traditional atherosclerotic outcome definitions when estimates were available from
risk factors: age, sex, race (black vs non-black), smoking three or more cohorts.
status (current vs former or never), systolic blood Using Cox proportional-hazards models, we first
pressure, antihypertensive drug use, diabetes (defined as quantified the associations of eGFR and albuminuria
fasting blood glucose 70 mmol/L, non-fasting blood with peripheral artery disease outcomes in the general
glucose 111 mmol/L, HbA1c 65%, use of antidiabetes population and high cardiovascular risk cohorts after
drugs, or self-reported diabetes), and blood concentrations adjusting for each other and traditional risk factors. We
of total and HDL cholesterol. A history of other modelled eGFR and ACR with linear splines, with knots
cardiovascular disease (coronary heart disease, stroke, for eGFR at 30, 45, 60, 75, and 90 mL/min per 173 m,
and heart failure) was not an exclusion criterion and was and for ACR at 10, 30, and 300 mg/g. We set an eGFR of
treated as a covariate in our study. We took this approach 95 mL/min per 173 m and an ACR of 5 mg/g as
because risk factor profiles are not necessarily the same reference values.18 ACR values were log-transformed, as
between peripheral artery disease and other cardiovascular were all continuous data for traditional risk factors.22,28
diseases. For example, smoking and diabetes are We used Zellners seemingly unrelated regression29 to
particularly strong predictors of peripheral artery disease.1 assess whether the associations of eGFR and ACR with
Also, diagnostic and monitoring approaches are unique different definitions of peripheral artery disease were
for peripheral artery disease (eg, ankle brachial index and significantly different or not. We also quantified risk of
foot examination).2,23 Notably, a previous risk prediction peripheral artery disease by cross-categories of eGFR
tool for new development of intermittent claudication and albuminuria in the context of the new international
from the Framingham Heart Study24 incorporates a chronic kidney disease staging system.21 For this analysis
history of coronary heart disease as a predictor. of cross-categories of chronic kidney disease measures,
as previously done,28,30 we combined ACR with dipstick
Outcomes proteinuria: ACR less than 10 mg/g with proteinuria
In view of the heterogeneous scientific literature negative (reference); 1029 mg/g with (trace);
regarding how to define incident peripheral artery 30299 mg/g with 1+; and 300 mg/g or higher with 2+
disease,11,12,2426 we investigated the following definitions of or higher. We applied the same categories of dipstick
peripheral artery disease: study-specific peripheral artery proteinuria when general population and high
disease (comprehensively defined in each study on cardiovascular risk cohorts with data on dipstick
the basis of International Classification of Diseases proteinuria were investigated in other analyses.
[ICD] codes or self-report of peripheral artery disease Subsequently, we did subgroup analyses by age, sex,
diagnosis, leg revascularisation, leg amputation, inter race, diabetes, hypertension (defined as systolic
mittent claudication, or repeated ankle-brachial index, as blood pressure 140 mm Hg, diastolic blood pressure
available); peripheral artery disease-related hospital 90 mm Hg, or use of antihypertensive medications),
admissions (ICD-9 codes 440.2 [atherosclerosis of native use of statins, and a history of current cardiovascular
arteries of the extremities] and 440.4 [chronic total diseases. We tested interaction with meta-regression for
occlusion of an artery of the extremities] or equivalents average coefficients for spline terms weighted on the
in ICD-10); leg revascularisation (ICD-9 codes 38.18 number of events in each study (for eGFR, only spline
[endarterectomy, lower limb arteries], 39.25 [aorta-iliac- terms <90 mL/min per 173 m were taken into account).
femoral bypass], 39.29 [other peripheral vascular shunt or We also separately analysed the subpopulation with
bypass], 39.50 [angioplasty of other non-coronary vessel], chronic kidney disease, including participants with low
or self-report); and leg amputation (ICD codes 84.1x eGFR (<60 mL/min per 173 m) or high albuminuria
[amputation of lower extremity]). The appendix (pp 35) (ACR 30 mg/g or dipstick proteinuria 1+)17 from the See Online for appendix
details any deviations in definitions for each cohort. general population and the high cardiovascular risk
cohorts, and all participants in the four chronic kidney
Statistical analysis disease cohorts. For the analysis of the chronic kidney
We restricted analyses to patients aged 18 years or older disease population, we set an eGFR of 50 mL/min per
without a history of peripheral artery disease at baseline. 173 m and an ACR of 100 mg/g as reference values, and

www.thelancet.com/diabetes-endocrinology Published online July 14, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30183-3 3


4
Articles

n Age Female Black Smokers Hypertension Diabetes Total HDL History eGFR ACR Study- PAD PAD PAD Follow-up
(years) cholesterol cholesterol of CVD <60 mL/ 30 specific hospital revascular amputation (years)
(mmol/L) (mmol/L) min per mg/g PAD admission isation
173 m events
General population
ARIC 10256 63 (6) 5668 2251 1481 4770 (47%) 1656 52 (10) 13 (04) 1349 616 796 307 214 170 73 158
(55%) (22%) (14%) (16%) (13%) (6%) (8%) (142168)
BIS 1553 80 (6) 842 0 76 1419 (91%) 362 56 (12) 15 (05) 367 533 359 101 NA NA NA 40
(54%) (5%) (23%) (24%) (34%) (23%) (3941)
CHS 2824 78 (5) 1680 459 209 1448 (51%) 486 53 (10) NA 843 1162 551 135 NA NA NA 99
(59%) (16%) (7%) (17%) (30%) (41%) (20%) (56150)
ESTHER* 5467 62 (7) 2958 0 797 3281 (60%) 993 57 (13) 14 (04) 967 598 608 67 NA 67 NA 107
(54%) (15%) (18%) (18%) (11%) (11%) (53109)
KHS* 244763 44 (10) 163356 0 93459 63408 (26%) 15021 49 (09) 13 (03) 2706 50608 8790 1695 1695 NA NA 124
(67%) (38%) (6%) (1%) (21%) (4%) (106142)
MESA 6693 62 (10) 3532 1836 871 3005 (45%) 839 50 (09) 13 (04) 0 874 638 72 NA NA NA 85
(53%) (27%) (13%) (13%) (13%) (10%) (7786)
PREVEND 6481 51 (13) 3449 63 2173 2313 (36%) 270 57 (11) 13 (04) 377 172 742 63 NA 63 NA 125
(53%) (1%) (34%) (4%) (6%) (3%) (11%) (122128)
Rancho 1427 70 (12) 857 1 112 719 (50%) 196 55 (10) 14 (04) 181 521 203 157 NA NA NA 137
Bernardo (60%) (0%) (8%) (14%) (13%) (37%) (14%) (64182)
SCREAM_DIP* 106300 51 (14) 57102 0 NA 71857 (68%) 19131 54 (11) 14 (04) 13471 9842 5227 1263 1150 396 216 43
(54%) (18%) (13%) (9%) (5%) (2857)
Total 385764 48 (11) 239444 4610 99178 152220 (39%) 38954 51 (10) 13 (03) 20261 64926 17914 3860 3059 696 289 101
(62%) (1%) (26%) (10%) (5%) (17%) (5%) (84117)
High cardiovascular risk population
ADVANCE 10580 66 (6) 4489 35 1586 8732 (83%) 10580 52 (12) 13 (04) 2641 1656 3246 665 NA NA NA 50
(42%) (0%) (15%) (100%) (25%) (16%) (31%) (4550)
Geisinger 40704 61 (14) 20737 1101 6182 30132 (74%) 31381 48 (11) 12 (04) 11882 8191 10839 911 667 387 249 32
(51%) (3%) (15%) (77%) (29%) (20%) (27%) (1750)
GLOMMS-II 9752 66 (14) 4896 0 85 442 (5%) 646 NA NA 774 3622 2650 271 NA 198 115 49
(50%) (1%) (7%) (8%) (37%) (27%) (2775)
Maccabi 212198 58 (14) 104245 0 4588 122703 (58%) 80188 49 (11) 13 (03) 8080 27717 34820 6669 NA NA NA 50
(49%) (2%) (38%) (4%) (13%) (16%) (2381)
Mt Sinai 4086 57 (13) 2481 1395 719 3510 (86%) 2358 48 (11) 14 (05) 693 1127 1249 543 156 66 NA 41
BioMe (61%) (34%) (18%) (58%) (17%) (28%) (31%) (2653)
NZDCS 25904 61 (14) 12796 67 3755 19171 (80%) 25904 53 (11) 13 (04) 4825 6234 1954 2021 1592 415 468 93
(49%) (0%) (14%) (100%) (19%) (24%) (8%) (73106)
RCAV 54114 63 (12) 1761 9405 NA 40839 (75%) 39926 46 (11) NA 7029 NA 11583 1529 1313 302 334 74
(3%) (17%) (74%) (13%) (21%) (6483)
SCREAM ACR 61321 53 (13) 26795 0 NA 52313 (85%) 34173 51 (11) 13 (04) 11426 8217 16196 1283 1148 392 272 36
(44%) (56%) (19%) (13%) (26%) (2351)
SMART 3181 57 (13) 921 0 922 2075 (66%) 801 51 (14) 12 (04) 1808 602 987 105 NA 93 27 58
(29%) (29%) (25%) (57%) (19%) (31%) (2496)
Total 421840 59 (13) 179121 12003 17837 279917 (66%) 225957 49 (11) 13 (03) 49158 57366 83524 13997 4876 1853 1465 49
(42%) (3%) (4%) (54%) (12%) (14%) (20%) (3363)
(Table continues on next page)

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categorised dipstick proteinuria into negative or trace

Follow-up
(reference), 1+, 2+, and 3+ or higher, as done previously.31

(2044)

(5789)
(2034)
(1748)
(2750)

(2021)
revascular amputation (years)

Data are n, n (%), mean (SD), or median (IQR). SCREAM Dip and SCREAM ACR are subsets of the same cohort. See appendix for definitions of study acronyms and references. CVD=cardiovascular disease. eGFR=estimated glomerular filtration rate.
Next, we estimated the difference in Harrells

28
28

29
48

74
20
c-statistics,32 a parameter of risk discrimination accounting
for censoring, between prediction models that included or
excluded kidney measures (eGFR, albuminuria, or both).

0
NA
NA
NA
NA

1754
PAD
To mitigate the methodological advantage for kidney
measures having several spline terms, in these prediction
analyses, eGFR was modelled with two linear terms with a

isation

0
NA
NA
NA
NA

2549
knot at 60 mL/min per 173 m, as previously done.18

PAD
All models showed good calibration according to visual

admission
assessment of predicted versus observed risk in almost

specific hospital
all cohorts.33 The assessment of heterogeneity was based

79
NA
79
NA
NA

8014
on the I statistic and the test. We did a random-effects Study- PAD

meta-regression analysis to assess sources of hetero


events

18261
404
73
127
130
74
geneity when heterogeneity was high (I statistic >75%34).
PAD

All analyses were done with Stata/MP 13 and p values of

107717
6279
629
2006
2565
1079
less than 005 were regarded as significant.

(66%)
(64%)
(79%)
(57%)
(74%)

(13%)
mg/g
ACR
30

Role of the funding source


of CVD <60 mL/

130286
min per

7994
489
2497
1463

3545
173 m

(100%)

(99%)
The funders of the study had no role in study design,

(84%)
(50%)
(79%)

(16%)
History eGFR

data collection, data analysis, data interpretation, or


writing of the report. KM and JC had full access to all the

72183
(36%)

(29%)
2764
357
576
440

1391
(30%)

(23%)
(31%)

(9%)
data in the study and all authors had final responsibility
for the decision to submit for publication, informed by
cholesterol

discussions with collaborators.


(mmol/L)

14 (05)

13 (04)
14 (05)
12 (04)

13 (03)
HDL

Results
NA

A total of 817 084 individuals without a history of

ACR=urine albumin-to-creatinine ratio. PAD=peripheral artery disease. NA=not applicable. *Studies with dipstick proteinuria.
cholesterol
(mmol/L)

peripheral artery disease from 21 cohorts in the CKD-PC,


49 (13)

50 (10)
43 (13)

51 (14)
55 (13)

51 (15)
Diabetes Total

with a mean age of 54 years (SD 12), were followed up for


a median of 74 years (IQR 5789, table). Overall,
268385
3474
396
876
1498
704

268385 (33%) had diabetes and 72183 (9%) had a history


(48%)

(40%)
(35%)
(33%)

(33%)
(37%)

of cardiovascular disease. The prevalence of an eGFR of


less than 60 mL/min per 173 m was 17% (64926 of
385764 patients) in the general population cohorts,
441173 (54%)
Hypertension

841 (86%)
2436 (96%)
4325 (96%)
1434 (98%)

9036 (95%)

14% (57366 of 421840) in high cardiovascular risk


cohorts, and 84% (7994 of 9480) in chronic kidney disease
cohorts. The prevalence of high albuminuria (30 mg/g)
was 5% (17 914 of 385 764 patients) in the general
Smokers

117803
788
(8%)
93
(9%)
NA
695
NA

population cohorts, 20% (83524 of 421840) in high


(14%)
(15%)

cardiovascular risk cohorts, and 66% (6279 of 9480) in


chronic kidney disease cohorts.
16638
25
(0%)
0
0
0
25
(2%)

Table: Demographic characteristics of included cohorts


Black

(2%)

During follow-up, 18261 incident cases of peripheral


artery disease were reported on the basis of study-specific
422275
3710
447
848
1845
Female

570

definitions across all cohorts, in addition to 8014 cases of


(39%)
(39%)

(45%)
(34%)
(41%)

(52%)

peripheral artery disease-related hospital admissions


from eight cohorts, 2549 cases of leg revascularisation
Chronic kidney disease population

63 (14)
60 (12)

61 (18)

54 (12)
67 (15)
(years)

67 (13)

from ten cohorts, and 1754 cases of leg amputation from


(Continued from previous page)
Age

seven cohorts.
The adjusted risk of incident peripheral artery disease
817084
9480
983
2527
4502
n

1468

was largely constant above an eGFR of 60 mL/min


per 173 m and steadily increased below an eGFR of
CanPREDDICT

60 mL/min per 173 m, with a similar risk gradient


Sunnybrook

All cohorts
SRR-CKD

across the four definitions of peripheral artery disease


GCKD

Total
Total

(figure 1). Compared with an eGFR of 95 mL/min


per 173 m, the hazard ratio (HR) of incident study-

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specific peripheral artery disease was 122 (95% CI 30 mL/min per 173 m, and 206 (170248; p<00001)
114130; p<00001) at an eGFR of 45 mL/min per at an eGFR of 15 mL/min per 173 m (figure 1). The risk
173 m, 168 (152186; p<00001) at an eGFR of gradient was slightly steeper for an eGFR based on
cystatin C than when based on a serum creatinine
A Study-specific peripheral artery disease B Study-specific peripheral artery disease concentration of less than 90 mL/min per 173 m
8 (appendix p 11), although we were only able to meta-
analyse study-specific peripheral artery disease in this
Adjusted hazard ratio (95% CI)

analysis because of the limited availability of cystatin C


4
measurements.
The associations of ACR with peripheral artery disease
2 outcomes were generally linear on the log-log scale (figure
1), with significantly increased risk even within the range
1
below the current clinical threshold of abnormality (<30
mg/g). Compared with an ACR of 5 mg/g, the HR for
0
incident study-specific peripheral artery disease was 110
C By hospital admission D By hospital admission
(95% CI 106114; p<00001) at an ACR of 10 mg/g, 150
8 (141159; p<00001) at an ACR of 30 mg/g, and 228
(212244; p<00001) at an ACR of 300 mg/g (figure 1).
Adjusted hazard ratio (95% CI)

The risk association seemed largely similar for study-


4 specific peripheral artery disease, peripheral artery
disease-related hospital admission, and leg
2 revascularisation, but was steepest for leg amputation
(figure 1). For example, the adjusted HR at an ACR of
300 mg/g versus 5 mg/g was 368 (95% CI 300452;
1
p<00001) for leg amputation and about 25 for the other
0 three outcomes. Moreover, the adjusted HR for leg
amputation for log-ACR as a linear term was significantly
E By leg revascularisation F By leg revascularisation
greater than that of study-specific peripheral artery disease
8
(p<00001 by the seemingly unrelated regressions).
Adjusted hazard ratio (95% CI)

Although qualitatively consistent associations were seen


4 in most cohorts, we saw high heterogeneity (I statistic
>75%) for HR at an eGFR of 45 mL/min per 173 m
2 versus 95 mL/min per 173 m for study-specific
peripheral artery disease and peripheral artery disease-
1 related hospital admission (appendix p 12). However, in
the meta-regression analyses, none of the covariates
0 seemed to account for the difference in HRs across studies
(appendix p 27). HR at an ACR of 30 mg/g versus 5 mg/g
G By leg amputation H By leg amputation did not show high heterogeneity in any peripheral artery
8 disease outcomes (appendix p 13). Regarding subgroups,
although significant interactions were seen in some
Adjusted hazard ratio (95% CI)

4 combinations of peripheral artery disease definitions and


subgroups (appendix pp 1420), chronic kidney disease
2
measures were generally associated with increased risk of
incident peripheral artery disease in every subgroup
tested. Similar patterns were seen when we analysed the
1
chronic kidney disease population (appendix p 21).
0
We confirmed multiplicative contributions of eGFR and
15 30 45 60 75 90 105 120 25 5 10 30 300 1000 albuminuria to increased risk of peripheral artery disease
eGFR (mL/min per 173 m) ACR (mg/g) by modelling their cross-categories in the general and high
cardiovascular risk cohorts, including cohorts with dipstick
Figure 1: Relative risk of incident peripheral artery disease, by eGFR and ACR
Graphs show adjusted hazard ratios (red lines) and 95% CIs (shaded areas) for the four definitions of peripheral artery proteinuria (figure 2). Irrespective of peripheral artery
disease, according to eGFR (A,C,E,G) and ACR (B,D,F,H). The reference value is an eGFR of 95 mL/min per 173 m and an disease definition, the highest risk was seen in the category
ACR of 5 mg/g (diamonds), and blue dots indicate statistical significance compared to the reference. Analyses are of severely reduced eGFR (<30 mL/min per 173 m) plus
adjusted for age, sex, race or ethnic origin, smoking status, systolic blood pressure, antihypertensive drug use, diabetes,
severely raised ACR (300 mg/g) or dipstick proteinuria
total and HDL cholesterol concentrations, and albuminuria (ACR or dipstick) or eGFR, as appropriate. Panels A, C, E, and G
included cohorts with dipstick proteinuria, and panels B, D, F, and H were based on cohorts with ACR data. (2+), with, for example, adjusted HRs of 576 (490677)
eGFR=estimated glomerular filtration rate. ACR=urine albumin-to-creatinine ratio. for incident peripheral artery disease and 1061

6 www.thelancet.com/diabetes-endocrinology Published online July 14, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30183-3


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(5701977) for amputation compared with the reference disease outcomes in the general and high cardiovascular
category of an eGFR of 90 mL/min per 173 m or higher risk cohorts with ACR data (figure 3). The addition of
plus an ACR of less than 10 mg/g or negative dipstick chronic kidney disease measures significantly improved
proteinuria. The categories with mild-to-moderate peripheral artery disease risk discrimination beyond
abnormality of both eGFR (3059 mL/min per 173 m) traditional risk factors. For all peripheral artery disease
and ACR (30299 mg/g) showed 2144 times higher risk outcomes, the improvement in risk discrimination was
of peripheral artery disease outcomes. Lower eGFR and more evident with ACR than with eGFR (eg, difference
higher ACR were associated with increased risk of in the c-statistic was 0018 [95% CI 00150020] vs
peripheral artery disease, even when the other chronic 0010 [00080011] for study-specific peripheral artery
kidney disease measure was normal (eg, an eGFR of disease). The improvement was especially evident for
3059 mL/min per 173 m showed HRs of 1224, even leg amputation when ACR was added, with a difference
when the ACR was less than 10 mg/g; and an in the c-statistic of 0058 (95% CI 00450070). We
ACR of 30299 mg/g showed a HR of 1822, even when identified some incremental improvements in c-statistics
the eGFR was 90 mL/min per 173 m or higher). Generally when eGFR and ACR were added simultaneously
similar patterns were apparent when we analysed the (figure 3). The greater risk discrimination with ACR
chronic kidney disease population (appendix p 22). over eGFR was also seen when cystatin C was taken as
C-statistics based on traditional risk factors ranged the filtration marker rather than serum creatinine
from 0750 to 0772 across the four peripheral artery (appendix p 23).

Study-specific peripheral artery disease Hospital admissions


ACR/dipstick measurement ACR/dipstick measurement
<10/dipstick 1029/dipstick 30299/dipstick 300/dipstick <10/dipstick 1029/dipstick 30299/dipstick 300/dipstick
eGFR
measurement measurement measurement 1+ measurement 2+ Overall measurement measurement measurement 1+ measurement 2+ Overall

90 Reference 131 182 316 Reference Reference 138 206 435 Reference
(119145) (165201) (261384) (119160) (176241) (316598)
7589 094 122 184 314 095 101 145 242 342 103
(087101) (111134) (168203) (261379) (091101) (091113) (125168) (208280) (240488) (096112)
097 129 187 297 098 116 148 241 401 114
6074
(089104) (118141) (171205) (254348) (093104) (104130) (127173) (208279) (307523) (105124)
124 163 207 339 123 157 205 282 449 149
4559
(113136) (146181) (187229) (293392) (116131) (135183) (167251) (235338) (334603) (134166)

178 199 251 392 157 215 246 302 609 177
3044 (156202)
(158201) (172230) (223283) (336458) (146170) (176263) (190320) (241379) (449826)
284 284 358 576 242 253 383 482 721 231
<30 (220266)
(228353) (218371) (306419) (490677) (180357) (270542) (379612) (550946) (195275)

Overall Reference 131 179 280 Reference 135 200 327


(125137) (171186) (262300) (125145) (186215) (290369)

Leg revascularisation Leg amputation


ACR/dipstick measurement ACR/dipstick measurement

<10/dipstick 1029/dipstick 30299/dipstick 300/dipstick <10/dipstick 1029/dipstick 30299/dipstick 300/dipstick


eGFR
measurement measurement measurement 1+ measurement 2+ Overall measurement measurement measurement 1+ measurement 2+ Overall

90 Reference 163 179 464 Reference Reference 159 217 802 Reference
(130203) (141228) (337641) (121208) (162290) (5451180)
7589 099 140 229 265 097 090 194 316 721 104
(082119) (109179) (182288) (153459) (086110) (072113) (147255) (244411) (4341199) (090120)

6074 115 140 208 345 106 102 183 325 517 109
(095140) (109181) (164265) (216551) (093121) (081130) (136248) (250423) (302886) (093127)

4559 152 234 244 351 142 154 281 396 930 161
(118196) (175313) (182328) (227545) (121166) (112214) (195406) (287548) (6111415) (132196)

3044 242 242 278 496 160 212 437 443 1027 213
(176333) (163358) (185417) (325757) (131196) (133338) (284674) (290676) (6031750) (168269)
265 294 318 714 260 316 577 739 1061 259
<30
(146481) (146589) (203497) (4591111) (204331) (167599) (2871160) (4721157) (5701977) (197340)

Overall Reference 145 177 299 Reference 188 282 604


(129162) (158199) (247364) (164216) (247323) (497735)

Figure 2: Categorical analysis of outcome definitions of peripheral artery disease with eGFR and ACR in the combined general population and high cardiovascular risk cohorts
Panels show adjusted hazard ratios derived from categorical analysis of the general population and high cardiovascular risk cohorts. Dipstick proteinuria categories (negative, trace, 1+, and 2+) were
combined with ACR categories, as appropriate. Units for ACR are mg/g. Colour coding is based on the following cutoffs: green indicating less than 15; yellow indicating 15 to less than 2; orange indicating 2
to less than 4; and red indicating 4 or higher. Bold indicates statistical significance (p<005). eGFR=estimated glomerular filtration rate. ACR=urine albumin-to-creatinine ratio.

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To compare the contributions of the kidney measures demographic predictors (age, sex, and race; figure 4). Of
and traditional risk factors to predicting risk of peripheral the traditional risk factors, diabetes and a history of other
artery disease, we added each of them in turn to cardiovascular diseases were consistently the strongest
predictors. Notably, ACR consistently improved the risk
Study-specific Hospital admission Leg revascularisation Leg amputation prediction more than these two potent predictors,
(15 studies; (6 studies; (9 studies; (6 studies; irrespective of peripheral artery disease outcome
451 074 people; 196 385 people; 215 799 people; 205 232 people;
14 832 cases) 5090 cases) 2086 cases) 1538 cases)
assessed. The contribution of eGFR to risk prediction of
peripheral artery disease was similar to or slightly greater
Traditional model
0757 (07520761) 0750 (07420759) 0767 (07540781) 0772 (07560789) than traditional risk factors, other than diabetes and
history of cardiovascular disease. The risk discrimination
improvement of peripheral artery disease was confirmed
+eGFR
0010 (00080011) 0010 (00070013) 0011 (00050017) 0019 (00110028)
with dipstick, but not as much as with ACR data
(appendix pp 2425). When we investigated the chronic
kidney disease population, the pattern for the
+ACR contributions of eGFR, ACR, and traditional risk factors
0018 (00150020) 0025 (00200030) 0022 (00150029) 0058 (00450070) to peripheral artery disease risk prediction was largely
similar (appendix p 26), with ACR as one of the most
potent predictors.
+eGFR and ACR
0022 (00200025) 0029 (00240034) 0025 (00170033) 0062 (00490075)
Discussion
0 01
0 01

0 01
0 01

002
0 3
05
002
03

002
03
002
03

This international collaborative meta-analysis of


07
0
0
0

0
0

individual-level data in about 08 million individuals


Figure 3: Difference in c-statistics for each definition of peripheral artery disease after addition of kidney
without peripheral artery disease at baseline shows that
measures to traditional models
Analyses shown were in the combined general population and high cardiovascular risk cohorts. Traditional models both eGFR and ACR were independently associated
included adjustment for age, sex, race, smoking status, systolic blood pressure, antihypertensive drug use, diabetes, with future risk of peripheral artery disease. Even mild-
total and HDL cholesterol concentrations, and history of cardiovascular disease. Bars show 95% CI. eGFR=estimated to-moderate chronic kidney disease conferred
glomerular filtration rate. ACR=urine albumin-to-creatinine ratio.
154-times increased risk of peripheral artery disease
beyond traditional risk factors. For ACR, we identified a
Study-specific Hospital admission Leg revascularisation Leg amputation risk gradient even within the range currently regarded
(15 studies; (6 studies; (9 studies; (6 studies;
451 074 people; 196 385 people; 215 799 people; 205 232 people; as normal or mildly raised (ie, <30 mg/g).21 The
14 832 cases) 5090 cases) 2086 cases) 1538 cases) associations were largely consistent across different
Demographic 0681 (0676 to 0687) 0637 (0627 to 0647) 0659 (0641 to 0677) 0628 (0605 to 0651) cohorts and across key demographic and clinical
model subgroups such as participants with versus without
+eGFR diabetes or hypertension. Reflecting their strong
0019 (0016 to 0022) 0018 (0012 to 0023) 0020 (0010 to 0031) 0024 (0009 to 0038) associations, both kidney measures improved the
+ACR prediction of peripheral artery disease risk beyond
0045 (0041 to 0049) 0071 (0062 to 0079) 0062 (0048 to 0077) 0115 (0094 to 0137) traditional risk factors, with more evident improvements
+eGFR and with ACR than with eGFR. Notably, the contribution of
ACR 0051 (0047 to 0055) 0076 (0067 to 0086) 0066 (0052 to 0081) 0120 (0099 to 0142)
these kidney measures (particularly ACR) to peripheral
+Total artery disease risk prediction was greater than or similar
cholesterol 0004 (0002 to 0007) 0009 (0003 to 0014) 0000 (0006 to 0005) 0000 (0008 to 0009)
to any modifiable traditional risk factors, including
+HDL diabetes and history of cardiovascular disease.
cholesterol 0008 (0006 to 0011) 0012 (0005 to 0018) 0016 (0002 to 0035) 0019 (0001 to 0037) Additionally, ACR substantially improved the prediction
+SBP of leg amputation.
0014 (0010 to 0018) 0024 (0015 to 0034) 0025 (0010 to 0041) 0012 (0004 to 0027) Although most previous studies have not analysed the
+Smoking chronic kidney diseaseperipheral artery disease
0006 (0004 to 0009) 0015 (0006 to 0024) 0019 (0007 to 0032) 0004 (0006 to 0015) association longitudinally with both eGFR and
+Diabetes albuminuria,712 two previous investigations by Bello and
0025 (0021 to 0030) 0041 (0031 to 0051) 0030 (0014 to 0046) 0077 (0056 to 0099)
colleagues13 and Garimella and colleagues14 have observed
+History
of CVD 0029 (0025 to 0033) 0044 (0038 to 0051) 0040 (0027 to 0054) 0033 (0017 to 0049)
their prospective association. However, Bello and
colleagues study13 included individuals with a history of
peripheral artery disease at baseline and used a wide
04

04
08

08
04

04
08

08

12
0

0
0

0
0

0
0

definition of peripheral artery disease, including


Figure 4: Difference in c-statistics for each definition of peripheral artery disease after addition of kidney atherosclerotic events beyond lower-extremity peripheral
measures and traditional risk factors to the demographic model
artery disease such as aortic aneurysm and renal artery
Analyses shown were in the combined general population and high cardiovascular risk cohorts. The demographic
model includes age, sex, and race. Bars show 95% CI. eGFR=estimated glomerular filtration rate. ACR=urine stenosis. Garimella and colleagues study14 used a decrease
albumin-to-creatinine ratio. SBP=systolic blood pressure. CVD=cardiovascular disease. in ankle-brachial index below 09 as an outcome variable.

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Therefore, our study expanded these findings to clinical implications because the diagnosis and management of
lower-extremity peripheral artery disease, including leg peripheral artery disease has some unique features.
amputation. Other unique aspects of our study include a Although the AHA/ACC 2016 guideline on peripheral
meta-analysis of individual-level data (mostly unpublished artery disease does not specify chronic kidney disease as
data), a collaborative investigation of international a risk factor of peripheral artery disease,15 our results
cohorts, detailed subgroup analyses, and a sophisticated suggest that individuals with chronic kidney disease,
evaluation of c-statistics. even at mild-to-moderate stages, might warrant clinical
Overall, our results suggest important patho attention to leg signs and symptoms of peripheral artery
physiological contributions of chronic kidney disease to disease. Annual foot care is currently recommended in
the development of peripheral artery disease above and patients with diabetes,23 but adherence to this
beyond traditional risk factors, although the present recommendation is only about 30%.44 As such, a
study is not designed to elucidate mechanisms. reasonable first step to improve this low adherence
Nonetheless, it is worth emphasising that both chronic could be to target people with both diabetes and chronic
kidney disease measures contributed to peripheral artery kidney disease (particularly when albuminuria is
disease risk, even among participants without diabetes or present). From a practical point of view, it is important
hypertension, suggesting that eGFR and albuminuria are that the assessment of kidney function and albuminuria
not merely end-organ damage markers of these is already recommended in patients with diabetes and
traditional atherosclerotic risk factors. Several plausible in patients with hypertension.21,23,45 As such, in these
mechanisms exist linking chronic kidney disease to clinical populations, chronic kidney disease measures
peripheral artery disease, including, but not limited to, should be readily available to classify the risk of
activation of the reninangiotensin system, oxidative peripheral artery disease. Moreover, a few research
stress, inflammation, hypercoagulability, abnormal groups have proposed prediction models for the risk of
calcium-phosphate metabolism, increase of peripheral artery disease in the general population,24,33
lipoprotein(a), and accumulation of uraemic toxins.35 but none of these models take into consideration
Additionally, albuminuria is linked to endothelial measures of chronic kidney disease. In this context, the
dysfunction and microvascular damage.36 This link might improvement of peripheral artery disease risk prediction
account for the particularly strong contribution of with measures of chronic kidney disease in our study,
albuminuria to the risk of leg amputation. The even among individuals without diabetes or
development of critical limb ischaemia as a severe form hypertension, is an important finding.
of peripheral artery disease has been suggested to be due Although to our knowledge this is the most
to a compromised microcirculation, resulting in an comprehensive study done so far to investigate the
impaired collateral formation and wound healing.37,38 prospective association of chronic kidney disease with
Notably, increased ACR was associated with incident incident peripheral artery disease, the results should be
peripheral artery disease even within the range currently interpreted with appropriate caution. As mentioned, the
considered normal or mildly raised (ie, <30 mg/g).21 definitions of peripheral artery disease outcomes varied
This pattern was also seen for other cardiovascular across cohorts. Additionally, some definitions (eg, clinical
outcomes (eg, cardiovascular mortality, coronary heart diagnosis and hospital admission for peripheral artery
disease, and heart failure),18,28 prompting some experts disease included as a part of study-specific peripheral
to propose a lower threshold of elevated albuminuria.39 artery disease in several studies) might be prone to
Decisions about thresholds for albuminuria should ascertainment bias, particularly among patients with
involve comprehensive consideration of the distribution advanced chronic kidney disease. Nonetheless, it is
of a relevant biomarker in the target population, the important that the results were consistent across
need for age-specific or sex-specific thresholds, the different peripheral artery disease outcomes, including
contribution to clinical outcomes, and the cost- a harder outcome of leg amputation. Similarly, the
effectiveness of clinical management triggered by methods used to assess creatinine, albuminuria, and
identification of abnormal values of that biomarker.28,4042 traditional risk factors were not necessarily consistent
In terms of distribution, 191% of participants in our across cohorts, although we standardised their
general population cohorts had an ACR of less than definitions as much as possible (appendix pp 67). Our
10 mg/g. Nonetheless, it seems worth paying attention study population predominantly consisted of white and
to any future evidence informing this important issue, black people, and, as such, confirmatory investigation is
particularly the cost-effectiveness of any interventions needed for other racial and ethnic groups. Additionally,
targeting mildly raised ACR below 30 mg/g. as with any observational study, residual confounding
The strong association between chronic kidney due to unassessed potential confounders (eg, physical
disease and peripheral artery disease might not be activity) could have occurred.
surprising because chronic kidney disease is sometimes In conclusion, our results show that even mild-to-
regarded as an equivalent atherosclerotic disease in moderate chronic kidney disease conferred about
terms of prognosis;43 however, our study has clinical 154 times higher risk of incident peripheral artery

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Articles

disease beyond and above traditional atherosclerotic risk Acknowledgments


factors. The association between albuminuria and The Chronic Kidney Disease Prognosis Consortium (CKD-PC) Data
Coordinating Center is partly funded by a programme grant from the
amputation was remarkably strong. Our results suggest US National Kidney Foundation and National Institute of Diabetes and
that clinical attention should be paid to the development Digestive and Kidney Diseases (R01DK100446-01). This specific study
of leg symptoms and clinical signs of peripheral artery was supported by a grant from the American Heart Association
disease in people with any stage of chronic kidney (#14CRP20380886). Several sources have supported enrolment and data
collection, including laboratory measurements, and follow-up in the
disease. collaborating cohorts of the CKD-PC. These funding sources include
Contributors government agencies (such as national institutes of health and medical
KM, JC, RTG, CPK, VS, and MW conceived the study concept and research councils), foundations, and industry sponsors (appendix
design. KM, SHB, JC, and the Chronic Kidney Disease Prognosis pp 910).
Consortium (CKD-PC) investigators and collaborators acquired the data. References
KM and the Data Coordinating Center members analysed the data. All 1 Mozaffarian D, Benjamin EJ, Go AS, et al, on behalf of the
authors contributed to the interpretation of the data. KM, SHB, JC, and American Heart Association Statistics Committee and Stroke
FK drafted the report, and all authors provided critical revisions of the Statistics Subcommittee. Executive summary: heart disease and
report for important intellectual content. All collaborators shared data stroke statistics2016 update: a report from the American Heart
and were given the opportunity to comment on the report. JC obtained Association. Circulation 2016; 133: 44754.
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CKD-PC Steering CommitteeJosef Coresh (chair), Ron T Gansevoort, 12 Wattanakit K, Folsom AR, Selvin E, et al. Risk factors for peripheral
Morgan E Grams, Stein Hallan, Csaba P Kovesdy, Andrew S Levey, arterial disease incidence in persons with diabetes:
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project director), Jingsha Chen (programmer), Josef Coresh (principal 13 Bello AK, Hemmelgarn B, Lloyd A, et al, for the Alberta Kidney
investigator), Morgan E Grams (director of nephrology initiatives), Disease Network. Associations among estimated glomerular
Lucia Kwak (programmer), Kunihiro Matsushita (director), filtration rate, proteinuria, and adverse cardiovascular outcomes.
Yingying Sang (lead programmer), and Mark Woodward (senior Clin J Am Soc Nephrol 2011; 6: 141826.
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Declarations of interest the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis
KM reports grants from the American Heart Association, the US 2015; 65: 3340.
National Kidney Foundation, and the US National Institutes of Health 15 Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC
(NIH); and grants and personal fees from Kyowa Hakko Kirin and guideline on the management of patients with lower extremity
Fukuda Denshi. JA reports personal fees from AstraZeneca. JC reports peripheral artery disease: executive summary: a report of the
grants from the NIH and the National Kidney Foundation. JC also has a American College of Cardiology/American Heart Association Task
patent (precise estimation of glomerular filtration rate from multiple Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;
biomarkers: PCT/US2015/044567 provisional patent) filed on 69: 14651508.
Aug 15, 2014. MW reports personal fees from Amgen. MGS reports 16 Matsushita K, Ballew SH, Astor BC, et al, for the Chronic Kidney
personal fees from Cricket Health and stock options in TAI Diagnostics. Disease Prognosis Consortium. Cohort profile: The Chronic Kidney
All other authors declare no competing interests. Disease Prognosis Consortium. Int J Epidemiol 2013; 42: 166068.

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