0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

Using Proteinuria and Estimated Glomerular Filtration Rate to Classify Risk in Patients With Chronic Kidney Disease: A Cohort Study

Marcello Tonelli, MD, SM; Paul Muntner, PhD; Anita Lloyd, MSc; Braden J. Manns, MD, MSc; Matthew T. James, MD; Scott Klarenbach, MD, MSc; Robert R. Quinn, MD, PhD; Natasha Wiebe, MMath, PStat; Brenda R. Hemmelgarn, MD, PhD, for the Alberta Kidney Disease Network
[+] Article and Author Information

From the University of Alberta, Edmonton, Alberta, Canada; University of Alabama, Birmingham, Alabama; and University of Calgary, Calgary, Alberta, Canada.


Note: Drs. Tonelli, Muntner, and Hemmelgarn participated in the 2010 Kidney Disease: Improving Global Outcomes Controversies Conference, which brought investigators from around the world together to discuss how the current NKF KDOQI CKD staging system might be refined.

Grant Support: By an interdisciplinary research team grant from the Alberta Heritage Foundation for Medical Research (AHFMR), career salary awards from the AHFMR (Drs. Hemmelgarn, Tonelli, and Klarenbach), New Investigator Awards from the Canadian Institutes of Health Research (Drs. Hemmelgarn, Tonelli, and Manns), a joint initiative between Alberta Health and Wellness and the Universities of Alberta and Calgary (Drs. Hemmelgarn, Klarenbach, Manns, and Tonelli), and a Shire Biochem—KRESCENT Joint Fellowship and an AHFMR research Award (Dr. James).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0837.

Reproducible Research Statement:Study protocol: Not available. Statistical code: Code for AKDN data is available from Dr. Tonelli (e-mail, mtonelli-admin@med.ualberta.ca). Code for NHANES III data is not available. Data set: AKDN data are not available. NHANES III data are available at www.cdc.gov/nchs/nhanes.htm.

Corresponding Author: Marcello Tonelli, MD, SM, 7-129 Clinical Science Building, 8440 112 Street, Edmonton, Alberta T6B 2G3, Canada.

Current Author Addresses: Dr. Tonelli: University of Alberta, 7-129 Clinical Science Building, 8440 112th Street, Edmonton, Alberta T6B 2G3, Canada.

Dr. Muntner: University of Alabama at Birmingham, RPHB 230J, Birmingham, AL 35294.

Ms. Lloyd: University of Alberta, 3049 RTF, 8308 114th Street, Edmonton, Alberta T6G 2V2, Canada.

Drs. Manns, James, and Quinn: Foothills Medical Center, 1403 29th Street Northwest, Calgary, Alberta T2N 2T9, Canada.

Dr. Klarenbach: Department of Medicine, University of Alberta, 11-107 Clinical Sciences Building, 8440 112th Street, Edmonton, Alberta T6G 2G3, Canada.

Ms. Wiebe: University of Alberta, 3048 RTF, 8308 114th Street, Edmonton, Alberta T6G 2V2, Canada.

Dr. Hemmelgarn: Division of Nephrology, Foothills Hospital, 1403 29th Street Northwest, Calgary, Alberta T2N 2T9, Canada.

Author Contributions: Conception and design: M. Tonelli, P. Muntner, M.T. James, S. Klarenbach, R.R. Quinn, N. Wiebe, B.R. Hemmelgarn.

Analysis and interpretation of the data: M. Tonelli, P. Muntner, A. Lloyd, B.J. Manns, M.T. James, S. Klarenbach, R.R. Quinn, N. Wiebe, B.R. Hemmelgarn.

Drafting of the article: M. Tonelli, A. Lloyd, R.R. Quinn, B.R. Hemmelgarn.

Critical revision of the article for important intellectual content: M. Tonelli, P. Muntner, B.J. Manns, M.T. James, S. Klarenbach, R.R. Quinn, N. Wiebe, B.R. Hemmelgarn.

Final approval of the article: M. Tonelli, P. Muntner, A. Lloyd, B.J. Manns, M.T. James, S. Klarenbach, R.R. Quinn, N. Wiebe, B.R. Hemmelgarn.

Provision of study materials or patients: B.R. Hemmelgarn.

Statistical expertise: P. Muntner, A. Lloyd, R.R. Quinn, N. Wiebe, B.R. Hemmelgarn.

Obtaining of funding: M. Tonelli, B.J. Manns, S. Klarenbach, B.R. Hemmelgarn.

Collection and assembly of data: P. Muntner, B.R. Hemmelgarn.


Ann Intern Med. 2011;154(1):12-21. doi:10.7326/0003-4819-154-1-201101040-00003
Text Size: A A A

Background: The staging system for chronic kidney disease relies almost exclusively on estimated glomerular filtration rate (eGFR), although proteinuria is also associated with adverse outcomes.

Objective: To validate a 5-category system for risk stratification based on the combination of eGFR and proteinuria.

Design: Retrospective cohort study.

Setting: A provincial laboratory registry in Alberta, Canada, and a representative sample of noninstitutionalized U.S. adults.

Patients: A derivation data set of 474 521 adult outpatients, 2 independent internal validation cohorts with 51 356 and 460 623 patients, and an external validation cohort of 14 358 patients.

Measurements: Glomerular filtration rate, estimated by using the Modification of Diet in Renal Disease Study equation, and proteinuria, measured by using urine albumin-to-creatinine ratio or dipstick urinalysis. Outcomes included all-cause mortality and a composite renal outcome of kidney failure or doubling of serum creatinine level.

Results: Over a median follow-up of 38 months in the internal validation cohorts, higher risk categories (indicating lower eGFR or more proteinuria) were associated with a graded increase in the risk for the composite renal outcome. The projected number of U.S. adults assigned to risk categories 3 and 4 in the alternate system was 3.9 million, compared with 16.3 million assigned to stage 3 and 4 in the current staging system. The alternate system was more likely to correctly reclassify persons who did not develop the renal outcome than those who did, although some persons developed the renal outcome despite reclassification to a lower category. However, all analyses of patients reclassified to a lower category showed that substantially fewer such patients developed the renal outcome than did not. Correct reclassification by the alternate system was more likely when proteinuria was measured by using albumin-to-creatinine ratio than with dipstick testing, and also more likely for the composite renal outcome than for mortality.

Limitation: The study had a short follow-up time.

Conclusion: Using proteinuria in combination with eGFR may reduce unnecessary referrals for care at the cost of not referring or delaying referral for some patients who go on to develop kidney failure.

Primary Funding Source: Alberta Heritage Foundation for Medical Research interdisciplinary research team grant.

Figures

Grahic Jump Location
Figure 1.
Current NKF KDOQI CKD staging system and alternate system of CKD risk categories.

The composite renal outcome comprised end-stage renal disease or doubling of serum creatinine level. Although the current NKF KDOQI staging system also considers persons with abnormal renal imaging to have stage 1 or stage 2 CKD, this information was not available in the internal or external validation data sets. CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; NKF KDOQI = National Kidney Foundation Kidney Disease Outcomes Quality Initiative.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.
Study flow diagram.

ACR = albumin–creatinine ratio; AKDN = Alberta Kidney Disease Network; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; NHANES III = Third National Health and Nutrition Examination Survey.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Rates of the composite renal outcome and all-cause mortality, per 1000 patient-years, in the AKDN ACR derivation cohort.

Rates of the 12 categories are ranked from lowest to highest risk. ACR = albumin–creatinine ratio; AKDN = Alberta Kidney Disease Network; eGFR = estimated glomerular filtration rate; NKF KDOQI = National Kidney Foundation Kidney Disease Outcomes Quality Initiative.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Adding Proteinuria to Chronic Kidney Disease Classification
Posted on January 23, 2011
Micah L. Thorp
Kaiser Permanente Northwest
Conflict of Interest: None Declared

To the Editor, In their excellent study, Tonelli et. al. demonstrate that a chronic kidney disease (CKD) classification system that includes the addition of proteinuria to estimated glomerular filtration rate (eGFR) reduces misclassification of patients when compared to the National Kidney Foundation's (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) classification system (1). While the proposed system appears to be more reliable than the KDOQI system, the comparison suffers on two counts. First, the study used the Modification of Diet in Renal Disease (MDRD)(2) GFR estimation equation which tends to underestimate GFR among patients in early stage 3 disease. While KDOQI recommends the MDRD be used to estimate GFR, it does not require it as a part of the definition. More contemporary equations are available (3) which reduce the numbers of stage 3 patients identified, decreasing misclassification. Secondly, the Tonelli study does not require three months of GFR within a particular range before staging patients, as in the KDQOI system (4). Requiring at least two eGFRs more than three months apart reduces the number of patients with CKD with only a modest reduction in the number of patients who are ultimately progress to end stage disease (5). It is unclear from this study whether or not the addition of proteinuria to a single eGFR using the MDRD equation improves the ability to predict whether or not a patient will develop ESRD compared to a KDOQI system that includes both the best available equation and three months of decreased eGFR. The addition of proteinuria to any system may add significant predictive value. It would be intriguing to how a system like the one described by Tonelli that includes proteinuria, an improved eGFR equation and longer period of renal disease would improve prediction of ESRD.

Micah L. Thorp, DO, MPH Kaiser Permanente Northwest, Department of Nephrology Portland, Oregon

References

1. Tonelli M, Muntner P, Lloyd A, Manns BJ, James MT, Klarenbach S, Quinn RR, Wiebe N, Hemmelgarn BR; for the Alberta Kidney Disease Network. Using Proteinuria and Estimated Glomerular Filtration Rate to Classify Risk in Patients With Chronic Kidney Disease: A Cohort Study. Ann Intern Med. 2011 Jan 4;154(1):12-21.

2. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-70.

3. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12.

4. NKF KDOQI clinical practice guidelines for chronic kidney disease. Am J Kidney Dis. 2002;39 Suppl 1:S76.

5. Thorp ML, Weinstein J, DeVille J, Johnson ES, Petrik A, Yang X, Smith DH. Comparison of renal replacement therapy and mortality using 1 versus 2 estimated glomerular filtration rates. Popul Health Manag. 2009 Jun;12(3):149-55.

Conflict of Interest:

None declared

Proteinuria and eGFR to classify risk in patients with CKD
Posted on January 30, 2011
Hiroshi Nonoguchi
Hyogo College of Medicine
Conflict of Interest: None Declared

To the Editor,

Tonelli and colleagues proposed a new chronic kidney disease (CKD) risk category based on quite large scale retrospective cohost study (1). Their new system took proteinuria into consideration for the risk of the progression to end-stage renal failure and made a large progress from the current staging system by KDOQI. However, their analyses overestimated the risk of low estimated glomerular filtration rate (eGFR) by using inappropriate renal outcomes.

The current CKD staging system, mainly based on eGFR, is useful to know the mortality and the risk of progression of cardiovascular disease (2), since low renal function is a risk factor for high mortality. However, the current system is not useful to know the risk of the progression of CKD itself since the severity of proteinuria, which has larger role for the progression of CKD than eGFR, has not been taken into account. The authors corrected this weak point of the current staging and proposed the risk category. The main problem of the study is the determination of renal outcomes. The authors used end-stage renal failure and the doubling of serum creatinine as renal outcome same as their previous studies (3. 4). Renal outcomes were mainly depended upon the doubling of the serum creatinine. However, the doubling of serum creatinine, which means the loss of 50% renal function, should not be used for the comparison of the progression of renal failure in patients with different renal function (5). If eGFR is 30 and 60 ml/min/1.73m2, the doubling of serum creatinine means the loss of eGFR by 15 and 30 ml/min/1.73m2, respectively. The comparison of time for the doubling of serum creatinine in different renal function is meaningless and gives poorer outcome in patients with advanced renal failure. Since eGFR was used for the classification, the reduction of certain amount of eGFR should be used for renal outcome.

We should be aware that low eGFR does not mean the rapid progression to end-stage renal failure. A new CKD staging and risk category based on the severity of proteinuria should be considered by measuring appropriate renal outcomes.

Hiroshi Nonoguchi, M.D. Satoshi Hazeki, M.D. Masaharu Kaibe, M.D. Kahori Hori, M.D. Takeshi Nakanishi, M.D. Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine

References

1. Tonelli M, Muntner P, Lloyd A, Manns BJ, James MT, Klarenbach S, et al.; Alberta Kidney Disease Network. Using proteinuria and estimated glomerular filtration rate to classify risk in patients with chronic kidney disease: a cohort study Ann Intern Med, 2011; 154:12-21 [PMID: 21200034]

2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305 [PMID: 15385656]

3. Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, et al.; Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303:423-9. [PMID: 20124537]

4. James MT, Hemmelgarn BR, Wiebe N, Pannu N, Manns BJ, Klarenbach SW, et al.; Alberta Kidney Disease Network. Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study. Lancet. 2010;376(9758):2096-103. [PMID: 21094997]

5. Nonoguchi H, Nanami M, Nakanishi T. Kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303:2030 [PMID: 20501920]

Conflict of Interest:

None declared

Response to Dr. Thorp
Posted on February 22, 2011
Marcello Tonelli
University of Alberta
Conflict of Interest: None Declared

We thank Dr. Thorp for his thoughtful letter.

As in most large studies examining the association between kidney function and outcomes, classification of kidney function in our study was based on a single measure of eGFR - and estimated using the MDRD equation.

The CKD-EPI equation (1) is a promising alternative to the MDRD equation, but its benefits have not yet been fully elucidated and (to our knowledge) it is not currently recommended for use by any national or international guideline body. Perhaps other equations might improve performance further. The Kidney Disease: Improving Global Outcomes (KDIGO) international working group on the classification of chronic kidney disease will soon complete their recommendations - which should provide more guidance about which equation should be used to stage eGFR. For our study (2), we chose to use the MDRD equation as currently recommended (3). Prior data suggests that any changes in classification that would result from using the CKD-EPI equation rather than MDRD equation would likely be modest (1).

While we did not require two measures of eGFR at least three months apart to define CKD, we did base our estimate of baseline kidney function on the mean of all eGFR estimates in a six-month period to reduce the potential for misclassification.

We agree with Dr. Thorp that it is always preferable to use the most accurate equation available, and to use repeated measures of eGFR to classify people with respect to kidney function. Although worthy of consideration, the incremental benefit of using the CKD-EPI eGFR estimating equation and multiple eGFR measures spaced at least three months apart would be unlikely to affect our conclusion -- that incorporating information on proteinuria would improve the prognostic power of the current staging system.

Marcello Tonelli MD SM Paul Muntner PhD Brenda Hemmelgarn PhD MD

References

1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12.

2. Tonelli M, Muntner P, Lloyd A, Manns BJ, James MT, Klarenbach S, Quinn RR, Wiebe N, Hemmelgarn BR; for the Alberta Kidney Disease Network. Using Proteinuria and Estimated Glomerular Filtration Rate to Classify Risk in Patients With Chronic Kidney Disease: A Cohort Study. Ann Intern Med. 2011 Jan 4;154(1):12-21.

3. NKF KDOQI clinical practice guidelines for chronic kidney disease. Am J Kidney Dis. 2002;39 Suppl 1:S76.

Conflict of Interest:

None declared

Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)