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Differences in Kidney Function and Incident Hypertension: The Multi-Ethnic Study of Atherosclerosis

Bryan Kestenbaum, MD, MS; Kyle D. Rudser, PhD; Ian H. de Boer, MD, MS; Carmen A. Peralta, MD; Linda F. Fried, MD, MPH; Michael G. Shlipak, MD, MPH; Walter Palmas, MD, MS; Catherine Stehman-Breen, MD, MS; and David S. Siscovick, MD, MPH
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From the University of Washington, Harborview Medical Center, Seattle, Washington; San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California; Veterans Affairs Pittsburgh Healthcare System and Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Columbia University, New York, New York; and Amgen, Thousand Oaks, California.

Acknowledgment: The authors thank the other investigators, the staff, and the participants of MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.

Grant Support: By contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by a National Institutes of Health Career Development Award (K23 DK63274-01).

Potential Financial Conflicts of Interest:Employment: C. Stehman-Breen (Amgen). Grants pending: L.F. Fried (Merck).

Reproducible Research Statement:Study protocol: The complete MESA protocol is available online at http://www.mesa-nhlbi.org/moreinfo.aspx. Statistical code: Statistical code for these analyses is available from Dr. Kestenbaum (e-mail, brk@u.washington.edu). Data set: The MESA data are available for researchers with a MESA sponsor and approved manuscript proposal. A list of participating institutions and principal investigators can be found at http://www.mesa-nhlbi.org/institutions.aspx.

Requests for Single Reprints: Bryan Kestenbaum, MD, MS, University of Washington, Division of Nephrology, Harborview Medical Center, Room 10EH11, 325 Ninth Avenue, Seattle, WA 98104-2499; e-mail, brk@u.washington.edu.

Current Author Addresses: Dr. Kestenbaum: University of Washington, Division of Nephrology, Harborview Medical Center, Room 10EH11, 325 Ninth Avenue, Seattle, WA 98104.

Dr. Rudser: University of Washington, 1705 Northeast Pacific Street, Box 357232, Seattle WA 98195.

Dr. de Boer: University of Washington, 1959 Northeast Pacific Street, Box 356521, Seattle, WA 98195.

Dr. Peralta: University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143.

Dr. Fried: Veterans Affairs Pittsburgh Healthcare System, University Drive, Pittsburgh, PA 15240.

Dr. Shlipak: San Francisco Veterans Affairs Medical Center, 4150 Clement Street, 111A-1, San Francisco, CA 94131.

Dr. Palmas: Columbia University, 622 West 168th Street, New York, NY 10032.

Dr. Stehman-Breen: Amgen, 1 Amgen Center Drive, Thousand Oaks, CA 91320.

Dr. Siscovick: Cardiovascular Health Research Unit, Metropolitan Park, East Tower, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101.

Author Contributions: Conception and design: B. Kestenbaum, K.D. Rudser, I.H. de Boer, C. Stehman-Breen.

Analysis and interpretation of the data: B. Kestenbaum, K.D. Rudser, I.H. de Boer, C.A. Peralta, L.F. Fried, M.G. Shlipak, C. Stehman-Breen, D.S. Siscovick.

Drafting of the article: B. Kestenbaum, K.D. Rudser, W. Palmas, C. Stehman-Breen.

Critical revision of the article for important intellectual content: B. Kestenbaum, K.D. Rudser, I.H. de Boer, C.A. Peralta, L.F. Fried, M.G. Shlipak, W. Palmas, C. Stehman-Breen, D.S. Siscovick.

Final approval of the article: B. Kestenbaum, K.D. Rudser, I.H. de Boer, C.A. Peralta, L.F. Fried, M.G. Shlipak, W. Palmas, C. Stehman-Breen, D.S. Siscovick.

Provision of study materials or patients: M.G. Shlipak, D.S. Siscovick.

Statistical expertise: B. Kestenbaum, K.D. Rudser.

Collection and assembly of data: W. Palmas.

Ann Intern Med. 2008;148(7):501-508. doi:10.7326/0003-4819-148-7-200804010-00006
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Of the 6814 MESA participants, we excluded 3508 because of baseline hypertension, 151 because of an estimated GFR less than 60 mL/min per 1.73 m2, and 182 because of microalbuminuria (Figure 1). In addition, we excluded 43 participants because of a missing cystatin C value or urinary albumin–creatinine ratio, 1 for an implausible cystatin C value, and 162 for not returning for future follow-up visits. These 162 participants had cystatin C levels (63.6 vs. 62.2 nmol/L) and urinary albumin–creatinine ratios (5.6 vs. 5.2 mg/g) similar to those of included participants. After exclusions, we analyzed 2767 participants.

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Grahic Jump Location
Figure 1.
Study flow diagram.

GFR = glomerular filtration rate; MESA = Multi-Ethnic Study of Atherosclerosis.

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Figure 3.
Association of each 15-nmol/L increase in serum cystatin C level with incident hypertension within subgroups.
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Figure 2.
Incident hypertension rates within quartiles of serum cystatin C and sex-specific urinary albumin–creatinine ratio.

Results are adjusted for age, race, and sex.

Grahic Jump Location




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Submit a Comment/Letter
Incident hypertension or masked hypertension?
Posted on April 5, 2008
Iddo Z. Ben-Dov
Hadassah - Hebrew University Medical Center
Conflict of Interest: None Declared

Kestenbaum et al (1) reported that the incidence of hypertension in individuals without evident kidney disease associates with variations in kidney function assessed by cystatin C levels. This implicates covert kidney dysfunction in the pathogenesis of hypertension. I wish to address issues concerning surrogates of clinical disease.

The authors excluded subjects with overt kidney disease defined by reduced creatinine-based estimated glomerular filtration rate (eGFR). However the outcome analyses were conducted using serum cystatin C levels. Would the results materially differ if serum creatinine or eGFR estimates had been used? If not, what is the added value of obtaining cystatin C levels?

The surrogate for arterial hypertension was the mean of the second two (out of three) sphygmomanometric measurements taken at each visit. Although blood pressure levels at the office are the basis for clinical practice, the sensitivity and specificity of clinic blood pressure measurements for diagnosing hypertension are imperfect. This limited validity may complicate the interpretation of causality in this cohort study. Indeed, the authors acknowledge that misclassification of subjects may partially account for their findings. More specifically, I suggest that masked hypertension mediates (and may thus mitigate) some of the reported associations. Masked hypertension is a prevalent phenomenon, in which normal blood pressure in the office conceals out-of-office hypertension (2). Home blood pressure and 24-hour ambulatory blood pressure monitoring can disclose such hypertensive subjects (3). Masked hypertension is known to associate with outcome (4), and specifically with arterial damage (5). Thus, failure to identify individuals with masked hypertension at baseline may falsely generate a sense of causality between elevated cystatin C levels and incident hypertension, while undiagnosed masked hypertension at follow-up visits would lead to underestimation of the association under study. I sum, as one optimizes the detection of target organ damage (in this case serum cystatin C to detect subtle kidney dysfunction), refining the diagnosis of the offending state should not be left behind (in this case ambulatory blood pressure monitoring to diagnose hypertension).


1. Kestenbaum B, Rudser KD, de Boer IH, Peralta CA, Fried LF, Shlipak MG, Palmas W, Stehman-Breen C, Siscovick DS. Differences in kidney function and incident hypertension: the multi-ethnic study of atherosclerosis. Ann Intern Med 2008;148:501-8.

2. Ben-Dov IZ, Ben-Arie L, Mekler J and Bursztyn M. In clinical practice, masked hypertension is as common as isolated clinic hypertension: predominance of younger men. Am J Hypertens 2005;18:589-93.

3. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med 2006;354:2368-74.

4. Ben-Dov IZ, Kark JD, Mekler J, Shaked E, Bursztyn M. The white coat phenomenon is benign in referred treated patients: A 14-year ambulatory blood pressure mortality study. J Hypertens 2008;26:699-705.

5. Matsui Y, Eguchi K, Ishikawa J, Hoshide S, Shimada K, Kario K. Subclinical arterial damage in untreated masked hypertensive subjects detected by home blood pressure measurement. Am J Hypertens 2007;20:385- 91.

Conflict of Interest:

None declared

Response to Letter
Posted on June 9, 2008
Bryan Kestenbaum
University of Washington
Conflict of Interest: None Declared

Response to letter to Annals of Internal Medicine

We chose cystatin C as a serologic marker of kidney function for three reasons. First, serum cystatin C levels provide a more precise estimate of the glomerular filtration rate (GFR) than serum creatinine levels. In a recent pooled analysis, cystatin C levels explained 82% of the variation in radionulceotide measured GFR, whereas serum creatinine levels explained 74%.1 Second, cystatin C levels are more accurate than serum creatinine levels for detecting early disturbances in kidney function.2,3 Third, the Modification of Diet in Renal Disease (MDRD) equation incorporates terms for age, race, and gender, potentially confusing associations with incident hypertension. In our adjusted models, neither serum creatinine levels nor estimated GFR by the MDRD equation were significantly associated with incident hypertension.

We agree that sphygmomanometric measurements of blood pressure are imperfect for detecting hypertension. 24-hour ambulatory or home blood pressure measurements were not available for this study population. Masked hypertension, in which participants with true hypertension may be missed by a single set of blood pressure measurements, could have obscured the temporal relationship between kidney function and incident hypertension. We performed a sensitivity analyses restricted to participants with normal baseline blood pressure (systolic blood pressure less than 120 mm Hg and diastolic blood pressure less than 80 mm Hg). Associations of cystatin C levels with incident hypertension were similar in this subgroup analysis. We look forward to future studies of kidney function and hypertension that include more precise measurements of both blood pressure and kidney function to help further clarify temporal relationships.

Bryan Kestenbaum, MD MS Seattle, WA


1. Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J, Rossert J, Van Lente F, Bruce RD, 3rd, Zhang YL, Greene T, Levey AS. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis. Mar 2008;51(3):395-406.

2. Coll E, Botey A, Alvarez L, Poch E, Quinto L, Saurina A, Vera M, Piera C, Darnell A. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis. Jul 2000;36(1):29-34.

3. Randers E, Erlandsen EJ, Pedersen OL, Hasling C, Danielsen H. Serum cystatin C as an endogenous parameter of the renal function in patients with normal to moderately impaired kidney function. Clin Nephrol. Sep 2000;54(3):203-209.

Conflict of Interest:

None declared

Submit a Comment/Letter

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