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Research Letter |

Association of Loop Diuretic Use With Higher Parathyroid Hormone Levels in Patients With Normal Renal Function FREE

Kristin M. Corapi, MD, MMSc1; Gearoid M. McMahon, MBBCh2; Julia B. Wenger, MPH1; Julian L. Seifter, MD2; Ishir Bhan, MD, MPH1
[+] Author Affiliations
1Division of Nephrology, Massachusetts General Hospital, Boston
2Division of Nephrology, Brigham and Women’s Hospital, Boston, Massachusetts
JAMA Intern Med. 2015;175(1):137-138. doi:10.1001/jamainternmed.2014.5857.
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Published online

Elevations in parathyroid hormone (PTH) level have been associated with adverse clinical outcomes, including cardiovascular disease and mortality.1,2 Loop diuretics have been linked to increased PTH levels in patients with chronic kidney disease (CKD),3,4 but this association has not been investigated in the general population. We used data from the National Health and Nutrition Examination Survey (NHANES)5,6 to test the hypothesis that loop diuretic use associates with elevated PTH in adults with preserved renal function.

We studied participants from NHANES 2003 to 20045 and 2005 to 20066 because PTH measurements were available in these years. Participants were excluded for age younger than 18 years, estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73 m2 (using the CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equation), or missing PTH value. “Loop users” had prescriptions for furosemide, bumetanide, or torsemide.

Baseline characteristics of loop users and nonusers were compared using t tests or χ2 tests. A multivariable linear regression model was constructed to test the association between loop use and natural log-transformed PTH level. Covariates were age, sex, body mass index (BMI), history of congestive heart failure (CHF); smoking; dietary calcium and phosphorus intake; eGFR; and levels of serum 25-(OH) vitamin D, calcium, phosphorus, uric acid, albumin, and alkaline phosphatase. Least-square means were used to estimate natural log-transformed PTH levels of loop users and nonusers. These values were exponentiated and the adjusted geometric means of PTH level from the final model are reported. Multivariable logistic regression was used to test the association between loop use and odds of a PTH level higher than 65 pg/mL.

Of 20 470 participants, 9287 were younger than 18 years; 2217 had an eGFR lower than 60 mL/min/1.73 m2, and 3 were missing a PTH value. The remaining 8963 participants were included in the analysis. After application of survey weights, 1.8% of participants were loop users.

Loop users were more likely to be female, older, nonsmokers, and have a higher BMI (Table). They had significantly higher uric acid and alkaline phosphatase levels but lower eGFR, 25-(OH) vitamin D, and albumin levels. Loop users had a lower dietary intake of calcium and phosphorus and were more likely to have a history of CHF. Race and serum calcium and phosphorus levels were similar between groups.

Table Graphic Jump LocationTable.  Characteristics of Non–Loop Users and Loop Users

The Figure depicts the range of PTH levels among loop users and nonusers. Using the final multivariable model, the adjusted geometric mean PTH level in loop users was significantly higher than in nonusers (43.4 pg/mL compared with 38.8 pg/mL; P < .001). Using multivariable logistic regression, loop use was associated with significantly increased odds of a PTH level higher than 65 pg/mL (odds ratio, 1.83 [CI, 1.16-2.88]; P = .01).

Place holder to copy figure label and caption
Figure.
The Range of Parathyroid Hormone (PTH) Levels Among Loop Users and Nonusers

Levels are depicted in increments of 30 pg/mL. More loop users have PTH values above the upper limit of normal.

Graphic Jump Location

Our results demonstrate that loop use associates with higher PTH, even after adjustment for potential confounders. While previous studies have found similar associations in CKD, we demonstrate that this relationship extends to patients with preserved kidney function, having an impact on a considerably larger population. Clinicians often monitor for electrolyte changes after initiation of loop diuretics but may not measure PTH level. Many loop users are elderly or have CHF, both of which contribute to bone loss. Use of a different diuretic class, repletion of vitamin D, or increased dietary calcium intake may combat a rise in PTH and reduce the risk of adverse outcomes.

This study included a large, representative sample of adults. Many variables known to influence PTH level were included in the analysis. Missing data limited our ability to examine the relationship between loop use and clinical outcomes, and while we tried to control for potential confounders, residual confounding may exist. Prospective studies are needed to define the direct effect of loop use on PTH level. Nonetheless, our work suggests that loop diuretic use may lead to elevation in PTH level and consequently other adverse clinical effects.

Corresponding Author: Kristin M. Corapi, MD, MMSc, Division of Nephrology, Massachusetts General Hospital, 165 Cambridge St, Ste 302, Boston, MA 02114 (kcorapi@partners.org).

Published Online: November 24, 2014. doi:10.1001/jamainternmed.2014.5857.

Author Contributions: Dr Corapi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Corapi, McMahon, Seifter, Bhan.

Acquisition, analysis, or interpretation of data: Corapi, McMahon, Wenger, Bhan.

Drafting of the manuscript: Corapi, Wenger.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Corapi, Wenger.

Administrative, technical, or material support:

Study supervision: McMahon, Wenger, Bhan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases Program at the National Institutes of Health (NIH) (training grant T32DK007540).

Role of the Sponsor: The NIH had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: Data from this research were presented in poster form at the American Society of Nephrology Annual Meeting; November 10, 2013; Atlanta, Georgia.

Yu  N, Donnan  PT, Leese  GP.  A record linkage study of outcomes in patients with mild primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol (Oxf). 2011;75(2):169-176.
PubMed   |  Link to Article
Hagström  E, Hellman  P, Larsson  TE,  et al.  Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation. 2009;119(21):2765-2771.
PubMed   |  Link to Article
Isakova  T, Anderson  CA, Leonard  MB,  et al; Chronic Renal Insufficiency Cohort (CRIC) Study Group.  Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort. Nephrol Dial Transplant. 2011;26(4):1258-1265.
PubMed   |  Link to Article
Reichel  H, Deibert  B, Geberth  S, Schmidt-Gayk  H, Ritz  E.  Frusemide therapy and intact parathyroid hormone plasma concentrations in chronic renal insufficiency. Nephrol Dial Transplant. 1992;7(1):8-15.
PubMed
National Health and Nutrition Examination Survey Data. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003-2004.
National Health and Nutrition Examination Survey Data. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2005-2006.

Figures

Place holder to copy figure label and caption
Figure.
The Range of Parathyroid Hormone (PTH) Levels Among Loop Users and Nonusers

Levels are depicted in increments of 30 pg/mL. More loop users have PTH values above the upper limit of normal.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Characteristics of Non–Loop Users and Loop Users

References

Yu  N, Donnan  PT, Leese  GP.  A record linkage study of outcomes in patients with mild primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol (Oxf). 2011;75(2):169-176.
PubMed   |  Link to Article
Hagström  E, Hellman  P, Larsson  TE,  et al.  Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation. 2009;119(21):2765-2771.
PubMed   |  Link to Article
Isakova  T, Anderson  CA, Leonard  MB,  et al; Chronic Renal Insufficiency Cohort (CRIC) Study Group.  Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort. Nephrol Dial Transplant. 2011;26(4):1258-1265.
PubMed   |  Link to Article
Reichel  H, Deibert  B, Geberth  S, Schmidt-Gayk  H, Ritz  E.  Frusemide therapy and intact parathyroid hormone plasma concentrations in chronic renal insufficiency. Nephrol Dial Transplant. 1992;7(1):8-15.
PubMed
National Health and Nutrition Examination Survey Data. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003-2004.
National Health and Nutrition Examination Survey Data. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2005-2006.

Correspondence

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