Skip to main content

Advertisement

SpringerLink
Log in

Association between serum phosphorus and mortality in NHANES 2003–2006: the effect of gender and renal function

  • Original Article
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

Background

The impact of high serum phosphorus in the general population is still debated. Studies are heterogeneous, most lack an adjustment for parathyroid hormone, vitamin D and phosphorus intake and the effect might differ by gender and renal function. We investigated the association between serum phosphorus and mortality in American adults.

Methods

We prospectively analyzed 5698 non-pregnant and non-CKD adults from the National Health and Nutrition Examination Survey (NHANES) 2003–2006. Serum phosphorus and potential confounders including parathyroid hormone, 25(OH)vitamin D and phosphorus intake were evaluated. All-cause, cardiovascular- and cancer-related deaths were recorded through December 31st, 2015. Sex-specific terciles of serum phosphorus were used to fit adjusted Cox proportional hazard models for mortality. Analysis was stratified by gender and renal function.

Results

A total of 590 deaths were recorded over a median follow-up of 81 months. Women showed higher serum phosphorus than men. The adjusted hazard ratio (HR) for all-cause mortality was 1.35 (95% CI 1.08–1.58) (p = 0.033) for the third tercile (versus second tercile). This increased risk was present in participants with estimated glomerular filtration rate (eGFR) below 90 ml/min/1.73 m2 but not above, although interaction was not significant (p = 0.12). Interaction by gender, phosphorus intake, PTH and fasting time was also not detected. For cardiovascular and cancer mortality, the adjusted HR was 0.81 (95% CI 0.33–2.00) (p = NS) and 1.45 (95% CI 0.77–2.72) (p = NS), respectively.

Conclusions

We demonstrated that the highest tercile of serum phosphorus is associated with increased all-cause mortality, irrespective of PTH, 25(OH)vitamin D or phosphorus intake. This association may differ by gender and renal function, but larger studies testing for effect modification are needed.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Code and data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Martin KJ, González EA (2007) Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol 18(3):875–885

    Article  CAS  PubMed  Google Scholar 

  2. Block GA, Klassen PS, Lazarus JM et al (2004) Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15(8):2208–2218. https://doi.org/10.1097/01.asn.0000133041.27682.a2

    Article  CAS  PubMed  Google Scholar 

  3. Da J, Xie X, Wolf M et al (2015) Serum phosphorus and progression of CKD and mortality: a meta-analysis of cohort studies. Am J Kidney Dis 66(2):258–265. https://doi.org/10.1053/j.ajkd.2015.01.009

    Article  CAS  PubMed  Google Scholar 

  4. Bellasi A, Mandreoli M, Baldrati L et al (2011) Chronic kidney disease progression and outcome according to serum phosphorus in mild-to-moderate kidney dysfunction. Clin J Am Soc Nephrol 6(4):883–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Campos-Obando N, Lahousse L, Brusselle G et al (2018) Serum phosphate levels are related to all-cause, cardiovascular and COPD mortality in men. Eur J Epidemiol 33(9):859–871. https://doi.org/10.1007/s10654-018-0407-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yoo KD, Kang S, Choi Y et al (2016) Sex, age, and the association of serum phosphorus with all-cause mortality in adults with normal kidney function. Am J Kidney Dis 67(1):79–88. https://doi.org/10.1053/j.ajkd.2015.06.027

    Article  CAS  PubMed  Google Scholar 

  7. Onufrak SJ, Bellasi A, Cardarelli F et al (2009) Investigation of gender heterogeneity in the associations of serum phosphorus with incident coronary artery disease and all-cause mortality. Am J Epidemiol 169(1):67–77

    Article  PubMed  Google Scholar 

  8. Bergwitz C, Juppner H (2010) Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 61:91–104. https://doi.org/10.1146/annurev.med.051308.111339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang B, Lu C, Wu Q et al (2016) Parathyroid hormone, cardiovascular and all-cause mortality: a meta-analysis. Clin Chim Acta 455:154–160. https://doi.org/10.1016/j.cca.2016.01.034

    Article  CAS  PubMed  Google Scholar 

  10. Wulaningsih W, Michaelsson K, Garmo H et al (2013) Inorganic phosphate and the risk of cancer in the Swedish AMORIS study. BMC cancer 13(1):257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bai W, Li J, Liu J (2016) Serum phosphorus, cardiovascular and all-cause mortality in the general population: a meta-analysis. Clin Chim Acta 461:76–82. https://doi.org/10.1016/j.cca.2016.07.020

    Article  CAS  PubMed  Google Scholar 

  13. Chang WX, Xu N, Kumagai T et al (2016) The impact of normal range of serum phosphorus on the incidence of end-stage renal disease by a propensity score analysis. PLoS ONE 11(4):e0154469. https://doi.org/10.1371/journal.pone.0154469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang D, Maalouf NM, Adams-Huet B et al (2014) Effects of sex and postmenopausal estrogen use on serum phosphorus levels: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES) 2003–2006. Am J Kidney Dis 63(2):198–205

    Article  CAS  PubMed  Google Scholar 

  15. Block GA (2000) Prevalence and clinical consequences of elevated Ca x P product in hemodialysis patients. Clin Nephrol 54(4):318–324

    CAS  PubMed  Google Scholar 

  16. Hou Y, Li X, Sun L et al (2017) Phosphorus and mortality risk in end-stage renal disease: a meta-analysis. Clin Chim Acta 474:108–113. https://doi.org/10.1016/j.cca.2017.09.005

    Article  CAS  PubMed  Google Scholar 

  17. Caravaca F, Villa J, Garcia de Vinuesa E et al (2011) Relationship between serum phosphorus and the progression of advanced chronic kidney disease. Nefrologia 31(6):707–715. https://doi.org/10.3265/Nefrologia.pre2011.Sep.11089

    Article  CAS  PubMed  Google Scholar 

  18. Wannamethee SG, Sattar N, Papcosta O et al (2013) Alkaline phosphatase, serum phosphate, and incident cardiovascular disease and total mortality in older men. Arterioscler Thromb Vasc Biol 33(5):1070–1076. https://doi.org/10.1161/ATVBAHA.112.300826

    Article  CAS  PubMed  Google Scholar 

  19. Dominguez JR, Kestenbaum B, Chonchol M et al (2013) Relationships between serum and urine phosphorus with all-cause and cardiovascular mortality: the Osteoporotic Fractures in Men (MrOS) Study. Am J Kidney Dis 61(4):555–563. https://doi.org/10.1053/j.ajkd.2012.11.033

    Article  CAS  PubMed  Google Scholar 

  20. Larsson TE, Olauson H, Hagstrom E et al (2010) Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arterioscler Thromb Vasc Biol 30(2):333–339. https://doi.org/10.1161/ATVBAHA.109.196675

    Article  CAS  PubMed  Google Scholar 

  21. Chang AR, Anderson C (2017) Dietary phosphorus intake and the kidney. Annu Rev Nutr 37:321–346. https://doi.org/10.1146/annurev-nutr-071816-064607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Parmar MS (2018) Phosphorus in kidney disease: culprit or bystander? Cleve Clin J Med 85(8):639–642. https://doi.org/10.3949/ccjm.85a.18013

    Article  PubMed  Google Scholar 

  23. Kawamura H, Tanaka S, Ota Y et al (2018) Dietary intake of inorganic phosphorus has a stronger influence on vascular-endothelium function than organic phosphorus. J Clin Biochem Nutr 62(2):167–173. https://doi.org/10.3164/jcbn.17-97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang AR, Lazo M, Appel LJ et al (2014) High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am J Clin Nutr 99(2):320–327. https://doi.org/10.3945/ajcn.113.073148

    Article  CAS  PubMed  Google Scholar 

  25. Chang AR, Grams ME (2014) Serum phosphorus and mortality in the Third National Health and Nutrition Examination Survey (NHANES III): effect modification by fasting. Am J Kidney Dis 64(4):567–573. https://doi.org/10.1053/j.ajkd.2014.04.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. de Boer IH, Rue TC, Kestenbaum B (2009) Serum phosphorus concentrations in the third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 53(3):399–407. https://doi.org/10.1053/j.ajkd.2008.07.036

    Article  CAS  PubMed  Google Scholar 

  27. Santamaria R, Diaz-Tocados JM, Pendon-Ruiz de Mier MV et al (2018) Increased phosphaturia accelerates the decline in renal function: a search for mechanisms. Sci Rep 8(1):13701. https://doi.org/10.1038/s41598-018-32065-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blaine J, Chonchol M, Levi M (2015) Correction. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol 10(10):1886–1887. https://doi.org/10.2215/cjn.08840815

    Article  CAS  PubMed  Google Scholar 

  29. Rashid G, Bernheim J, Green J et al (2007) Parathyroid hormone stimulates endothelial expression of atherosclerotic parameters through protein kinase pathways. Am J Physiol Renal Physiol 292(4):F1215–F1218. https://doi.org/10.1152/ajprenal.00406.2006

    Article  CAS  PubMed  Google Scholar 

  30. Hagstrom E, Hellman P, Larsson TE et al (2009) Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation 119(21):2765–2771. https://doi.org/10.1161/circulationaha.108.808733

    Article  PubMed  Google Scholar 

  31. Gutierrez OM (2013) The connection between dietary phosphorus, cardiovascular disease, and mortality: where we stand and what we need to know. Adv Nutr 4(6):723–729. https://doi.org/10.3945/an.113.004812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mathew S, Tustison KS, Sugatani T et al (2008) The mechanism of phosphorus as a cardiovascular risk factor in CKD. J Am Soc Nephrol 19(6):1092–1105. https://doi.org/10.1681/asn.2007070760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Camalier CE, Young MR, Bobe G et al (2010) Elevated phosphate activates N-ras and promotes cell transformation and skin tumorigenesis. Cancer Prev Res (Phila) 3(3):359–370. https://doi.org/10.1158/1940-6207.CAPR-09-0068

    Article  CAS  Google Scholar 

  34. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group (2009) KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 113:S1

    Google Scholar 

  35. Wheeler DC, Winkelmayer WC (2017) KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) foreword. Kidney Int Suppl 7(1):1–59

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank the participants and staff of the NHANES. The authors thank João Sérgio Neves, MD, from Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário de São João, Faculdade de Medicina, Universidade do Porto (Porto, Portugal) who provided insight that greatly assisted the statistical analysis.

Funding

This work was supported through the Cardiovascular Research Center (UnIC, FCT 51/94) by the Portuguese Foundation for Science and Technology and by the project NETDIAMOND (POCI-01-0145-FEDER-016385, supported by European Structural and Investment Funds and Lisbon's Regional Operational Program 2020). Funders of this study had no role in the study design; collection, analysis, or interpretation of the data; writing of the report; or the decision to submit this report for publication.

Author information

Authors and Affiliations

  1. Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, Alameda Professor Hernâni Monteiro, 4200-319, Porto, Portugal

    Luís Mendonça, Francisco Gonçalves & Paulo Castro-Chaves

  2. Serviço de Nefrologia, Centro Hospitalar Universitário São João, Porto, Portugal

    Luís Mendonça, Francisco Gonçalves, Susana Sampaio & Luciano Pereira

  3. Cardiovascular Research Centre, Porto, Portugal

    Luís Mendonça, Francisco Gonçalves & Paulo Castro-Chaves

  4. Serviço de Medicina Interna, Centro Hospitalar Universitário São João, Porto, Portugal

    Paulo Castro-Chaves

  5. Nephrology and Infectious Diseases R&D Group, INEB-I3S—Instituto Nacional de Engenharia Biomédica, University of Porto, Porto, Portugal

    Susana Sampaio & Luciano Pereira

Authors
  1. Luís Mendonça
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco Gonçalves
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susana Sampaio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paulo Castro-Chaves
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luciano Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Research idea: LM. Literature search, study design, data analysis and first manuscript draft preparation: LM, FG, LP. Interpretation of the results and critical revision of the manuscript: SS, PCC, LP. Each author contributed important intellectual content during manuscript drafting or revision, accepts personal accountability for the author’s own contributions, read and approved the final manuscript and agrees to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Luís Mendonça.

Ethics declarations

Conflict of interest

The authors declare that they have no relevant financial interests.

Ethics approval

NHANES protocols were approved by the National Center for Health Statistics Ethics Review Board: NHANES 2003–2004 (Protocol #98-12) and NHANES 2005–2006 (Protocol #2005-06).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mendonça, L., Gonçalves, F., Sampaio, S. et al. Association between serum phosphorus and mortality in NHANES 2003–2006: the effect of gender and renal function. J Nephrol 35, 165–178 (2022). https://doi.org/10.1007/s40620-021-00969-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-021-00969-4

Keywords

Search

Navigation