Abstract
Summary
Doctors do not know whether treatment of high parathyroid hormone levels is linked to better outcomes in their patients with kidney disease. In this study, lower parathyroid hormone levels at baseline were linked to lower risk of fracture, vascular events, and death in people with kidney disease.
Purpose
Chronic kidney disease (CKD) affects ~ 20% of older adults, and secondary hyperparathyroidism (HPT) is a common condition in these patients. To what degree HPT predicts fractures, vascular events, and mortality in pre-dialysis CKD patients is debated. In stage 3 and 4 CKD patients, we assessed relationships between baseline serum PTH levels and subsequent 10-year probabilities of clinical fractures, vascular events, and death.
Methods
We used Marshfield Clinic Health System electronic health records to analyze data from adult CKD patients receiving care between 1985 and 2013, and whose PTH was measured using a second-generation assay. Covariates included PTH, age, gender, tobacco use, vascular disease, diabetes, hypertension, hyperlipidemia, obesity, GFR, and use of osteoporosis medications.
Results
Five thousand one hundred eight subjects had a mean age of 68 ± 17 years, 48% were men, and mean follow-up was 23 ± 10 years. Fractures, vascular events, and death occurred in 18%, 71%, and 56% of the cohort, respectively. In univariate and multivariate models, PTH was an independent predictor of fracture, vascular events, and death. The hazards of fracture, vascular events and death were minimized at a baseline PTH of 0, 69, and 58 pg/mL, respectively.
Conclusions
We found that among individuals with stage 3 and 4 CKD, PTH was an independent predictor of fractures, vascular events, and death. Additional epidemiologic studies are needed to confirm these findings. If a target PTH range can be confirmed, then randomized placebo-controlled trials will be needed to confirm that treating HPT reduces the risk of fracture, vascular events, and death.
Similar content being viewed by others
References
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS (2007) Prevalence of chronic kidney disease in the United States. Jama 298:2038–2047
National Institute of Diabetes and Digestive and Kidney Diseases (2016) kidney disease statistics for the United States. Accessed November 27, 2018
Saran R, Li Y, Robinson B et al (2015) US renal data system 2014 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis 66(Svii):S1–S305
Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL (2007) Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 71:31–38
Stavroulopoulos A, Porter CJ, Roe SD, Hosking DJ, Cassidy MJ (2008) Relationship between vitamin D status, parathyroid hormone levels and bone mineral density in patients with chronic kidney disease stages 3 and 4. Nephrology (Carlton) 13:63–67
Ramos AM, Albalate M, Vazquez S, Caramelo C, Egido J, Ortiz A (2008) Hyperphosphatemia and hyperparathyroidism in incident chronic kidney disease patients. Kidney Int Suppl 74:S88–S93
(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):S1–130 https://doi.org/10.1038/ki.2009.188
Bianchi ML, Colantonio G, Montesano A, Trevisan C, Ortolani S, Rossi R, Buccianti G (1992) Bone mass status in different degrees of chronic renal failure. Bone 13:225–228
Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K (1999) Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int 56:1084–1093
Tsuchida T, Ishimura E, Miki T, Matsumoto N, Naka H, Jono S, Inaba M, Nishizawa Y (2005) The clinical significance of serum osteocalcin and N-terminal propeptide of type I collagen in predialysis patients with chronic renal failure. Osteoporos Int 16:172–179
Przedlacki J, Manelius J, Huttunen K (1995) Bone mineral density evaluated by dual-energy X-ray absorptiometry after one-year treatment with calcitriol started in the predialysis phase of chronic renal failure. Nephron 69:433–437
Rix M, Eskildsen P, Olgaard K (2004) Effect of 18 months of treatment with alfacalcidol on bone in patients with mild to moderate chronic renal failure. Nephrol Dial Transplant 19:870–876
(2003) K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42:S1–S201
KDIGO (2017) Clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 7:1–59
Gao P, D'Amour P (2005) Evolution of the parathyroid hormone (PTH) assay--importance of circulating PTH immunoheterogeneity and of its regulation. Clin Lab 51:21–29
Herberth J, Monier-Faugere MC, Mawad HW, Branscum AJ, Herberth Z, Wang G, Cantor T, Malluche HH (2009) The five most commonly used intact parathyroid hormone assays are useful for screening but not for diagnosing bone turnover abnormalities in CKD-5 patients. Clin Nephrol 72:5–14
Magnan EM, Palta M, Johnson HM, Bartels CM, Schumacher JR, Smith MA (2015) The impact of a patient's concordant and discordant chronic conditions on diabetes care quality measures. J Diabetes Complicat 29:288–294
Johnson HM, Bartels CM, Thorpe CT, Schumacher JR, Pandhi N, Smith MA (2015) Differential diagnosis and treatment rates between systolic and diastolic hypertension in young adults: a multidisciplinary observational study. J Clin Hypertens (Greenwich) 17:885–894
Therneau TM, Grambsch PM (2000) Modeling survival data: extending the cox model. Springer-Verlag, New York
Hastie T, Tibshirani R, Friedman JH (2009) The elements of statistical learning : data mining, inference, and prediction. Springer, New York, NY
Iki M, Fujita Y, Tamaki J, Kouda K, Yura A, Sato Y, Moon JS, Harano A, Hazaki K, Kajita E, Hamada M, Arai K, Tomioka K, Okamoto N, Kurumatani N (2017) Incident fracture associated with increased risk of mortality even after adjusting for frailty status in elderly Japanese men: the Fujiwara-kyo osteoporosis risk in men (FORMEN) cohort study. Osteoporos Int 28:871–880
Cauley JA, Lui LY, Ensrud KE, Zmuda JM, Stone KL, Hochberg MC, Cummings SR (2005) Bone mineral density and the risk of incident nonspinal fractures in black and white women. Jama 293:2102–2108
Stehman-Breen C (2004) Osteoporosis and chronic kidney disease. Semin Nephrol 24:78–81
(July 2016) QickFacts; Marshfield, Wisconsin. United States Census Bureau,
Komaba H, Taniguchi M, Wada A, Iseki K, Tsubakihara Y, Fukagawa M (2015) Parathyroidectomy and survival among Japanese hemodialysis patients with secondary hyperparathyroidism. Kidney Int 88:350–359
Tentori F, Wang M, Bieber BA, Karaboyas A, Li Y, Jacobson SH, Andreucci VE, Fukagawa M, Frimat L, Mendelssohn DC, Port FK, Pisoni RL, Robinson BM (2015) Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study. Clin J Am Soc Nephrol 10:98–109
Lishmanov A, Dorairajan S, Pak Y, Chaudhary K, Chockalingam A (2012) Elevated serum parathyroid hormone is a cardiovascular risk factor in moderate chronic kidney disease. Int Urol Nephrol 44:541–547
Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutiérrez OM, Steigerwalt S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, Feldman HI, Wolf M, Chronic Renal Insufficiency Cohort (CRIC) Study Group (2011) Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. Jama 305:2432–2439
Scialla JJ, Xie H, Rahman M, Anderson AH, Isakova T, Ojo A, Zhang X, Nessel L, Hamano T, Grunwald JE, Raj DS, Yang W, He J, Lash JP, Go AS, Kusek JW, Feldman H, Wolf M, the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators (2014) Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol 25:349–360
Yu N, Donnan PT, Flynn RWV, Murphy MJ, Smith D, Rudman A, Leese GP (2010) Increased mortality and morbidity in mild primary hyperparathyroid patients the parathyroid epidemiology and audit research study (PEARS). Clin Endocrinol 73:30–34
Yu N, Leese GP, Donnan PT (2013) What predicts adverse outcomes in untreated primary hyperparathyroidism? The parathyroid epidemiology and audit research study (PEARS). Clin Endocrinol 79:27–34
Wetzel J, Pilz S, Grubler MR et al (2017) Plasma parathyroid hormone and cardiovascular disease in treatment-naive patients with primary hyperparathyroidism: the EPATH trial. J Clin Hypertens (Greenwich) 19:1173–1180
Shekarkhar S, Foroughi M, Moatamedi M, Gachkar L (2014) The association of serum parathyroid hormone and severity of coronary artery diseases. Coron Artery Dis 25:339–342
Maeda S, Wu S, Juppner H, Green J, Aragay AM, Fagin JA, Clemens TL (1996) Cell-specific signal transduction of parathyroid hormone (PTH)-related protein through stably expressed recombinant PTH/PTHrP receptors in vascular smooth muscle cells. Endocrinology 137:3154–3162
Benson T, Menezes T, Campbell J, Bice A, Hood B, Prisby R (2016) Mechanisms of vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34 in rat bone resistance arteries. Osteoporos Int 27:1817–1826
Acknowledgments
We thank Bryan Robeson, Technical Manager at Marshfield Clinic Laboratory for supplying information on the parathyroid assays used at Marshfield Clinic.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Geng, S., Kuang, Z., Peissig, P. et al. Parathyroid hormone independently predicts fracture, vascular events, and death in patients with stage 3 and 4 chronic kidney disease. Osteoporos Int 30, 2019–2025 (2019). https://doi.org/10.1007/s00198-019-05033-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-019-05033-3