Management of secondary hyperparathyroidism and mineral metabolism abnormalities in adult predialysis patients with chronic kidney disease
- L Darryl Quarles, MD
L Darryl Quarles, MD
- Section Editor — Renal Osteodystrophy
- Director, Division of Nephrology
- Associate Dean for Research
- The University of Tennessee Health Science Center
- Michael Berkoben, MD
Michael Berkoben, MD
- Associate Professor of Medicine
- Duke University Medical Center
The treatment of secondary hyperparathyroidism in chronic kidney disease (CKD) is based upon our understanding of the pathogenesis and clinical features of this disorder and the recognition that abnormal calcium and phosphate homeostasis may increase morbidity and mortality.
Because of the interdependence of calcium, phosphate, vitamin D, and parathyroid hormone (PTH), it is difficult to elucidate the individual contributions of each of the various causes of parathyroid gland dysfunction in patients with CKD. In addition, no single pharmacologic intervention is sufficient to completely restore disordered calcium and phosphate homeostasis in the setting of advancing deterioration of renal function.
The following topic review addresses issues related to the treatment of secondary hyperparathyroidism and mineral metabolism abnormalities (also referred to as chronic kidney disease-mineral bone disorder [CKD-MBD]) in patients with stage 3 to 5 CKD not yet on dialysis. Among patients with CKD but normal or near-normal kidney function (stage 1 to 2 CKD), issues related to bone disease and abnormalities in calcium and phosphorus levels are discussed separately. The treatment of secondary hyperparathyroidism in adult dialysis patients is also presented separately. (See "Overview of the management of osteoporosis in postmenopausal women" and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients".)
The pathogenesis of secondary hyperparathyroidism is also discussed separately. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Overview'.)
PATHOGENESIS OF SECONDARY HYPERPARATHYROIDISM
To understand the management of secondary hyperparathyroidism and mineral metabolism abnormalities in patients with CKD, it is important to understand the pathogenesis and clinical features of these disorders. This is discussed separately. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Overview' and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients", section on 'Clinical features'.)
- Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16:2205.
- Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol 2012; 23:1407.
- Chue CD, Townend JN, Moody WE, et al. Cardiovascular effects of sevelamer in stage 3 CKD. J Am Soc Nephrol 2013; 24:842.
- Schiavi SC, Tang W, Bracken C, et al. Npt2b deletion attenuates hyperphosphatemia associated with CKD. J Am Soc Nephrol 2012; 23:1691.
- Hill KM, Martin BR, Wastney ME, et al. Oral calcium carbonate affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease. Kidney Int 2013; 83:959.
- Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; :S1.
- Wetmore JB, Quarles LD. Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift? Nat Clin Pract Nephrol 2009; 5:24.
- Navaneethan SD, Palmer SC, Craig JC, et al. Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials. Am J Kidney Dis 2009; 54:619.
- Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 2013; 382:1268.
- Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005; 16:520.
- Dhingra R, Sullivan LM, Fox CS, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 2007; 167:879.
- Tonelli M, Sacks F, Pfeffer M, et al. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 2005; 112:2627.
- Eddington H, Hoefield R, Sinha S, et al. Serum phosphate and mortality in patients with chronic kidney disease. Clin J Am Soc Nephrol 2010; 5:2251.
- Tentori F, Blayney MJ, Albert JM, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2008; 52:519.
- Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15:2208.
- National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42:S1.
- Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 1985; 61:601.
- Russo D, Miranda I, Ruocco C, et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int 2007; 72:1255.
- Oliveira RB, Cancela AL, Graciolli FG, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 2010; 5:286.
- Zoccali C, Ruggenenti P, Perna A, et al. Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition. J Am Soc Nephrol 2011; 22:1923.
- Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol 2006; 1:825.
- Norris KC, Greene T, Kopple J, et al. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol 2006; 17:2928.
- KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013; 3:5.
- Al-Aly Z, Qazi RA, González EA, et al. Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD. Am J Kidney Dis 2007; 50:59.
- Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of ergocalciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease. Am J Nephrol 2007; 27:36.
- Kooienga L, Fried L, Scragg R, et al. The effect of combined calcium and vitamin D3 supplementation on serum intact parathyroid hormone in moderate CKD. Am J Kidney Dis 2009; 53:408.
- Kandula P, Dobre M, Schold JD, et al. Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol 2011; 6:50.
- Kramer H, Berns JS, Choi MJ, et al. 25-Hydroxyvitamin D testing and supplementation in CKD: an NKF-KDOQI controversies report. Am J Kidney Dis 2014; 64:499.
- Stubbs JR, Idiculla A, Slusser J, et al. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol 2010; 21:353.
- Hamdy NA, Kanis JA, Beneton MN, et al. Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure. BMJ 1995; 310:358.
- Slatopolsky E, Berkoben M, Kelber J, et al. Effects of calcitriol and non-calcemic vitamin D analogs on secondary hyperparathyroidism. Kidney Int Suppl 1992; 38:S43.
- Rix M, Eskildsen P, Olgaard K. Effect of 18 months of treatment with alfacalcidol on bone in patients with mild to moderate chronic renal failure. Nephrol Dial Transplant 2004; 19:870.
- Coyne D, Acharya M, Qiu P, et al. Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis 2006; 47:263.
- Ting SM, Iqbal H, Kanji H, et al. Functional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation. J Am Soc Nephrol 2014; 25:187.
- Kovesdy CP, Lu JL, Malakauskas SM, et al. Paricalcitol versus ergocalciferol for secondary hyperparathyroidism in CKD stages 3 and 4: a randomized controlled trial. Am J Kidney Dis 2012; 59:58.
- Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003; 349:446.
- Charytan C, Coburn JW, Chonchol M, et al. Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis 2005; 46:58.
- Chonchol M, Locatelli F, Abboud HE, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. Am J Kidney Dis 2009; 53:197.
- PATHOGENESIS OF SECONDARY HYPERPARATHYROIDISM
- OVERVIEW OF THERAPY
- Step 1
- Step 2
- Step 3
- Step 4
- GOAL TARGET LEVELS
- KDOQI target levels
- - Parathyroid hormone levels
- - Calcium and phosphate levels
- KDIGO guidelines
- - Laboratory values
- ASSESSMENT AND MONITORING
- TREATMENT OPTIONS
- Dietary phosphate restriction and phosphate binders
- - Dietary restriction
- - Phosphate binders
- Vitamin D, calcitriol, and vitamin D analogs
- Vitamin D deficiency
- Calcitriol and synthetic vitamin D analogs
- SUMMARY AND RECOMMENDATIONS