Click HERE to view the Symposium on the Virtual Meeting

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Vifor Fresenius Medical Care

The decline of kidney function in CKD patients is accompanied by progressive disruption of serum concentrations of phosphate and calcium, as well as changes in circulating levels of parathyroid hormone (PTH) and calcitriol, eventually leading to disorders of bone metabolism and vascular calcifications. The condition is termed chronic kidney disease-mineral and bone disorder (CKD-MBD) to describe the broader clinical syndrome encompassing mineral, bone, parathyroid, and cardiovascular abnormalities that develop as a complication of CKD (1, 2). It contributes extensively to increased morbidity and mortality of CKD patients and still represents a major treatment challenge in nephrology, even though therapeutic strategies for hyperphosphatemia and secondary hyperparathyroidism (SHPT) have been established.
The 2020 ERA-EDTA virtual conference offered an opportunity to share the latest expert views on the current and future management of hyperphosphatemia and SHPT in CKD patients. At the virtual panel meeting, chaired by dr Smeeta Sinha, professor Mario Gennaro Cozzolino and professor Kamyar Kalantar-Zadeh shared insights on the management of SHPT and views on the relationship between serum phosphate control and protein intake.

Evolving opportunities to optimize SHPT management
SHPT may occur as early as in stage 2 CKD, followed by disturbances in serum calcium and phosphate levels, which, themselves, appear later in the course of the disease (3). Since SHPT is independently associated with an increased risk of bone fractures, vascular events and mortality, and its rise prior to the initiation of dialysis is predictive of more difficult management of SHPT later on dialysis, early recognition of this condition and adequate action are mandatory (4, 5).

Another important issue affecting non-dialysis patients is vitamin D insufficiency, which affects an estimated 71-89% of patients with CKD stage 3 to 5 (6). Vitamin D is a key player in the regulation of calcium and phosphate levels, and may also have a renoprotective role and reduce mortality (6). Low vitamin D levels promote the progression of SHPT via multiple pathways, as presented in Figure 1.

Figure 1. The complex pathways of progression of secondary hyperparathyroidism (2, 3)

The latest KDIGO guidelines for the diagnosis, evaluation, prevention and treatment of CKD-MBD suggest the optimum PTH level for patients on dialysis, but have no target PTH level as yet for the non-dialysis CKD patients. The current approach to this population is based on careful monitoring and acting when PTH progressively rises and persistently stays above the upper limit of normality. Even though there are several available vitamin D based therapies on the market, not all of them are indicated and suitable for the treatment of SHPT in CKD patients (8).

Nutritional vitamin D can correct vitamin D levels to a certain degree, but fails to consistently reduce PTH levels (9). Active vitamin D analogs, on the other hand, modify PTH, but are associated with an increased risk of hypercalcemia (10, 11, 12). Thus, the KDIGO guidelines no longer recommend routine use of calcitriol and active vitamin D analogs in non-dialysis CKD 3-5 patients (7). As for calcimimetics, they are currently recommended, either alone or combined with vitamin D analogs, only in the treatment of SHPT in dialyzed patients (7). The currently available SHPT treatments and their effects on calcium, phosphorus, vitamin D and PTH are summarized in Figure 2.


Figure 2. Current treatment options for secondary hyperparathyroidism in chronic kidney disease (13-17)

Recent clinical studies evaluated a novel SHPT therapy, the extended-release calciferol (ERC), which gradually increases serum total 25-hydroxyvitamin D (14, 15, 18). According to the latest results, a once daily dose ERC provided gradual rise of 25-hydroxyvitamin D, resulting in a physiologically controlled increase in serum 1,25D and a sustained reduction of PTH in patients with CKD stages 3 to 4, with minimal effects on serum calcium and phosphate levels, suggesting that it is a safe and effective treatment option for SHPT in CKD patients (15, 18). An especially important observation was that ERC therapy produced 25-hydroxyvitamin D level dependent reductions in plasma iPTH and bone turnover markers when mean serum total 25-hydroxyvitamin D reached at least 50.8 ng/mL, indicating that CKD patients may require higher vitamin D target levels than those currently recommended (19). Furthermore, ERC exhibited similar encouraging efficacy results with a favorable safety profile in a real world setting as in the clinical trials (20). Of note, ERC is currently licensed in the USA and Canada, but marketing authorization is pending for countries in Europe.

Effective control of hyperphosphatemia: the phosphate-protein dilemma
Disorders of mineral metabolism are well-known and potentially modifiable risk factors for all-cause and cardiovascular mortality in dialysis patients (21-23). An especially strong association has been observed between mortality and high serum phosphorus levels in these patients, calling for special consideration in the management of hyperphosphatemia. The KDOQI guidelines recommend target serum phosphorus levels between 1.1 and 1.78 mmol/l (3.5-5.5 mg/dl), while KDIGO guidelines suggest even lower upper threshold (7, 23). Interestingly, low phosphorus levels are observed in older hemodialysis patients, in whom it is associated with increased mortality, thus raising the question of whether this was an effect of lower protein intake which is commonly associated with older age (24). Furthermore, it seems that residual kidney function also has a substantial impact on the mortality risk associated with serum phosphorus among HD patients, with higher residual renal urea clearance associated with higher serum phosphorus and higher mortality (25).

The knowledge about the mechanisms involved in phosphorus homeostasis in CKD patients is constantly improving. In healthy persons, about 60 to 80% of ingested phosphorus is absorbed through the gastrointestinal tract, and most of it is removed by the kidneys. However, in dialysis patients, phosphorus absorption is difficult to quantitate as the dialysis treatments complicate metabolic balance studies (26). Furthermore, vitamin D therapy and hyperparathyroidism also have an important effect on the absorption rate (27, 28).

The currently recommended daily phosphorus intake is 1000mg for healthy persons, and <800mg for CKD patients (27). The main food sources of phosphorus are the protein-rich food groups, including dairy products, meat, and fish, thus emphasizing the important liaison between protein intake and phosphorus burden (29). Namely, to comply with the recommended daily phosphorus intake of <800mg, one should only ingest 50-60g of protein per day. This may represent a challenge for some patients, as recommended protein intake for dialysis patients is >1g/kg/day. In addition to the absolute amount of dietary phosphorus, its type (organic versus inorganic) and source (animal versus plant-derived) may also be important (Figure 1). The rate of phosphorus absorption varies from 20-40% from plant-based sources, to 40-60% from animal proteins. Inorganic phosphorus, present in processed, preserved, or enhanced foods or soft drinks that contain additives, in which phosphorus is not bound to proteins, is much more readily absorbed, at a rate of 90 to 100%. The main implication of this for patient management is that the phosphorus burden from food additives may be disproportionately higher relative to organic sources, thus shifting the focus from the strict protein restriction to avoiding processed food (29).

Figure 3. Dietary sources of phosphorus (30)


Even though numerous studies have shown that decreased dietary protein intake is longitudinally associated with increased mortality risk in hemodialysis patients, the current recommendations for daily protein intake for this patient group remain at 1.2g/kg, in an attempt to avoid the phosphate burden (31, 32). Considering these facts, the nephrologists nowadays are faced with a conundrum of whether controlling phosphorus by decreasing dietary protein intake is beneficial or harmful to their CKD patients. Studies show that the risk of controlling serum phosphorus by restricting dietary protein intake may outweigh the benefit of controlled phosphorus, and lead to greater mortality (33, 34). One possible way to effectively control the phosphorus level without imposing strict dietary restrictions is to use phosphorus binders (35, 36). However, a possible obstacle for successful application of this measure may be the pill burden, since dialysis patients take an average of 12 to 19 medications and phosphate binders may make up to up to half of this number (37). In recent years, however, new binders have been introduced that require a lower daily number of pills with comparable binding capacity, thus possibly offering a solution to the problem of reducing phosphate burden without excessive limiting of protein intake (38). Namely, sucroferic oxyhydroxide exhibited high potency in long-term maintaining of KDOQI target phosphate levels with low pill burden and flexible administration, and thus higher compliance. This, in turn, allowed for higher protein intake and less wasting from dietary restrictions, offering patients more freedom in their dietary intake and food choice without increasing the morbidity and mortality risks (39-46).


1. KDIGO clinical practice guidelines for the diagnosis, evaluation, prevention and treatment of CKD-MBD. Kidney Int 2009;76(Suppl 113):S1-S130.

2. Cunningham J, Locatelli F, Rodriguez M. Secondary Hyperparathyroidism: Pathogenesis, Disease Progression, and Therapeutic Options. Clin J Am Soc Nephrol 2011;6:913-921.

3. Levin A, Bakris GL, Molitch M, et al. 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 2007; 71:33-38.

4. Geng S, Kuang Z, Pleissig PL, Page D, Maursetter L, Hansen KE. Parathyroid Hormone Independently Predicts Fracture, Vascular Events, and Death in Patients With Stage 3 and 4 Chronic Kidney Disease Osteoporosis Int 2019;30:2019-2025.

5. Young EW et al. Abstract FR-PO128, presented at ASN 2019, 5-10 Nov 2019, Washington, DC; USA.

6. Doorenbos CR, van den Born J, Navis G, de Borst MH. Possible Renoprotection by Vitamin D in Chronic Renal Disease: Beyond Mineral Metabolism. Nat Rev Nephrol 2009;5:691-700.

7. 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 2017;(Suppl)7:1-59.

8. Cozzolino M, Kettler M. Evaluating extended-release calcifediol as a treatment option for chronic kidney disease-mineral and bone disorder (CKD-MBD). Expert Opin Pharmacother 2019;20(17):2081-2093.

9. Zoccali C, Mallamaci F. Moderator’s view: Vitamin D deficiency treatment in advanced chronic kidney disease: a close look at the emperor’s clothes. Nephrol Dial Transplant 2016;31:706-713

10. Csomor Poster presentation at ISPOR Europe, 2019.

11. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease: The PRIMO Randomized Controlled Trial JAMA 2012;307(7):674-684.

12. Wang A, Fang F, Chan J, et al. Effect of Paricalcitol on Left Ventricular Mass and Function in CKD—The OPERA Trial J Am Soc Nephrol 2014;25:175-186

13. Block GA, Bushinsky DA, Cheng S, et al. Effect of Etelcalcetide vs Cinacalcet on Serum ParathyroidHormone in Patients Receiving HemodialysisWith Secondary Hyperparathyroidism – A Randomized Clinical Trial JAMA 2017;317:156-164.

14. Sprague SM, Strugnell SA, Bishop CW. Extended-release calcifediol for secondary hyperparathyroidism in stage 3-4 chronic kidney disease Exp Rev Endocrinol Metab 2017;12:289-301.

15. Petkovich M, Melnick J, White S, et al. Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation. J Steroid Biochem Mol Biol 2015;148:283-289.

16. Chertow GM, Block GA, Correa-Rotter R, et al. Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis N Engl j Med 2012;367:2482-2494.

17. Moe SM, Chertow GM, Parfrey PS, et al. The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation 2015;132:27-39.

18. Sprague SM, Crawford PW, Melnick JZ, et al. Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease Am J Nephrol 2016;44(4):316-325.

19. Strugnell SA, Sprague SM, Ashfaq A, Petkovich M, Bishop CW. Rationale for Raising Current Clinical Practice Guideline Target for Serum 25-Hydroxyvitamin D in Chronic Kidney Disease Am J Nephrol 2019;49:284

20. Fadda G. Poster #206, presentation at the national Kidney Foundation virtual congress, March 26-29, 2020.

21. Block GA, Klassen PS, Lazarus MJ, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004;15:2208-2218.

22. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 2006;70:771

23. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003;42(4 Suppl 3):S1-201.

24. Lertdumlongruk P, Rhee CM, Park J, et al. Association of serum phosphorus concentration with mortality in elderly and nonelderly hemodialysis patients. J Ren Nutr 2013;23:411-421.

25. Wang M, Obi Y, Streja E, et al. Association of parameters of mineral bone disorder with mortality in patients on hemodialysis according to level of residual kidney function. Clin J Am Soc Nephrol 2017;12:1118-1127.

26. Ramirez JA, Emmett M, White MG, et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int 1986;30:753-759.

27. Kalantar-Zadeh K, Fouque D. Nutritional management of chronic kidney disease. New Engl J Med 2017;377:1765-1776.

28. Streja E, Lau WL, Goldstein L, et al. Hyperphosphatemia is a combined function of high serum PTH and high dietary protein intake in dialysis patients. Kidney Int Suppl 2013:3;462-468.

29. Kalantar-Zadeh K, Gutekunst L, Mehrotra R, et al. Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease. Clin J Am Soc Nephrol 2010;5:519-530.

30. Cupisti A, Kalantar-Zadeh. Management of natural and added dietary phosphorus burden in kidney disease. Semin Nephrol 2013;33:180-190.

31. Shinaberger CS, Kilpatrick RD, Regidor DL, et al. Longitudinal associations between dietary protein intake and survival in hemodialysis patients. Am J Kidney Dis 2006;48:37-49.

32. Eriguchi R, Obi Y, Streja E, et al. Longitudinal associations among renal urea clearance–corrected normalized protein catabolic rate, serum albumin, and mortality in patients on hemodialysis. Clin J Am Soc Nephrol 2017;12:1109-1117.

33. Shinaberger C, Greenland S, Kopple JD, et al. Is controlling phosphorus by decreasing dietary protein intake beneficial or harmful in persons with chronic kidney disease? Am J Clin Nutr 2008;88:1511-1518.

34. Lynch KE, Lynch R, Cuhran GC, et al. Prescribed dietary phosphate restriction and survival among hemodialysis patients. Clin J Am Soc Nephrol 2011;6:620-629.

35. Isakova T, Gutierrez OM, Chang Y, et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol 2009;20:388-396.

36. Kovesdy CP, Kuchmak O, Lu JL, et al. Outcomes associated with phosphorus binders in men with non–dialysis-dependent CKD. Am J Kidney Dis 2010;56:842-851.

37. Manley HJ, Garvin CG, Drayer DK et al. Medication prescribing patterns in ambulatory haemodialysis patients: comparisons of USRDS to a large not-for-profit dialysis provider. Nephrol Dial Transplant 2004;19:1842-1848.

38. Gutekunst L. An update on phosphate binders: a dietitian’s perspective. J Renal Nutrition 2016;26:209-218.

39. Floege J, Covic AC, Ketteler M, et al. Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients Nephrol Dial Transplant 2015;30:1037-1046

40. Koiwa F, Yokoyama K, Fukagawa M, Akizawa T. Long-Term Assessment of the safety and efficacy of PA21 (Sucroferric Oxyhydroxide) in Japanese hemodialysis patients with hyperphosphatemia: An Open-Label, Multicenter, Phase III Study. J Ren Nutr 2017;27:346-354.

41. Floege J, Covic AC, Ketteler M, et al. A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients Kidney Int 2014;86:638-647.

42. Coyne DW, Ficociello LH, Parameswaran V, et al. Real-world effectiveness of sucroferric oxyhydroxide in patients on chronic hemodialysis: a retrospective analysis of pharmacy data. Clin Nephrol 2017;2:59-67.

43. Kendrick J, Parameswaran V, Ficociello LH, et al. One-year historical cohort study of the phosphate binder Sucroferric Oxyhydroxide in patients on maintenance hemodialysis. J Ren Nutr 2019;29:428-437

44. Gray K, Ficociello LH, Hunt AE, et al. Phosphate binder pill burden, adherence, and serum phosphorus control among hemodialysis patients converting to sucroferric oxyhydroxid. Int J Nephrol Renovasc Dis 2019;12:1-8.

45. Eriguchi R, obi Y, Streeja E, et al. Longitudinal associations among renal urea clearance–corrected normalized protein catabolic rate, serum albumin, and mortality in patients on hemodialysis Clin J Am Soc Nephrol 2017;12:1109-1117.

46. Kalantar-Zadeh K, Ficociello LH, Parameswaran V, et al. Changes in serum albumin and other nutritional markers when using sucroferric oxyhydroxide as phosphate binder among hemodialysis patients: a historical cohort study. BMC Nephrol 2019;20:396.

NDT-E Summary Articles