Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD):

Understanding the Clinical Burden and Current KDIGO Guideline Recommendations for Hyperphosphatemia

An illustration of kidneys

Hyperphosphatemia Is Highly Prevalent in Patients With CKD and Can Be Multicausal

Hyperphosphatemia Prevalence1,*

38% Prevelance over 5.5 mg/dL

*Among patients undergoing hemodialysis.
KDIGO=Kidney Disease: Improving Global Outcomes.

Common causes of Hyperphosphatemia2

CKD, Hypoparathyroidism, Pseudohyperphosphatemia, Excessive intake of phosphate, Excessive cellular injury†, Metabolic acidosis, and Vitamin D toxicity

†Rhabdomyolysis and tumor lysis syndrome.

Phosphate and Calcium Homeostasis3-8

Modulated through intestinal absorption, bone turnover and mineralization, and renal regulation.

Parathyroid hormone (PTH), calcitriol, and fibroblast growth factor 23 (FGF23) also play a key regulatory role.3,4

Parathyroid gland

Kidneys

Bone

GI=gastrointestinal (system); Ca=calcium; P=phosphate.

PTH stimulates bone resorption of phosphate and calcium. It also increases the elimination of phosphate and the retention of calcium4-6

Calcitriol promotes the absorption of dietary phosphate and calcium, stimulates bone resorption, and signals the kidneys to retain calcium.4,5,7

FGF23 signals the kidney to eliminate phosphate4

Dysregulation of Phosphate Worsens With CKD Progression

The capacity for phosphate filtration is reduced in the kidney of patients with CKD, leading to hyperphosphatemia.2-3

As CKD progresses(2-3), An arrow down for GFR and Phosphaturia, and an arrow up for Serum phosphate

Urinary phosphate excretion decreases as CKD progresses3

GFR=glomerular filtration rate.

Serum phosphate level increases as GFR decreases9,‡

‡An observational study of 1814 patients with CKD.

Hyperphosphatemia Is Associated With Increased Risk of Cardiovascular Disease, Mortality, and Bone Disease3,10

Associated Clinical Burdens With HP

CV=cardiovascular; HP=hyperphosphatemia.

KDIGO Guidelines Recommendations for the Management of Patients With CKD-MBD12

Management of phosphate levels for patients with CKD is important to avoid poor clinical outcomes. The KDIGO Guidelines offer recommendations for monitoring and managing levels towards the normal range.5,10

1

Diet

Illustration of various food items

Reduce phosphate intake

Phosphate intake should not exceed 1000 mg/day.

2

Dialysis

Illustration of a dialysis bag

Increase phosphate removal

3

Phosphate binders

Illustation of pills

Decrease intestinal absorption of phosphate

Upper body

Evaluate together over time10,#

  • Phosphate level
  • Calcium level
  • PTH level

#When considering treatment for CKD-MBD

Kidneys

Lower phosphate levels towards normal range10,**

  • Limit dietary phosphate intake (±other treatments)
  • Treatment decision should be based on the progression or persistency of elevated serum phosphate levels

**For CKD stage G3a (mildly to moderately decreased GFR) to G5D (kidney failure).

Thyroid

Avoid hypercalcemia10,††

  • Restricting the dose of calcium-based phosphate binders in patients receiving phosphate-lowering treatment††
  • Excess exposure to calcium may be harmful across all CKD stages

††In adult patients with CKD G3a-G5D.
‡‡In adult patients with CKD.

  • Evidence suggest higher calcium concentrations may be associated with increased mortality‡‡ and nonfatal cardiovascular events
  • The available evidence does not conclusively demonstrate that calcium-free phosphate binders are superior to calcium-based phosphate binders
References:
  1. United States Renal Data System. 2020 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2020.
  2. Shaman AM, Kowalskib SR. Hyperphosphatemia management in patients with chronic kidney disease. Saudi Pharm J. 2016;24(4):494–505.
  3. Ketteler M, Wüthrick RP, Floege J. Management of hyperphosphataemia in chronic kidney disease-challenges and solutions. Clin Kidney J. 2013;6(2):128-136.
  4. Stremke ER. Intestinal phosphorus absorption in chronic kidney disease. Nutrients. 2018;10:1364.
  5. Blaine F. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol. 2015;10(10): 1257–1272.
  6. Penido MG, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012;27(11):2039-2048.
  7. Bikle DD. Vitamin D and bone. Curr Osteoporos Rep. 2012;10(2):151–159.
  8. Ritter SC, Slatopolsky E. Phosphate toxicity in CKD: The killer among us. Clin J Am Soc Nephrol. 2016;11(6):1088–1100.
  9. 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(1):31-38.
  10. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. 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 (2011). 2017;7(1):1-59.
  11. 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(2):520-528.
  12. Vervloet MG, van Ballegooen AJ. Prevention and treatment of hyperphosphatemia in chronic kidney disease. Kidney Int. 2018;93(5):1060-1072.
  13. Lopes MB, Karaboyas A, Bieber B, et al. Impact of longer term phosphorus control on cardiovascular mortality in hemodialysis patients using an area under the curve approach: results from the DOPPS. Nephrol Dial Transplant. 2020;35(10):1794-1801.
  14. Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant. 2009;24(9):2792-2796.
  15. McNerny EMB, Nickolas TL. Bone Quality in Chronic Kidney Disease: Definitions and Diagnostics. Curr Osteoporos Rep. 2017;15(3):207-213.
  16. Nickolas TL, McMahon, Shane E. Relationship between moderate to severe kidney disease and hip fracture in the United States. J Am Soc Nephrol. 2006;17(11):3223-3232.