Guideline sources The following summarized guidelines for the evaluation and management of chronic kidney disease- mineral and bone disorder (CKD-MB) are prepared by our editorial team based on guidelines from the Japanese Society of Nephrology (JSN 2019), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2017; 2013; 2009), the Japanese Society of Dialysis Therapy (JSDT 2013), and the United Kingdom Kidney Association (UKKA 2011). 1 2 3 4 5 6 7 7 8 9 9 Definition CKD-MB is a systemic disorder of mineral and bone metabolism due to CKD. 7 Epidemiology The injured kidney produces circulating signals that directly affect the vasculature, myocardium, and skeleton. 9 Pathophysiology https://web.pathway.md/diseases/recdn5vnoWEQUgo40 1/8 6/29/23, 3:54 AM Chronic kidney disease-mineral and bone disorder Pathway Among patients with end-stage renal disease undergoing dialysis, the prevalence of CKD-MB is up to 86%. 8 Disease course CKD-MB manifests as abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, growth, or strength; and vascular or other soft-tissue calcification. 7 Prognosis and risk of recurrence Disruptions in bone architecture increase the risk of fracture, while vascular calcification promotes the development of LV hypertrophy, contributing to the excess cardiovascular risk and excess cardiac mortality seen in patients with CKD. 9 Guidelines 1. Diagnostic investigations Routine laboratory evaluation: As per KDIGO 2017 guidelines: Consider measuring serum PTH or bone-specific ALP for the evaluation of bone disease in patients with CKD stages 3-5D as markedly high or low values predict underlying bone turnover. C Consider measuring 25-hydroxyvitamin D levels in patients with CKD stages 3-5D and repeat testing determined by baseline values and therapeutic interventions. C As per JSDT 2013 guidelines, consider measuring serum phosphorus, calcium, albumin, PTH, and alkaline phosphate levels in the routine evaluation for CKD-mineral and bone disorder. C Show 2 more As per KDIGO 2013 guidelines, measure serum levels of calcium, phosphate, PTH, and ALP activity at least once in adult patients with GFR < 45 mL/min/1.73 m , in order to determine baseline values and inform prediction equations. B As per UKKA 2011 guidelines, consider monitoring serum levels of calcium, phosphate, ALP, PTH, and 25-hydroxyvitamin D in patients with CKD stages 3-5 and patients on dialysis, with a frequency based on stage, rate of progression, and whether specific therapies have been initiated. Bone-derived turnover markers: As per KDIGO 2017 guidelines, avoid obtaining bone-derived turnover markers of collagen synthesis (such as procollagen type I C-terminal propeptide) and breakdown (such as type I collagen cross-linked telopeptide, cross-laps, pyridinoline, or deoxypyridinoline) routinely in patients with CKD stages 3-5D. D https://web.pathway.md/diseases/recdn5vnoWEQUgo40 2/8 6/29/23, 3:54 AM Chronic kidney disease-mineral and bone disorder Pathway As per JSDT 2013 guidelines, consider measuring bone markers in patients with CKD stages 1- 2 and in patients with CKD stage 3 without biochemical abnormalities as in the general population. C Bone mineral density testing: As per KDIGO 2017 guidelines, consider obtaining bone mineral density testing to assess fracture risk if results will impact treatment decisions in patients with CKD stages G3a-G5D with evidence of CKD-mineral and bone disorder and/or risk factors for osteoporosis. C As per JSDT 2013 guidelines, consider obtaining bone mineral density testing in patients with CKD stages 1-2 and in patients with CKD stage 3 without biochemical abnormalities as in the general population. C As per KDIGO 2013 guidelines, avoid obtaining bone mineral density testing routinely in patients with CKD and an eGFR < 45 mL/min/1.73 m , as information may be misleading or unhelpful. D 2. Diagnostic procedures Bone biopsy: As per KDIGO 2017 guidelines: Consider performing a bone biopsy in patients with CKD stages G3a-G5D with biochemical abnormalities of CKD-mineral and bone disorder and low bone mineral density and/or fragility fractures. C Consider performing a bone biopsy in patients with CKD stages G3a-G5D if knowledge of the type of renal osteodystrophy will impact treatment decisions. As per JSDT 2013 guidelines: Consider performing a bone biopsy in patients with bone pain, recurrent pathological fracture, delayed healing of a bone fracture, any other bone symptoms requiring treatment, or bone conditions of unknown etiology. C Perform a bone biopsy in patients with predialysis CKD for the same indication as in patients receiving maintenance dialysis. 3. Medical management General principles: As per KDIGO 2017 guidelines, base treatment decisions on trends rather than on a single laboratory value in patients with CKD stages 3-5D, taking into account all available assessments. B Show 3 more As per JSDT 2013 guidelines, base therapeutic decisions on the trends of several measurements rather than a single result of laboratory tests. B Show 4 more https://web.pathway.md/diseases/recdn5vnoWEQUgo40 3/8 6/29/23, 3:54 AM Chronic kidney disease-mineral and bone disorder Pathway As per UKKA 2011 guidelines, make therapeutic decisions based on trends rather than a single laboratory value and take into account the entire available dataset rather than isolated variables. Treatment targets: As per JSDT 2013 guidelines, maintain serum phosphorus level in the target range of 3.5-6.0 mg/dL. Show 2 more As per UKKA 2011 guidelines, consider maintaining serum calcium, adjusted for albumin concentration, within the normal reference range for the laboratory used in patients with CKD stage 3-5. C Show 4 more Management of hyperphosphatemia: As per JSN 2019 guidelines: Consider administering phosphate binders to reduce the possibility of reducing progression to mortality in patients with non-dialysis CKD with hyperphosphatemia. C Consider administering non-calcium-containing phosphate binders to prevent progression to mortality and vascular calcification progression in patients with non-dialysis CKD with hyperphosphatemia. C As per KDIGO 2017 guidelines, consider lowering elevated phosphate levels toward the normal range in patients with CKD stages G3a-G5D. C Show 6 more As per JSDT 2013 guidelines, keep serum concentrations of phosphorus, corrected calcium, and PTH within the target ranges and control serum phosphorus as the highest priority, followed by calcium and then PTH. B Show 2 more Management of hyperparathyroidism: As per JSN 2019 guidelines, consider administering active vitamin D to lower PTH levels and reduce proteinuria in patients with non-dialysis CKD. Recognize that active vitamin D can cause hypercalcemia, thus, make therapeutic decisions on a case-by-case basis and start active vitamin D with small doses. Reduce or discontinue active vitamin D in case of hypercalcemia or worsening renal function. C As per KDIGO 2017 guidelines, consider evaluating patients with levels of intact PTH progressively rising or persistently above ULN for modifiable factors, including hyperphosphatemia, hypocalcemia, high phosphate intake, and vitamin D deficiency. C Show 4 more As per JSDT 2013 guidelines, consider setting the target range of intact PTH between 60 and 240 pg/mL. C Show 7 more As per UKKA 2011 guidelines, consider initiating treatment for hyperparathyroidism in patients with CKD stages 3b-5 when serum PTH levels are progressively increasing and remain https://web.pathway.md/diseases/recdn5vnoWEQUgo40 4/8 6/29/23, 3:54 AM Chronic kidney disease-mineral and bone disorder Pathway persistently higher than the upper reference limit for the assay, despite correction of modifiable factors. C Management of hypocalcemia: As per KDIGO 2017 guidelines, consider tolerating mild and asymptomatic hypocalcemia (in the context of calcimimetic treatment) in adult patients with CKD, in order to avoid inappropriate calcium loading. Consider correcting symptomatic or severe hypocalcemia to prevent adverse consequences, such as bone disease, hyperparathyroidism, and QTc interval prolongation. Show 2 more As per JSDT 2013 guidelines, consider administering calcium-containing phosphorus binders and/or oral vitamin D receptor activators and adjust their doses to control serum calcium levels. Show 4 more Management of vitamin D deficiency: consider correcting vitamin D deficiency and insufficiency using treatment strategies recommended for the general population. C Management of osteoporosis: As per JSN 2019 guidelines, consider administering anti-osteoporotic agents, such as active vitamin D, bisphosphonates, selective estrogen receptor modulators, teriparatide, and denosumab to reduce fracture risk in patients with non-dialysis CKD. C As per KDIGO 2017 guidelines, manage patients with CKD stages 1-2 with osteoporosis and/or high risk of fracture, as identified by the WHO criteria, as for the general population. B Show 2 more As per JSDT 2013 guidelines, manage osteoporosis in patients with CKD stage 1-2 meeting the criteria for the initiation of medications to prevent fragility fractures similar to the general population. A Consider using therapeutic strategies in patients with CKD stage 3 without biochemical abnormalities of CKD-mineral and bone disorder similar to recommendations for the general population. B As per KDIGO 2009 guidelines, avoid prescribing bisphosphonates without a strong clinical rationale in patients with GFR < 30 mL/min/1.73 m . D 4. Nonpharmacologic interventions Dietary phosphate restriction: As per KDIGO 2017 guidelines: Advise limiting dietary phosphate intake, alone or in combination with other therapeutic options, in the treatment of hyperphosphatemia in patients with CKD stages G3a-G5D. B Take into account phosphate sources (such as animals, vegetables, and additives) in making dietary recommendations. As per JSDT 2013 guidelines, advise dietary phosphorus restriction in order to maintain appropriate serum phosphorus B and PTH levels. Show 2 more https://web.pathway.md/diseases/recdn5vnoWEQUgo40 5/8 6/29/23, 3:54 AM Chronic kidney disease-mineral and bone disorder Pathway 5. Therapeutic procedures Percutaneous ethanol injection therapy: consider offering selective percutaneous ethanol injection therapy if only one parathyroid gland is enlarged and is located at a puncturable site. 6. Surgical interventions Indications for parathyroidectomy: As per KDIGO 2017 guidelines, consider performing parathyroidectomy in patients with CKD stages 3-5D with severe hyperparathyroidism failed to respond to pharmacological therapy. C As per JSDT 2013 guidelines, perform parathyroidectomy in patients with severe secondary hyperparathyroidism refractory to medical treatment. B 7. Specific circumstances Pediatric patients: As per JSN 2019 guidelines, treat CKD-mineral and bone disorder in pediatric patients with CKD to improve bone lesions and cardiovascular function. Consider maintaining the corrected serum levels of calcium and phosphorus within normal ranges in accordance with the patient's age. B As per KDIGO 2017 guidelines, consider maintaining serum calcium in the age-appropriate normal range in pediatric patients with CKD stages G3a-G5D. C Consider administering calcitriol and vitamin D analogs to maintain serum calcium levels in the age-appropriate normal range in pediatric patients. Show 3 more As per JSDT 2013 guidelines, consider starting monitoring of serum phosphorus, calcium, albumin, PTH, ALP, and bicarbonate ion concentration in stage 2 of CKD. C Show 4 more Kidney transplant recipients: As per KDIGO 2017 guidelines, consider measuring 25-hydroxyvitamin D levels in patients with chronic kidney stages 1-5T, and repeat testing determined by baseline values and interventions. C Show 7 more As per JSDT 2013 guidelines, manage bone and mineral metabolism adequately before kidney transplantation to achieve good control of mineral metabolism after transplantation. B Show 8 more Patients with vascular calcifications: As per KDIGO 2017 guidelines, consider using a lateral abdominal XR to detect the presence or absence of vascular calcification, and an echocardiography to detect the presence or absence of valvular calcification, as reasonable alternatives to CT-based imaging in patients with CKD stages 3-5D. C https://web.pathway.md/diseases/recdn5vnoWEQUgo40 6/8 6/29/23, 3:54 AM Chronic kidney disease-mineral and bone disorder Pathway As per JSDT 2013 guidelines, consider evaluating vascular calcification, whenever clinically necessary, since it is frequently observed in dialysis patients and is an important factor for prognosis. B Show 3 more Patients with dialysis-associated amyloidosis: Obtain radiological imaging to establish the diagnosis of bone complications associated with dialysis-related amyloidosis. B Consider offering properly modified blood purification therapy to retard the development of bone complications associated with dialysis-related amyloidosis. C 8. Follow-up and surveillance Serial laboratory monitoring, non-transplant: As per KDIGO 2017 guidelines, monitor serum levels of calcium, phosphorus, PTH, and ALP activity beginning in CKD stage 3. B As per JSDT 2013 guidelines, consider measuring serum phosphorus, calcium, and alkaline phosphate levels at intervals based on the CKD stage: Situation Guidance Every 6-12 months Stage 3 Every 3-6 months Stage 4 1-3 months. Stage 5 Show 3 more Serial laboratory monitoring (post-transplant): measure serum calcium and phosphorus at least weekly in patients in the immediate post-kidney-transplant period until stable. B Clinical findings Symptoms Past medical history Bone pain Bone fracture Diffuse aches CKD Joint pain Osteoporosis Vitamin D deficiency Anthropomorphic exam Lab findings Growth restriction Hypocalcemia PTH https://web.pathway.md/diseases/recdn5vnoWEQUgo40 7/8 6/29/23, 3:54 AM Chronic kidney disease-mineral and bone disorder Pathway serum ALP h h t Studies 2012 EVOLVE In patients with moderate-to-severe secondary hyperparathyroidism (median level of intact PTH, 693 pg/mL) who were undergoing hemodialysis, cinacalcet was not superior to placebo with respect to death, myocardial infarction, hospitalization for unstable angina, HF, or a peripheral vascular event. EVOLVE Trial Investigators et al. N Engl J Med. 2012 Dec 27. References 1. KDIGO Executive Committee. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. KDIGO. 2013 Jan;3 1 . Open 2. Masafumi Fukagawa, Keitaro Yokoyama, Fumihiko Koiwa et al. Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder. Ther Apher Dial. 2013 Jun;17 3 247 88. Open 3. 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. 2017 Jul;7 1 1 59. Open 4. Simon Steddon, Edward Sharples. Renal Association Clinical Practice Guideline in mineral and bone disorders in CKD. Nephron Clin Pract. 2011;118 Suppl 1:c145 52. Open 5. 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 Aug; 113 S1 130. Open 6. Japanese Society of Nephrology. Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018. Clin Exp Nephrol. 2019 Jan;23 1 1 15. Open 7. Ranjani N Moorthi, Sharon M Moe. CKD-mineral and bone disorder: core curriculum 2011. 2011 Dec;58 6 1022 36.2011 Dec;58 6 1022 36. Open 8. Shen Hui Chuang, Hung Chew Wong, Anantharaman Vathsala et al. Prevalence of chronic kidney disease-mineral and bone disorder in incident peritoneal dialysis patients and its association with short- term outcomes. 2016 Nov;57 11 603 609.2016 Nov;57 11 603 609. Open 9. Keith A Hruska, Toshifumi Sugatani, Olga Agapova et al. The chronic kidney disease Mineral bone disorder CKD MBD Advances in pathophysiology. 2017 Jul;100 80 86.2017 Jul;100 80 86. Open 10. Ketteler M, Block GA, Evenepoel P et al. Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update. 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