Nephrology Hypertension

Medical Management of the Dialysis Patient: Secondary Hyperparathyroidism

Does this patient have secondary hyperparathyroidism?

Overview of diagnosis

  • Elevation in parathyroid hormone (PTH) levels secondary to mineral metabolism abnormalities that accompany CKD

  • KDOQI definition: intact PTH levels above the 150-300 pg/ml range

  • KDIGO definition: intact PTH levels above 2-9 times the upper normal limit for the intact PTH assay

  • Usually diagnosed by routine lab tests performed in the context of longitudinal CKD/dialysis care

  • Nearly universal complication of ESRD

  • Part of the laboratory component of CKD-MBD

Key elements in the history

  • Usually diagnosed by routine lab tests performed in the context of longitudinal CKD/dialysis care

  • Classically accompanies other mineral metabolism abnormalities: hyperphosphatemia, hypocalcemia, vitamin D deficiency

Key symptoms

  • Bone/muscle pain

  • Weakness, limited mobility, postural instability

  • Fractures

  • Pruritus

Key signs and physical findings

  • Calciphylaxis

  • Vascular calcification on imagining

  • Brown tumors

Other diseases or syndromes with similar appearances

  • Primary hyperparathyroidism: PTH is secreted from parathyroid adenomas autonomously and not in response to physiologic stimuli

  • Tertiary hyperparathyroidism: autonomous PTH secretion from parathyroid tissue in patients with prior history of secondary hyperparathyroidism; is typically unresponsive to physiologic stimuli

Controversies in the differential diagnosis

  • Differences in cut off values according to KDIGO/KDOQI

    • KDOQI cut off based on second generation PTH assay

    • KDIGO cut off is more flexible, allows for variability between available PTH assays in use

What tests to perform?

Lab testing

Tests to order

  • Intact PTH

  • Serum calcium

  • Serum phosphate

  • 25-hydroxyvitamin D

How to interpret test results?

  • KDIGO: emphasis on overall trend and not a single value

How often to order tests?

  • KDOQI: every 3 months for PTH, every month for serum calcium and phosphate; more frequently if therapy is being titrated

  • KDIGO: every 3-6 months for PTH, every 1-3 months for serum calcium and phosphate

What are the next steps?

  • Response to treatment will determine subsequent management

Imaging

  • Radionucleotide scanning of parathyroid glands may be used by some surgeons prior to planning parathyroidectomy

  • Detection of vascular calcification on imaging for other reasons may influence treatment decisions

    • vascular calcification --> avoidance of calcium based binders

  • No good imaging study to assess renal bone disease

Biopsy

  • Bone biopsy considered gold standard for diagnosing renal bone disease

  • Not available in most clinical settings

Overall Interpretation of test results

  • Diagnosis

    • Typically not difficult to make, often precedes dialysis initiation

  • Prognosis

    • Response to treatment will determine subsequent management

    • Severe and resistant hyperparathyroidism may necessitate medical (cinalcet) or surgical parathyroidectomy

Controversies in diagnostic testing

  • Differences in cut off values according to KDIGO/KDOQI

    • KDOQI cut off based on second generation PTH assay

    • KDIGO cut off is more flexible, allows for variability between available PTH assays in use

How should patients with secondary hyperparathyroidism be managed?

Overview of key treatment concepts

  • Medical therapy includes calcium supplementation, dietary phosphorus restriction, oral phosphate binders, active vitamin D analogs, calcimimetics

  • surgical removal with severe secondary hyperparathyroidism

What to do first

  • Obtain/review additional tests including

    • Serum calcium

    • Serum phosphate

    • 25-hydroxyvitamin D

    • PTH trend

  • Review current medications, compliance with medication regimen, dialysis prescription, dietary intake

Next steps

  • Control hyperphosphatemia

    • Dietary phosphorus restriction

    • Oral phosphate binders

    • Maximize dialysis adequacy

  • Maintain adequate calcium levels

  • Active vitamin D analogs

  • Consider nutritional vitamin D repletion if deficient

Specific circumstances

  • Severe secondary hyperparathyroidism

    • Cinacalcet

    • Parathyroidectomy

      • ▪ KDOQI: parathyroidectomy indicated when PTH levels are persistently above 800 pg/ml, are associated with hypercalcemia and/or hyperphosphatemia that are refractory to medical therapy

      • ▪ KDIGO: severe hyperparathyroidism with failure to respond to medical therapy

  • Calciphylaxis

    • Sometimes also managed with parathyroidectomy especially if severe and refractory hyperparathyroidism is present

Controversies in patient management

  • Cinacalcet with low dose vitamin d vs. vitamin D alone

  • Calcium based phosphate binders vs. non-calcium based binders

  • Non-calcium based binders + D vs. calcium based binders + cinacalcet

  • When is it appropriate to hold vitamin D?

  • Should dialysate calcium be titrated down to be able to use calcium-based binders?

What happens to patients with secondary hyperparathyroidism?

Natural history

  • Secondary hyperparathyroidism is a nearly universal complication of CKD

  • Recent discoveries have resulted in reformulation of pathogenetic mechanisms

  • Traditional view encompasses phosphate retention, calcitriol deficiency due to decreasing renal mass and hypocalcemia as triggers for PTH release

  • The discovery of fibroblast growth factor 23, a phosphate and vitamin D regulating hormone, has led to a reformulation of the traditional framework

    • FGF23 is an endocrine hormone that is produced by osteocytes

    • FGF23 secretion is increased when dietary phosphorus intake is increased or when renal phosphate excretion is impaired, as in CKD

    • Effector organs of FGF23 are the kidney and parathyroid glands

    • In the kidney FGF23

      1. Decreases proximal tubular reabsorption of phosphate --> increased fractional excretion of phosphate

      2. Inhibits 1-alpha-hydroxylase --> decreased levels of calcitriol

      3. Stimulates 24-hydroxylase --> decreased levels of storage and active vitamin D

    • In the parathyroid gland FGF23 inhibits PTH secretion, though with progressive CKD/ESRD there is resistance to this FGF23 action at the level of the parathyroid

  • Updated view therefore implicates increased FGF23 secretion in CKD as the primal pathogenic event that leads to calcitriol deficiency and secondary hyperparathyroidism

    • Classic studies of children with CKD in whom secondary hyperparathyroidism was reversed and calcitriol levels normalized following dietary phosphorus restriction support this paradigm

    • Other supportive studies include experimental studies with animal models of CKD and use of FGF23 antibodies, observational studies of patients with early CKD

  • On dialysis, once secondary hyperparathyroidism is established disturbances in calcitriol, calcium and phosphate levels potently induce PTH secretion

Epidemiology

  • PTH and outcomes

    • Elevations associated with adverse outcomes

    • Meeting of KDOQi targets associated with improve outcomes

    • Meta-analysis

  • Treatment with vitamin D and outcomes

    • Associated with improved survival

  • Treatment with binders and outcomes

    • Associated with improved survival

Anatomic and/or pathologic consequences

  • Bone disease

  • Exacerbation of anemia/epo resistance

Physiologic and/or pathophysiologic implications

  • Tertiary hyperpara and hypercalcemia

Pharmacologic considerations

  • Paricalcitol - vitamin D analog that potentially causes less hypercalcemia and hyperphosphatemia

  • Dose titration of phosphate binders and or switching to an alternate class may be required in the event hypercalcemia develops on therapy

How to utilize team care?

Specialty consultations

  • Surgeons; consulted for parathyroidectomy

  • If bone biopsy is available, pathologists assist in interpretation of results

Nurses

  • Administer IV vitamin D

  • Assist in medication compliance and education

Dietitians

  • Review dietary intake and provide dietary counseling

  • Assist in phosphate binder compliance and education

Are there clinical practice guidelines to inform decision making?

Applications

  • Detailed above under each section

Limitations

  • KDOQI guidelines written in 2003

  • KDIGO more updated, incorporate newer data, but still limited by lack of data from randomized controlled trials

What is the evidence?

Nassar, GM, Ayus, JC. "Images in clinical medicine. Brown tumors in end-stage renal disease". N Eng J Med. vol. 341. 1999. pp. 1652.

(This article contains images of brown tumors in end-stage renal disease.)

Sprague, SM, cCoyne, D. "Control of secondary hyperparathyroidism by vitamin D receptor agonists in chronic kidney disease". CJASN. vol. 5. 2010. pp. 512:518.

(This review summarizes the data on use of active vitamin D analogs in chronic kidney disease and provides practical considerations for use in the clinical setting.)

Wolf, M. "Forging forward with 10 burning questions on FGF23 in kidney diseas". JASN. vol. 21. 2010. pp. 1427:35.

(This review summarizes the findings on the role of FGF23 in chronic kidney disease.)

Portale, AA, Booth, BE, Halloran, BP, Morris, RC. "Effect of dietary phosphorus concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency". JCI. vol. 73. 1984. pp. 1580-9.

(This report describes the effect of dietary phosphate restriction on disordered mineral metabolism in children with chronic kidney disease.)

Hasegawa, H, Nagano, N, Urakawa, I, Yamazaki, Y, Iijima, K, Fujita, T, Yamashita, T, Fukumoto, S, Shimad, T. "Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease". Kidney Int. vol. 78. 2010. pp. 975-980.

(This report elegantly documents the central role of FGF23 in disordered mineral metabolism in chronic kidney disease.)

Chertow, GM, Block, GA, Correa-Rotter, R, Drüeke, TB, Floege, J, Goodman, WG, Herzog, CA, Kubo, Y, London, GM, Mahaffey, KW, Mix, TC, Moe, SM, Trotman, ML, Wheeler, DC, Parfrey, PS. "Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis". N Engl J Med. vol. 367. 2012. pp. 2482-94.

Bushinsky, DA, Block, GA, Martin, KJ, Bell, G, Huang, S, Sun, Y, Spiegel, DM, Walsh, L, Mix, TC, Kewalramani, R. "Treatment of Secondary Hyperparathyroidism: Results of a Phase 2 Trial Evaluating an Intravenous Peptide Agonist of the Calcium-Sensing Receptor". Am J Nephrol. vol. 42. 2015. pp. 379-88.

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