Does this patient have hypercalcemia?

Key elements in the history

Diagnosed through routine labs
If severe may be associated with symptoms (see below)
Typically accompanied with other mineral metabolism abnormalities

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May be a consequence or may be exacerbated by therapy used to treat disordered mineral metabolism
An indicator of severity of secondary hyperparathyroidism

Key symptoms

Classic symptoms related to hypercalcemia include:

bone pain

anxiety, depression, confusion, drowsiness, decreased level of consciousness

loss of appetite, nausea, constipation

muscle weakness

Key signs and physical findings

Classic signs related to hypercalcemia include:

Shortened QT interval

Hypertension

Arrhythmias and bradycardia

Vascular, valvular and soft tissue calcification

Calciphylaxis

Other diseases or syndromes with similar appearances

Recognize that other medical conditions could cause hypercalcemia in a dialysis patient, including

Cancer
Primary hyperparathyroidism

Controversies in the differential diagnosis

Kidney Disease Outcomes Quality Initiative: corrected total Ca levels should be maintained within the lower end of normal (8.4 – 9.5 mg/dl); hypercalcemia defined as corrected total calcium of > 10.2 mg/dl
Kidney Disease: Improving Global Outcomes: maintain Ca levels within the normal range

What tests to perform?

Lab Testing

Which tests should I order?

Total calcium, serum albumin, intact PTH,serum phosphate
Ionized calcium may be helpful to confirm diagnosis

How do I interpret test results?

Kidney Disease Outcomes Quality Initiative: emphasis on corrected total calcium levels, and some consideration to calcium-phosphorus product
Kidney Disease: Improving Global Outcomes: trend more important than single values

How often should I order test?

Kidney Disease Outcomes Quality Initiative: every 3 months; more frequent (every month) with adjustments of therapy
Kidney Disease: Improving Global Outcomes: every 1-3 months; more frequent with adjustments of therapy

What are the next steps?

Response to therapeutic changes will determine next steps
If hypercalcemia is resistant to therapeutic changes and accompanied by severe hyperparathyroidism, parathyroidectomy may be indicated

Imaging

If parathyroidectomy is being considered, imaging (sestamibi scan most sensitive) may be used to delineate parathyroid gland anatomy.

Overall Interpretation of test results

Diagnosis should be based on trend rather than single values, and consideration should be given to other mineral metabolites (Phosphate, PTH).

Prognosis dependent on initial or past response to therapy.

Controversies in diagnostic testing

Kidney Disease Outcomes Quality Initiative recommends stricter adherence to normal levels; allows use of active D only if levels of calcium are within the low normal range; also with some emphasis on calcium-phosphorus product

Kidney Disease: Improving Global Outcomes recommends a bit more lenient adherence to normal range and greater emphasis on overall trend rather than single abnormal values; importance of calcium-phosphorus product is deemphasized, though both calcium and phosphate levels should be monitored and both considered comprehensively when making therapeutic decisions

How should patients with hypercalcemia be managed?

Key treatment concepts

What to do first

Recognize that other reasons for hypercalcemia (outside of bone mineral metabolism disorders) could exist; ensure that these are ruled out

Medication adjustments:

Kidney Disease Outcomes Quality Initiative: reduce dose Ca-based phosphate binders, or switch to non-calcium binder; discontinue vitamin D analogs until total corrected serum calcium returns to the target range (8.4 – 9.5 mg/dl)
Kidney Disease: Improving Global Outcomes: restrict dose of ca-based phosphate binders; and/or dose of vitamin D analog
Dialysate calcium adjustments:

Kidney Disease Outcomes Quality Initiative: if hypercalcemia persists, low dialysis calcium (1.5 to 2.0 mEq/L) should be used for 3-4 weeks

Kidney Disease: Improving Global Outcomes: general recommendation to maintain dialysate calcium between 2.5 to 3.0 mEq/L but not higher; provision for individualization of prescription for different patient. Dialysate calcium of 2.5 mEq/L thought to maintain neutral balance.

Next steps

Surgical treatment, especially if accompanied by severe secondary hyperparathyroidism and resistant to treatment
Medical parathyroidectomy: cinacalcet may be tried prior to surgery

Specific circumstances

Severe hyperparathyroidism: as above
Calciphylaxis: if resistant to medical therapy, including cinacalcet, parathyroidectomy has been tried in some cases, especially if caciphylaxis is accompanied by severe hyperparathyroidism

Controversies in patient management

Due to insufficient knowledge on the state of calcium balance in a dialysis patient receiving therapy for mineral metabolism abnormalities, there are controversies as to the appropriate combination of available agents to use to manage the disorder. Some argue that it is best to prevent abnormalities in serum levels by using products that are less likely to cause hypercalcemia; while others argue that given the observational data that suggest survival benefit for vitamin D and any phosphate binders that less attention should be paid to serum levels. Possible combinations, without high-level evidence, are listed below.

low dialysis calcium bath and Ca-based phosphate binders

low dose vitamin D and Ca-based binders with cinacalcet (cinacalcet lowers calcium levels)

non-ca based binders with full dose vitamin D
Proponents of use of active vitamin D analogs suggest that it may not be appropriate to withhold vitamin D completely when serum calcium levels are elevated. They advocate use of lower dose of vitamin D analogs. In support of this approach is a recent meta-analysis that shows that serum calcium levels do not predict outcomes in patients with chronic kidney disease.

What happens to patients with hypercalcemia?

Natural history, anatomic and/or pathologic consequences, physiologic and/or pathophysiologic implications

Normal physiology

PTH levels are tightly regulated by serum calcium
additional regulators include serum phosphate, calcitriol levels, FGF23

Genesis and maintenance of secondary hyperparathyroidism

Progressive CKD leads to increased FGF23 secretion, which in turn leads to suppressed calcitriol levels and secondary hyperparathyroidism
On dialysis, once secondary hyperparathyroidism is established disturbances in calcitriol, calcium and phosphate levels potently induce PTH secretion and parathyroid hyperplasia
On the cellular level, in CKD there is decreased expression of calcium sensing receptor, vitamin D receptor and fibroblast growth factor receptor and Klotho

Parathyroid hyperplasia

once secondary hyperparathyroidism has been established, it is often accompanied by parathyroid hyperplasia
as a result, higher levels of serum calcium will be needed to suppress PTH release
this may lead to hypercalcemia

Autonomous parathyroid secretion

parathyroid hyperplasia may lead to autonomous secretion from individual nodules

Therapy with Vitamin D and Ca-based binders

These therapies are often associated with hypercalcemia, especially when the extra calcium load is not taken up by bone (such as in adynamic bone disease)

Epidemiology

common in individuals with severe hyperparathyroidism
may be exacerbated by therapy with Vitamin D and Ca-based binders

Pharmacologic considerations

Binders: Hypercalcemia more common with Ca-based binders compared to non-ca based binders
Active Vitamin D analogs: Newer non-calcemic analogs of Vitamin D developed to limit hypercalcemia, though hypercalcemia is still present
Cinacalcet: associated with hypocalcemia and typically requires co-treatment with calcemic agents

How to utilize team care?

Specialty consultations

Surgeons when considering parathyroidectomy

Nurses

Assist in monitoring levels, response to therapy

Dietitians

May assist in ascertaining dietary calcium intake and instituting changes as needed

Are there clinical practice guidelines to inform decision making?

Applications

Listed above under individual sections

Limitations

Main limitations for both sets of guidelines are:

Lack of detailed studies evaluating calcium balance in dialysis patients who are being treated with Ca-based binders and active vitamin D analog

Uncertainty regarding appropriate level of dietary calcium intake for dialysis patient

insufficient amount of patient-level outcomes data in the studies reviewed by both guidelines

What is the evidence?

Kumar, R, Thompson, JR. “The regulation of parathyroid hormone secretion and synthesis”. JASN. vol. 22. 2011. pp. 216-224. (This article reviews the physiology of PTH hormone regulation in health and also describes the mechanisms for secondary hyperparathyroidism develoment in chronic kidney disease.)

Bazari, H, Jaff, MR, Mannstadt, M, Yan, S. “Case records of the Massachusetts General Hospital. Case 7-2007. A 59-year-old woman with diabetic renal disease and nonhealing skin ulcers”. N Engl J Med. vol. 20; 356. 2007. pp. 1049-1057. (This clinical case presentation of calciphylaxis provides the differential diagnosis and reviews current clinical management strategies for this condition.)

Teng, M, Wolf, M, Lowrie, E, Ofsthun, MN, Lazarus, JM, Thadhani, R. “Survival in patients undergoing hemodialysis with paricalcitol or calcitriol therapy”. N Engl J Med. vol. 349. 2003. pp. 446-456. (This observational study is one of many that demonstrate survival benefit with use of active vitamin D analogs in dialysis.)

Isakova, T, Gutierrez, OM, Chang, Y, Shah, A, Tamez, H, Smith, K, Thadhani, R, Wolf, M. “Phosphorus binders and survival on hemodialysis”. JASN. vol. 20. 2009. pp. 388-396. (This observational study demonstrates survival benefit with use of phosphate binders in dialysis.)

Palmer, SC, Hayen, A, Macaskill, P, Pellegrini, F, Craig, JC, Elder, GJ, Strippoli, GF. JAMA. vol. 16;305. 2011 Mar. pp. 1119-27. (Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis.
This meta-analysis reports no association between serum calcium and the risk of death and cardiovascular events in chronic kidney disease.
Prescription patterns and mineral metabolism abnormalities in the cinacalcet era: results from the MBD-5D study.)

Fukagawa, M, Fukuma, S, Onishi, Y, Yamaguchi, T, Hasegawa, T, Akizawa, T, Kurokawa, K, Fukuhara, S. Clin J Am Soc Nephrol. vol. 7. 2012 Sep. pp. 1473-80. (This observational study reports on use of cinacalcet in the dialysis population and its effects on serum calcium levels.)

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Nephrology Hypertension

Medical Management of the Dialysis Patient: Hypercalcemia