Secondary hyperparathyroidism in dialysis

Management of secondary hyperparathyroidism in adult dialysis patients

Management of secondary hyperparathyroidism in adult DX patients

 

In DX ptns, we assess serum SCa⁺ & PO⁴ every 1-3 mo & parathyroid hormone (PTH) every 3-6 mo, and vit D yearly. These values may be tested more frequently with the presence of therapeutic agents affecting these levels. Hyper-PO⁴ should be controlled before treating hyperparathyroidism (Hpr). Current reports have denoted higher mortalities at S.PO⁴ values > 5.5 mg/dL.  

 

Management of PTH values > 2-9 times upper limit for PTH assay. A high-turnover bone disorders are related to PTH >400 pg/mL (i.e., 6 times upper limit of normal of 65 pg/mL). Keep SCa⁺<9.5 mg/dL (<2.37 mmol/L). Do not suppress PTH to less than or equal to two times the upper limit for PTH assay. Oversuppression of PTH > adynamic bone disease.  

Therapeutic options of the high PTH include calcimimetics (Cmm), calcitriol (Calt), or synthetic vit D analogs. A combination of Cmm + calcitriol or synthetic vit D analogs can also be used. All these agents reduce PTH, but no data about ptn- outcome. We should correct vit D deficits. Vit D deficiency may induce hypocalcemia & high PTH.  

 

TREATMENT

 

Treat hyper-PO⁴:  high PO⁴ (i.e., >5.5 mg/dL) should be ttt before ttt high PTH. Specific agents for high PTH may increase S.PO⁴. Decisions in regard to ttt of hyper-PO⁴ should depend upon trends rather than single value.  

Keep normo-Ca⁺: maintain SCa⁺<9.5 mg/dL (<2.37 mmol/L). Do not ttt asymp-tomatic & mild hypo-Ca⁺ (i.e., >7.5 mg/dL with normal albumin) with either Ca⁺ or vit D derivatives (e.g. Calt or synthetic vit D analogs), as significant hyper-Ca⁺ can be induced.

Treat vit D deficits: Correct vit D deficiency in a similar strategy recommended for general population. Among HDX ptns, both ergocalciferol & cholecalciferol are effective. Except for nutritional repletion, there’s no definit evidence supporting vit D replacement in DX ptns. Nevertheless, there’s no significant toxicity related to its use. Of note, studies have reported no difference in risk of hyper-Ca⁺, hyper-PO⁴, or vascular calcification among vit-D-treated HDX ptns.

 

Treatment of high parathyroid hormone

Therapeutic options: include calcimimetics, Calt, or synthetic vit D analogs. Combined Cmm + Calt or synthetic vit D can also be used. KDIGO was divided as to whether calcimimetics, Calt /synthetic vit D analogs, or a combination of the two be regarded as 1^st-line therapy. ALL diminish PTH levels.

Calcitriol & synthetic vit D: Calt (oral or IV) & synthetic vit D all decrease PTH, but not sufficient as monotherapy for very high PTH. Calt or synthetic vit D should be avoided, given at low dose, or hold if PO⁴ > 5.5 mg/dL or if SCa⁺ > 10.2 mg/dL. However, they can be continued with clear reversible cause for hyper-Ca⁺ (e.g., non-adherence to cinacalcet (Cin) or hyper-PO⁴ (e.g., non-adherence to PO⁴ binders). After resolution of hyper-Ca⁺ or hyper-PO⁴, Calt or synthetic vit D can be resumed at one-half the prior dose, or Cin can be started or its dose increased. Calt & synthetic vit D elevate Ca⁺ & PO⁴ that can induce metastatic & vascular calcification. 6 active vit D derivatives are available, including Calt & 5 synthetic vit D: paricalcitol, doxer-calciferol, alfacalcidol , falecalcitriol, & 22-oxacalcitriol. Generally, start dose of Calt, oral or IV, or of vit D analog should be low (e.g., 0.25 mcg thrice/wk). Dose modification at 4-8/wk intervals. ptns responding to ttt typically show significant decline in PTH within 1^st 3-6 mo of therapy.

Calcimimetics (Cmm):  Ca⁺-sensing receptors (CaSR) of parathyroid gland regulate PTH secretion. Cmm increase sensitivity of CaSR to Ca⁺, declining PTH & decreasing SCa⁺ & PO⁴. However, despite the controlled Hpr, their use has not been proved to improve CVS or all-cause mortality among DX ptns. Widely available Cmm: Cin (oral) & Etelcalcetide (Etlc) (IV). If Cmm is indicated, Cin over Etlc is preferred, as it’s relatively inexpensive & has a similar side effects. Etlc can be used among ptns failing to respond to Cin. Adding Cin to current ttt (Calt or an active vit D + PO⁴ binder) augment the chance of PTH decline without hyper-Ca⁺ or hyper-PO⁴. Cin also decreases the need for Pec. However, in severe secondary Hpr (baseline PTH > 800 pg/mL), Cin monotherapy may be not sufficient to manage PTH. Combined therapy of active vit D + Cin may be suggested.

 

Cin does not seem to be beneficial on mortality & CVS outcome, especially with ptns <65 ys. In “Evaluation of Cinacalcet Hydrochloride Therapy to Lower CVS Events (EVOLVE) RCT, ptns receiveD Cin or placebo in addition to PO⁴ binders and/or active vit. D or synthetic analogs. After follow-up of < 2 ys, a difference between g.s in outcome until death or 1^st nonfatal CVS event was not given. Cin may provide a benefit to older ptns, who’re at higher CVS risk in comparison with younger ptns. In EVOLVE, effect of Cin was tried among HDX ptns who were ≥65 ys & <65 ys. Among older ptns, Cin diminished the risk of major CVS events & death. In younger ptns, Cin-related AHRs for CVS events & mortality were 0.97 & 0.99, resp. Effect of Cin on severe Hpr was the same between older & younger ptns. There was also a trend toward a diminished fracture risk in Cin ttt ptns ≥ 65 ys. SE of Cin noted in the EVOLVE trial included hypoC+ & GI Sms.

 

Etelcalcetide (Etlc): IV Etlc was compared to placebo & to oral Cin in 3 RCT. All of them were of short period & did not test ptn outcome. In 2 parallel RCT, Etlc was compared to placebo. Etlc was more effective than placebo in decreasing PTH (74-75 % of ptns >30 % decline in PTH vs 8.3-9.6 % in placebo) by 27 wks. However, Etlc-ttt ptns had more SE as compared to placebo (hypoCa⁺, muscle spasm, nausea & vomiting). A RCT compared IV Etlc vs oral placebo & oral Cin vs IV placebo among HDX ptns with Hpr. Etlc was superior to Cin in decreasing PTH by > 30 %. Nausea & vomiting were comparable between g.s. However, hypocalcemia was more evident in Etlc g requiring increasing S.Ca⁺ (e.g. increasing dialysate Ca & giving Ca-containing PO⁴ binders, oral Ca+ supplements, Calt & active vit D). Etlc therapy > prolonged QT interval in many ptns. As it’s provided IV, compliance is not certain.