Management of secondary hyperparathyroidism in adult patients on dialysis

INTRODUCTION — Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder characterized by biochemical abnormalities (calcium, phosphate, parathyroid hormone [PTH], and vitamin D), abnormalities in bone turnover, and extraskeletal calcification.

Secondary hyperparathyroidism refers to the biochemical abnormalities that characterize CKD-MBD.

This topic reviews the management of secondary hyperparathyroidism in patients on dialysis. The treatment of secondary hyperparathyroidism in the predialysis patient with CKD and indications for parathyroidectomy in patients with end-stage kidney disease (ESKD) are presented separately.

●(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

●(See "Management of hyperphosphatemia in adults with chronic kidney disease".)

●(See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis".)

MONITORING — To monitor for secondary hyperparathyroidism, we routinely measure serum levels of calcium, phosphate, and parathyroid hormone (PTH) [1]. Some clinicians use bone-specific alkaline phosphatase in addition to PTH as indication for parathyroidectomy. However, we do not believe there are sufficient high-quality data to support its use. In a large bone biopsy study, both PTH and bone-specific alkaline phosphatase were able to predict high-turnover bone disease, and the combination of the two tests added minimal additional predictive value [2].

The optimal frequency of monitoring is unknown. It is reasonable to measure phosphate and calcium levels approximately every one to three months and PTH levels every three to six months [1]. All of these levels may be assessed more frequently (ie, monthly) in response to changes in therapeutic measures that affect these levels.

Many clinicians measure vitamin D concentrations yearly.

TREATMENT GOALS — For all patients on dialysis, we suggest the following guidelines [3]:

●Serum levels of phosphate should be maintained between 3.5 and 5.5 mg/dL (1.13 to 1.78 mmol/L).

●Serum levels of corrected total calcium should be maintained <9.5 mg/dL (<2.37 mmol/L).

●Parathyroid hormone (PTH) values should be maintained less than two to nine times the upper limit for the PTH assay [1].

These targets are consistent with the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [3]. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest that, in patients on dialysis, elevated phosphate levels should be lowered toward the normal range; however, a specific target level is not given. We believe that clearer guidance is needed.

The target value of 5.5 mg/dL was suggested by a meta-analysis of 12 studies that included 92,345 patients with chronic kidney disease (CKD), over 97 percent of whom were on dialysis [4]. Among 10 studies that were perceived to be adequately adjusted (in which seven studies were of patients on dialysis), serum phosphate >5.5 mg/dL (1.78 mmol/L) was associated with increased mortality. Based upon 13 studies that reported a continuous relative risk for each mg/dL increase in phosphate, the mortality risk increased by 18 percent (95% CI 1.12-1.25).

There are no studies that have conclusively shown that outcomes are improved by treatment-related reduction of phosphate [5]. Some observational studies have suggested that patients on dialysis prescribed phosphate binders have improved survival [6-8].

Once hyperphosphatemia is treated, we treat PTH values that are persistently more than two to nine times the upper limit for the PTH assay [1]. Because of variability in assays, an absolute PTH threshold for treatment should not be specified, and decisions regarding treatment should be based upon trends rather than single laboratory values [1].

Numerous studies have suggested that the high-turnover bone disorders, osteitis fibrosa and mixed uremic osteodystrophy, are associated with serum levels of intact PTH >400 pg/mL (ie, approximately six times the upper limit of normal of 65 pg/mL) [9,10].

Suppression of PTH to less than two times the upper limit for the specific PTH assay is not desirable, since it is associated with a higher prevalence of adynamic bone disease [5,11]. (See "Adynamic bone disease associated with chronic kidney disease".)

TREATMENT

Treat hyperphosphatemia — Persistently high phosphate (ie, >5.5 mg/dL) should be treated before treating high parathyroid hormone (PTH). Specific therapies for high PTH may increase the serum phosphate.

Decisions regarding treatment of hyperphosphatemia should be based upon trends rather than single laboratory values [1]. Specific treatment approaches are discussed elsewhere [1,3,5-8,12]. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Treatment approach'.)

Maintain normocalcemia — It is important to maintain serum calcium <9.5 mg/dL (<2.37 mmol/L). We do not specifically treat asymptomatic and mild hypocalcemia (ie, >7.5 mg/dL in the setting of normal albumin) with either calcium or vitamin D derivatives (such as calcitriol or synthetic vitamin D analogs). There is a significant risk of hypercalcemia with these agents.

Treat vitamin D deficiency — We correct vitamin D deficiency [1]. Limited evidence from a nested case-control study suggests that low vitamin D levels are associated with increased early mortality among patients on hemodialysis [13].

We use a similar treatment strategy as is recommended for the general population. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

Among patients on hemodialysis, both ergocalciferol and cholecalciferol are effective in repleting vitamin D levels [14-17].

Other than accomplishing nutritional repletion, there is no conclusive evidence to support a benefit of vitamin D replacement in patients on dialysis. Nevertheless, there is no significant toxicity associated with its use in this setting, although long-term studies have not been performed. In particular, studies have shown no difference in risk of hypercalcemia, hyperphosphatemia, or vascular calcification among vitamin-D-treated patients [14-17].

Treat high parathyroid hormone

Treatment options — Treatment options for increased PTH include calcimimetics, calcitriol, or synthetic vitamin D analogs [5]. A combination of calcimimetics with calcitriol or synthetic vitamin D analogs may also be used.

The Kidney Disease: Improving Global Outcomes (KDIGO) work group was divided as to whether calcimimetics, calcitriol/synthetic vitamin D analogs, or a combination of the two be regarded as first-line therapy [1].

All approaches reduce PTH. No studies have convincingly demonstrated a benefit on patient-centered outcomes.

Calcitriol and synthetic vitamin D analogs — Calcitriol (oral or intravenous [IV]) and synthetic vitamin D analogs all reduce PTH [13,18-20], although these agents are not sufficiently effective as monotherapy if the PTH is very high [21,22].

No randomized trials have shown a convincing benefit of calcitriol or synthetic vitamin D analogs on survival, bone pain, in preventing parathyroidectomy, or other important clinical outcomes [23,24].

Calcitriol or synthetic vitamin D analogs should be avoided, administered at a low dose, or discontinued if the serum phosphate exceeds 5.5 mg/dL or if the serum calcium exceeds 10.2 mg/dL [3]. However, they may be continued if there is a clearly reversible cause identified for hypercalcemia (eg, nonadherence to cinacalcet) or hyperphosphatemia (eg, nonadherence to phosphate binders).

After resolution of hypercalcemia or hyperphosphatemia, calcitriol or the synthetic vitamin D analog can be resumed at one-half the previous dose, or cinacalcet therapy can be initiated or its dose increased. Calcitriol and synthetic vitamin D analogs increase serum calcium and phosphorus, which can cause metastatic calcification and vascular calcification.

Six active (ie, 1-hydroxylated) vitamin D derivatives are available. These include calcitriol [25,26] and five synthetic vitamin D analogs: paricalcitol [19,27], doxercalciferol [28-30], alfacalcidol (not available in the United States) [31-33], falecalcitriol (not available in the United States), and 22-oxacalcitriol (not available in the United States) [26,34-36]. All of the available vitamin D derivatives are considered acceptable, and there are no convincing studies that support one particular agent over another [37]. As an example, in one observational study of patients on hemodialysis, three vitamin D derivatives (calcitriol, paricalcitol, and doxercalciferol) were associated with similar rates of calcium, phosphate, and PTH control, as well as similar rates of hospitalization and survival [38].

In general, the starting dose of calcitriol, whether oral or IV, or of the vitamin D analog should be low (eg, 0.25 mcg thrice weekly). Dose adjustments may be made at four- to eight-week intervals. Patients who are responsive to therapy typically show significant reductions in PTH levels within the first three to six months of therapy [11,21,29,39-46].

Calcimimetics — The calcium-sensing receptor (CaSR) of the parathyroid gland regulates secretion of PTH. Calcimimetics increase the sensitivity of the CaSR to calcium [47], thereby reducing the plasma PTH concentration and, in turn, decreasing the serum calcium and phosphate levels [48-63]. However, despite the improved control of hyperparathyroidism, their use has not been shown to improve cardiovascular or all-cause mortality among patients on dialysis [63]. (See "Parathyroid hormone secretion and action", section on 'Calcimimetic drugs'.)

Widely available calcimimetics include cinacalcet (oral) and etelcalcetide (intravenous). When a calcimimetic is indicated, we prefer cinacalcet over etelcalcetide because it is relatively inexpensive and has a similar adverse event profile. We use etelcalcetide among patients who fail to respond sufficiently to cinacalcet.

●Cinacalcet ─ The addition of cinacalcet to current treatment regimens (usually calcitriol or an active vitamin D analog plus phosphate binder) increases the chances of decreasing PTH to target values without causing hypercalcemia or hyperphosphatemia [55,59,61,62,64]. Cinacalcet also decreases the chances of requiring a parathyroidectomy [65].

However, among patients with advanced secondary hyperparathyroidism (baseline PTH levels above 800 pg/mL), monotherapy with cinacalcet may be inadequate to control PTH [66]. Such patients might be better treated with combination therapy of an active vitamin D analog and cinacalcet.

Cinacalcet does not appear to provide a benefit on mortality and cardiovascular outcomes, at least among patients <65 years of age [65,67]. In the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) randomized trial, patients were assigned to receive cinacalcet or placebo in addition to conventional therapy including phosphate binders and/or active vitamin D or synthetic analogs [67]. At a median follow-up of less than two years, a difference between groups in the composite outcome of time until death or the first nonfatal cardiovascular event was not shown.

The interpretation of this trial is limited by both a high dropout rate in the cinacalcet group (62 percent) and a high rate of crossover in the placebo group: Nearly 20 percent of patients in the placebo group ended up taking commercially available cinacalcet. The high rate of crossover may have diminished between-group differences.

Cinacalcet may provide a benefit to older individuals, who are at higher cardiovascular risk compared with younger patients. In EVOLVE, the effect of cinacalcet was examined among patients on hemodialysis who were ≥65 years (n = 1005) and <65 years (n = 2878) [68]. Among older patients, cinacalcet reduced the risk of major cardiovascular events (adjusted hazard ratio [AHR] 0.70, 95% CI 0.60-0.81) and death (AHR 0.68, 95% CI 0.51-0.81). Among younger patients, the cinacalcet-associated AHRs for cardiovascular events and mortality were 0.97 (95% CI 0.86-1.09) and 0.99 (95% CI 0.86-1.13), respectively. The effect of cinacalcet on severe hyperparathyroidism was the same between older and younger individuals.

There was also a trend toward a decreased fracture risk among individuals ≥65 years who were treated with cinacalcet (AHR 0.69, 95% CI 0.49-0.95) [69].

Side effects of cinacalcet noted in the EVOLVE trial included hypocalcemia and gastrointestinal symptoms [67].

●Etelcalcetide ─ Intravenous etelcalcetide was compared with placebo and with oral cinacalcet in three randomized trials [70,71]. All trials were of short duration and did not examine patient-important outcomes [72].

In two parallel randomized trials, etelcalcetide was compared with placebo among a total of 1023 patients on hemodialysis with hyperparathyroidism [70]. Etelcalcetide was more effective than placebo in reducing PTH (with 74 to 75 percent of patients achieving >30 percent reduction in PTH versus 8.3 to 9.6 percent in placebo) by 27 weeks. However, etelcalcetide-treated patients had more side effects compared with placebo (hypocalcemia, muscle spasms, nausea and vomiting).

A randomized trial compared intravenous etelcalcetide versus oral placebo (n = 340) and oral cinacalcet versus intravenous placebo (n = 343) among patients on hemodialysis with hyperparathyroidism [71]. Etelcalcetide was superior to cinacalcet in reducing PTH by greater than 30 percent (68 in etelcalcetide groups versus 58 percent in cinacalcet group).

Nausea and vomiting were comparable between groups. However, hypocalcemia was more common in the etelcalcetide group and required interventions to increase serum calcium concentrations (such as raising the dialysate calcium concentrations and prescribing calcium-containing phosphate binders, oral calcium supplements, calcitriol, and active vitamin D analogs). Etelcalcetide administration led to prolongation of corrected QT intervals in many patients. Because it is administered intravenously, compliance can be assured.

Treatment approach — Both drug classes lower PTH levels but have disparate effects on calcium and phosphate levels; thus, we choose different treatment approaches based on serum phosphate and calcium levels. Our approach is largely consistent with the 2017 KDIGO guidelines [1].

We treat patients with phosphate <5.5 mg/dL (<1.78 mmol/L) and calcium <9.5 mg/dL (<2.37 mmol/L) with calcitriol monotherapy. However, other vitamin D analogs are also effective in reducing PTH. (See 'Calcitriol and synthetic vitamin D analogs' above.)

Some clinicians treat such patients with a calcimimetic rather than calcitriol or a synthetic vitamin D analog, although studies have not shown a convincing benefit of cinacalcet on important clinical outcomes (see 'Calcimimetics' above). Cinacalcet should not be used if the serum calcium level is <8.4 mg/dL (<2.1 mmol/L), since it lowers calcium concentration. Such patients are treated with calcitriol.

Our dosing strategy is empiric, with the goal of administering increasing doses of calcitriol or synthetic vitamin D analogs to achieve target plasma PTH level while maintaining serum phosphate ≤5.5 mg/dL [3]. Measures to maintain goal serum phosphate values are used concurrently. (See 'Treat hyperphosphatemia' above and "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Patients on dialysis'.)

Among patients with inadequate reduction of PTH on calcitriol, we add cinacalcet, provided the calcium is >8.4 mg/dL. Up to one-half of patients with severe hyperparathyroidism show little or no decline in plasma PTH levels with calcitriol therapy [21,22]. The addition of cinacalcet increases the chances of achieving target PTH values and allows the use of lower doses of the vitamin D analog, which are less likely to cause hypercalcemia or hyperphosphatemia [55,59,61,62,64,73,74].

Cinacalcet is initiated at a dose of 30 mg/day orally, with stepwise increments to 60, 90, and 180 mg/day. The dose can be increased every four weeks until goals are achieved. We use etelcalcetide among patients who fail to respond sufficiently to cinacalcet. (See 'Calcimimetics' above.)

Among patients with serum phosphate ≥5.5 mg/dL (≥1.78 mmol/L) or serum calcium level ≥9.5 mg/dL (≥2.37 mmol/L) and persistently elevated PTH, despite maximal therapies to reduce phosphate, we initiate therapy with a calcimimetic rather than calcitriol or a synthetic vitamin D analog. Calcitriol and synthetic vitamin D analogs should not be used in such patients at least initially, since they both raise serum calcium and phosphate levels.

Calcimimetics should not be started if serum calcium is <8.4 mg/dL (<2.1 mmol/L), since these agents cause low calcium [75].

During treatments, serum levels of corrected total calcium should be maintained between 8.4 and 9.5 mg/dL (2.10 to 2.37 mmol/L).

Among patients who do not sufficiently reduce PTH with cinacalcet alone, we add calcitriol or a synthetic vitamin D analog, providing the phosphate <5.5 mg/dL (<1.78 mmol/L) and calcium <9.5 mg/dL (<2.37 mmol/L).

REFRACTORY HYPERPARATHYROIDISM — We define refractory hyperparathyroidism as persistent and progressive elevations of serum parathyroid hormone (PTH) that cannot be lowered to levels <600 pg/mL despite treatment with vitamin D derivatives and calcimimetics and without causing significant hyperphosphatemia or hypercalcemia. Patients with severe disease may require parathyroidectomy [3]. (See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis".)

MEDICAL TREATMENT FOLLOWING PARATHYROIDECTOMY — Patients who have had a parathyroidectomy for tertiary hyperparathyroidism should be managed the same as others with end-stage kidney disease (ESKD) and secondary hyperparathyroidism with respect to goals and medical therapy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease-mineral and bone disorder".)

SUMMARY AND RECOMMENDATIONS

●Monitoring – Among patients on dialysis, we measure serum levels of phosphate and calcium levels approximately every one to three months and parathyroid hormone (PTH) levels every three to six months. We measure vitamin D concentrations yearly. All of these levels may be assessed more frequently in response to changes in therapeutic measures that affect these levels. (See 'Monitoring' above.)

●Treat hyperphosphatemia – We treat hyperphosphatemia prior to treating hyperparathyroidism. Observational studies have suggested increased mortality at serum phosphate values above 5.5 mg/dL. (See 'Treat hyperphosphatemia' above.)

●Treatment goals – We suggest treating PTH values that are more than two to nine times the upper limit for the PTH assay (Grade 2C). Studies have suggested that the high-turnover bone disorders are associated with serum levels of PTH >400 pg/mL (ie, approximately six times upper limit of normal of 65 pg/mL). We maintain serum calcium <9.5 mg/dL (<2.37 mmol/L). (See 'Treatment goals' above.)

We suggest not suppressing PTH to less than or equal to two times the upper limit for the PTH assay (Grade 2C). Oversuppression of PTH is associated with adynamic bone disease. (See 'Treatment goals' above.)

●Treatment approach – Treatment options for increased PTH include calcimimetics, calcitriol, or synthetic vitamin D analogs. A combination of calcimimetics with calcitriol or synthetic vitamin D analogs may also be used. All approaches reduce PTH, but no studies have shown a benefit on patient-centered outcomes. Our approach depends on the serum phosphate and calcium concentrations. (See 'Treatment approach' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert E Cronin, MD, and Michael Berkoben, MD, who contributed to earlier versions of this topic review.