Management of secondary hyperparathyroidism in adult patients with nondialysis chronic kidney disease

INTRODUCTION — 

The secondary hyperparathyroidism of chronic kidney disease (CKD) is defined by persistent elevations of circulating parathyroid hormone (PTH) and is characterized by adaptive parathyroid gland hyperplasia. Secondary hyperparathyroidism develops because of the disordered calcium and vitamin D metabolism present in patients with impaired kidney function and is a major feature of chronic kidney disease mineral and bone disorder (CKD-MBD). This topic reviews our approach to the treatment of secondary hyperparathyroidism in patients with CKD who are not on dialysis.  

The management of secondary hyperparathyroidism in patients on dialysis, treatment of hyperphosphatemia, indications for parathyroidectomy in patients with end-stage kidney disease, evaluation of bone disease in CKD, and the pathogenesis and clinical features of CKD-MBD are presented separately:

●(See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

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

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

●(See "Evaluation of renal osteodystrophy".)

●(See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation".)

●(See "Osteoporosis in patients with chronic kidney disease: Management".)

●(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

RATIONALE FOR TREATMENT — 

Treatment of secondary hyperparathyroidism in patients with nondialysis chronic kidney disease (CKD) has not been shown to improve clinically important outcomes. However, the aims of treatment are to prevent severe bone disease (osteitis fibrosa), reduce the risk of bone fracture, and mitigate the progression of parathyroid hyperplasia that can lead to refractory hyperparathyroidism after patients transition to dialysis. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength'.)

An additional rationale for treating secondary hyperparathyroidism is based on observational studies of patients with nondialysis CKD that report an association between higher parathyroid hormone (PTH) levels and increased mortality [1,2], possibly mediated by excess PTH contributing to vascular calcification (see "Vascular calcification in chronic kidney disease"). For example, in a study of over 500 individuals with nondialysis CKD, the adjusted hazard ratio (aHR) of all-cause mortality associated with increased levels of intact PTH (in pg/mL) is as follows [1]:

●PTH <65           – aHR 1.00 (referent)

●PTH 65 to 110   – aHR 1.49 (95% CI 0.91 to 2.43)

●PTH 111 to 179 – aHR 1.67 (95% CI 0.95 to 2.94)

●PTH >179         – aHR 2.00 (95% CI 1.06 to 3.80)

ASSESSMENT AND MONITORING — 

We monitor all patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² for the development of secondary hyperparathyroidism by measuring circulating concentrations of intact parathyroid hormone (PTH). In addition to PTH, we measure other serum parameters of CKD-MBD, including levels of calcium, phosphorus, and 25-hydroxyvitamin D [3]. The frequency of monitoring depends on the eGFR and whether baseline abnormalities are present or therapeutic measures have been taken; our approach is detailed elsewhere (see "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Monitoring'). The optimal frequency of monitoring is unknown.  

PTH levels generally start to increase when eGFR is <60 mL/min/1.73 m² [4]. By the time eGFR is <30 mL/min/1.73 m², approximately 70 percent of patients will have secondary hyperparathyroidism [4,5].

INITIAL THERAPY — 

Serial assessments of parathyroid hormone (PTH), phosphorus, calcium, and vitamin D levels are used to guide treatment. We treat all patients with persistently elevated PTH for modifiable risk factors, including vitamin D deficiency, high phosphorus intake, and hyperphosphatemia. However, no randomized trials have determined the optimal approach, or whether treatment of secondary hyperparathyroidism improves patient-centered outcomes.

Our approach is broadly consistent with the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [3].

Treat vitamin D deficiency — We replenish vitamin D (with cholecalciferol or ergocalciferol) among patients with chronic kidney disease (CKD). The preparations and doses of vitamin D are the same as for the general population. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

Vitamin D deficiency is a common finding in patients with CKD. Vitamin D deficiency is associated with elevated PTH levels and may worsen hypocalcemia. We do not use vitamin D supplements (eg, cholecalciferol, ergocalciferol) to suppress PTH in the absence of documented vitamin D deficiency (ie, low 25-hydroxyvitamin D level) [6].

The efficacy of vitamin D supplementation on mineral metabolism and/or other outcomes has not been established in patients with CKD [7]. In addition, the conversion of 25-hydroxyvitamin D to “active” 1,25-dihydroxyvitamin D in the kidney becomes progressively impaired as kidney function declines. However, studies have found that normalization of serum 25-hydroxyvitamin D levels with vitamin D supplementation modestly decreases PTH levels [8-10]. A meta-analysis that included nine observational studies comprising 286 patients with nondialysis CKD reported improvements in vitamin D and PTH levels associated with vitamin D supplementation [11]. A low incidence of hypercalcemia and hyperphosphatemia was reported in this study.

Control phosphorus — Higher levels of dietary and serum phosphorus contribute to the development and severity of secondary hyperparathyroidism.

Restrict dietary phosphorus — For patients with secondary hyperparathyroidism who have serum phosphorus levels in or above the normal range, we suggest a moderate dietary phosphorus restriction of between 800 and 1000 mg/day (25.8 and 32.3 mmol/day) provided this can be done without compromising nutritional status (table 1A-B). Phosphorus restriction should primarily include processed foods and colas and not high-biologic-value foods such as meat and eggs, and some nephrologists recommend a more vegetarian-based diet to control phosphorus. Details of dietary phosphorus restriction in CKD are presented elsewhere. (See "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Phosphorus intake' and "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Dietary phosphorus restriction in all patients'.)

Animal models of CKD demonstrate that dietary phosphorus restriction markedly attenuates the development of secondary hyperparathyroidism [12]. However, in humans with nondialysis CKD the effect of dietary phosphorus restriction on secondary hyperparathyroidism is unclear. Some studies report that reductions in phosphorus intake lower PTH [13], while others do not [14].  

Treat hyperphosphatemia — Our management of hyperphosphatemia in patients with secondary hyperparathyroidism is the same as that for all patients with nondialysis CKD: we treat serum phosphorus levels that are persistently above normal. The first step in treating hyperphosphatemia is dietary phosphorus restriction (see 'Restrict dietary phosphorus' above). For patients with serum phosphorus levels persistently >5.5 mg/dL (1.78 mmol/L) despite dietary restriction, we add phosphate binder therapy. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

For patients with nondialysis CKD, the effect of phosphate binders on PTH levels appears to be variable. Some studies report that phosphate binders lower or stabilize PTH [15,16], while others do not [17,18].

Patients with hypocalcemia — Hypocalcemia, if it occurs, is a late manifestation of advanced CKD and contributes to hyperparathyroidism [3]. The hypocalcemia associated with nondialysis CKD is typically mild (ie, albumin-corrected serum calcium >7.5 mg/dL [1.87 mmol/L]), asymptomatic, and accompanied by hyperphosphatemia. Hypocalcemia in this setting is addressed by treatment with calcium-based phosphate binders and, if present, the treatment of vitamin D deficiency. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Choice of phosphate binder' and 'Treat vitamin D deficiency' above.)

Some patients with advanced CKD may present with more severe hypocalcemia (ie, albumin-corrected serum calcium ≤7.5 mg/dL [1.87 mmol/L]), secondary hyperparathyroidism, and marked hyperphosphatemia. In addition to treatment with calcium-containing phosphate binders and correction of vitamin D deficiency as above, some of these patients also may require calcitriol to raise serum calcium levels. Unless the hypocalcemia is symptomatic, which is rare in such patients, we typically aim to lower serum phosphorus to ≤5.5 mg/dL (1.78 mmol/L) before starting calcitriol therapy. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

SUBSEQUENT THERAPY — 

For patients with persistent secondary hyperparathyroidism despite treatment of modifiable risk factors (see 'Initial therapy' above), the optimal treatment is unknown. Our approach is broadly consistent with the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [3].

Calcitriol for severe and persistent hyperparathyroidism — For most patients with nondialysis chronic kidney disease (CKD) in whom serum PTH remains significantly and persistently elevated despite initial therapy (see 'Initial therapy' above), we treat with an active vitamin D formulation (ie, calcitriol or a synthetic vitamin D analog). We do not administer active vitamin D to patients with hypercalcemia, and we generally do not use active vitamin D in patients with hyperphosphatemia. Although the threshold for treating persistently elevated parathyroid hormone (PTH) with active vitamin D is not well defined, we treat most patients who have intact PTH persistently >2.3 to 3 times the upper normal limit for the assay (eg, 150 to 200 pg/mL).

A preferred starting dose of calcitriol is 0.25 mcg three times weekly. We adjust the dose to maintain PTH between one to approximately two times the upper normal limit for the PTH assay while avoiding the development of hypercalcemia or hyperphosphatemia. However, some clinicians target a broader range of PTH values during treatment (eg, PTH levels between one to three times the upper normal limit). For patients taking calcitriol, we monitor serum calcium and phosphorus since levels of these CKD-MBD parameters can increase as a result of active vitamin D therapy (see "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Monitoring'). Hypercalcemia is a contraindication to treatment with calcitriol or a synthetic vitamin D analog.

Approaches to the use of calcitriol in patients with nondialysis CKD vary widely. For example, some clinicians use low-dose calcitriol early in the course of secondary hyperparathyroidism (eg, PTH levels persistently greater than normal) to mitigate the development of parathyroid gland hyperplasia. In this setting, low-dose calcium carbonate with meals is sometimes added to calcitriol therapy to augment PTH suppression and prevent the development of calcitriol-mediated hyperphosphatemia. Such an approach requires close monitoring of serum calcium levels to avoid the development of hypercalcemia.

Calcitriol and synthetic vitamin D derivatives have been shown to reduce or stabilize PTH and improve bone histology [19-22]. However, these agents have not been shown to improve clinically important outcomes and have been associated with an increased risk of hypercalcemia [23,24]. In one randomized trial, the synthetic vitamin D derivative, paricalcitol, had no effect on left ventricular mass index or diastolic function but increased the risk of hypercalcemia, defined as two consecutive measurements >10.5 mg/dL (23 percent versus 1 percent in placebo) [24].

The comparative effects of calcitriol or the different synthetic vitamin D derivatives have not been established in patients with nondialysis CKD. As a result, any one of the available oral agents (calcitriol, alfacalcidol, doxercalciferol, or paricalcitol) may be administered [19,25].

Approaches we do not use — For treatment of secondary hyperparathyroidism, calcimimetic therapy or parathyroidectomy is reserved for select patients on dialysis or with a kidney transplant. (See "Management of secondary hyperparathyroidism in adult patients on dialysis" and "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

Calcimimetics — We do not use calcimimetics (eg, cinacalcet) to suppress PTH in patients with nondialysis CKD, except in select patients with a kidney transplant who have persistent posttransplant hyperparathyroidism (see "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation"). Although cinacalcet decreases PTH levels, it is associated with increased serum phosphorus and hypocalcemia [26,27].

The KDIGO 2017 guidelines do not provide recommendations on the use of cinacalcet [3]. Prior KDIGO guidelines suggested that cinacalcet not be used given the paucity of data concerning efficacy and safety in patients with nondialysis CKD [28].

Parathyroidectomy — We do not refer patients with nondialysis CKD and secondary hyperparathyroidism for parathyroidectomy; the exception is for select patients with a kidney transplant who have persistent posttransplant hyperparathyroidism (see "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation"). The efficacy and safety of parathyroidectomy in patients with nondialysis CKD has not been established.

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

●Rationale for treatment – Treatment of secondary hyperparathyroidism in patients with nondialysis chronic kidney disease (CKD) has not been shown to improve clinically important outcomes. However, the aims of treatment are to prevent severe bone disease (osteitis fibrosa), reduce the risk of bone fracture, and mitigate the progression of parathyroid hyperplasia that can lead to refractory hyperparathyroidism after patients transition to dialysis. (See 'Rationale for treatment' above.)

●Monitoring – To monitor secondary hyperparathyroidism among patients with nondialysis CKD, we routinely measure serum levels of intact parathyroid hormone (PTH), phosphorus, and calcium. We also measure serum 25-hydroxyvitamin D levels. The frequency of monitoring depends on whether baseline abnormalities are present or therapeutic measures have been taken. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Monitoring'.)

●Initial therapy – We treat all patients with persistently elevated PTH for modifiable risk factors, including vitamin D deficiency, high phosphorus intake, and hyperphosphatemia

•Treat vitamin D deficiency – We treat vitamin D deficiency according to guidelines for the general population. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

•Restrict dietary phosphorus – Higher levels of dietary phosphorus contribute to the development and severity of secondary hyperparathyroidism. For patients with nondialysis CKD and secondary hyperparathyroidism who have serum phosphorus levels in or above the normal range, we suggest a moderate dietary phosphorus restriction of between 800 and 1000 mg/day (25.8 and 32.3 mmol/day) (Grade 2C) provided this can be done without compromising nutritional status. (See 'Restrict dietary phosphorus' above.)

•Treat hyperphosphatemia – Our management of hyperphosphatemia in patients with secondary hyperparathyroidism is the same as that for all patients with nondialysis CKD: we treat serum phosphorus levels that are persistently above normal. For patients with serum phosphorus levels persistently >5.5 mg/dL (1.78 mmol/L) despite dietary restriction, we add phosphate binder therapy. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

●Subsequent therapy – For patients with nondialysis CKD who have intact PTH values persistently >2.3 to 3 times the upper normal limit for the assay despite initial therapy, we suggest calcitriol or an active vitamin D analog (Grade 2C). We do not administer active vitamin D formulations to patients with hypercalcemia, and we generally do not use active vitamin D in patients with hyperphosphatemia. A preferred agent and starting dose is calcitriol at 0.25 mcg three times weekly. We monitor serum calcium and phosphorus during treatment since levels of these CKD-MBD parameters can increase as a result of active vitamin D therapy. (See 'Calcitriol for severe and persistent hyperparathyroidism' above.)

ACKNOWLEDGMENT — 

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