Version May 2024
INTRODUCTION — Chronic kidney disease mineral and bone disorder (CKD-MBD) is characterized by biochemical abnormalities (calcium, phosphate, parathyroid hormone [PTH], and vitamin D); abnormalities in bone turnover, mineralization, volume linear growth, or strength; and by extraskeletal calcification.
Secondary hyperparathyroidism is defined as adaptive parathyroid gland hyperplasia and increased production of PTH. However, the term is more generally used to encompass the biochemical abnormalities of CKD-MBD (ie, calcium, phosphate, PTH, vitamin D).
This topic reviews our approach to the treatment of secondary hyperparathyroidism in CKD patients who are not on dialysis.
The management of secondary hyperparathyroidism in dialysis patients, the treatment of hyperphosphatemia, and indications for parathyroidectomy in patients with end-stage kidney disease 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".)
The pathogenesis and clinical features of CKD-MBD are discussed separately. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Overview'.)
RATIONALE — Sustained elevation in parathyroid hormone (PTH) levels can cause high-turnover bone disease (osteitis fibrosa cystica) and subsequent fracture. In addition, such elevation of PTH can also contribute to the development of vascular calcification and calciphylaxis. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
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 parathyroid hormone (PTH) concentration. Secondary hyperparathyroidism is common in CKD and is present in the majority of patients with eGFR <60 mL/min/1.73 m2 [1]. In addition to PTH, we measure serum levels of calcium, phosphate, 25-hydroxy vitamin D, and tissue non-specific alkaline phosphatase (and, when available, bone-specific alkaline phosphatase) [2].
With the advent of biochemical measurements of hyperparathyroidism, we do not routinely perform bone biopsies, although they are the gold standard for the diagnosis of bone disease in CKD patients. There are specific circumstances in which a bone biopsy may be indicated. (See "Evaluation of renal osteodystrophy".)
We do not routinely screen for vascular calcification with imaging tests. Although vascular calcification is part of the spectrum of chronic kidney disease mineral and bone disorder (CKD-MBD) and may identify patients at increased cardiovascular mortality, documenting whether or not it is present does not change our approach to patients; we assume all patients are at risk for or have some degree of vascular calcification. (See "Vascular calcification in chronic kidney disease", section on 'Introduction'.)
The optimal frequency of monitoring is unknown. Our approach depends on the eGFR [2].
The use of bone mineral density (DXA) testing in CKD patients is discussed elsewhere:
●(See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Monitoring therapy'.)
eGFR 30 to 59 mL/min/1.73 m2 — For patients with estimated glomerular filtration rate (eGFR) 30 to 59 mL/min/1.73 m2, we measure serum calcium and phosphate every 6 to 12 months. We measure PTH every 12 months. These levels may be assessed more frequently in patients who are being treated for abnormal values. As an example, patients who are treated for hyperphosphatemia may be assessed every three months. However, it is unusual to observe hyperphosphatemia until the eGFR decreases to <30 mL/min/1.73 m2.
We measure vitamin D concentrations at least yearly. Patients who have increased PTH or who are being treated for 25(OH)D deficiency are tested every six months.
eGFR 15 to 29 mL/min/1.73 m2 — For patients with estimated glomerular filtration rate (eGFR) 15 to 29 mL/min/1.73 m2, we measure serum calcium and phosphate every three to six months. We measure PTH every 6 to 12 months. These levels may be assessed more frequently in patients who are being treated for abnormal values.
We measure vitamin D concentrations at least yearly. Patients who have increased PTH or who are being treated for 25(OH)D deficiency are tested every six months.
eGFR <15 mL/min/1.73 m2 — For patients with estimated glomerular filtration rate (eGFR) <15 to 29 mL/min/1.73 m2, we measure serum calcium and phosphate every one to three months. We measure PTH a minimum of every three to six months. The frequency of testing depends on whether the patient is being treated or not.
We measure vitamin D concentrations at least yearly. Patients who have increased PTH or who are being treated for 25(OH)D deficiency are tested every six months.
INITIAL TREATMENT — Serial assessment of phosphate, calcium, vitamin D, and parathyroid hormone (PTH) levels provides indications for treatment. Our approach is consistent with the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [2].
Treat hyperphosphatemia — We generally treat patients who have a serum phosphate that is persistently above normal. We first start with dietary phosphate restriction in all patients with elevated phosphate levels. We only use phosphate binders in patients with persistently elevated serum phosphate >5.5 mg/dL despite dietary restriction. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Patients with nondialysis chronic kidney disease'.)
Hypocalcemia — Our approach to hypocalcemia is individualized and depends on severity and presence of symptoms [2].
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). These agents are associated with an increased risk of hypercalcemia or positive calcium balance even without hypercalcemia.
However, we do use these agents to treat severe and progressive hyperparathyroidism. (See 'Treat persistent and progressive hyperparathyroidism' below.)
Mild hypocalcemia may be addressed in part by the treatment of vitamin D deficiency. Nutritional vitamin D deficiency contributes to hypocalcemia. (See 'Treat vitamin D deficiency' below.)
In addition, the treatment of hyperphosphatemia may also help to treat mild hypocalcemia. (See 'Treat hyperphosphatemia' above and "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Patients with nondialysis chronic kidney disease'.)
Hypocalcemia has been associated with higher mortality in observational studies including dialysis patients [3] and contributes to hyperparathyroidism [2].
However, there is concern that the administration of oral calcium (ie, calcium-containing phosphate binders) and vitamin D analogs increases the risk of vascular calcification. Because normal dietary calcium intake is roughly 1000 mg per day, prescription of 1500 mg elemental calcium per day (calcium carbonate 1250 mg three times daily with meals) increases calcium ingestion by roughly 2.5-fold. In addition, calcium excretion is reduced in CKD because of a reduced filtered load of calcium. The combination of increased calcium ingestion and decreased calcium excretion could lead to positive calcium balance, even in the absence of hypercalcemia. This was demonstrated in a study of eight CKD patients (mean eGFR 36 mL/min/1.73 m2) [4]. The patients received a controlled diet containing 957 mg calcium and received either placebo or calcium carbonate (1500 mg elemental calcium per day) given with meals during two three-week balance periods in a randomized crossover design. Balance studies were performed after seven days of equilibration. Patients were in neutral calcium balance while receiving placebo and in positive calcium balance (508 mg per day) while receiving calcium carbonate. Calcium kinetics demonstrated positive net bone balance in those receiving calcium carbonate. However, positive net bone balance was less than overall positive calcium balance, suggesting deposition of calcium in soft tissue.
Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate, suggesting that it is futile to rely solely on blood concentrations to determine mineral excess or accumulation.
The interpretation of these data may be limited by the short-term nature of the study. It is possible that patients were not in steady state after only one week of calcium administration. If so, the short-term positive calcium balance that was observed may have been an appropriate response to correct years of bone calcium depletion and thus may decrease over time [5]. In studies of longer duration in predialysis CKD, 24-hour phosphate excretion substantially declined when calcium-containing binders were used [6].
Treat vitamin D deficiency — We replenish vitamin D (with cholecalciferol or ergocalciferol) among patients with CKD who are deficient with the exception of [7]:
●Patients who have elevated serum phosphate levels, until they achieve phosphate control
●Patients who have hypercalcemia (elevated corrected serum total calcium concentration above the upper limit of normal for the laboratory)
The preparations and doses of vitamin D are same as for the general population. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)
The use of activated vitamin D (calcitriol) is limited to patients with progressive hyperparathyroidism. (See 'Treat persistent and progressive hyperparathyroidism' below.)
Vitamin D deficiency is a common finding in CKD patients. Vitamin D deficiency is associated with elevated PTH levels and may worsen hypocalcemia.
The efficacy of vitamin D supplementation on mineral metabolism and/or other outcomes has not been established in CKD patients [8]. A few studies have found that such therapy normalizes serum 25(OH)D levels and modestly decreases PTH levels [9-11]. A meta-analysis that included nine observational studies comprising 286 nondialysis patients reported improvements in vitamin D and PTH levels associated with vitamin D supplementation [12]. A low incidence of hypercalcemia and hyperphosphatemia was reported in this study.
Treat persistent and progressive hyperparathyroidism — We treat all patients with persistently elevated or progressively rising PTH for modifiable risk factors including hyperphosphatemia, high phosphate intake, and vitamin D deficiency.
Treatment should not be initiated based on a single elevated value, as modest or transient elevations of PTH may reflect an adaptive response to declining kidney function (ie, related to phosphaturic effects and bone resistance to PTH).
If the PTH remains significantly and progressively elevated despite treating modifiable risk factors, we treat with the vitamin D derivative, calcitriol. The threshold for treating persistently elevated PTH with calcitriol or synthetic vitamin D analogs is not well defined and varies among clinicians. We treat most patients who have PTH >2.3 to 3 times the upper limit for the assay (ie, 150 to 200 pg/mL if upper limit for the assay is 65 pg/mL).
A preferred dose is 0.25 mcg three times weekly. We adjust the dose to maintain PTH <150 pg/mL. We do not use calcitriol if the serum phosphate is above normal range or if the corrected serum total calcium concentration is ≥9.5 mg/dL (≥2.37 mmol/L).
Calcitriol and synthetic vitamin D derivatives have been shown to reduce or stabilize PTH and improve bone histology [13-16]. However, these agents have not been shown to improve clinically important outcomes and have been associated with an increased risk of hypercalcemia [17,18]. 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) [18].
The comparative effects of calcitriol or the different synthetic vitamin D derivatives have not been established in nondialysis CKD patients. As a result, any one of the available oral agents (calcitriol, alfacalcidol, doxercalciferol, or paricalcitol) may be administered [13,19].
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) [7].
We do not use the calcimimetics, such as cinacalcet, to suppress PTH among nondialysis CKD patients. Although cinacalcet decreases PTH levels, it is associated with hypocalcemia, increased urinary calcium excretion, and increased serum phosphate levels [20,21]. Because of the risk of hypocalcemia, laboratory values require close monitoring (weekly after starting therapy or change in dose), which may be difficult in the outpatient setting.
The KDIGO 2017 guideline does not provide recommendations on the use of cinacalcet [2]. Prior KDIGO guidelines suggested that cinacalcet not be used given the paucity of data concerning efficacy and safety in predialysis patients with CKD [22].
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
●Assessment and monitoring – To monitor for secondary hyperparathyroidism among patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, we measure serum levels of calcium, phosphate, parathyroid hormone (PTH), and vitamin D (25-hydroxy vitamin D or calcidiol). Our approach depends on the eGFR and is defined above. (See 'Assessment and monitoring' above.)
●Evaluate modifiable risk factors – Patients with persistently elevated or progressively rising PTH should be evaluated for modifiable risk factors such as hyperphosphatemia, high phosphate intake, and vitamin D deficiency. (See 'Treat persistent and progressive hyperparathyroidism' above.)
●Treat hyperphosphatemia – We generally treat patients who have a serum phosphate that is persistently above normal. We only use phosphate binders in patients with persistently elevated serum phosphate >5.5 mg/dL despite dietary restriction. (See 'Treat hyperphosphatemia' above and "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Patients with nondialysis chronic kidney disease'.)
●Approach to hypocalcemia – Our approach to hypocalcemia is individualized and depends on severity and presence of symptoms. We do not specifically treat mild and asymptomatic hypocalcemia, because of the associated risk of hypercalcemia or positive calcium balance, although hypocalcemia may be addressed in part by correction of vitamin D deficiency and treatment of hyperphosphatemia. (See 'Hypocalcemia' above and "Clinical manifestations of hypercalcemia" and "Clinical manifestations of hypocalcemia".)
●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".)
●Use of calcitriol in select patients – Among patients who have PTH values that are persistently greater than 150 to 200 pg/mL (or approximately 2.3 to 3.0 times an upper limit of normal of 65 pg/mL) despite treatment of hyperphosphatemia and vitamin D deficiency, we suggest calcitriol or an active vitamin D analog (Grade 2C). Calcitriol and synthetic vitamin D analogs reduce or stabilize PTH and improve bone histology, though have not been shown to provide benefits in clinically important outcomes. A preferred agent and starting dose is calcitriol at 0.25 mcg three times weekly. We adjust the dose to maintain PTH <150 pg/mL. We do not use calcitriol if the serum phosphate is above normal range or if the corrected serum total calcium concentration is ≥9.5 mg/dL (≥2.37 mmol/L). (See 'Treat persistent and progressive 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.
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