Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD)


Paul Cockwell - Review Date July 2015 (Senior Editor Paul Cockwell)

Chronic Kidney Disease – Mineral Bone Disorder (CKD-MBD) is the term used to describe the pathophysiological changes that occur in the vascular and skeletal system in association with chronic kidney disease (CKD) (Moe et al). ­It has been classified by KDIGO in August 2009.­CKD-MBD has replaced the terms renal osteodystrophy and renal bone disease in routine clinical practice. The changes that occur in CKD-MBD include biochemical abnormalities, bone changes and extra-osseus (including vascular) calcification.

CKD- MBD can be diagnosed if a patient with CKD has evidence of one or more of:

1. ­Abnormalities of calcium, phosphate, PTH or vitamin D metabolism
2. ­Vascular and/or soft tissue calcification
3. ­Abnormalities in bone turnover, metabolism, volume, linear growth or strength

The development of CKD-MBD starts early in the course of CKD. Changes in serum levels of parathyroid hormone (PTH), 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D are often present in patients with an estimated glomerular filtration rate (eGFR) of <60mL/min/1.73m2. Significant changes in serum calcium and phosphate levels can be seen with an eGFR <40mL/min. Whilst there are strong associations between CKD-MBD and adverse outcomes (both cardiovascular disease (CVD) morbidity and mortality and progressive CKD) (Eddington et al) there is little good quality evidence for interventions to address CKD-MBD in patients with less severe CKD (stages 3 and 4). Thus most clinicians focus treatment on patients with stage 5 CKD (eGFR <15mL/min/1.73m2).

To understand the pathophysiology of CKD-MBD requires an understanding of the central role of the kidney in calcium and phosphate homeostasis.

Pathophysiology of CKD-MBD

Calcium and Phosphate Homeostasis

Pathways that regulate calcium and phosphate homeostasis are shown in figures 1 and 2. Calcium and phosphate are of major importance in most biological processes within the body and their regulation is complex. Intestinal absorption of calcium occurs in the duodenum and more distally in the colon.

In the kidney, passive reabsorption of calcium occurs in the proximal tubule and thick ascending limb of the loop of Henle. Furthermore calcium is reabsorbed against an electrochemical gradient via an active process in the distal convoluted tubule and collecting duct; this is regulated by a number of factors including PTH, 1,25 dihydroxy vitamin D (1,25(OH)2 vitamin D), insulin, oestrogen, acidity, calcium ions, magnesium ions and klotho. Medications including diuretics and calcineurin inhibitors can also affect cellular calcium transport within the kidney and therefore also have an impact on calcium regulation.

Figure 1 - Calcium Homeostasis

There are many organs involved in phosphate regulation and these include the kidney, gastrointestinal tract, parathyroid glands and bone. The fine regulation of phosphate occurs in the proximal tubule of the kidney with 80-97% of the phosphate filtered load reabsorbed through Sodium-Phosphate co-transporters. Gastrointestinal tract absorption of phosphate is increased in the presence of 1,25(OH)2 vitamin D. As phosphate levels rise, phosphaturic hormones are released to promote increased renal phosphate excretion; the best characterised of these is fibroblast growth factor 23 (FGF23; a phosphatonin), one of a number of molecules that regulate phosphate excretion and reabsorption. Other mediators of phosphate metabolism include PTH, acidosis, glucocorticoids, calcium levels, oestrogens and medications such as diuretics.

Figure 2 - Phosphate Homeostasis


FGF23 and Klotho

FGF23 is 32Kda protein secreted by osteocytes in bone in response to increasing phosphate concentration (Rodriguez et al). FGF23 is dependent on the presence of klotho to allow interaction with the FGF receptor­(Martin et al).­Klotho is predominantly expressed in the distal tubule and can be found in a membrane bound or in a soluble form.­In the kidney the majority of FGF-Klotho complexes are found in the distal tubule, although phosphate excretion occurs at the proximal tubules. The mechanism of action is currently unknown. though a possible paracrine pathway has been hypothesised. FGF23 also acts as a counter regulatory hormone to 1,25 dihydroxyvitamin D by inhibiting 1α hydroxylase and therefore the levels of active 1,25 dihydroxyvitamin D in circulation.

In addition to a role as a cofactor with FGF23 for FGF receptor activation, soluble klotho inhibits internalisation of a calcium channel within the kidney and is important in calcium regulation. Soluble klotho may also affect calcium by partly regulating PTH secretion; klotho deficient mice were found to have less PTH secretion on hypocalcaemic stimulation than wild type.

­The role of FGF23 in CKD–MBD and cardiovascular disease has been reviewed by Larsson in 2009.

Normal Parathyroid Regulation

Parathormone (PTH) is an 84 amino acid single chain protein that is released from the chief cell in the parathyroid glands. This secretion is regulated via the calcium sensing receptor and the vitamin D receptor by mediating changes in gene transcription and hormone synthesis. FGF23 receptors and klotho are present on parathyroid cells and FGF23 has been shown to have a suppressive effect on PTH release. Furthermore some studies have shown that 1,25 dihydroxyvitamin D and PTH stimulate FGF23 expression and secretion therefore closing a feedback loop.

Magnesium, adrenaline, and histamine can also affect PTH release; longstanding hypomagnesaemia both inhibits PTH synthesis and impairs PTH actions in target tissues. Adrenaline and histamine both stimulate PTH release via specific receptors.

The main actions of PTH (figure 4) are to increase plasma calcium and decrease plasma phosphate; this is accomplished through a direct effect on bone and kidneys and an indirect effect on the gastrointestinal tract.

In the kidney, PTH blocks the reabsorption of phosphate at the proximal tubule stimulating an increase in phosphate excretion and increases reabsorption of calcium from the distal tubule.

In bone, PTH promotes recruitment and differentiation of osteoclasts, therefore increasing breakdown of bone mineral and degradation of bone collagen. Osteoclasts, however, have no PTH receptors and the PTH effect is mediated via cytokines and other factors released from osteoblasts and other local cells. PTH also promotes bone formation by direct action on osteoblasts, increasing both the number and activity of these cells.

In the gastrointestinal tract, PTH stimulates 1α hydroxylation of 25 hydroxyvitamin to produce active 1,25 dihydroxyvitamin D. This then acts to increase gastro-intestinal absorption of calcium and phosphate. High calcium and active vitamin D levels and low phosphate levels fall act as negative feedback on the PTH gland and therefore homeostasis is maintained.

Figure 3 - Regulation of PTH Production

Vitamin D

The single term ‘Vitamin D’ is used to describe vitamin D at varying stages of hydroxylation; the stage of hydroxylation has a profound effect of the activity of the hormone and therefore is important to state which ‘vitamin D’ is being referred to.

Cholecalciferol (Vitamin D3) is converted from 7-dehydrocholesterol in the skin on exposure to Ultraviolet-B radiation. Native vitamin D, which can include cholecalciferol and ergocalciferol (vitamin D2), can be converted in the liver to 25 hydroxyvitamin D (aka calcidol) and stored. The 25 hydroxyvitamin D is then hydroxylated to 1,25 dihydroxyvitamin D (aka calcitriol) for local autocrine and paracrine pathways as well as the endocrine pathway already mentioned. The two main feedback mechanisms are shown in figure 4.


Figure 4 - As CKD develops pertubation in the homeostatic pathways described above lead to hypocalcaemia, hyperphosphataemia and Vitamin D deficiency and the development of secondary hyperparathyroidism.


Hypocalcaemia stimulates release of para­thyroid hormone­(PTH) directly by inactivation of the calcium sensing receptors (CaR) on para­thyroid cells. The plasma PTH concentration increases within minutes of fall in serum calcium levels. Reduction of extracellular calcium levels for weeks or months promotes the development of parathyroid gland hyper­plasia, which is the characteristic of­hyperparathyroidism (Goodman, 2003).


Metastatic calcification has been attributed to hyperphosphataemia since the early 1960s (Parfitt, 1969). However, the clinical impact and toxicity of hyperphosphataemia was not widely emphasised until the groundbreaking studies carried out of Bricker et al­(Bricker, 1969). Using animal models, this group delineated the pathophysiological cascade triggered by hyperphosphatemia, leading to hypocalcaemia, secondary hyperparathyroidism, reduced 1,25 vitamin D3, and progressive metabolic bone disease.

Hyperphosphataemia does not become evident until the glomerular filtration rate (GFR) has decreased to between 25 and 40% of normal (CKD4).

Until that stage, in the course of CKD, compensatory hyperparathyroidism results in increased phosphate excretion and main­tains serum phosphate levels within the normal range (Alfrey, 2004). Due to declining GFR, phosphate retention leads to a decrease in serum free calcium levels, which in turn stimulates PTH secretion (Drueke, 1995).This is the 'trade-off' hypothesis (Bricker, 1972). It also leads to decreased production of calcitriol by the kidney, which in turn decreases intestinal calcium absorption leading to hypocalcaemia and consequently, stimulation of PTH secretion (Tallon, 1996).

Hyperphosphataemia is associated with resistance to the actions of calcitriol on the parathyroid glands, which also leads to increased PTH secretion - and­causes resistance to the action of PTH on bone (Llach, 1995). Also high phosphate levels have a direct stimulatory effect on PTH secretion, independent of changes in calcium and 1,25 vitamin D3 levels (Almaden, 1998).

Vitamin D Deficiency

The kidney is a major site for calcitriol production. In CKD, calcitriol production falls. Calcitriol has several direct and indirect effects on parathyroid glands. In CKD, vitamin D receptors (VDR) in parathyroid glands are down regulated as a consequence of low levels of calcitriol. This direct mechanism leads to stimulation of PTH gene expression and increases PTH secretion.

Administration of calcitriol increases vitamin D receptors in the parathyroid glands and suppresses PTH secretion. Also, low circulating calcitriol levels may facilitate parathyroid cell proliferation (Drueke, 2000). Thus, calcitriol deficiency indirectly leads to secondary hyperpara­thyroidism­(Friedman, 2005)­in addition to causing skeletal resistance to the calcaemic actions of PTH in CKD.

Metabolic Acidosis

This is a common complication of CKD and is caused by decreased renal ammonia synthesis and hydrogen ion excretion. There are a number of consequences of chronic metabolic acidosis (Ortega and Arora 2012), including increasing bone turnover due to compensatory mechanisms activated as a consequence of the buffering effect of bone in acidosis.

Hyperparathyroidism in CKD

Parathyroid glands develop nodular hyperplasia, in which is situ VDR expression and CaR expression are significantly decreased. This contributes to the reduced capacity of the parathyroid glands to respond to therapy such as vitamin D, as well as changes in serum calcium levels (Locatelli, 2002). Hyperparathyroidism starts early in the course of CKD (figure 5):


Figure 5: The relationship between CKD and PTH

Clinical Features of CKD MBD

Early bone disease in patients with CKD is usually asymptomatic. Musculoskeletal symptoms usually appear late in the course of CKD-MBD (Llach, 2003). Skin symptoms are also important for patients with advanced CKD-MBD who are receiving treatment with dialysis; in this group pruritis is very common.

Clinical signs and end-organ damage is associated both with bone and cardiovascular disease. Where CKD-MBD has contributed to the development of cardiovascular disease, the presentations of cardiac disease, cerebrovascular disease and peripheral vascular disease are similar to those seen in patients where CKD-MBD does not have a pathopysiological role. Calciphylaxis is a rare but important skin complication of CKD-MBD.

Musculoskeletal symptoms and signs. Most of the data is derived from dialysis patients. Bone pain, which occurs in the low back, hips and legs and is aggravated by weigh bearing. Bone deformities are common in patients with severe hyperparathyroidism; this can be due to verterbral fractures which can lead to kypho-scoliosis or chest wall deformity. There is also an increased incidence of fractures of major joints and major long bones. A significant fracture risk is present with increasing PTH levels.

Cardiovascular calcification. Coronary artery calcification is commoner and more severe in patients on haemodialysis than in persons without renal failure (Braun, 1996) and is probably due to excessive use of calcium-containing phosphate binders and vitamin D analogues.

Coronary artery calcification is found in the majority of patients on RRT and can be detected by non-invasive electron-beam computed tomography (EBCT). In addition to coronary artery calcification, calcium deposits on the heart valves (especially mitral and aortic valves), and in the myocardium - causing arrhythmias, left ventricular dysfunction, aortic and mitral stenosis, ischaemia, congestive heart failure, and death.

A relation between left ventricular hyper­trophy (LVH) and PTH has been described in patients with CKD and secondary hyper­parathyroidism. PTH induces hypertrophic growth of cardiomyocytes and smooth muscle cells through the activation of the cardiomyocyte protein kinase (De Fransisco, 2004).

Pruritus. Pruritus occurs in advanced CKD, especially in patients on dialysis, and has a major impact on the quality of life of patients on dialysis. It may­relate to deposition of calcium and phosphate in the skin.

Calciphylaxis. Another serious complication of secondary hyperparathyroidism is soft tissue calcification. This is called calcific uraemic arteriolopathy (CUA), also known as calci­phylaxis. It is a syndrome of calcification of small arterioles and venules with severe intimal hyperplasia. It is often complicated by thrombosis and recanalisation, which results in painful skin necrosis. It carries a high mortality rate due to secondary infection, sepsis and ischaemia.

Calciphylaxis is caused by high PTH levels, hyperphosphatemia and hypercalcaemia; induced by high calcium­dialysate and use of calcium-containing phosphate binders. Obesity, hypo-albuminaemia and diabetes increase the risk of calciphy­laxis (Llach, 2003); as does warfarin usage and hyper­coagulable states (protein C and protein S deficiency) (Willmer, 2002). The management of CUA includes: stopping oral calcium; using non-calcium containing binders; and parathyroidectomy if PTH levels are high and cannot be controlled.

Diagnosis of­CKD-MBD

Bone biopsy remains the gold standard for the definitive diagnosis of CKD-MBD, however this is not carried out in routine clinical practice in the large majority of centres, and the diagnosis is usually based on bio­chemical parameters. Some of the histological features seen in the bone in CKD-MBD are demonstrated in figure 6.

PTH levels greater than 50 pcmol/L are highly indicative of osteitis fibrosa, whereas an adynamic lesion is suspected when levels are below 10 pcmol/L. The serum alkaline phosphatase level may be elevated in hyperparathyroidism indicating increased osteoblastic activity (Gonzalez, 2001). The radiological manifestations of bone disease are shown in figure 7 and figure 8.

Pathology of Secondary Hyperparathyroidism

Bone involvement in CKD-MBD can be divided into high turnover states and low turnover states.

High turnover states (osteitis fibrosa) are a consequence of hyperparathyroidism which increases bone turnover and bone resorption. This then contributes to bone pain and fractures at skeletal sites and systemic vascular injury including vascular calcification that is associated with an increased cardiovascular mortality.

Low turnover states are a consequence of PTH oversuppression and also vitamin D deficiency and (uncommonly) aluminium deposition in bone. Low turnover states are also associated with bone pain and an increased fracture rate and cardiovascular disease progression.

High turnover and low turnover changes can co-exist. Whilst the pathogenic pathways associated with this are different, ultimately they have the same clinical consequences for the patient.
Figure 6: A bone biopsy obtained from a patient with secondary hyperparathyroidism - this­biopsy shows zones of decalcification and­increased numbers of osteoclasts

Radiology of Secondary Hyperparathyroidism

Figure 7: Resorption of distal clavicles; usually bilateral and symmetrical­

Figure 8: Subperiosteal resorption along the radial surface of the proximal and middle phalanges of the second and/or third digits

Adynamic and Other Bone Diseases

Adynamic bone disease (ABD) is a common skeletal lesion in adult patients with CKD (figure 9) and a manifestation of low bone turnover. It is characterised histopatho­logically by a marked decrease in osteoblasts and osteoclasts with an increase in osteoid formation (Salusky, 2001). Adynamic bone disease is also caused by over-suppression of PTH levels by aggressive use of high-calcium dialysate, calcium-containing phosphate binders and vitamin D analogues. It is frequently seen in patients on peritoneal dialysis and those with­diabetes.


Figure 9: Adynamic bone disease in a patient on long-term haemodialysis


Osteomalacia is characterised by a reduction in the number of osteoblasts and osteoclasts, with an increase in the amount of osteoid. It is related to aluminum accumulation due to use of aluminum-containing phosphate binders. Long standing severe metabolic acidosis may also cause osteomalacia.

DIalysis (β2-Microglobulin) Amyloidosis

ESRD patients typically have serum concentrations of β2-microglobulin (β2M) 30-50 fold higher than normal, and are risk of developing dialysis amyloidosis (Aβ2M) affecting the skeletal system. Risk factors include: older patients; duration on dialysis; and, loss of residual renal function.

Dialysis amyloidosis can affect any joint, but especially affects the shoulder joint. So the disease often presents as shoulder pain in a dialysis patient, who has had many years on dialysis. Other clinical manifestations include carpal tunnel syndrome, tendon rupture/contracture, spondyloarthropathy, osseous involvement, subcutaneous masses and renal calculi.

MRI is the best radiological test. Histological evidence is required to make a definite diagnosis. Although of unproven benefit, it is reasonable to consider using biocompatible HD membranes, haemofiltration or haemodiafiltration at high flow rates, with ultrapure dialysate. Successful transplantation will restore β2M levels to the normal range. But it is unclear whether this causes the lesions to regress.






Phosphate Binders

Principles of Treatment

Key Point: The aim of treatment is is to reduce: (1) the occurrence and/or severity of uraemic bone disease; and, (2) cardiovascular morbidity and mortality caused by elevated serum levels of PTH and high phosphate levels and calcium overload.

Key Point: Treatment includes control of phosphate retention, maintaining serum calcium concentration within the normal range and prevention of excess PTH secretion. However the evidence base within this area is poor and the monitoring and interventions are based on observational associations and our understanding of pathophysiology. Few high quality randomised controlled trials have been performed that show a benefit of intervention.

Key Points: Renal Association Treatment Guidelines­

  1. The UK Renal Association recommends measuring serum calcium, phosphate and PTH levels when GFR is < 60ml/min/1.73m 2 (CKD stage 3 and above). It also recommends, in dialysis patients:
  2. Serum calcium, should be maintained within the normal range and be between 2.2 and 2.5 mmol/L, with avoidance of hypercalcaemic episodes
  3. Serum phosphate should be maintained between 1.1 and 1.7 mmol/L
  4. The target range for parathyroid hormone (measured using an intact PTH assay) should be 2-9 times the upper limit of normal for the assay used

Dietary Phosphate Restriction

Restricting phosphate intake can be achieved by reducing intake of dairy products, certain vegetables, and colas. Many physicians recommend phosphate restriction (to 800-1000 mg daily) when the serum phosphate level is > 1.8 mmol/L in patients with stage 5 CKD. Phosphate restriction can be challenging for the patient, and is best delivered by an individualised prescription designed and implemented by renal dieticians.

Phosphate Binders

Phosphate Binders are long established in the management of hyperphosphataemia in patients with CKD-MBD. The figure below shows the site of action of phosphate binders and also the target for calcitriol or active vitamin D analogs (discussed in detail under other treatments).


Figure 10: Therapeutic targets for phosphate binders and calcitriol

Aluminium-Containing Phosphate Binders

Aluminium hydroxide was first used as a phosphate binder by Freeman and Freeman in 1941. Aluminium-containing phosphate binders were, for many years, the phosphate binders of choice, forming insoluble and non­absorbable aluminium phosphate precipitates in the intestinal lumen. They are still the most effective phosphate binders but due to their renal elimination, patients with impaired renal function have a gradual tissue accumulation of absorbed aluminium with resultant toxicity (Ritz, 2004). The major manifestations of aluminium toxicity are­in­skeletal muscle, CNS and bone (leading to low-bone turnover osteomalacia, adynamic bone disease). Clinically, refractory micro­cytic anaemia, bone and muscle pain, and dementia develop (Salusky, 1991).

However, some physicians still prescribe low doses of aluminium hydroxide. The K/DOQI guidelines recommend the use of aluminium-containing phosphate binders only in patients with serum phosphorus levels >7.0 mg/dL (2.26 mmol/L). If used, one course of short-term therapy (4 weeks) is recommended; then replaced by another phosphate binder.

Calcium-Containing Phosphate Binders

Problems with aluminium-containing phosphate binders led to the development of­calcium salts to bind intestinal phosphate. In addition to lowering plasma phosphate concentration, absorption of some­calcium can­raise plasma calcium concentration, providing an additional mecha­nism by which PTH secretion can be reduced.

Calcium carbonate has been the most widely used calcium salt. However calcium acetate is a more efficient phosphate binder than calcium car­bonate, as it dissolves in both acid and alkaline environments; whilst calcium carbonate dissolves only in acid pH and many patients with advanced renal failure have achlorhydria or are taking H2-blockers or proton pump inhibitors (Emmett, 2004).

The required dose of calcium carbonate to control phosphate level ranges from 6 gm up to 15 gm/day (40 % of which is elemental calcium). Calcium salts are most effective if taken with meals, because they bind dietary phosphate - and therefore, leave less free calcium available for absorption.

However calcium salts in patients with ESRD can lead to hypercalceamia and metastatic calcification including coronary artery calcification, which are in turn is asso­ciated with cardiovascular mortality. To avoid metastatic calcification, K/DOQI guidelines suggest that the total dose of elemental calcium (including dietary sources) should not exceed 2000 mg/day. The identification of problems associated with calcium overload - and a total suggested calcium intake well below the level required for effective phosphate control - has led to a new generation of phosphate binders being increasingly used in clinical practice.

Non-Calcium, Non-Aluminium Phosphate Binders

Sevelamer hydrochloride
This was­the first synthetic non-calcium, non-aluminum phosphate binder to become widely available in the USA and Europe for the treatment of hyperphosphataemia in patients with CKD (Hutchinson, 2004). This cross linked poly allylamine hydrochloride exchange resin binds phosphate and releases chloride.

While the potency of sevelamer is low when compared with aluminium, beneficial effects of this drug include attenuation of the progression of coronary and aortic calcification, seen with­calcium­-containing phosphate binders. Also, a significant improvement in lipid profile, with reduction in­total and low-density lipoprotein (LDL) cholesterol, has been noted with sevelamer­(Sturtevant, 2004).

Sevelamer hydrochloride causes metabolic acidosis, which can exacerbate secondary hyperparathyroidism and renal osteodystrophy. Each 800 mg tablet of sevelamer hydrochloride could theoretically lead to an acid load equivalent to 4 mEq hydrochloric acid (Brezina, 2004). More recently, Sevelamar Carbonate has been introduced to avoid this problem with metabolic acidosis.

Sevelamer hydrochloride is considered a moderate phosphate binder because its optimal phosphate binding capacity occurs at a pH of 7; whereas the pH of the stomach and first part of the duodenum is much lower than this level. Also, high doses of this drug may reduce the absorption of vitamin D from the gut. Additionally, sevelamer hydrochloride is not selective for phosphate ions only, as it can bind other negatively charged ions such as chloride and bicarbonate. The dose range of 2.4g to 4.8g daily provides effective phosphate control without hypercalcaemia.

Lanthanum carbonate
This is a­more recent non-­calcium, non-aluminium phosphate binder. ­It is a salt of a rare earth metal, and is­a highly effective phosphate binder (Hutchison, 2004). It is minimally absorbed from the gastrointestinal tract and is not excreted by the kidneys (D'Haese, 2003). Lanthanum carbonate has been shown to be as effective as aluminium in binding phosphate but without the asso­ciated toxic effects.

It has minimal tissue accumulation when compared to aluminium, but long-term toxicity with bone accumulation cannot be ruled out. A dose between 1350 and 2250mg daily­is effective in reducing and maintaining phosphate levels in most patients. And the effect is seen within three weeks of treatment. Also, the incidence of hypercalcaemia is lower, and the calcium x phosphorus product reduced, when compared to calcium carbonate (De Broe, 2004).

Both calcium-based phosphate binders and other non-calcium, non-aluminium containing phosphate-binding agents are effective in lowering serum phosphate levels and may be used as the primary therapy.

Other Phosphate Binders

Magnesium salts may be used as an alter­native to calcium-containing phosphate binders in patients who develop hypercalcemia. Magnesium carbonate reduces PTH and phosphorus levels when used with magnesium-­free dialysate (O'Donovan, 1986).

Summary of Phosphate Binders

Calcium or Aluminium Containing Non-Calcium, Non-Aluminium Containing
Aluminium Hydroxide Lanthanum Carbonate
Calcium Acetate Magnesium Carbonate
Calcium Carbonate Sevelamar Hydrochloride and Carbonate




Other Treatments

Correction of Metabolic Acidosis

Correction of metabolic acidosis may be useful because studies of alkali therapy in patients who are not in renal failure suggest an improvement in bone parameters (Domrongkitchaiporn, 2002). Current dialysis prescriptions are tailored so that patients do not sustain significant acidosis.


Calcitriol is the most active metabolite of vitamin D and direct effects on the para­thyroid gland by suppressing the synthesis and secretion of PTH and limiting parathyroid cell growth. It was first­shown to be effective by Berl in 1978.

It can be administered orally and intravenously for the treatment of secondary hyperparathyroidism. It may cause hyperphos­phataemia and hypercalcaemia by increasing absorption of both calcium and phosphate. Intravenous 'pulse' therapy has a greater effect in reducing bone turnover by diminishing the number of active ostoblasts rather than the reduction in PTH levels. There is indirect evidence that pulse therapy with calcitriol, combined with use of calcium-containing phosphate binding agents, increases the prevalence of adynamic bone disease (Coburn, 2003).

Due to the potential of calcitriol to cause hyperphosphataemia, hypercalcaemia and an increase in calcium x phosphate product, new vitamin D analogues have been developed. These analogues are relatively selective for the­parathyroid gland with lesser effect on intestinal absorption of calcium and phosphate. 22-oxacalcitriol has a decreased affinity for vitamin D binding protein and a short plasma half-life - resulting in rapid clearance from the circulation. This may be the mechanism for its lesser effect on calcium and phosphate levels. It also decreases PTH secretion without affecting bone turnover (Tsukamoto, 2000).

The effects of calcitriol and 22-oxacalcitriol­on serum calcium and phosphate levels are similar, and­the suppressive effects of these drugs on PTH secretion are not significantly different (Hayashi, 2004).

Paricalcitol adequately controls PTH secretion with minimal hypercalcaemia and hyperphosphataemia com­pared to calcitriol (Llach, 2001). Also, doxercalciferol has the same suppressive effect on PTH with minimal changes in serum calcium and phosphate levels (Salusky, 2005). 22-oxacalcitriol and doxercalciferol are not yet available in the UK.

The American Food and Drug Administration (FDA) has indicated that there is no difference in the ability of intravenous paricalcitol and calcitriol to suppress PTH, and control calcium and phosphate levels, in paediatric haemodialysis patients (Cunningham, 2004). Of interest, other studies have suggested that none of the newer vitamin D analogues is superior to calcitriol or alfacalcidol in suppressing PTH; or controlling calcium, phosphate, or calcium x phosphate product.

For stages 3 and 4 CKD the efficacy of paricalcitol had been assessed in a randomised controlled trial with cardiovascular surrogates for long-term outcome as the study end-points. This showed­no difference in left ventricular mass index or left ventricular diastolic dysfunction for patients who received paracalcitol compared to patients who received treatment with placebo (Thadani et al, 2012).

According to KDIGO guidelines, both haemodialysis and peritoneal dialysis patients with serum PTH levels > 300 pg/ml (31.9 pmol/L), should receive an active vitamin D sterol such as calcitriol, alfacalcidol, pari­calcitol, or doxercalciferol to reduce the serum levels of PTH to the target range.


Therapy with calcimimetics is another, more recent, approach for the treatment of secondary hyperpara­thyroidism. These agents act at the level of the CaR, which is found in the parathyroid and C thyroid glands as well as renal tubular cells (Urena, 2003). Activation of this receptor by calci­mimetics increases intracellular calcium concentration, which causes rapid reduction in PTH secretion, serum phosphate, and the calcium x phosphate product, which remain suppressed for up to three years (Block, 2003).

Cinacalcet is a CaR sensitiser which is usually used in dialysis patients when parathyroid hormone exceeds­85 pmol/L, or at lower levels with hypercalcaemia, despite conventional treatment. Doses are titrated from 30 mg to 180 mg daily. Cinacalcet has the advantage of lowering levels of parathyroid hormone, and serum calcium and phosphate ; whereas vitamin D tends to increase serum calcium. It should be taken at the same hour every day to avoid overdose and adverse effects.

The patient should be started with a low dose, which is increased progressively every two weeks until target PTH levels are achieved. The serum PTH, phosphate and calcium levels should be checked regularly. Transient hypocalcaemia may occur which can be corrected by increasing the dialysate calcium levels, or­dose of calcium-containing phosphate binders and vitamin D (Block, 2004).

Transient episodes of nausea, vomiting have occurred in patients who were treated with cinacalcet. Also, upper respiratory tract infe­ctions, hypotension, diarrhoea and headache have been observed­(Lindberg, 2005).

There was great interest in the renal community in the results of a large randomised trial of cinacalcet in patients requiring chronic dialysis treatment. The study reported recently and showed that cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients wtih hyperparathyroidism who were undergoing chronic dialysis treatment (EVOLVE, 2012).


The need for surgical para­thyroidectomy in patients with secondary hyperparathyroidism has decreased signi­ficantly in recent years. This is due to increased efficacy of medical measures that can suppress parathyroid hormone (PTH) secretion, especially vitamin D (Kestenbaum, 2004).

Parathyroid sestamibi scan (with technetium Tc 99m-MIBI) demonstrating uptake in all 4 glands consistent with 4-gland hyperplasia

The main indications for PTx include: therapy-resistant hypercalcaemia and/or hyper­phosphatemia in the presence of a high PTH level; pruritus that does not respond to medical or dialysis therapy; progressive extra-skeletal calcification or calciphylaxis; un­explained symptomatic myopathy; and in renal transplant recipients with persistent hyper­parathyroidism and hyper­calcaemia.

Indications for Parathyroidectomy = High PTH levels +

  • Uncontrollable hyercalcaemia
  • Uncontrollable hyperphosphataemia
  • Unresponsive to phosphate binders and Vitamin D
  • Metastatic calcification
  • Calciphylaxis
  • Potential renal transplant recipient

There are two main types of parathyroidectomy: subtotal PTx; or total PTx with or without re-implantation of parathyroid tissue in the forearm. The latter is considered the procedure of choice in patients with metastatic calcification. Subtotal or total PTx with re-implantation­is performed to avoid hypoparathyroidism, particularly after renal transplantataion.

Dialysis dose

Dialysis dose is one of the major determinants of phosphate levels and hyperparathyroidism in patients with stage 5 CKD requiring chronic dialysis therapy. High phosphate levels are associated with inadequate dialysis dosing. Indeed, in patients who have daily or extended nocturnal dialysis, phosphate control is usually excellent; and there is less requirment for dietary phosphate restriction or the use of phosphate binders and vitamin D analogues.



Top Tip: Utilise dietary phosphate restriction, a phosphate binder and calcitriol in all ESRD patients. Tailor dosing to guideline targets.

  1. Secondary hyperparathyroidism occurs as a result of hyperphosphataemia, hypocalcaemia and impaired synthesis of renal vitamin D with reduction in serum calcitriol levels
  2. Patients with secondary hyperparathyroidism have a range of symptoms
  3. The aim of treatment is is to reduce: (1) the occurrence and/or severity of uraemic bone disease; and, (2) cardiovascular morbidity and mortality caused by elevated serum levels of PTH and 'calcium x phosphate' product
  4. Treatment includes control of phosphate retention, maintaining serum calcium concentration within the normal range and prevention of excess PTH secretion
  5. The UK Renal Association recommends measuring serum calcium, phosphate and PTH levels when GFR is < 60ml/min/1.73m 2 (CKD stage 3 and above). It­also recommends, in dialysis patients:
  6. Serum calcium, should be maintained within the normal range and be between 2.2 and 2.5 mmol/L, with avoidance of hypercalcaemic episodes
  7. Serum phosphate should be maintained between 1.1 and 1.7 mmol/L
  8. The target range for parathyroid hormone (measured using an intact PTH assay) should be 2-9 times the upper limit of normal for the assay used





Akizawa T, Shiizaki K, Hatamura I, et al. New strategies for the treatment of secondary hyperparathyroidism. Am J Kidney Dis 2003; 41(3 Suppl 1): S100-3

Alfrey AC. The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification. Kidney Int Suppl 2004; (90): S13-7

Almaden Y, Hernandez A, Torregrosa V, et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 1998; 9(10):1845-52

Berl T et al. 1,25 dihydroxycholecalciferol effects in chronic dialysis. A double-blind controlled study. Ann Intern Med 1978; 88(6): 774-80

Block GA. The impact of calcimimetics on mineral metabolism and secondary hyper­parathyroidism in end-stage renal disease. Kidney Int Suppl 2003; (87): S131-6­

Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperpara­thyroidism in patients receiving hemodialysis. N Engl J Med 2004; 350(15): 1516-25

Braun J, Oldendorf M, Moshage W, et al. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 1996; 27(3): 394-401

Brezina B, Qunibi WY, Nolan CR. Acid loading during treatment with sevelamer hydrochloride: mechanisms and clinical impli­cations. Kidney Int Suppl 2004; (90): S39-45

Bricker NS et al.­Calcium, phosphorous, and bone in renal disease and transplantation. Arch Intern Med 1969; 123: 543-553

Bricker NS. On the pathogenesis of the uremic state. An exposition of the "trade-off hypothesis." N Engl J Med 1972; 286: 1093-1099

Coburn JW. An update on vitamin D as related to nephrology practice: 2003. Kidney Int Suppl 2003; (87): S125-30

Cunningham J. New Vitamin D analogues for osteodystrophy in chronic kidney disease. Pediatr Nephrol 2004; 19(7): 705-8

D'Haese PC, Spasovski GB, Sikole A, et al. A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients. Kidney Int Suppl 2003; (85): S73-8­

De Broe ME, D'Haese PC. Improving outcomes in hyperphosphataemia. Nephrol Dial Transplant 2004; 19 Suppl 1: i14-8

De Francisco AL. Secondary hyperpara­thyroidism: review of the disease and its treatment. Clin Ther 2004; 26(12):1976-93

Domrongkitchaiporn S, Pongskul C, Sirikulchayanonta V, Stitchantrakul W, Leeprasert V, Ongphiphadhanakul B, et al. Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Kidney Int 2002; 62: 2160-6

Drueke TB. The pathogenesis of parathyroid gland hyperplasia in chronic renal failure. Kidney Int 1995; 48(1): 259-72

Drueke TB. Cell biology of parathyroid gland hyperplasia in chronic renal failure. J Am Soc Nephrol 2000; 11(6): 1141-52

Emmett M. A comparison of clinically useful phosphorus binders for patients with chronic kidney failure. Kidney Int Suppl 2004; 90: S25-32
This is a very good summary of phosphate binding agents, and worth reading

EVOLVE Trial Investigators, Chertow GM et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012 Dec 27; 367(26): 2482-94

Freeman S, Freeman WMC. Phosphorus retention in children with chronic renal insufficiency. The effect of diet and of the ingestion of aluminum hydroxide. Am J Dis Child 1941; 61: 981-1002

Friedman EA. Consequences and manage­ment of hyperphosphatemia in patients with renal insufficiency. Kidney Int Suppl 2005; (95): S1-7

Gonzalez EA, Martin KJ. Renal osteodystrophy. Rev Endocr Metab Disord 2001; 2(2):187-93

Goodman WG. Medical management of secondary hyperparathyroidism in chronic renal failure. Nephrol Dial Transplant 2003;18 Suppl 3:iii2-8

Hayashi M, Tsuchiya Y, Itaya Y, et al. Comparison of the effects of calcitriol and maxacalcitol on secondary hyperparathyroidism in patients on chronic haemodialysis: a randomized prospective multicentre trial. Nephrol Dial Transplant 2004; 19(8): 2067-73

Hutchison AJ. Improving phosphate-binder therapy as a way forward. Nephrol Dial Transplant 2004; 19 Suppl 1: i19-24

Hutchison AJ, Speake M, Al-Baaj F. Reducing high phosphate levels in patients with chronic renal failure undergoing dialysis: a 4-week, dose-finding, open-label study with lanthanum carbonate. Nephrol Dial Transplant 2004; 19(7): 1902-6

Kestenbaum B, Seliger SL, Gillen DL, et al. Parathyroidectomy rates among United States dialysis patients: 1990-1999. Kidney Int 2004; 65(1): 282-8

Larsson TE. The role of FGF-23 in CKD–MBD and cardiovascular disease: friend or foe? Nephrol. Dial. Transplant. (2010) 25 (5): 1376-1381

Lindberg JS, Culleton B, Wong G, et al. Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperpara­thyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multi­center study. J Am Soc Nephrol 2005; 16(3): 800-7

Llach F. Secondary hyperparathyroidism in renal failure: the trade-off hypothesis re­visited. Am J Kidney Dis 1995;25(5): 663-79

Llach F, Yudd M. Paricalcitol in dialysis patients with calcitriol-resistant secondary hyperparathyroidism. Am J Kidney Dis 2001; 38(5 Suppl 5): S45-50

Llach F. The evolving clinical features of calciphylaxis. Kidney Int Suppl 2003; (85): S122-4

Llach F, Fernandez E. Overview of renal bone disease: causes of treatment failure, clinical observations, the changing pattern of bone lesions, and future therapeutic approach. Kidney Int Suppl 2003; (87): S113-9

Locatelli F, Cannata-Andia JB, Drueke TB, et al. Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 2002; 17(5): 723-31

Martin KJ, Olgaard K, Coburn JW, et al. Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodys­trophy. Am J Kidney Dis 2004; 43(3): 558-65

Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 69: 1945-53

Navaneethan SD et al. Benefits and Harms of Phosphate Binders in CKD: A Systematic Review of Randomized Controlled Trials. Am J Kid Dis 2009; 54 (4): 619-637

O'Donovan R, Baldwin D, Hammer M, et al. Substitution of aluminium salts by magnesium salts in control of dialysis hyper­phosphataemia. Lancet 1986; 1(8486): 880-2

Parfitt AM. Soft-tissue calcification in uremia. Arch Intern Med 1969; 124: 544-556

Ritz E. Managing mineral balance in end­stage renal disease. Nephrol Dial Transplant 2004;19 Suppl 1: i1-3

Roberts DM,­Singer RF. Management of renal bone disease. Aust Prescr 2010; 33: 34-7
Good practical guide to prescribing in CKD-MBD

Salusky IB, Foley J, Nelson P, Goodman WG. Aluminum accumulation during treatment with aluminum hydroxide and dialysis in children and young adults with chronic renal disease. N Engl J Med 1991; 324(8): 527-31

Salusky IB, Goodman WG. Adynamic renal osteodystrophy: is there a problem? J Am Soc Nephrol 2001;12(9):1978-85

Salusky IB. Are new vitamin D analogues in renal bone disease superior to calcitriol? Pediatr Nephrol 2005; 20(3): 393-8

Sturtevant JM, Hawley CM, Reiger K, et al. Efficacy and side- effect profile of sevelamer hydrochloride used in combination with conventional phosphate binders. Nephrology (Carlton) 2004; 9(6): 406-13

Tallon S, Berdud I, Hernandez A, et al. Relative effects of PTH and dietary phosphorus on calcitriol production in normal and azotemic rats. Kidney Int 1996; 49(5):1441-6

Tsukamoto Y, Hanaoka M, Matsuo T, et al. Effect of 22-oxacalcitriol on bone histology of hemodialyzed patients with severe secondary hyperparathyroidism. Am J Kidney Dis 2000; 35(3): 458-64

Urena P. Use of calcimimetics in uremic patients with secondary hyperparathyroidism: review. Artif Organs 2003; 27(9): 759-64

Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial 2002;15(3): 172-86


Moorthi RN, Moe SM. CKD–Mineral and Bone Disorder: Core Curriculum 2011.­ American Journal of Kidney Diseases 2011;­58 (6):­1022-1036


Australasian/CARI (April 2006). Haematological and Biochemical Targets

Australasian/CARI (April 2006). Vitamin D, Calcimimetics and Phosphate Binders

Canada/Canadian Society of Nephrology (May 2010).­Canadian Society of Nephrology Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD–Mineral and Bone Disorder (CKD-MBD)

Europe/European Best Practice Guideline (September 2010).­Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guidelines: a European Renal Best Practice (ERBP) commentary statement

Global/KDIGO (August 2009).­KDIGO Guideline for Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

US/KDOQI (May 2010).­KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD–Mineral and Bone Disorder (CKD-MBD)

UK/Renal Association (December 2010). CKD-MBD guideline. Steddon S, Sharples E