In focus: CKD mineral and bone disorder

Chronic kidney disease (CKD) is a highly prevalent and progressive condition, affecting more than 10 per cent of the global population. Disturbances in the metabolism of mineral and bone are common in patients with the disease, which in turn, carries additional morbidity for an already burdened population. Ireland has a notably high incidence of CKD, and most of this population will experience some degree of disordered mineral metabolism and bone disease.

According to Kidney Disease: Improving Global Outcomes (KDIGO), the term ‘renal osteodystrophy’ exclusively defines the bone morphological changes which are associated with CKD, while the term CKD-mineral and bone disorder (CKD-MBD) refers to the broader clinical syndrome which develops as a systemic disorder secondary to CKD.

Therefore, CKD-MBD encompasses bone and extra-skeletal changes, such as vascular calcification, along with bone alterations and laboratory abnormalities. Extra-skeletal calcification, in particular, has been associated with increased mortality secondary to cardiovascular events.

Renal osteodystrophy

Because renal osteodystrophy represents the histological changes occurring in CKD-MBD, it is therefore classified according to bone turnover, mineralisation, and volume – or the TMV system. Using this classification system, renal osteodystrophy may be classified into four distinct categories: Osteitis fibrosa cystica (OFC), mixed uraemic osteodystrophy, adynamic bone disease, and osteomalacia. Each of these patterns differ histologically and are brought about by different patholophysiological processes.

At the high turnover end of the spectrum there is OFC, which starts quite early on in the course of CKD – typically when the estimated glomerular filtration rate (eGFR) falls below 60mL/min/1.73m² – and occurs as a response to increased parathyroid hormone (PTH) secretion.

OFC is rare and is characterised by increased bone turnover alongside elevated activity and number of osteoblasts and osteoclasts, variable changes in osteoid deposition, typically with a woven picture, and variable quantities of peritrabecular fibrosis.

At the other end of the spectrum is osteomalacia, which is defined by a much lower bone turnover rate and a significant accumulation of unmineralised osteoid. Mixed uraemic osteodystrophy is a complex disorder characterised by increased bone turnover coexisting with features of osteomalacia.

Adynamic bone disease develops secondary to suppressed PTH levels. It results in low bone turnover and inadequate mineralisation which lacks the excess osteoid accumulation seen in osteomalacia.

Adynamic bone disease has become increasingly prevalent over time due to factors including aggressive calcium and vitamin D supplementation, diabetes, continuous ambulatory peritoneal dialysis, and skeletal resistance to PTH, among others. All forms of the disease require a multidisciplinary approach.

CKD-MBD

CKD-MBD occurs due to either one or a combination of three main processes:

1. Abnormalities in mineral metabolism – including disruption of calcium, phosphorus, vitamin D, PTH, or fibroblast growth factor-23 (FGF23) levels. The Dialysis Outcomes and Practice Patterns Study (DOPPS) showed that there is an independent and direct association between abnormal mineral metabolism and all-cause and cardiovascular mortality.

2. Bone abnormalities – may be due to changes in bone turnover, volume, mineralisation, linear growth, or strength. Osteoporosis and subsequent risk of fragility fractures is a concern for many CKD patients.

3. Extra-skeletal calcification – vascular and/or soft-tissue. Manifestations include cardiac abnormalities (eg, atrial fibrillation, cardiac fibrosis), vascular calcifications, neurologic events (eg, dementia, cognitive decline), gastro-intestinal effects (eg, liver inflammation, constipation), infections, and malnutrition.

Diagnosis

Despite the fact that a history of CKD suggests CKD-MBD, it is empirical to rule out other bone disorders such as osteopenia, osteopetrosis, vitamin D-resistant rickets, and Paget’s disease of bone so as to ensure correct diagnosis and proper management. The presenting symptoms of CKD-MBD are generally due to the predominant metabolic abnormalities and associated skeletal disease.

Hyperparathyroidism and many bone issues may initially be asymptomatic, but over time, affected patients may develop pronounced symptoms such as proximal myopathy and bone pain. These symptoms are usually under-reported as a result of their gradual onset.

The gold standard for diagnosis is bone biopsy, however, it is not feasible in most cases owing to its invasiveness and availability. Furthermore, the 2017 KDIGO guideline update no longer advises performing a bone biopsy before initiating treatment.

Radiological studies are crucial in characterising bone disease associated with CKD-MBD, and dual-energy x-ray absorptiometry (DXA) scans are commonly used to measure bone mineral density. As per the 2017 KDIGO guidelines, it is recommended that bone mineral density testing is considered in the evaluation of fracture risk in patients with CKD and other risk factors for osteoporosis.

All patients with CKD exhibiting signs and symptoms of skeletal disease or structural deformities should undergo evaluation including calcium, phosphate, PTH, and bone-specific alkaline phosphatase (BsALP) levels. PTH plays a crucial role in CKD-MBD pathogenesis and can be used to differentiate between low and high bone turnover states. The diagnostic cut-off for PTH varies on the basis of whether the patient is on dialysis or not. If elevated PTH is noted, the next sensible step would be to assess the level of serum vitamin D.

FGF23 is an emerging biomarker which has recently gained attention in diagnosis of CKD-MBD. However, despite its reported clinical usefulness, it is rarely used due to its instability, high cost, diurnal variability, and lack of precision.

Cases of secondary hyperparathyroidism are generally monitored by measurement of serum levels of calcium, phosphate, and PTH. There is no standard frequency of monitoring for CKD-MBD. Usually, measurement of serum calcium and phosphate (BsALP) levels every four to 12 weeks and PTH every three to six months is deemed adequate. However, these intervals should be modified according to changes in therapy or the patient’s condition which could impact these levels.

MANAGEMENT

Based on the 2017 KDIGO guidelines, treatment of CKD-MBD varies according to the predominant metabolic abnormality, the characteristic bone disease, and the severity of the underlying renal impairment. Management hinges on strict control of calcium, phosphate, PTH, and vitamin D levels.

Treatment for adult non-dialysis patients

All CKD patients with an eGFR less than 60mL/min/1.73m² are susceptible to develop secondary hyperparathyroidism. Serial assessment of calcium, phosphate, PTH, 25-hydroxyvitamin D, and BsALP (if available) guides treatment of these patients. The management plan for this cohort includes the following considerations:

Phosphate: It is crucial to keep serum phosphate levels less than 5.5mg/dL so as to lower increased PTH levels. These patients are strongly encouraged to follow a diet restricted in phosphorus. The initiation of phosphate binders is reserved for patients with persistently high serum phosphate levels despite a phosphorus-restricted diet.

Calcium: Patients with asymptomatic and mild hypocalcaemia (more than 7.5mg/dL with normal albumin levels) usually do not require treatment with calcium or vitamin D analogues. When addressing vitamin D deficiency, mild hypocalcaemia may be corrected. When administering calcium and vitamin D derivatives, there is concern for the increased risk of vascular calcification.

It is recommended the daily dietary calcium intake is maintained at around 1g, and prescription of 1.5g of elemental daily calcium substantially more than doubles calcium intake. Along with decreased calcium excretion related to CKD, this leads to a positive calcium balance, which in turn promotes vascular calcification and other ramifications of the disease.

Vitamin D deficiency: This is prevalent among patients with CKD and may manifest as an initial laboratory abnormality. There is a correlation between vitamin D deficiency and hyperparathyroidism and this may exacerbate hypocalcaemia.

With the exception of patients with hypercalcaemia and hyperphosphataemia, vitamin D-deficient CKD patients are usually supplemented with cholecalciferol or, alternatively, ergocalciferol. Calcitriol, that is, activated vitamin D, is reserved for cases of advancing hyperparathyroidism.

Hyperparathyroidism: CKD patients with progressive or persistent hyperparathyroidism should receive treatment which targets modifiable risk factors such as hyperphosphataemia, vitamin D deficiency, and excessive phosphate intake. The use of calcitriol should be considered if the mentioned measures fail to lower PTH levels.

Usually, treatment with calcitriol or vitamin D derivatives is initiated when PTH levels increase to two to three times the upper limit of normal and the recommended initial dose is 0.25mcg administered thrice weekly, with appropriate titration aiming to achieve a PTH level of less than 150pg/mL. It is important to note that calcitriol is contraindicated in instances where the phosphate levels are higher than the normal range or if the concentration of free calcium is equal to or higher than 2.37mmol/L.

Treatment of adult dialysis patients

For patients on dialysis, the recommended levels for phosphate are typically targeted to be in the range of 3.5 to 5.5mg/dL whilst serum calcium levels are ideally kept below 9.5mg/dL. For PTH levels, the recommended levels for dialysis patients are less than two to nine times the upper limit for the respective assay.

Once the hyperphosphataemia is controlled, the management of PTH levels is based upon trends rather than isolated lab values. It is important to note that suppression of PTH to less than twice the upper limit is not advisable as this may lead to the development of adynamic bone disease.

Phosphate: Management of phosphate levels is critical for patients with persistent high phosphate levels exceeding 5.5mg/dL. This is because hyperphosphataemia may complicate treatments for high PTH levels secondary to potential rises in serum phosphate levels. Initiation of treatment should take place if serum phosphate levels exceed 5.5mg/dL because such levels are associated with elevated mortality among patients on dialysis.

Initial measures typically include restricting phosphate intake and the use of phosphate binders. Additionally, clinicians should ensure that these patients are appropriately dialysed and achieving the recommended ratio of cleared urea (Kt) to the volume of distribution (v), that is, the Kt/V targets.

Calcium: It is essential to maintain calcium levels below 9.5mg/dL (2.37mmol/L). Asymptomatic and mild hypocalcaemia does not necessitate treatment in view of the risk of hypercalcaemia. In patients on dialysis, serum calcium levels are maintained close to the upper limit of normal by adjusting the concentration of calcium in the dialysate. There is an association between hypocalcaemia and increased mortality along with worsening hyperparathyroidism.

An alternative approach is adopted for patients with low bone turnover subtypes. An effort should be made to prevent the suppression of PTH by decreasing calcium and vitamin D levels. In order to prevent PTH suppression, non-calcium-containing phosphate binders (such as sevelamer) are used to maintain phosphate levels without causing an increase in the calcium levels. This approach has been shown to raise bone formation rates. For similar reasons, the concentration of calcium in the dialysate is also kept at a lower level than the standard dialysate levels.

Vitamin D: Given the association between low vitamin D levels and increased mortality rates among haemodialysis patients, correction of vitamin D deficiency is imperative. Cholecalciferol and ergocalciferol have both been deemed effective in the correction of vitamin D levels.

Hyperparathyroidism: Calcimimetics, calcitriol, or synthetic vitamin D derivatives are all treatment options used for hyperparathyroidism. Most cases require a combination as single agents are insufficient if PTH levels are tremendously elevated. If calcium levels increase more than 10.2mg/dL and phosphate levels above 5.5mg/dL, then synthetic vitamin D analogues or calcitriol are discontinued or administered at the minimum effective dose.

Once hyperphosphataemia or hypercalcaemia has resolved, the patient may either be started on cinacalcet or the previous agents may be restarted at half the initial dose. Vitamin D derivatives or calcitriol are usually initiated at a low dose, typically 0.25mcg thrice weekly and response to treatment is commonly observed within the initial three to six months. Doses may be adjusted at one to two month intervals if needed. The combination of calcimimetics and ongoing treatment with vitamin D derivatives or calcitriol along with phosphate binders increases the chance of achieving ideal PTH levels without causing hypercalcaemia or hyperphosphataemia.

Conclusion

CKD-MBD is a complex condition involving alterations in bone morphology as well as systemic effects. It is one of many complications of CKD, and most people with the disease will exhibit some degree of MBD. Symptoms range from mild early forms of osteodystrophy to serious bone fractures and systemic manifestations.

Effective management requires extensive patient education that necessitates a multidisciplinary, collaborative approach. Concordance with a difficult renal regime is challenging in a variety of ways, therefore psychological support is also essential. In some cases, surgical input and parathyroidectomy may also be required. Overall, CKD-MBD carries many challenges for clinicians and patients.

References available on request