Kidney Clinic - Hearts and bones: CKD-MBD

NOTE: This article was first published in May 2021 in Issue 13 of our Kidney Matters magazine

Bone is made of collagen, a protein that provides a soft framework, and calcium phosphate, a mineral that adds strength and hardens the framework. In healthy people, nearly all (more than 99%) of the body’s calcium is contained in the bones and teeth.

There are two types of bone: cortical and trabecular. Cortical bone is dense and compact and forms the rigid outer layer. Trabecular bone forms the inner layer and has a honeycomb-like structure. Cortical and trabecular bone gives the skeleton the strength and flexibility to withstand stress and resist fracture.

Bone is a living, growing structure that constantly changes as worn-out bone is broken down and replaced by new bone—called turnover or remodelling. Since the kidneys play an important role in bone remodelling, kidney disease upsets the delicate balance of minerals in the bones and blood, resulting in hormonal imbalances that lead to CKD-MBD.

What is CKD-MBD?

As Dr Colin Geddes explains: “The primary role of the kidney is to maintain the correct amount and composition of the fluid that bathes our cells (the extracellular fluid). Calcium and phosphate are two very important minerals that have to be controlled in that fluid. It is essential that the level of calcium in the fluid is kept in a narrow range (2.2-2.6 mmol/L); if not, our heart, nerves and muscles cannot function properly.” Colin is a Consultant Nephrologist at NHS Greater Glasgow and Clyde.

The kidney controls the amount of calcium that passes from food into the bloodstream by activating vitamin D, a hormone that is mostly produced in the skin in response to sunlight. When the calcium levels in the extracellular fluid and bloodstream fall—for example, if we have not eaten any calcium-containing food—this low level is detected by the parathyroid glands in the neck, which release parathyroid hormone (PTH).

In response to rising PTH, the body breaks down bone to release calcium into the bloodstream and raise the calcium level back to normal range. When we eat calcium-containing food, calcium is absorbed back into the bone, levels of PTH fall, and things are back to normal.

“That is what happens with healthy kidneys. When you have reduced kidney function, especially when your kidneys have failed completely and you are on dialysis, your kidneys do not activate vitamin D. As a result, the calcium level in your blood tends to be low, so your parathyroid glands are permanently overactive (secondary hyperparathyroidism) leading to a high level of PTH in the blood. The result is damage to the structure of the bones and abnormal deposits of calcium in the blood vessels and sometimes the joints and the skin, which is why the condition is called CKDMBD (see Table),” explains Colin.

Defining CKD-MBD

Guidelines for doctors define CKD-MBD as systemic disorder of mineral and bone metabolism due to CKD manifested by one or a combination of:

• Abnormalities of calcium, phosphorus, parathyroid hormone, or vitamin D metabolism
• Or abnormalities in bone turnover, mineralisation, volume, linear growth, or strength
• Or vascular or other soft-tissue calcification.

How common is CKD-MBD?

The abnormalities in blood levels of calcium, phosphate and PTH that characterise CKD-MBD are present in virtually everyone who is on dialysis. CKDMBD tends to develop when eGFR is less than 30ml/min/1.732 (CKD stage 4), although subtle abnormalities can be detected at earlier CKD stages. Generally, the worse the kidney function and the lower the eGFR, the greater the likelihood of CKD-MBD.

CKD-MBD is not the same as osteoporosis, another slowly developing condition that affects the structure and strength of the bones. Osteoporosis is caused by age-related changes in bone remodelling, in which breakdown of old bone outpaces formation of new bone. Osteoporosis affects both women and men, but women have a higher risk due to loss of oestrogen hormone at the menopause.

“Kidney patients have the same risk factors for osteoporosis as the rest of the population, so it is possible to have both CKD-MBD and osteoporosis— for example, if you are a post-menopausal woman on dialysis. It can be difficult to differentiate between the two conditions, and most kidney specialists find CKD-MBD challenging to diagnose definitively. This is because our current tests to monitor and assess CKD-MBD do not give us the full picture of what is happening to the bones and the blood vessels,“ comments Colin.

How do I know that I have CKD-MBD?

Subtle changes that indicate CKD-MBD can be detected on X-ray. However, routine X-rays are not recommended, because they subject people to unnecessary radiation and the results are unlikely to change treatment.

The gold-standard investigation to confirm CKD-MBD is a bone biopsy, in which a doctor uses a special needle under X-ray guidance to take small sample of bone for examination under microscope. However, bone biopsy is rarely used to diagnose and monitor CKD-MBD because it is invasive and potentially painful, and is again unlikely to affect the choice of treatment.

Colin adds: “Other possible indications of CKD-MBD are complications such as bone pain, low-impact fractures, muscle aches and pains, calcium deposits in the blood vessels that can reduce the blood supply to that part of the body including the blood vessels around the heart (coronary arteries), calcium deposits on heart valves and calcium deposits in soft tissues. However, these problems have other potential causes, so their presence does not definitely diagnose CKD-MBD.”

The one complication that is almost always specific to CKD-MBD is calciphylaxis. This very rare condition develops when calcium deposits cause narrowing in the small blood vessels supplying the skin. This reduces the blood supply to the skin, causing severe pain and painful ulcers that do not heal well.

“At present kidney doctors have to rely on blood tests to infer that a kidney patient has CKD-MBD. This is why we regularly test the levels of calcium, phosphate and PTH in your blood,” says Colin.

Does a transplant improve CKD-MBD?

A well-functioning kidney transplant restores the kidney’s ability to maintain levels of phosphate, calcium and PTH within the normal ranges. It may take a few months for levels to normalise even if the kidney is working very well, but eventually most kidney transplant recipients do not need to follow dietary restrictions or take phosphate binders. Conversely, if the transplanted kidney does not work well or starts to fail, CKD-MBD will develop in the same way as when native kidneys are failing.

“While the parathyroid glands remain overactive, a patient with a well-functioning kidney may have very low phosphate levels in the blood. We usually manage this simply with diet until things settle down—and most patients are absolutely delighted when I tell them to eat lots of dairy products, nuts and the other foods that they used to be advised to avoid,” adds Colin.

Conclusion

Current treatments change the results of blood tests, but there remains a lack of high-quality clinical trials in CKD-MBD. It therefore remains unclear whether these treatments, given in the right combination, reduce the risk of ‘hard endpoints’ like heart attack that really matter to kidney patients. Large, pragmatic randomised trials— for example, HiLo in the USA and PHOSPHATE in Australia, New Zealand, Canada and the UK—are now under way. These trials are recruiting dialysis patients to compare the effects of different target blood levels of phosphate on outcomes such as quality of life, heart attack, hospitalisation and survival.

Colin says: “Until these trials report their results, my number one priority when reviewing someone on dialysis will continue to be whether they are on the transplant list and if not, why not. And if they are suitable for a transplant, whether they have explored all the options for living donation. My next priority is whether they have good access for dialysis. All the other issues like phosphate and haemoglobin levels are much less important.

“My message is not to worry too much about slight, short-term changes in your phosphate results on your blood tests. And you should definitely not blame yourself and think that you have heart problems because your phosphates are too high, because the evidence for that is not definitive,” he concludes.