CKD- Mineral and Bone Disorder

Chronic kidney disease impacts roughly 30 million people in the US and comes with many complications. In this post, I will be covering the Mineral and Bone disorder associated with CKD which has historically been the most confusing topic related to CKD. 

Follow along and let’s simplify this disorder. 

When learning any disease state, always start with the pathophysiology. If you are not able to fully understand what is going wrong, the management of it or the drugs used will not make sense. 

So what is going wrong in this case. 

There are 4 key players 

1. Parathyroid hormone (PTH)
2. Vitamin D 
3. Calcium 
4. Phosphate 

When there is renal impairment, there are two things that start the whole mess. 

1. Kidneys cannot excrete excess phosphate as they would normally do —> phosphate levels start rising in blood
2. Kidneys cannot convert the inactive vitamin D i.e. 25- hydroxyvitamin D or often referred as 25-OHD to its active form calcitriol
   1. This causes vitamin D deficiency 
   2. Active vitamin D is required for calcium absorption- Calcium absorption in the gut is decreased – we now have low serum Calcium levels as well 

We have established three problems now:

• Our phosphate levels are high
• Our calcium levels are low 
• Vitamin D levels are low 

The body has compensatory mechanisms to return to homeostasis. 

Both high phosphate levels and low calcium levels stimulate the release of PTH. PTH wants to correct the calcium levels. The calcium levels would normally be corrected by activating vitamin D, increasing the reabsorption of calcium in the kidneys, however we already know our kidneys are impaired and unable to do these tasks effectively so in this case, PTH starts to extract calcium from the bones to compensate for the low serum calcium levels which leads to bones de-mineralization. Bones start getting weaker and prone to fractures. 

Ideally, when calcium levels have returned to normal, this process should stop but we still have the chronically elevated phosphate levels which keep stimulating the PTH release and calcium keeps getting pulled from the bones and now we have reached a state of hypercalcemia which comes with its own problems. Calcium starts depositing in the vasculature over time and the calcifications now lead to vascular disease.

Hyperphosphatemia is really the devil here because it leads to chronically elevated PTH levels and PTH is going to keep causing bone demineralization leading to weaker bones with fractures. 

How are we going to fix this mess? We have to decrease our phosphate levels!!! 

Treatment 

1. Start with restricting dietary phosphate to 900mg/day 
2. Use phosphate binders if levels remain high 

Nutritionists can be referred at this time to help the patient get a diet plan but just to give a quick reference, here are some foods high in phosphate: 

• Poultry, fish 
• Beans, lentils
• Nuts
• Dairy 
• Oatmeal 
• Cola

If dietary restriction is not sufficient and levels continue to stay high then we resort to phosphate binders which in most cases we do. The KDIGO guidelines suggest lowering phosphate levels towards the normal range i.e. < 4.5mg/dL

What are phosphate binders?

These are drugs that will “bind” to the ingested phosphate in the intestines and block its absorption. 

There are different kind of phosphate binders and we usually break them down into calcium containing or non calcium containing and aluminum based. 

The first category is Calcium-Based binders

Calcium Carbonate	Tums and others	500-1000 mg PO TID with meals	constipation, N/V, diarrhea, hypercalcemia, calcifications
Calcium Acetate  (Rx)	PhosLo and others	667- 1,334 mg PO TID with meals

Key points: 

• These contain calcium, the total dose of elemental calcium including dietary sources should not exceed 2000mg per day and the amount contained in the phosphate binder should not exceed 1500mg. 
• The dosing will vary formulation to formulation and the dose has to be titrated per the phosphate levels of the patient
• They are cheap! More affordable however KDIGO guidelines recommend non-calcium containing binders over these due to adverse events associated with hypercalcemia
• They bind to other agents such as quinolones, tetracyclines, iron, zinc, bisphosphonates, levothyroxine so many drug interactions 

 

The second Category is Non-Calcium containing Binders: 

Sevelamer	Renvela	800-1600mg PO TID with meals	lowers LDL Large pills, difficult to swallow, cannot crush Reduces absorption of vitamin D,E,K and folic acid- may need supplementation  Do not use in bowel obstruction
Lanthanum	Fosrenol	500mg PO TID with meals	Risk of GI perforation Do not use if bowel obstruction
Ferric Citrate	Auryxia	420mg PO TID with meals	Contains iron that is absorbed
Sucroferric oxyhydroxide	Velphoro	500mg PO TID with meals

Key points:

• They bind to other agents such as quinolones, levothyroxine, and antacids; must separate from other drugs. 

 

Lastly, there is an Aluminum- based binder:

Aluminum hydroxide

Alu-Cap and others

300-600mg PO TID with meals

Aluminum accumulation, bone disease N/V, constipation

Aluminum hydroxide is a very potent binder however its use is reserved as a last resort in patients that are not responding to other binders or cases of severe hyperphosphatemia. Important to note that their use is limited to 4 weeks only! There is a high risk of aluminum accumulation that can cause bone disease and nervous system toxicities. 

You may have noticed that all binders must be taken with meals. That is important because the mechanism is to absorb the phosphate in your diet. If the patient already ate, food is absorbed and they forgot to take their medicine, then the dose should be skipped because it serves no purpose to take it once the food is already absorbed. 

Now that we have corrected the elevated phosphate levels by dietary restriction and introducing phosphate binders, let’s shift focus to our second problem here i.e.

Vitamin D deficiency leading to reduced Ca absorption and PTH still being stimulated. 

To tackle this problem, we use vitamin D or its analogs to promote intestinal absorption of Calcium which will provide negative feedback to the parathyroid gland and stop its release.

Nutritional Vitamin D —> These are inactive forms of vitamin D which have to be converted to the active form. If they kidneys are unable to activate vitamin D, these are not suited for the patient 

• Ergocalciferol D2
• Cholecalciferol D3

Active Vitamin D —> Highest risk of hypercalcemia and hyperphosphatemia due to increased GI absorption 

• Calcitriol
• Calcifediol 

Vitamin D Analogs —> These are more specific for receptors located in the parathyroid gland and not in the GI tract therefore have the least effect on raising calcium and phosphate levels. 

• Paricalcitol
• Doxercalciferol 

Key points from vitamin D section is important to know which form is inactive, active and which ones are analogs. Be mindful of the fact that if a patient is unable to convert vitamin D to active form, giving ergocalciferol and cholecalciferol serves no benefit. And lastly note that calcitriol is associated with the highest risk of hypercalcemia and hyperphosphatemia and vitamin D analogs have the lowest risk. (important exam question). 

This concludes the end of this topic. Hope this helped simplify some of the concepts.

Comment below with any questions or concerns.