Guide
Patients with chronic kidney disease (CKD) and end-stage renal disease (ESKD) are at higher risk of calcification outside of their bones. Vascular calcification, soft tissue calcification may even appear organ calcification, and the calcification of the above parts will not only affect the patient's cardiovascular system, but also affect the patient's other normal physiological functions.
On February 1, 2022, experts from cleveland Clinic summarized the mechanisms, diagnostics, and treatment options for calcification problems in patients with CKD and ESKD.
Mechanism¹
As CKD progresses, anomalies occur in the following 3 areas:
(1) Abnormal levels of serum calcium, phosphorus, parathyroid hormones (PTH) and vitamin D;
(2) Abnormal bone metabolism (renal bone disease);
(3) The risk of calcification of blood vessels and soft tissues is increased.
The above abnormalities are closely related to the deterioration of renal function. As CKD progresses, kidney function gradually deteriorates, phosphate levels increase, and decreased calcium ion levels will lead to increased PTH, which will promote the secretion of FGF-23 from bones, raising their serum levels. FGF-23 can directly inhibit the kidneys and parathyroid glands, such as inhibiting tubular phosphorus reabsorption and reducing blood phosphorus levels; increasing calcium reabsorption, increasing blood calcium levels, and inhibiting PTH.
But it can also affect the intestines through 1,25-(OH)₂D. FGF-23 secreted by the bones directly inhibits the secretion of 1,25-(OH)₂D, while inhibiting PTH, blocking the synthesis of 1,25-(OH)₂D. However, blood phosphorus stimulates the secretion of 1,25-(OH)₂D. A decrease in 1,25-(OH)₂D increases the absorption of calcium ions and the excretion of phosphate.
It is important to note that the above may also occur in patients with an estimated glomerular filtration rate (eGFR) of 69 ml/min/1.73㎡. Calcification problems are not "exclusive" problems in patients with advanced CKD or ESKD, but rather risks that can occur in all patients with CKD and ESKD.
Diagnostic¹
Calcification problems can be divided into calcified defenses, soft tissue calcifications, or vascular calcifications, depending on the patient's location and severity.
01 Calcified Defense
Although soft tissue calcification is fairly common in patients with CKD or ESKD, some patients develop more severe soft tissue calcification, known as calcified defense. Skin lesions due to calcified defenses can lead to a variety of clinical manifestations, from hardening of the epidermis to ulceration. Although skin biopsies can help with diagnosis, they carry serious surgical risks such as increased pain, poor healing, and secondary infections. (Related reading: From mechanism to treatment, an article summarizes the tricky calcification defenses)
02 Soft tissue calcification
Conversely, for most people with soft tissue calcification, they do not feel pain. Most of these patients are associated with a decrease in the range of motion of the affected joint. The affected joints usually include hip, elbow, shoulder, foot, and wrist joints (in a positive order of incidence). Diagnosis can be based on the patient's X-ray or calcium deposit location (Figure 1).
Figure 1 X-ray results of patients with soft tissue calcification
03 Vascular calcification
In addition to traditional cardiovascular risk factors such as advanced age, male age, family history, smoking, and increased C-reactive protein levels, secondary disease and treatment of kidney disease can also increase the risk of vascular calcification. For example, long-term hemodialysis, hyperphosphatemia, calcium-based phosphate binders, secondary hyperparathyroidism, renal bone disease, vitamin D deficiency or excessive vitamin D, hypercalcium dialysate, hypomagnesemia, hypoalbuminemia, etc. may increase the risk of vascular calcification. High-risk populations should be examined by X-ray, CT, and magnetic resonance imaging (MRI).
Treatment options
So, how to treat the calcification problem in patients with CKD and ESKD? Experts believe that there are 5 interventions that need to be understood by physicians, namely dietary interventions, bone absorption inhibitors, calcium-like agents, sodium thiosulfate, and vitamin K.
01 Dietary interventions
Phosphate levels are the source and core of calcification problems, so phosphorus levels need to be controlled. Dietary interventions, control of phosphate intake, and administration of phosphate binders are the cornerstones of preventing calcification problems. The most commonly used phosphate binder is a calcium-based phosphate binder, which can be widely used in patients with CKD and ESKD. However, some studies have found that high levels of calcium can also increase the risk of vascular calcification. Therefore, current studies recommend the use of non-calcium-based phosphate binders. While managing phosphate intake, calcium intake should also be managed, and blood phosphorus and blood calcium levels should be checked regularly¹.
It must be clear that dietary interventions and phosphate binders are the cornerstones of calcification in patients with CKD and ESKD, and require the attention of doctors and patients. KDIGO guidelines recommend that patients with CKD should consume no more than 800 to 1000 mg of phosphate per day and that phosphorus levels should be controlled to normal or near normal as much as possible. Nuts, animal muscle proteins, flavorings, and certain oral medications also contain large amounts of phosphate. Patients should try to consume foods with a low phosphorus/protein ratio².
02 Bone resorption inhibitor¹
(1) Bisphosphate
Bisphosphate is currently the most effective bone resorption inhibitor, which can effectively inhibit osteoclast activity, and some studies have also found that it can also induce osteoclast apoptosis. However, these drugs are usually excreted through the kidneys.
Current data show that such drugs can be safely used in early CKD patients, that is, eGFR> 35ml/min/1.73㎡, but the data on CKD stage 4 or 5 and ESKD are limited, and there are theoretically certain safety issues.
If the eGFR < 30 ml/min/1.73㎡, zoledronic acid should be avoided because it is more strongly associated with tubular injury, acute kidney injury, and decreased eGFR. For patients with advanced CKD, intravenous pamiphosphate may be an ideal option, with focal segmental glomerulosclerosis rarely.
(2) Dinomab
Denosumab is a bone resorption inhibitor with a unique mechanism of action, which specifically targets the nuclear factor kappaB receptor activator ligand (RANKL), inhibits osteoclast activation and development, reduces bone resorption, and increases bone density. However, there is no evidence that it relieves soft-tissue calcification. Small-scale observational studies have confirmed that denotumab can delay coronary artery calcification. Overall, however, more research is needed on dinomonumab.
(3) Teripatotide
Teriparatide is a synthetic hormone that is consistent with PTH function. However, there are currently no reports of its use in patients with CKD.
03 Calcium-like agent¹
Calcium-mimetic agents represented by sinacasse are a new type of drug that activates calcium receptors in the parathyroid glands and reduces the secretion of PTH. Current research suggests that Sinacasse can be effective in lowering PTH levels. A meta-analysis of patients with ESKD showed that sinacaces may reduce the risk of all-cause or cardiovascular death in patients. Other types of calcium-mimetics are in preclinical studies.
04 Sodium thiosulfate¹
Sodium thiosulfate can be used for calcification problems including calcification defenses. One randomized controlled trial showed that patients in the sodium thiosulfate group had reduced arterial calcification and arteriosclerosis compared with placebo. A series of cases have also shown that the drug reduces the degree of soft tissue calcification in the shoulder and hip joints, reduces symptoms, and in some cases reduces the volume of calcification sites.
05 Vitamin K¹
Deficiency of vitamin K or associated with vascular calcification, and in people with problems with calcification, a general lack of vitamin K. Some scholars believe that if you can supplement with sufficient vitamin K in time, you may be able to improve related problems.
In the case of vitamin K antagonists, warfarin, which can accelerate medial arterial calcification in patients with ESKD, is an important risk factor. Patients with ESKD should avoid vitamin K antagonists and may be switched to other anticoagulants.
However, there are currently no accurate data showing that vitamin K supplementation is beneficial for vascular calcification or other calcification problems in patients with CKD.
In addition, drugs such as SNF472, magnesium supplements, vitamin D, etc. are also being studied in preclinical or clinical trials with varying degrees of success, although more studies are needed to confirm their risk-benefit¹.
In addition to drug therapy, soft tissue calcification and calcification defense can also be treated with surgical treatments such as debridement surgery and hyperbaric oxygen therapy. Individualized treatment regimens need to be designed according to the patient's situation¹.
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Typography: Don
bibliography:
1.Bartolomeo K, Tan XY, Fatica R. Extraosseous calcification inkidney disease. Cleve Clin J Med. 2022 Feb 1;89(2):81-90
2. Chen Yipu, Yu Xueqing, Zhao Minghui, etc. Nephrology[M].People's Medical Publishing House. Beijing.2021.