Disorders of calcium and phosphorus metabolism and their bone disease are among the important complications of chronic renal failure, especially in dialysis patients. When the glomerular filtration rate (GFR) decreases from 60 ml/(min-1.73 m2) to 20 ml/(min-1.73 m2), the incidence of hyperphosphatemia increases from 1% to 30%, and the incidence of secondary hyperparathyroidism (SHPT) increases from 17% to 85%. In the past, it was thought that disorders of calcium and phosphorus metabolism caused mainly skeletal lesions and were called “renal osteodystrophy (ROD)”. Recently, it has been recognized that long-term abnormal bone mineral metabolism in chronic kidney disease (CKD) can cause systemic vascular calcification, which is closely related to the occurrence of cardiovascular events and death.
There have been many studies on the status of calcium and phosphorus metabolism in patients with CKD stage 5, especially those who have entered long-term renal replacement therapy, and its impact on prognosis. 2011 study by Floege et al [4] showed that the relationship between blood iPTH, calcium and phosphorus concentrations and the risk of all-cause mortality showed a U-shaped curve relationship, i.e., too high or too low values (iPTH >600 pg/mL or < 75 pg/mL, Ca >2.75 mmol/L or <2.10 mmol/L, P <1.13 mmol/L or >1.78 mmol/L) resulted in an increased risk of all-cause mortality. Among the indicators of abnormal mineral metabolism, hyperphosphatemia was independently associated with death in CKD patients.
The results of the study showed that for every 1 mg/dl increase in blood phosphorus in CKD patients, the risk of all-cause mortality increased by 18%, and its impact on patient survival was much more significant than that of blood calcium and iPTH. The monitoring and management of calcium and phosphorus metabolic status is quite important for CKD patients whether they enter dialysis or not.
I. Definition of CKD-MBD
CKD-MBD refers to systemic disorders of mineral and bone metabolism in patients with chronic kidney disease, including any one or more of the following:
(1) Abnormalities in calcium, phosphorus, parathyroid hormone (PTH) or vitamin D metabolism;
(2) Abnormalities in bone conversion, mineralization, volume, linear growth, or strength;
(3) Calcification of blood vessels or other soft tissues.
II. Diagnosis and evaluation of CKD-MBD
1. Biochemical indicators
The abnormal biochemical indexes in adult CKD patients appear in CKD stage 3, therefore, KDIGO and KDOQI
The new guidelines place more emphasis on the joint assessment of serum calcium and phosphorus in individual patients with CKD stages 3-5 to guide clinical treatment, with particular emphasis on phosphorus-lowering therapy rather than calcium-phosphorus multiplication to guide clinical treatment.
In 2013, the Clinical Practice Guidelines for the Assessment and Management of CKD published by the Kidney Disease Prognosis Improvement Global Organization (KDIGO): recommend testing blood calcium, phosphorus, PTH and alkaline phosphatase ( ALP) activity at least once as baseline levels when GFR is <45 ml/(min-1.73 m2) (GFR classification G3b-G5).
For blood phosphorus, KDIGO recommends maintaining serum phosphorus within the normal range according to local laboratory reference values when GFR < 45 ml/(min-1.73 m2) (GFR classification G3b-G5).
The optimal PTH level for patients with GFR < 45 ml/(min-1.73 m2) (GFR class G3b-G5) is currently unclear. kDIGO recommends that patients with PTH levels above the upper limit of normal should first be evaluated for high blood phosphorus, low blood calcium and vitamin D deficiency. kDIGO studies have found that patients with CKD stage 5D The KDIGO study found that PTH concentrations in patients with CKD stage 5D did not predict the pathological type of bone disease or the occurrence of fractures, and that whole-segment PTH concentrations maintained at two to nine times the high limit of normal (130-600 ng/L) had little change in bone histology [13]. Therefore, KDIGO recommends that patients with CKD stage 5D have PTH
concentrations should be maintained at 2-9 times the high limit of normal values, and within this range, when PTH concentrations change, treatment should be promptly adjusted to prevent PTH concentrations from exceeding this range.
2. Bone lesions
The importance of PTH and ALP for monitoring bone transformation is emphasized in the examination of bone disease. The routine use of bone mineral density (BMD) is not recommended because, unlike in the general population, BMD does not predict fracture risk and BMD does not predict the type of renal osteodystrophy. Bone biopsy is mainly used in patients with CKD stages 3-5 in the presence of various conditions such as, but not limited to, unexplained fractures, persistent bone pain, unexplained hypercalcemia, unexplained hypophosphatemia, possible aluminum toxicity and pathologic fractures without an obvious cause (e.g., low PTH, low ALP, suspected aluminum toxicity, etc.) prior to treatment with diphosphonates in patients with CKD-MBD [renal transplant patients] or When clinical evaluation is difficult and difficult to treat.
3. Vascular calcification
Extraosseous calcification is a component of CKD-MBD, including arterial calcification and cardiac valve calcification, the incidence and severity of which increases with deterioration of renal function. While atheromatous plaque calcification is associated with cardiovascular events in the general population, coronary and systemic vascular calcification is more prevalent and more severe in the CKD population.
Although CT techniques are more accurate, X-ray plain radiographs of vascular fistulae in the forearm or abdomen are also sufficient to determine the presence of vascular calcification. Echocardiography can determine cardiac valve calcification, and patients with stage 3-5 CKD who already have vascular or valve calcification are at highest risk for cardiovascular events.
4. Phosphorus binding agents
Many clinical trials have shown that phosphorus binding agents can effectively reduce blood phosphorus levels and improve the prognosis of bone disease and tissue calcification. Recent evidence suggests that phosphorus binding agents not only reduce serum phosphorus and PTH levels, but also reduce fibroblast growth factor-23 (FGF-23).
FGF-23 can reduce phosphate reabsorption by inhibiting sodium and phosphorus co-transport proteins in renal proximal tubular epithelial cells, which leads to an increase in phosphate excretion, and it also decreases 1-alpha hydroxylase activity, leading to a decrease in 1,25(OH)2D3 production, which reduces blood phosphorus. The effect of phosphorus-binding agents in reducing FGF-23 is different from that in improving
SHPT and renal bone disease, especially in patients with early CKD.
The use of various phosphorus binding agents should be selected in conjunction with the patient’s blood calcium concentration and other factors.
Clinically used phosphorus binding
III. Drugs
Daily dose
Aluminum hydroxide
1.425-2.85g
Calcium citrate
1.5-3g
Magnesium carbonate
0.7-1.4g(add calcium carbonate 0.33-0.66g)
Calcium acetate and magnesium carbonate combination
Calcium acetate 435mg plus calcium carbonate 235mg, 3-10 tablets daily
Calcium carbonate
3-6g
Calcium acetate
3-6g
Lanthanum carbonate
3g
Sevelamer hydrochloride
4.8-9.6g
Sevelamer carbonate
4.8-9.6g
3.Adjustment of dialysis prescription
Hemodialysis removes 800 mg of phosphorus per session and peritoneal dialysis removes 300 mg of phosphorus per day, and conventional dialysis modalities are not sufficient to remove excess phosphorus. A multicenter randomized controlled study involving 493 hemodialysis patients with different treatment modalities showed that after 6 months of treatment, blood phosphorus levels in the hemodialysis filtration group decreased significantly from baseline values (P < 0.001), while blood phosphorus levels in the hemodialysis group did not change significantly from baseline values (P = 0.5), and after correcting for the use of phosphorus-binding agents, hemodialysis filtration had an advantage over low-flux hemodialysis still had an advantage over low-flux hemodialysis. Studies have shown that prolonged nocturnal hemodialysis (5-6 nights/week, 6-10 h/night) can significantly reduce blood phosphorus levels and reduce phosphorus-binding agent use. Therefore, blood phosphorus control can be improved in hemodialysis patients by changing the dialysis prescription.
(ii) Adjustment of blood calcium
The DOPPS study also found a significant increase in mortality in CKD patients when blood calcium was above 2. 50 mmol/L or below 2. 10 mmol/L. Therefore, KDIGO recommends controlling calcium concentrations within the normal range (2.1-2.5 mmol/L). Patients with hypoproteinemia need to calculate a corrected calcium value, corrected Ca(mg/dL) = total serum Ca(mg/dL) + [4-serum Alb(g/dL)], and if total serum calcium is below normal, if there are clinical signs of hypocalcemia or if serum iPTH is above the target value, calcium salts or vitamin D preparations can be administered.
KDIGO does not recommend routine administration of vitamin D supplements or vitamin D analogs to suppress elevated PTH concentrations in non-dialysis CKD patients in the absence of evidence of vitamin D deficiency. If blood calcium is higher than the target value, treatment that may cause elevated blood calcium levels should be adjusted such as reducing or discontinuing calcium-containing phosphorus-binding agents, reducing or discontinuing vitamin D preparations, and applying low-calcium dialysis solutions.
(iii) Correction of hyperparathyroidism
Secondary hyperparathyroidism (SHPT) is a disease that seriously affects the quality of life of patients due to secondary hyperplasia of parathyroid glands and excessive secretion of PTH, resulting in high-transport bone disease and multiple metastatic calcifications in blood vessels, soft tissues and heart valves, and is the most important pathological type of CKD-MBD. Active vitamin D can inhibit PTH secretion at the mRNA level; inhibit parathyroid cell proliferation by increasing intracellular calcium ion concentration; promote intestinal calcium absorption to increase serum calcium levels and indirectly inhibit PTH secretion by parathyroid glands.
The best time to use active vitamin D is when blood calcium is low and iPTH is elevated. Usage includes low-dose continuous therapy:mainly for mild SHPT or moderate to severe SHPT maintenance treatment phase. Dosage:0.25μg, once daily. High-dose shock therapy: mainly used for moderate to severe SHPT, the recommended dose in our 2005 expert consensus on the rational application of active vitamin D in chronic kidney disease secondary to hyperparathyroidism is: iPTH
300-500 pg/ml, 1 to 2 g each time, twice a week; iPTH 500-1000 pg/ml, 2 to 4 g each time, twice a week; iPTH > 1000 pg/ml, 4 to 6 g each time, twice a week. Common side effects of active vitamin D application include elevated blood calcium and increased hyperphosphatemia, so blood calcium and phosphorus levels should be monitored closely during treatment. If elevated blood calcium occurs, the amount of calcium-containing phosphorus binding agent should be reduced or a calcium-free phosphorus binding agent should be used, along with dialysis with low-calcium dialysis solution. In case of severe hypercalcemia, active vitamin D should be reduced or discontinued. If blood phosphorus is not well controlled and blood calcium levels rise with treatment, this leads to an increased calcium-phosphorus product and an increased risk of metastatic calcification.
There are other active vitamin D derivatives that have the same inhibitory effect on PTH and less likely to lead to high blood calcium and phosphorus; calcium-sensitive receptor (CaR) agonists can lower the patient’s blood calcium while significantly reducing PTH and inhibiting parathyroid hyperplasia, which facilitates the application of calcium-containing phosphorus binding agents; parathyroidectomy (PTX) therapy is recommended for patients with refractory SHPT for whom drug therapy is ineffective.
D. Chinese medicine treatment of chronic renal failure calcium and phosphorus metabolism disorders
There is no clear concept of calcium and phosphorus metabolism disorder in Chinese medicine for chronic renal failure, but most scholars now classify it as “bone impotence”, “bone paralysis”, “bone dryness”, “bone polarization”, “bone failure”, and “bone paralysis” in Chinese medicine. “The disorders of bone and phosphorus metabolism have no clear concept in Chinese medicine. As early as in the Nei Jing, there is a discussion of “kidney energy is injured, high bone is broken”, which has similarities with the modern medicine of renal bone disease. Since ancient times, Chinese medicine believes that the bones are dominated by the kidneys, and the kidneys produce the bone marrow, which is filled in the bones. The kidney essence is abundant to nourish the bone marrow, and the bone marrow is full, so the bone is nourished, the growth and metabolism are balanced, and the tendons and bones are strong and healthy.
Various pathological factors make the kidney weak, resulting in chronic kidney failure, so that the essence can not produce marrow, the bone is not nourished and the disease occurs. Therefore, Chinese medicine believes that the symptoms of renal bone disease are in the bones and the origin is in the kidneys. The calcium and phosphorus levels of CRF patients differ among the TCM types, with the most serious disorders of calcium and phosphorus metabolism in the blood of Yin and Yang deficiency patients, followed by Liver and Kidney Yin deficiency patients, Spleen and Kidney Yang deficiency patients, and Qi and Yin deficiency patients, and the lower disorders of calcium and phosphorus metabolism in the blood of Spleen and Kidney Qi deficiency patients.
Most renal bone diseases are based on kidney deficiency. However, renal bone disease is not a simple kidney bone disease, not only can the method of tonifying the kidneys and bones be effective, but also cannot be pure, brutal or severe tonic, otherwise it will easily lead to the disadvantage of closing the door and keeping the invaders; based on the identification of the evidence, flexible use is commonly used in clinical practice according to the characteristics of different symptoms, such as tonifying the kidneys and blood, strengthening the spleen and kidneys, regulating the qi and blood, and detoxifying the drainage method, etc., to attack and tonic at the same time, to support the righteousness and eliminate the evil, so that the kidney essence is sufficient, and the marrow nourishes the tendons and bones, because it is common in both liver and spleen diseases, It is common to see dampness, blood stasis and toxins, so it is necessary to apply them flexibly in the process of diagnosis and treatment, to identify the location of the disease, to eliminate the evil and help the righteousness, in order to achieve the therapeutic effect.