Review

Having high levels of phosphate - or phosphorus - in your blood is known as hyperphosphatemia. Phosphate is an electrolyte, which is an electrically charged substance that contains the mineral phosphorus.

Your body needs some kind of phosphate to strengthen your bones and teeth, and build cell membranes. However, in larger than normal amounts, phosphate can cause bone and muscle problems and increase the risk of heart attacks and strokes.

High phosphate levels are often a sign of kidney damage. It is more common in people with chronic kidney disease (CKD), especially those with end-stage kidney disease.

Symptoms What are symptoms?

Most people with high phosphate levels have no symptoms. In some people with chronic kidney disease, high levels of phosphate cause low calcium levels in the blood.

Symptoms of low calcium include:

• muscle cramps or spasms
• numbness and tingling around the mouth
• pain in bones and joints
• weak bones
• itchy skin

Causes What causes it?

Most people get between 800 and 1,200 milligrams (mg) of phosphorus daily from foods such as red meat, dairy products, chicken, fish and fortified grains. In the body, phosphate is found in bones and teeth, inside cells and in much smaller quantities in the blood.

Your kidneys help remove excess phosphate from your body to maintain balance. When your kidneys are damaged, your body cannot remove phosphate from your blood quickly enough. This can lead to chronically elevated phosphate levels.

Your blood phosphate levels may also rise sharply if you receive a phosphate-containing laxative as a colonoscopy drug.

Other possible causes of hyperphosphatemia include:

• low levels of parathyroid hormones (hypoparathyroidism)
• cell damage
• high levels of vitamin D
• diabetic ketoacidosis - high levels of acids called ketones in the blood of people with diabetes
• injuries - including those that cause muscle damage
• serious infections of the whole body

Complications and associated conditions What are its complications and associated conditions?

Calcium combines with phosphate, resulting in low calcium levels in the blood (hypocalcemia). Low blood calcium levels increase your risks of:

• high levels of parathyroid hormones (secondary hyperparathyroidism)
• seizures
• a bone disease called renal osteodystrophy

Because of these complications, people with severe kidney disease with high phosphate levels in their blood face an increased risk of death.

Treatment How to treat it?

Your doctor may do a blood test to check if you have high phosphate levels.

If your kidneys are damaged, you can lower your blood phosphate levels in three ways:

• reduce the amount of phosphate in your diet
• remove extra phosphate with dialysis
• reduce the amount of phosphate that your intestines absorb using medicine

First, limit foods high in phosphorus, such as:

• milk
• red meat
• chicken and other types of poultry
• nuts
• beans > egg yolks
• Diet alone probably won't lower your phosphate levels to solve the problem. You may also need dialysis. This treatment takes care of your damaged kidneys. It removes waste, salt, extra water and chemicals such as phosphate from your blood.

In addition to diet and dialysis, you will likely need medication to help your body remove excess phosphate. Several medications help reduce the amount of phosphate your intestines absorb from the foods you eat. These include:

Calcium-based phosphate binders (calcium acetate and calcium carbonate)

• Lanthanum (Phosrenol)
• sevelamer hydrochloride (Renagel)
• Prevention Can it be prevented?

Hyperphosphatemia is often a complication of chronic kidney disease. One way to reduce your risk is to slow down kidney damage. Protect your kidneys by addressing the cause of your kidney disease.

High blood pressure can weaken the blood vessels that supply oxygenated blood to the kidneys. Taking high blood pressure medications, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers, may lower your blood pressure and protect your kidneys.

• The extra fluid in your body can overwhelm your damaged kidneys. Taking a water tablet (diuretic) can help restore the proper fluid balance in your body.
• Protein in your diet causes your body to produce more waste from protein metabolism, which your kidneys then filter out. Eating a low protein diet can help reduce this waste and take some of the load off your kidneys.
• OutlookOutlook

High levels of phosphate in the blood can increase the risk of serious medical problems and other complications. Treating hyperphosphatemia with dietary changes and medications as soon as possible will prevent these complications. Treatment may also slow bone problems associated with chronic kidney disease.

Hyperphosphatemia is a serum phosphate concentration greater than 4.5 mg/dL (more than 1.46 mmol/L). Causes include chronic renal failure, hypoparathyroidism, metabolic or respiratory acidosis. Clinical symptoms of hyperphosphatemia may be associated with concomitant hypocalcemia and may include tetany. Diagnosis is based on determining serum phosphate levels. Treatment involves limiting phosphate intake and administering phosphate-binding antacids, which include calcium carbonate.

ICD-10 code

E83 Disorders of mineral metabolism

Causes of hyperphosphatemia

Hyperphosphatemia usually results from decreased renal excretion of PO2. Progressive renal failure (GFR less than 20 ml/min) reduces excretion sufficiently to increase plasma PO2 levels. Impaired renal phosphate excretion in the absence of renal failure is also observed in pseudohypoparathyroidism and hypoparathyroidism. Hyperphosphatemia also develops with excessive ingestion of PO2 and excessive use of enemas containing PO2.

Hyperphosphatemia sometimes develops as a result of a massive release of PO2 ions into the extracellular space, which exceeds the excretory capabilities of the kidneys. This mechanism most often develops with diabetic ketoacidosis (despite a general decrease in PO2 content in the body), injuries, non-traumatic rhabdomyolysis, as well as with systemic infections and tumor collapse syndrome. Hyperphosphatemia also plays a major role in the development of secondary hyperparathyroidism and renal osteodystrophy in patients on dialysis. Hyperphosphatemia may be false with hyperproteinemia (multiple myeloma or Waldenstrom's macroglobulinemia), hyperlipidemia, hemolysis, hyperbilirubinemia.

Symptoms of hyperphosphatemia

In most patients, hyperphosphatemia is asymptomatic, but in the case of concomitant hypocalcemia, symptoms of the latter, including tetany, may be observed. Soft tissue calcification is commonly seen in patients with chronic renal failure.

Diagnosis of hyperphosphatemia is to determine a PO2 level of more than 4.5 mg/dL (> 1.46 mmol/L). If the etiology of the condition is not obvious (eg, rhabdomyolysis, tumor breakdown syndrome, renal failure, abuse of PO laxatives), additional testing is necessary to exclude hypoparathyroidism or pseudohypoparathyroidism, which is characterized by end-organ resistance to PTH. It is also necessary to exclude incorrect determination of PO2 levels by measuring serum protein, lipids and bilirubin levels.

Treatment of hyperphosphatemia

The mainstay of treatment for hyperphosphatemia in patients with renal failure is to reduce PO2 intake. It is recommended to avoid foods containing large amounts of PO2, and it is also necessary to take phosphate binders with meals. Due to the possibility of osteomalacia associated with aluminum accumulation, calcium carbonate and calcium acetate are recommended as antacids in patients with end-stage renal disease. Recently, the likelihood of developing vascular calcification due to excessive formation of Ca and PO2 binding products in patients who have a condition such as hyperphosphatemia and are on dialysis and taking Ca-binding drugs has been identified. For this reason, dialysis patients are recommended to take the PO2 binding resin, sevelamer, at a dose of 800-2400 mg three times daily with meals.

It is important to know!

Phosphorus in the body is contained in inorganic (calcium, magnesium, potassium and sodium phosphates) and organic (carbohydrates, lipids, nucleic acids, etc.) compounds. Phosphorus is essential for bone formation and cellular energy metabolism. Approximately 85% of the total phosphorus in the body is found in the bones, most of the rest is found within cells, and only 1% is found in extracellular fluid.

Hyperphosphatemia is a pathological condition of the body in which there is an excess content of phosphates in the blood. Along with calcium, phosphorus is part of the main composition of bone tissue and participates in important metabolic reactions at the cellular level.

Most of the phosphates (90%) are found in bone tissue, 10% in blood plasma. The phosphate level ranges from 0.8 to 1.46 mmol/l. An excess of this chemical element causes various disorders in nervous, muscular, renal and cardiac activity. If the amount of phosphorus in the body increases, it begins to accumulate not only in bone tissue, but also in other organs. This process leads to calcification of various organs and blood vessels, which leads to premature atherosclerosis, joint diseases, visual and hearing impairment.

Causes of the disease

1. Decreased ability of the kidneys to remove phosphates from the blood. Such phenomena are observed in patients with a history of true and false hypoparathyroidism and pathologies of the renal tubules.
2. Excess phosphates in food or long-term use of medications containing them.
3. Diabetic pathology - ketoacidosis, internal organ damage, trauma, tumors, protracted infectious processes.
4. Overdose in the treatment of vitamin D deficiency.
5. Disorders of the basal metabolism, when the absorption of phosphates in the gastrointestinal tract increases.
6. Deficiency of parathyroid hormone, a regulator of calcium-phosphorus metabolism in the body.
7. Myopathies of various origins in severe stages.
8. The growth of malignant neoplasms, their decay and long-term therapy with antitumor drugs.
9. Poisoning with chemicals containing phosphates.

Clinical picture, symptoms of hyperphosphatemia

With small increases in the phosphate content in the body, the disease occurs latently, the general condition of the patients remains virtually unchanged, they remain active and efficient.

Constant pain in the joints and bones, which is accompanied by weakness and increased fatigue, may suggest the presence of hyperphosphatemia. When the calcification process begins, patients begin to notice problems in the functioning of the kidneys and heart, pain in the muscles, cramps and various neurological disorders.

Patients often complain of numbness in the limbs or a feeling of tension in them, tingling, crawling, itching and pinpoint rashes on the face and body. On physical examination, an increased level of basic reflexes is noted.

Diagnostics

The disease is detected using laboratory tests of blood and urine. There is an increase in phosphate levels in the blood, more than 1.5 mmol/liter. Phosphorus salts may be found in urinary sediment.

To identify the cause of hyperphosphatemia, a number of additional studies are carried out, tests for the level of parathyroid hormones, ultrasound of internal organs, biochemical analysis for blood sugar, lipid levels, bilirubin and cholesterol.

Treatment of hyperphosphatemia

Therapy is carried out depending on the identified cause of hyperphosphatemia. In case of endocrine disorders, hormonal correction is carried out; in case of kidney diseases, excess phosphorus is removed from the body with the help of pharmacological agents that bind phosphates during meals.

Patients taking medications are strictly monitored for phosphate content. It is recommended to follow a diet that excludes or limits the consumption of certain foods that contain phosphates; restorative therapy, giving up bad habits, taking vitamins, and moderate physical activity are considered useful.

• Decreased renal excretion
  • Acute renal failure
  • Chronic renal failure
• Acute overload of the body with phosphates
  • Tumor lysis syndrome
  • Rhabdomyolysis
  • Colon infarction
  • Severe hemolysis
• Vitamin D toxicity
• Excessive reabsorption of phosphate in the kidneys
  • Hypoparathyroidism
  • Acromegaly
  • Thyrotoxicosis
  • Taking medications (bisphosphonates)
  • Tumor calcification
• Psvedohyperphosphatemia

Hyperphosphatemia may result from renal failure, acute overload of exo- or endogenous phosphate, or increased reabsorption of phosphate in the proximal renal tubules.

Kidney failure- the most common cause of hyperphosphatemia, causing its development in 90% of cases. As GFR begins to decline, fractional excretion of phosphate increases. When GFR falls below 30 mL/min, renal tubular phosphate reabsorption is maximally reduced. A further increase in their fractional excretion becomes impossible. As a result, renal excretion does not balance the intake of phosphates from food and their concentration in the intravenous fluid begins to increase. This increase continues until a new equilibrium state is established with an increased concentration of phosphorus in the blood serum.

Hyperphosphatemia can also lead to sudden load of the body with large amounts of phosphates. Large amounts of phosphate can enter the ECF from tissues (for example, due to tumor lysis or rhabdomyolysis) or externally (for example, due to vitamin D intoxication). Hyperphosphatemia due to tumor lysis syndrome is most often observed in the treatment of malignant, rapidly growing neoplasms, such as leukemias and lymphomas. Sometimes it develops during the lysis of solid tumors - small cell carcinomas, breast cancer, neuroblastomas. The risk of such a complication of antitumor therapy for solid tumors is especially high if the patient has kidney disease, increased lactate dehydrogenase (LDH) activity in the blood, and hyperuricemia before starting treatment.

Primary enhancement of phosphate reabsorption in the renal tubules detected less frequently than other causes of hyperphosphatemia. Such enhancement can develop with hypoparathyroidism, acromegaly (as a result of direct stimulation of reabsorption by insulin-like growth factor), as a result of the use of bisphosphonates (due to their direct effect on the rate of phosphate reabsorption) and with tumor calcification. Tumor calcification is caused by an abnormality of the proximal tubules of the kidneys, leading to increased reabsorption of phosphate.

Symptoms and signs of hyperphosphatemia

Clinical symptoms with an acute increase in serum phosphate concentrations are secondary and are a consequence of concomitant hypocalcemia. Hypocalcemia develops due to the deposition of a significant part of Ca2+ in the form of precipitates in soft tissues, leading to a drop in p. In addition, with hyperphosphatemia, the activity of 1α-hydroxylases and the level of calcitriol production sometimes decrease.

Diagnosis of hyperphosphatemia

If clinically unexplained hyperphosphatemia is detected in a patient, it should be assumed that this is so-called pseudohyperphosphatemia. Most often it occurs with paraproteinemia. The type of immunoglobulin, the production of which is excessive, is not significant. In fact, the patient does not have hyperphosphatemia, and the overestimated serum phosphorus test result is due to a method error caused by a paraprotein. Unfortunately, the paraprotein greatly interferes with spectrophotometric methods in many cases. If paraproteinemia is absent, the cause of hyperphosphatemia is most likely chronic renal failure or acute renal failure.

Treatment for hyperphosphatemia

Treatment for hyperphosphatemia should be primarily aimed at reducing the absorption of phosphate in the small intestine. This is achieved through the use of phosphate binders, for example calcium carbonate or acetate, some hydrochlorides, and aluminum oxide. All of these compounds are taken with food during meals. In patients with kidney disease, due to the risk of nephrotoxicity, aluminum oxide can only be used for a short time. If the patient has concomitant hypocalcemia, it is preferable to reduce the serum phosphorus concentration to a level of less than 6 mg/100 ml when correcting hyperphosphatemia. This must be done before correcting hypocalcemia. Otherwise, there is a danger of tissue calcification due to the deposition of calcium phosphates in them.

Catad_tema Chronic kidney disease - articles

Choosing a phosphate binder for the treatment of hyperphosphatemia in chronic kidney disease: effects on arterial calcification and mortality

Hyperphosphatemia in patients with chronic kidney disease (CKD) not only plays an important role in the development of bone tissue damage, but also increases the risk of death from all causes and cardiovascular causes. Results from controlled clinical trials have shown that calcium-free phosphate binders may delay the development of coronary and other artery calcifications and improve survival in predialysis and dialysis patients with CKD.

Keywords. Hyperphosphatemia, mineral and bone disorders, chronic kidney disease, phosphate binders, sevelamer.

Cardiovascular diseases are one of the leading causes of mortality in patients with end-stage renal failure. The risk of death from cardiovascular causes, adjusted for age, race, sex, and diabetes, in patients receiving renal replacement therapy is 10-20 times higher than in the general population. According to coronary angiography, a significant decrease in glomerular filtration rate is associated with a significant increase in the incidence of severe coronary atherosclerosis, including damage to the three coronary arteries and the left main coronary artery. In addition to traditional risk factors, such as arterial hypertension, smoking, diabetes mellitus, etc., additional risk factors play an important role in the development of cardiovascular diseases in patients with chronic kidney pain (CKD), in particular mineral and bone disorders (MBD), which in the terminal stage occur in almost all patients. According to the KDIGO guidelines, MCI-CKD is a systemic condition that is characterized not only by disturbances in the metabolism of calcium, phosphorus, vitamin D, parathyroid hormone (PTH) and bone damage, but also by widespread calcification of the coronary and other arteries, causing increased cardiovascular and overall mortality. Key role in development

Phosphate retention and hyperphosphatemia play a role in MCI-CKD. Numerous studies have established an association between increased serum phosphorus levels and mortality in patients with CKD. For example, in a study of 40,538 Americans undergoing hemodialysis treatment, a U-shaped association was found between baseline serum phosphorus levels and the risk of death from all causes. A 1 mg/dL increase in serum phosphorus levels was associated with a 4% and 9% increase in risk from all causes and cardiovascular causes, respectively. Current recommendations indicate the need to normalize serum phosphate levels in patients with stage 3-5 CKD, including those receiving dialysis treatment. For this purpose, calcium-containing and calcium-free phosphate binders are used, which have comparable efficacy in the treatment of hyperphosphatemia, but may differ in their effect on serum calcium levels and the development of vascular calcification and, accordingly, cardiovascular outcomes.

Pathogenesis of hyperphosphatemia and vascular calcification in CKD
The exchange of phosphorus and calcium in the body is mainly regulated by PTH, which increases the excretion of phosphates in the urine, and the active metabolite of vitamin D - 1,25-dihydroxyvitamin D 3 (calcitriol), which activates vitamin D receptors and enhances the absorption of phosphates in the intestine. In recent years, other factors (phosphatonins) have been identified that also control renal excretion of phosphate. One such hormone is fibroblast growth factor-23 (FGF-23), secreted by osteocytes. It reduces the expression of sodium-dependent phosphate co-transporter type 2a (NaPi-2a) in proximal renal tubular cells and the activity of 1a-hydroxylase, which converts 25-hydroxyvitamin D3 to calcitriol. The action of FGF-23 is mediated by Klotho becs, which form a complex with FGF receptors and act as obligate coreceptors. Klotho proteins are expressed in the distal collecting tubule but have a primary effect in proximal renal tubule cells. Klotho proteins are also synthesized in the tissue of the parathyroid glands. PTH and Klotho proteins increase the secretion of FGF-23 by osteocytes, while FGF-23 inhibits the release of PTH.

Already in the early stages of CKD, phosphate retention occurs due to a gradual decrease in phosphate clearance by the kidneys. The development of hyperphosphatemia is prevented by an increase in the secretion of FGF-23 and PTH, which suppress the reabsorption of phosphates in the kidneys and their absorption in the intestines (due to a decrease in the formation of calcitriol). If normally FGF-23 reduces the secretion of PTH, then when renal function is impaired, resistance to its action develops due to a decrease in the expression of Klotho proteins in the parathyroid glands and kidneys. As the mass of functioning glomeruli progressively decreases, these homeostatic mechanisms no longer allow the maintenance of normal serum phosphate levels, leading to the development of hyperphosphatemia despite high levels of PTH and FGF-23.

Hyperphosphatemia is common in patients with end-stage renal failure. According to an international study conducted in 2005 in representative samples of dialysis patients in 7 countries (France, Germany, Italy, Japan, Spain, UK and USA), the prevalence of hyperphosphatemia did not differ significantly and was 49.4% in European countries and 53. 6% in Japan, although most patients received phosphate binders. However, the DOPPS study has noted a decrease in the incidence of hyperphosphatemia in patients with end-stage renal disease in recent years.

Changes in mineral metabolism in CKD lead to the development of renal osteodystrophy, which is characterized by increased bone resorption and impaired bone formation and mineralization. The classic histological feature of renal osteodystrophy is osteitis fibrosa, which is accompanied by increased bone remodeling and bone marrow fibrosis. Renal osteodystrophy causes fractures, bone pain, bone deformities, and growth retardation in children.

Characteristic manifestations of MCI-CKD also include ectopic calcification - the deposition of calcium phosphate in the arteries, cardiac valves, myocardium, and soft tissues, which accelerates as the mass of active nephrons decreases and occurs in patients with CKD much more often than in the general population. Initially, it was believed that calcification was a passive precipitation of calcium phosphate when the concentration of calcium and phosphate ions in the serum increased. However, it was later found that vascular calcification is an active process based on the transformation of smooth muscle cells into osteoblast-like cells, which occurs as a result of the interaction of various factors, including hyperphosphatemia, uremic toxins and reactive oxygen radicals, as well as a decrease in the expression of inhibitory oxygen radicals. proteins such as matrix Gla protein and fetuin A. Elevated serum levels of phosphate and Ca X P in patients with end-stage renal failure were closely associated with the severity of arterial calcification, and incubation of smooth muscle cells with a phosphate solution caused their differentiation into osteoblast-like cells. A certain contribution to the development of uremic arteriopathy is made by a violation of the protective effect of FGF-23 on blood vessels, which is partly associated with a decrease in the expression of Klotho proteins.

Vascular calcification can occur in the area of ​​both the inner and middle (muscular) lining of the arteries. In the first case, it contributes to the accelerated development of the atherosclerotic process, which underlies the development of angina, myocardial infarction and stroke. In the second case, calcification increases the stiffness of the arterial walls, causes an increase in pulse wave velocity and pulse pressure, and ultimately leads to left ventricular hypertrophy and heart failure, and contributes to the development of coronary insufficiency. A rarer but more severe form of calcification of the muscular wall of small arteries is calciphylaxis, or calcific uremic arteriopathy, which is characterized by the development of painful ischemic skin ulcers and bacterial superinfections. Vascular calcification is often accompanied by calcification of the heart valves.

Diagnosis of arterial calcification
The most reliable methods for assessing arterial calcification are electron beam and multispiral computed tomography. The severity of coronary artery calcification is determined using the Agatson scale, taking into account the density and area of ​​calcium deposition. Based on these indicators, the calcification index, or calcium score, will be calculated as the product of the density and area of ​​calcium deposits using special software. The disadvantage of computed tomography is the high cost of the method, which prevents its widespread use for screening purposes. Alternative methods include measurement of pulse pressure and pulse wave velocity, thickness of the intima-media complex of the carotid arteries, radiography of the abdominal aorta in the lateral projection, echocardiography (valvular calcification). In one study, there was no correlation between pulse pressure and coronary artery calcification index, while abdominal aortic and valvular calcification, assessed by conventional radiography and echocardiography, respectively, correlated closely with coronary electron beam computed tomography findings. Pulse wave velocity can also serve as a surrogate marker for coronary artery calcification, but special equipment is required to measure it. At the same time, the thickness of the intima-media complex turned out to be a little informative indicator. The KDIGO guidelines indicate that in patients with CKD stages 3-5D, lateral abdominal radiography and echocardiography can be used instead of high-resolution computed tomography to diagnose vascular calcification.

The same guidelines analyzed the results of 25 studies that examined the incidence of vascular and valvular calcification in more than 4,000 patients with various stages of CKD (most stage 5D). In adult patients treated with dialysis, the incidence of coronary artery calcification was 51-93%, and the incidence of heart valve calcification was 20-47%. Eight studies examined the natural history of vascular calcification over 1–3 years. Overall, calcification has been shown to be generally progressive and to be an independent predictor of cardiovascular and all-cause mortality. Accordingly, the risk of developing cardiovascular outcomes in patients with stage 3-5D CKD, in whom vascular and/or valve calcification is determined, should be considered very high. Screening for vascular calcification is justified in patients with persistent hyperphosphatemia requiring the use of phosphate binders, patients on the kidney transplant waiting list, and in all other cases where information about the presence of calcification or its severity may be important for the choice of further management of the patient.

Treatment methods for hyperphosphatemia
The basis for monitoring serum phosphate levels in patients with CKD is the results of epidemiological studies indicating that hyperphosphatemia increases the risk of death from all causes and cardiovascular causes and contributes to the development of ectopic calcification of blood vessels, valves and soft tissues. Recently, the DOPPS study showed that the association between increasing serum phosphorus levels and the relative risk of death from any cause is consistent across countries. In most studies, the risk of death began to increase when phosphorus levels exceeded 1.6-1.8 mmol/L. Epidemiological evidence is supported by experimental studies showing a direct causal relationship between elevated phosphate levels and other components of MCI-CKD, including secondary hyperparathyroidism, bone disease, calcitriol deficiency, and ectopic calcification.

The national MCI-CKD guidelines recommend maintaining serum phosphate levels in the normal range in patients with CKD stages 3–5 (adjusted for local laboratory standards), and in patients on dialysis, aiming to reduce phosphate levels to normal values. The proportion of patients with phosphate levels below 1.9 mmol/L in the dialysis center should be at least 70%. To control hyperphosphatemia in patients with CKD, diet and phosphate binders are used, as well as increasing the duration of dialysis. Significant restriction of phosphorus in food is unjustified in patients with CKD and can lead to a deterioration in their overall nutrition, especially protein intake, the reduction of which in dialysis patients is justified only to a certain limit (at least 1 g/kg/day). However, choosing foods with lower phosphate content should be given top priority. Hemodialysis causes a decrease in the serum level of phosphorus, but it quickly increases again after dialysis (after 4 hours) due to the redistribution of the element from the intracellular space. Given the frequency of hemodialysis treatment, a persistent decrease in serum phosphorus levels using this method alone is impossible, therefore, to adequately control phosphate concentrations, the use of phosphate binders is necessary.

Drugs that lower serum phosphate levels include (1) calcium supplements (calcium carbonate and calcium acetate); (2) sevelamer hydrochloride (Renagel) and sevelamer carbonate (Renvela); (3) aluminum hydroxide; (4) lanthanum carbonate. Aluminum preparations are characterized by the highest effectiveness in the treatment of hyperphosphatemia, but their use is limited by the toxicity of this metal, manifested by “dialysis” dementia, neuropathy, microcytic anemia and osteomalacia. In the past, the main source of aluminum entering the patient's body during hemodialysis was the water used to prepare the dialysate solution. Currently, due to the high degree of water purification, the concentration of aluminum in the dialysate solution is minimal, and some studies have not noted its accumulation with long-term use of phosphate binders containing aluminum. However, the potential risk of toxicity does not allow us to recommend the use of such drugs in patients on dialysis.

Calcium salts are affordable and effective phosphate binders that are widely used to control hyperphosphatemia in patients with CKD. When using them, it is necessary to take into account the risk of absorption of a significant proportion of calcium entering the gastrointestinal tract. In addition, treatment with calcium supplements may be associated with increased serum calcium levels, the development of episodes of hypercalcemia and decreased PTH levels, and may also contribute to the development of vascular and soft tissue calcification. In this regard, the recommendations

KDIGO suggests limiting the use of calcium supplements in patients with persistent or recurrent hypercalcemia, arterial calcification, adynamic bone disease, and persistently decreased serum PTH levels. The national guidelines for MCI-CKD also do not recommend the use of calcium salts if the calcium level increases more than 2.6 mmol/l (two measurements in a row) and the PTH level decreases less than 100 pg/ml. The total elemental calcium content in phosphate binders should not exceed 1.5 g/day, and the total calcium intake should not exceed 2 g/day. To exclude episodes of hypercalcemia, more frequent (monthly) monitoring of serum calcium levels is necessary.

Lantana carbonate is not inferior to calcium preparations in the treatment of hyperphosphatemia. Lanthanum is partially absorbed in the gastrointestinal tract and can accumulate in bone tissue.

Sevelamer hydrochloride is the most studied non-calcium phosphate binder. It is a polymer that is not absorbed from the gastrointestinal tract, does not cause hypercalcemia, and provides phosphate control while significantly reducing total and low-density lipoprotein (LDL) cholesterol levels. The results of a number of comparative studies indicate that sevelamer hydrochloride is at least as effective as calcium salts, but unlike the latter, it can delay the development of arterial and soft tissue calcification and improve long-term outcomes in patients with CKD.

Effects of phosphate binders on vascular calcification and mortality
The vast majority of controlled studies compared the development of vascular calcification and the risk of adverse clinical outcomes between sevelamer hydrochloride and calcium salts.

Vascular calcification. The 52-week randomized, open-label Treat to Goal trial compared the effects of sevelamer hydrochloride and calcium salts (acetate in the US and carbonate in Europe) on the progression of arterial calcification in 200 patients undergoing hemodialysis treatment. Serum calcium, phosphorus, and PTH levels were maintained within target values ​​during the study. The coronary artery and aortic calcification index was calculated using electron beam computed tomography. Serum phosphate levels at the end of the study were comparable between sevelamer and calcium salts. At the same time, when using calcium salts, the serum calcium concentration was higher (p = 0.002), hypercalcemia was more common (16% and 5%, respectively; p = 0.04) and the proportion of patients with an intact PTH concentration below the target level was higher ( 57% and 30%; p=0.001). After 52 weeks, the median calcium count increased significantly in the group of patients receiving calcium salts and did not change in the sevelamer hydrochloride group (coronary arteries: 36.6 and 0, respectively; p = 0.03; aorta: 75.1 and 0; p =0.01). The median change in calcium count in the coronary arteries and aorta in patients with an initial value of >30 during treatment with calcium preparations also significantly exceeded that when using sevelamer hydrochloride (Fig. 1).

Rice. 1. Median increase in coronary artery calcium score (%) with sevelamer hydrochloride and calcium salts in dialysis patients with baseline calcium score >30. p=0.01 at 26 weeks and p=0.02 at 52 weeks

The RIND study compared changes in coronary calcium counts using electron beam computed tomography after 6, 12, and 18 months of treatment with sevelamer or calcium salts in 129 patients starting hemodialysis therapy. Approximately one third of patients initially had no signs of coronary artery calcification. In this sample, no case showed an increase in calcium score >30 at 18 months. In patients with a baseline calcium score >30, an increase was observed with both calcium salts and sevelamer hydrochloride. However, in patients receiving calcium salts, it increased faster and to a greater extent than when treated with sevelamer hydrochloride (p = 0.056 after 12 months and p = 0.01 after 18 months; Fig. 2).

Rice. 2. Median calcium count in the coronary arteries in dialysis patients receiving sevelamer hydrochloride and calcium salts

After 18 months, the median increase in calcium count with calcium supplementation was 11 times higher than that with sevelamer hydrochloride (127 and 11, respectively; p=0.01).

Similar results were obtained in another study of 183 adult patients receiving hemodialysis treatment. Changes in coronary artery calcification were assessed using multislice computed tomography 12 months after initiation of treatment with sevelamer or calcium carbonate. Calcium counts in the two groups increased by an average of 82 and 194, respectively (p=0.001 between groups). The proportion of patients whose calcification index increased by at least 15% was significantly lower in the sevelamer group (35% and 59%, respectively; p=0.002).

Some studies have reported no difference in the progression of arterial calcification between sevelamer hydrochloride and calcium salts. For example, it was comparable in the CARE 2 study with intensive lipid control. However, this study had significant limitations, including a short follow-up duration of 1 year and a high rate of early treatment discontinuation.

In one study, the effects of diet, sevelamer hydrochloride, and calcium salts on coronary artery calcification were compared in 90 patients with CKD stages 3–5 not receiving hemodialysis treatment. After 2 years, the coronary artery calcification index increased in patients treated with a low-phosphate diet or diet and calcium carbonate, and did not change in patients treated with diet and sevelamer hydrochloride. A significant reduction in the incidence of coronary artery calcification and slower progression of coronary artery calcification with sevelamer in predialysis patients with CKD was also observed in the INDEPENDENT randomized trial. Development of coronary artery calcification de novo observed in 12.8% and 81.8% of patients receiving sevelamer hydrochloride and calcium carbonate, respectively. In addition, regression of coronary artery calcification was significantly more common in the sevelamer group.

In summary, the majority of controlled clinical trials have shown that treatment with sevelamer hydrochloride delays the progression of coronary artery calcification compared with calcium salts in CKD patients with and without renal replacement therapy. Coronary artery calcification is a “surrogate” criterion for the effectiveness of phosphate binders, since the ability to improve clinical outcomes while slowing its progression in dialysis patients is considered unproven. However, in the RIND study, baseline coronary artery calcification index in dialysis patients was a significant predictor of death from all causes (adjusted for age, race, sex, and diabetes mellitus in multivariate analysis).

Mortality. The largest 3-year randomized trial, DCOR, examined morbidity and mortality in 2103 dialysis patients treated with sevelamer or calcium salts. There was no significant difference in overall or cardiovascular mortality between the two groups, although the risk of death decreased in the sevelamer group by 7%. Treatment with this drug was associated with a reduction in all-cause hospitalizations and length of stay. In a sample of patients >65 years of age, a significant reduction in overall mortality by 23% (p = 0.02) was found in the sevelamer group compared with that in patients receiving calcium salts. Sevelamer hydrochloride also had a significant (p=0.02) advantage over calcium salts in terms of its effect on mortality in patients who continued treatment for at least 2 years (43% of the sample).

According to the analysis post hoc According to the results of the RIND study, over a median 44 months, mortality in the group of patients treated with sevelamer hydrochloride was lower than in the group of patients treated with calcium salts (5.3 and 10.6 per 100 patient-years, respectively; p =0.05) . Multivariate analysis showed that treatment with calcium salts was associated with a higher risk of death (odds ratio 3.1, 95% confidence interval 1.23–7.61) (Fig. 3).

Rice. 3. Adjusted survival with calcium salts and sevelamer. Multivariate analysis adjusted for age, race, sex, diabetes, cardiovascular disease, C-reactive protein, albumin, and baseline calcium score.

A retrospective cohort study compared 2-year survival in 1377 dialysis patients treated with calcium supplements or sevelamer hydrochloride. Survival was estimated using a Cox regression model adjusted for age, sex, race, marital status, region, diabetes, hypertension, and comorbidity index. Treatment with sevelamer hydrochloride was associated with a 33% reduction in the risk of death from any cause compared with calcium supplements.

The results of the 2-year randomized INDEPENDENT trial were recently published, which compared mortality in 212 patients with stage 3-4 CKD who received sevelamer or calcium carbonate. In the sevelamer hydrochloride group, a significant decrease in overall mortality was found compared to the comparison group. According to the study authors, the beneficial effect of sevelamer could be partly explained by its pleiotropic effects (decreasing levels of C-reactive protein, total cholesterol and LDL cholesterol).

In summary, clinical trial results suggest that treatment with sevelamer hydrochloride may reduce overall mortality in dialysis patients compared with calcium salts, although further studies are needed to confirm this effect.

Conclusion
One of the reasons for increased overall and cardiovascular mortality in patients with CKD is MCI, which occurs in almost all patients receiving dialysis treatment and is accompanied by the development and progression of calcification of the coronary and other arteries. Phosphate retention and hyperphosphatemia play a key role in the development of MCI. Large epidemiological studies have found that hyperphosphatemia increases the risk of death from all causes and cardiovascular causes. To control serum phosphate levels in patients with CKD on dialysis, a low-phosphate diet and phosphate binders are used. Results from clinical studies have shown that treatment with calcium salts not only increases serum calcium levels and the incidence of hypercalcemia, but may also promote the development of calcification of coronary and other arteries. Therefore, the KDIGO and national MCI-CKD guidelines recommend avoiding the use of calcium salts in patients with hypercalcemia or severe arterial calcification. At the same time, the calcium-free phosphate binder sevelamer hydrochloride delayed the progression of arterial calcification in CKD patients with and without renal replacement therapy. Some studies have found a reduction in overall mortality in patients with CKD when treated with sevelamer hydrochloride. In the largest study, this effect was observed in elderly patients with stage 5D CKD, as well as with longer use of the drug (more than 2 years). It is of interest to study disorders of phosphate metabolism in the predialysis stages of CKD. It can be assumed that a phosphate-restricted diet and the use of phosphate binders in the early stages of CKD will help prevent cardiovascular complications in such patients.

Literature
1. Foley R., Parfrey P., Sarnak M. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis., 1998, 32, S112-S119.
2. Chonchol M., Whittle J., Desbien A. et al. Chronic kidney disease is associated with angiographic coronary artery disease. Am. J. Nephrol., 2008, 28 (2), 354-360.
3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int., 2009, 76(Suppl. 113), S1-S130.
4. Blacher J., Guerin A., Pannier B. et al. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension, 2001, 38, 938-942. 5. Roman-Garcia P., Carrillo-Lopez N., Cannata-Andia J. Pathogenesis of bone and mineral related disorders in chronic kidney disease: Key role of hyperphosphatemia. J.Ren. Care, 2009, 35(Suppl. 1), 34-38.
6. Milovanova L.Yu., Nikolaev A.Yu., Milovanov Yu.S. Hyperphosphatemia as a risk factor for cardiovascular diseases in patients with chronic renal failure on chronic hemodialysis. Nephrol. dial., 2002, 2 (4), 113-117.
7. Block G., Klassen P., Lazarus J. et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J. Am. Soc. Nephrol., 2004, 15 (8), 2208-2218.
8. Young et al. 2005
9. National recommendations on mineral and bone disorders in chronic kidney disease. Russian Dialysis Society (May 2010). Nephrology and Dialysis, 2011, 13 (1), 33-51.
10. Milovanova L.Yu., Milovanov Yu.S., Kozlovskaya L.V. Disorders of phosphorus-calcium metabolism in chronic kidney disease stage III-V. Wedge. nephrology, 2011, 1, 58-68.
11. Berndt T., Kumar R. Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda), 2009, 24, 17-25.
12. Gupta D., Brietzke S., Hay M. et al. Phosphate metabolism in cardiorenal metabolic disease. Cardiorenal. Med., 2011, 1, 261-270.
13. Dobronravov V.A. Modern view on the pathophysiology of secondary hyperparathyroidism: the role of fibroblast growth factor 23 and Klotho. Nephrology, 2011, 4, 11-20.
14. Milovanov Yu.S., Kozlovskaya L.V., Bobkova I.N. and others. Mechanisms of disturbance of phosphorus-calcium homeostasis in the development of cardiovascular complications in patients with chronic kidney disease. The role of fibroblast growth factor-23 and Klotho. Ter. archive, 2010, 6, 66-72.
15. Tentori F., Blayney M., Albert J. et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am. J. Kidney Dis., 2008, 52, 519-530.
16. Sowers K., Hayden M. Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches. Oxid. Med. Cell. Longev., 2010, 3, 109-121.
17. Tomilina N.A., Volgina G.V., Bikbov B.T. Calcification of heart valves in patients with end-stage chronic renal failure. Ross. Journal of Cardiology, 2003, 2, 23-29.
18. Bellasi A., Ferramosca E., Muntner P. et al. Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients. Kidney Int., 2006, 70, 1623-1628.
19. Kestenbaum B., Sampson J., Rudser K. et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J. Am. Soc. Nephrol., 2005, 16, 520-528.
20. Block G., Hulbert-Shearon T., Levin N. et al. Association of serum phosphorus and calcium X phosphate product mortality risk in chronic hemodialysis patients: a national study. Am. J. Kidney Dis., 1998, 31, 607-617.
21. Rodriguez-Benot A., Martin-Malo A., Alvarez-Lara M. et al. Mild hyperphosphatemia and mortality in hemodialysis patients. Am. J. Kidney Dis. , 2005, 46, 68-77.
22. Ganesh S., Stack A., Levin N. et al. Association of elevated serum PO(4), Ca X PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J. Am. Soc. Nephrol., 2001, 12, 2131-2138.
23. Giachelli C. Vascular calcification mechanisms. J. Am. Soc. Nephrol., 2004, 15, 2959-2964.
24. Mucsi I, Hercz G. Control of serum phosphate in patients with renal failure-new approaches. Nephrol. Dial. Transplant., 1998, 13 (10), 2457-2460.
25. Chertow G., Burke S., Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int., 2002, 62, 245-252.
26. Block G., Spiegel D., Ehrlich J. et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int., 2005, 68, 1815-1824.
27. Kakuta T., Tanaka R., Hyodo T. et al. Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients. Am. J. Kidney Dis., 2011, 57 (3), 422-431.
28. Barreto D., Barreto F., de Carvalho A. et al. Phosphate binder impact on bone remodeling and coronary calcification-results from the BRiC study. Nephron Clin. Pract., 2008, 110, 273-283.
29. Qunibi W., Moustafa M., Muenz L. et al. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study. Am. J. Kidney Dis., 2008, 51, 952-965.
30. Russo D., Miranda I., Ruocco C. et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int., 2007, 72, 1255-1261.
31. Di Iorio B., Bellasi A., Russo D. on behalf of the INDEPENDENT Study Investigators Mortality in Kidney Disease Patients Treated with Phosphate Binders: A Randomized Study. Clin. J. Am. Soc. Nephrol., 2012, 7 (3), 487-493.
32. Block G., Raggi P., Bellasi A. et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int., 2007, 71, 438-441.
33. Suki W., Zabaneh R., Cangiano J. et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int., 2007, 72, 1130-1137.
34. St Peter WL, Liu J, Weinhandl E, Fan Q. A comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemodialysis: a secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) randomized trial using claims data. Am. J. Kidney Dis., 2008, 51, 445-454.
35. Borzecki A., Lee A., Wang S. et al. Survival in end stage renal disease: calcium carbonate vs. sevelamer. J. Clin. Pharmacy & Ther., 2007, 32, 617-624.