Drug therapy for kidney damage caused by disorders of purine metabolism

Glomerular filtration rate

Glomerular filtration rate (Reberg-Tareev test) – Reberg test is a method for determining glomerular filtration rate (effective renal blood flow). This is a method by which the excretory capacity of the kidneys is assessed, based on the determination of the renal clearance of endogenous creatinine. The clearance of endogenous creatinine can be determined based on the concentration of creatinine in the blood and urine and the volume of urine excreted per day (daily diuresis). Having determined the level of creatinine in the blood and urine, minute diuresis, glomerular filtration rate (GFR) and tubular reabsorption are calculated.

Indications for use: Assessment of kidney function in acute and chronic nephritis, hypertension.

Preparation for the study To carry out the analysis, you need to submit a daily portion of urine and blood from a vein to the laboratory. Taking blood in the morning is strictly on an empty stomach, 10-12 hours after the last meal.

Rules for collecting 24-hour urine for laboratory research

• Before each urine collection, toilet the external genitalia;
• The first morning urine sample is not collected, but the time of urination is noted. Subsequently, all urine excreted in 24 hours from the marked time of the first urination to the same hour a day later is collected;
• 24-hour urine collection is carried out in a clean, dry container with a lid or in a specialized 2.7-liter graduated plastic container;
• Urine should be stored in a closed container in the refrigerator on the bottom shelf, avoiding freezing;

At the end of the collection (the last urination at the same time, which is marked as the time of the first urination, but one day later), the daily volume of urine in a closed container is shaken and poured into a small container for clinical urine analysis of 125 ml, a 100 ml portion is poured.

When submitting daily urine to the laboratory, it is necessary to indicate the volume of urine excreted per day.

Execution time 1 day, in cito mode – 1.5 – 2 hours

Reference values ​​Glomerular filtration rate

Tubular reabsorption - 97 - 99%

Make an appointment through the application or by calling +7 +7 We work every day:

• Monday—Friday: 8.00—20.00
• Saturday: 8.00–18.00
• Sunday is a day off

The nearest metro and MCC stations to the clinic:

• Highway of Enthusiasts or Perovo
• Partisan
• Enthusiast Highway

Driving directions

Drug therapy for kidney damage caused by disorders of purine metabolism

Purine metabolism is a complex cascade of biochemical reactions in which many enzyme systems take part. The content of purines in the body consists of their intake from food and endogenous synthesis. Most of the salts of uric acid - urates - are formed endogenously during the metabolism of nucleic acids, but there are other ways of biosynthesis of these substances. In all variants, the most important intermediate is inosinic acid, which subsequently undergoes hydrolysis. The resulting hypoxanthine is converted into xanthine and uric acid under the influence of the enzyme xanthine oxidase. From a biochemical point of view, disorders of purine metabolism represent various types of imbalance between the enzyme systems responsible for the synthesis and transport of uric acid and its precursors. The intake of a significant amount of purines from food is also essential.

It is believed that the body of an adult healthy person contains about 1000 mg of uric acid. If purine metabolism is impaired, this figure can increase several times. The content of uric acid in the body is not a rigid parameter and does not have any diagnostic value. Even the main indicator of the state of purine metabolism - the concentration of uric acid in the blood serum is not particularly harsh. The minimum and maximum normal values ​​differ by approximately 2.5 times - 200–450 µmol/l in men and 160–400 µmol/day in women. In healthy people, approximately 750 mg or 2/3 of the total volume of uric acid is excreted and synthesized again per day. Of this amount, about 80% or 600 mg is excreted by the kidneys. The remaining 20% ​​is excreted through the gastrointestinal tract. According to P. M. Klimenko et al. (2010) the normal clearance of uric acid is 5.4–9.0 ml/min [1].

Renal excretion of urate is a complex and multistep process. Filtration of plasma urate occurs in the glomeruli. The urates that enter the ultrafiltrate are almost completely reabsorbed in the proximal tubule and then secreted into the lumen of the nephron. Some of the secreted urate is reabsorbed. The process of active secretion of urates is very sensitive to various chemical agents. It is believed that renal secretion of urates is increased by orotic acid, losartan, estrogens, and tetracycline breakdown products (expired tetracyclines are highly toxic!); renal excretion of urate is reduced by ethambutol, thiazides and thiazide-like diuretics, and to a lesser extent by furosemide and acetazolamide [2]. It is quite obvious that the severity of the observed effects varies greatly from drug to drug and does not always have clinical application. In particular, the uricosuric properties of estrogens are not significant. Losartan has recently begun to appear in treatment regimens for gouty tubulointerstitial nephritis in patients who do not have nephrolithiasis [3]. The tendency of thiazides and indapamide to reduce the renal excretion of urates and increase their serum concentration is quite pronounced, which makes these drugs at least undesirable for articular gout and, especially, for gouty nephropathy.

Clinical variants of kidney damage due to impaired purine metabolism

Diseases associated with disorders of purine metabolism are relatively common, which makes issues related to their treatment relevant. Urology specialists, as well as most general practitioners, are well aware of the features of urate nephrolithiasis. At the same time, these specialists often have no idea at all about the existence of other, sometimes more serious, diseases caused by disorders of purine metabolism. Meanwhile, they all occur with varying frequency in hospitals, as well as in the provision of outpatient medical care.

The most significant consequence of disorders of purine metabolism is an increase in the level of uric acid in the blood - hyperuricemia, which is the main etiological factor of various pathological conditions. Depending on the etiology, hyperuricemia is divided into primary (without an obvious cause) and secondary to a disease.

The clinical consequence of primary hyperuricemia is gout in the broad sense of the term. This includes classic acute microcrystalline arthritis, and various variants of gouty nephropathy, one of which is urate nephrolithiasis, and tophi of various locations, and complications of all these conditions.

In the group of diseases associated with primary hyperuricemia, genetically determined disorders of purine metabolism stand somewhat apart. Among them are Lesch-Nychen syndrome, Gierke's disease, various variants of hereditary defects in the transport systems of the renal tubules and others. Distinctive signs of hyperuricemia inherited as a monogenic type (that is, associated with a defect in a specific gene that determines the development of the entire symptom complex) are manifestation in early childhood, high overproduction of uric acid, rapid, sometimes even “malignant” progression of the disease up to the formation of end-stage renal failure , often very moderate effectiveness of treatment measures, despite the most active therapy [4].

Clinical diagnosis of disorders of purine metabolism inherited in a polygenic manner is currently difficult. The manifestations and course of the disease in this case vary greatly depending on external factors, and the biological effect of a significant part of the genes is still not completely clear [3, 4].

In nephrological and general therapeutic practice, the concept of “gouty kidney” was introduced several decades ago to determine kidney damage due to hyperuricemia, which in modern medicine has been transformed into “gouty nephropathy”. Considering the experimentally proven damaging effect of uric acid salts on renal structures, the term “urate nephropathy” was also proposed. All these concepts are generalizing and combine several processes that are quite different in their pathogenesis: acute uric acid nephropathy, urate nephrolithiasis and chronic tubulointerstitial nephritis. Some authors also note the possibility of immune complex glomerulonephritis, the triggering factor of which is overproduction of uric acid [5].

In urological practice, patients with urate nephrolithiasis are most often encountered. Up to 80% of such patients had an episode of acute arthritis at least once in their lives, and not necessarily of the classical localization - the first metatarsophalangeal joint. Recently, atypical variants of gouty arthritis, for example, gout, have become increasingly common. In addition, the widespread and uncontrolled use of non-steroidal anti-inflammatory drugs often blurs the clinical picture, increasing the proportion of arthritis with less activity of the inflammatory process. It can be noted that the combination of arthritis and urate nephrolithiasis is not mandatory, but rather characteristic [5, 6].

The clinical picture of a kidney or ureteral calculus is well known, so there is no point in describing it in detail again. The only thing worth noting is that in the most severe, “malignant” course, along with the formation of urate stones in the lumen of the urinary tract, there may also be deposition of urate crystals in the renal interstitium, which is called “nephrocalcinosis”. Unlike nephrolithiasis, nephrocalcinosis in gout is always bilateral. Nephrocalcinosis does not have any specific symptoms. Clinical manifestations are reduced to the progression of renal failure due to nephrosclerosis. Nephrocalcinosis is in most cases detected by ultrasound scanning and requires specific therapy.

Chronic tubulointerstitial nephritis is a characteristic and common variant of gouty nephropathy. However, due to the less vivid clinical picture, it is known mainly to nephrologists and rheumatologists.

In the initial stages of tubulointerstitial nephritis, the pathological process mainly affects the tubules and renal interstitium, so the leading symptom is a violation of the concentration function of the kidneys - polyuria with low urine density (hyposthenuria). Proteinuria does not exceed 1 g/day or is completely absent - it is associated with impaired protein reabsorption by the tubules. Gouty interstitial nephritis is characterized by persistent uraturia, as well as persistent or episodic microhematuria, especially after a respiratory viral infection.

The level of blood urate is also naturally increased, but it must be remembered that the very fact of the presence of chronic renal failure is also the cause of hyperuricemia. With an obvious clinical picture of chronic tubulointerstitial nephritis, its connection with disorders of purine metabolism is beyond doubt with the following ratios of blood urate and creatinine levels: respectively > 536 µmol/l and < 132 µmol/l; > 595 µmol/l and 132–176 µmol/l; > 714 µmol/l and > 176 µmol/l [7].

In an immunohistochemical study of renal biopsy specimens, some patients with a clinical picture of gouty tubulointerstitial nephritis showed fluorescence of the C3 fraction of complement and IgG, which is characteristic of immune complex glomerulonephritis. This made it possible to identify chronic glomerulonephritis as a separate variant of gouty nephropathy [6].

With the progression of gouty tubulointerstitial nephritis, the development of arterial hypertension and nephrosclerosis is natural.

Acute uric acid nephropathy (acute gouty kidney) is based on obstruction of the renal tubules by urate crystals, which leads to acute renal failure. The disease begins with oliguria. Some patients simultaneously complain of renal colic-type pain and gross hematuria, which may be explained by the migration of large urate crystals through the ureter. Pathognomonic is high uraturia, which is not typical for acute renal failure of other etiologies, as well as a significant increase in the level of uric acid in the blood (above 850–900 µmol/l). In modern nephrological practice, it is believed that the diagnosis of acute uric acid nephropathy is beyond doubt when the ratio of blood urate and creatinine levels (in mg) is > 1 [8].

The assumption of acute uric acid nephropathy is based on a combination of three clinical signs - highly active arthritis with characteristic localization, a sharp decrease in diuresis and brick-brown urine. The diagnosis is all the more likely if the patient indicates hypohydration of any origin - from visiting a bathhouse and physical work at high temperatures to inadequate infusion therapy and overdose of diuretics, as well as consuming significant amounts of meat products and/or alcohol. In the natural course of the disease, oliguria almost always progresses to anuria with a detailed clinical picture of acute renal failure.

The problem of acute uric acid nephropathy is closely related to secondary hyperuricemia. The reasons for increased levels of uric acid in the blood serum are quite numerous and varied. Among them: chronic renal failure, regardless of etiology, obesity, especially high degrees, poorly compensated diabetes mellitus, acromegaly, hypothyroidism, hypoparathyroidism, toxicosis of pregnancy, myeloproliferative diseases, sarcoidosis, chronic lead intoxication, chronic alcoholism. There is a clear connection between the increased risk of urate nephrolithiasis and the presence of severe psoriasis in the patient, especially articular psoriasis. In most cases, the severity of hyperuricemia in these diseases is mild, less often moderate. Thus, disorders of purine metabolism rarely significantly affect the clinical picture of the disease.

The most striking and clinically significant variant of secondary hyperuricemia is “tumor lysis syndrome” (“tumor disintegration syndrome”), which develops during chemotherapy and radiotherapy for lymphoproliferative diseases, less often for tumors of other localizations. A key component of this syndrome, along with hyperphosphatemia and hyperkalemia, is the overproduction of uric acid, leading to the development of acute uric acid nephropathy, often in intact kidneys [11]. However, severe hyperuricemia caused by genetic disorders extremely rarely leads to acute uric acid nephropathy [3, 4].

Drug therapy for kidney diseases caused by disorders of purine metabolism

Conservative therapy of any variant of gouty nephropathy is based on reducing the level of hyperuricemia, and therefore hyperuricuria, as well as increasing the solubility of urate in urine.

All patients are required to be prescribed a diet, the purpose of which is to reduce the intake of purines into the body from food. This is achieved by completely excluding meat from young animals, offal, meat broths, sausages, etc. from the diet; meat from full-aged animals and fish are allowed to a limited extent. Patients are recommended to have a predominantly plant-based diet, plenty of alkaline drinks, citrus fruits and drinks based on them, as well as complete abstinence from alcohol.

In the presence of renal failure, arterial hypertension, circulatory failure, and obesity, additional restrictions are introduced. First of all, it is recommended to reduce the consumption of table salt, since the effectiveness of ACE inhibitors, especially indicated for nephropathies complicated by arterial hypertension, and indeed all antihypertensive therapy directly depends on the amount of sodium entering the body. With severe filtration deficiency, there is a need to limit protein intake. In case of obesity, reduce the total caloric intake of the diet.

In a number of patients, for example, with rarely recurrent urate nephrolithiasis without renal failure, with sufficient motivation on the part of the patient, it is generally possible to confine oneself to the correction of diet and drinking regimen, without resorting to the prescription of medications.

Medicines used for the pathogenetic treatment of gouty nephropathy are divided into:

• drugs that affect purine metabolism (allopurinol, febuxostat);
• drugs that increase the renal excretion of purines (probenecid, benzbromarone);
• drugs that increase the solubility of uric acid and its salts (citric acid and its salts - citrates).

The basic drug that affects purine metabolism is allopurinol, which is an inhibitor of the enzyme xanthine oxidase. Under the influence of this enzyme, the last stage of uric acid synthesis occurs. The urate precursors xanthine and hypoxanthine have almost 10 times higher solubility in water compared to uric acid. Stopping purine metabolism at this stage reduces the risk of crystal formation, and therefore microcrystalline arthritis and nephropathy, to almost zero.

Allopurinol is indicated for gouty tubulointerstitial nephritis, acute uric acid nephropathy, urate nephrolithiasis in combination with hyperuricemia, as well as chemotherapy for malignant neoplasms to prevent the development of secondary hyperuricemia and acute renal failure. The minimum effective dosage is 200 mg/day, the average therapeutic dosage is 300–400 mg/day. Chemotherapy for malignant neoplasms requires high, close to maximum, dosages of allopurinol - 600–900 mg/day [2].

Allopurinol tends to cause dyspeptic disorders and skin rashes, which occur in almost every fifth patient. The side effects of this drug are often unpleasant, but not dangerous, and due to the almost complete (until recently) lack of alternatives to this drug, most patients still continue treatment.

Recently, a new xanthine oxidase inhibitor febuxostat has appeared on the domestic market, which differs from allopurinol in higher selectivity [3]. Domestic experience with febuxostat is still extremely limited, but foreign researchers note its higher effectiveness against hyperuricemia [9]. However, it can already be noted that this drug is a complete replacement for allopurinol in conditions of intolerance, allergies, etc.

In conclusion, xanthine oxidase inhibitors are contraindicated in patients receiving azathioprine and 6-mercaptopurine, as this enzyme is involved in their metabolism. When administered together, the risk of toxicity, primarily bone marrow toxicity, increases sharply.

Recombinant urate oxidase, rasburicase, is also used abroad. The drug is significantly more effective than allopurinol in reducing hyperuricemia and is used mainly in hematological practice for the prevention of acute urate nephropathy [3].

Medicines that increase the renal excretion of purines - uricosuric drugs - inhibit the process of reabsorption of urate from the lumen of the renal tubules. In modern clinical practice, this group of drugs is used very limitedly. Not all patients demonstrate sufficient effectiveness. In addition, the direct pharmacological effect of increasing renal excretion of urate results in an increased risk of nephrolithiasis. The most famous uricosuric drug, probenecid, is currently practically absent from the domestic market. Benzbromarone is registered in Russia, but is available only in very small quantities. All uricosuric drugs undergo hepatic metabolism in the body and have some hepatotoxicity. Another feature of these drugs is the huge number of drug interactions, which complicates their use as part of multicomponent regimens.

Citrate therapy is an integral part of the drug treatment of gouty nephropathy. The effect of citric acid salts on the process of crystal formation in urine is multifaceted. The solubility of uric acid varies significantly depending on the reaction of the medium. In an acidic environment, urates have very poor solubility and easily pass into the solid phase - they crystallize. With a neutral or alkaline reaction, the solubility of these salts increases. The main effect of citrates is the ability to alkalize urine, which prevents crystallization of urates and creates conditions for the dissolution of already formed crystals. This is the basis of litholytic therapy. However, with an alkaline reaction of the environment, the solubility of phosphates decreases. The layering of a phosphate film on the urate stone makes the process of further litholysis practically hopeless. This dictates the need for careful monitoring of the urine reaction throughout the course of treatment. In modern conditions, the empirical use of plant materials rich in citric acid and its salts has been replaced by drugs that include chemically pure citrate and a set of test strips for monitoring urine reactions.

Research 1980–90s demonstrated the effectiveness of litholysis of urate stones using citrate mixtures in monotherapy in the order of 75–80% [10, 11]. Currently, as a result of improving the technique, the efficiency of litholysis has been increased to 85–90%, depending on the characteristics of the chemical composition of the stones [1, 12, 13].

In recent years, studies have appeared indicating the advisability of including citrate preparations in multicomponent treatment regimens. In particular, with urate stones of the ureter, especially in its distal third, combination therapy, including citrate and tamsulosin, led to spontaneous passage of 84.8% of stones, which significantly differs from the groups of patients receiving monotherapy with these drugs (68.8% and 58. 8%, respectively), as well as from patients receiving placebo (26.1%) [14].

There is convincing evidence for the effectiveness of the combination of allopurinol and citrate in gouty interstitial nephritis. A twelve-week course of combination therapy, including citrate 3 g/day and allopurinol 100–200 mg/day, led to an increase in glomerular filtration rate by an average of 15 ml/min compared with the control group. The clearance of uric acid also increased significantly. Note the low dosage of allopurinol. 200 mg/day is considered minimally effective, and 100 mg/day is generally a subclinical dosage; nevertheless, it turned out to be effective. An assumption can be made about the possible potentiation of the effects of allopurinol and citrate. An additional positive consequence should be a reduction in the frequency of side effects of allopurinol, which is a significant limiting factor in the drug treatment of gouty nephropathy. Unfortunately, the authors did not focus on this [15].

A more striking effect of citrate on renal function was noted in the treatment of chronic interstitial nephritis caused by hyperuricemia in obese patients [16].

The mechanism of action of citrate is not limited to alkalinization of urine. Citrate is one of the physiological inhibitors of crystal formation. Since urine is normally a supersaturated saline solution, the presence of crystal formation inhibitors in it is a necessary condition for the adequate functioning of the entire urinary system. Hypocitraturia is one of the factors contributing to stone formation. This may explain the effectiveness of citrate mixtures not only for urate, but also for calcium-oxalate nephrolithiasis [17–19].

Along with the mechanisms of action described above, citric acid salts additionally have antiseptic, cytoprotective and metabolic effects, which can also be used in clinical practice. In particular, C. Strassner and A. Friesen reported the disappearance of candiduria in 16 out of 18 patients during therapy with citrate mixtures, which is likely due to a change in urine reaction [20]. The conclusion about the cytoprotective effect of citrate was made based on the successful attempts of P. Bruhl et al. with its help, prevent chemical injury to the bladder mucosa during therapy with drugs from the oxazaphosphorine group - cyclophosphamide and ifosfamide [21] (in modern oncological and nephrological practice, a drug from the mucolytic group - mesna, which has practically no effect on the acid-base state, is used for this purpose). In addition, the use of citrate to correct acidosis due to ureterosigmostomy has been reported [22].

The main difficulty in citrate therapy for urate nephrolithiasis is selecting an adequate dosage of the drug. N.K. Dzeranov, who has studied and developed this aspect for many years, recommends starting with prescribing a diet and assessing the urine reaction for 5 days at a strictly defined time of day. Based on the obtained average values ​​of urine pH level, the initial dose of the drug and, most importantly, its distribution during the day are determined. After 5 days of treatment, the average urine reaction values ​​are determined again at a strictly similar time of day and, if necessary, the dosage of the drug is adjusted [23]. “Interactive”, that is, in real time, changing the dosage of citrate is ineffective and even unsafe, as it leads to jumps in pH levels, which can cause phosphate crystallization.

Due to the fact that citrate is normally present in the body, drugs based on it are practically free of toxicity. However, there are clinical situations where the use of these drugs requires caution. The use of citrate mixtures is undesirable for acute uric acid nephropathy and, in general, for acute renal failure of any etiology. The limiting factor here is not the citrate ion, but potassium, the removal of which is difficult in this clinical situation. In acute uric acid nephropathy, it is advisable to administer a 4% sodium bicarbonate solution, saline solution, etc. in combination with loop diuretics. It is necessary to maintain diuresis at a level of at least 100–150 ml/hour, and urine pH at least 6.5. If possible, xanthioxidase inhibitors are prescribed. Citrate mixtures are advisable when diuresis is restored and the glomerular filtration rate reaches 25–30 ml/min, when the risk of hyperkalemia is practically absent [5, 6].

In severe circulatory failure, the limiting factor is the increased intake of sodium into the body, also contained in citrate mixtures. Sometimes acetazolamide is preferable in this situation. This drug from the group of diuretics - carbonic anhydrase inhibitors strongly, and most importantly, uncontrollably alkalinizes the urine, which makes it uncompetitive compared to citrate in the drug therapy of urate nephrolithiasis. However, acetazolamide is practically the only way to increase the pH level of urine without resorting to the introduction of salts, which is extremely undesirable in conditions of severe heart failure.

Thus, drug treatment of patients with kidney diseases caused by disorders of purine metabolism, despite the very limited choice of drugs and the apparent simplicity of their choice, is a complex and multifaceted problem that requires an interdisciplinary approach.

Literature

1. Klimenko P. M., Chabanov V. A., Akinshevich I. Yu. Possibilities of conservative treatment of patients with urate nephrolithiasis // News of medicine and pharmacy. 2010. No. 3. P. 5–7.
2. Federal guidelines for the use of medicines (formulary system). Issue X. 2009. Ed. Chuchalina A.G., Belousova Yu.B., Yasnetsova V.V.M.: JSC RIC “Man and Medicine”.
3. Shcherbak A., Bobkova I., Kozlovskaya L. Prevention and treatment of kidney damage in patients with urate dysmetabolism // Doctor. 2013. No. 6. P. 6–10.
4. Doherty M. New insights into the epidemiology of gout // Rheumatology. 2009; 48 (2): 2–8.
5. Nephrology. Guide for doctors. Edited by I. E. Tareeva. M.: Medicine. 2000. 688 p.
6. Nephrology. National leadership. Ed. N. A. Mukhina. M.: GEOTAR-Media. 2009. 716 p.
7. Kenny J., Goldfarb D. Update on the pathophysiology and management of uric and renal stones // Curr. Rheumatol. Rep. 2010. 12: 125.
8. Coffier B., Altman A., Pui CH Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review // J. Clin. Oncol. 2008; 26:27–67.
9. Becker M., Kisicki J., Khosravan R. Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in heathy volunteers // Nucleos. Nucleic Acids. 2004; 23:1111.
10. Chugtai MN, Khan FA, Kaleem M., Ahmed M. Management of uric acid stone // J Pak Med Assoc. 1992, July; 42 (7): 153–155.
11. Petritsch PH Uric acid calculi: results of conservative treatment // Urology. 1977 Dec; 10(6):536–538.
12. Eliseev M. S., Denisov I. S., Barskova V. G. Use of Uralit-U citrate in patients with gout and nephrolithiasis // Modern rheumatology. 2012. No. 3. pp. 13–15.
13. Pasechnikov S.P., Mitchenko M.V. Modern aspects of citrate therapy for urolithiasis. Experience of using the drug Uralit-U // Men's health. 2007. No. 3. pp. 109–113.
14. El-Gamal O., El-Bendary M., Ragab M., Rasheed M. Role of combined use of potassium citrate and tamsulosin in the management of uric acid distal ureteral calculi // Urological Research. 2012, June, Vol. 40, Issue 3, p. 219–224.
15. Saito J., Matsuzawa Y., Ito H., Omura M., Ito Y., Yoshimura K., Yajima Y., Kino T., Nishikawa T. The alkalizer citrate reduces serum uric acid levels and improves renal // Endocr Res. . 2010; 35 (4): 145–154.
16. Saito J., Matsuzawa Y., Ito H., Omura M., Kino T., Nishikawa T. Alkalizer Administration Improves Renal Function in Hyperuricemia Associated with Obesity // Japanese Clinical Medicine. 2013: 4.
17. Butz M. Oxalate stone prophylaxis by alkalinizing therapy // Urologe A. 1982, May; 21 (3): 142–6.
18. Ito H. Combined administration of calcium and citrate reduces urinary oxalate excretion // Hinyokika Kiyo. 1991, Oct; 37(10):1107–1110.
19. Berg C., Larsson L., Tiselius HG Effects of different doses of alkaline citrate on urine composition and crystallization of calcium oxalate // Urological Research 1990, February, Vol. 18, Issue 1, p. 13–16.
20. Strassner C., Friesen A. Therapy of candiduria by alkalinization of urine. Oral treatment with potassium-sodium-hydrogen citrate. https://www.ncbi.nlm.nih.gov/pubmed/7498850.
21. Bruhl P., Hoefer-Janker H., Scheef W., Vahlensieck W. Prophylactic alkalization of the urine during cytostatic tumor treatment with the oxazaphosphorine derivatives, cyclophosphamide and ifosfamide // Onkologie. 1979, Jun; 2 (3): 120–124.
22. Sasagama I., Nakada T., Ishgooka M., Kubota Y., Sawamura T. Effect of standardized mixture of potassium and sodium citrate and citric acid (Uralit-U) on the correction of postoperative acidosis in patients who suffered uriterosigmostomy // Nephron . 1994; 66:477–478.
23. Dzeranov N.K., Rapoport L.M. Litholytic therapy. Practical recommendations. M.: LLC "Informpoligraf". 2011. 16 p.

S. K. Yarovoy1, Doctor of Medical Sciences R. R. Maksudov

Federal State Budgetary Institution Research Institute of Urology, Ministry of Health of the Russian Federation, Moscow

1 Contact information

Hyperphosphatemia in chronic kidney disease

Medical advice No. 5-6 2013.

S.A. MARTYNOV

, Ph.D.,
M.S.
BIRAGOVA ,
M.SH.
SHAMKHALOVA , MD,
M.V.
SHESTAKOVA , Doctor of Medical Sciences, Professor,
Federal State Budgetary Institution "Endocrinological Research Center" of the Ministry of Health of Russia
Kidneys play a leading role in regulating and maintaining the physiological level of phosphorus in the body. Normal serum phosphorus levels range from 0.81 to 1.45 mmol/l [1].

The largest amount of phosphorus consumed in food is excreted by the kidneys (800–900 mg out of 1200–1500 mg), the rest in feces (400–600 mg). In the kidneys, in the epithelium of the proximal tubules, reabsorption of filtered phosphorus occurs with the help of sodium-dependent transporters - IIa, IIc and PIT2. The leading hormones that regulate phosphorus homeostasis in the body are parathyroid hormone (PTH), produced by the parathyroid glands, and fibroblast growth factor 23 (FGF-23), produced by osteoblasts (bone growth cells, precursors of osteocytes) and osteocytes in bones. In healthy individuals, increasing the intake of phosphorus-containing foods causes a compensatory increase in the production of PTH and FGF-23 to increase phosphaturia by reducing the expression of tubular phosphorus transporters. In addition, FGF-23 reduces the production of calcitriol (1,25 (OH)2 D3) in renal tissue by inhibiting 1α-hydroxylase and stimulating 24-hydroxylase, and thereby reduces the amount of phosphorus absorbed in the intestine [2, 3]. Health Professional Follow-up Study, conducted among 1,261 people. with a predominance of individuals with preserved renal function, confirmed the presence of a direct relationship between dietary phosphorus intake and the level of FGF-23 in the blood [4].

Among the causes that cause the development of hyperphosphatemic syndrome, such as idiopathic hyperparathyroidism, pseudohypoparathyroidism, FGF-23 deficiency, tumor decay and others, kidney damage occupies a special place due to the steady increase in the number of patients with chronic kidney disease (CKD) around the world. A decrease in the excretion of phosphorus in the urine and an increase in its concentration in the blood develops when the filtration function of the kidneys decreases to stages 4 and 5 of CKD, i.e., when the glomerular filtration rate (GFR) is less than 30 ml/min/1.73 m2. It was revealed that before this GFR value is reached, normophosphatemia is maintained by hyperproduction of FGF-23, which, in the presence of renal pathology, is observed already with the initial decrease in nitrogen excretory function of the kidneys - from the 2nd stage of CKD (GFR less than 90 ml/min/1.73 m2), and much exceeds the formation of PTH itself (Fig. 1) [5].

One of the initial links involved in the pathogenesis of hyperphosphatemia was considered to be a decrease in the formation of calcitriol in affected (sclerotic) kidneys. At the same time, calcium absorption in the intestine decreases with the development of hypocalcemia, which stimulates the production of PTH. In turn, PTH, in addition to increasing the excretion of phosphorus by the kidneys, increases the reabsorption of calcium in the tubules and the absorption of calcium in the intestine by inducing the synthesis of calcitriol. The result of the action of PTH is an increase in the concentration of calcium in the blood and a decrease in the content of calcium in the bones (demineralization of the bone matrix) and phosphorus in the blood. However, according to modern concepts, the initiator of the development of secondary hyperparathyroidism may be FGF-23, the increased production of which already in the early stages of CKD suppresses the formation of calcitriol by the kidneys and thereby triggers the mechanism of “hypocalcemia - hyperproduction of PTH.” It is believed that an increase in the concentration of circulating FGF-23 with a decrease in the filtration function of the kidneys also has a retention nature, since the catabolism and degradation of FGF-23 occurs in the renal tissue [2–5]. It should be noted that in patients undergoing dialysis treatment, its level in the blood exceeds the physiological level by 1,000 times [6]. Moreover, in renal failure, one possibly positive effect of FGF-23 is eliminated - suppression of PTH gene expression in the parathyroid glands by stimulating mitogen-activated protein kinase (MAPK). This is due to a decrease in the amount of the main FGF-23 co-receptor, Klotho, in uremia, which forms the active FGF-23-Klotho-receptor complex (FGFR1c) in the parathyroid glands and kidneys, and inactivation of lysines in this complex [5, 7]. Recent studies have shown that increased FGF-23 is associated with progression of renal failure, left ventricular hypertrophy, and increased mortality from cardiovascular events in patients with CKD [8].

Epidemiological studies have demonstrated that increases in serum phosphorus are directly and independently associated with total and cardiovascular mortality in patients with predialysis CKD and dialysis [9]. The role of hyperphosphatemia in the survival of patients with CKD on dialysis was convincingly demonstrated in a large retrospective study based on the US Renal Data System and Dialysis Morbidity and Mortality Study Wave [10]. The study found that the relative risk of death from all causes with a serum phosphorus level of more than 6.5 mg/dL (2.09 mmol/L) was 1.27 compared with a population of patients with a serum phosphorus value of 2.4 (0. 77 mmol/l) to 6.5 mg/dl. At the same time, risk factors for increased blood phosphorus, in addition to hypercreatininemia, were the formation of end-stage renal failure at a young age, the presence of diabetes mellitus, female gender, and smoking. A similar risk of death (1.27 (95% CI 1.02–1.58)) was found in the CARE (Cholesterol And Reccurent Events) study among 4,127 patients with myocardial infarction for every 1 mg/dL increase in blood phosphorus levels (0.32 mmol/L) [11] Studies conducted among patients with CKD clearly demonstrated that serum phosphorus exceeding 3.5 mg/dL (1.13 mmol/L) was associated with a significant increase in the risk of death, and its increase for every 1 mg/dL increased it by 18% [12, 13].

The population-based study The Framingham Offspring Study showed that for every 1 mg/dL increase in phosphorus, the risk of developing cardiovascular events (angina pectoris, heart failure (HF), cerebral stroke, peripheral arterial disease) [14]. In 10% of participants in the 15-year prospective CARDIA (Coronary Artery Risk in Young Adults) study, baseline serum phosphorus levels were found to be strongly associated with coronary artery calcification [15]. A close association between hyperphosphatemia and left ventricular (LV) hypertrophy has been identified, the formation of which is a predictor of mortality in patients with CKD. Thus, among 208 patients at stages 2–4 CKD (mean phosphorus value was 1.1 mmol/l), an association was found between increased serum phosphorus and LV myocardial mass index (LVMI), measured using magnetic resonance [16]. Moreover, even high-normal blood phosphorus levels within the reference range were associated with an increased risk of developing LV hypertrophy, which was 1.27 (95% CI 1.09–1.47) in 4,055 young people with normal renal function [17]. The risk of developing HF increased by 1.74 times for every 1 mg/dL increase in blood phosphorus in 3,300 participants in a study without HF and CKD that assessed the association between blood phosphorus levels and echocardiographic evidence of LV hypertrophy [18].

In addition to deteriorating arterial compliance and increasing arterial stiffness, hyperphosphatemia is closely involved in mechanisms of development and progression of vascular calcification, including mineralization of vascular smooth muscle cells (VSMCs) via phosphorus flux through sodium-dependent transporters, apoptosis of VSMCs, and suppression of differentiation of monocytes/macrophages into osteoclast-like cells. , increased FGF-23 levels and altered expression of the Klotho co-receptor. Vascular calcification, as an outcome of impaired mineral metabolism, is closely associated with increased bone resorption and adynamic bone remodeling, but often precedes bone changes. Consequently, hyperphosphatemia and changes in the balance of inducers and inhibitors of calcification, the presence of systemic inflammation, and oxidative stress contribute to the formation of mediacalcinosis in CKD [19–22]. As in the above-mentioned CARDIA work, the MESA (Multi-Ethnic Study of Atherosclerosis) study found an association between hyperphosphatemia and calcification. Thus, in 439 young and middle-aged CKD patients with normal renal function, an increase in serum phosphorus levels for every 1 mg/dL was associated with an increase in the formation of coronary artery calcification by 21%, aortic and mitral valve calcification by 25% and 62%, respectively [23 ].

Hyperphosphatemia contributes not only to the progression of renal failure (doubling of blood creatinine, the onset of end-stage renal failure), but also to a decrease in the nephroprotective effect of the angiotensin-converting enzyme inhibitor ramipril, which was demonstrated in the REIN (Ramipril Efficacy In Nephropathy Study) study involving 331 CKD patients with albuminuria and with GFR from 20 to 70 ml/min/1.73 m2 [24]. In addition, the Framingham Heart Study showed that serum phosphorus levels exceeding the limit of 2.5–3.49 mg/dL (0.80–1.13 mmol/L) increased the risk of developing CKD by 2.14 times (95). % CI 1.07–4.28), which is confirmed by data from the NHANES III study (the Third National Health and Nutritional Examination Survey), which found that an increase in phosphorus more than 4 g/dL (1.29 mmol/L) increased the relative the risk of developing end-stage renal failure by 1.9 times (95% CI 1.03–3.53) [25].

Currently, monitoring the level of phosphorus in the blood in patients with CKD occupies one of the leading positions in the complex of therapeutic and dietary measures in patients with CKD. The target value of phosphorus in the blood in patients at the pre-dialysis stage of CKD and on dialysis should not exceed 1.45 mmol/l [1]. The main measures to correct hyperphosphatemia are diet modification (limiting phosphorus to 0.8–1 g per day, in special cases up to 0.4–0.7 g) and the use of phosphate binders. Theoretically, a hypophosphate diet should be recommended starting from stages 3–4 of CKD, even in the absence of an increase in the level of phosphorus in the blood according to laboratory data. Studies have shown that low dietary phosphate intake, up to and including a vegetarian diet, resulted in normalization of blood phosphorus levels, reduction in phosphaturia and serum FGF-23 levels [26]. But limiting phosphorus in the food consumed is very difficult due to the very high content of phosphates in modern foods and drinks, and the absence of a mass of phosphates in the description of the contents of food products. The presence of phosphates in protein foods forces the amount of protein to be limited in dialysis patients, i.e., with difficult-to-control hyperphosphatemia, it is necessary to take into account the phosphorus-protein coefficient of the product.

The action of most phosphate binders is based on the combination of the drug with phosphorus ions with further precipitation in the intestine, in the form of insoluble and non-absorbable complexes that are excreted in feces [5]. The first phosphate binders, used since the 1970s, are preparations containing aluminum (Al) (aluminum salts). An additional effect of aluminum hydroxide in the regulation of phosphorus metabolism disorders is its ability to form a “compound” with phosphorus ions in the blood, which masks the phosphorus itself. Although aluminum salts were highly effective, when accumulated (0.1% Al is absorbed in the intestines) they led to aluminum intoxication. This is manifested by cognitive impairment (Al penetrates the blood-brain barrier), the development of osteomalacia (Al blocks the mineralization of osteoid) and increased anemia (Al binds to ferritin and transferrin) [27]. In current practice, they are used short-term (2–4 weeks) as an “ambulance” when it is necessary to quickly eliminate excessive hyperphosphatemia.

Calcium and magnesium salts are widely used as phosphate binders. One of the undesirable effects of calcium salts is the development of persistent hypercalcemia in every second patient, especially when combined with vitamin D analogues, which enhances the processes of tissue calcification [28]. Consequently, the maximum daily dose of drugs should be no more than 1.5 g of elemental calcium per day with the condition of dynamic control of calcium levels in the blood [1]. Calcium carbonate has a long decomposition time, binds with phosphorus in the acidic environment of the stomach (pH 5.0), alkalizing it, and there it partially loses its effectiveness due to the competition of hydrogen ions with phosphorus. Therefore, the effect of calcium carbonate may be limited when patients with CKD take proton pump inhibitors. The advantage of calcium acetate is that it causes hypercalcemia 3 times less and binds phosphorus as much more effectively than calcium carbonate, but causes a greater number of side effects from the gastrointestinal tract. Less commonly used calcium salts are calcium alginate, calcium lactate and calcium ketoglutarate [5].

An alternative to aluminum and calcium-containing phosphate binders, but less effective, are preparations containing magnesium salts. Although some studies have shown that these drugs protect against vascular calcification and improve carotid intima-media thickness in patients on dialysis, their effect remains incompletely studied. The experiment showed that magnesium has a negative effect on vascular calcification and osteogenic differentiation by increasing and restoring the activity of potential channel receptors like melastatin 7 and increasing the expression of anti-calcification proteins (osteopontin, bone morphogenetic protein (BMP-7) and Gla protein), and also reduces serum PTH levels. A new combined phosphate binder, consisting of calcium acetate and magnesium carbonate, showed a good phosphate-binding effect in dialysis patients, except for a slight increase in total calcium in the blood without changing its ionized fraction and the development of asymptomatic hypermagnesemia [5].

Lantana carbonate, discovered in 1839, has only recently been successfully used in the USA and Europe. In addition to the absence of calcium in it, one of the advantages of the drug is that its phosphorus-binding action can occur at pH values ​​ranging from 1 to 7, i.e. it is equally effective in the acidic environment of the stomach and at the higher pH of the duodenum and small intestine. Moreover, lanthanum carbonate is a highly insoluble compound, and only 0.001% of the drug is absorbed in the intestine. When prescribing it, it is necessary to take into account that the drug has the property of inhibiting cytochrome 450, which can lead to disruption of the metabolism of various pharmacological drugs [5].

One of the effective phosphate binders recently registered in Russia is sevelamer hydrochloride, a synthetic, water-insoluble polymer that does not contain calcium (poly(allylamine hydrochloride)). The drug, in addition to its highly effective phosphorus-binding effect, combines with bile acids in the gastrointestinal tract, which is considered to be the cause of a decrease in the level of low-density lipoproteins in the blood. Studies initiated by Genzyme Corp. have not confirmed the binding of sevelamer hydrochloride to commonly used lipophilic drugs such as enalapril, metoprolol, digoxin and warfarin [29, 30]. Moreover, the use of sevelamer hydrochloride led to an improvement in arterial wall compliance in hemodialysis patients. So, taking the drug for 11 months. contributed to a significant decrease in pulse wave velocity, which is largely explained by the lack of calcium in the drug [31, 32]. These additional effects of the drug can slow down the development of atherosclerosis and vascular calcification, reduce the incidence of adverse cardiovascular complications, thereby reducing overall and cardiovascular mortality in the population of patients with CKD.

The latest data on the effectiveness of various phosphate binders will be obtained from the recently completed clinical trial "A Double Blind Randomized Placebo Trial of Maintenance of Normal Serum Phosphorus in CKD" (comparing the effect of calcium acetate, lanthanum carbonate, sevelamer hydrochloride with placebo on arterial stiffness and coronary calcification in CKD patients with GFR 20–45 ml/min/1.73 m2), “Effects of Phosphate Binding With Sevelamer in Stage 3 Chronic Kidney Disease” (studying the effect of sevelamer hydrochloride compared with placebo on LVMI and arterial stiffness) and The “Impact of Phosphate Reduction On Vascular End-points in CKD” study initiated at the end of 2011 (evaluating the effect of lanthanum carbonate on arterial stiffness and aortic calcification in patients with stages 3b and 4 CKD) [33–35].

Thus, early detection of hyperphosphatemia, prescription of a hypophosphate diet and the prescription of modern effective phosphorus-binding drugs with careful monitoring of phosphorus-calcium balance indicators is one of the initial dietary and therapeutic approaches to prevent the development of severe disabling complications not only from mineral-bone metabolism, but also the cardiovascular system.

Literature

1. National recommendations on mineral and bone disorders in chronic kidney disease // Nephrology and dialysis. 2011. T. 13. No. 2. pp. 33–51. 2. Hruska KA, Mathew S., Lund R. et al. Hyperphosphatemia of chronic kidney disease // Kidney International. 2008. No. 74. R. 148–157. 3. Jüppner H. Phosphate and FGF-23 // Kidney Int. 2011. No. 79. S24–S27. 4. Gutiérrez OM, Wolf M., Taylor EN Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the health professionals follow-up study // Clin. J. Am. Soc. Nephrol. 2011. No. 6. R. 2871–2878. 5. Hutchison AJ, Smith CP, Brenchley PEC Pharmacology, efficacy and safety of oral phosphate binders // Nat. Rev. Neprol. 2011. No. 7. R. 578–589. 6. Imanishi Y., Inaba M., Nakatsuka K. et al. FGF-23 in patients with end-stage renal disease on hemodialysis // Kidney Int. 2004. No. 65. R. 1943–1946. 7. Kuro-o M. Phosophate and Klotho // Kidney Int. 2011. No. 79. S20–S23. 8. Heine GH, Seiler S., Fliser D. FGF-23: the rise of a novel cardiovascular risk marker in CKD // Nephrol. Dial. Transplant. 2012. No. 27. R. 3072–3081. 9. Kestenbaum B., Sampson JN, Rudser KD et al. Serum phosphate levels and mortality risk among people with chronic kidney disease // J. Am. Soc. Nephrol. 2005. No. 16. R. 520–528. 10. Block G., Hulbert-Shearon T. et al. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study // Am. J. Kidney Dis. 1998. No. 31. R. 607–617. 11. Tonelli M., Sacks F., Pfeffer M. et al. Relationship between serum phosphate level and cardiovascular event rate in people with coronary disease // Circulation. 2005. No. 112. R. 2627–2633. 12. Kestenbaum B., Sampson JN, Rudser KD et al. Serum phosphate levels and mortality risk among people with chronic kidney disease // J. Am. Soc. Nephrol. 2005. No. 16. R. 520–528. 13. Palmer SC, Hayen A, Macaskill P et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: A systematic review and meta-analysis // JAMA. 2011. No. 305. R. 1119–1927. 14. Dhingra R., Sullivan L., Fox S. et al. Relations of serum phosphorus nd calcium levels to the incidence of cardiovascular disease in the community // Arch. Int. Med. 2007. No. 167. R. 879–885. 15. Foley RN, Collins AJ, Herzog CA et al. Serum phosphorus levels associate with coronary atherosclerosis in young adults // J. Am. Soc. Nephrol. 2009. No. 20. R. 397–404. 16. Chue CD, Edwards NC, Moody WE et al. Serum phosphate is associated with left ventricular mass in patients with chronic kidney disease: A cardiac magnetic resonance study // Heart. 2012. No. 98. R. 219–224. 17. Foley RN, Collins AJ, Herzog CA et al. Serum phosphate and left ventricular hypertrophy in young adults: The coronary artery risk development in young adults study // Kidney Blood Press. Res. 2009. No. 32. R. 37–344. 18. Dhingra R, Gona P, Benjamin EJ et al. Relations of serum phosphorus levels to echocardiographic left ventricular mass and incidence of heart failure in the community // Eur. J. Heart. Fail. 2010. No. 12. R. 812–818. 19. Blacher J., Guerin AP, Pannier B. et al. Impact of aortic stiffness on survival in end-stage renal disease // Circulation. 1999. No. 99. R. 2434–2439. 20. Vlachopoulos C., Aznaouridis K., Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis // J. Am. Coll. Cardiol. 2010. No. 55. R. 1318–1327. 21. Kendrick J., Chonchol M. The role of phosphorus in the development and progression of vascular calcification // Am. J. Kidney Dis. 2011. No. 58. R. 826–834. 22. Giachelli CM Vascular calcification: In vitro evidence for the role of inorganic phosphate // J. Am. Soc. Nephrol. 2003. No. 14. R. 5300–5304. 23. Adeney KL, Siscovick DS, Ix JH et al. Association of serum phosphate with vascular and valvular calcification in moderate CKD // J. Am. Soc. Nephrol. 2009. No. 20. R. 381–387. 24. Zoccali C., Ruggenenti P., Perna A. et al. Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition // J. Am. Soc. Nephrol. 2011. No. 22. R. 1923–1930. 25. O'Seaghdha CM, Hwang SJ, Muntner P., Melamed ML, Fox CS Serum phosphorus predicts incident chronic kidney disease and end-stage renal disease // Nephrol. Dial. Transplant. 2011. No. 26. R. 2885–2890. 26. Moe SM, Zidehsarai MP, Chambers MA et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease // Clin. J. Am. Soc. Nephrol. 2011. No. 6. R. 257–264. 27. Wills MR, Savory J. Aluminum poisoning: dialysis encephalopathy, osteomalacia, and anemia // Lancet. 1983. No. 2. R. 29–34. 28. Schaefer K., Umlauf E., von Herrath D. Reduced risk of hypercalcemia for hemodiaylisis patients by administering calcitriol at night // Am. J. Kidney Dis. 1992. No. 19. R. 460–464. 29. Burke S., Amin N., Incerti C., Plone M., Watson N. Sevelamer hydrochloride (Renagel), a nonabsorbed phospaht-binding polymer, does not interfere with digoxin or warfarin pharmacokinetics. J. Clin. Pharmacol. 2001. No. 41. R. 193–198. 30. Burke S., Amin N., Incerti C., Plone M., Lee JW Sevelamer hydrochloride (Renagel), a phospaht-binding polymer, does not alter the pharmacokinetics of two commonly used antihypertensives in healthy volunteers // J. Clin . Pharmacol. 2001. No. 41. R. 199–205. 31. Othmane TEH, Bakonyi G., Egresits J. et al. Effect of sevelamer on aortic pulse wave velocity in patients on hemodialysis: A prospective observational study // Hemodial. Int. 2007. No. 11. S13–S21. 32. Takenaka T., Suzuki H. New strategy to attenuate pulse wave velocity in haemodialysis patients // Nephrol. Dial. Transplant. 2005. No. 20. R. 811–816. 33. https://www.clinicaltrials.gov/ct2/show/NCT00785629?term=A+Double+Blind+Randomized+Placebo+Trial+of+M… 34. https://www.clinicaltrials.gov/ct2/ show/NCT00806481?term=Effects+of+Phosphate+Binding+With+Sevelamer+… 35. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=335812