RU2628866C1 - Method for nephrosclerosis prediction in children with chronic pyelonephritis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: homocysteine level s determined in the patient's blood and at a value of more than 7 mcmol/l in children under 10 years and 9 mcmol/l in children older than 10 years, a high risk of sclerotic changes in the kidney tissue is predicted. The proposed method allows prediction of development of sclerotic changes in kidney tissue for children with chronic pyelonephritis, which will allow, to prescribe nephroprotective therapy to patients in need at the earliest possible date. In turn, timely and adequate nephroprotection will help slow the progression of chronic kidney disease.

EFFECT: invention allows more accurate prediction of nephrosclerosis development of in children, as well as to not subject patients to additional blood sampling and invasive diagnostic methods, does not require additional invasive intervention, application of expensive equipment and radiopharmaceutical and can be performed on an outpatient basis.

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Description

The invention relates to medicine, in particular to nephrology and pediatrics, and can be used to predict the formation of nephrosclerosis in children with chronic pyelonephritis.

One of the urgent problems of pediatric nephrology is the development of nephrosclerosis in patients with chronic pyelonephritis, leading to a gradual decrease in renal function and the formation of chronic kidney disease (CKD). The factors of damage to the renal parenchyma in chronic pyelonephritis include: intrarenal reflux, activity of the microbial-inflammatory process, slowed kidney growth due to hemo- and (or) urodynamic disturbances, toxic effects of drugs, arterial hypertension, hyperfiltration in intact nephrons, proteinuria, pathogen properties (Burbige RA, Retik AB Urinarytractinfectionsinboys. // J. of Urology. - 1984. - V. 132. - P. 541).

It is known that tubulointerstitial disorders significantly lead to renal failure than glomerulosclerosis. The development of interstitial nephrosclerosis goes through several stages: inflammation, proliferation of interstitial fibroblasts, the spread of interstitial extracellular matrix, leading to fibrosis (Eddy AA Molecular basis of renal fibrosis. - PediatrNephrol. - 2000. - Vol. 15, No. 3-4. - P. 290 -301). In connection with the foregoing, it is relevant to determine the prognostic criteria for the formation of nephrosclerosis in children with chronic pyelonephritis.

There are several ways to diagnose the formation of nephrosclerotic changes. Quite informative methods are radionuclide studies - dynamic and static nephroscintigraphy. The principle of the method is based on the study of the functional-structural state of the renal parenchyma by recording the distribution of the labeled compound, slowly excreted from the kidneys. However, for pediatric nephrology, the prevention of the progression of renal tissue damage and the possibility of early prediction of the development of nephrosclerosis for the selection of the necessary nephroprotective therapy are of great importance. Moreover, the arsenal of methods for predicting the adverse course of the pathological process in the renal tissue is very limited.

There is a method for predicting the rate of progression of chronic kidney disease (CKD) based on the identification of laboratory markers of hemostasis. The essence of the method is that they determine the coagulation characteristics of blood: activated partial thromboplastin time (APTT), prothrombin time (PV), thrombin time (TB), antithrombin III (ATIII), von Willebrand factor (PVIII), endothelin-1 (E -1), D-dimer. With APTT indices ranging from 28 to 35 seconds, PV from 12 to 15 seconds, TV from 9 to 13 seconds, ATIII level from 29 to 70%, PV level from 105 to 115%, E-1 not more than 0.32 fmol / ml and D-dimer from 245 to 520 ng PEE / ml predict a slow progression of the course of CKD. With the same values of APTT, PV, TV, ATIII level, and PV level of more than 115%, E-1 more than 0.32 fmol / ml, D-dimer more than 620 ng PEE / ml, accelerated progression of CKD is predicted. (A method for predicting the nature of the progressive course of chronic kidney disease. (RU 2430364): Zibnitskaya L.I., Kalyuzhina E.V., Kalyuzhin V.V., Sibireva O.F., Bukharova E.O., Grankina V.Yu. )

However, this forecasting method was designed for adult patients and cannot be extrapolated to childhood due to age-related morphofunctional differences in the course of chronic kidney disease. In addition, this method requires the determination of a large number of markers of the pathology of hemostasis. This requires an additional sampling of a large amount of blood, which is not optimal for patients with chronic kidney disease. And also leads to additional material costs. The existing disadvantages do not allow the use of these diagnostic procedures for long-term dynamic monitoring of the functional state of the kidneys in children.

A known method for predicting the development of nephrosclerosis in children by calculating the "index of early kidney damage." The index is calculated as the ratio of urinary concentrations of VEGF (vascular endothelial growth factor) and type IV collagen. And with its value above 10, a high risk of developing nephrosclerosis is predicted. (Lakomova D.Yu. Early diagnosis and prognosis of nephrosclerosis in children with vesicoureteral reflux. Diss. For the competition ... Ph.D. Saratov, 2011.) However, this method has its drawbacks. Firstly, the method was developed for a group of children with vesicoureteral reflux and reflux nephropathy and was not investigated in children with chronic pyelonephritis without vesicoureteral reflux. Secondly, the determination of the necessary indicators is expensive and requires special equipment and supplies. In this regard, this method cannot be used in wide clinical practice.

Closest to the claimed is a method based on the determination of cystatin C as a predictor of decreased filtration function of the kidneys. In children with an initially high level of cystatin C (in blood serum> 1288 ng / ml), with a normal blood creatinine content over 5 years, pathology progresses. (Komarova OV Clinical and molecular basis for the progression of chronic kidney disease in children. Diss. ... MD, Moscow, 2014.) However, this method has some drawbacks: 1. When assessing the functional ability of the kidneys, the quality of determination of glomerulotropic markers in biological fluids is of particular importance. Insufficient sensitivity or specificity of the corresponding analytical method can significantly discredit the results of the study and lead to incorrect clinical conclusions. Cis C is usually determined using three methods. ELISA - most suitable for detecting Cis C in low concentrations. The disadvantage of this method is the long time (several days) necessary to obtain a result. Two other methods do not give the necessary accuracy of the result at low concentrations of Cis C, which are just characteristic of childhood. 2. There is evidence that the concentration of Cis C may be influenced by age, gender, body weight, height, smoking, elevated levels of C-reactive protein, glucocorticoids, immunosuppressants and antitumor agents. 3. A significant limitation is the relatively high cost of measuring Cis. (I.G. Kayukov, A.V. Smirnov, V.L. Emanuel. Cystatin C in modern medicine. Nephrology. 2012. V. 16. No. 1.)

The present invention is to develop a simple, accurate and economical method for predicting the risk of developing nephrosclerosis in children with chronic pyelonephritis.

The technical result achieved by achieving the task is to increase the accuracy of predicting the development of nephrosclerosis in children with chronic pyelonephritis.

We first developed a method for predicting the formation of nephrosclerosis in children with chronic pyelonephritis.

The problem is solved in that the concentration of homocysteine in the blood serum is determined, and with its value greater than 7.0 μmol / L in children under 10 years old and 9.0 μmol / L in children over 10 years old, a high risk of developing sclerotic changes in the renal tissue is predicted. Thus, boundary values for homocysteine levels in children of different age groups were first established.

Homocysteine, due to the presence of the SH group, has prooxidant activity: with a high level of homocysteine in the blood, it undergoes oxidation, during which free radicals are formed [Lentz S.R., Haynes W.G. Homocysteine: Is It a clinically important cardiovascular risk factor? Clev. Clin. J. Med. 2004; 71: 729-734]. The anion O- and hydroxyl ion OH formed during homocysteine oxidation initiate lipid peroxidation, which leads to damage to endothelial cells and the formation of oxidized plasma lipoproteins [Ciaccio M., Bivona G., Bellia C. Therapeuticalapproachtoplasmahomocysteineandcardiovascularriskreduction. Therap. and clin. RiskManag. 2008; 4: 219-224].

Oxidative modification of low density lipoproteins promotes the formation of foam cells, which, in turn, stimulates oxidative stress. Homocysteine also disrupts the normal production of NO by endothelial cells, reduces the bioavailability of NO, as the synthesis of the latter decreases. The enhancement of lipid peroxidation with the participation of homocysteine leads to both a decrease in NO production by the NO synthase enzyme and direct NO degradation [Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: ameta-analysis. JAMA. 2002; 288: 2015-2022]. Violation of the fine balance of the nitric oxide system, primarily due to the development of oxidative stress, enhances endothelial dysfunction. One of the effects of high concentration of homocysteine is a significant increase in the density of the vascular wall due to increased synthesis and accumulation of collagen in it, proliferation of smooth muscle cells, which also leads to its deformation and increased rigidity [Tsuda K. Plasma Homocysteine Levels and Endothelial Dysfunction in Cerebro- and Cardiovascular Diseases in the Metabolic Syndrome.AmJHypertens. 2015 Dec; 28 (12): 1489].

The negative effects of hyperhomocysteinemia are fairly well understood in patients with a cardiological profile. Information on the importance of elevated homocysteine levels in patients with renal pathology, especially in the pediatric population, is extremely limited. Moreover, it is known that the kidneys play a significant role in the metabolism of homocysteine. More than 99.5% of homocysteine is reabsorbed and transformed in the tubule cells, mainly along the trans-sulfonation pathway or, to a lesser extent, along the remethylation pathway.

The method can be carried out as follows. In a patient with chronic pyelonephritis on an empty stomach, blood serum is examined for homocysteine, and with its value greater than 7.0 μmol / L in children under 10 years old and 9.0 μmol / L in children over 10 years old, a high risk of developing sclerotic changes in the kidney tissue is predicted .

This method for predicting the development of nephrosclerosis was developed on the basis of a study conducted in 60 children with secondary chronic pyelonephritis who are in hospital treatment and examination at the clinic of faculty pediatrics of the Design Bureau named after S.R. Peacemaker Saratov. The study included 44 girls (73%) and 16 boys (27%). The study did not include children with exacerbation of the underlying disease, with severe concomitant diseases, who had acute infectious diseases in the last 3 months. All children underwent examination, which included general clinical blood and urine tests, bacteriological examination of urine, cumulative tests, ultrasound and X-ray examination, Dopplerographic examination of the kidneys. The level of homocysteine (GC) was determined on an Immulite-2000 apparatus (Siemens Healthcare Diagnostics Inc., USA) in 2014. To identify foci of nephrosclerosis, a nephroscintigraphy was performed with Tc-99 m-technomec 37 MBC. The study was carried out in a PhilipsBrightViewSpect dual-detector scintigraphic gamma camera. The follow-up period was 1.5-2 years. Nephroscintigraphy was performed in 2014 and 2016.

Statistical processing of the obtained data was carried out using the program Statistica 6.1. Hypotheses on the form of distributions were tested (Shapiro-Wilks test). Not all data satisfied the law of normal distribution; therefore, the Mann-Whitney U test was used to compare values. The critical level of reliability of the null statistical hypothesis (p) is taken as 0.05. The relationship between serum homocysteine (HC) levels and the development of nephrosclerosis was analyzed using the Spearman correlation test. Relative risk (rr) with a confidence interval (CI) was also calculated.

The generally accepted norm for the content of HC is the corridor of 5.0-12.0 μmol / L. Before puberty, the concentration levels in boys and girls are approximately the same (about 5 μmol / L). During puberty, the metabolite level rises to 6-7 mmol / ml, in adults it already fluctuates around 5-15 mmol / ml. It is known that with age, the level of HC increases, and therefore children were divided into groups of 5-10 years and 10-15 years. We divided the children in the younger age group (5-10 years) according to the level of GC into 3 groups - less than 5 micromol / l, 5-7 micromol / l and more than 7 micromol / l and analyzed the development of nephrosclerosis in each group after 1.5- 2 years (Table 1.) In the older age group, children were also divided according to the level of GC into 3 groups - less than 6 μmol / L, 6-9 μmol / L and more than 9 μmol / L (table 2.) Increased homocysteine was identified in patients in 2014. We hypothesized that this group of patients may have an increased risk of nephrosclerosis. In the future, we observed patients with repeated in-patient examination (with scintigraphy) in 2015-2016. we really found the formed foci of nephrosclerosis in a group of children with high homocysteine levels.

Moreover, in the group of children 5-10 years old with a homocysteine level above 7 μmol / L, signs of nephrosclerosis developed in 78% of patients, and in the group of children over 10 years old with a homocysteine level above 9 μmol / L, foci of nephrosclerosis were detected in 75% of patients with follow-up observation.

The correlation analysis showed a close relationship between homocysteine levels and the development of nephrosclerosis (coefficient 0.64).

Note: B / n - without signs of nephrosclerosis;

N - with foci of nephrosclerosis.

Thus, in children 5-10 years old with a GC level of less than 5 μmol / L, there were no signs of nephrosclerosis with a follow-up of 2 years. With an increase in the level of HC to 7 μmol / L, there is an increase in the risk of sclerotic changes, this increase is not statistically significant. Children with a HC level of more than 7 μmol / L have a high risk of sclerotic changes (rr = 2.154, 95% CI 1.004-4.621, specificity 0.750, sensitivity 0.667). In the group of children 10-15 years old with a GC level of less than 6 μmol / L, no sclerotic changes were detected 2 years after the examination. In the group with a HC level of 6–9 μmol / L, the number of children with foci of nephrosclerosis increased; the data were not statistically significant. In the group of children with a HC level of more than 9 μmol / L, there is a high risk of nephrosclerosis formation (rr = 3.667, 95% CI 1.853-7.255, sensitivity 0.647, specificity 1.000).

According to our method, if the level of homocysteine in the blood is more than 7 μmol / L in children under 10 years old and 9 μmol / L in children over 10 years old, a high risk of developing sclerotic changes in the kidney tissue is predicted.

Clinical examples

1. Patient Sofia V., 10 years old. Clinical diagnosis: secondary obstructive (doubling of the left kidney) and dysmetabolic pyelonephritis, chronic course. Congenital malformation of the urinary system was diagnosed at the age of 1.5 years. Subsequently, signs of pyelonephritis appeared on the background of IAMS, dysmetabolic disorders (hyperphosphaturia) were revealed. Exacerbations of chronic pyelonephritis were noted quite rarely - 1 time / 2-3 years. Refluxes were not received. Blood urea level is 3.5 mmol / L, creatinine 54.7 mmol / L, GFR by calculation method 104.8 ml / min / 1.73 m ² . An increased homocysteine level of 9.16 μmol / L was detected in 2014. After 1.5 years with a routine in-patient examination, instrumental methods for diagnosing the state of renal function confirmed the presence of single lesions of the renal parenchyma (2015).

2. Patient Christina I., 6 years old. Clinical diagnosis: secondary obstructive (intrarenal vessels on both sides) pyelonephritis, chronic course. Pyelonephritis debuted at the age of 4. Urea level 3.9 mmol / L, creatinine 50.3 mmol / L. GFR by the calculation method (according to Schwartz) 102.1 ml / min / 1.73 m ² . The level of homocysteine is 7.35 μmol / L (detected in 2014). Data of duplex scanning of blood vessels of the kidneys did not reveal hemodynamic disturbances; according to static nephroscintigraphy, the inclusion of the radiopharmaceutical in the right kidney was reduced by 10%, its distribution was uneven. The development of parenchymal lesions arose 2 years after the debut of pyelonephritis and the detection of hyperhomocysteinemia (2016).

3. Patient Ilyas Z., 14 years old. Clinical diagnosis: secondary obstructive (aberrant vessel) and dysmetabolic pyelonephritis, chronic course.

The level of urea is 2.8 mmol / l, creatinine 67.4 mmol / l. GFR by the calculation method (according to Schwartz) 107.5 ml / min / 1.73 m ³ . Pyelonephritis was diagnosed in 2009. The homocysteine level was 7.29 μmol / L (determined in 2014). Duplex scanning of renal vessels, static nephroscintigraphy during an in-patient examination in 2016 revealed no signs of damage to the renal parenchyma.

As can be seen from the description and the above examples, the proposed method allows to predict the development of nephrosclerosis in children with chronic pyelonephritis, which will allow to appoint nephroprotective therapy to those patients who need it as soon as possible. In turn, timely and adequate nephroprotection will help slow the progression of chronic kidney disease.

Our proposed method for predicting the early development of nephrosclerosis in children with chronic pyelonephritis, based on measuring serum homocysteine levels, is simple and accurate. Blood sampling to determine the level of homocysteine is carried out as part of a general clinical examination. Its advantage is also that it does not require additional invasive intervention, the use of expensive equipment and radiopharmaceuticals and can be performed on an outpatient basis. Unlike the currently existing methods, the method allows you to more accurately predict the development of nephrosclerosis in children, as well as not expose patients to additional blood sampling and invasive diagnostic methods.

Claims (1)

A method for predicting nephrosclerosis in children with chronic pyelonephritis, including a blood test, characterized in that the level of homocysteine is additionally determined in the blood serum and when it is greater than 7 μmol / L in children under 10 years old and 9 μmol / L in children over 10 years of age, a high the risk of developing sclerotic changes in the kidney tissue.