RU2430364C1 - Method of predicting character of progressing course of chronic kidney disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: essence of method of predicting character of progressing course of chronic kidney disease (CKD) lies in determination of blood coagulation characteristics: activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), antithrombin III (ATIII) level, von Willebrand factor (WF), endothelin-1 (E-1), D-dimer. If aPTT indices are within the range from 28 to 35 seconds, PT is from 12 to 15 seconds, TT is from 9 to 13 seconds, ATIII level is from 29 to 70%, WF level is from 105 to 115%, E-1 does nor exceed 0.32 fmol/ml and D-dimer is from 245 to 520 ng/ml FEU slow progressing of CKD is predicted. If aPTT, PT, TT, ATIII level are the same, and WF is higher than 115%, E-1 is higher than 0.32 fmol/ml, D-dimer is higher than 620 ng/ml FEU, accelerated CKD progressing is predicted.

EFFECT: increase of accuracy and reliability of chronic kidney disease diagnostics.

2 ex, 2 tbl

Description

The invention relates to medicine, nephrology, and relates to methods for predicting the nature of the progressive course of chronic kidney disease (CKD).

Known methods for predicting the progressive course of CKD, which include assessing the clinical picture of the disease, the presence of arterial hypertension, hyperuricemia, hyperhomocysteinemia and hyperlipidemia, the severity of proteinuria (PU), data on the dynamics of indicators of the functional state of the kidneys, as well as the results of morphological studies of nephrobiopathies and dopplerography (1, 2, 3, 4, 5, 6, 7, 8).

CKD is a nadnosological concept that includes damage to the kidneys of various origins (immunocomplex, autoimmune, metabolic, toxic, etc.) with the obligatory activation of the hemostatic system (9, 10, 11, 12, 13, 14). Out of 23 test tubes, such as spontaneous coagulation time, plasma recalcification time, silicone time, cephalin time, plasma heparin tolerance, plasma heparin time, total fibrinolytic activity, total non-enzymatic, fibrinolytic activity of heparin complex compounds (13) are outdated and non-standard methods for the study of hemostasis, many methods duplicate each other without adding information, many of them are very laborious and require quite a long time e time for their execution. Despite the large number of tests, they do not fully reflect the state of all parts of the hemostatic system, in particular, they do not affect vascular-platelet (primary) hemostasis at all.

However, the known criteria in varying degrees affect the progression of CKD. In many cases, there is a combination of the listed risk factors for the progression of CKD. To assess their role in the formation of chronic renal failure (CRF), it takes a long time to monitor the dynamics of risk factors and CKD progression processes with high economic costs and in the absence of numerical criteria predicting the progressive course of CKD.

Closest to the proposed is a method for predicting the progressive course of CKD, which consists in assessing changes in the hemostatic system (15).

To characterize the hemostasis system, coagulogram data was used, including 23 test tubes and 21 indicators of thromboelastogram. However, the method of thromboelastography is low-sensitive, which does not allow to reveal subtle shifts in the process of blood coagulation. This method is applicable for rough determination of gross deviations of coagulation parameters; it is not standardized much. To study hemostasis in this way requires a lot of time, on average 120-150 minutes.

A new technical problem is improving accuracy, reproducibility, information content and reducing research time.

To solve the problem in a method for predicting the nature of the progressive course of CKD, including the determination of blood coagulation characteristics: activated partial thromboplastin time (APTT), prothrombin time (PV), thrombin time (TB), and antithrombin III (ATIII) level, additionally determine the level of von Willebrand factor (PV), endothelin-1 (E-1) and D-dimers in blood plasma and with aPTT values ranging from 28 to 36 seconds, prothrombin time from 12 to 15 seconds, TV from 9 to 13 seconds, ATIII level from 29 up to 70%, ur For von Willebrand factor from 105 to 115%, endothelin level - 1 no more than 0.32 fmol / ml, D-dimer from 245 to 520 ng PEE / ml predict a slow progression of the course of CKD, and at the same rates of APTT, PTV, TV, ATIII level and PV level of more than 115%, E-1 of more than 0.32 fmol / ml, D-dimer of more than 620 ng PEE / ml predict accelerated progression of CKD.

The method is as follows: after applying the tourniquet, the vein is punctured with a dry silicone needle, the tourniquet is removed immediately after receiving the first drop of blood. Blood sampling is carried out in two siliconized tubes, the blood is stabilized with sodium citrate, centrifuged, followed by the determination of APTT, PV, TV (16, 17, 18), the level of PV on the AMS 600 (Russia, St. Petersburg), ATIII optical method on ACL 200 device (USA), D-dimer by immunochemoluminescent method on an Immulyte 1000 device (USA) and E-1 enzyme immunoassay method on a Well Tes 288 device (USA) using the Biomedics kit (USA), according to the attached instructions to the sets and devices .

With APTT indices ranging from 28 to 36 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, D-dimer from 245-520 ng PEE / ml predict a slow progression of the course of CKD, and with the same APTT, TB, PV, ATIII level and PV level of more than 115%, D-dimer more than 620 ng PEE / ml and E-1 more than 0.32 fmol / ml predict accelerated progression of the course of CKD.

The course of various forms of CKD, their progression depends on the state of microcirculation and hemorheological status of patients.

The proposed criteria of the method were selected on the basis of an analysis of data from a survey of 90 patients aged 18 to 55 years with a diagnosis of CKD, of which 50 patients with chronic mesangioproliferative glomerulonephritis and 40 patients with diabetes mellitus (DM) with symptoms of diabetic nephropathy (MD) who were hospitalized in Nephrology and endocrinology departments of the hospital. All patients retained nitrogen excretory function of the kidneys. When studying laboratory parameters of the hemostasis system in the examined patients, the state of hypercoagulation with the presence of intravascular coagulation was established in 20 patients with CGN (group 1) and in 17 patients with DN (group 2), which was confirmed, as can be seen from the data presented (Table 1, Indicators of the hemostatic system in patients with chronic kidney disease Me (LQ-UQ), where Note. * - statistically significant differences with the control parameter p <0.05, ** - p <0.01; Ґ - differences with the 1st group , p <0.05, ҐҐ - p <0.01; ♦ - differences with the 2nd group p <0.05, ♦♦ - p <0.01) acceleration APTT, on average, up to 34.37 (29.3; 38.7) and 35.15 (30.9; 40.83) seconds, (respectively in the 1st and 2nd groups) in comparison with the indices in the control 44 , 7 (41.4; 49.2) seconds, p <0.05; AC acceleration on average 13.84 (13.34; 15.57) and 13.6 (13.0; 14.1) seconds (respectively in the 1st and 2nd groups) in comparison with the indicators in the control 15, 46 (15.0; 16.1) seconds, p <0.05; a decrease in the level of ATIII to 54.55 (22.02; 74.36)% and 57.23 (24.33; 72.8)% (respectively in the 1st and 2nd groups in comparison with the indicators in control 101, 85 (88.8; 126.6)%, p <0.05; increasing the level of PV to 126.92 (121.2; 146.5)% and 128.7 (119.6; 139.3)% ( respectively in the 1st and 2nd groups) in comparison with the control 103.75 (92.0; 115.5)%, p <0.01 and an increase in the level of E-1 on average 2.11 (0.98; 2.43) and 1.86 (1.12; 2.3) fmol / ml (respectively in the 1st and 2nd groups) in comparison with the control 0.25 (0.18; 0.31) fmol / ml, p <0.01; an increase in the level of D-dimer to 2918.44 (724.32; 3388.421) and 2816.4 (917.34; 4126.6) ng PEU / ml (respectively, in groups) in comparison with a control of 357.7 (240.6; 543.6) ng PEE / ml, p <0.05. In the remaining 30 examined patients with CGN (group 3) and 23 patients with DN (group 4), statistically significant changes in the hemostatic system compared with the group of healthy individuals were established only by such indicators as APTT, TV, PV, ATIII level at a normal level of PV, E-1 and D-dimer.

A further analysis of the dynamics of diseases in the examined individuals during two years of observation revealed the following: in the 3rd and 4th groups of patients with a normal level of PV E-1 and D-dimer, but in the presence of activation of the hemostatic system according to the values of APTT, PV, TV and ATIII level, there was no statistically significant negative dynamics in the indicators of the functional state of the kidneys (specific gravity of urine, glomerular filtration rate (GFR), creatinine level), with the exception of two patients of the 3rd group and four patients of the 4th group, in which was negative Dynamics of indicators of renal function. In the 1st and 2nd groups of patients with hypercoagulable syndrome (acceleration of APTT, decreased PV and TB, decreased level of ATIII, increased level of PV and E-1) and the presence of signs of intravascular coagulation, the marker of which is an increase in the level of D-dimer, negative dynamics of indicators reflecting the functional state of the kidneys (statistically significant increase (S) in creatinine level, a drop in (S) GFR, decrease in the concentration function of the kidneys) was observed in 17 of 20 patients (85%) of the 1st group and in 14 of 17 (82 , 3%) patients of the 2nd group (table 2, Dynamics of the indicator the functional state of the kidneys in patients with chronic kidney disease for two years Me (LQ-UQ), where Note: The numerator is the initial indicator, the denominator is 2 years. * Statistically significant differences with the initial indicator p <0.05, ** - p <0.01; # - differences with the 1st group, p <0.05, ♦ - differences with the 2nd group p <0.05), that. confirms the progressive course of CKD in patients of the 1st and 2nd groups.

Example 1. As an example of using the proposed method for predicting the nature of the progressive course of CKD, the medical history of a patient D., 35 years old, who was treated in the nephrology department of the OKB from 09.16.07 to 10.21.07 and from 15.10.09 to 13.11.09, can serve as an example. Upon admission, she complained of headaches in the temporal areas, a feeling of heaviness in the lumbar region, periodic swelling of the legs and face.

From the anamnesis it was revealed that edema on the face and legs first appeared in 1998 after suffering a sore throat. However, the swelling was transient in nature, I did not give up urine tests, I did not go to the doctors, because I felt normal. However, at the age of 25, during pregnancy, changes in urine were detected (proteinuria, hematuria), blood pressure increased. These changes were regarded as part of the nephropathy of pregnant women; it was recommended to examine the condition of the kidneys in the postpartum period. For family reasons, the patient did not seek medical help, despite the fact that swelling and headaches began to appear. Reception of diuretics brought relief.

In July 2007, after hypothermia, the condition worsened sharply: swelling on the legs, feet, and paraorbital tissue, headaches, increase in blood pressure to 170/100 mmHg. At first she was treated on an outpatient basis, and later she entered a specialized department for examination. Upon receipt, the condition is satisfactory. Active position, clear consciousness. Body weight 64 kg, height 173 cm, normal skin color and moisture. The subcutaneous fat layer is moderately developed. The thyroid gland is not enlarged. Pastosity of the legs and paroorbital, blood pressure 160/100 mm Hg, pulse 70 beats per minute. From the respiratory and digestive systems without significant deviations from the norm. Heart sounds are clear, the rhythm is correct, the accent of the 2nd tone above the aorta. The apical impulse is shifted to the left. Deep palpation of the kidney area is moderately painful. The symptom of striking is positive on both sides.

The following studies were carried out:

1. Complete blood count (OAK): HB 140 g / l, erythrocytes 3.9 T / l, white blood cells 6.8 G / l, eoz - 3%, s / I - 5%, s / I - 56%, lymph - 27%, mon - 7%, ESR - 16 mm / hour.

2. Urinalysis (OAM): specific gravity 1013 (fluctuations 1010; 1015), protein 1.11 g / l, (daily proteinuria 1.94 g), white blood cells (L) up to 10 in the field of view, red blood cells (E) 3-4 in sight. According to Nechiporenko L - 4000 / ml, E - 10000 / ml.

3. Biochemical analysis of blood: glucose 4.6 mmol / l, bilirubin 16.6 mmol / l, urea 6.6 mmol / l, creatinine 100 μmol / l, fibrinogen 4.0 g / l, protein 72 g / l, albumin - 54.5%, globulins 45.5%, ACT 48 U / L, ALT 36 U / L.

4. The glomerular filtration rate of 96 ml / min, tubular reabsorption of 99%.

5. Bacteriological examination of urine: there is no growth of microbial flora.

6. Ultrasound examination of the kidneys: kidneys - left 105 cm, right - 105 cm, right nephroptosis 1 degree. The ratio of the layers is 1: 1, the pyelocaliceal system is somewhat densified, the contours are lubricated.

7. Excretory urography: no signs of pyelonephritis and kidney abnormality

8. The study of the coagulogram according to the proposed method, including the determination of APTT = 34 seconds, PV = 14.2 seconds, TV = 10 seconds, level ATIII = 64%. PV = 128%, E-1 = 1.31 fmol / ml and D-dimer = 2558 ng PEU / ml.

The data obtained allowed us to conclude that the patient has hypercoagulable syndrome (GCS) and intravascular coagulation (SCC). The patient performed diagnostic nephrobiopsy.

9. Morphological study of nephrobiopathy: signs of chronic mesangioproliferative glomerulonephritis with phenomena of high activity of the inflammatory process: epithelial crescent, mesangium interposition, mesangium infiltration and proliferation, 2 sclerosis glomeruli. Morphological activity index was 9.0 points, sclerosis index 6.8 points.

Based on clinical, instrumental, laboratory and morphological data, a diagnosis of chronic mesangioproliferative glomerulonephritis in the exacerbation phase is made. Nephrogenic arterial hypertension. Prediction of the nature of CKD progression: accelerated progression of the course of the disease in this patient is assumed.

The patient was prescribed pathogenetic therapy with cyclophosphamide to stop the inflammatory process in the kidneys and prevent the progression of the disease for 2 years in a total dose of 19 g while taking dipyridamole and enalapril.

During the observation period for two years, the patient had no signs of exacerbation of the pathological process both clinically and according to urinalysis. The numbers of blood pressure ranged from 130 / 80-140 / 80 mm Hg, daily proteinuria 400-500 mg / day, erythrocyturia according to Nechiporenko 3000-4000 / ml, fluctuations in the specific gravity of urine were in the range 1010-1015.

Glomerular filtration rate of 75 ml / min, 98% reabsorption.

Indicators of biochemical parameters of blood: creatinine 112 μmol / l, protein 68 g / l.

Coagulogram: thrombin time 12 seconds, fibrinogen 3 g / l, prothrombin time 15 seconds, activated partial thromboplastin time 42 seconds, antithrombin III 120%, D-dimer 1984.3 ng PEU / ml, von Willebrand factor 115%, endothelin-1- 1.52 fmol / ml.

Conclusion: signs of hypercoagulation and intravascular coagulation persist.

Nephrobiopsy was performed to determine the management tactics of the patient. A morphological study of nephrobiopathy revealed mesangioproliferative glomerulonephritis with moderate signs of process activity (morphological activity index 6 points) and increased fibroplastic processes (sclerosis index 9 points).

Negative dynamics of glomerular filtration rate, renal concentration ability, creatinine level was noted.

Thus, the prognosis of the disease, determined using the proposed method, was confirmed by its further course. The application of the proposed method for predicting the progressive course of CKD, which consists in determining the aggregate of coagulation characteristics of the blood with the determination of the level of PV, E-1 and D-dimer, revealed a high accuracy in predicting the progressive course of CKD, which will allow timely early pathogenetic nephroprotective therapy to prevent the development of sclerotic changes and progression CKD with outcome in chronic renal failure in patients with CGN and DN.

Example 2. As an example of the application of the method for predicting the nature of the progressive course of CKD, a case history of patient K., 37 years old, under the supervision of the endocrinological and outpatient departments of the Regional Clinical Hospital since 05/19/2007 is given.

Was admitted to the department with complaints of weakness, sweating, dry mouth, periodic aching pain in the lumbar region, symmetrical swelling of the legs, feet and lower eyelids, increased blood pressure to 140/90 mmHg, accompanied by headache, visual impairment. From the medical history of the disease it was revealed that in 2002 she began to note dry mouth, thirst, an increase in blood pressure to 140/90 mmHg, weight loss, and sometimes swelling on the legs. Examination revealed hyperglycemia, glucosuria. He was diagnosed with diabetes and insulin therapy was prescribed.

In the next 3 years, arterial hypertension became permanent, accompanied by headache, dizziness. Repeatedly noted episodes of hypoglycemia after errors in the diet, paraorbital edema appeared, and proteinuria was detected in urinalysis. The patient received antihypertensive therapy on the background of insulin therapy. An in-depth study of the condition of the kidneys was not performed.

With an objective study, the general condition is satisfactory. Consciousness is clear. Full contact. The skin of normal color, clean. The subcutaneous fat layer is moderately developed, there is swelling of the paraorbital tissue, pasticity of the legs. Sclera normal color. The thyroid gland and peripheral lymph nodes with normal properties. On respiratory organs without pathology. The boundaries of the heart are within normal limits, with auscultation of the heart, tones are clear, rhythmic. HELL 140/90 mm Hg, pulse - 76 per minute. In the study of the digestive system: the tongue is dry, coated with a white coating on the root. The abdomen is soft, painless on palpation. The liver along the edge of the costal arch, the edge is sharp, smooth, painless. Bubble symptoms are negative. The symptom of “striking” is slightly positive on the right and left. Diuresis is sufficient, adequate. Height - 171 cm, body weight - 66 kg.

Studies were conducted:

Complete blood count: Hb - 126 g / l, red blood cells - 3.9 × 10 ¹² / l, white blood cells - 6.4 × 10 ⁹ / l, eosinophils - 2%, stab - 5%, segmented - 65%, lymphocytes - 24%, monocytes - 3%, ESR - 21 mm / hour, platelets - 264 × 10 ⁹ / L.

General urine analysis: beats. weight - 1018, protein - 0.46 g / l, white blood cells - 2-5 in the field of view, red blood cells - 1-2 in the field of view.

Urinalysis according to Nechiporenko: leukocytes - 3000, red blood cells - 4000.

Daily urine protein - 0.4 g.

Biochemical blood test: urea - 6.2 mmol / l; creatinine - 103 μmol / l; bilirubin - 11.4 μmol / l; fibrinogen - 2.6 g / l; protein - 79 g / l; albumin - 45%, cholesterol - 4.0 mmol / L.

Fasting glycemia - 5.5-10.2 mmol / L, HbAlc - 8.3%.

Bacteriological examination of urine 3-fold: there is no growth of microbial flora. Radioisotope radiography of the kidneys (RRH): moderate decrease in secretion and excretion.

Ultrasound examination of the kidneys: the left kidney is 101 × 48 mm, the parenchyma is 14 mm, the right kidney is 100 × 43 mm, the parenchyma is 15 mm. The contours are even. The parenchyma is homogeneous on both sides; in the renal sinuses of the middle third up to 13 mm, a hypertrophic renal column (normal variant) appears. Details of the renal sinus are clearly not differentiated, in its projection there are many small linear echo-dense inclusions. Reliably calculi are not determined. The situation is normal. Conclusion: moderate diffuse changes in the kidneys.

Excretory urography: no signs of pyelonephritis and kidney abnormality

Glomerular filtration rate - 92 ml / min, tubular reabsorption - 99%.

Ophthalmologist consultation: signs of preproliferative retinopathy.

The coagulogram according to the proposed method included the determination of APTT (39 sec), PV (13.9 sec), TV (10 sec), ATS level (66%), PV (105%), E-1 (0.31 fmol / ml) and D-dimer (350 ng PEE / ml).

The data obtained allowed us to conclude that the patient has GCS without signs of SCC and diabetic nephropathy with arterial hypertension, which predicted a slow progression of the course of CKD.

Dipyridamole and enalapril therapy was prescribed with insulin therapy.

Over the course of a two-year observation period, the patient's blood pressure stabilized (fluctuations within 130 / 75-135 / 80 mmHg), daily proteinuria from 0.2 to 0.3 g / day, erythrocyturia - 2000-2500 / ml, fluctuations in the specific gravity of urine in the range of 1015-1022. Glomerular filtration rate - 90 ml / min, tubular reabsorption - 99%.

Indicators of biochemical parameters of blood: urea - 6.3 mmol / l; creatinine - 105 μmol / l; protein - 76 g / l; cholesterol - 4.1 mmol / l.

Fasting glycemia - 5.2-9.9 mmol / L, HbAlc - 7.2%.

Negative dynamics of ultrasound of the kidneys and RGG was not detected.

The indicators of the coagulogram performed according to the proposed method: APTT - 36 sec, PV - 13 sec, TV - 12 sec, ATSH level - 67%, PV - 106%, E-1 - 0.31 fmol / ml, D-dimer - 360 ng PEE / ml). Conclusion: Signs of GCS without SCCC are preserved.

Analyzing the data obtained, it can be stated that there was no negative dynamics of the indicators characterizing the renal processes, namely the glomerular filtration rate, tubular reabsorption, and creatinine level. That is, there was a slow progression of CKD and the prognosis of the disease, determined using the proposed method, was confirmed by its further course.

When calculating the prognostic significance of positive and negative results of the proposed method, the authors found that the sensitivity of the test of the proposed method was 83.8%, specificity 88.6%, predictive value of a positive result 83.7%, predictive value of a negative result 88.6%, test accuracy (forecast) - the share of correct forecasting results in the total number of results (both positive and negative) 86.6% (17).

The nature of the damage to the hemostatic system, identified using the proposed method for predicting the progressive course of the process in CKD, allows to determine the progressive course of the process in CKD with a higher probability (in 83.7% of cases) without nephrobiopsy, which is very important in cases where its implementation it is impossible or for dynamic observation in order to assess the effectiveness of the therapy.

Thus, the application of the proposed method for predicting the progressive course of CKD allows doctors to obtain prognostically accurate laboratory confirmation of the progressive course of the renal process at an earlier date, which contributes to more effective therapy and a better prognosis of the course of CGN.

Information sources

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Claims (1)

A method for predicting the nature of the progressive course of chronic kidney disease (CKD), including the determination of blood coagulation characteristics - activated partial thromboplastin time (APTT), prothrombin time (PV), thrombin time (TB) and antithrombin III (ATIII) level, characterized in that it is additional determine the level of von Willebrand factor (PV), endothelin-1 (E-1) and D-dimers and with APTT indices ranging from 28 to 35 s, PV from 12 to 15 s, TV from 9 to 13 s, ATIII level from 29 up to 70%, level of PV from 105 to 115%, E-1 not more than 0.32 fmol / m and D-dimer from 245 to 520 ng PEE / ml predict a slow progression of the course of CKD, and with the same values of APTT, PV, TB, ATIII level, and PV level more than 115%, E-1 more than 0.32 fmol / ml, D-dimers of more than 620 ng PEE / ml predict accelerated progression of CKD.