CARDIORENAL SYNDROME IN PATIENTS WITH CHRONIC HEART FAILURE AS A STAGE OF THE CARDIORENAL CONTINUUM (PART I): DEFINITION, CLASSIFICATION, PATHOGENESIS, DIAGNOSIS, EPIDEMIOLOGY

The combination of heart failure and renal failure is called cardiorenal syndrome. It is a stage of the cardiorenal continuum and, possibly, a small link of the cardiorenal-cerebral-metabolic axis. Despite the fact that the phrase “cardiorenal syndrome” and its five types have become a part of the medical lexicon, many aspects of this problem are still not clear. Cardiorenal syndrome can be diagnosed in 32-90.3% of patients with heart failure. Cardiorenal syndrome type 1 or 2 develops in most cases of heart failure: cardiorenal syndrome presents with the development ofchronic kidney disease in patients with chronic heart failure and acute kidney injury in patients with acute heart failure. Impaired renal function has an unfavorable prognostic value. It leads to an increase in the mortality of patients with heart failure. It is necessary to timely diagnose the presence of cardiorenal syndrome and take into account its presence when managing patients with heart failure. Further researches are needed on ways toprevent the development and prevent the progression of kidney damage in patients with heart failure, to which the efforts of the multidisciplinary team should be directed. The first part of this review examines the currently definition, classification, pathogenesis, epidemiology and prognosis of cardiorenal syndrome in patients with heart failure.

The understanding of the development of cardiovascular disease (CVD) is currently based on the concept of the cardiovascular, cardio-cerebral and renal continuum (Figure 1) [73][74][75]82].The cardiovascular continuum is a chain of interrelated changes in the cardiovascular system from exposure to risk factors (hypertension, diabetes mellitus (DM), dyslipidemia, obesity, smoking, etc.) through the gradual emergence and progression of endothelial dysfunction, atherosclerosis, left ventricular (LV) hypertrophy, coronary artery disease (CAD), myocardial infarction (MI) to the development of heart failure (HF) and fatal outcome [3].This is accompanied by brain damage from exposure to risk factors through the development of encephalopathy to stroke, cognitive impairment, dementia and fatal outcome.Concurrently with these processes, in most cases, kidney pathology develops and progresses from risk factors, most of which are common for cardiovascular and renal diseases, through the appearance of albuminuria of varying severity (A1, A2, A3, A4 levels), a decrease in glo merular filtration rate (GFR) to the development of end-stage ren al failure (RF) and fatal outcome [35].
Over the past 10 years, there has been more discussion on the issue of the "double epidemic" of heart and kidney failure [141], because many patients have both manifestations of these two clinical conditions, which has led to the ever-growing use of the concept of "cardiorenal syndrome" [4,19,23,28].

Definition of CRS
Cardiorenal syndrome is the simultaneous presence in the patient of cardiac and renal dysfunction/failure [43,46,87,160].Initially, a patient with cardiorenal syndrome may have kidney pathology, leading to the development of RF, and then cardiovascular complications and HF.Conversely, primary heart disease can lead to HF, which can lead to the development of dysfunction and damage to the kidneys and end-stage RF [23].

HEMODYNAMIC MECHANISMS OF CRS PATHOGENESIS
Hemodynamic mechanisms for the development of cardiorenal syndrome in HF include a decrease in cardiac output (CO), the development of venous stagnation and increased intra-abdominal pressure (IAP).
For a long time it was believed that the main cause of kidney injury in HF is decreased cardiac output (CO), which leads to a decrease in renal blood flow, hypoxia, ischemia, kidney injury and their reduced functional ability [48,98].However, in HF with preserved left ventricular (LV ) ejection fraction (E F) and normal CO, as in CHF with reduced LVEF, acute kidney injury (AKI) and chronic kidney disease (CKD) often develop [38,134].Hence, a decrease in CO, hypoperfusion and ischemia of the kidneys alone may not explain kidney injury in patients with HF.Great importance in the decline of kidney performance in recent years is given to venous stagnation and an increase in central venous press ure (CVP).These lead to a decrease in the filtration pressure in the capillaries of the glomeruli and contribute to a decrease in the glomerular filtration rate (GFR) [105,110].Also, an increase in CVP and renal venous pressure leads to an overgrowth of the venules around the distal nephron, which contributes to the compression of the tubules, increased pressure in the tubules and reverse flow of filtrate into the interstitial.Renal venous congestion can lead to interstitial hypoxia, inflammation and nephron damage, deterioration of kidney function, proteinuria and tubular dysfunction [8,130].
Table 1.Classification of cardiorenal syndrome [146,147] Increased IAP is also associated with impaired renal function [128,131].Even healthy individuals had significantly reduced GFR, secondary to abdominal compression with increased IAP >20 mm Hg [135].This can be explained by the compression of renal veins and parenchyma outside, which leads to a decrease in filtration pressure and GFR [135].
It was shown that the elevated CVP and IAP contribution to reducing GFR in HF is greater than that of the reduction of systemic blood pressure (BP), reduction of CO and increase in pulmonary capillary wedge pressure (PCWP) [110].

NEUROENDOCRINE MECHANISMS OF CRS PATHOGENESIS
Neuroendocrine mechanisms involved in CRS development in HF are ac tivation of reninangiotensin-aldosterone (RAAS), sympathoadrenal system (SAS), excess production of endothelin, vaso-pressin (ADH), etc. Products of activation of all these systems lead to vasoconstriction, including narrowing of renal vessels, and, consequently, contribute to the reduction of renal blood flow, the development of chronic hypoxia, ischemia and kidney damage with a decrease in their functional abilities [156,158].In addition, vasoconstriction leads to an increase in afterload, which can contribute to the worsening of myocardial dysfunction [116].

IN CRS PATHOGENESIS
It is known that the effect of RAAS on the kidneys is diverse.Angiotensin II increases sodium reabsorption (Na + ) [34,84,116], which contributes to water retention and the development of edema, which increases preload on the heart and exacerbates its dysfunction.

Reduced renal blood flow Hypoxia Ischemia Necrosis Apoptosis
Acute or chronic injury of tubules and glomeruli of kidneys -   A -adenosine, ADH -antidiuretic hormone, IAP -intra-abdominal pressure, HDDhemodynamic disorders, NUP -natriuretic peptides, NEA -neuroendocrine activation, ADHF -acute decompensation of chronic heart failure, AKI -acute kidney injury, AHF -acute heart failure, PG -prostaglandins, RAAS -renin-angiotensin-aldosterone system, SASsympathoadrenal system, CO -cardiac output, GFR -glomerular filtration rate, CVP -central venous pressure, CKD -chronic kidney disease, CRF -chronic renal failure, ET -endothelium In addition, angiotensin II leads to a spasm of the glomerular arterioles, wherein the narrowing of efferent arterioles prevails over the narrowing of afferent ones (Figure 3).Therefore, in the early stages of CHF, despite the decrease in renal blood flow, renal perfusion pressure and filtration fraction (FF) increase, which contributes to the preservation of normal values of GFR [116,158].On the one hand, this mechanism contributes to the maintenance of GFR.On the other hand, hyperfiltration can lead to damage to renal glomeruli: increased permeability of the basal membrane and loss of its negative charge.In addition, hyperfiltration helps to reduce hydrostatic pressure and to increase oncotic pressure in the peritubular capillaries.This leads to increased reabsorption of water and edematous syndrome, increased preload on the heart and aggravation of its dysfunction [116].With the progression of CHF and further decrease in CO, renal blood flow decreases so much that renal perfusion pressure and FF fall, which leads to a decrease in GFR [14,25,37,92,118].Angiotensin II also contributes to the development of albuminuria and proteinuria by increasing the intraglomerular pressure, the permeability of the basal membrane of the glomeruli and the loss of its negative charge.Excessive flow of plasma proteins into the lumen of the tubules leads to an increase in their reabsorption by epithelial cells of the proximal tubules, the accumulation of proteins in the cytoplasm of tubular cells, which ultimately leads to swelling and destruction of lysosomes, rupture of the basal membranes of the tubules, tubular dysfunction and the flow of plasma proteins in the interstitial.This causes activation of inflammatory and vasoactive genes, secretion of inflammatory mediators.They attract monocytes and T-lymphocytes to the interstitial space, which in turn leads to the activation of fibroblasts, synthesis of extracellular matrix and the development of interstitial fibrosis and nephrosclerosis -morphological substrate for the development of RF [6].Activation of fibroblasts is also promoted by vasoconstriction of peritubular vessels with the development of ischemia [6].In addition, angiotensin II causes hyperplasia of glomerular mesangial cells, stimulates their production of transforming growth factor b, which increases the synthesis of extracellular matrix components, which leads to the development of glomerulosclerosis [103,119].Angiotensin II enhances the synthesis and release of aldosterone [116,158], which promotes sodium reabsorption at the level of distal tubules and collecting tubes and the development of edematous syndrome [25,70].In addition, aldosterone promotes connective tissue growth in patients with CHF, which contributes to the development of renal fibrosis and glomerulosclerosis [143].

THE ROLE OF SYMPATHOADRENAL SYSTEM IN CRS PATHOGENESIS
Activation of the sympathoadrenal system (SAS) also contributes to the development of renal dysfunction in patients with CHF [50].Activation of α-adrenoreceptors in the basal membrane of the proximal tubules leads to an increase in sodium and water reabsorption [25].Stimulation of α 1 -adrenoreceptors in afferent and efferent arterioles leads to a narrowing of these vessels and, consequently, a decrease in renal blood flow.Stimulation of β 1 -adrenoreceptors in the cells of the juxtaglomerular apparatus increases the release of renin and increases the activity of RAAS [70,116].

OTHER ASPECTS OF NEUROENDOCRINE ACTIVATION IN THE GENESIS OF KIDNEY DAMAGE IN CHF
Antidiuretic hormone (ADH, vasopressin, argininevasopressin), endothelins and adenosine, the concentration of which increases with CHF, lead to vasoconstriction, and, consequently, to a decrease in renal blood flow, as well as an increase in water reabsorption, an increase in preload on the heart and venous stagnation [34,116,164,165].This contributes to the development of damage to the glomeruli and renal interstitium [36,41], and to reduced GFR [25,81,85,110,168].That is, it seems that compensatory neurohumoral mechanisms are not sufficiently adaptive in the long term.Vasoconstriction leads to the development of ischemia, damage to kidney structures.Retention of sodium and water by the kidneys, mediated by neurohumoral activation, leads to the progression of cardiac dysfunction, and this, in turn, contributes to more pronounced renal dysfunction.The vicious circle closes leading to the progression of CHF and the development of kidney damage [43].
Resistance to NUP may be due to a decrease in sodium flow into the collecting tubes due to a drop in GFR or an increase in proximal sodium reabsorption [116,158].In addition, resistance to NUP may be associated with its destruction by the proximal endopeptidase, including neprilysin.Prostaglandins E2 and I2, the production of which increases in a compensatory manner in CHF in response to an increase in the plasma concentration of vasoconstrictors, have a vasodilating effect, increase renal blood flow and natriuresis [25,164,165,167].Nitric oxide (NO, endothelium relaxant factor) is an even stronger vasodilator than prostaglandins E2 and I2.NO plays an important role in the regulation of the volume of extracellular fluid by the kidneys through vasodilation, natriuresis and desensitization of the tubulointerstitial feedback mechanism.It is shown that in patients with CHF, the activity of NO-synthase may decrease, which leads to a decrease in the production of NO [164,165].The dysregulation of NO is considered a major factor of endothelial dysfunction in patients with HF.Keilstein et al. have shown that there was a relationship between decreased renal perfusion, impaired NO-mediated endothelial vasodilation and a high concentration of endogenous NO-synthase inhibitor -asymmetric dimethylarginine in patients with CHF [35].An increase in the activity of NADPH oxidase under the action of angiotensin II leads to NO inactivation.This is another potential mechanism of endothelial dysfunction in HF [42].
In addition, an increase in tumor necrosis factor (TNF) in CHF and CKD can lead to a decrease in the activity of NO-synthetase and an increase in the rate of endothelial cell apoptosis [87].
Over time, the nephroprotective effect of NUP, prostaglandins and NO is depleted, which contributes to the progression of renal hemodynamic disorders and reduced functional state of the kidneys [25,37,92,118].

Oxidative stress, inflammation, apoptosis
Along with hemodynamic and neuroendocrine mechanisms, the main links involved in the development of kidney damage during HF are oxidative stress, activation of the inflammatory system and apoptosis (Figure 2) [46,87,88].The development of oxidative stress can contribute to the activation of RAAS, as angiotensin II activates NADPH oxidase, which leads to the formation of active oxygen radicals (ARC) [46].Also, according to experimental studies, increased production of ARC can contribute to the activation of SAS [33].
Adverse effects of oxidative stress are associated with damage to cardiomyocytes, endotheliocytes and renal tubular cells [127,172].In addition, ARCs lead to the proliferation of cells of intrarenal blood vessels and, consequently, the progression of renal blood supply disorders, and also launch a proapoptotic cascade in the cells of the proximal tubules [39,40,46].Oxidative damage to the tubules and interstitial inhibit feedback mechanisms involved in the secretion of renin [46].This may contribute to increased RAAS activity and its adverse effects on the kidneys.In addition, ARCs under oxidative stress in rats in vivo and in vitro increase the activity of pre-ganglion sympathetic neurons and, consequently, contribute to the increase of SAS activity [112,161].That is, oxidative stress can contribute to altered functional state of the kidneys, both directly and by activating neurohumoral systems [46].In addition to oxidative stress, inflammation leads to kidney damage during HF [46,62,173,174].In an environment of mechanical overload and ischemia, cardiomyocytes are able to produce a large number of cytokines and provide an immune response [57].In addition, venous stagnation increases the absorption of toxins in the intestine, increasing the inflammatory response [58].Patients with CHF were found to have elevated levels of such markers of inflammation as C-reactive protein (CRP), interleukin-1 (IL-1), IL-1β, IL-6, IL-18, cell adhesion molecules, t umor necrosis factor alpha (TNF-α) and its soluble receptors in plasma and myocardium, as well as the relationship of these markers with the severity and progression of the disease [47,62,170].Elevated levels of proinflammatory cytokines are associated with the activation of apoptosis, which is observed not only in cardiomyocytes, but also in smooth muscle cells of the vascular wall, renal tubular cells and glomeruli [8].
ARCs also lead to the activation of the inflammation system.They contribute to the production of pro-inflammatory cytokines, attraction and activation of leukocytes [45,46].In addition, the products of neurohumoral activation contribute to the development of inflammation.Angiotensin II increases tissue level of activated nuclear factor kappa B (NF-κB), induces expression of TNF-α, IL-6, chemoattractant protein of monocytes (MSR-1) [46,154].SAS can also lead to the activation of the inflammation system through norepinephrine-mediated production of cytokines in the liver and heart and neuropeptide Y [45,46], a high level of which is found in patients with CHF.It is involved in long-term vasoconstriction, acts as a factor of vascular proliferation, can lead to increased hypoxia and activation of inflammation [46,129].
Oxidative stress and inflammation can contribute to structural damage and fibrosis in the kidneys, although direct evidence is currently insufficient [62,77,111,114].Further research is required to obtain said evidence [46].

ANEMIA
Anemia can develop in CHF due to inhibition of erythropoiesis (due to relative or absolute deficiency of erythropoietin) and due to increased content of hepatic peptide hepcidin, which reduces iron absorption in the intestine and reduces the release of iron from hepatocytes and macrophages [87,175].Anemia contributes to the development of chronic hypoxia, ischemia and damage to the structures of the heart and kidneys [104].Further studies are needed to prove the importance of anemia in the pathogenesis of kidney damage in CHF.

OTHER POSSIBLE PATHOGENETIC MECHANISMS OF KIDNEY DAMAGE IN HF
Episodes of acute decompensation of HF are also considered a factor that predisposes to the progression of HF and kidney damage [62].The frequency of CHF decompensation is independently related to the development of CKD [166].This is due to the frequent development of AKI in ADHF, which may not result in complete recovery of kidney structure and function and may therefore contribute to the development and subsequent progression of CKD [55,62].
Another pathogenetic link involved in the development of kidney damage in HF can be atherosclerosis.On the one hand, kidney disease and reduced functional ability are known risk factors for atherosclerosis.On the other hand, atherosclerosis can lead to impaired blood supply, damage and dysfunction of the kidneys and in some cases to ischemic kidney disease.In this regard, atherosclerosis and kidney disease can mutually reinforce each other and contribute to the progression of cardiorenal syndrome [87].
In some studies, dyslipidemia, impaired coagulation and vascular-platelet hemostasis are also listed among the mechanisms of renal dysfunction in CHF [71,124].

Forms of cardiorenal syndrome type 1 in patients with HF
CRS of type 1, which is the development of AKI with initially normal renal function or with pre-existing CKD, may be prerenal, renal and less oftenpostrenal in nature [18].

Prerenal AKI in CRS of type 1
The following conditions can lead to the development of prerenal AKI in HF. 1) Decrease in CO (with ADHF, AHF of different etiology, including cardiogenic shock, arrhythmias, conduction disorders, PE, cardiac tamponade, etc.).2) Hypovolemia (excessive loss of extracellular fluid with a decrease in intravascular volume due to bleeding, vomiting, diarrhea, as well as burns and forced diuresis).Randomized DOSE study (n=308, ADHF) demonstrated that the administration of high (2.5 times higher than maintenance dose) compared with low (equal to maintenance) doses of loop diuretics led to a more rapid decrease in stagnation, but a greater reduction in GFR [79].In this regard, it is recommended to administer diuretics in the minimum effective doses that do not cause excessive reduction of intravascular volume to avoid hypotension and AKI [7].3) Peripheral vasodilation (hypoxemia, sepsis, etc.) with a decrease in systemic BP. 4) Spasm of renal vessels in shock, hypercalcemia, inhibition of prostaglandin synthesis (including during treatment with non-steroidal antiinflammatory drugs -NSAIDs).5) Administration of angi otensin-converting enzyme inhibitors (ACE) / sartans [18].Under the influence of these drugs, afferent glomerular arterioles are mainly dilated (Figure 3), which may contribute to a decrease in renal perfusion pressure and FF [70,120,133] and, consequently, a decrease in GFR [29,70].In most patients with CHF, despite dilatation of efferent arterioles, GFR with ACE inhibitors / sartans remains stable due to increased renal blood flow resulting from dilation of arterioles [70,120].The development of prerenal AKI under the influence of ACE inhibitors / sartans in most cases is associated with a drop in systemic BP.
To prevent this, it is necessary to start treatment with low doses, administer the first dose at night, slowly perform dose titration, avoid simultaneous administration of NSAIDs [120].In most cases, prerenal AKI is accompanied by hypotension (SBP <90 mm Hg).Without adequate treatment, hypoxic nephron damage develops, which leads to progressive tubular dysfunction and, in some cases, ischemic acute tubular necrosis.

Renal AKI in CRS of type 1
The main types of renal AKI in HF are: 1) acut e tubular necrosis (ATN); 2) acute tubulointerstitial nephritis (TIN); 3) occlusion of renal vessels [18].Acute tubular necrosis (ATN, tubular necrosis) may be ischemic and toxic.As mentioned above, ischemic ATN can develop without adequate treatment of prerenal AKI (in this case, AKI will have a combined nature: prerenal and renal).Toxic tubular necrosis may occur as a result of the influence of drugs (including massive doses of diuretics, contrast agents, anesthetics, etc.), exo-and endogenous toxins (including organic pigments myoglobin and hemoglobin).After cessation of exposure and excretion of the nephrotoxic agent, renal function is usually restored.Intratubular deposits in acute urate nephropathy, multiple myeloma, severe hypercalcemia and primary hyperoxaluria may be regarded as more rare causes of ATN [18].The causes of acute TIN can be drugs, infectious diseases, uric acid salts, etc. [18,146].Occlusion of renal vessels may occur in thrombosis of the renal veins, thrombosis or embolism of the renal arteries [18].Renal thrombosis with the development of AKI is often observed in disseminated intravascular coagulation.Atheroembolism (embolism with small fragments of atherosclerotic plaques) of the renal arteries develops quite rarely.It can be spontaneous, provoked by injuries and interventions such as angiography, angioplasty, intra-aortic balloon counterpulsation, vascular surgery and thrombolysis.Obstruction of small renal arteries leads to the development of ischemia, inflammatory reaction around emboli, hypertension and AKI.More than half of the inflammatory infiltrate cells are eosinophils, because cholesterol crystals of atherosclerotic plaque fragments have a direct chemotactic effect on them.The development of acute TIN exacerbates renal dysfunction in atheroembolism of the renal arteries.This condition is often undetected.The possible atheroembolism of the renal arteries is evidenced by the presence of systemic atherosclerosis, marble pattern of the skin, embolism with cholesterol crystals of the retinal arterioles (bright yellow Hollenhorst plaques), petechiae and ischemia of the toes with a preserved pulse on the rear artery of the foot.Laboratory examination often reveals eosinophilia of blood and eosinophiluria, hypercomplementemia, elevated levels of lactate dehydrogenase, erythrocyte sedimentation rate (ESR), leukocytosis.The diagnosis is confirmed by a kidney biopsy, in which cholesterol crystals are found in arterioles.Changes in the kidneys caused by atheroembolism of the renal arteries are often irreversible [23].

Postrenal AKI in CRS of type 1
The causes of postrenal AKI in HF may be acquired obstructive nephropathy due to nephrolithiasis, acute uric nephropathy or other causes that violate the passage of urine through the ureters; tumors (prostate, uterus, large intestine, etc.); endometriosis; retroperitoneal fibrosis (posttraumatic, secondary to aortic aneurysm, iatrogenic, idiopathic), etc. [18].Diagnosis is based mainly on the results of imaging methods of examination.

Diagnosis of cardiorenal syndrome type 1 in patients with HF
For the diagnosis of CRS type 1 in patients with AHF/ADHF, it is advisable to use modern recommendations for the diagnosis of AKI, according to which AKI should be diagnosed in the presence of at least 1 of 3 criteria: 1) increase in creatinine by >26.5 μmol/l for 48 hours; 2) increase in creatinine by 1.5 times for 7 days; 3) decreased diuresis <0.5 ml/kg/h for 6 hours [9].The approach to diagnosis of AKI severity is presented in Table 2.

Stage
Serum creatinine Diuresis, ml/kg/h 1 1.5-1.9times increasing from the baseline OR 0.3 mg/dL (26.5 μmol/L) increase <0.5 during >6 <12 hours 2 2.0-2.9 times increasing from the baseline <0.5 during >12 <24 hours Biomarkers for the diagnosis of early stages of AKI may be cystatin C, KIM-1, L-FABR-liver type of fatty acid binding protein, IL-18-interleukin 18, NGAL [146].Said biomarkers are being actively studied and may soon be introduced into the standards for the diagnosis of AKI, including in HF.In ultrasound examination in AKI, kidneys are usually of normal or enlarged size with preserved cortical-medullary ratio, and in color Doppler there is increased resistive index (RI) >0.8 cm/s [86,96,146].

Diagnosis of cardiorenal syndrome type 2 in patients with HF
For the diagnosis of cardiorenal syndrome type 2 in patients with CHF, it is advisable to use modern recommendations for the diagnosis and treatment of CKD [21].CKD should be diagnosed in all patients with 1 or more markers of kidney damage for 3 months or more, regardless of glomerular filtration rate (GFR) and/or in patients with GFR values <60 ml/min/1.73m 2 for 3 months or more, regardless of the presence of markers of kidney damage.The "3 months or more" interval during which decrease in GFR or markers of kidney damage should be detected is due to the fact that the acute variants of renal dysfunction during this period result in recovery, or lead to the emergence of CKD symptoms.The use of GFR <60 ml/min/1.73m 2 as a diagnostic criterion is due to the fact that such a decrease in GFR corresponds to a loss of 50% of the mass of active nephrons, which is clinically significant.
For calculation of GFR, the latest and most accurate CKD-EPI formula should be used.Calculations can be made using the on-line calculator of the National Kidney Foundation, available on the website http://www.kidney.org/professionals/kdoqi/gfr_calculator.In accordance with modern recommendations on CKD, the degree of decline in GFR is divided into 5 stages of kidney damage (Table 3) [9,21].
For the diagnosis of CKD a marker of kidney injury must be identified at least 2 times with an interval of 3 months or more.Histological changes in the kidneys or irreversible structural changes in imaging methods can be detected once [21].Quantification of UAE (albuminuria) should be made in daily urine or in the first morning portion of urine to determine albumin/creatinine ratio.

The prevalence of decreased GFR in patients with HF
According to the national register of patients with AHF and ADHF ADHERE [32], which includes about 100,000 patients of different ages and with various comorbidities hospitalized in 270 US hospitals, the mean GFR calculated by the Cockroft-Gault formula was 48.9 ml/min/m 2 in men and 35.0 ml/min/m 2 in women [37,89].
A retrospective analysis of CONSENSUS, SOLVD, DIG, CIBIS-II, COMET, CHARM, CARE-HF databases of large clinical studies revealed that a decrease in creatinine clearance calculated by Cockroft-Gault formula or a decrease in GFR calculated by MDRD formula of <60 ml/min/1.73m 2 was revealed in 32-50% of patients with CHF [125].
According to Russian researchers, a decrease in MDRD GFR of <60 ml/min/1.73m 2 was found in 77.1%, CKD of different stages -in 90.3% of patients with CHF with low LVEF [15].
In a large population-based study called NHANES III, it was shown that among the US population over 20 years of age, stage 1 of CKD was in 3.3%, stage 2 -in 3.0% and stage 3 -in 4.3% of the population [30,31,101].Clearly, the prevalence of GFR reduction in patients with CHF is many times higher than that in the general population.

Urine albumin excretion in patients with CHF: epidemiological and pathogenetic aspects
In According to Russian researchers, in assessing albumin/creatinine ratio in morning urine, microalbuminuria (A2) was detected in 58.6% (95% CI 45.7-71.5), a high normal level of albuminuria (A1) -in 10.0% of patients.In daily urine, microalbuminuria (A2) was detected in 67.1% (95% CI 54.7-79.5),high normal level (A1) -in 22.9%, macroalbuminuria (A3) -in 5.7% of patients [17].The higher level of UAE, as well as the lower values of GFR in the Russian Federation, seems to be due to the fact that UAE was determined not in a random single sample, but in the first morning and daily urine.It may also be due to ethnic differences, greater clinical symptoms, systolic dysfunction, and less adherence to therapy.It should be noted that the incidence of albuminuria in patients with CHF is much higher than its prevalence in the general population, in patients with diabetes and hypertension, which is 6.6-8.3%, 16-32% and 11-40%, respectively [26,52,67,83,93].
There is currently no clear answer to the question on the reason for increased UAE and the development of albuminuria in HF.On the one hand, albuminuria may be a manifestation of kidney damage: altered function of the semi-permeable glomerular filter and increased intraglomerular pressure [138].
On the other hand, the increased permeability of the glomerular filter for albumin may reflect the presence of generalized endothelial dysfunction [4,139] and be associated with capillaropathy secondary to atherosclerosis [69,91,93].
In diabetic nephropathy at early stages, the development of albuminuria is associated with a change in the charge of anionic components of the glomerular basal membrane.Then, in these patients, the pore size in the glomerular basal membrane increases, which can lead to the progression of albuminuria and the development of macroalbuminuria.In patients with CHF, albuminuria is possibly also first associated with charge-mediated, and then with structural changes in glomerular basal membrane [14].
It was previously assumed that albumin molecules in the process of filtration and passage through the tubules remained unchanged.Then it was found that in patients with DM, before the development of albuminuria, 90-95% of the filtered albumin is destroyed in the tubules to small fragments with a molecular weight of 1-15 kDa, which are not determined by standard immunochemical methods.As kidney damage progresses, the fragmentation of albumin in the tubules decreases, which contributes to the development of albuminuria [138].
In addition, the filtered albumin can be reabsorbed by the cells of the proximal tubules via receptor-dependent endocytosis.Disruption of this process can also contribute to the improvement of UAE and the development of albuminuria [14].
In patients with DM, the relationship of microalbuminuria with changes in Willebrand factor, fibrinogen, thrombomodulin and plasminogen activator inhibitor 1 was revealed.This suggested that disruption of the coagulation and fibrinolytic systems in CVD also contributes to the development of albuminuria [90].
Cystatin C is an inhibitor of serine proteases with a low molecular weight (13 kDa), which is released from various nucleated cells at a relatively constant rate, is freely filtered by glomeruli, not secreted, slightly reabsorbed.Unlike creatinine and blood urea nitrogen, it does not depend on protein intake, muscle mass and catabolic processes [135].Serum cystatin C was supposed to be a more sensitive marker of glomerular filtration disorders than creatinine [109].However, cystatin C did not demonstrate specificity with respect to kidney function.Its level varies with age [159], may depend on immunosuppressive therapy [80], the presence of diabetes, thyroid function [151,155].To increase its diagnostic value, formulas have been developed for calculating GFR based on the concentration of this substance, as well as on its combination with creatinine.
Recently, blood cystatin C has been shown to be an independent predictor of mortality, heart transplantation, and hospitalizations for HF [167].
A close relationship between blood cystatin C and myocardial damage, the level of NT-pro-BNP and ventricular dysfunction was revealed [107,108,113,167].The relationship between the level of cystatin C and the duration of hospitalization in patients with CAD, CHF and AHF was not revealed [53].However, patients with elevated cystatin levels had an increased risk of death and death/re-hospitalizations [54].And cystatin has shown itself as a predictor, stronger than the usual markers of kidney function [107,117,132].In combination of cystatin C with NT-Pro-BNP, the predictive value increased [53][20] [8].
Another new marker of kidney damage is lipocalin, which is associated with neutrophil gelatinase (NGAL).It is a protein with a molecular weight of 25 kDa, which is produced and secreted by immune cells, hepatocytes and renal tubular cells in various pathological conditions [115].Experimental and clinical studies have shown that the expression of NGAL increases in the heart in HF and myocarditis, as well as in atherosclerotic plaques.In clinical studies, blood and urine levels of NGAL were correlated with creatinine or GFR, as well as with clinical and biochemical markers (e. g., NUP) and in some, but not all, studies with the severity of HF [61].Blood NGAL levels have also been linked with increased mortality and the frequency of hospitalizations for HF [44,62,162].Similar results are published for KIM-1 and NAG.KIM-1 is a glycoprotein expressed by proximal tubules in kidney injury.It is referred to as "renal troponin".Its presence in patients with HF and its correlation with NT-proBNP indicates that kidney injury is present in many patients with severe HF [59].The level of KIM-1 in urine increases compared to the control in clinically apparent HF [102].Levels of KIM-1 and NAG were correlated with severity of HF and were predictors of total mortality and hospitalizations for HF [63][64][65][66].Quiescin 6 (QuiescinQ6, QSOX1) is a protein involved in the formation of disulfide bonds.
According to the results of large-scale genomic studies, it (along with BNP) was associated with ADHF.
Its biological significance and feasibility of clinical use is currently being studied [49,126,140].

Renal hemodynamics
Early diagnosis of CRS in patients with CHF can be facilitated by imaging technology [86].Renal hemodynamics can be studied by duplex scanning of renal arteries [2].At the same time, patients with CHF compared with the norm showed a decrease in peak systolic (Vps) and final diastolic blood flow (Ved) rates [171], an increase in pulsation (PI), resistive (RI) indices, systolic-diastolic ratio (S/D), and decrease in renal blood flow parameters [11-14, 17, 171].
Changes in parameters of renal hemodynamics in patients with CHF may be associated with edema of interstitial tissue and changes in the intrarenal vascular bed, such as renal arteriolar hyalinosis and fibroplastic thickening of the intima of small arteries [92, 152,153], which are typical for nephrosclerosis, which develops in severe CHF.Renal hemodynamic disorders in patients with CHF are similar to changes detected in kidney pathology of another etiology.This may be due to the common mechanisms underlying renal hemodynamic disorders in these diseases, which determines the common approaches to nephroprotection [10,14,17].Doppler characteristics of renal blood flow in patients with CHF are interrelated with the generally recognized manifestations of renal dysfunction: serum creatinine concentration, GFR and UAE [14,17].A similar relationship between doppler ultrasonography at different levels of the renal arterial tree with serum creatinine concentration, creatinine clearance and GFR is indicated in patients with hypertension and CRF, secondary to chronic glomerulonephritis, DM and chronic pyelonephritis [14].The relationship of RI and PI with the level of albuminuria was revealed in patients with hypertension [5].
According to B. Krumme, intrarenal resistance indices are not so much specific markers of kidney damage, as a complex indicator of compliance, pulsation and peripheral resistance of the entire arterial vascular bed.The change in compliance and peripheral resistance of the arterial vascular bed is accompanied by similar changes in renal vessels, which contributes to a decrease in GFR and an increase in UAE [106].Thus, cardiorenal syndrome is a natural and integral part of the cardiorenal continuum.It may be only a small part of the cardiorenal-metabolic axis [142]

3 3 . 2 <0. 3
0 times increasing from the baseline OR 4.0 mg/dL (353.6 μmol/L) increase OR Initiation of renal replacement therapy OR In patients younger than 18 years old, a decrease in glomerular filtration rate <35 ml/min/1.73m during 24 hours OR Аnuria during 12 hours