It is well known that CRS is characterized by complex interactions between the cardiac and renal mediated by hemodynamic, neurohormonal and endothelial dysfunction. The kidneys play a key role in maintaining hemodynamic balance, which is often disturbed in patients with HF [17, 18]. In addition, kidney disease is an independent risk factor for sudden cardiac death due to the higher frequency of cardiac arrhythmias in patients with CKD .
Literature data indicate that CHF and CKD coexist in 45–63% [20, 21]. In our work, we observed that patients suffered from primary heart injury either due to coronary artery disease or dilated cardiomyopathy. The pathophysiology of CRS-T2 includes renal hyperemia with hypoperfusion resulting from an increase in right atrial pressure and a low cardiac output . In clinical practice, when treating a patient with CRS-T2, we should effectively treat all the pathophysiological causes of cardiorenal syndrome. One of the treatment methods for patients with symptomatic systolic heart failure with concomitant intraventricular conduction block, despite optimal pharmacological therapy is CRT. Resynchronization is one of the most promising therapies with proven benefits for HF patients, such as: improvement of left ventricular function, reduction of CHF symptoms, and reduced mortality from any cause [23, 24]. CRT involves two-chamber stimulation to allow coordinated contraction or greater synchronization between both ventricles. This intervention should improve myocardial function and may be particularly attractive in selected individuals with CKD . It is known, however, that patients who do not respond to such CRT treatment (non - responders) have a much higher risk of re-hospitalization and mortality . Therefore, it is important to identify patients who do not respond to CRT therapy. Meanwhile, few randomized controlled studies have been undertaken to assess the effect of resynchronization in patients with kidney damage [27, 28].
In clinical settings, evaluation of sCr and the eGFR as potential biomarkers of renal function are inaccurate. Many factors independent of renal function affect sCr, including: age, gender, muscle mass, metabolism, drugs, and hydration rate . For these reasons, either the absolute or the relative increases in baseline sCr are indicative of a worsening of renal function. In our study, no differences were observed in the concentrations of sCr and eGFRCKD−EPI in in the entire group of patients both before and 3 months after CRT. Moreover, in our study we did not observe differences in the concentrations of sCr and eGFRCKD−EPI both in the CRT responders group and in the CRT non-responders group. This observation confirms the limited utility of sCR and eGFRCKD−EPI in the assessment of renal function in patients with CRS-T2 receiving resynchronization. Our observations are also confirmed by the other researchers [27, 28, 30, 31].
Therefore, considering the limitations of sCr and eGFR as biomarkers of renal function in people after CRT, we have explored new alternative biomarkers.
NGAL is one of the low molecular weight proteins (25 kDa) whose role in the assessment of renal function after cardiac resynchronization therapy was investigated in a population of patients with CRS-T2. It is a low molecular weight protein associated with human neutrophil gelatinase, whose urine assay is considered a useful indicator of the course of acute kidney injury in the prerenal mechanism . The appearance of this protein in the urine of patients in the early stages of CKD, gives useful diagnostic information as to the sites and degree of injury to the renal interstitium . In patients with CHF, increased uNGAL may be a marker of tubulo-interstitial injury and is associated with an increased risk of worsening renal function, increased hospitalization and overall mortality . In addition, it was observed in a study by Damman et al., that in a group of patients with CHF, an increase in the NGAL-to-creatinine ratio in the urine was an indication of renal tubular injury . In our study, it was observed that in the group of non - responder patients 3 months after CRT treatment, the concentration of NGAL in urine was significantly higher compared with concentrations before CRT. Hence, the increase in uNGAL should be considered as a biomarker of nonresponse to resynchronization 3 months after CRT therapy. The role of NGAL as an indicator of inflammation in the body should also be noted . Studies by other scientists confirm the important role of NGAL in the pathogenesis of atherosclerosis and its associated inflammation [35, 36]. In contrast, slight inflammation is a component of the pathomechanism HF [37, 38]. Therefore, the increased concentration of NGAL in urine that we observed in our study in the group of CRT non - responders may be a sign of more intense systemic inflammation and tubulitis than that observed in the CRT responders group.
Another biomarker whose significant change we observed in the non - responders in our study was urine cystatin C. CysC is a low molecular weight (13-kDa) polypeptide. It is an endogenous inhibitor of cysteine proteinases, produced by all nuclear cells, that is released into the blood. Under normal physiological conditions, CysC is freely filtered from the blood into the primary urine through the glomeruli, then reabsorbed and catabolized by proximal tubules cells, and its concentration in blood serum is not dependent on age, gender, race or body weight. CysC plays the role of an early marker for both acute and chronic kidney injury [39, 40]. In the study by Menon et al., it was observed that in a population of patients with CKD, a higher concentration of serum CysC was associated with an increased risk of renal failure, and overall mortality from cardiovascular causes . However, in the research of Dupont M. et al.  in a group of patients with CHF, the concentration of sCysC was strongly correlated with classic renal function biomarkers like creatinine and eGFR, and remained an independent predictor of serious adverse cardiovascular events. In our study, we did not observe changes in sCysC after CRT both in the whole group and in groups divided according to the response to CRT. However, we did observe a significant decrease in CysC in the urine of CRT non - responders. The relationship we observed was probably due to impaired free sCysC filtration in the glomerulus during the course of CRS-T2 in those patients whose myocardial function did not improve after CRT. Both CysC and albuminuria represent biomarkers of glomerular filtration barrier and its integrity in CRS. According to current recommendations, uAlb concentrations in the daily urine collection of less than 30 mg/dL, and an urinary albumin-to-creatinin ratio (uACR) in the first morning portion of urine of less than 30 mg/g, indicate normal kidney function . Based on 3 large studies conducted in a population of patients with HF, it is known that albuminuria has a strong prognostic value for all-cause mortality, cardiovascular death, and rehospitalization [44–46]. In our study, 3 months after CRT therapy, we observed a decrease in albuminuria in the entire group of CRT responders. This observation was probably the effect of a decrease in glomerular filtration pressure in those patients with an improvement cardiac function in CRT responders group. In nephrological practice, a decrease in albuminuria is an important treatment goal for most nephropathy, due to the proven relationship between albuminuria normalization and long-term improvement in renal function and reduced cardiovascular complications in nephrological patients . Therefore, a significant decrease in uACR three months after CRT, seems to have important clinical significance and may be a useful prognostic tool for cardiologists and nephrologists treating patients with CRS-T2.
Lipocalin-type prostaglandin D2-synthase (PGD2S), also known as β-Trace protein (BTP), is another biomarker whose usefulness in assessing kidney function in patients 3 months after CRT. sPGD2S is a low molecular weight (23 to 29 kDa) glycoprotein that converts prostaglandin H2 to prostaglandin D2. The sPGD2S protein is unique among prostaglandins due to its presence in high concentrations in the mammalian brain. The serum gradient of sPGD2S concentration in the cerebrospinal fluid is 32:1 . Its low molecular weight allows free filtration in the glomeruli, with minimal non-renal excretion and no secretion into the renal tubules. BTP is stable in urine for 24 hours regardless of urine pH . In recent years, sPGD2S has proved to be a promising new endogenous, non-age, gender or ethnic origin glomerular filtration biomarker as an alternative to CysC. In addition to its role in assessing kidney function, sPGD2S is also a new biomarker for cardiovascular risk [49–51]. It was observed in the study by Manzano-Fernández S. et al. that sPGD2S predicts the risk of death and / or HF hospitalization and is superior to standard measures of renal function in patients treated with diuretics due to decompensated HF . In the available literature, we did not find any studies that evaluated the usefulness of sPGD2S in assessing kidneys in response to CRT. In our study, sPGD2S proved to be a biomarker that correlated with classic renal function assessment biomarkers such as sCr and eGFRCKD−EPI. Also sPGD2S, with the highest statistical significance, positively correlated with clinical improvement, assessed on the NYHA scale, in patients 3 months after CRT.
Anemia is one of the more common associated diseases of HF. In the Study of Left Ventricular Dysfunction (SOLVD), anemia occurred in 22% of patients with HF and contributed to the severity of HF symptoms . The incidence of anemia increases with the worsening of cardiac failure symptoms from 9% in NYHA class I to 79% in NYHA class IV . In a retrospective analysis of the SOLVD study results, low absolute hematocrit values in patients with HF were associated with increased mortality and a higher frequency of hospitalization . Hence, in our study, the increased hematocrit observed after cardiac resynchronization therapy in our population would seem to be a good prognostic marker. This conclusion, however, requires confirmation over a longer follow-up period. Anemia pathomechanisms in patients with CHF include overhydration (which is also indirectly demonstrated by a decrease in hematocrit), deterioration of endocrine kidney function (reduced production of renin, increased production of erythropoietin), and the presence of subclinical inflammation associated with CHF . In our study, we observed a statistically significant increase in hemoglobin and erythrocyte counts in CRT respondents. The increase in Hb concentration and the RBC numbers indicate the "silencing" of many pathomechanisms of anemia in patients with improved cardiac performance after CRT. The simultaneous, statistically significant increase in HCT in the CRT responders group may indicate a lower fluid retention in patients with HF after CRT.
Despite some interesting observations and results, in our opinion, the current research work has its limitations. The limitations of the study is that the majority of the biomarkers tested were assessed using methods that could not be used in clinical conditions at the patient's bedside. In the future, it would be reasonable to assess the sensitivity and specificity of the biomarkers sPGD2S, uACR, uCysC, and uNGAL in a larger group of patients after cardiac resynchronization therapy, with a longer follow-up period, and an evaluation of the correlation of results with the frequency of rehospitalization and mortality.