**3. Chronic kidney disease**

CKD is classified into five stages according to the degree of kidney damage or glomerular filtration rate (GFR). Thus, patients with stage five CKD have a GFR of less than 15 ml/min/1.73 m2 and are in the terminal stage of the disease: end-stage renal disease (ESRD). A better understanding of CKD, accompanied by the technological and scientific assumptions of dialysis techniques and kidney transplantation, has significantly improved the prognosis and survival of patients with ESRD. Despite the improvement of technology and clinical and scientific progress in treatment with RRT methods, the frequency of non-renal complications that significantly affect the morbidity and mortality of patients is increasing. The most important are cardiovascular complications, which impact treatment outcomes the most. Cardiovascular diseases are frequent in CKD, especially in ESRD, and are responsible for 40–60% of mortality in that population, according to data from national registries. The importance of cardiovascular diseases has been increasing in recent years with the appearance of an increasing number of elderly patients in whom diabetes and vascular diseases have led to CKD. In recent years, we have witnessed significant progress in understanding the causes and pathophysiology of cardiovascular diseases (CVD) and the possibilities of diagnosis, treatment, and prevention. Knowledge of the pathogenesis of cardiovascular complications, modern diagnostic options, methods of recognition, and treatment of these complications is of great importance to nephrologists and other doctors who care for ESRD patients.

Cardiovascular risk factors appear in the earlier stages of CKD and become more frequent in patients who begin treatment with renal replacement therapy. Risk factors for cardiovascular disease in patients with CKD include those that favor the development of ischemic heart disease, CHF, and left ventricular hypertrophy. Numerous risk factors, of which only general ones present in the general population, cannot explain the high incidence of cardiovascular diseases in patients with CKD. Timely diagnosis of CKD and effective treatment can delay the progression of CKD and the onset of ESRD. In the first and second stages of CKD, patients are usually checked by their family doctor. In the third stage of CKD, it is necessary to pay attention to the early metabolic complications of the disease. The fourth stage of CKD is the introduction to ESRD, and at that stage, the patient needs to be thoroughly familiarized with the RRT methods. Kidney and heart disease interaction manifests in the cardiorenal syndrome, which could significantly cause the worsening of both diseases. The clinical course of CKD is accompanied by numerous complications: renal anemia, mineral-bone disorders, progression of atherosclerosis, deterioration of CHF, development of protein-energy wasting, dyslipidemia, CVD, infections, diseases of the immune system, gastrointestinal disorders, neurological disorders, and others.

*Advanced Treatment of Refractory Congestive Heart Failure by Peritoneal Ultrafiltration… DOI: http://dx.doi.org/10.5772/intechopen.114022*

### **4. Cardiorenal syndrome and chronic heart failure treatment**

#### **4.1 Cardiorenal syndrome: classification and pathophysiology**

Cardiorenal syndrome (CRS) results from inadequate heart and kidney function. It is caused by acute or chronic dysfunction of one of the mentioned organs, which then leads to acute or chronic dysfunction of another organ. The heart and kidneys jointly aim to regulate numerous processes in the human body, such as blood pressure, electrolyte and fluid homeostasis, and endocrine functions through natriuretic peptide, renin, erythropoietin, and vitamin D3. Because of the above, it is unsurprising that one organ's dysfunction leads to another's disorder. The term CRS itself was mentioned in 1951, and since then, numerous papers have been written to explain the pathophysiological mechanisms of the syndrome [13]. One of the most significant works on the mentioned topic was published in 2009. It resulted from the consensus conference of the Acute Dialysis Quality Initiative [14]. The paper above describes five subtypes of the syndrome, depending on whether it is caused by a primary disorder of the heart or the kidneys, and whether the onset is acute or chronic or is a result of a secondary process. Types 1 and 2 imply an acute or chronic heart disorder that leads to kidney dysfunction. Types 3 and 4 represent the opposite situation when acutely or chronically impaired kidney function leads to cardiac dysfunction. Type 5 represents a systemic process that leads to dysfunction of both organs.

Many authors have used observational and retrospective studies as precious sources to determine the epidemiological data of the syndrome. Uduman concluded that CRS type 1 is the most common. Given the lack of data sources, it is tough to distinguish the frequency of chronic types 2 and 4 [15]. A group of authors in India concluded with a cross-sectional study that around half of the observed patients with CRS had type 1, type 2, and type 4 prevalences of around 20% each. Representation of types 3 and 5 was only a few percent [16].

Recent papers by American scientists show how CKD affects 15–20% of adults globally. The leading cause of death in that population is CVD [17]. Also, a group of authors from Japan in the prospective cohort study called CKD-ROUTE have shown that the prevalence of CVD among CKD patients is around 26.8% [18]. The British authors did a similar study called CRISIS, presenting a slightly higher prevalence of 47.2% [19]. Vice versa, studies have shown that the prevalence rate of CKD in HF patients is 11 times higher than in the general population [20].

#### *4.1.1 Type 1: acute CRS*

CRS type 1 represents an acute worsening of heart function caused by AHF, acute coronary syndrome (ACS), or cardiogenic shock, leading to kidney injury and/or dysfunction [14]. All treatment strategies are explained in ESC guidelines, depending on the event's cause. Avoiding all potential nephrotoxins, such as contrast solution, and carefully monitoring cardiac and renal biomarkers is very important. The studies have shown that almost 30% of the patients hospitalized due to AHF had worsening renal function, which led to a higher number of deaths, complications, and longer length of stay [21]. One of the most important mechanisms leading to acute kidney injury (AKI) is lower kidney perfusion due to lower cardiac output and activation of the renin-angiotensin-aldosterone system (RAAS) [22]. Also, the critical mechanism is diuretic resistance of the kidneys, probably caused by sodium retention and the already-mentioned contrast-induced nephropathy.

#### *4.1.2 Type 2: chronic CRS*

Chronic CRS is caused by CHF, which leads to kidney injury or dysfunction. This mechanism has several causes, including chronic hypoperfusion of the kidneys, venous congestion, endothelial dysfunction, subclinical inflammation, and rapid atherosclerosis. Management strategy of this type is the same as the previous one: treat the primary cause of HF according to ESC guidelines and avoid nephrotoxins and prerenal factors that can lead to AKI. Due to CHF as a cause, kidney injury or dysfunction often progresses to CKD. As mentioned before, sometimes it is tough to distinguish the primary cause of CRS, whether CHF or CKD arose and caused CRS type 2 or 4. In some cases, cardiac re-synchronization or RRT can be used. A critical study was published in 2007 in the prestigious American Journal of Cardiology. In this clinical trial, almost 8000 patients with CKD were divided into two groups, depending on their EF. The patients were divided into systolic and diastolic HF subgroups; the cut-off value was EF 45%. The study has shown that CKD-associated mortality was higher in those with diastolic than systolic HF. Precisely, in the diastolic HF group, extra deaths per 10,000 person-years were 71% higher [23].

#### *4.1.3 Type 3: acute renocardiac syndrome*

In types 3 and 4 CRS, as the word order tells, the worsening of the kidney function leads to heart injury and/or dysfunction. Type 3 represents an acute worsening of kidney function or AKI. According to Kidney Disease: Improving Global Outcomes (KDIGO) foundation guidelines, the criteria for AKI are an absolute 0.3 mg/dL rise within 48 hours or a 50% relative rise in serum creatinine over 7 days. It is essential to mention that KDIGO was established by the National Kidney Foundation of the United States, and the mentioned guidelines are from 2012 [24]. The causes of AKI are numerous, and some of them are acute pyelonephritis, glomerular or tubular diseases, hypoperfusion of the kidneys, and obstruction of the urinary tract. Consequences of AKI can be fluid and sodium retention, a disorder of electrolytes or humoral mediators and toxemia. All mentioned could cause ACS, cardiac arrhythmias, or AHF. Sometimes, it is hard to determine whether the heart or kidney acute dysfunction appeared first. An excellent example of the connection between types 1 and 3 is called cardiac surgery-associated AKI. The probable etiology of AKI is renal hypoperfusion during the procedure, as well as hemodilution, hypothermia, and inflammatory responses, which cause constriction of afferent arterioles. After the procedure, a low cardiac output state with persistent hypotension worsens the patient's condition. It leads to CRS type 1 [25]. Consequently, AKI leads to fluid overload, which causes further deterioration of cardiac dysfunction or CRS type 3.

#### *4.1.4 Type 4: chronic renocardiac syndrome*

In some patients, CKD leads to heart disease, injury, and dysfunction. It is described as type 4 CRS. As mentioned before, the leading cause of death in patients with CKD is CVD, and the prevalence of CVD correlates with the stage of CKD. It is essential to define the criteria for CKD as abnormalities of kidney structure or function for more than 3 months. Cause, GFR, and albuminuria categories must be classified [26]. Very often, CKD has a place in cardiology guidelines together with arterial hypertension and diabetes. Those three chronic conditions coexist in most patients, leading to vascular stiffness, cardiac and renal fibrosis, left ventricular

#### *Advanced Treatment of Refractory Congestive Heart Failure by Peritoneal Ultrafiltration… DOI: http://dx.doi.org/10.5772/intechopen.114022*

hypertrophy, sodium, and volume overload. Another important mechanism is anemia in CKD, which can cause peripheral ischemia and activation of RAAS and, consequently, sodium and volume retention. Vascular stiffness is one of the leading causes of CVD. It results from numerous events such as chronic inflammation and oxidative stress of the vessel, mineral and bone disorder, chronic uremia, and hyperphosphatemia, which causes soft tissue calcification.

#### *4.1.5 Type 5: secondary CRS*

The last type of CRS is caused by a systemic condition that leads to heart and kidney injury and/or dysfunction. That condition can be acute or chronic. Some causes are sepsis, amyloidosis, diabetes, and systemic lupus erythematosus. Recently, published papers have shown that sepsis-associated AKI (S-AKI) is a frequent complication with 12% up to 33% incidence [27, 28]. As expected, patients with S-AKI had much worse outcomes. A group of Chinese authors published a systematic review and meta-analysis, which included 47 observational studies and more than 55 thousand patients [29]. The study has shown that 20 factors were statistically significant as predisposing for S-AKI. Some are septic shock, hypertension, diabetes mellitus, abdominal infection, vasopressor administration, etc. Type 5 is probably the most complex type to determine because chronic conditions, such as hypertension, diabetes, or amyloidosis, can be a part of some other CRS subtype. Similar to previous types, to prevent *circulus vitiosus,* the aim is to cure the primary cause.

#### **4.2 Treatment of heart failure with reduced ejection fraction (HFrEF)**

The main goals of treatment of HFrEF (EF ≤ 40%) are reduction in overall mortality, prevention of recurrent hospitalizations, and improvement in quality of life. The cornerstone of treatment consists of pharmacological therapy that should be applied before other interventions, according to the 2021 European Society of Cardiology Guidelines for diagnosing and treating acute and chronic HF and the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

Renin-angiotensin-aldosterone system (RAAS) blockers, beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA) are recommended as the baseline treatment for these patients. In addition to this therapy, the sodium-glucose cotransporter two inhibitors (SGLT2I) are recommended to reduce cardiovascular and all-cause mortality due to worsening HF regardless of diabetes status. A general recommendation is to titrate all these drugs to maximally tolerated doses to improve outcomes (**Figure 4**). Loop diuretics are recommended for the reduction of symptoms and improvement in clinical status. Diuretics reduce the number of hospitalization days but do not decrease the risk of death in these patients. Angiotensin-converting enzyme (ACE) inhibitors are the first group of drugs that reduced mortality in clinical trials, including patients with HFrEF. The primary mechanism of action is a reduction in afterload, preload, and sheer stress on the myocardial wall, which results in increased cardiac output and renal blood flow and a reduction in myocardial remodeling. Angiotensin-receptor blockers (ARB) are recommended to reduce cardiovascular mortality and hospitalizations related to HF in patients intolerant to ACE inhibitors. However, according to clinical trials, ARBs did not show a decrease in all-cause mortality.

In addition to ACE inhibitors with diuretics, BB substantially decreases mortality and morbidity and improves quality of life. It should be initiated immediately in


#### **Figure 4.**

*Treatment of HFrEF for all patients - to reduce mortality.*

hemodynamically stable, euvolemic patients. Bisoprolol, carvedilol, and metoprolol succinate are three BBs that reduce mortality and the number of hospitalization days. MRA, alongside ACE inhibitors and BB, also reduce the mortality risk of hospitalization days and improves symptoms; therefore, they should also be initiated as the firstline treatment in patients with reduced EF, but with caution in patients with impaired renal function and elevated serum potassium. Eplerenone is preferred because of its fewer side effects.

Newer clinical studies with angiotensin-receptor-neprilysin inhibitors, in comparison with ACE inhibitors, showed high superiority in reduction of cardiovascular and all-cause mortality, the number of hospitalizations due to worsening of HF, as well as improvement in clinical status and possible diuretic reduction [30].

Another significant approach to managing HFrEF is cardiac device treatment and rhythm control (**Figures 5** and **6**). Some antiarrhythmic drugs reduce sudden death rates but do not reduce all-cause mortality. Some may even increase mortality in primary prevention of sudden cardiac death (SCD); implantable cardioverter defibrillators (ICD) are used instead to reduce all-cause mortality and prevent SCD in patients with reduced EF, which are expected to survive for more than 1 year with good functional status [31].

In primary prevention, ICD is indicated in patients with symptomatic HF of ischemic etiology and EF of 35% and lower despite OMT in 3 months or more to


#### **Figure 5.**

*Treatment of HFrEF for selected patients -to reduce hospitilisation/mortality.*


#### **Figure 6.**

*Management of comorbidities.*

*Advanced Treatment of Refractory Congestive Heart Failure by Peritoneal Ultrafiltration… DOI: http://dx.doi.org/10.5772/intechopen.114022*

reduce all-cause mortality. The same criteria should be considered in other etiologies of HF as clinical trials in those patients also showed a reduction of all-cause mortality with significant evidence but with lower absolute benefit because patients with nonischemic cardiomyopathy have a lower risk of SCD.

In secondary prevention, it is recommended to use ICD in patients who suffer from a ventricular arrhythmia causing hemodynamic instability unless there is a reversible cause or a recent myocardial infarction occurred in the last 48 hours before arrhythmia. Cardiac resynchronization therapy (CRT) implies the implantation of a threeelectrode pacemaker or implantable defibrillator (one electrode for the right atrium and two for each ventricle) that improves cardiac function and quality of life. This type of therapy showed a reduction of morbidity and mortality in selected patients with vast QRS complexes who are symptomatic and have low EF (<35%) despite optimal medical therapy. In case of high-degree atrioventricular (AV) block and indication for ventricular pacing, CRT is preferred rather than right ventricular pacing, and in patients with worsening HF with EF of 35% and lower who already have implanted pacemaker or ICD, an upgrade to CRT device should be considered [5].

### **4.3 Treatment of heart failure with mildly reduced and preserved ejection fraction (HFmrEF and HFpEF)**

Although there are no specific clinical trials in patients with mildly reduced EF, considering that these patients have some similar clinical characteristics to patients with reduced EF, equal medical treatment can be deemed to act on further myocardial remodeling, prevent worsening HF, and reduce hospitalizations related to HF. There are some retrospective trials in which HFrEF treatment in these patients was potentially beneficial, but more tests are required to draw evidence-based conclusions.

In the DELIVER trial, dapagliflozin (SGLT2I) reduced the combined risk of worsening HF or cardiovascular death in patients with an EF of 40% and more [32].

In the case of HFpEF (EF ≥ 50%), no specific treatment showed a reduction in all-cause mortality. Besides dapagliflozin, empagliflozin reduced the combined risk of the primary outcome (first hospitalization and cardiovascular mortality) in HFpEF patients, mainly due to reduced risk of hospitalization related to HF despite diabetes status [33].

Loop diuretics are used to reduce symptoms of congestion and improve quality of life, but they do not reduce overall mortality. Moreover, in HFpEF patients, there is a general emphasis on screening for comorbidities and reducing and managing underlying risk factors.

#### **4.4 Advanced heart failure management**

Management of advanced HF includes pharmacological therapy, RRT, short- and long-term mechanical circulatory support (MSC), and heart transplantation (HTx) (**Figure 7**). Regarding pharmacological treatment, inotropes (milrinone, dobutamine) and inodilatators (like levosimendan) may improve symptoms, hemodynamics, and cardiac output. It can help improve heart, lung, and kidney perfusion [34]. They can also be used in chronic settings as palliative therapy in patients with no other therapeutic options.

Advanced HF is often characterized by worsening kidney function and diuretic resistance. Sometimes, high doses of intravenous potent diuretics (even in combination, like furosemide with acetazolamide, hydrochlorothiazide, indapamide,

#### **Figure 7.**

*Treatment for selected advanced heart failure patients.*

or mineralocorticoid antagonists) are needed to commence diuresis with relief of symptoms and signs of congestion. When failure of pharmacological therapy occurs, RRT should be considered. It can be used in patients with or without kidney disease. The most used modality of RRT is UF, either by central venous catheter (extracorporeal therapy) or by peritoneal catheter. Extracorporeal treatment is used more in acute settings, and central venous catheters can be placed in the internal jugular, subclavian, or femoral, usually with ultrasound guidance using the Seldinger technique. PUF is a chronic treatment modality in selected patients with resistant congestion, either as destination therapy (in patients not candidates for MCS or HTx) or in patients waiting for MCS or HTx.

In terms of insertions, MCS can be percutaneous, intracorporeal, or extracorporeal, and considering the time of their use, they can be short- and long-term support. Percutaneous MCS are intra-aortic balloon pumps, the Impella family of devices, Tandemheart, and extracorporeal membrane oxygenation (ECMO). ECMO is also considered extracorporeal MCS and can be placed peripherally or centrally. Intracorporeal MCSs are left ventricular assist devices (LVAD), right ventricular assist devices (RVAD), or biventricular assist devices (BiVAD). They are surgically placed.

Short-term MCS is used in a few clinical scenarios in patients that require urgent circulatory support (cardiogenic shock, primarily refractory to medical therapy). It can be used as a bridge to recovery, bridge to bridge, or bridge to decision. Long-term MCS, such as LVAD, can be used as a bridge to HTx, a bridge to candidacy for HTx, or as destination therapy [5].

HTx is the gold standard for treating advanced HF [5]. There must be no contraindication for HTx. Post-transplantation survival is around 90%, with improved quality of life and physical status.

Management of advanced HF is complex, challenging, and expensive. It requires dedicated expertise in highly specialized centers. There must always be a plan for stopping procedures when they become futile due to disease trajectory and disease progression with conversion to symptom control in dignified end-of-life care (palliative care).
