**5. Ultrafiltration, hemodialysis-induced hypotension and metabolic acidosis**

In patients with end stage CKD, fluid removal is achieved by extracorporeal UF with HD or intracorporeal UF with continuous PD. Unlike intermittent HD, continuous PD is not associated with "stunned" myocardium, which largely explains the slower progression of CHF in patients treated with PD [64]. However, clinical studies showed contradictory results on the benefits of PD. *V.* Panday et al. found in a retrospective analysis of 139 patients with CKD stage 5 and concomitant CHF no difference in two-year mortality, cardiac outcomes, and hospitalization rates between patients on PD and HD [65]. In a study using the Taiwan National Database with over 35,000 patients, I. Wang et al. showed lower survival of ESRD patients and comorbid CHF on the PD treatment [66]. However, the findings could be related to difficulties in hydration management on PD, complete loss of residual renal function, and/or shortcomings and limitations of the analysis performed. In a registry analysis in Lombardy, F. Locatelli et al. found no significant difference in the magnitude of cardiovascular risk in the groups treated with HD compared to that on PD [67]. Recent studies based on the Taiwan National Registry (2016), which included over 45,000 patients with end stage CKD, showed the 29% higher risk of cardiovascular disease in patients treated with HD compared to those treated with PD [68].

The development of intradialysis hypotension on regular HD is caused by uremic polyneuropathy and CHF, when, in response to dialysis UF, the vascular bed fills inadequately slowly, causing hypovolemia and hypotension. Dialysis CRS with hypotension is often complicated by thrombosis of vascular access, resulting in rapid formation of underdialysis syndrome with hypercatabolism. Blood loss and sinus tachycardia combined with hemodialysis-induced hypotension significantly increase the risk of acute coronary syndrome and cerebrovascular accident (CVA). Patients with diabetic nephropathy often develop severe hemodialysisinduced hypotension refractory to conservative therapy. The hypotension can provoke target organ ischemia. Vasopressors and alpha-adrenergic agonists are not safe in treating hemodialysis-induced hypotension. Controlled UF with "dry weight" monitoring by bio-impedance, transfer to PD, or daily (nighttime) HD are recommended.

Metabolic acidosis is common in patientswith ESRD because of a decreased ability to excrete acids and reduced renal synthesis of bicarbonate. It leads to malnutrition, inflammation, bone disease disorders, and even a higher death risk [69]. Significant acid–base variations during dialysis may play an important role in CVD development in HD patients. One study [70] has shown an association between low serum bicarbonate concentrations and cardiovascular disease in patients on dialysis. It is important to avoid large variations in serum bicarbonate levels in dialysis patients because these variations can increase CVD.

### **6. Stenotic atherosclerosis**

MIA syndrome is characterized by rapid stenosing of the major arteries by the progressing atherosclerosis combined with calcinosis. Frequent complications are ischemic kidney disease with uncontrolled renin-dependent hypertension, stenotic

#### *Cardiorenal Syndrome in Patients on Renal Replacement Therapy DOI: http://dx.doi.org/10.5772/intechopen.100493*

atherosclerosis of cerebral arteries with the risk of CVA, ischemic occlusive enteropathy with malabsorption syndrome aggravating PEM and anemia.

In dialysis CRS with the expanded PEM, coronary heart disease (CHD) is typical with unstable angina and elevated blood CRP correlating with LDL levels [71, 72]. Hyperparathyroidism is associated with progressive coronary artery calcification, increasing atherosclerosis [73, 74]. Stenosis of the proximal coronary artery is typical, which causes high mortality in patients on dialysis [75]. Early diagnosis of myocardial infarction in dialysis CRS is difficult because of confounding uremic polyneuropathy, dyselectrolitemia, myocardial calcification, and coronary calcinosis. Coronarography in 60% of patients with CKD stage 5 admitted for regular HD treatment in Japan reveals low-symptomatic stenosis of one coronary artery and of several coronary arteries (multivessel disease) in some patients.

To prevent acute coronary syndrome, risk factors should be addressed in HD: hemodialysis-induced hypotension, sinus tachycardia, blood loss, and anemia. ACE inhibitors reduce the cardiac mortality [76]. Nitrates and beta-blockers are tolerated worse in dialysis CRS because of hemodynamic instability.

Hemodialysis-induced myocardial ischemiamight regress with the use of beta-blockers, which have substantially improved survival in patients with acute coronary syndromes and heart failure. In dialysis patients, carvedilol significantly improved cardiovascular mortality, LV function, and LV morphology. Dialysis patients treated with carvedilol had a 50% lower mortality rate than patients receiving placebo [77, 78]. The efficacy of statins on regular HD has not been proven conclusively, and the incidence of side effects is higher than in the early stages of CKD [79].

Current guidelines by KDIGO recommend not starting lipid-lowering therapy in dialysis patients. These recommendations are based on clinical trials which failed to show that statin therapy is beneficial in reducing cardiovascular mortality indialysis patients, in contrast to the general population [80]. High-density lipoprotein cholesterol (HDL-C) from HD patients compared to healthy controls has been much less effective in cholesterol efflux and regulation of inflammation [81]. HDL-C from HD patients promotes endothelial dysfunction via accumulation of symmetric dimethylarginine (SDMA), which is associated with increased all-cause and cardiovascular mortality [82].

Erythropoietin drugs cannot fully realize their cardioprotective effect because of more frequent side effects of the high doses. Survival rate after acute myocardial infarction is extremely low at conservative therapy of CHD on hemodialysis (by the end of the 1st year, 41%, after 2 years, 27%, after 3 years, 10%). This causes intolerance of uremic myocardium to ischemia with small coronary artery remodeling (uremic small vessel disease) and myocardial stunning on HD. In coronary angioplasty in patients with dialysis-related CRS, the acute postoperative mortality is over 3.5 times higher than the statistical average, and the long-term survival rate after stenting is significantly higher than in conservative therapy [83].

## **7. Progressive CHF with low cardiac output**

CHF in patients on HD is manifested by worsening chronic hypervolemia, causing both circuits decompensation and a significant decrease in ejection fraction preventing effective HD, and development of critical progressive hyponatremia with a high risk of cerebral edema. The 3-year survival rate of patients with CHF on regular HD does not exceed 20%, and sudden cardiac death is most frequent fatality in this group of patients on HD [84].

The rate of sudden cardiac death is 59 deaths in 1000 patient-years in the CKD stage 5D population, whereas it is 1 death in 1000 patient-years in the general population [85]. Patients on dialysis have a high incidence of coronary heart disease, but the rate of sudden cardiac death is disproportionately high compared with the incidence of coronary heart disease in these patients. Even a complete revascularization reduce the risk of sudden cardiac death only in part [86]. Dialysis, especially HD, is a risk factor for sudden cardiac death, providing the highest risk within the first 12 hours after dialysis and after a long dialysis-free interval [87]. Potential mechanisms include volume and sudden electrolyte shifts after dialysis, volume overload, and electrolyte disturbance.

These outcomes largely depend not on the severity of CHD, but on the value of the corrected QT-interval and QT dispersion and are caused by complex rhythm disturbances in dialysis malnutrition (hypercatabolism, acidosis, imbalance of potassium, sodium and calcium in dialysis solution, and hypomagnesemia) [88]. Cardioprotectors, antiarrhythmics, and vasopressors provide only short-term effect; myocardial reperfusion, artificial pacemaker, implanted cardioverterdefibrillator are more effective [84, 88].

PD may be the method of choice in the treatment of patients with CHF, providing effective UF and sodium excretion in the required volumes, especially when using icodextrin solution. In patients with CRS and severe ascites, PD can reduce intra-abdominal pressure. PD in patients with CHF has several advantages: continuous "mild" UF with minimal impact on hemodynamics and reduction of volume overload symptoms; weight reduction and correction of hypervolemia; increase in left ventricular ejection fraction; sodium "sieving" effect and better control of hypernatremia; removal of acute phase proteins, medium-molecular-weight molecules, abscence of pro-inflammatory activation of cytokines; reduction of intraabdominal pressure and improved quality of life in patients with severe ascites; and better control of serum potassium level with the possibility of using aldosterone receptor blockers and ACE inhibitors. Heart transplantation should be used in refractory cases, sometimes in combination with the kidney transplantation.

## **8. Vascular calcification**

Hyperparathyroidism, frequent in RRT patients, is prognostically unfavorable [89]. Elevation of serum fibroblast growth factor-23 (FGF-23) with the development of resistance to it precedes Mineral Bone Disease (MBD). Elevated FGF23 levels were independently associated with LVH.FGF23 caused LVH via FGF receptor-dependent activation of the calcineurin-nuclear factor of activated T-cells signaling pathway [90]. Klotho deficiency and FGF23 elevation are associated with poor outcomes and complications in dialysispatients. Klotho deficiency cause vascular calcification, cardiac fibrosis, and cardiac hypertrophy in patients with CKD [91].

Hyperphosphatemia and parathyroid hormone elevation increase with increasing stage of CKD and correlate with cardiac mortality [92]. This is largely because of vascular calcification, especially pronounced in dialysis patients, which is associated with the use of solutions for PD and HD with increased calcium content.

Vascular calcification (VC) is defined as vascular deposition of calciumphosphate mineral complexes. Traditionally, two forms of calcification are pointed out: 1) intimal calcification in proximity to lipid deposits, clinically relevant in obstructive arterial disease and 2) medial calcification with differentiation of smooth muscle cells into osteoblast-like cells is akin to bone formation, related to several genes as BMP2, Msh Homeobox 2, and gene of alkaline phosphatase [93].

*Cardiorenal Syndrome in Patients on Renal Replacement Therapy DOI: http://dx.doi.org/10.5772/intechopen.100493*

Medial calcification is common in dialysis patients with CKD.VC has a clearrelationship with atherosclerotic vascular disease [94]. Calcification of arterial vessels leads to arterial stiffness, contributes to increased pulse wave velocity, increased cardiac afterload, and thus heart failure [95]. Arterial stiffness is an independent predictor of cardiovascular mortality [96]. Arterial stiffness and medial calcification intensify each other, to create a vicious cycle [97]. Heart valve calcification occurs in stage 5 CKD in up to 88–99% of patients, increasing from 40% of patients in CKD stage 3 [98].

Calcinosis of heart valves leads to the formation of acquired heart valvular disease (aggravating CHF) and increases the risk of infective endocarditis. The extent of vascular calcifications in CKD herald a poor prognosis [99]. Resulting hemodynamic alterations induce left ventricular hypertrophy associated with a decrease in coronary perfusion [100].

In dialysis CRS, active vitamin D metabolites are contraindicated because of the risk of soft tissue calcification (including skin calcification with sepsis). Calciumfree phosphate binders are advisable: sevelamer, lanthanum carbonate [101]. Sevelamer corrects hyperphosphatemia and decreases mortality in dialysis patients by 1.5 times, slowing coronary calcification, reducing blood levels of atherogenic lipids, FGF-23, and pro-inflammatory cytokines [102]. Iron-containing phosphate binders effectively lower blood phosphate levels, but are often complicated by diarrhea and nutritional disorders exacerbation in PEM [103]. Total parathyroidectomy in patients with dialysis cachexia is effective in MBD and CHF progression but carries a risk of acute postoperative complications [104]. An alternative to parathyroidectomy is administration of calcimimetics. Prolonged-release cinalcet reduces the need for parathyroidectomy, slows arterial and cardiac valve calcification, and reduces cardiovascular mortality [105, 106].
