Cardiorenal syndrome type 4 (CRS 4)

Cardiorenal syndrome type 4 (CRS 4)

Cardiorenal syndrome type 4 also called chronic renocardiac disease, is characterized by cardiovascular involvement in patients affected by CKD at any stage.

Kidney dysfunction is an independent risk factor for cardiovascular disease with higher mortality for myocardial infarction and sudden death in Chronic Kidney Disease.

How common is Cardiorenal syndrome type 4

What is the incidence and prevalence of Cardiorenal syndrome type 4?

All patients with CKD are at increased risk of cardiovascular outcomes. This was shown in a meta-analysis by Tonelli et al that looked at 1.4 million patients and found higher mortality rates as eGFR declined, with the odds ratio going from 1.9 to 2.6 to 4.4 for eGFRs of 80, 60, and 40 mL/min, respectively. The single largest epidemiological study to look at this was done by Go et al. on over 1 million people. They found elevated cardiovascular risk in patients with K/DOQI stage IIIb–IV CKD, as well as patients undergoing RRT (hemodialysis, peritoneal dialysis, and transplant).

The Chronic Renal Insufficiency Cohort (CRIC) Study investigators focused their attention on 190 patients with stage III to end-stage kidney disease (ESKD) and performed serial echocardiograms. Over the 2-year evaluation period, during which patients shifted from stage 5 to ESKD, EF dropped from 53% to 50%, and the fraction of patents with an EF less than 50% increased by a fifth.

Pathophysiology of CRS-4 role of risk factors and CKD comorbidities

CRS-4 shows close interactions between CKD and cardiovascular involvement. CKD can indirectly (exacerbating ischemic heart disease) and directly (pressure and volume overload leading to left ventricular hypertrophy) contribute to heart disease. ² Left ventricular hypertrophy is highly prevalent in patients starting hemodialysis and is associated with subsequent hospitalizations for HF. Left ventricular hypertrophy results from comorbid conditions, such as hypertension and calcific valvular disease, which are particularly prevalent in hemodialysis and pre-dialysis patients. Hyperphosphatemia and secondary hyperparathyroidism can cause calcification of coronary vessels and valves due to osteoblastic transformation of vascular smooth muscle cells. Hypertension itself can contribute to vascular calcification. CKD patients, especially those undergoing dialysis, are prone to arrhythmias, especially atrial fibrillation and ventricular tachyarrhythmias.

Almost half of cardiovascular deaths in ESKD are related to cardiac arrhythmia or sudden death. An increased risk for sudden death is associated with prolonged dialytic intervals in subjects undergoing thrice-weekly hemodialysis treatment. This may be due to large shifts of electrolytes and fluids.

In the CRIC study, atrial fibrillation had a prevalence of 18%.

Volume overload is common in CKD due to anemia plus sodium and water retention, and it can be exacerbated by hemodialysis vascular access.

Chronic inflammation, insulin resistance, and lipid abnormalities also contribute to cardiovascular disease in CKD patients.

What are the main available diagnostic tools in CRS-4?

Cardiac function is widely assessed by N-terminal (NT)-proBNP serum levels, while eGFR represents the primary biochemical test to evaluate kidney function.

Kidney ultrasound shows features of CKD, such as thin and hyperechogenic cortex with the reduced corticomedullary ratio.

Echocardiography reveals signs of volume overload, and left and right ventricular dysfunction, especially in ESKD and hemodialysis patients. Increased atrial volumes and pleural or pericardial effusion suggest volume overload. It is quite common to describe valvular calcifications (related to secondary hyperparathyroidism) and signs of right heart dysfunction, such as high pulmonary artery pressure, low tricuspid annulus plane systolic excursion, or right chamber dilation.

How should CRS-4 patients be managed?

The Irbesartan Diabetic Nephropathy Trial study was designed to evaluate renoprotective effects of irbesartan versus amlodipine or placebo in type 2 diabetes. The results showed that the irbesartan group had a lower incidence of HF compared to the amlodipine or placebo groups. The use of carvedilol together with ACE inhibitors or ARBs is associated with better cardiovascular and kidney outcomes in dialysis patients with dilated cardiomyopathy. Although the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events study did not meet its primary end-point, the investigators did note a reduction in the first HF episode with cinacalcet in ESKD patients. Di Lullo et al. found that treating pre-dialysis patients with sevelamer chloridrate (1600 mg/day), a calcium-free phosphate binder, reduced cardiac valve calcifications and delayed kidney function decline was observed. However, Bellasi et al. found an increase in cardiac calcification and no change in CKD progression with the use of phosphorus binders in pre-dialysis patients. (54.5) Dyslipidemia represents another potential target in managing cardiovascular complications in CKD patients. The Study of Heart and Renal Protection (SHARP) trial was the largest trial on statin use in CKD patients and showed a significant benefit with the combination of simvastatin and ezetimibe on major atherosclerotic events, although all-cause mortality was not improved.