Cardiorenal syndrome type 5 (CRS 5)

What is Cardiorenal syndrome type 5?

Cardiorenal syndrome type 5 occurs when cardiac and kidney injury occur simultaneously.

This can be seen in sepsis, where heart and kidney are involved secondary to a common underlying pathological trigger.

What is the pathophysiology?

The pathophysiology of Cardiorenal syndrome type 5 depends on the underlying disease.

Acute CRS-5 results from systemic processes: for example, sepsis, infections, drugs, toxins, and connective tissue disorders, such as lupus, granulomatosis with polyangiitis, and sarcoidosis.

The temporal course of the development of CRS-5 is variable. For example, in sepsis-induced acute CRS-5, there is a fulminant disease process with an acute impact on both the kidney and heart.

On the other hand, in cirrhosis, CRS-5 has a more insidious onset, and the kidney and cardiac dysfunction may develop slowly until a crucial point is reached and full decompensation occurs.

The development of Cardiorenal syndrome type 5 can be divided into four categories:

  • 1. Hyper-acute, 0 to 72 hours after diagnosis
  • 2. Acute, 3 to 7 days
  • 3. Sub-acute, 7 to 30 days
  • 4. Chronic, over 30 days

Pathophysiological changes in sepsis-related CRS-5 depend on the systemic effects of sepsis, and from cross-talk between the damaged heart and kidney. \In early stages of sepsis microcirculatory perfusion derangements are found despite normal systemic hemodynamics, and they strongly correlate with morbidity and mortality rates.

Sepsis-associated cardiomyopathy represents one of the main predictors of mortality in septic patients.

Both the left and right ventricles can be injured with dilation and decreased EF, and are often unresponsive to fluid and catecholamine therapy. Septic cardiomyopathy, when severe, can mimic cardiogenic shock, but it is usually reversible.

Myocardial blood flow and oxygen consumption do not seem involved in the pathophysiology of septic cardiomyopathy. Proinflammatory mediators and complement factors have been proposed as crucial actors in the development of cardiac involvement during sepsis.

In sepsis-associated Acute Kidney Injury, there are clear signs of intraparenchymal blood flow compromise independent of systemic hemodynamic changes linked to the septic process.

Recent experimental animal data have demonstrated increased kidney vascular resistance and early rises in pro-inflammatory cytokines (IL-6) and oxidative stress markers in animals that later went on to Acute Kidney Injury.

Sepsis affects the autonomic nervous system (ANS), RAAS, and hypothalamus-pituitary-adrenal axis independently, each of which can impact cardiac and kidney function.

The severity of ANS dysfunction correlates with morbidity and mortality. Autonomic dysfunction can be assessed by observing decreased heart rate variability, often associated with the release of inflammatory biomarkers such as IL-6, IL-10, and CRP.

During combined heart and kidney dysfunction, as in sepsis, several cellular and molecular changes occur in both tissues. The activation and induction of cytokines (TNF-α and IL-6) and leukocytes (macrophages, neutrophils, and lymphocytes) are well documented in both the heart and kidney.

Myocardial contractility is decreased due to altered muscle protein expression. Increased secretion of lipopolysaccharide during sepsis alters bicarbonate transport, leading to abnormalities in urine acidification. Lipopolysaccharide also modifies megalin, a glomerular protein leading to increased albuminuria and intrarenal inflammation.

Are there Cardiorenal syndrome type 5 specific biomarkers?

A recent review has pointed out some characteristic biomarkers whose elevation is typical during the septic process: lipopolysaccharide binding protein, pro-calcitonin, CRP, and proinflammatory cytokines (IL-6, TGF-β).

The assessment of cardiac function in Cardiorenal syndrome type 5 is similar to other clinical situations with myocardial dysfunction.

Natriuretic peptides and troponins provide information about cardiac chambers (especially the left cardiac chambers) and myocardial cells damage.

In early stages of the septic process there is a low-output myocardial involvement; after starting fluid therapy, the clinical picture shifts to stereotypical distributive shock, which is characterized by increased cardiac output and systemic vasodilatation.

The diagnosis of kidney involvement in sepsis-related CRS-5 overlaps with other forms of AKI, relying primarily on acute changes in serum creatinine as defined by Risk, Injury, Failure, Loss and End stage (RIFLE), Acute Kidney Injury Network (AKIN), and Kidney Disease: Improving Global Outcomes (KDIGO) criteria.

How is Cardiorenal syndrome type 5 treated?

The primary goal of managing type-5 CRS is maintaining hemodynamic stability and tissue perfusion. Fluid therapy must be carefully managed to avoid fluid overload and other iatrogenic complications.

Since inflammation and immune disorders play an important role in the pathogenesis of sepsis, the removal of cytokines and immunomodulation can be obtained with high permeability membranes, although it is yet to be determined if this translates into better patient outcomes.

To manage heart complications, IV fluids, together with vasopressors, vasodilators, and inotropes, may be required to maintain filling pressures. Vasopressors must be carefully administered because of the depressive effects on cardiac output.

Levosimendan is a novel inotrope with some benefits in decompensated HF: for example, increasing stroke volume, heart rate, and coronary blood flow, while decreasing systemic vascular resistance, systolic blood pressure, wedge pressure, pulmonary artery pressure, and myocardial oxygen consumption. It has been shown to improve symptoms and BNP, although its efficacy is still unproven in CRS-5.

Renal support includes the removal and avoidance of nephrotoxins, the maintenance of adequate perfusion, and, if indicated, early intervention with RRT. There is no role for dopamine for improving kidney hemodynamics.

Likewise, fenoldopam has not shown improved outcomes in Acute Kidney Injury.

Norepinephrine decreases kidney perfusion in normal conditions but increases systemic blood pressure in septic patients, while vasopressin increases diuresis and GFR in septic patients.

RRT with CRRT should be started, when indicated, to control metabolite concentrations and fluid status.

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