Cardiorenal syndrome: Multi-organ dysfunction involving the heart, kidney and vasculature

Abstract

Cardiorenal syndrome (CRS) is a multi-organ disease, encompassing heart, kidney and vascular system dysfunction. CRS is a worldwide problem, with high morbidity, mortality, and inflicts a significant burden on the health care system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi-organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi-organ transplantation and innovative dialysis modalities have been considered but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrants further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uraemic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

FIGURE 1

Organ crosstalk in cardiorenal syndrome pathophysiology. RAAS and SNS overactivation and natriuretic peptide system (NPS) derangement initiates phenotypic and other molecular changes in the heart, kidney and vasculature. These changes cause organ dysfunction, leading to systemic implications which in turn affect other organs due to bidirectionality

FIGURE 2

Principle of cardiorenal syndrome management. Management of cardiorenal syndrome (CRS) encompasses several important perspectives. Diagnostic measures should aid early and effective diagnosis to address underlying diseases, with special encouragement of multi‐marker use. Treatments may involve pharmacological or non‐pharmacological or a combination of both as warranted by disease progression. Special care should be exercised in patients with systemic disease or other clinical conditions such as anaemia, and the treatment should consider cardiorenal impacts. Palliative care is essential; physicians should not treat just the disease but psychosocial issues that come with having cardiorenal syndrome and seek to improve patient quality of life

FIGURE 3

Therapeutic strategies for protein‐bound uraemic toxin accumulation. Protein‐bound uraemic toxins (PBUTs) are generated in the gut and normally cleared by the kidney. Renal impairment results in PBUT accumulation in the circulation, leading to deleterious effects. Strategies to mitigate the effects of PBUTs can therefore be summarized into (1) inhibition of PBUT production in the gut; (2) inhibition of targeted pathways activated by PBUTs that have gained entry into cells; and (3) improvement of dialytic modalities for PBUT removal

FIGURE 4

Sphingolipid imbalance and potential impacts on cardiorenal and vascular systems. Sphingolipid imbalance has potential negative cardiac, renal and vascular implications. Of particular interest is the non‐reversible conversion of dihydroceramide (dhCer) into ceramide (Cer) within the de novo synthesis pathway mediated by Des‐1, conceivably making Des‐1 an attractive target to restore sphingolipid (SL) imbalance. RAAS, particularly angiotensin II, has been postulated to interact with sphingolipids, though mechanisms remain obscure. N.B. the de novo SL synthesis pathway has been simplified for illustration purposes