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Cardiorenal fibrosis: Hallmark pathology of cardiorenal failure in CRS

Mr. Abhi Dutta

Author interview: Mr. Abhi Dutta is a PhD scholar in the Cardiometabolic Lab of the School of Biosciences and Bioengineering at IIT-Mandi. He is a UGC-JRF fellow. His primary interest is in understanding the pathological progressive mechanisms of inter-organ crosstalk in cardiorenal syndrome.

Twitter: @DuttaAbhi02

Lab: Dr. Trayambak Basak, Associate Professor, Indian Institute of Technology- Mandi.

Twitter: @trayambakbasak

Our research focuses on inter-organ fibrosis crosstalk mechanisms in cardiorenal syndrome, emphasizing extracellular matrix remodeling and its pathological implications.

What was the core problem you aimed to solve with this research?

Heart failure and renal dysfunction are growing global concerns, contributing significantly to early mortality from non-communicable diseases (NCDs). Changing population dynamics and evolving risk factors have amplified the global burden of cardiorenal syndrome (CRS) in both heart failure (HF) and acute kidney injury (AKI) patients. Each year, approximately 17.9 million people die from cardiovascular diseases (CVDs), 1.7 million from AKI, and a staggering 850 million individuals suffer from renal diseases globally. Notably, more than two-thirds of clinical HF patients also develop renal insufficiency, progressing to pathological CRS.

Traditionally, CRS progression has been attributed to hemodynamic alterations, oxidative stress, inflammation, and cell death. However, from a tissue perspective, the hallmark pathology of CRS is fibrosis in the heart and kidneys, characterized by excessive collagen deposition in the extracellular matrix of CRS patient biopsies. While preclinical research has recently offered some insights into the fibrotic pathways driving CRS-related cardiorenal fibrosis, a complete understanding remains elusive.

Two recent landmark clinical trials, FIBROTARGETS and HOMAGE, focus on alleviating fibrosis in CRS, underscoring the urgent need for a comprehensive understanding of this pathology to bridge the persistent gaps in research.

In this review, we have systematically evaluated and summarized the current knowledge of cardiorenal fibrosis in CRS, focusing on the intricate crosstalk between the heart and kidneys.

How did you go about solving this problem?

To understand the pathophysiology of cardiorenal fibrosis in CRS, a systematic search on PubMed using the keyword “Cardiorenal syndrome and Fibrosis.” Was undertaken. The search yielded 241 published articles. We excluded literature reviews, systematic reviews, books, and documents, narrowing the results to 146 articles.

We thoroughly analyzed these articles and included specific research articles that evaluated cardiac, renal, and cardiorenal fibrosis in CRS. The inclusion criteria involved studies using histopathological analysis, echocardiography, plasma/urine peptidome analysis, and tissue expression-based evaluations of fibrosis. We summarized the findings of the selected articles and used this understanding to describe the pathophysiology of cardiorenal fibrosis.

Additionally, we reviewed and discussed notable and pioneering findings related to CRS. To provide a comprehensive understanding, we attempted to decode the unifying cardiorenal fibrotic pathology, the role of interorgan crosstalk, and the dynamic relationship between the heart and kidneys in CRS.

How would you explain your research outcomes (Key findings) to the non-scientific community?

The inflammatory and fibrotic pathways interact as a unifying pathophysiological mechanism in cardiorenal syndrome (CRS). Injured cardiorenal cells experience oxidative stress and undergo cell death, triggering inflammatory responses. Acute or chronic inflammation further promotes myofibroblasts’ differentiation, proliferation, and activation. These active myofibroblasts produce excessive collagen and other ECM proteins, leading to the remodeling of the cardiorenal ECM. The remodeled ECM becomes stiffer, compromising organ function and increasing the risk of end-stage cardiorenal failure.

In response to any injury, our body’s first line of defense is clearing up the debris and recruiting the immune system to fight off any invaders, which is why inflammation occurs. Inflammatory response to potentially fight any foreign particle invasion and aid in clearing up the injured area for the final stage of the wound healing process. Once the immediate danger is handled, the body transitions to the repair phase which involves the deposition of layers of collagens and other matrix proteins that form a scar to smoothen the injury or cut. However, the body often struggles to regulate collagen deposition in response to injury efficiently. With repetitive insults or injuries, the body can produce excessive collagen, leading to excessive layering and the development of a condition known as fibrosis.

The heart, one of the most vital organs, works relentlessly to supply oxygen and nutrients to every cell in the body. Meanwhile, the kidneys play an equally crucial role in filtering harmful toxins and metabolic waste, ensuring the blood remains clean and balanced. Moreover, the kidneys receive a major chunk of blood that is ejected by the heart in each beat. Hence, an injury to either the heart or kidneys affects the other organ and creates an infinite loop of continuous insults due to circulatory connections beyond tissue-level control.

Such a malicious cardiorenal loop leads to acute or chronic injuries in both organs. While the initial injuries attempt to follow regular healing mechanisms, the disrupted inter-organ hemodynamics and communication prevent the heart or kidneys from successfully resolving the damage through repair. The situation worsens due to an ongoing inflammatory response, which drives a dysregulated and hyperactive repair phase, driven by one of the most fascinating cell types involved in healing, known as ‘myofibroblasts’.

Over time, both the heart and kidneys reach a state where active inflammation and fibrosis occur simultaneously. The tissues in both organs continue to produce excessive collagen and matrix proteins, resulting in thick, stiff tissue that disrupts normal cardiac and renal function. This process ultimately leads to heart failure and renal failure, hallmark features of cardiorenal syndrome.

In cardiorenal syndrome, the dual malfunction of the heart and kidneys makes the situation particularly challenging. Both organs experience a vicious cycle of fibrosis and damage, culminating in cardiorenal failure. To address and improve overall cardiorenal function in CRS, it is critical to study the mechanisms of fibrosis, inter-organ crosstalk, and the nature of fibrosis in this condition.

Although certain drugs have shown promise in preclinical mouse models of CRS, broader investigations are needed to better understand the pathogenesis of fibrosis and to develop effective therapeutic strategies for the clinical management of CRS.

“Deciphering Heart-Kidney Fibrotic crosstalk will unravel key pathological mechanisms in understanding the progression of Cardiorenal syndrome.” — Trayambak Basak

What are the potential implications of your findings for the field and society?

Our study provides a comprehensive and unified understanding of the pathophysiology of heart and kidney fibrosis in CRS. By summarizing and conceptualizing key fibrosis-related findings, including clinical insights, this article offers significant implications for the field and society.

A generalized understanding of fibrosis pathogenesis in CRS has broader applications, including:

  1. Identifying critical research gaps in CRS physiology, precisely aiming at cardiorenal fibrosis.
  2. Highlighting the need for evaluating circulatory biomarkers that indicate fibrosis in CRS, which could be used for clinical diagnosis and prognosis of the adverse onset of CRS-related pathologies.
  3. Guiding the identification of potential therapeutic approaches, ultimately aiding in the treatment and management of CRS patients.

This work has the potential to advance research, improve diagnostic strategies, and contribute to the development of effective treatments, addressing the pressing clinical challenges posed by CRS.

What was the exciting moment during your research?

The most intriguing aspect of our research was uncovering that fibrosis in the heart and kidneys resulting from CRS is deeply intertwined and follows a unified pathological pathway. This involves injury, inflammation, and fibrotic deposition, with progression depending on the specific organs involved. Interestingly, fibrosis in CRS is closely correlated with circulatory levels of profibrotic factors, which supposedly contribute to the ongoing fibrosis, indicating inter-organ crosstalk, essential for the pathogenesis.

As members of a cardiovascular disease lab, this finding sparked curiosity about how two organs can undergo fibrosis simultaneously under the influence of heart failure, significantly increasing comorbidity. This drove us to explore the long-overdue pathophysiology of cardiorenal fibrosis with renewed interest and focus.

Reference: Abhi Dutta, Sanchari Chakraborty, Antara Roy, Anupam Mittal, Trayambak Basak. Tissue fibrosis in cardiorenal syndrome: crosstalk between heart and kidneys, Nephrology Dialysis Transplantation, 2025;, gfaf009, https://doi.org/10.1093/ndt/gfaf009

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