Inflammation, regeneration and fibrosis in kidney-related cardiovascular diseases

The main aim of Merle Krebber’s thesis was to gain more insight into the processes involved in kidney-related cardiovascular disease (CFD). Our cell, animal and computer-driven models looked at inflammation, blood vessel and capillary function, regeneration and fibrosis. Leads have also been investigated for new treatments with emphasis on local tissue engineering (in situ tissue engineering) for vascular access.

All kidney-related CVD, such as chronic renal failure and obesity, have in common that the pathology is not limited to the primary organ. In pathological conditions such as CVD, communication between organs, including through signals from circulating monocytes, leads to a vicious circle of damage from inflammation, fibrosis and impaired tissue regeneration. However, the exact spatiotemporal contributions of these processes to impaired organ function remain unclear to date.

The role of inflammation after kidney transplantation

Patients with end-stage renal disease also develop cardiovascular problems, partly mediated by inflammation. Although a healthy donor kidney restores renal function after transplantation, it is unclear whether vessel wall stiffness, left ventricular hypertrophy, and cardiac fibrosis also improve. An important conclusion from the thesis is that inflammation, fibrosis and kidney tissue regeneration after kidney transplantation are determined by complex interactions between the status of recipient and donor kidney. Our rat model of kidney transplantation showed that a healthy donor kidney solely determined normal GFR and reduced kidney-specific inflammation, while recipient status solely determined aortic calcification. Within a period of six weeks, a healthy donor kidney was also able to reverse left ventricular hypertrophy but not fibrosis in the recipient’s heart. With RNA sequencing of cardiac tissue, we have identified molecular targets related to fibrosis formation. In the future, these may function as new treatment methods against cardiac fibrosis in kidney transplant patients.

In situ TE as a treatment for improved vascular access

Regenerative medicine and in situ tissue engineering (TE) may also bring new treatments, such as vascular access, to patients with end-stage renal failure. Vascular in situ TE means that a synthetic blood vessel directly replaces non-functional tissue, after which the body’s own cells slowly line and break down the blood vessel. This has the great advantage that the therapy can be offered ready for use, while the synthetic design changes over time to a body’s own blood vessel. This process has similarities to normal wound healing, with a crucial role for monocytes/macrophages. As patients with renal failure often exhibit a systemic pro-inflammatory profile, we investigated whether vascular in situ TE would lead to the same tissue results in rats with renal failure compared to healthy rats. We saw that the number of immune cells in vascular tissue from both groups was the same. The duration of inflammation and the types of tissue cells present were also similar. For now, vessel in situ TE therefore looks promising for kidney patients. The mechanical stability of the synthetic design appears to be more critical to tissue outcome than renal failure.

The complexity of multiple risk factors

Overall, our models have shown that inflammation, fibrosis and tissue regeneration are clearly related, but not necessarily collectively regulated. For example, in our kidney-transplanted rats, the surface area of ​​capillaries in the heart and the degree of inflammation were similar between hearts with and without fibrosis. For now, the presence of multiple risk factors in CVD patients is therefore a complicating factor in research into which comorbidity leads precisely to which consequence. More insight into (interactions between) comorbidities may reveal unique and overlapping molecular pathways. Combining cross-organ knowledge at the molecular and physiological level is likely to lead to a tailored treatment for the individual CVD patient.

The promotion

Merle Krebber got her Ph.D. on 11 January 2022 with his thesis ‘Reno-cardiovascular disease and regeneration: Focus on interactions with the immune system’ at Utrecht University. The promoter was Prof. MC Verhaar and the co-promoters Dr. JO Fledderus and Dr. KL Cheng, all from the Department of Nephrology and Hypertension, UMC Utrecht.

Krebber is currently continuing his work in nephrology as a postdoc.

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