The main aim of Merle Krebber’s thesis was to gain more insight into the processes involved in renal-related cardiovascular disease (CFD). Our cell-, animal- and computer-driven models looked at inflammation, function of blood vessels and capillaries, regeneration and fibrosis. Leads have also been investigated for new treatments with an emphasis on local tissue engineering (in situ tissue engineering) for vascular access.
All renal-related CVD, such as chronic renal failure and obesity, have in common that the pathology is not limited to the primary organ. Under pathological conditions such as CVD, communication between organs, including through signals from circulating monocytes, leads to a vicious cycle 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 failure also develop cardiovascular problems, partly mediated by inflammation. Although a healthy donor kidney restores kidney 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 renal tissue regeneration after kidney transplantation are determined by complex interactions between the status of the recipient and the donor kidney. Our rat model of kidney transplantation showed that a healthy donor kidney determined exclusively normal GFR and reduced kidney-specific inflammation, while recipient status determined exclusively aortic calcification. Within a period of six weeks, a healthy donor kidney was also able to remedy left ventricular hypertrophy but not fibrosis formation in the recipient’s heart. With RNA sequencing of cardiac tissue, we have identified molecular targets related to fibrosis formation. In the future, these could serve as new treatment methods against heart fibrosis in kidney transplant patients.
In situ TE as a treatment for improved vascular access
Regenerative medicine and in situ tissue engineering (TE) could also bring new therapies, such as vascular access, in 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-to-use, while the synthetic design eventually changes into a body’s own blood vessel. This process has similarities with normal wound healing, with a crucial role for monocyte/macrophages. Since patients with renal failure often display a systemic pro-inflammatory profile, we investigated whether vascular in situ TE would lead to the same tissue outcomes in rats with renal failure versus healthy rats. We saw that the number of immune cells in the vascular tissue of both groups was the same. Also, the duration of inflammation and the types of tissue cells present were similar. Thus, for now, vessel in situ TE seems promising for kidney patients. The mechanical stability of the synthetic design appears to be more determinative of tissue outcome than renal failure.
Complexity of multiple risk factors
Overarching, our models have shown that inflammation, fibrosis and tissue regeneration are clearly related but not necessarily collectively regulated. For example, in our kidney transplant 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 exactly leads to which consequence. More insight into (interactions between) comorbidities can reveal unique and overlapping molecular pathways. Combining organ-transcending knowledge at the molecular and physiological level will probably lead to a tailor-made treatment for the individual CVD patient.
The promotion
Merle Krebber obtained her PhD on January 11, 2022 with her 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 her work in nephrology as a postdoctoral researcher.