Kidney scarring is quietly shutting down the organs of hundreds of millions of people worldwide, and no drug exists to stop it. This matters because chronic kidney disease (CKD) has no treatment that specifically prevents the irreversible scarring—fibrosis—that leads to kidney failure. Patients who reach that point need dialysis or a transplant, but donated kidneys themselves often develop scarring and fail. The researchers will test whether avacopan, a drug that blocks an immune sensor called C5AR1 on kidney macrophages, can halt this process. They will recruit kidney transplant patients with scarring but no rejection, randomly assign them to avacopan or placebo for 12 months, then give all participants avacopan for another six months. If avacopan works, it could become the first therapy to prevent kidney failure in CKD, regardless of the underlying cause—whether from high blood pressure, diabetes, or autoimmune inflammation. That would reduce the need for dialysis and transplants, easing pressure on organ waiting lists and improving outcomes for millions of patients worldwide. The team will also analyse RNA from individual kidney cells to map exactly how the drug alters immune and tissue behaviour, providing a mechanistic blueprint for future drugs targeting the same pathway.
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Context: The kidneys play a vital role in cleaning the blood and controlling the body's water balance. Unfortunately, their function may be affected by a number of common diseases including high blood pressure, diabetes and autoimmune inflammation. Ultimately, these kidneys diseases cause scarring, leading to poor kidney function or 'chronic kidney disease' (CKD for short), a condition that becomes more common with increasing age, and affects hundreds of millions of people worldwide. In some patients with CKD, progressive scarring can lead to kidney failure, which is treated with blood cleaning therapy (dialysis) or a kidney transplant. However, because of organ shortage, and long waiting lists for a transplant, there is an increasing use of kidneys from older donors or those with medical problems that cause kidney damage. Therefore, some of these kidney transplants can also be affected by CKD and develop progressive scarring post-transplant, that ultimately leads to graft failure. The Challenge: There are currently no treatments that specifically prevent the development of irreversible kidney scarring in either native or transplanted kidneys. Project aims and outline: We will recruit kidney transplant patients with CKD that have scarring on a biopsy sample, but no rejection. We will ask them if they would be willing to try a new, immune-modifying treatment called avacopan. Avacopan blocks an immune sensing molecule (C5AR1) that we have found on the most abundant immune cell type found in kidneys - macrophages. Macrophages can contribute to kidney scarring. Patients entered into the study will be randomly assigned to receive avacopan, or a placebo tablet for 12 months. After the 12 months all patients (whether they were on placebo or avacopan at the beginning) will be given avacopan for another 6 months, so that all patients recruited can potentially benefit from the treatment. To understand how avacopan is working, and whether it can be used in CKD, we will take kidney tissue, as well as blood and urine samples. We will use standard measures of kidney function and kidney scar tissue, as well as new types of technologies to analyse immune and tissue cells, to produce a clearer picture of the effects of avacopan treatment. Some of these new technologies use information about how the genetic code of cells is translated into action, by measuring genetic messenger molecules called 'RNA'. The Clatworthy lab are international experts in studying RNA, down to the level of individual immune or tissue cells, and they can also match up this information with the location of these cells in the kidney, and to changes in blood and urine, providing a comprehensive view of the effects of the drug. Applications/benefits: This information will tell us whether avacopan (or other drugs affecting this immune pathway) could be used to prevent kidney failure in patients with CKD regardless of the underlying cause, helping millions of patients worldwide.
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