Nephrotic syndrome (NES) is a kidney condition that causes proteins to leak from organs into the urine. This is caused by defects in the filtration system of the kidney and, in some cases, this can lead the patient to develop kidney failure. Most patients have typical clinical manifestations, including massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Patients without typical NES and 24-hour urine protein <3.5 g/day are defined as having membranous nephritis (MEN) with non-nephrotic proteinuria (NNP). Glomerular sclerosis (GLS) is a pathological damage that can be divided into spherical sclerosis and segmental sclerosis. It is characterized by reduced glomerular endothelial cells, accumulation of mesangial matrix, proliferation of podocytes, and thickening of the basement membrane. It is an important pathologic basis for end-stage CKD and the outcome of nearly all progression of chronic kidney disease.
Previous studies have shown that deposition of subcutaneous immune complexes on the glomerulus can damage podocyte attachment and basement membrane, and exfoliation of epithelial cells and basement membrane can lead to GLS. Although a rare disease, NES affects around 10,000 people each year in the UK with the majority of cases linked to non-genetic causes. The impact it has on patients, many of whom will be children, can be devastating. With funding from the charity Kidney Research UK, scientists at Bristol Medical School have identified a new treatment pathway for patients with non-genetic (idiopathic) nephrotic syndrome (INS), targeting a yet unknown factor that causes progression towards renal failure. Scientists knew there could be one or more factors in the blood that caused the kidneys to fail in INS patients, but so far they have been unable to find out exactly what they might be.
However, the team tried a different approach as they tried to identify how the factor worked and attempted to prevent it from activating. Using blood plasma from INS patients who were undergoing dialysis, the Bristol team wanted to confirm whether a receptor known as PAR-1 works together with the unknown factor. The researchers used the patients’ plasma and a separate PAR-1 activator to study its effects on kidney cells in the laboratory. Both treatments caused discomfort in the kidney cells. Having confirmed the link between PAR-1 and the unknown factor, their findings suggest that drugs to block the receptor could be a viable option. Steroids are currently the most effective treatment for INS, but these have unpleasant side effects and don’t work equally well in all patients. Also, with the unknown factor circulating in the patient’s blood, a transplant may offer some respite,
However, the disease often comes back and damages the new kidney, sometimes almost instantly. This finding could revolutionize treatment options for INS patients and offers the potential to eradicate steroid use and make transplantation a more viable option. In fact, using anti-PAR-1 therapeutic options would not only eliminate the need for steroids, but would also allow transplantation to be a more beneficial treatment since newly transplanted kidneys would no longer be susceptible to the effects of the unknown factor. Anti-PAR-1 treatments are currently undergoing clinical trials for other health conditions to ascertain their efficacy and safety. The work conducted in Bristol opens new avenues for testing these treatments for patients with non-genetic (idiopathic) nephrotic syndrome. If the safety of these treatments can be confirmed, patients with INS could be taken off steroids and put on new treatments in the next few years.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
May CJ et al. Kidney Internat 2023 Mar 20 in press.
Sun J et al. Reanl Failure 2023; 45(1):2188088.
Ye Q et al. Clin Immunol. 2023 Apr; 249:109273.
Wei C et al. Int Urol Nephrol. 2021; 53(3):505-14.