The cause of Focal Segmental Glomerulosclerosis is  unknown, but advances in clinical studies link the disease to reflux  nephropathy . Reflux nephropathy is a condition in which kidneys are damaged from a backward influx of urine into the kidney. Valves that connect the kidney to the ureter evolved to keep urine flow in a one-way direction. However, genetic abnormalities damage these valves, allowing urine to relay back into the effected kidney. Because there is more pressure contained in the bladder, the urine that is returned to the kidney causes scarring after prolonged exposure without treatment.

　　Other causes of FSGS involve the abnormal length of the ureter that extends into the bladder. Normally, the ureter is buried well into the bladder with a genetically programmed length. When abnormalities in bladder tunnels are present, the pressure in the bladder overcomes the closed structure and pushes urine back into the kidneys. A shortened ureter also facilitates the opened tunnels giving way to the pressure.