Serendipity and Prof David Salant's odyssey to find a human autoantigen

Professor David Salant

He spoke on serendipity and his personal odyssey to find a human autoantigen and described how it was as a medical student at Wits and later as a registrar at the Johannesburg General Hospital that he became fascinated by disorders of autoimmunity.

He was puzzled in particular by one of the persistent conundrums of modern medicine: the so-called collagen or autoimmune diseases like rheumatoid arthritis, lupus erythematosus, rheumatic carditis and various forms of nephritis, where the body's immune system attacks and destroys healthy body tissue by mistake.

For many years, identifying the target in the organs under attack has been considered a holy grail of medical science.

While in the Renal Unit in Johannesburg, Salant treated a 35-year-old male patient who was diagnosed with membranous nephrology and ended up on dialysis. According to Salant, what followed has been something of a personal odyssey.

Among the organ-specific autoimmune diseases is a condition called membranous nephropathy, a relatively common form of kidney disease that intrigued Salant. However, the death of his patient gave him the impetus to learn more about this particular autoimmune disease.

Membranous nephropathy is a leading cause of nephrotic syndrome in adults, a condition that leads to total body swelling (oedema) because of leakage of albumin from the blood plasma into the urine (proteinuria) when the glomeruli, the filtering units of the kidney, are damaged. Various diseases such as diabetes, infections such as HIV, hepatitis B or C, lupus erythematosus, may cause glomerular injury and nephrotic syndrome and other diseases limited to the kidney. However, membranous nephropathy is among the most frequent causes, especially in adult males in their 40s to 60s.

It has a variable clinical course. About 15-30% of patients may enter spontaneous remission, up to 30% progress to end-stage kidney disease and the remainder have persistent proteinuria unless treated with potent immunosuppressive agents. It has been reported that 30-50% of patients with end-stage membranous nephropathy who receive a kidney transplant will experience a recurrence of the disease in the allograft.

Until recently, the diagnosis of membranous nephropathy has relied exclusively on kidney biopsy and there was no immunoassay available for the diagnosis or to detect active disease.

Extensive research

Supported by grants from the National Institutes of Health, Salant over the years has conducted extensive research on immune disorders of the kidneys; his work has focused on mechanisms of immune deposition and the role of complement in glomerular diseases and, on the structural biology of the podocyte. He was one of the earliest proponents of the notion that podocyte injury forms the basis of most, if not all, proteinuric kidney diseases. In particular, he was among the first to identify the podocyte as the primary target of injury in antibody-mediated glomerular injury.

Salant and his colleagues recently made a remarkable discovery by identifying the major target autoantigen in human membranous nephropathy.

Discovery leads to simple means of diagnosis

On his journey to the discovery of a human autoantigen, Salant said, "At times, as a result of happenstance, I have had the luck of being in the right place at the right time. At others times I have benefited from true serendipity."

Salant's discovery of the protein that is the target of this common form of autoimmune kidney disease has yielded a simple means to diagnose the condition and may lead to more specific treatment than cortisone and other immune suppressant drugs commonly used today.

There are still many questions, but this means there is now a useful diagnostic test in cases that are not amenable to kidney biopsy and a means to follow the response to treatment and possibly to predict the recurrence of membranous nephropathy after transplantation.

Salant credits his clinical education at Wits and the lasting friendships he made there that gave him the ability to take the first steps on an odyssey that has brought him much success. He is looking forward to the rest of the journey and what new discoveries the future may hold.