Law 2. Outliers by Mukherjee, not Gladwell.

 “Single patient anecdotes are often dismissed…But here, exactly such an anecdote had turned out to be a portal to a new scientific direction.”

In The Laws of Medicine by Dr. Siddhartha Mukherjee, he describes a researcher who noticed an outlier in a clinical trial of a new drug for bladder cancer who responded to the treatment when others had not. Through genetic studies, they were able to find specific mutations in the tumor that conferred a higher likelihood of response, thus opening new avenues for therapy. He argues that you should pay attention to those outliers as much (or more) as you do the rest of the population, because they probably have something very valuable to teach us. I couldn’t agree more.

Pediatric nephrology is full of anecdotes that have informed nephrologists about the most basic kidney physiology. Congenital nephrotic syndrome was first described in the 1950s by Finnish nephrologists. While nephrologists were very familiar with typical minimal change nephrotic syndrome, these extremely rare children were different. They presented shortly after birth with massive proteinuria and died usually within the first year of life from infection. With improvements in supportive care, these children survived to kidney transplantation, however they still didn’t respond to our now standard treatment of steroids for nephrotic syndrome. It wasn’t until 1998, that the gene mutation responsible for this disorder was identified as nephrin (NPHS1), a slit diaphragm protein required for maintenance of the glomerular filtration barrier. This opened up a decade of fundamental research into the role of the podocyte in glomerular disease and helped to inform us about how the glomerular filtration barrier works.

In a less glomerulocentric view of the world (yes, I suppose there is such a thing), children with an unusual form of autosomal dominant hypertension were identified in the 1960s who had early onset disease with hypokalemia, suppressed renin and aldosterone, and responsiveness to triamterene but not spironolactone or dexamethasone. What on earth was going on in the tubule? It was long suspected that there was a defect in a sodium channel leading to salt and water retention, however the exact cause was elusive. Finally, in 1994, mutations in genes encoding the epithelial sodium channel (ENaC) [SCNN1B, SCNN1G] were found to be the cause of Liddle syndrome, opening new doors into research on blood pressure homeostasis and sodium handling in the kidney.

Genetic kidney diseases are one of my favorite parts about pediatric nephrology. You can learn so much about normal physiology when just one little thing goes wrong. But, you have to recognize the outlier and start to think about how they got there. Is this a thing of the past? Have all the genetic causes of disease been discovered already? Of course not. Keep your eyes open for that zebra.


Commentary by Michelle Rheault, Minneapolis