Stories about: Friedhelm Hildebrandt

Galloway-Mowat mutations have dual target: kidney cells, neurons

Evidence of disease in GAMOS patients
Disease phenotype of GAMOS patients. Left: Kidney cells show signs of nephrotic syndrome. Right: Anomalies in brain development

With the help of more than 100 clinical collaborators around the world, Friedhelm Hildebrandt, MD has received thousands of blood samples from patients with nephrotic syndrome. They have helped Hildebrandt’s lab determine several underlying causes of this serious kidney disorder, in which high levels of protein are expelled in the urine.

“Nephrotic syndrome is not one disease; in fact, we already know that it is 55 different diseases,” says Hildebrandt, chief of the Division of Nephrology at Boston Children’s Hospital.

Over the course of time, Hildebrandt’s lab has discovered 35 of the more than 55 genes that can cause nephrotic syndrome. Identifying the different genetic pieces of the puzzle can help tailor a precision medicine approach to treating patients.

The latest piece, published earlier this month in Nature Genetics, is a set of four single-gene mutations that cause Galloway-Mowat syndrome (GAMOS) a rare disorder causing early-onset nephrotic syndrome and, often, microcephaly (abnormally small head size). Until now, the genetic changes underlying GAMOS and why they affect two disparate organs — the brain and kidney — have not been well understood. 

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Personalized medicine for kidney stones

Kidney stones

One in 10 people in their lifetime will have a kidney stone — a small, hard deposit of mineral and acid salts that can obstruct the drainage of urine, cause intense pain and, if not treated properly, lead to long-term kidney issues. Kidney stones are relatively uncommon in children, but the number of cases over the past two decades has risen.

The treatment for kidney stones has remained the same for decades — increased fluid intake, limited sodium intake, diuretics and potassium citrate therapy. Lifestyle factors are typically blamed for kidney stones, yet twin studies suggest a genetic component. In fact, new research supports pursuing a genetic diagnosis for this common condition, especially in kids.

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Nephrotic syndrome: Unexpected insights from genomic sequencing

nephrotic syndrome - SNRS -a glomerulus
Magnified views of a glomerulus from a rat kidney. (Source for all images: Braun DA; et al. Nat Genet 2015 doi:10.1038/ng.3512)

About 1 in 5 cases of the kidney-destroying condition nephrotic syndrome don’t respond to steroid treatment. They are a leading cause of end-stage kidney failure in children and young adults, who are quickly forced to go on dialysis or wait for a kidney transplant.

Thanks in large part to the lab of Friedhelm Hildebrandt, MD, chief of the Division of Nephrology at Boston Children’s Hospital, more is becoming known about this severe condition. Mutations in more than 30 genes have been implicated, all causing dysfunction of glomeruli, the kidney’s filtering units, specifically in cells known as podocytes. Test panels are now clinically available. Yet, in 70 percent of patients, the causative gene is still unknown.

A new study by Hildebrandt and colleagues in this week’s Nature Genetics pinpoints three new, completely unexpected genes, revealing the power of whole-genome sequencing and potentially opening a new treatment route for at least some steroid-resistant cases.

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A 28-gene test for kidney disease

dialysis nephrotic syndrome
Understanding the genetic causes of nephrotic syndrome could lead to better drug treatments that reduce the need for dialysis or a kidney transplant. (Image: Wikimedia Commons)

Nephrotic syndrome is one of the worst diseases a child can have. It strikes the filtering units of the kidney, structures known as glomeruli. There’s no good treatment: Steroids are the main therapy used, but 20 percent of cases are steroid-resistant. In the syndrome’s most severe form, focal segmental glomerulosclerosis (FSGS), children are forced onto chronic dialysis and often require a kidney transplant—often only to have their disease recur in the new organ.

Until recently, no one knew what caused nephrotic syndrome; the first causative gene was identified just a dozen years ago. The lab of Friedhelm Hildebrandt, MD, PhD, at Boston Children’s Hospital is one of a handful that’s been chipping away at the others.

Hildebrandt receives, on average, one blood sample a day from patients all over the world.

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