New insights into Alport syndrome have shown that the inherited kidney disease previously thought to be untreatable does respond to therapy, according to a review of Alport developments, prospects and obstacles to treatment.
The review writer, Dr. Clifford Kashtan of the University of Minnesota Medical School, also contended that the medical profession needs to change two terms used to describe the disease to make sure patients don’t fall though treatment cracks.
One term can lead to Alport patients with single, rather than double, gene mutations failing to get treatment or being treated late, Kashtan said. The other can lead to Alport patients receiving the wrong diagnosis for their condition.
Positive Alport developments include the fact that more sensitive and affordable gene sequencing tools have changed scientists’ view of who might have the disease, said Kashton. He has extensive experience in nephrology, or kidney treatment, and is executive director of the Alport Syndrome Treatments and Outcomes Registry (ASTOR).
Studies indicate that Alport patients with one genetic mutation rather than two — whose Alport diagnosis some doctors might miss — should receive closer monitoring and treatment, Kashtan said.
He contended in his review, “Alport syndrome: facts and opinions,” that changing some of the terminology dealing with the disease could help doctors do a better job of treating it.
For example, Alport patients who carry only one mutated gene, but still have symptoms of the disease, should no longer be referred to as carriers, he said, because that label may prevent them from being treated, or result in them being treated late.
He also advised doctors not to use the term thin basement membrane nephropathy when referring to Alport because it may lead to reduced vigilance and inadequate treatment of the disease. Thin basement membrane nephropathy is the most common cause of hematuria, or blood in the urine, but Alport can also cause the condition. So there can be confusion between the two conditions.
Kashtan’s article appeared in the journal F1000Research.
Earlier research suggested that X-linked abnormalities constitute about 80% of all Alport cases, and autosomal recessive and autosomal dominant forms 15%, and 5%, respectively.
But newer studies, using modern sequencing techniques, indicate that the one-mutated-gene form of the disease, whose scientific name is autosomal dominant Alport, is more common than thought.
Since today’s sequencing techniques are fast and affordable, doctors should use them to do an initial screening of patients at high risk of having Alport, such as those with a family history of the disease, Kashtan suggested.
Scientists have long known that boys with X-linked Alport (caused by a mutated COL4A5 gene), or patients with two mutated gene copies of COL4A3 or COL4A4, have more serious kidney disease, and reach end-stage kidney disease earlier in life.
But women with only one affected COL4A5 gene, or patients heterozygous (only one defective copy of the gene) for COL4A3 or COL4A4 mutations have a higher risk of kidney failure. For this reason, Kashtan said it is crucial that these patients also receive proper management.
One way to help women with a COL4A5 gene mutation is for researchers to stop referring to them as carriers, Kashtan said. The term implies they have no symptoms, so they need no monitoring or treatment.
“The designation of a woman with a COL4A5 mutation as a carrier creates an expectation of a benign outcome and a potential impediment to regular monitoring and early therapeutic intervention,” he said.
Kashtan said referring to single-gene-mutation patients with Alport symptoms as people with autosomal Alport syndrome may prompt doctors to treat them earlier. Delaying treatment can lead to worse outcomes.
Educating patients and insurers as well as doctors about this change in terminology would help them become aware that kidney failure is not inevitable in Alport syndrome, Kashtan said.
Another group whose treatment for Alport can be delayed is people those whom doctors have mistakenly diagnosed as having the kidney disease known as thin basement membrane nephropathy. Since many patients with this diagnosis turn out to have progressive kidney disease, Kashtan argues that the diagnosis can lead to insufficient treatment and genetic counseling.
He suggested that patients with known mutations be referred to as people with hematuria with thin glomerular basement membrane. This group should be closely monitored, with yearly analyses of urine and blood pressure to identify those who may benefit from treatment, he said.
As for developments in Alport treatment, Kashtan said studies suggest that earlier use of angiotensin blockade could be even more beneficial to patients with overt proteinuria, or excessive levels of protein in their urine.
An ongoing clinical trial (NCT01485978) is exploring this idea by testing the effectiveness and safety of Ramipril in children with Alport Syndrome, he said.
Angiotensin blockade is a cheap and readily available treatment, noted Kashtan, who said he hopes pharmaceutical companies don’t let fear of high development costs deter them from coming up with better Alport therapies.
The author ended his piece by acknowledging “the families, advocacy groups, clinicians, and investigators who make up the international Alport syndrome community of interest, whose objective it is to optimize outcomes for people with this disease. As in any community, there are differences in opinion and emphasis, but there is no disagreement concerning our ultimate goal.”