Issue: November 2020
Disclosures: Disclosures: Glassock and Mehr report no relevant financial disclosures. Rheault reports the University of Minnesota receives financial support from Reata Pharmaceuticals for clinical trial work on bardoxolone methyl. Mariani is on the CKD advisory board of Reata. She has received grant funding from Boehringer-Ingelheim.
November 12, 2020
5 min read
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Clinical trials, consortiums place glomerular disease in the spotlight

Issue: November 2020
Disclosures: Disclosures: Glassock and Mehr report no relevant financial disclosures. Rheault reports the University of Minnesota receives financial support from Reata Pharmaceuticals for clinical trial work on bardoxolone methyl. Mariani is on the CKD advisory board of Reata. She has received grant funding from Boehringer-Ingelheim.
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Glomeruli play a vital role in the kidney filtration process, and failure of this network of small blood vessels is a key determinant in progression toward end-stage kidney disease.

However, research into the causes of nephropathies has been on the back burner until now.

“Clinical trials for glomerular diseases are leading a renaissance in nephrology,” Ali Poyan Mehr, MD, regional director of the Glomerular Disease Program at Kaiser Permanente Northern California, told Nephrology News & Issues. “Ten years ago, we had nothing but hypothesis. Today we have a plethora of clinical trials, and hope.” Mehr directs two clinical trials at Kaiser Permanente to treat nephrotic syndrome. “Not all of these treatments will make it to the market, but there is a lot of hope and there is a lot of optimism that we will see alternatives to what we can prescribe now” to treat glomerular diseases, he said.

One of those possibilities is a phase 2/3 trial on the use of bardoxolone methyl in patients with Alport syndrome. The international, multicenter trial is conducted by Reata Pharmaceuticals and will study the safety, tolerability and efficacy of bardoxolone methyl in qualified patients with Alport syndrome. The phase 2 portion of the clinical trial, according to clinicaltrials.gov, will be open-label and is enrolling up to 30 patients. The phase 3 portion of the trial will be double-blind, randomized and placebo-controlled and will enroll up to 180 patients.

“There is a great deal of interest in Alport syndrome, IgA nephropathy, lupus nephritis, [focal segmental glomerulosclerosis] FSGS, C3 glomerulopathy, vasculitis and membranous nephropathy,” Richard J. Glassock, MD, a nephrologist working with Mehr on a program aimed at educating fellows about glomerular disease, told Nephrology News & Issues. “There are about two dozen small and large bio-tech and pharmaceutical companies pursuing novel drugs that are now in phase 2 and phase 3 trials.”

Michelle Rheault, MD, an associate professor in the department of pediatrics and director of the division of pediatric nephrology at the University of Minnesota, said she is optimistic about the development of new approaches for the treatment of Alport syndrome and other glomerular diseases.

Source: Alport Syndrome Foundation.

Early detection

Diagnosis and treatment of the many variants of glomerular diseases are complex. “Glomerular diseases ... share clinical presentations, yet result from multiple biological mechanisms,” Laura H. Mariani, MD, and colleagues wrote in 2018 in the American Journal of Kidney Diseases. “Challenges to identifying underlying mechanisms, biomarkers and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death.”

Mariani is an investigator at the Data Coordinating Center at the University of Michigan for a study funded by the National Institutes of Diabetes and Digestive and Kidney Diseases that will take a closer look at glomerular diseases. The study, called Cure Glomerulonephropathy, or CureGN, has enrolled 2,447 adults and children with a diagnosis of minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy or IgA nephropathy (including IgA vasculitis).

“Patients are followed with detailed clinical data, biosamples, digital kidney biopsy images and patient surveys, building a resource for the nephrology research community that can be used to answer a wide range of questions that impact care in glomerular disease,” Mariani told Nephrology News & Issues. “That includes gaining a better understanding of disease diagnosis, including integration of clinical, pathologic, molecular and genetic biomarkers to improve classification.

“We also hope to provide better prognostic information, both in terms of kidney function and complications of the disease and its current treatments. And we anticipate that the biosamples will be used to understand disease pathogenesis and help to guide the development of new, less toxic therapies,” Mariani said.

Four participating clinical center networks, managed by Columbia University, Midwest Pediatric Nephrology Consortium, University of North Carolina, and University of Pennsylvania, represent 66 clinic sites in the United States and abroad in the study.

Members of the group have already had articles published using the CureGN data.

Physician education

The National Kidney Foundation reports that glomerulonephritis is the third leading cause of end-stage kidney disease in the U.S. However, because individual glomerular diseases are rare, there is variability in the level of comfort in treating these diseases, especially if first line therapy is unsuccessful. Mehr established a regional program to engage nephrologists in Northern California to discussing complex cases.

“Kaiser Permanente has approximately 4.5 million members in Northern California,” Mehr said. “It is the place where the rare disease is common.”

He meets once per week with 13 nephrologists to review difficult cases and discuss treatment options. Those gatherings are a smaller version of GlomCon, a web-based consortium that Mehr started in 2016 to share information on an international level about glomerular disease.

“It is a broad, international collaborative that is grass-roots based,” Mehr said.

The group has also launched its first fellowship program. Fellows and experienced nephrologists can participate to gain more education about glomerular diseases. The program had 12 slots available, but more than 450 applicants were received.

“There were a substantial number from the United States,” Mehr said. “We had to make some difficult choices.” Eventually, they settled on accepting 52 applicants.

Glassock is one of the educators in the program.

“Social media with interactive real-time formats has a great future for education of physicians in training on the nuances of glomerular disease,” he told Nephrology News & Issues. “The GlomCon fellowship is at the vanguard of this new era in education. Let’s hope that medical schools upgrade their efforts in teaching their students about the basics so that their graduates can take full advantage of how they will learn new details later in their medical educational experience.”

Alport syndrome

While the different types of glomerular diseases can be treated with immunosuppressant medication until better treatments come along, Alport syndrome is somewhat unique, pediatric nephrologist Michelle Rheault, MD, told Nephrology News & Issues.

“It has a genetic component, so it can be diagnosed early on,” Rheault said. “But we cannot treat it with immunosuppressants like other glomerular diseases.”

The genetic connection can be difficult to find depending on which mutation of the gene patients have, Rheault said.

“There are different types of Alport syndrome. It can be either X-linked, where it is mostly found in males in the family, or it can be recessive, so you are the only patient in the family, or dominant,” she said.

Microscopic hematuria is a common sign that Alport syndrome may be present, but “pediatricians may not recognize that and may ignore it” as a risk for Alport syndrome. The other sign – progressive hearing loss – may be a more obvious indicator.

“If there is a history of Alport syndrome in the family, an audiologist may make the connection,” she said. The other sign is development of proteinuria.

While immunosuppressant drugs are not effective, new research shows ACE inhibitors can be used safely and can extend kidney health, Rheault said. In addition, results from the EARLY-PROTECT trial with ramipril showed it was likely effective in decreasing the risk of progression in early stages of the disease, diminishing the slope of albuminuria progression and the decline in GFR, she said.

Looking forward

Much of the effort to diagnose glomerular diseases more effectively is understanding that dialysis should not be the default treatment.

“The field is evolving fast. The management of these disorders is becoming more complex,” Mehr said. “But one of the most important aspects of this work is that we are no longer satisfied with just having the option of dialysis. Kidney disease matters. Treatment of kidney disease matters more and more.” – by Mark E. Neumann