Solving the Diagnostic Challenge is Key to Managing Primary Hyperoxaluria Type 1 (PH1)
Sponsored by Alnylam Pharmaceuticals, Inc. Intended for U.S. audiences only.
Jack, diagnosed with primary hyperoxaluria type 1 (PH1)
Jack had a history of periodic stomach and bladder pain, unexplained vomiting and susceptibility to dehydration and fatigue in hotter weather, but in isolation, none of these symptoms seemed serious enough to raise concerns according to his mother, Courtney. At age 8, Jack’s symptoms worsened: His pain moved to his hips and back, and he began to experience dizziness and painful urination.
A trip to urgent care turned into a visit to the emergency room, and initial testing suggested kidney abnormalities. An ultrasound was ordered, revealing kidneys riddled with stones – highly unusual for a child his age. His local hospital didn’t have instruments small enough to address his many stones, so Jack was referred to a major medical center in Pittsburgh, where multiple tests, including a CT scan, were ordered, but none were conclusive. Jack was treated for his kidney stones and sent home without a confirmatory diagnosis.
The stomach pain and kidney stones returned, so Jack’s parents brought him back to Pittsburgh, where the on-call nephrologist developed a working theory of the case. He ordered additional tests, which found elevated levels of oxalate in Jack’s urine and blood. Subsequent genetic testing confirmed the diagnosis: primary hyperoxaluria type 1 (PH1) – a rare, progressive, inherited metabolic disease.1-3
Importance of Early PH1 Detection and Management
Normally, the liver enzyme alanine:glyoxylate aminotransferase (AGT) processes glyoxylate, which is generated by glycolate oxidase (GO).2,3 In PH1, mutations in the AGXT gene impair the function of AGT, causing glyoxylate to instead be converted to oxalate.2 Oxalate combines with calcium, creating calcium oxalate crystals which can aggregate to form kidney stones or be deposited into kidney tissue, leading to nephrocalcinosis.2,4 Over time, these oxalate deposits can cause a progressive decline in the glomerular filtration rate and develop into end-stage kidney disease (ESKD) and systemic oxalosis.2,4-6
Kidney stones are the most common clinical manifestation of PH1 and the one that most often leads to diagnosis, though not all patients may be stone formers.5,7,8 Patients may also present with dysuria, UTIs, difficulty with urination and in infants, failure to thrive.1,2
PH1 affects people of all ages, from infants to adults.1 Approximately 1 to 3 of every million people in Europe and North America have PH1, with a higher prevalence of the disease in people of Middle Eastern and North African descent.1,3,9,10
As Jack’s story illustrates, one of the challenging aspects of the disease is the heterogeneity of symptom presentation, and his relatively quick diagnosis may not always be the case. In fact, for many patients, PH1 is not diagnosed immediately, with a 5.5-year median delay between onset of clinical manifestations and diagnosis in adults.11
Dr. Raymond Quigley, pediatric nephrologist at Children’s Health℠ and Professor of Pediatrics at UT Southwestern Medical Center
“There is no typical PH1 journey or symptom presentation,” explains Dr. Raymond Quigley, a pediatric nephrologist at Children’s Health℠ and a Professor of Pediatrics at UT Southwestern Medical Center. “In my own experience and in speaking with other physicians, each patient arrives at the diagnosis in a completely different way. There's a lot of heterogeneity. Certainly, the level of suspicion for PH1 should increase in any child presenting with a kidney stone.”
PH1 is primarily treated by nephrologists; however, urologists and pediatricians are critical parts of the care team and may be a first point of contact. A well-coordinated care team is key to diagnosing and managing this disease. For Jack and Courtney, the diagnostic journey could have been much more challenging and drawn out had it not been for each of the facilities and providers ordering different tests and referring to other physicians, including the nephrologist who suspected and tested for PH1.
Because the consequences of PH1 can worsen significantly with delayed diagnosis and management, it’s important for urologists and pediatricians to keep the signs of PH1 in mind and make appropriate referrals. Testing has advanced significantly, and treatment options are available to help manage the disease.
Treatment Breakthrough for PH1
In 2020, the U.S. Food and Drug Administration approved OXLUMO® (lumasiran), the first FDA-approved treatment for PH1. Today, it is indicated to lower urinary and plasma oxalate levels in pediatric and adult patients.12
OXLUMO is an RNA interference (RNAi) therapeutic, administered by a healthcare professional as a subcutaneous injection, that acts at the main site of oxalate overproduction. By targeting the GO enzyme upstream of AGT, OXLUMO inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1.12
The ILLUMINATE studies, including ILLUMINATE-A, ILLUMINATE-B and ILLUMINATE-C, demonstrated the safety and efficacy of OXLUMO across all ages and stages of kidney function for patients diagnosed with PH1.12 OXLUMO was demonstrated to be effective in reducing levels of oxalate in urine in infants, children and adults, as well as reducing oxalate in blood in patients with advanced kidney disease, including patients on hemodialysis.12 The most common side effect in OXLUMO clinical trials was injection site reaction, which included erythema, swelling, pain, hematoma, pruritus and discoloration. Symptoms were generally mild, resolved within one day of injection, and did not lead to discontinuation of treatment.12
“Twenty-five years ago, if I had a young patient with PH1, there wasn't a whole lot we could do,” says Dr. Quigley. “We would just dialyze, dialyze, dialyze. Then, finally they would get a transplant and go into the adult world with uncertainty of what the final outcome would be. RNA interference treatment is a notable advance in the management landscape.”
Receiving OXLUMO has become a routine part of Jack's life. Jack follows his doctor’s recommendation to stay hydrated. He loves sports and plays baseball, basketball and football. He also enjoys hunting, fishing and riding four-wheelers. This is Jack’s experience with OXLUMO, and others may have a different experience.
Jack taking a break from fishing
Jack’s mother Courtney says she is grateful that doctors listened throughout Jack’s diagnostic journey and made the appropriate referrals, first to the ER and onto a larger medical center where they were able to see a nephrologist. Once Jack was diagnosed, the care team gave her the opportunity to ask questions and helped the family understand PH1 and treatment with OXLUMO.
“My son still struggles with periodic nausea and pain, and he does still experience kidney-related pain and lethargy,” she says. "However, Jack is grateful to be armored with a support system to help him manage his PH1, and he has hope for his future."
“As a pediatric nephrologist, it’s been incredibly rewarding to know I’m able to have an impact on somebody's life so early on,” says Dr. Quigley. “I hope the advances we have seen with genetic testing and treating PH1, as an example, will help inspire the next generation of nephrologists.”
Family photo including Jack and his mother, Courtney
For more information on OXLUMO, visit OXLUMOHCP.com.
Indication and Important Safety Information
INDICATION
OXLUMO® (lumasiran) is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in children and adults.
IMPORTANT SAFETY INFORMATION
Adverse Reactions
The most common (≥20%) adverse reaction reported in patients treated with OXLUMO was injection site reaction. Injection site reactions included erythema, swelling, pain, hematoma, pruritus, and discoloration.
Pregnancy and Lactation
No data are available on the use of OXLUMO in pregnant women. No data are available on the presence of OXLUMO in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or the underlying maternal condition.
For additional information about OXLUMO, please see the full Prescribing Information.
Dr. Quigley and Courtney are paid consultants of Alnylam Pharmaceuticals.
OXLUMO and its associated logo are trademarks of Alnylam Pharmaceuticals.
©2024 Alnylam Pharmaceuticals, Inc. All rights reserved. OXL-USA-00430
References
- Hoppe B. Nat Rev Nephrol. 2012;8(8):467-475.
- Milliner DS, Harris PC, Cogal AG, Lieske JC. https://www.ncbi.nlm.nih.gov
/books/NBK1283/. Updated November 30, 2017. Accessed October 16, 2019. - Cochat P, Rumsby G. N Engl J Med. 2013;369(7):649-658.
- Leumann E, Hoppe B. J Am Soc Nephrol. 2001;12(9):1986-1993.
- Hoppe B, Beck BB, Milliner DS. Kidney Int. 2009;75(12):1264-1271.
- Cochat P, Rumsby G. N Engl J Med. 2013;369(7):649-658.
- Edvardsson VO, Goldfarb DS, Lieske JC, et al. Pediatr Nephrol. 2013;28(10):1923-1942.
- Hoppe B, Langman CB. Pediatr Nephrol. 2003;18:986-991.
- Rare Kidney Stone Consortium. http://www.rarekidneystones.org
/hyperoxaluria/. Published July 2015. - Bhasin B, Ürekli HM, Atta MG. World J Nephrol. 2015;4(2):235-244.
- van der Hoeven SM, van Woerden CS, Groothoff JW. Nephrol Dial Transplant. 2012;27:3855-3862.
- OXLUMO (lumasiran) [Package Insert]. Cambridge, MA. Alnylam Pharmaceuticals.
