When Primary Hyperoxaluria Evades Detection Until Systemic Oxalosis Stage
When an 83-year-old woman arrived at a kidney stone prevention clinic, her medical history read like a decades-long mystery. She had begun passing kidney stones at age 50, endured multiple stone removal surgeries, and had recently started hemodialysis for uremia. Her sister had similarly suffered from recurrent nephrolithiasis before dying of CKD of unknown etiology. The puzzle pieces finally came together when genetic testing revealed she had primary hyperoxaluria type 1 (PH1)—at 83, she became the oldest person ever diagnosed with this rare genetic disease. What followed was even more remarkable: after starting targeted treatment, her plasma oxalate levels normalized and she ultimately discontinued hemodialysis altogether 1 .
This case exemplifies both the diagnostic challenges and therapeutic promises surrounding primary hyperoxaluria, especially when diagnosed late in the systemic oxalosis stage.
PH1 is a rare genetic disorder that causes excessive oxalate production, leading to kidney stones, kidney damage, and eventually systemic oxalosis—where oxalate crystals accumulate throughout the body. With an estimated median diagnostic delay of 5.5 years in adults, many patients experience significant kidney damage before receiving appropriate treatment 9 . This article explores the journey of PH1 from initial symptoms to systemic oxalosis, the reasons behind diagnostic delays, and the promising new therapies revolutionizing patient care.
Primary hyperoxaluria refers to a group of rare inherited metabolic disorders where the body produces too much oxalate, a natural waste product. In healthy individuals, the liver efficiently breaks down glyoxylate, preventing excessive oxalate formation. However, in PH1—the most common and severe form representing approximately 80% of cases—mutations in the AGXT gene impair the function of alanine-glyoxylate aminotransferase (AGT), a liver-specific enzyme 4 5 .
This enzyme deficiency disrupts normal glyoxylate metabolism, causing the body to overproduce oxalate—in some patients, up to three to ten times the normal amount. The excess oxalate combines with calcium in the kidneys to form insoluble calcium oxalate crystals, which aggregate into stones and deposit in kidney tissue 2 9 .
PH1 follows an autosomal recessive inheritance pattern, meaning a child must inherit two mutated copies of the AGXT gene—one from each parent—to develop the disease. Parents who each carry one mutated copy are typically unaffected carriers, with each of their children having a 25% chance of inheriting the condition 4 .
Affected
Carrier
Unaffected
Consanguinity (genetic relatedness between parents) significantly increases the risk, as evidenced by a Saudi Arabian study where 90.5% of pediatric PH1 patients were born to consanguineous parents 5 . Researchers have identified over 150 pathogenic variants in the AGXT gene, with certain populations showing specific common mutations 5 .
The heterogeneous symptom profile across ages contributes significantly to diagnostic delays. While approximately 50% of affected individuals experience symptoms before age 5, others may not develop symptoms until adulthood—sometimes as late as their 60s or beyond 1 4 .
| Age Group | Common Presenting Symptoms | Notes |
|---|---|---|
| Infants (<1 year) | Nephrocalcinosis, failure to thrive, kidney failure | Most severe form; known as "infantile oxalosis" 4 |
| Children | Recurrent kidney stones, blood in urine, urinary tract infections, painful urination | Median age at diagnosis is 8 years 1 |
| Adults | Recurrent kidney stones, declining kidney function, established CKD | Often have history of stones dating back to childhood 1 |
The median diagnostic delay for adults with PH1 is approximately 5.5 years between the onset of clinical manifestations and definitive diagnosis 9 . This delay stems from several factors:
Patient experiences first kidney stone or related symptoms
Symptoms attributed to common kidney stones
Multiple stone events over several years
Progressive kidney damage becomes apparent
PH1 identified after median 5.5 years 9
A recent study highlighted the consequences of delayed diagnosis, finding that patients with PH1 and chronic kidney disease face significantly higher healthcare costs—approximately 1.5 times higher for those with advanced CKD compared to those with early CKD 3 .
When PH1 progresses to end-stage kidney disease, a dangerous cascade begins. The kidneys can no longer filter oxalate from the blood, causing plasma oxalate levels to rise dramatically. Once the saturation threshold is exceeded, calcium oxalate crystals begin depositing in virtually every organ and tissue—a condition called systemic oxalosis 2 7 .
Bones & Joints
Heart
Skin
Eyes
Nerves
Lungs
Case reports illustrate the dramatic presentations of systemic oxalosis. One 22-year-old man with eight years of end-stage renal disease presented with bicytopenia (low counts of two blood cell types) and chronic joint pain. A bone marrow biopsy revealed widespread oxalate crystal deposits with extensive replacement of normal marrow tissue, explaining his blood abnormalities 7 . Another patient in their late 30s developed subcutaneous calcifications and recurrent arteriovenous fistula occlusions after kidney transplant failure 8 .
| Parameter | Typical Finding in Systemic Oxalosis | Clinical Significance |
|---|---|---|
| Plasma Oxalate | >80 μmol/L (normal: ≤2 μmol/L) 1 | Indicates saturation and tissue deposition risk |
| Bone Marrow Biopsy | Rosette-shaped deposits of needle-shaped crystals with giant cell reaction 7 | Pathognomonic for oxalosis |
| Imaging (X-ray, CT) | Nephrocalcinosis, soft tissue calcifications, osteosclerosis 8 | Supports diagnosis of systemic involvement |
Traditional PH1 treatment focused on symptom management and delaying disease progression:
Recent breakthroughs have transformed PH1 management:
After starting targeted treatment, her plasma oxalate levels normalized and she ultimately discontinued hemodialysis altogether—an outcome previously unimaginable in advanced PH1 1 .
RNA Interference (RNAi) Therapy: Lumasiran (Oxlumo), approved in 2020, is a subcutaneously administered RNAi therapeutic that targets glycolate oxidase (HAO1) in the liver, upstream of the defective AGT enzyme. By reducing the substrate available for oxalate production, lumasiran significantly lowers urinary and plasma oxalate levels 9 .
The ILLUMINATE clinical trials demonstrated lumasiran's effectiveness across all ages and kidney function stages. In one remarkable case, an 83-year-old woman showed normalization of plasma oxalate six months after starting lumasiran and ultimately discontinued hemodialysis—an outcome previously unimaginable in advanced PH1 1 .
Emerging Approaches: The pipeline includes nedosiran (another RNAi therapeutic) and investigational agents like ABO-101—a CRISPR-based gene editing treatment designed to permanently knock down HAO1 gene expression. The FDA recently cleared ABO-101 for clinical trials, representing a potential one-time curative approach 6 .
| Therapy | Mechanism | Development Stage | Key Feature |
|---|---|---|---|
| Lumasiran | RNAi targeting HAO1 mRNA | FDA-approved (2020) 9 | First targeted therapy for PH1 |
| Nedosiran | RNAi targeting LDHA mRNA | Phase 3 trials 6 | Once-monthly subcutaneous dosing |
| ABO-101 | CRISPR-based gene editing of HAO1 | Phase 1/2 trials planned | Potential one-time curative treatment |
Advances in PH1 understanding and treatment development rely on specialized research approaches:
Next-generation sequencing panels allow comprehensive AGXT, GRHPR, and HOGA1 gene analysis 5 .
PH1 mouse models with AGXT mutations help researchers study disease progression 5 .
Delivery vehicles for RNAi therapeutics and gene editing components to hepatocytes .
In vitro systems that simulate calcium oxalate crystal formation and inhibition 2 .
Hepatocyte models for studying AGT enzyme function and trafficking 5 .
The landscape of PH1 management is undergoing a dramatic transformation. From a condition once considered uniformly fatal without organ transplantation, PH1 has become a manageable disease thanks to scientific advances. The development of RNAi therapies and upcoming gene editing approaches promises increasingly effective interventions that target the root cause rather than just symptoms.
Despite these therapeutic advances, the critical challenge remains early diagnosis. As cases like the 83-year-old woman illustrate, even patients with advanced disease can benefit from modern treatments. Increased clinician awareness, appropriate metabolic testing for recurrent stone formers, and accessible genetic testing are essential to reduce the diagnostic odyssey so that interventions can begin before irreversible kidney damage or systemic oxalosis occurs.
The journey of PH1 from a mysterious crystal disease to a model for targeted metabolic therapy represents both the power of modern genetics and the importance of persistent clinical investigation. For patients with this rare condition, the future is increasingly bright—offering hope where once there was only progressive decline.