RARE DISEASE
Primary hyperoxaluria
Primary hyperoxaluria
Primary hyperoxaluria
Drug discovery
17
drugs
With orphan designations
Overview
Primary hyperoxaluria (PH) is a rare autosomal recessive disorder characterized by hepatic oxalate overproduction due to enzyme deficiencies (AGXT, GRHPR, or HOGA1 mutations). This leads to hyperoxaluria, recurrent calcium oxalate nephrolithiasis, nephrocalcinosis, and progressive chronic kidney disease. Systemic oxalosis occurs with renal impairment, causing multiorgan damage. PH1 (≈80% of cases) is the most severe subtype, often progressing to end-stage renal disease (ESRD). Diagnosis involves genetic testing and urinary oxalate quantification [1][2][6][12].
Burden
Clinical: Recurrent stones (57% prevalence), UTIs (57%), ESRD in >70% of PH1 patients, and systemic oxalosis (bone, cardiac, ocular) [4][5][9].
Economic: Annual healthcare costs 65% higher vs. non-PH patients, frequent hospitalizations (84%), and invasive procedures (e.g., lithotripsy: 37%) [9][12][17].
Quality of life: Disrupted schooling/work, sleep loss, and emotional stress from unpredictable disease progression [5][7][15].
Therapies
Supportive care: High fluid intake (>3 L/day/m²), potassium citrate, and pyridoxine (30% of PH1 patients show >30% urinary oxalate reduction) [3][8][12].
Targeted therapy: RNA interference (lumasiran) reduces urinary oxalate by up to 76% in PH1 [3][7].
Transplant: Combined liver-kidney transplantation for PH1 with ESRD; kidney-alone transplants contraindicated due to recurrence [8][12][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare renal diseases, rare transplant-related disorders
Research Papers
807 drug discovery papers about Primary hyperoxaluria, with 3 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
807 drug discovery papers about Primary hyperoxaluria, with 3 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-28 | Data from the French Daily-Luma cohort suggest predictors of a lumasiran response.
Primary Hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disorder with genotype/phenotype correlation. The RNA interfering therapy lumasiran has revolutionized its prognosis but with heterogeneous response amongst patients. Here, we assessed a possible association between genotype and lumasiran response. In the ongoing French DAILY-LUMA cohort evaluating real-life efficacy and safety of lumasiran, we collected data at treatment initiation and at months three, six and 12 of treatment. The main outcomes were composite criteria, namely normalization and/or reduction over 30% from baseline in the urinary ratio of oxalate and creatinine (UOx/Creat) or in blood oxalate levels (POx) in patients with estimated glomerular filtration rate (eGFR) over or under 30 mL/min/1.73 m2, respectively. The primary endpoint was the proportion of patients reaching this criterion at three months, and secondary endpoints were the same analysis at six and 12 months. Genotype was classified into three groups depending on the vitamin B6 response: resistance, sensitivity, uncertain response (Ile244Thr variant of alanine-glyoxylate aminotransferase). In total, 76 patients (54 children) were included, at a median (inter quartile range) age at lumasiran initiation of 13 (4-33) years with 24 patients on dialysis. After three months treatment, 73 % of patients met the primary endpoint (% calculated on available data). There was no significant association between the underlying genotype and lumasiran response, albeit with a trend towards a lesser response in vitamin B6- sensitive forms. The only significant determinants found to be associated with the primary outcome were age at diagnosis and age at lumasiran initiation, the best response being observed in pediatric patients. Our study suggests a better response to lumasiran in children independent of the underlying genotype. In patients with pyridoxine sensitivity, we suggest continuing or initiating pyridoxine even after lumasiran initiation. After lumasiran initiation, a close follow-up and re-evaluation should be systematically performed.
2026-08-12 | Case Report: A rare AGXT pathogenic variant associated with young-adult-onset end-stage kidney disease.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in AGXT, leading to hepatic oxalate overproduction, recurrent nephrolithiasis, nephrocalcinosis, progressive kidney dysfunction, and, in advanced stages, systemic oxalosis. Here, we report a family in which two brothers developed recurrent nephrolithiasis and progressed to end-stage kidney disease (ESKD) in young adulthood. The proband, a 32-year-old man, presented with bilateral kidney stones, rapidly progressive renal failure, and extensive extra-renal tissue oxalate deposition on follow-up imaging. Genetic testing identified a homozygous AGXT variant, c.740T>G, p.(Leu247Arg), in both affected siblings, while the proband's mother and daughter were heterozygous carriers, consistent with autosomal recessive inheritance. Plasma oxalate levels were markedly higher in the proband than in his brother and in non-PH ESKD controls. During follow-up, the proband received maintenance hemodialysis alone, whereas his older brother underwent combined hemodialysis, hemofiltration, and hemoperfusion, and appeared to achieve better plasma oxalate control. These findings suggest that intensified blood purification may serve as a potential bridging strategy in advanced PH1 while definitive treatment is being arranged. This report expands the genotypic and phenotypic spectrum of PH1 and underscores the importance of early genetic evaluation in patients with recurrent or early-onset nephrolithiasis, especially when accompanied by rapid renal decline or a positive family history.
2026-07-14 | Clinical Characteristics, Genetic Spectrum, and Treatment Outcomes in Children With Primary Hyperoxaluria: Results From a National Turkish Registry.
Primary hyperoxaluria (PH) is a rare autosomal recessive disorder characterized by excessive oxalate production, leading to nephrolithiasis, nephrocalcinosis, and kidney failure. Data from large pediatric cohorts remain limited. This national, multicenter, retrospective study included 88 pediatric patients with PH followed in 15 centers in Türkiye between 2010 and 2024. Clinical, genetic, and treatment-related data were collected via a web-based registry, and disease progression and outcomes were analyzed. The median age at diagnosis was 2.6 (IQR: 0.5-8.4) years in PH1, with an approximate diagnostic delay of 2 years. At diagnosis, nearly half (49.4%) had kidney failure. Genetic diagnosis was performed in 59 (71.1%) patients. The most frequently detected variants were p.Val324Glyfs (n = 12, 20.3%) and p.Gly170Arg (n = 9, 15.2%). During a median follow-up of 58 months (IQR: 24-109), dialysis was initiated at 51.8% and mortality reached 27.7%, particularly among patients presenting with kidney failure. Pyridoxine was used in 55.4% of patients, although response rates were limited, partly due to late diagnosis and non-genotype-guided use. Transplantation was performed in 24.1% of patients. Sequential liver-kidney transplantation provided favorable long-term renal outcomes and remains the most effective treatment for advanced disease by correcting the underlying metabolic defect. Patients with PH2 and PH3 exhibited a milder clinical course, preserved kidney function, and no mortality during follow-up. Delayed diagnosis remains a major challenge in pediatric PH. Early recognition, genotype-guided therapy, and timely implementation of appropriate transplantation strategies are essential to improve outcomes.
2026-05-27 | Targeting the Highly Deleterious G161C and Y260C SNP Variants of the AGXT Protein Involved in Glyoxylate Metabolism Using Tauroursodeoxycholic Acid: A Computational Study.
Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by mutations in the AGXT gene, leading to impaired glyoxylate metabolism and excessive oxalate accumulation, resulting in nephrolithiasis, nephrocalcinosis, and end-stage renal disease. As a rare and often neglected disease, PH1 poses a significant challenge to modern healthcare systems due to its progressive nature and limited therapeutic options. In this study, an integrated in silico approach was employed to identify pathogenic single-nucleotide polymorphisms (SNPs) and evaluate potential therapeutic candidates. Computational analyses using ConSurf, Align-GVGD, INPS-MD, CUPSAT, and iStable identified G161C and Y260C as highly deleterious variants affecting protein stability. Virtual screening, followed by ADME and toxicity assessments, identified Tauroursodeoxycholic acid (TUDCA) as a promising candidate with favorable pharmacokinetic and safety profiles. Molecular docking revealed that TUDCA exhibited higher binding affinity than the reference drug pyridoxine across native and SNP variants of AGXT proteins. Molecular dynamics simulations (300 ns) demonstrated enhanced structural stability of TUDCA-bound complexes, indicated by reduced RMSD and RMSF, improved compactness, and sustained hydrogen bonding. Furthermore, free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) analyses confirmed improved conformational stability and coordinated residue motions in SNP variant structures. Overall, these findings suggest that TUDCA may effectively stabilize structural alterations induced by pathogenic AGXT variants, highlighting its potential as a precision medicine-based therapeutic strategy for PH1.
2026-04-01 | Urine microscopy revealing a metabolic disorder: a case report.
BACKGROUND: Primary hyperoxaluria type 3 is a rare autosomal recessive disorder caused by HOGA1 mutations, leading to recurrent calcium oxalate nephrolithiasis. Diagnosis is often delayed, and 24-hour urine oxalate measurements can be unreliable in patients with normal kidney function. Urine microscopy can detect high-density calcium oxalate monohydrate crystals, providing a rapid diagnostic clue. CASE PRESENTATION: A 31-year-old woman with recurrent nephrolithiasis since age 9 had undergone prior percutaneous nephrolithotomy and ureteroscopy. Urine microscopy revealed abundant calcium oxalate monohydrate crystals (280/mm³), and stone analysis showed mixed calcium phosphate, calcium oxalate dihydrate and monohydrate. Genetic testing confirmed homozygous HOGA1 mutation (c.700 + 5G > T). Conservative management with hydration, dietary calcium, and potassium citrate normalized citrate but not crystalluria. Adjunctive phytate therapy led to disappearance of calcium oxalate monohydrate crystals within weeks. Renal function and residual stones remained stable over 24 months. CONCLUSION: Detection of > 200 calcium oxalate monohydratecrystals/mm³ is highly suggestive of primary oxaluria type 3. Urine microscopy is rapid, inexpensive, and complements genetic testing. Conservative therapy remains central, and adjunctive measures like phytate may help reduce crystallization risk.
cell therapies
2026-06-08 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation.
Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver-kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions - high fluid intake, crystallization inhibitors, and pyridoxine - can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2026-06-01 | P102 From stone disease to survival: sequential liver and kidney transplantation for type i primary hyperoxaluria in a resource-limited setting
Introduction
Type I primary hyperoxaluria is a rare autosomal recessive metabolic disorder caused by hepatic alanine-glyoxylate aminotransferase deficiency, leading to excessive oxalate production resulting in nephrolithiasis, nephrocalcinosis, end-stage renal disease, and systemic oxalosis. Definitive treatment is sequential or combined liver–kidney transplantation, where liver replacement corrects the metabolic defect and kidney transplantation restores renal function. We aimed to evaluate clinical characteristics and transplant outcomes of patients undergoing sequential liver with or without kidney transplantation in a resource-limited setting where diagnostic delay is common.
Methods
We retrospectively analyzed patients with primary hyperoxaluria who underwent liver transplantation with or without kidney transplantation at a tertiary care transplant center. The variables in our study are demographics, age at renal stone onset, diagnostic delay, age at time of liver transplant, prior urological interventions, duration of hemodialysis pre-liver transplant, graft-recipient weight ratio (GRWR), cold ischemia time, liver graft type, biliary ductal anatomy (single duct vs ductoplasty), cardiac involvement, one-year survival, liver-to-kidney transplant interval, and causes of mortality. Continuous variables are reported as mean ± standard deviation and categorical variables as frequencies and percentages.
Results
Fourteen patients were included, with a mean age at transplantation of 24.1 ± 11.4 years; 12 (85.7%) were male. Mean age at first renal stone was 10.79±8.78 years, while mean age at diagnosis was 23.29±11.17 years, resulting in a mean diagnostic delay of 11.89±13.40 years. Prior urological interventions were present in 11(78.6%). Mean duration of hemodialysis prior to liver transplantation was 17.07±9.07 months. Living donor liver transplantation was performed in all patients; mean GRWR was 1.26±0.72 and mean cold ischemia time was 35.71±18.80 minutes. Most grafts had single bile duct anatomy, with ductoplasty required in a minority. Cardiac involvement was common and predominantly manifested by diastolic dysfunction and pulmonary hypertension, with less frequent non-ischemic cardiomyopathy and largely preserved systolic function. One-year survival after liver transplantation was 10(71.4%). Mortality occurred early and was primarily attributable to sepsis, cardiac complications, and multiorgan failure
Conclusion
When contrasted with European registry cohorts that register earlier diagnosis and >85% one-year survival, patients in low-middle income settings present later with prolonged dialysis exposure and cardiac involvement yet can achieve acceptable short-term outcomes. Early metabolic screening, reduced diagnostic delay, and rigorous cardiac stratification may help to improve outcomes.
2026-01-13 | Don’t think that combined liver–kidney transplant can solve everything in primary hyperoxaluria type 1!
Sandrine Lemoine, Anne-Laure Sellier-Leclerc, Alice Koenig, Charlène Levi, Justine Bacchetta; Don’t think that combined liver kidney transplant can solve e
2026-01-01 | Combined Liver and Kidney Transplant for Primary Hyperoxaluria Type 2
Primary hyperoxaluria type 2 (PH2) is a rare autosomal recessive disorder of oxalate overproduction that frequently leads to end-stage renal disease (ESRD). While isolated kidney transplantation is often performed, it carries a high risk of graft failure from recurrent oxalate nephropathy. We present the case of a 23-year-old female with PH2 and ESRD on maintenance hemodialysis who underwent combined liver-kidney transplantation (CLKT). Her postoperative course was complicated by delayed graft function, with serial biopsies revealing acute tubular injury and early oxalate crystal deposition. This was successfully managed with a short course of continuous renal replacement therapy to ensure aggressive oxalate clearance, leading to full recovery of graft function. This case highlights that while CLKT is a definitive treatment for severe PH2, its success is critically dependent on proactive, multidisciplinary intensive care to manage postoperative complications and prevent early graft loss from oxalate recurrence.
2025-12-15 | Combined liver and kidney transplantation: Experience and outcomes at Baskent university
Introduction Combined liver and kidney transplantation (CLKT) is a complex but essential procedure in selected patients with dual organ failure. We present our single-center experience with CLKT in children and adults. Materials and Methods We retrospectively analyzed 11 patients who underwent CLKT at our center between 1988 and 2024 regarding demographic and clinical data, including age, sex, transplant type (simultaneous/sequential), etiology, dialysis status, graft/patient survival, rejection, and oxalate levels. We also evaluated lymphocyte cross-match, panel reactive antibody screening, and complement-dependent cytotoxicity testing. Results Patients included 7 female and 4 male patients (mean age 18 years); 8 were pediatric and 3 were adult recipients. One patient with primary hyperoxaluria underwent a simultaneous liver-kidney transplant, and 10 patients received sequential transplants. Six patients were diagnosed with primary hyperoxaluria. The patient with simultaneous deceased donor transplant experienced early graft loss due to oxalate deposition and humoral rejection. Four patients experienced kidney graft rejection (1 cellular, 3 humoral). One patient with cryptogenic cirrhosis and persistent hepatorenal syndrome died from sepsis in the early postoperative period. A patient with progressive familial intrahepatic cholestasis later developed focal segmental glomerulosclerosis, which was potentially related to long-term tacrolimus exposure. Another patient required graft nephrectomy following thrombotic microangiopathy. The remaining 8 patients had favorable long-term outcomes without significant complications. Conclusions Our experience supports the staged transplant approach for hyperoxaluria and highlights the importance of individualized immunosuppressive strategies. Renal grafts were more susceptible, underscoring the need for vigilant immunologic assessment. Further multicenter studies are warranted to optimize transplant timing and improve outcomes in this complex patient population.
gene therapies
2026-05-13 | Primary Hyperoxaluria type 3, first case reported in Uruguay
Primary hyperoxaluria (PH) comprises a heterogeneous group of autosomal recessive disorders of glyoxylate metabolism.Three genotypic forms (PH1-PH3) are recognized, and diagnosis can be challenging because of marked phenotypic heterogeneity.PH3, the least common form, is caused by pathogenic variants in the HOGA1 gene and generally follows a milder clinical course than PH1 and PH2.We report the case of a young woman with mild hyperoxaluria and preserved renal function with a genetic diagnosis of PH3.Genetic testing identified two pathogenic HOGA1 variants: c.208C>T, p.(Arg70Ter) and c.700+5G>T.This case highlights the broad clinical spectrum of PH3 and underscores the importance of genetic testing in establishing the diagnosis.
2026-04-20 | Clinical and molecular spectrum of primary hyperoxaluria type 1 in Tunisia: pediatric presentation and minimum observed prevalence.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by pathogenic variants in the AGXT gene. In regions with a high prevalence of consanguinity, the burden of PH1 is expected to be increased; however, data on its epidemiology in Tunisia remain scarce. This study aimed to estimate the minimum observed clinical prevalence of PH1 in Tunisia, to assess the expected genetic burden based on published pathogenic allele frequency data, and to describe the clinical and molecular spectrum of the disease in this cohort. We retrospectively analyzed genetically confirmed PH1 patients referred to a major national tertiary referral center in Tunisia between 2011 and 2025, in whom molecular diagnosis was established by systematic Sanger sequencing of the AGXT gene. The minimum observed clinical prevalence was estimated using national population data. The expected genetic burden was derived using Hardy-Weinberg equilibrium based on published gene-based pathogenic AGXT allele frequency estimates from large population databases (gnomAD). A sensitivity analysis incorporating population-level consanguinity was performed. A total of 104 PH1 patients from 55 unrelated families were identified. Most patients presented during childhood (at least 77%), mainly with nephrolithiasis or nephrocalcinosis, while kidney failure (CKD stage 5) was already present in at least half of the probands. The minimum observed clinical prevalence of PH1 in Tunisia was estimated at 8.7 cases per million inhabitants. By contrast, gene-based estimates suggested that approximately 200-300 individuals would be expected to be affected in an outbred population of 12 million. A marked founder effect was observed for the c.731 T>C (p.Ile244Thr) variant. PH1 represents a significant cause of pediatric kidney disease in Tunisia and is likely underdiagnosed. These findings support the need for increased clinical awareness, early genetic testing, and timely diagnosis to optimize patient management in the era of disease-modifying therapies.
2026-04-13 | Novel AAV843 Vector-Mediated Gene Replacement Therapy Rescues Primary Hyperoxaluria Type I in Mice.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder resulting from mutations in the alanine-glyoxylate aminotransferase (AGXT) gene, leading to excessive systemic deposition of calcium oxalate. This condition is an important cause of end-stage renal disease in children and poses a serious threat to patient survival. Current therapeutic approaches are limited primarily to conservative management and organ transplantation, underscoring the need for more effective treatments. Gene replacement therapy represents a promising alternative strategy. In this study, Agxt-/- mice lacking exons 3-8 were characterized, confirming the complete loss of hepatic alanine-glyoxylate aminotransferase (AGT) expression and the presence of early-onset hyperoxaluria. Exposure to glyoxylic acid induced pronounced renal calcium oxalate crystal deposition, establishing a robust and previously unreported induction approach in gene-edited PH1 mouse models. Using this platform, human AGXT cDNA was delivered via the liver-tropic, low-immunogenic AAV843 vector, which has been employed in clinical trials for hemophilia. Gene therapy resulted in normalization of urinary oxalate levels, restoration of hepatic AGT expression, and significant attenuation of renal injury and nephrocalcinosis. These therapeutic effects were accompanied by significant suppression of key mediators involved in renal inflammation, necroptosis, and fibrosis. Moreover, transgene expression was highly specific to the liver and was not associated with hepatotoxicity. These results demonstrate that AAV843-mediated AGXT gene replacement is a safe and effective approach that achieves phenotypic correction in a murine model of PH1, warranting further evaluation in preclinical studies.
2026-04-03 | Primary Oxalosis with Extensive Nephrocalcinosis: A Case Report
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by deficiency of the liver enzyme alanine-glyoxylate aminotransferase, leading to excessive oxalate production, recurrent nephrolithiasis, and progressive nephrocalcinosis. We report a case of a 14-year-old boy with genetically confirmed PH1 (EXON 4 homozygous pathogenic mutation) diagnosed at 3 years of age, who presented with progressively decreasing urine output and abdominal pain. He was undergoing ambulatory peritoneal dialysis for stage V chronic kidney disease. Laboratory evaluation revealed elevated serum oxalate (215 μmol/L) and serum creatinine (5.0 mg/dL post-dialysis). Plain radiographs demonstrated bilateral dense nephrocalcinosis. Ultrasound showed markedly echogenic renal cortices with posterior acoustic shadowing and shrunken kidneys. CT imaging confirmed extensive symmetrical cortical nephrocalcinosis with tram-line calcifications sparing the medulla. The patient had a history of recurrent renal calculi since 2012, requiring pyelolithotomy at age 2 and percutaneous nephrolithotomy with DJ stenting in 2015. Complications included oxalate cardiomyopathy with pulmonary arterial hypertension (>60 mmHg), dilated left atrium, left ventricular hypertrophy, and pulmonary regurgitation. FDG PET-CT revealed mild asymmetrical increased uptake in the left triradiate epiphysis and sacral ala, suggesting early skeletal oxalosis. The patient is currently awaiting combined liver-kidney transplantation. This case highlights the characteristic imaging findings of cortical nephrocalcinosis in PH1 and the importance of early diagnosis and multidisciplinary management to prevent systemic oxalosis.
2026-02-21 | Genomic testing in pediatric urology: Implications for diagnosis and management.
Genomic medicine is becoming increasingly relevant to pediatric urology. Developing an understanding of which children might benefit from genomic testing and how genomic results might impact clinical decision-making will become a necessary skill in the next few years. A genetic diagnosis can provide certainty, prompt screening of other organ systems, guide treatment and surveillance, enable testing of family members and inform reproductive counselling. In this review, we provide an overview of several monogenic conditions that might be encountered in the pediatric urology clinic and guidance on when to refer for genomic testing. We discuss monogenic congenital uropathies and how knowledge of the genetic basis of these conditions has improved understanding of disease pathophysiology. We summarise recommendations for genomic testing in pediatric stone formers, of whom around 20 % have a monogenic cause, and show how this can facilitate access to targeted therapies (e.g. primary hyperoxaluria type 1). Finally, we review how genotype-phenotype correlations can be used to guide risk stratification, surveillance protocols and screening of other organ systems in children at risk of Wilms tumour.
oligonucleotides
2026-09-12 | CORTICAL-PREDOMINANT NEPHROCALCINOSIS AS AN EARLY RADIOLOGIC MARKER OF FULMINANT INFANTILE PRIMARY HYPEROXALURIA TYPE 1: A CASE REPORT
Background: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of glyoxylate metabolism leading to hepatic oxalate overproduction, progressive nephrocalcinosis, and early end-stage renal disease (ESRD), particularly in its severe infantile form. Early radiological recognition is critical for prompt metabolic and genetic evaluation. Case Presentation: A 3-month-old infant born to consanguineous parents presented with status epilepticus secondary to severe acute kidney injury (AKI), anuria, profound electrolyte disturbances (hyponatremia 113–122 mmol/L; hyperkalemia 6.8 mmol/L), metabolic acidosis (pH 7.00), and severe anemia (Hb 4.3 g/dL). Renal ultrasound demonstrated bilaterally normal-sized kidneys with diffuse, intense hyperechogenicity involving both cortex and medulla, complete loss of corticomedullary differentiation, and no obstruction. The pattern appeared cortical-predominant. Follow-up ultrasounds confirmed persistent symmetric “bright kidney” appearance. Non-contrast CT revealed dense symmetric cortico-medullary nephrocalcinosis (>100–200 HU) without obstructing calculi or hydronephrosis. Renal biopsy showed abundant birefringent calcium oxalate crystals, highly suggestive of oxalate nephropathy in the context of infantile fulminant disease. Conclusion: Diffuse cortical-predominant nephrocalcinosis on ultrasound in infants with severe unexplained AKI should prompt urgent suspicion of PH1. Early radiologic recognition accelerates metabolic evaluation, renal biopsy confirmation, and multidisciplinary management, including potential RNAi therapy.
2026-07-03 | Primary hyperoxaluria type 1-current practice in the siRNA era: an ERA Genes & Kidney Working Group survey.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder leading to the formation of kidney stones, nephrocalcinosis, and kidney failure. Besides, PH1 poses the risk of developing systemic oxalosis, a life-threatening condition with oxalate deposits in multiple organ systems. The rarity of the disorder combined with recent major additions to therapeutic options based on small interfering RNA (siRNA) therapeutics make a formal assessment of current practice and implementation of treatment recommendations an important asset. An international questionnaire survey was conducted among medical doctors involved in the treatment of patients with chronic kidney disease. The survey included 32 questions addressing demographics, diagnostics and therapeutics, and educational needs related to the care for PH1 patients. 176 participants from 43 countries completed the survey, the majority of them were from Europe. The results indicate clear shortcomings in the availability of recommended diagnostics, especially with regards to plasma oxalate. Genetic testing strategies often do not include patients who may have PH1, e.g. when the underlying cause of kidney failure is unknown or in patients with nephrolithiasis or nephrocalcinosis. Treatment modalities are only partly harmonized and intensified dialysis is not fully implemented across centers. Strategies toward combination of conventional therapeutics such as hyperhydration and pyridoxine with new siRNA therapeutics depend on the treating physician's expertise. The survey identifies clear needs regarding implementation of current treatment recommendations as well as important educational gaps. The advent of targeted treatment opportunities for PH1 comes with an increased need to provide guidance to the field. Filling the existing gaps will ensure that a growing number of patients get access to optimal care and novel life-changing therapies.
2026-05-04 | Isolated Kidney Transplant in Primary Hyperoxaluria-1 Enabled by Small Interfering RNA (siRNA) Therapy. Is It Time for Change? Case Report and Review of the Literature.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by excessive oxalate production that leads to nephrocalcinosis or nephrolithiasis and progressive kidney failure, associated with systemic oxalosis that is not reversed by dialysis. Pharmacological treatment is limited. Combined or sequential liver and kidney transplant is standard of care for PH1. Recently approved RNA-interference (RNAi) therapy with lumasiran or nedosiran targeting glycolate oxidase and lactate dehydrogenase A, respectively, reduces hepatic oxalate synthesis. This makes kidney-only (isolated) transplantation (iKT) a potentially successful, novel approach for managing PH1 patients with advanced kidney disease combined with hyperhydration, urine alkalinization, and vitamin B6 (where applicable). We analyzed the course of a young PH1 kidney transplant recipient at our institution and performed a literature review of patients with small interfering RNA-enabled iKT. A patient with PH1 due to a homozygous, pathogenic variant in AGXT exon 1 (c.121G>A; p.Gly41Arg) received a deceased donor kidney transplant after 6.5 years of hemodialysis and 4.3 years of RNAi therapy with lumasiran. He maintained good kidney allograft function 9 months post-transplant despite the occurrence of an asymptomatic calyceal stone within the graft prior to transition to adult nephrology care. At 14 months, he experienced a T cell-mediated rejection, associated with a rise in serum creatinine and plasma oxalate, and a partially obstructing stone. A review of all 10 accessible cases of RNAi-supported iKT, including our own, revealed several instances of kidney stone formation (20%), stent obstruction (20%), and mild, mostly transient crystal deposition in the graft (37.5%). This report enriches the limited experience of RNAi-enabled kidney-only transplantation in PH1. RNA interference therapy has the potential to challenge the current standard of dual liver and kidney transplantation in children and young adults with this devastating disease but requires uninterrupted access to the drug with individualized, eGFR and oxalate level adjusted dosing, continued vigilance, and reporting of long-term outcomes.
2026-05-01 | Rescue of Renal Function After Novel RNA Interference Therapy (Lumasiran) for Catastrophic Post–Kidney Transplant Recurrent Oxalate Nephropathy in Primary Hyperoxaluria Type 1
Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive genetic disorder of hepatic glyoxylate metabolism leading to overproduction of oxalate commonly resulting in nephrocalcinosis, renal failure and subsequent systemic oxalosis. The advent of small interfering RNA (siRNA) therapies such as lumasiran and nedosiran could represent a paradigm shift in the management of PH1 and may avoid the need for liver transplantation in some. However, to date, limited evidence on the management of patients exists when the diagnosis of PH1 is made only after renal transplantation. This report details a case of late diagnosis of PH1 in a 23-year-old adult who only received the diagnosis after renal transplantation and subsequent declining graft function. Missed opportunities for genetic testing included no investigation of echogenic kidneys on ultrasound at presentation, and no consideration of the diagnosis at the first transplant biopsy despite oxalate deposition. Genotyping revealed a pyridoxine-resistant phenotype and the patient's transplant function was stabilised by the use of lumasiran. To our knowledge, this case represents the first time lumasiran has been reported as a salvage therapy in an adult patient who was only diagnosed with PH1 following renal transplantation. This case highlights the importance of genetic testing in young patients with otherwise unexplained renal disease and should inform future guidelines regarding salvage therapy in adult patients who receive a late diagnosis.
2026-04-28 | Late Diagnosis of Primary Hyperoxaluria Type 1 After Kidney Transplant
Primary hyperoxaluria type 1 is a rare and often unrecognized cause of renal allograft dysfunction and loss, particularly when renal disease is attributed to recurrent nephrolithiasis. We report the case of a 62-year-old woman with a history of bilateral nephrolithiasis and prolonged use of anti-inflammatory drugs who underwent kidney transplantation with immediate graft function and an initially favorable course. After an extended period of stability, late and progressive graft dysfunction occurred. Allograft biopsy demonstrated tubular injury associated with extensive calcium oxalate crystal deposition, suggesting oxalosis. Serum oxalate was 18.6 µmol/L, and urinary oxalate was 94.9 mg/24 h. Genotyping identified a homozygous pathogenic variant in the AGXT gene, confirming the diagnosis of primary hyperoxaluria type 1. Review of the medical history revealed nephrocalcinosis in native kidneys, and family screening identified a sibling with nephrolithiasis. Pharmacological-dose pyridoxine was initiated as first-line therapy based on the responsive genotype, followed by RNA interference therapy with lumasiran due to the high risk of graft loss, resulting in initial stabilization of graft function. This report emphasizes that primary hyperoxaluria type 1 should be considered in transplant recipients with a history of nephrolithiasis, even in adulthood, and that post-transplant identification has direct implications for graft prognosis, therapeutic approach, and family screening, highlighting the need for metabolic and genetic investigation in selected cases before transplantation.
other
2026-04-14 | Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.
Phosphorylation is a fundamental post-translational modification that contributes to the dynamic control of protein function and stability. More than 300,000 site-specific phosphorylation sites have been detected across > 20,000 human proteins, yet only a small fraction (~ 5%) have been experimentally characterized, and their roles in health and disease remain largely unexplored. In particular, the functional consequences of most phosphorylation events in metabolic enzymes remain unknown. Here, we investigated the functional impact of modifying Ser81 in alanine:glyoxylate aminotransferase (AGT), the key enzyme responsible for glyoxylate detoxification and whose loss-of-function causes Primary Hyperoxaluria Type I (PH1). We examined phosphomimetic substitutions at Ser81 in the WT (wild-type) enzyme, the common polymorphic minor allele (LM, containing two variations, p.P11L and p.I340M), and the two most frequent PH1-associated variants (LM-p.G170R and LM-p.I244T). Using biochemical, biophysical and cell-based approaches, we found that introducing a negative charge at Ser81 (through the S81D substitution) strongly perturbs PLP (pyridoxal 5´-phosphate)/PMP (pyridoxamine 5´-phosphate) binding pose and disrupts catalytic activity, while preserving secondary and tertiary structure as well as peroxisomal localization. In contrast, the non-charged S81A substitution produced milder effects. These results indicate that Ser81 contributes to stabilizing the cofactor interaction network at the AGT active site. Our findings therefore identify Ser81 as a previously uncharacterized regulatory position that can critically influence AGT activity. Although further work is required to determine the physiological frequency and regulatory context of this modification in vivo, our results suggest that phosphorylation at this position could represent an additional modulatory layer influencing AGT function and genotype-phenotype relationships in PH1, with potential implications for understanding regulatory mechanisms affecting AGT activity in disease.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-11-18 | Interleukin-17A Mediates Cardiorenal Injury In Oxalate Nephropathy
Abstract Aims Cardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD). While CKD is known to give rise to systemic inflammation, its inciting factors remain poorly defined. Oxalate, long implicated in rare genetic kidney disorders, accumulates with decreased kidney function and has emerged as a driver of inflammation and independent risk factor for CVD. Here, we investigate the immunological mechanisms linking oxalate nephropathy to systemic inflammation, cardiac damage and kidney injury. Methods and Results Oxalate nephropathy was induced in C57Bl6/N mice via an oxalate-enriched diet. Oxalate induced systemic immune activation, renal fibrosis, and cardiac remodeling, including pulmonary congestion with systolic and diastolic dysfunction. Flow cytometry analysis identified interleukin (IL)-17A as a dominant inflammatory effector, with expansion of Th17 and Th17-like Treg in the kidney, intestine, and spleen. Bulk mRNA sequencing confirmed these findings. Confirming the oxalate-IL-17A relationship, plasma IL-17A was elevated in patients with primary hyperoxaluria. Gut microbiome analysis by 16S amplicon sequencing showed only mild oxalate-induced alterations in mice. However, soluble oxalate directly enhanced Th17 polarization and disrupted mitochondrial respiration in vitro . In vivo, antibody-mediated (clone: 17F3) IL-17A blockade decreased cardiac fibrosis, reduced neutrophil infiltration, and partially restored cardiac function in oxalate-fed mice. Conclusions Our study identifies oxalate as a systemic immunometabolic stressor and IL-17A as a central mediator of oxalate-induced cardiorenal injury. These findings establish the oxalate–IL-17A axis as a mechanistic link between CKD and CVD and suggest IL-17A inhibition as a potential therapeutic strategy to reduce cardiovascular damage in CKD. Translational Perspective This study advances our understanding of targetable mediators of the cardiovascular risk in chronic kidney disease (CKD). We identify the organic anion oxalate, beyond its traditional role in crystal-induced kidney damage, as a systemic immunometabolic stressor. We demonstrate that oxalate induces IL-17A–mediated inflammation and thereby contributes to maladaptive cardiac remodeling. Therapeutic blockade of IL-17A protects against oxalate-induced cardiorenal injury, highlighting the oxalate–IL-17A axis as a relevant and druggable link between CKD and cardiovascular disease.
2025-06-13 | Therapeutic potential of oxalate decarboxylase (OxDC) in the treatment of urolithiasis (kidney stone diseases).
Kidney stone disease is a devastating medical condition that affects 12 % of the global population. The pathophysiology of renal stones is significantly influenced by calcium oxalate, which is present in most renal stones. Oxalate is obtained by humans from increasing dietary oxalate intake as well as from endogenous synthesis. High amounts of oxalate cause hyperoxaluria, which is a significant risk factor for recurrent nephrolithiasis. The available treatments for people with primary and secondary hyperoxaluria are insufficient and do not always result in a noticeable decrease in the excretion of oxalate in the urine. The best course of action for kidney stone treatment and prevention is to focus on the early stages of stone formation such as crystallization events. In recent years, enzymatic therapy has emerged as a viable alternative, notably the use of oxalate-degrading enzymes such as oxalate decarboxylase (OxDC). It is a Mn-dependent hexameric enzyme breaks down oxalate into carbon dioxide and formate, which helps dissolve and shrink CaOx stones that have already developed in the urinary system. The scientific community has recently become interested in OxDC due to its potential applications in biotechnology and medicine for the treatment of hyperoxalurias. Currently, oral delivery of this enzyme capable of digesting oxalate is being explored as a treatment option. This review investigates the therapeutic potential of OxDC in the treatment of kidney stone disease. It explores biochemical properties of OxDC, method of action and the results of preclinical and clinical trials to establish its efficacy and safety. The review also addresses the problems and future directions in the development of OxDC-based therapeutics, such as delivery modalities, stability and potential side effects.
2025-04-17 | Nanobodies as therapies for loss-of-function misfolding diseases
Abstract Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by mutations in the alanine:glyoxylate aminotransferase 1 (AGT) enzyme. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (enhanced aggregation and mitochondrial mistargeting). The main therapeutic approach to increase patients’ lifespan and quality of life is a double kidney and liver transplantation. Alternative treatments such as gene and enzyme replacement and pharmacological chaperones are currently being introduced, but other alternatives are necessary. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics for PH1 misfolding. We show that NB-AGTs are very stable proteins and bind to pathogenic and non-pathogenic variants of AGT with extreme affinities (with K d values from low nM to low pM). Structural studies showed that NB-AGTs bind to different epitopes of AGT with selectivity for different AGT variants. Experiments in cellular PH1 models showed that internalization of engineered NB-AGT-3 enhanced the specific activity of disease-associated variants. Overall, we show that NBs are a novel and promising approach to treat PH1 and other loss-of-function misfolding diseases.
small molecules
2026-09-28 | Data from the French Daily-Luma cohort suggest predictors of a lumasiran response.
Primary Hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disorder with genotype/phenotype correlation. The RNA interfering therapy lumasiran has revolutionized its prognosis but with heterogeneous response amongst patients. Here, we assessed a possible association between genotype and lumasiran response. In the ongoing French DAILY-LUMA cohort evaluating real-life efficacy and safety of lumasiran, we collected data at treatment initiation and at months three, six and 12 of treatment. The main outcomes were composite criteria, namely normalization and/or reduction over 30% from baseline in the urinary ratio of oxalate and creatinine (UOx/Creat) or in blood oxalate levels (POx) in patients with estimated glomerular filtration rate (eGFR) over or under 30 mL/min/1.73 m2, respectively. The primary endpoint was the proportion of patients reaching this criterion at three months, and secondary endpoints were the same analysis at six and 12 months. Genotype was classified into three groups depending on the vitamin B6 response: resistance, sensitivity, uncertain response (Ile244Thr variant of alanine-glyoxylate aminotransferase). In total, 76 patients (54 children) were included, at a median (inter quartile range) age at lumasiran initiation of 13 (4-33) years with 24 patients on dialysis. After three months treatment, 73 % of patients met the primary endpoint (% calculated on available data). There was no significant association between the underlying genotype and lumasiran response, albeit with a trend towards a lesser response in vitamin B6- sensitive forms. The only significant determinants found to be associated with the primary outcome were age at diagnosis and age at lumasiran initiation, the best response being observed in pediatric patients. Our study suggests a better response to lumasiran in children independent of the underlying genotype. In patients with pyridoxine sensitivity, we suggest continuing or initiating pyridoxine even after lumasiran initiation. After lumasiran initiation, a close follow-up and re-evaluation should be systematically performed.
2026-08-12 | Case Report: A rare AGXT pathogenic variant associated with young-adult-onset end-stage kidney disease.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in AGXT, leading to hepatic oxalate overproduction, recurrent nephrolithiasis, nephrocalcinosis, progressive kidney dysfunction, and, in advanced stages, systemic oxalosis. Here, we report a family in which two brothers developed recurrent nephrolithiasis and progressed to end-stage kidney disease (ESKD) in young adulthood. The proband, a 32-year-old man, presented with bilateral kidney stones, rapidly progressive renal failure, and extensive extra-renal tissue oxalate deposition on follow-up imaging. Genetic testing identified a homozygous AGXT variant, c.740T>G, p.(Leu247Arg), in both affected siblings, while the proband's mother and daughter were heterozygous carriers, consistent with autosomal recessive inheritance. Plasma oxalate levels were markedly higher in the proband than in his brother and in non-PH ESKD controls. During follow-up, the proband received maintenance hemodialysis alone, whereas his older brother underwent combined hemodialysis, hemofiltration, and hemoperfusion, and appeared to achieve better plasma oxalate control. These findings suggest that intensified blood purification may serve as a potential bridging strategy in advanced PH1 while definitive treatment is being arranged. This report expands the genotypic and phenotypic spectrum of PH1 and underscores the importance of early genetic evaluation in patients with recurrent or early-onset nephrolithiasis, especially when accompanied by rapid renal decline or a positive family history.
2026-07-14 | Clinical Characteristics, Genetic Spectrum, and Treatment Outcomes in Children With Primary Hyperoxaluria: Results From a National Turkish Registry.
Primary hyperoxaluria (PH) is a rare autosomal recessive disorder characterized by excessive oxalate production, leading to nephrolithiasis, nephrocalcinosis, and kidney failure. Data from large pediatric cohorts remain limited. This national, multicenter, retrospective study included 88 pediatric patients with PH followed in 15 centers in Türkiye between 2010 and 2024. Clinical, genetic, and treatment-related data were collected via a web-based registry, and disease progression and outcomes were analyzed. The median age at diagnosis was 2.6 (IQR: 0.5-8.4) years in PH1, with an approximate diagnostic delay of 2 years. At diagnosis, nearly half (49.4%) had kidney failure. Genetic diagnosis was performed in 59 (71.1%) patients. The most frequently detected variants were p.Val324Glyfs (n = 12, 20.3%) and p.Gly170Arg (n = 9, 15.2%). During a median follow-up of 58 months (IQR: 24-109), dialysis was initiated at 51.8% and mortality reached 27.7%, particularly among patients presenting with kidney failure. Pyridoxine was used in 55.4% of patients, although response rates were limited, partly due to late diagnosis and non-genotype-guided use. Transplantation was performed in 24.1% of patients. Sequential liver-kidney transplantation provided favorable long-term renal outcomes and remains the most effective treatment for advanced disease by correcting the underlying metabolic defect. Patients with PH2 and PH3 exhibited a milder clinical course, preserved kidney function, and no mortality during follow-up. Delayed diagnosis remains a major challenge in pediatric PH. Early recognition, genotype-guided therapy, and timely implementation of appropriate transplantation strategies are essential to improve outcomes.
2026-05-27 | Targeting the Highly Deleterious G161C and Y260C SNP Variants of the AGXT Protein Involved in Glyoxylate Metabolism Using Tauroursodeoxycholic Acid: A Computational Study.
Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by mutations in the AGXT gene, leading to impaired glyoxylate metabolism and excessive oxalate accumulation, resulting in nephrolithiasis, nephrocalcinosis, and end-stage renal disease. As a rare and often neglected disease, PH1 poses a significant challenge to modern healthcare systems due to its progressive nature and limited therapeutic options. In this study, an integrated in silico approach was employed to identify pathogenic single-nucleotide polymorphisms (SNPs) and evaluate potential therapeutic candidates. Computational analyses using ConSurf, Align-GVGD, INPS-MD, CUPSAT, and iStable identified G161C and Y260C as highly deleterious variants affecting protein stability. Virtual screening, followed by ADME and toxicity assessments, identified Tauroursodeoxycholic acid (TUDCA) as a promising candidate with favorable pharmacokinetic and safety profiles. Molecular docking revealed that TUDCA exhibited higher binding affinity than the reference drug pyridoxine across native and SNP variants of AGXT proteins. Molecular dynamics simulations (300 ns) demonstrated enhanced structural stability of TUDCA-bound complexes, indicated by reduced RMSD and RMSF, improved compactness, and sustained hydrogen bonding. Furthermore, free energy landscape (FEL) and dynamic cross-correlation matrix (DCCM) analyses confirmed improved conformational stability and coordinated residue motions in SNP variant structures. Overall, these findings suggest that TUDCA may effectively stabilize structural alterations induced by pathogenic AGXT variants, highlighting its potential as a precision medicine-based therapeutic strategy for PH1.
2026-04-01 | Urine microscopy revealing a metabolic disorder: a case report.
BACKGROUND: Primary hyperoxaluria type 3 is a rare autosomal recessive disorder caused by HOGA1 mutations, leading to recurrent calcium oxalate nephrolithiasis. Diagnosis is often delayed, and 24-hour urine oxalate measurements can be unreliable in patients with normal kidney function. Urine microscopy can detect high-density calcium oxalate monohydrate crystals, providing a rapid diagnostic clue. CASE PRESENTATION: A 31-year-old woman with recurrent nephrolithiasis since age 9 had undergone prior percutaneous nephrolithotomy and ureteroscopy. Urine microscopy revealed abundant calcium oxalate monohydrate crystals (280/mm³), and stone analysis showed mixed calcium phosphate, calcium oxalate dihydrate and monohydrate. Genetic testing confirmed homozygous HOGA1 mutation (c.700 + 5G > T). Conservative management with hydration, dietary calcium, and potassium citrate normalized citrate but not crystalluria. Adjunctive phytate therapy led to disappearance of calcium oxalate monohydrate crystals within weeks. Renal function and residual stones remained stable over 24 months. CONCLUSION: Detection of > 200 calcium oxalate monohydratecrystals/mm³ is highly suggestive of primary oxaluria type 3. Urine microscopy is rapid, inexpensive, and complements genetic testing. Conservative therapy remains central, and adjunctive measures like phytate may help reduce crystallization risk.
cell therapies
2026-06-08 | From recurrent flank pain to systemic oxalosis: a case of primary hyperoxaluria type 1 requiring dual organ transplantation.
Primary hyperoxalurias (PH) are rare autosomal recessive inherited disorders that disrupt the metabolism of glyoxylate and oxalate. The most common type, primary hyperoxaluria type 1 (PH1), is caused by a deficiency in the liver enzyme alanine-glyoxylate aminotransferase (AGT), leading to the overproduction and excessive urinary excretion of oxalate. On routine evaluation, the patient presented with deranged renal function and echogenic kidneys. Imaging via KUB X-ray revealed radio-opaque kidney stones, small shrunken kidneys, and nephrocalcinosis, indicating progression to end-stage kidney disease (ESKD). Additional systemic manifestations included increased lumbar bone density and pulmonary fibrosis. Diagnosis was definitively confirmed through elevated 24-hour urinary oxalate levels and genetic screening showing an AGXT gene mutation. This necessitated combined liver-kidney transplantation (CLKT): the liver graft provides the missing AGT enzyme to stop oxalate production, while the kidney graft replaces damaged organs and discontinues chronic dialysis. PH1 must be suspected in pediatric patients presenting with recurrent urolithiasis or nephrocalcinosis, especially in clinical cases of consanguinity. Early interventions - high fluid intake, crystallization inhibitors, and pyridoxine - can help preserve kidney function. For patients reaching ESKD, combined transplantation is the most effective approach to correct the underlying metabolic error and stop oxalate accumulation. This case highlights the diagnostic challenge of PH1, where the initial presentation with flank pain and urinary symptoms may mimic a urinary tract infection, placing the patient at potential risk of urosepsis if misdiagnosed or untreated. CLKT remains the definitive treatment in advanced disease.
2026-06-01 | P102 From stone disease to survival: sequential liver and kidney transplantation for type i primary hyperoxaluria in a resource-limited setting
Introduction
Type I primary hyperoxaluria is a rare autosomal recessive metabolic disorder caused by hepatic alanine-glyoxylate aminotransferase deficiency, leading to excessive oxalate production resulting in nephrolithiasis, nephrocalcinosis, end-stage renal disease, and systemic oxalosis. Definitive treatment is sequential or combined liver–kidney transplantation, where liver replacement corrects the metabolic defect and kidney transplantation restores renal function. We aimed to evaluate clinical characteristics and transplant outcomes of patients undergoing sequential liver with or without kidney transplantation in a resource-limited setting where diagnostic delay is common.
Methods
We retrospectively analyzed patients with primary hyperoxaluria who underwent liver transplantation with or without kidney transplantation at a tertiary care transplant center. The variables in our study are demographics, age at renal stone onset, diagnostic delay, age at time of liver transplant, prior urological interventions, duration of hemodialysis pre-liver transplant, graft-recipient weight ratio (GRWR), cold ischemia time, liver graft type, biliary ductal anatomy (single duct vs ductoplasty), cardiac involvement, one-year survival, liver-to-kidney transplant interval, and causes of mortality. Continuous variables are reported as mean ± standard deviation and categorical variables as frequencies and percentages.
Results
Fourteen patients were included, with a mean age at transplantation of 24.1 ± 11.4 years; 12 (85.7%) were male. Mean age at first renal stone was 10.79±8.78 years, while mean age at diagnosis was 23.29±11.17 years, resulting in a mean diagnostic delay of 11.89±13.40 years. Prior urological interventions were present in 11(78.6%). Mean duration of hemodialysis prior to liver transplantation was 17.07±9.07 months. Living donor liver transplantation was performed in all patients; mean GRWR was 1.26±0.72 and mean cold ischemia time was 35.71±18.80 minutes. Most grafts had single bile duct anatomy, with ductoplasty required in a minority. Cardiac involvement was common and predominantly manifested by diastolic dysfunction and pulmonary hypertension, with less frequent non-ischemic cardiomyopathy and largely preserved systolic function. One-year survival after liver transplantation was 10(71.4%). Mortality occurred early and was primarily attributable to sepsis, cardiac complications, and multiorgan failure
Conclusion
When contrasted with European registry cohorts that register earlier diagnosis and >85% one-year survival, patients in low-middle income settings present later with prolonged dialysis exposure and cardiac involvement yet can achieve acceptable short-term outcomes. Early metabolic screening, reduced diagnostic delay, and rigorous cardiac stratification may help to improve outcomes.
2026-01-13 | Don’t think that combined liver–kidney transplant can solve everything in primary hyperoxaluria type 1!
Sandrine Lemoine, Anne-Laure Sellier-Leclerc, Alice Koenig, Charlène Levi, Justine Bacchetta; Don’t think that combined liver kidney transplant can solve e
2026-01-01 | Combined Liver and Kidney Transplant for Primary Hyperoxaluria Type 2
Primary hyperoxaluria type 2 (PH2) is a rare autosomal recessive disorder of oxalate overproduction that frequently leads to end-stage renal disease (ESRD). While isolated kidney transplantation is often performed, it carries a high risk of graft failure from recurrent oxalate nephropathy. We present the case of a 23-year-old female with PH2 and ESRD on maintenance hemodialysis who underwent combined liver-kidney transplantation (CLKT). Her postoperative course was complicated by delayed graft function, with serial biopsies revealing acute tubular injury and early oxalate crystal deposition. This was successfully managed with a short course of continuous renal replacement therapy to ensure aggressive oxalate clearance, leading to full recovery of graft function. This case highlights that while CLKT is a definitive treatment for severe PH2, its success is critically dependent on proactive, multidisciplinary intensive care to manage postoperative complications and prevent early graft loss from oxalate recurrence.
2025-12-15 | Combined liver and kidney transplantation: Experience and outcomes at Baskent university
Introduction Combined liver and kidney transplantation (CLKT) is a complex but essential procedure in selected patients with dual organ failure. We present our single-center experience with CLKT in children and adults. Materials and Methods We retrospectively analyzed 11 patients who underwent CLKT at our center between 1988 and 2024 regarding demographic and clinical data, including age, sex, transplant type (simultaneous/sequential), etiology, dialysis status, graft/patient survival, rejection, and oxalate levels. We also evaluated lymphocyte cross-match, panel reactive antibody screening, and complement-dependent cytotoxicity testing. Results Patients included 7 female and 4 male patients (mean age 18 years); 8 were pediatric and 3 were adult recipients. One patient with primary hyperoxaluria underwent a simultaneous liver-kidney transplant, and 10 patients received sequential transplants. Six patients were diagnosed with primary hyperoxaluria. The patient with simultaneous deceased donor transplant experienced early graft loss due to oxalate deposition and humoral rejection. Four patients experienced kidney graft rejection (1 cellular, 3 humoral). One patient with cryptogenic cirrhosis and persistent hepatorenal syndrome died from sepsis in the early postoperative period. A patient with progressive familial intrahepatic cholestasis later developed focal segmental glomerulosclerosis, which was potentially related to long-term tacrolimus exposure. Another patient required graft nephrectomy following thrombotic microangiopathy. The remaining 8 patients had favorable long-term outcomes without significant complications. Conclusions Our experience supports the staged transplant approach for hyperoxaluria and highlights the importance of individualized immunosuppressive strategies. Renal grafts were more susceptible, underscoring the need for vigilant immunologic assessment. Further multicenter studies are warranted to optimize transplant timing and improve outcomes in this complex patient population.
gene therapies
2026-05-13 | Primary Hyperoxaluria type 3, first case reported in Uruguay
Primary hyperoxaluria (PH) comprises a heterogeneous group of autosomal recessive disorders of glyoxylate metabolism.Three genotypic forms (PH1-PH3) are recognized, and diagnosis can be challenging because of marked phenotypic heterogeneity.PH3, the least common form, is caused by pathogenic variants in the HOGA1 gene and generally follows a milder clinical course than PH1 and PH2.We report the case of a young woman with mild hyperoxaluria and preserved renal function with a genetic diagnosis of PH3.Genetic testing identified two pathogenic HOGA1 variants: c.208C>T, p.(Arg70Ter) and c.700+5G>T.This case highlights the broad clinical spectrum of PH3 and underscores the importance of genetic testing in establishing the diagnosis.
2026-04-20 | Clinical and molecular spectrum of primary hyperoxaluria type 1 in Tunisia: pediatric presentation and minimum observed prevalence.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by pathogenic variants in the AGXT gene. In regions with a high prevalence of consanguinity, the burden of PH1 is expected to be increased; however, data on its epidemiology in Tunisia remain scarce. This study aimed to estimate the minimum observed clinical prevalence of PH1 in Tunisia, to assess the expected genetic burden based on published pathogenic allele frequency data, and to describe the clinical and molecular spectrum of the disease in this cohort. We retrospectively analyzed genetically confirmed PH1 patients referred to a major national tertiary referral center in Tunisia between 2011 and 2025, in whom molecular diagnosis was established by systematic Sanger sequencing of the AGXT gene. The minimum observed clinical prevalence was estimated using national population data. The expected genetic burden was derived using Hardy-Weinberg equilibrium based on published gene-based pathogenic AGXT allele frequency estimates from large population databases (gnomAD). A sensitivity analysis incorporating population-level consanguinity was performed. A total of 104 PH1 patients from 55 unrelated families were identified. Most patients presented during childhood (at least 77%), mainly with nephrolithiasis or nephrocalcinosis, while kidney failure (CKD stage 5) was already present in at least half of the probands. The minimum observed clinical prevalence of PH1 in Tunisia was estimated at 8.7 cases per million inhabitants. By contrast, gene-based estimates suggested that approximately 200-300 individuals would be expected to be affected in an outbred population of 12 million. A marked founder effect was observed for the c.731 T>C (p.Ile244Thr) variant. PH1 represents a significant cause of pediatric kidney disease in Tunisia and is likely underdiagnosed. These findings support the need for increased clinical awareness, early genetic testing, and timely diagnosis to optimize patient management in the era of disease-modifying therapies.
2026-04-13 | Novel AAV843 Vector-Mediated Gene Replacement Therapy Rescues Primary Hyperoxaluria Type I in Mice.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder resulting from mutations in the alanine-glyoxylate aminotransferase (AGXT) gene, leading to excessive systemic deposition of calcium oxalate. This condition is an important cause of end-stage renal disease in children and poses a serious threat to patient survival. Current therapeutic approaches are limited primarily to conservative management and organ transplantation, underscoring the need for more effective treatments. Gene replacement therapy represents a promising alternative strategy. In this study, Agxt-/- mice lacking exons 3-8 were characterized, confirming the complete loss of hepatic alanine-glyoxylate aminotransferase (AGT) expression and the presence of early-onset hyperoxaluria. Exposure to glyoxylic acid induced pronounced renal calcium oxalate crystal deposition, establishing a robust and previously unreported induction approach in gene-edited PH1 mouse models. Using this platform, human AGXT cDNA was delivered via the liver-tropic, low-immunogenic AAV843 vector, which has been employed in clinical trials for hemophilia. Gene therapy resulted in normalization of urinary oxalate levels, restoration of hepatic AGT expression, and significant attenuation of renal injury and nephrocalcinosis. These therapeutic effects were accompanied by significant suppression of key mediators involved in renal inflammation, necroptosis, and fibrosis. Moreover, transgene expression was highly specific to the liver and was not associated with hepatotoxicity. These results demonstrate that AAV843-mediated AGXT gene replacement is a safe and effective approach that achieves phenotypic correction in a murine model of PH1, warranting further evaluation in preclinical studies.
2026-04-03 | Primary Oxalosis with Extensive Nephrocalcinosis: A Case Report
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive metabolic disorder caused by deficiency of the liver enzyme alanine-glyoxylate aminotransferase, leading to excessive oxalate production, recurrent nephrolithiasis, and progressive nephrocalcinosis. We report a case of a 14-year-old boy with genetically confirmed PH1 (EXON 4 homozygous pathogenic mutation) diagnosed at 3 years of age, who presented with progressively decreasing urine output and abdominal pain. He was undergoing ambulatory peritoneal dialysis for stage V chronic kidney disease. Laboratory evaluation revealed elevated serum oxalate (215 μmol/L) and serum creatinine (5.0 mg/dL post-dialysis). Plain radiographs demonstrated bilateral dense nephrocalcinosis. Ultrasound showed markedly echogenic renal cortices with posterior acoustic shadowing and shrunken kidneys. CT imaging confirmed extensive symmetrical cortical nephrocalcinosis with tram-line calcifications sparing the medulla. The patient had a history of recurrent renal calculi since 2012, requiring pyelolithotomy at age 2 and percutaneous nephrolithotomy with DJ stenting in 2015. Complications included oxalate cardiomyopathy with pulmonary arterial hypertension (>60 mmHg), dilated left atrium, left ventricular hypertrophy, and pulmonary regurgitation. FDG PET-CT revealed mild asymmetrical increased uptake in the left triradiate epiphysis and sacral ala, suggesting early skeletal oxalosis. The patient is currently awaiting combined liver-kidney transplantation. This case highlights the characteristic imaging findings of cortical nephrocalcinosis in PH1 and the importance of early diagnosis and multidisciplinary management to prevent systemic oxalosis.
2026-02-21 | Genomic testing in pediatric urology: Implications for diagnosis and management.
Genomic medicine is becoming increasingly relevant to pediatric urology. Developing an understanding of which children might benefit from genomic testing and how genomic results might impact clinical decision-making will become a necessary skill in the next few years. A genetic diagnosis can provide certainty, prompt screening of other organ systems, guide treatment and surveillance, enable testing of family members and inform reproductive counselling. In this review, we provide an overview of several monogenic conditions that might be encountered in the pediatric urology clinic and guidance on when to refer for genomic testing. We discuss monogenic congenital uropathies and how knowledge of the genetic basis of these conditions has improved understanding of disease pathophysiology. We summarise recommendations for genomic testing in pediatric stone formers, of whom around 20 % have a monogenic cause, and show how this can facilitate access to targeted therapies (e.g. primary hyperoxaluria type 1). Finally, we review how genotype-phenotype correlations can be used to guide risk stratification, surveillance protocols and screening of other organ systems in children at risk of Wilms tumour.
oligonucleotides
2026-09-12 | CORTICAL-PREDOMINANT NEPHROCALCINOSIS AS AN EARLY RADIOLOGIC MARKER OF FULMINANT INFANTILE PRIMARY HYPEROXALURIA TYPE 1: A CASE REPORT
Background: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of glyoxylate metabolism leading to hepatic oxalate overproduction, progressive nephrocalcinosis, and early end-stage renal disease (ESRD), particularly in its severe infantile form. Early radiological recognition is critical for prompt metabolic and genetic evaluation. Case Presentation: A 3-month-old infant born to consanguineous parents presented with status epilepticus secondary to severe acute kidney injury (AKI), anuria, profound electrolyte disturbances (hyponatremia 113–122 mmol/L; hyperkalemia 6.8 mmol/L), metabolic acidosis (pH 7.00), and severe anemia (Hb 4.3 g/dL). Renal ultrasound demonstrated bilaterally normal-sized kidneys with diffuse, intense hyperechogenicity involving both cortex and medulla, complete loss of corticomedullary differentiation, and no obstruction. The pattern appeared cortical-predominant. Follow-up ultrasounds confirmed persistent symmetric “bright kidney” appearance. Non-contrast CT revealed dense symmetric cortico-medullary nephrocalcinosis (>100–200 HU) without obstructing calculi or hydronephrosis. Renal biopsy showed abundant birefringent calcium oxalate crystals, highly suggestive of oxalate nephropathy in the context of infantile fulminant disease. Conclusion: Diffuse cortical-predominant nephrocalcinosis on ultrasound in infants with severe unexplained AKI should prompt urgent suspicion of PH1. Early radiologic recognition accelerates metabolic evaluation, renal biopsy confirmation, and multidisciplinary management, including potential RNAi therapy.
2026-07-03 | Primary hyperoxaluria type 1-current practice in the siRNA era: an ERA Genes & Kidney Working Group survey.
Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder leading to the formation of kidney stones, nephrocalcinosis, and kidney failure. Besides, PH1 poses the risk of developing systemic oxalosis, a life-threatening condition with oxalate deposits in multiple organ systems. The rarity of the disorder combined with recent major additions to therapeutic options based on small interfering RNA (siRNA) therapeutics make a formal assessment of current practice and implementation of treatment recommendations an important asset. An international questionnaire survey was conducted among medical doctors involved in the treatment of patients with chronic kidney disease. The survey included 32 questions addressing demographics, diagnostics and therapeutics, and educational needs related to the care for PH1 patients. 176 participants from 43 countries completed the survey, the majority of them were from Europe. The results indicate clear shortcomings in the availability of recommended diagnostics, especially with regards to plasma oxalate. Genetic testing strategies often do not include patients who may have PH1, e.g. when the underlying cause of kidney failure is unknown or in patients with nephrolithiasis or nephrocalcinosis. Treatment modalities are only partly harmonized and intensified dialysis is not fully implemented across centers. Strategies toward combination of conventional therapeutics such as hyperhydration and pyridoxine with new siRNA therapeutics depend on the treating physician's expertise. The survey identifies clear needs regarding implementation of current treatment recommendations as well as important educational gaps. The advent of targeted treatment opportunities for PH1 comes with an increased need to provide guidance to the field. Filling the existing gaps will ensure that a growing number of patients get access to optimal care and novel life-changing therapies.
2026-05-04 | Isolated Kidney Transplant in Primary Hyperoxaluria-1 Enabled by Small Interfering RNA (siRNA) Therapy. Is It Time for Change? Case Report and Review of the Literature.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by excessive oxalate production that leads to nephrocalcinosis or nephrolithiasis and progressive kidney failure, associated with systemic oxalosis that is not reversed by dialysis. Pharmacological treatment is limited. Combined or sequential liver and kidney transplant is standard of care for PH1. Recently approved RNA-interference (RNAi) therapy with lumasiran or nedosiran targeting glycolate oxidase and lactate dehydrogenase A, respectively, reduces hepatic oxalate synthesis. This makes kidney-only (isolated) transplantation (iKT) a potentially successful, novel approach for managing PH1 patients with advanced kidney disease combined with hyperhydration, urine alkalinization, and vitamin B6 (where applicable). We analyzed the course of a young PH1 kidney transplant recipient at our institution and performed a literature review of patients with small interfering RNA-enabled iKT. A patient with PH1 due to a homozygous, pathogenic variant in AGXT exon 1 (c.121G>A; p.Gly41Arg) received a deceased donor kidney transplant after 6.5 years of hemodialysis and 4.3 years of RNAi therapy with lumasiran. He maintained good kidney allograft function 9 months post-transplant despite the occurrence of an asymptomatic calyceal stone within the graft prior to transition to adult nephrology care. At 14 months, he experienced a T cell-mediated rejection, associated with a rise in serum creatinine and plasma oxalate, and a partially obstructing stone. A review of all 10 accessible cases of RNAi-supported iKT, including our own, revealed several instances of kidney stone formation (20%), stent obstruction (20%), and mild, mostly transient crystal deposition in the graft (37.5%). This report enriches the limited experience of RNAi-enabled kidney-only transplantation in PH1. RNA interference therapy has the potential to challenge the current standard of dual liver and kidney transplantation in children and young adults with this devastating disease but requires uninterrupted access to the drug with individualized, eGFR and oxalate level adjusted dosing, continued vigilance, and reporting of long-term outcomes.
2026-05-01 | Rescue of Renal Function After Novel RNA Interference Therapy (Lumasiran) for Catastrophic Post–Kidney Transplant Recurrent Oxalate Nephropathy in Primary Hyperoxaluria Type 1
Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive genetic disorder of hepatic glyoxylate metabolism leading to overproduction of oxalate commonly resulting in nephrocalcinosis, renal failure and subsequent systemic oxalosis. The advent of small interfering RNA (siRNA) therapies such as lumasiran and nedosiran could represent a paradigm shift in the management of PH1 and may avoid the need for liver transplantation in some. However, to date, limited evidence on the management of patients exists when the diagnosis of PH1 is made only after renal transplantation. This report details a case of late diagnosis of PH1 in a 23-year-old adult who only received the diagnosis after renal transplantation and subsequent declining graft function. Missed opportunities for genetic testing included no investigation of echogenic kidneys on ultrasound at presentation, and no consideration of the diagnosis at the first transplant biopsy despite oxalate deposition. Genotyping revealed a pyridoxine-resistant phenotype and the patient's transplant function was stabilised by the use of lumasiran. To our knowledge, this case represents the first time lumasiran has been reported as a salvage therapy in an adult patient who was only diagnosed with PH1 following renal transplantation. This case highlights the importance of genetic testing in young patients with otherwise unexplained renal disease and should inform future guidelines regarding salvage therapy in adult patients who receive a late diagnosis.
2026-04-28 | Late Diagnosis of Primary Hyperoxaluria Type 1 After Kidney Transplant
Primary hyperoxaluria type 1 is a rare and often unrecognized cause of renal allograft dysfunction and loss, particularly when renal disease is attributed to recurrent nephrolithiasis. We report the case of a 62-year-old woman with a history of bilateral nephrolithiasis and prolonged use of anti-inflammatory drugs who underwent kidney transplantation with immediate graft function and an initially favorable course. After an extended period of stability, late and progressive graft dysfunction occurred. Allograft biopsy demonstrated tubular injury associated with extensive calcium oxalate crystal deposition, suggesting oxalosis. Serum oxalate was 18.6 µmol/L, and urinary oxalate was 94.9 mg/24 h. Genotyping identified a homozygous pathogenic variant in the AGXT gene, confirming the diagnosis of primary hyperoxaluria type 1. Review of the medical history revealed nephrocalcinosis in native kidneys, and family screening identified a sibling with nephrolithiasis. Pharmacological-dose pyridoxine was initiated as first-line therapy based on the responsive genotype, followed by RNA interference therapy with lumasiran due to the high risk of graft loss, resulting in initial stabilization of graft function. This report emphasizes that primary hyperoxaluria type 1 should be considered in transplant recipients with a history of nephrolithiasis, even in adulthood, and that post-transplant identification has direct implications for graft prognosis, therapeutic approach, and family screening, highlighting the need for metabolic and genetic investigation in selected cases before transplantation.
other
2026-04-14 | Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.
Phosphorylation is a fundamental post-translational modification that contributes to the dynamic control of protein function and stability. More than 300,000 site-specific phosphorylation sites have been detected across > 20,000 human proteins, yet only a small fraction (~ 5%) have been experimentally characterized, and their roles in health and disease remain largely unexplored. In particular, the functional consequences of most phosphorylation events in metabolic enzymes remain unknown. Here, we investigated the functional impact of modifying Ser81 in alanine:glyoxylate aminotransferase (AGT), the key enzyme responsible for glyoxylate detoxification and whose loss-of-function causes Primary Hyperoxaluria Type I (PH1). We examined phosphomimetic substitutions at Ser81 in the WT (wild-type) enzyme, the common polymorphic minor allele (LM, containing two variations, p.P11L and p.I340M), and the two most frequent PH1-associated variants (LM-p.G170R and LM-p.I244T). Using biochemical, biophysical and cell-based approaches, we found that introducing a negative charge at Ser81 (through the S81D substitution) strongly perturbs PLP (pyridoxal 5´-phosphate)/PMP (pyridoxamine 5´-phosphate) binding pose and disrupts catalytic activity, while preserving secondary and tertiary structure as well as peroxisomal localization. In contrast, the non-charged S81A substitution produced milder effects. These results indicate that Ser81 contributes to stabilizing the cofactor interaction network at the AGT active site. Our findings therefore identify Ser81 as a previously uncharacterized regulatory position that can critically influence AGT activity. Although further work is required to determine the physiological frequency and regulatory context of this modification in vivo, our results suggest that phosphorylation at this position could represent an additional modulatory layer influencing AGT function and genotype-phenotype relationships in PH1, with potential implications for understanding regulatory mechanisms affecting AGT activity in disease.
2026-01-02 | Nanobodies as therapies for loss-of-function misfolding diseases: the example of Primary Hyperoxaluria Type 1.
Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary Hyperoxaluria Type 1 (PH1) is a rare genetic disorder caused by the deficit of alanine:glyoxylate aminotransferase (AGT), which leads to excessive endogenous oxalate formation translating into progressive renal damage due to stones formation. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (leading to enhanced degradation, aggregation and/or mitochondrial mistargeting). The main therapeutic approach is a double kidney and liver transplantation, but treatments based on RNA silencing are currently available, although they normalize urinary oxalate excretion only in about 50 % of patients, calling for the need of alternative options. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics counteracting PH1 misfolding. We show that NB-AGTs are very stable proteins and bind pathogenic and non-pathogenic variants of AGT with high affinities (Kd values from low nM to low pM). Structural studies indicate that NB-AGTs bind to different protein epitopes thus being selective for different variants. Preliminary experiments in a cellular model of PH1 show that internalization of engineered NB-AGT-3 enhances the specific activity of disease-associated variants. Overall, our results provide the basis to consider NBs as a promising approach for PH1 as premise for their application to other loss-of-function misfolding diseases.
2025-11-18 | Interleukin-17A Mediates Cardiorenal Injury In Oxalate Nephropathy
Abstract Aims Cardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD). While CKD is known to give rise to systemic inflammation, its inciting factors remain poorly defined. Oxalate, long implicated in rare genetic kidney disorders, accumulates with decreased kidney function and has emerged as a driver of inflammation and independent risk factor for CVD. Here, we investigate the immunological mechanisms linking oxalate nephropathy to systemic inflammation, cardiac damage and kidney injury. Methods and Results Oxalate nephropathy was induced in C57Bl6/N mice via an oxalate-enriched diet. Oxalate induced systemic immune activation, renal fibrosis, and cardiac remodeling, including pulmonary congestion with systolic and diastolic dysfunction. Flow cytometry analysis identified interleukin (IL)-17A as a dominant inflammatory effector, with expansion of Th17 and Th17-like Treg in the kidney, intestine, and spleen. Bulk mRNA sequencing confirmed these findings. Confirming the oxalate-IL-17A relationship, plasma IL-17A was elevated in patients with primary hyperoxaluria. Gut microbiome analysis by 16S amplicon sequencing showed only mild oxalate-induced alterations in mice. However, soluble oxalate directly enhanced Th17 polarization and disrupted mitochondrial respiration in vitro . In vivo, antibody-mediated (clone: 17F3) IL-17A blockade decreased cardiac fibrosis, reduced neutrophil infiltration, and partially restored cardiac function in oxalate-fed mice. Conclusions Our study identifies oxalate as a systemic immunometabolic stressor and IL-17A as a central mediator of oxalate-induced cardiorenal injury. These findings establish the oxalate–IL-17A axis as a mechanistic link between CKD and CVD and suggest IL-17A inhibition as a potential therapeutic strategy to reduce cardiovascular damage in CKD. Translational Perspective This study advances our understanding of targetable mediators of the cardiovascular risk in chronic kidney disease (CKD). We identify the organic anion oxalate, beyond its traditional role in crystal-induced kidney damage, as a systemic immunometabolic stressor. We demonstrate that oxalate induces IL-17A–mediated inflammation and thereby contributes to maladaptive cardiac remodeling. Therapeutic blockade of IL-17A protects against oxalate-induced cardiorenal injury, highlighting the oxalate–IL-17A axis as a relevant and druggable link between CKD and cardiovascular disease.
2025-06-13 | Therapeutic potential of oxalate decarboxylase (OxDC) in the treatment of urolithiasis (kidney stone diseases).
Kidney stone disease is a devastating medical condition that affects 12 % of the global population. The pathophysiology of renal stones is significantly influenced by calcium oxalate, which is present in most renal stones. Oxalate is obtained by humans from increasing dietary oxalate intake as well as from endogenous synthesis. High amounts of oxalate cause hyperoxaluria, which is a significant risk factor for recurrent nephrolithiasis. The available treatments for people with primary and secondary hyperoxaluria are insufficient and do not always result in a noticeable decrease in the excretion of oxalate in the urine. The best course of action for kidney stone treatment and prevention is to focus on the early stages of stone formation such as crystallization events. In recent years, enzymatic therapy has emerged as a viable alternative, notably the use of oxalate-degrading enzymes such as oxalate decarboxylase (OxDC). It is a Mn-dependent hexameric enzyme breaks down oxalate into carbon dioxide and formate, which helps dissolve and shrink CaOx stones that have already developed in the urinary system. The scientific community has recently become interested in OxDC due to its potential applications in biotechnology and medicine for the treatment of hyperoxalurias. Currently, oral delivery of this enzyme capable of digesting oxalate is being explored as a treatment option. This review investigates the therapeutic potential of OxDC in the treatment of kidney stone disease. It explores biochemical properties of OxDC, method of action and the results of preclinical and clinical trials to establish its efficacy and safety. The review also addresses the problems and future directions in the development of OxDC-based therapeutics, such as delivery modalities, stability and potential side effects.
2025-04-17 | Nanobodies as therapies for loss-of-function misfolding diseases
Abstract Misfolding diseases that result in loss of function represent a considerable burden for both individuals and society. Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by mutations in the alanine:glyoxylate aminotransferase 1 (AGT) enzyme. The underlying molecular mechanisms causing PH1 are associated with protein misfolding (enhanced aggregation and mitochondrial mistargeting). The main therapeutic approach to increase patients’ lifespan and quality of life is a double kidney and liver transplantation. Alternative treatments such as gene and enzyme replacement and pharmacological chaperones are currently being introduced, but other alternatives are necessary. In this work, we developed and characterized a novel biotechnological approach using six single-domain nanobodies (NB-AGT-1 to -6) as potential therapeutics for PH1 misfolding. We show that NB-AGTs are very stable proteins and bind to pathogenic and non-pathogenic variants of AGT with extreme affinities (with K d values from low nM to low pM). Structural studies showed that NB-AGTs bind to different epitopes of AGT with selectivity for different AGT variants. Experiments in cellular PH1 models showed that internalization of engineered NB-AGT-3 enhanced the specific activity of disease-associated variants. Overall, we show that NBs are a novel and promising approach to treat PH1 and other loss-of-function misfolding diseases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
17 orphan drug designations for Primary hyperoxaluria, including 2 approved therapies.
17 orphan drug designations for Primary hyperoxaluria, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Guide RNA against the human HAO1 gene, mRNA encoding an engineered variant of the Cas12 nuclease | gene editing enzymes | EMA | Chiesi Farmaceutici S.p.A. | |
Lanthanum carbonate octahydrate | small molecules | EMA | — | Amgmt |
mRNA encoding Cas12HF endonuclease, single guide RNA against the human HAO1 gene | gene editing enzymes | EMA | — | Voisin Consulting Life Sciences |
a lipid nanoparticle encapsulating a messenger RNA for the CRISPR-based gene editor Cas12i2v2.1, and an HAO1- specific guide RNA | gene editing enzymes | FDA | Arbor Biotechnologies, Inc. | |
lipid nanoparticles containing CRISPR/Cas12HF mRNA and a CRISPR RNA (crRNA) targeting the HAO1 gene | gene editing enzymes | FDA | Yoltech Therapeutics Co., Ltd | |
a small molecule dual inhibitor of the enzymes LDHA and LDHB. LDH catalyzes the last committed step in the synthesis of oxalate. | small molecules | FDA | — | Meta Pharmaceuticals (HK) Ltd |
Vamagloxistat | small molecules | EMA | — | Voisin Consulting Life Sciences |
Stiripentol | small molecules | FDA | Biocodex | |
glycolate oxidase inhibitor | small molecules | FDA | — | Cantero Therapeutics, Inc. |
Stiripentol | small molecules | EMA | Biocodex | |
Synthetic double-stranded siRNA oligonucleotide directed against lactate dehydrogenase A mRNA and containing four modified nucleosides which form a ligand cluster of four N-acetylgalactosamine residues | oligonucleotides | EMA | Dicerna Ireland Limited | |
nedosiran [Rivfloza] | RNAs | FDA | Approved | Dicerna Pharmaceuticals, Inc. (a wholly owned subsidiary of Novo Nordisk) |
Bacillus subtilis oxalate decarboxylase | proteins | EMA | Allena Pharmaceuticals Ireland Limited | |
Bacillus subtilis oxalate decarboxylase | proteins | FDA | Allena Pharmaceuticals, Inc. | |
Synthetic double-stranded siRNA oligonucleotide directed against hydroxyacid oxidase 1 mRNA and covalently linked to a ligand containing three N-acetylgalactosamine residues [Oxlumo] | RNAs | EMA | Approved | Alnylam Netherlands B.V. |
Oxalobacter formigenes | cell therapies | FDA | OxThera Inc. | |
Oxalobacter formigenes strain HC-1 | cell therapies | EMA | OxThera AB |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.