Hereditary Renal Hypouricemia

Hereditary renal hypouricemia is a distinctive autosomal recessive defect, expressing itself through diminished renal tubular reclamation of uric acid. The resultant biochemical profile is of low uric acid across blood specimens. Protheragen concentrates its research and development services on rare renal pathologies. Here, we offer a disease-specific solution for the management of hereditary renal hypouricemia.

Overview of Hereditary Renal Hypouricemia

Hereditary renal hypouricaemia, a rare autosomal condition, features low serum uric acid and high urinary uric acid excretion. The defect lies in renal tubules, crippling their ability to reclaim this metabolite. Although many individuals feel well after decades, a minority face problems tied to their unusual uric acid disposal, such as exercise-induced acute kidney injury (EIAKI) and uric acid stones. The syndrome has been recorded in numerous countries; however, figures are higher among East Asian populations, especially in Japan and Korea.

Fig.1 Proposed mechanism of EIAKI in hypouricemic kidneys. (Hosoyamada M., 2021)

Pathogenesis of Hereditary Renal Hypouricemia

The development of hereditary renal hypouricemia is traced back to variations in the renal uric acid transport genes. SLC22A12, which encodes the URAT1 protein, and SLC2A9, which encodes GLUT9, as well as ABCG2, which encodes the BCRP protein, are the genes most frequently associated. When a change in sequence interferes with transporter function, tubule cells fail to reabsorb the uric acid, with the consequence of too much uric acid lost in the urine and plasma levels falling below the reference range.

Fig.2 3D structure of the WT URAT1 protein. (Wolf et al., 2021)

When the kidneys fail to reabsorb uric acid effectively, changes in purine metabolism increase the risk for uric acid stones in the urine. Over the years, the sustained imbalance can lead to gradual kidney injury, although the impact can range broadly from mild to severe in different people. During any dehydration or other metabolic imbalance, the accumulation of uric acid may push the stone risk even higher, and, in the worst cases, it could lead the kidneys toward chronic failure.

Therapeutics Development for Hereditary Renal Hypouricemia

Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.

Our Services

Protheragen is dedicated to building sophisticated experimental disease models of hereditary renal hypouricemia while providing complete preclinical therapeutic development support. Our studies target the interplay of genetic defects and dysregulated uric-acid transport that underpins the disorder.

Therapeutic Development Platforms for Hereditary Renal Hypouricemia

• Small Molecule Drug
• Cell Therapy
• Gene Therapy

• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein

Disease Models Development for Hereditary Renal Hypouricemia

To fast-track finding effective therapies for hereditary renal hypouricemia, Protheragen develops cutting-edge disease models that replicate the condition's intricacies. Our preclinical platform integrates advanced cell-based models, kidney organoids, and disease-relevant animal models to reproduce the impaired uric-acid metabolism pathway characteristic of hereditary renal hypouricemia. These models provide an essential testing ground for assessing the efficacy, selectivity, and safety of emerging therapeutic agents.

Cell-based & Organoid Models

• Primary Cell Model
• SLC22A12 Knockout Cell Model
• GLUT9 Knockdown Cell Model
• iPSC-derived Cell Model
• iPSC-derived Kidney Organoids

Animal Models

The animal models for HRH typically involve genetic modifications to specific genes to mimic the human condition.

• Urat1/Uox Double Knockout Model
• SLC2A9 Mutation Model

Drug Pharmacokinetics & Safety Evaluation Services

In Vitro ADME Services

• Renal Clearance Assay
• Drug-Transporter Interaction Screening
• Metabolic Stability Assay
• CYP Inhibition Screening
• Plasma Protein Binding

In Vivo Pharmacokinetics Services

• PK Studies in Renal Impairment Models
• Kidney Tissue Distribution Study
• Blood-to-Plasma Ratio
• Metabolite Profiling

Drug Safety Evaluation

• General Toxicology Evaluation
• Genetic Toxicology Evaluation
• Developmental and Reproductive Toxicity Evaluation

• Immunogenicity and Immunotoxicity Evaluation
• Local Toxicity Evaluation
• Phototoxicity Evaluation

• Tissue Cross-Reactivity Evaluation
• Safety Pharmacology Evaluation
• Toxicokinetic Evaluation

Protheragen offers tailored preclinical development services focused exclusively on rare kidney diseases, hereditary renal hypouricemia included. Our team supports you from disease model creation through pharmacokinetics to drug safety assessment, ensuring a seamless transition from exploratory studies to preclinical validation. For a consultation or detailed discussion of how we can support your program, simply contact us.

References

1. Gupta, S., J. E. Ozimek-Kulik, and J. K. Phillips. "Hereditary Renal Hypouricemia-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease." Genes (Basel) 12.11 (2021).
2. Wolf, M. T. F., et al. "Hereditary Renal Hypouricemia: A Pathological and Genetic Perspective." Pediatr Nephrol 39.7 (2024): 1977-2000.
3. Hosoyamada, Makoto. "Hypothetical Mechanism of Exercise-Induced Acute Kidney Injury Associated with Renal Hypouricemia." Biomedicines 9.12 (2021): 1847.

All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.