Navigating the Evolving Landscape of Primary Hyperoxaluria: Traditional Management Defied by the Rise of Novel Molecular Drugs

Abstract

Primary hyperoxalurias (PHs) are inherited metabolic disorders marked by enzymatic cascade disruption, leading to excessive oxalate production that is subsequently excreted in the urine. Calcium oxalate deposition in the renal tubules and interstitium triggers renal injury, precipitating systemic oxalate build-up and subsequent secondary organ impairment. Recent explorations of novel therapeutic strategies have challenged and necessitated the reassessment of established management frameworks. The execution of diverse clinical trials across various medication classes has provided new insights and knowledge. With the evolution of PH treatments reaching a new milestone, prompt and accurate diagnosis is increasingly critical. Developing early, effective management and treatment plans is essential to improve the long-term quality of life for PH patients.

Keywords: AGXT; GRHPR; HOGA1; RNA interference; genetics; oxalate; primary hyperoxaluria.

Figure 1

Oxalate metabolism pathways and related therapeutic targets in hepatic cells. PH1 arises from a hepatic-specific deficiency in the AGT enzyme. PH2 arises from the scarcity of the GRHPR enzyme, mainly situated in hepatic cells, predominantly located in the cytoplasm of hepatic cells, with a lesser presence in mitochondria. PH3 arises from the functional loss of HOGA1, typically leading to hyperoxaluria through the inhibition of the GRHPR enzyme and the decomposition of the substrate HOG via an unknown pathway. Contemporary pharmacotherapy for PHs typically focuses on targeting the AGT, GO and LDH enzymes and their associated encoding genes. PHs: primary hyperoxalurias; PH1–3: primary hyperoxaluria type 1–3; AGT: alanine-glyoxylate aminotransferase; GO: glycolate oxidase; GRHPR: glyoxylate reductase/hydroxypyruvate reductase; LDH: lactate dehydrogenase; HOG: 4-hydroxy-2-oxoglutarate; HOGA1: 4-hydroxy-2-oxoglutarate aldolase. The figure was created with BioRender.com.

Figure 2

The diagnostic and therapeutic protocol for PH patients. PHs: primary hyperoxalurias; PH1–3: primary hyperoxaluria type 1–3; eGFR: estimated glomerular filtration rate; UOx: urinary oxalate; Cr: creatinine; POx: plasma oxalate. RNAi: RNA interference. The figure was created with BioRender.com.