Diabetic kidney disease (DKD), a major microvascular complication of diabetes, affects 30– 40% of patients and is the leading cause of end-stage renal disease. The Wnt/β-catenin signaling pathway plays a dual role in DKD pathogenesis: its moderate activation protects against hyperglycemia-induced mesangial apoptosis, while chronic overactivation exacerbates renal fibrosis, podocyte injury, and tubular dysfunction. This review synthesizes current evidence on the pathway’s context-dependent mechanisms. Emerging therapeutic strategies—including small-molecule inhibitors (eg, Dickkopf-1), monoclonal antibodies, and natural compounds like curcumin and Salvia miltiorrhiza extracts—show preclinical promise in modulating Wnt/β-catenin activity. However, clinical translation faces challenges such as pathway redundancy, off-target effects, and the need for precise dosing to balance protective and injurious outcomes. Recent advances in biomarker discovery (eg, urinary β-catenin) and ongoing clinical trials highlight the pathway’s potential as a therapeutic target. Future research must prioritize patient stratification, combination therapies (eg, Wnt inhibitors + RAAS blockers), and mechanistic studies to address unresolved controversies in Wnt signaling dynamics. This work underscores the therapeutic implications of targeting Wnt/β-catenin in DKD while advocating for a nuanced approach to harness its protective roles.

Rationale: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal tubular disorder caused by mutations in the CLDN16 or CLDN19 genes. This case demonstrates the critical role of whole-exome sequencing (WES) in diagnosing FHHNC, particularly when novel mutations, such as the homozygous CLDN16 variant (c.351G > T, p.W117C) found in this patient, are identified, which expands the genetic understanding of this condition. Patient concerns: A 17-year-old female presented with an 8-month history of persistent neck, shoulder, and upper limb pain that had worsened over the past month. Despite initial treatment for cervical degenerative disease at local hospitals, her symptoms showed minimal improvement. She also exhibited growth retardation, with a height of 145 cm (−2 SD), and experienced recurrent urinary tract infections, although she reported no visual disturbances or neurological symptoms. Diagnoses: Laboratory tests revealed hypomagnesemia and elevated parathyroid hormone levels. Imaging studies confirmed bilateral nephrocalcinosis and a medullary sponge kidney. Genetic testing using WES identified a homozygous pathogenic mutation in CLDN16 (c.351G > T), which was further validated by Sanger sequencing in the patient and her heterozygous parents. Interventions: During hospitalization, the patient received intravenous magnesium sulfate (2.5 g/day), oral calcium carbonate with vitamin D3 supplementation, and levofloxacin for urinary tract infection management. Upon discharge, she was maintained on oral magnesium oxide (500 mg twice daily) with regular monitoring of electrolyte levels and renal function. Outcomes: At the 2-year follow-up, the patient’s serum magnesium levels improved but remained below the normal range. Hypercalciuria persisted, although her renal function was stable. Notably, there was no progression to end-stage renal disease, and her symptoms were better managed with ongoing treatment. Lessons: This case underscores the importance of WES in the diagnosis of rare tubular disorders, especially when the clinical presentations are nonspecific. This finding highlights that CLDN16-related FHHNC can occur without ocular involvement, and this information may aid in differential diagnosis. Early and consistent magnesium supplementation appears to mitigate renal deterioration, emphasizing the need for prompt intervention. Additionally, this case reinforces the value of genetic counseling for families affected by autosomal recessive conditions.