Homocysteine and IgA Nephropathy: Observational and Mendelian Randomization Analyses
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide and a leading cause of end-stage renal disease (ESRD) in young adults. Despite its clinical significance, modifiable risk factors to slow disease progression remain limited. Elevated plasma homocysteine, a sulfur-containing amino acid intermediate, is a hallmark of chronic kidney disease (CKD) and nearly universal in ESRD. However, the role of homocysteine in IgAN—specifically its causal relationship with clinical-pathological features—has been understudied. This study combined observational and Mendelian randomization (MR) analyses to address three questions: (1) whether plasma homocysteine is elevated and associated with disease severity in IgAN; (2) whether genetic variants in homocysteine metabolism influence its levels; and (3) whether homocysteine exerts causal effects on IgAN outcomes.
Observational Analysis of Plasma Homocysteine in IgAN
The study enrolled 108 biopsy-proven IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls. Plasma homocysteine levels were measured using the ARCHITECT Homocysteine Reagent Kit. Strikingly, 93.52% (101/108) of IgAN patients exhibited hyperhomocysteinemia (>10 μmol/L), with a median level of 18.32 μmol/L (interquartile range [IQR]: 13.01–25.87). This was significantly higher than in MCD patients (median: 11.15 μmol/L, IQR: 9.43–14.03; Z = −5.29, P < 0.01) and healthy controls (median: 10.00 μmol/L, IQR: 8.34–12.14; Z = −8.76, P < 0.01) but comparable to LN patients (median: 14.50 μmol/L, IQR: 11.53–18.65; P = 0.19).
Associations with Clinical-Pathological Features
IgAN patients were stratified into quartiles based on homocysteine levels (Group 1: 25.87 μmol/L). Key findings included:
- Renal Function: Homocysteine correlated with worsening renal parameters. Serum creatinine rose progressively across quartiles (median: 77.00, 100.00, 129.00, and 150.00 μmol/L; P < 0.01), while estimated glomerular filtration rate (eGFR) declined (median: 100.52, 74.23, 52.68, and 42.67 mL/min/1.73 m²; P < 0.01).
- Blood Pressure: Systolic blood pressure increased from 120.00 mmHg (Group 1) to 130.00 mmHg (Group 4; P = 0.05). Diastolic blood pressure also rose significantly (P < 0.01).
- Pathological Lesions: Tubular atrophy and interstitial fibrosis (T lesions) worsened with higher homocysteine. In Group 1, 62.96% had T0 (no fibrosis), but this dropped to 14.81% in Group 4, where 48.15% had severe T2 lesions (P < 0.01).
Notably, homocysteine showed no association with proteinuria, serum IgA levels, or IgA/C3 deposition in renal biopsies, suggesting specificity to fibrotic and hemodynamic pathways.
Mendelian Randomization: Testing Causality
To disentangle causation from correlation, MR analysis leveraged the methylenetetrahydrofolate reductase (MTHFR) C677T variant (rs1801133), a missense mutation impairing homocysteine metabolism. The T allele is linked to reduced enzyme activity and elevated homocysteine.
Genetic Association with Homocysteine
In 108 IgAN patients, each T allele increased homocysteine by 7.12 μmol/L (P < 0.01) after adjusting for age and sex. Patients with the TT genotype had markedly higher levels (median: 25.93 μmol/L) versus CT (17.07 μmol/L) and CC (18.17 μmol/L; P = 0.01). A Cragg-Donald F-statistic of 18.3 (>10) confirmed the variant’s strength as a genetic instrument.
Causal Effects on IgAN Outcomes
In 1,686 IgAN patients, MR analysis revealed causal effects of genetically elevated homocysteine on:
- Serum Creatinine: A 1 μmol/L rise in homocysteine increased creatinine by 0.76 μmol/L (P = 0.02).
- Blood Pressure: Each μmol/L increase elevated systolic pressure by 0.26 mmHg (P = 0.02) and diastolic pressure by 0.20 mmHg (P = 0.01).
- T Lesions: Higher homocysteine directly worsened tubular atrophy/interstitial fibrosis (β = 0.01 per μmol/L; P = 0.01).
No causal relationships were observed with eGFR, proteinuria, or Oxford MEST scores (mesangial hypercellularity, endocapillary proliferation, segmental sclerosis).
Mechanistic and Clinical Implications
The consistency between observational and MR findings supports homocysteine’s role in IgAN progression. Mechanistically, homocysteine promotes endothelial dysfunction, oxidative stress, and inflammation—key drivers of hypertension and renal fibrosis. For example, homocysteine upregulates pro-inflammatory cytokines (IL-6, IL-8, MCP-1) and adhesion molecules, fostering vascular injury and collagen deposition. These pathways align with the observed associations with blood pressure and T lesions.
Clinically, over 90% of IgAN patients exhibited hyperhomocysteinemia, yet current guidelines lack targeted therapies. The MR results suggest homocysteine-lowering interventions (e.g., folate, vitamin B12) could mitigate renal decline. This aligns with prior trials showing folate reduces homocysteine by ~25% and slows CKD progression. However, dedicated randomized controlled trials in IgAN are warranted.
Study Limitations
The study’s cross-sectional design limits causal inferences from observational data. While MR strengthens causality, it relies on the MTHFR variant’s specificity. Pleiotropy—where the variant affects outcomes via pathways beyond homocysteine—cannot be fully excluded. Additionally, the homogeneous Chinese cohort may limit generalizability.
Conclusion
This dual analytical approach robustly links homocysteine to renal dysfunction, hypertension, and fibrosis in IgAN. The findings highlight homocysteine as a modifiable risk factor, urging further research into therapeutic strategies. Given folate’s safety and affordability, homocysteine-lowering regimens could offer a feasible adjunct to current IgAN management.
doi.org/10.1097/CM9.0000000000000613
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