SERPINA4 and Acute Kidney Failure

SERPINA4 has emerged as a candidate gene associated with acute kidney failure in the setting of septic shock, with genetic association studies hinting at its role in modulating the risk for acute kidney injury (PMID:22710204). Evidence comes from multi‐patient studies that evaluated over 1,200 subjects in one cohort and more than 2,500 in another, where single nucleotide polymorphisms in SERPINA4 were reported to correlate with a decreased risk of developing severe kidney injury (PMID:28270177).

The clinical validity of the association is supported by these population‐based studies; however, replication has been inconsistent as a review noted that many candidate gene studies failed to consistently reproduce significant associations (PMID:29161666). As such, the overall evidence for a direct causal role of SERPINA4 in disease remains limited by the lack of segregation data and familial studies.

Genetic evidence in these cohorts, while promising, is based on modest effect sizes identified via SNP analyses without detailed high‐resolution variant data such as complete HGVS‐formatted coding changes. The current data suggests a complex, multifactorial predisposition to acute kidney failure rather than a classic Mendelian inheritance pattern.

Although a specific HGVS variant from SERPINA4 was not provided in the reports, the genetic findings collectively underscore the importance of apoptosis‐related pathways in renal injury. In contrast to the absence of a clearly defined coding variant (e.g. a string such as “c.123A>T (p.Lys41Asn)”), further focused analyses may yield such data to improve diagnostic specificity.

Functional studies further support SERPINA4’s relevance; in vitro assays have demonstrated that kallistatin, the protein product of SERPINA4, exhibits a distinct inhibitory specificity toward human tissue kallikrein. Such kinetic and binding studies, which employed site‐directed mutagenesis and molecular modeling, suggest that altered regulatory effects on proteolytic pathways may contribute to the pathogenesis of acute kidney injury (PMID:10993887).

In summary, while the genetic data for SERPINA4 in acute kidney failure is presently limited by modest association signals and inconsistent replication across studies, the complementary functional evidence provides a plausible mechanistic link through the modulation of apoptotic pathways. Key take‑home: SERPINA4 holds potential as a diagnostic marker and therapeutic target in acute kidney injury, warranting further investigation.

References

• Critical care medicine • 2012 • BCL2 genetic variants are associated with acute kidney injury in septic shock PMID:22710204
• Critical care (London, England) • 2017 • Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock PMID:28270177
• Journal of critical care • 2018 • Genetic variants and acute kidney injury: A review of the literature PMID:29161666
• The Journal of biological chemistry • 2000 • Roles of the P1, P2, and P3 residues in determining inhibitory specificity of kallistatin toward human tissue kallikrein PMID:10993887

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