**6. Concluding Remarks**

NAPlr, isolated from the cytoplasmic fraction of group A streptococcus, has been shown to trap plasmin and maintain its activity and was originally considered as a nephritogenic protein for PSAGN. Indeed, NAPlr deposition and related plasmin activity have been observed to have an almost identical distribution in the glomeruli of early phase PSAGN patients at a high frequency. The interactions among NAPlr, plasmin activity, and SPEB and the association between these elements and complements or immune complexes, both *in vitro* and *in vivo*, should be investigated in future studies.

Some patients with other glomerular diseases, in whom a preceding streptococcal infection is clinically suggested, were found to also show glomerular NAPlr deposition and plasmin activity, and hence, these cases can be referred to as SIRN. Furthermore, such glomerular-staining patterns of NAPlr and plasmin activity are found in some patients with IRGN induced by other bacteria. The amino acid sequence of GAPDH from some types of bacteria show high similarity to the sequence of NAPlr and these bacterial GAPDH molecules appear to have a plasmin-binding ability. Even if the overall similarity is not so high, it is possible that some bacterial GAPDH molecules, which have a similar steric structure at the antibody-binding site, show cross-immunoreactivity to the anti-NAPlr antibody.

It has become evident that bacterial infections are more deeply involved in various renal diseases, including IRGN, than we previously considered. Although the development of noninvasive techniques to detect infections with high sensitivity and high specificity is undoubtedly crucial, the identification of bacterial proteins associated with the pathogenesis of IRGN is also an important ongoing effort. Thus, future studies evaluating the possibility of NAPlr and plasmin activity as common diagnostic biomarkers of bacterial IRGN are anticipated.

**Author Contributions:** Writing the manuscript draft: T.U.; manuscript revision: T.O. All authors have read and agreed to the published version of the manuscript.

**Acknowledgments:** We are grateful to Masayuki Fujino at the AIDS Research Center, National Institute of Infectious Diseases, for performing the database searches regarding amino acids and nucleotide sequences of bacterial GAPDH, and to Nobuyuki Yoshizawa at the Hemodialysis Unit, Showanomori Hospital, for his valuable advice and discussions.

**Conflicts of Interest:** The authors declare no conflict of interest.
