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. 2019 Jul 17;9(1):10350.
doi: 10.1038/s41598-019-46601-1.

SerpinA3 in the Early Recognition of Acute Kidney Injury to Chronic Kidney Disease (CKD) transition in the rat and its Potentiality in the Recognition of Patients with CKD

Andrea Sánchez-Navarro  1   2 , Juan M Mejía-Vilet  2 , Rosalba Pérez-Villalva  1   2 , Diego L Carrillo-Pérez  3   4 , Brenda Marquina-Castillo  5 , Gerardo Gamba  1   2   4 , Norma A Bobadilla  6   7
Affiliations

SerpinA3 in the Early Recognition of Acute Kidney Injury to Chronic Kidney Disease (CKD) transition in the rat and its Potentiality in the Recognition of Patients with CKD

Andrea Sánchez-Navarro et al. Sci Rep. .

Abstract

Recognizing patients at early phases of chronic kidney disease (CKD) is difficult, and it is even more challenging to predict acute kidney injury (AKI) and its transition to CKD. The gold standard to timely identify renal fibrosis is the kidney biopsy, an invasive procedure not usually performed for this purpose in clinical practice. SerpinA3 was identified by high-resolution-mass-spectrometry in urines from animals with CKD. An early and progressive elevation of urinary SerpinA3 (uSerpinA3) was observed during the AKI to CKD transition together with SerpinA3 relocation from the cytoplasm to the apical tubular membrane in the rat kidney. uSerpinA3/alpha-1-antichymotrypsin was significantly increased in patients with CKD secondary to focal and segmental glomerulosclerosis (FSGS), ANCA associated vasculitis (AAV) and proliferative class III and IV lupus nephritis (LN). uSerpinA3 levels were independently and positively associated with renal fibrosis. In patients with class V LN, uSerpinA3 levels were not different from healthy volunteers. uSerpinA3 was not found in patients with systemic inflammatory diseases without renal dysfunction. Our observations suggest that uSerpinA3 can detect renal fibrosis and inflammation, with a particular potential for the early detection of AKI to CKD transition and for the differentiation among lupus nephritis classes III/IV and V.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Urine high-resolution mass spectrometry in CKD rats. (A) Representative acrylamide gel under denaturing conditions and subsequent staining with Coomassie blue of urines from rats with CKD compared to control rats (sham). The identified proteins were mainly between 55 and 72 KDa. (B) SerpinA3 was identified with high-resolution mass spectrometry with a high coverage (44.7%) in urine samples from CKD rats.
Figure 2
Figure 2
Temporal course of renal dysfunction and fibrosis in AKI to CKD transition in the rat. (A) Proteinuria, (B) Renal blood flow (RBF), (C) Creatinine clearance, and (D) Tubulo-interstitial fibrosis since the 1st until the 4th month post-ischemia. Data are represented as the mean ± SE (for sham, n = 4, and for the AKI to CKD transition groups, n = 5 per period). White circles represent sham and black circles represent AKI to CKD transition groups. *p < 0.05 vs. sham group in their respective period.
Figure 3
Figure 3
Timely AKI to CKD transition detection by serpinA3. (A) SerpinA3 mRNA levels in renal cortex during the follow-up of the animals, (B) SerpinA3 protein levels in the renal cortex evaluated by Western Blot 4 months post-ischemia, (C,D) representative microphotographs of serpinA3 immunostaining in renal cortex from the control group, magnification 400 and 800x respectively, (E) Urinary serpinA3 levels during AKI to CKD transition and compared with the control group, (F) Spearman correlation between urine serpinA3 and tubulo-interstitial fibrosis, and (G,H) representative microphotographs of serpinA3 immunostaining in renal cortex from the AKI to CKD transition group, magnification 400 and 800x respectively. Data are represented as mean ± SE. (for sham, n = 4, and for the AKI to CKD transition groups, n = 5 per period). White circles or bar represent sham and black circles or bar represent AKI to CKD transition groups and. *p < 0.05 vs. the sham group in their respective period, ϕp < 0.05 vs. IR + UNx 2nd month and ωp < 0.05 vs. IR + UNx 3rd month.
Figure 4
Figure 4
Renal clinical characteristics and urinary serpinA3 in patients diagnosed with LN. (A) Serum creatinine, (B) Proteinuria, (C) Percentage of renal fibrosis, and (D) WB autoradiography for urinary serpinA3 levels showing all the patients included. (E) Densitometric analysis for WB. (F) Urinary serpinA3 corrected by urinary creatinine. (G) Urinary serpinA3 levels determined by ELISA. (H) Spearman’s correlation of urinary serpinA3 and tubule-interstitial fibrosis. LN III = class III lupus nephritis (n = 18); LN IV = class IV lupus nephritis (n = 18); LN V = class V lupus nephritis (n = 11). Data are presented as Tukey’s box and whiskers plots. Healthy volunteers (n = 20), *p < 0.001 vs. Healthy volunteers, ϕp < 0.001 vs. class V LN.
Figure 5
Figure 5
Serpin A3K immunohistochemistry in renal biopsies. (A–C) Representative micrographs of serpinA3 in a biopsy from healthy donor (Magnification 200x, 400x and 800x, respectively); (D–F) Representative micrographs of serpinA3 from a patient diagnosed with LN class III (Magnification 200x, 400x and 800x, respectively); (G–I) Representative micrographs of serpinA3 from a patient with LN class IV (Magnification 200x, 400x and 800x, respectively); (J–L) Representative micrographs of serpinA3 from patient with LN class V (Magnification 200x, 400x and 800x, respectively). Black arrows point the relocation to apical membrane in CKD patients.
Figure 6
Figure 6
Renal clinical characteristics and urinary serpinA3 in patients diagnosed with FSGS and AAV. (A) Serum creatinine, (B) Proteinuria, (C) Percentage of renal fibrosis, and (D) WB autoradiography for urinary serpinA3 levels showing all the patients included. (E) Densitometric analysis for WB. (F) Urinary serpinA3 corrected by urinary creatinine. (G) Urinary serpinA3 levels determined by ELISA. (H) Spearman’s correlation of urinary serpinA3 and tubule-interstitial fibrosis. Focal Segmental Glomerulosclerosis = FSGS (n = 14); ANCA-associated vasculitis = AAV (n = 19). Data are presented as Tukey’s box and whiskers plots. *p < 0.001 vs. Healthy volunteers, ϕp < 0.001 vs. FSGS.
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