Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. We previously reported that the prevalence of phospholipase A2 receptor (PLA2R)- and thrombospondin type 1 domain containing 7A (THSD7A)-associated MN patients in Japan is 52.7% and 9.1%, respectively. In addition to PLA2R and THSD7A, we assessed the presence of newly discovered target antigens, neural epidermal growth factor-like 1 (NELL-1), semaphorin 3B (SEMA3B), and exostosin 1/exostosin 2 (Ext1/Ext2), in renal specimens from patients with primary and secondary MN by immunohistochemistry. We found enhanced glomerular staining of PLA2R, THSD7A, NELL-1, and Ext1/Ext2 in 53.6%, 8.7%, 1.5%, and 13.0% of the renal samples, respectively, in patients with primary MN. None of the patient specimens showed enhanced staining of SEMA3B. Enhanced glomerular staining of PLA2R, NELL-1, and Ext1/Ext2 was detected in 5.7%, 8.6%, and 22.9% of the patients with secondary MN, respectively. Based on our findings, we recommend the assessment of PLA2R, THSD7A and NELL-1 in addition to clinical information and IgG4 staining to differentiate between primary and secondary MN. This would aid in distinguishing secondary MN patients from primary MN patients who coincidentally have some secondary characteristics.

Technological advances have allowed the discovery of 6 subtypes of membranous nephropathy based on target antigens: M-type phospholipase A 2 receptor (PLA 2 R), thrombospondin type 1 domain-containing 7A (THSD7A), neural epidermal growth factor-like 1 protein, semaphorin 3B, exostosin 1 (EXT1), and EXT2. EXT1/EXT2 are thought to be associated with secondary (autoimmune) membranous nephropathy. Although it has been reported that PLA 2 R-and THSD7A-associated membranous nephropathy have rarely been detected concomitantly, there have been no previous reports demonstrating PLA 2 R-or THSD7A-associated membranous nephropathy with enhanced glomerular staining of EXT1/EXT2. We describe 2 cases of primary membranous nephropathy with enhanced glomerular staining of EXT1/EXT2. Patient 1 was diagnosed with PLA 2 R-associated primary membranous nephropathy, and patient 2 was diagnosed with THSD7A-associated primary membranous nephropathy. Both patients achieved clinical remission in response to immunosuppressive therapy. Neither patient demonstrated signs of autoimmune diseases, and antinuclear antibodies were absent in their sera. Based on these 2 cases, enhanced staining of EXT1/EXT2 in glomeruli, although rare, can be detected in primary membranous nephropathy without autoimmune diseases.

BACKGROUND AND AIMS Acute kidney injury (AKI) is histologically characterized by tubular cell death and inflammation. It has demonstrated that cell death in renal tubule cells on AKI could be introduced by regulated necrosis or apoptosis, but the molecular mechanisms are reported to be different between AKI models [1]. Recently, Dipeptidyl -peptidase-4(DPP4) inhibitors have been reported to ameliorate cisplatin-induced AKI and ischemia-reperfusion-induced AKI [2, 3]. In this study, we examined the effect of teneligliptin, a DPP4 inhibitor, on folic acid (FA)-induced AKI(FA-AKI) model in mice, which is reported to be mainly induced by ferroptosis, one of the regulated necrotic pathways [4]. METHOD C57BL/6J mice (12–14 weeks old) received a single intraperitoneal injection of FA of 250 mg/kg in 0.3 mol/L sodium bicarbonate, and were euthanized 48 h later. Teneligliptin or vehicle were orally administered just before and 24 h after FA infusion, respectively. Blood samples and renal tissue samples were collected at the time of euthanasia for evaluation. RESULTS The increase of serum creatinine (mean 0.297 mg/dL in teneligliptin-treated mice versus 0.833 mg/dL in vehicle-treated mice; P < 0.01) and blood urea nitrogen (mean 72.22mg/dL in teneligliptin-treated mice versus 177.7mg/dL in teneligliptin-treated mice; P = 0.016) were suppressed in teneligliptin-treated mice, compared to vehicle-treated mice (Fig. 1A and B). Histologically, teneligliptin treatment reduced tubular injury score, tubular cell death evaluated with the terminal uridine nick-end labeling (TUNEL) and kidney injury molecule-1 (kim-1) expression in the kidney (Fig. 2A-C). In addition, number of infiltrating Ly6G + neutrophil and number of infiltrating F4/80 + macrophages were decreased in the kidney of teneligliptin-treated mice, compared with that of vehicle-treated mice (Fig. 2D and E). CONCLUSION We found that teneligliptin ameliorated FA-AKI in mice by suppressing necroinflammation in the kidney. Further studies are needed to clarify the underlying mechanisms of the renoprotection.

A 70-year-old man was referred to our department for evaluation of nephrotic syndrome. Renal biopsy revealed membranous nephropathy (MN). Immunohistochemical analysis demonstrated IgG4-positive staining in the glomeruli and interstitial cells. The presence of serum anti-phospholipase A2 receptor (PLA2R) antibody and enhanced staining of PLA2R in the glomeruli was noted. Computed tomography unidentified the extrarenal lesions of IgG4-related disease. He was diagnosed with PLA2R-associated MN possibly complicated with IgG4 related kidney disease (IgG4-RKD). Storiform fibrosis, a typical manifestation of IgG4-RKD, was not apparent. We herein describe a case of serologically and histologically confirmed PLA2R-associated MN with IgG4+ cell infiltration into the interstitium without any signs of IgG4-RD.

Background and Aims Cisplatin is an effective chemotherapeutic agent, but often induces acute kidney injury (AKI). Magnesium (Mg) deficiency is often found in cancer patients, and the nephrotoxicity of cisplatin is exacerbated under Mg deficiency [1]. We previously reported the potential of Dipeptidyl peptidase-4 (DPP-4) inhibitor to attenuate cisplatin nephrotoxicity in rats and diabetic cancer patients [2, 3]. However, it remains to be investigated whether DPP-4 inhibitor can preserve its renoprotective effect under Mg deficiency. The purpose of this study was to examine whether DPP-4 inhibitor can prevent cisplatin-induced AKI even under Mg deficiency. Method Sprague Dawley rats received Mg-deficient diet for 7days to induce Mg deficiency. AKI was induced in rats by injecting cisplatin intravenously. Oral administration of a DPP-4 inhibitor, once a day, was started 1day before injecting cisplatin. Mg sulfate was once injected intraperitoneally just before injecting cisplatin to correct Mg deficiency (Fig. 1A). By using our previous cohort data [3], we divided diabetic cancer patients treated with high-dose cisplatin (>50 mg/m2)-containing regimens into 4 groups according to the use/unused of Mg sulfate or DPP-4 inhibitor. The change of estimated glomerular filtration rate (eGFR) within 2 weeks after cisplatin treatment was compared between the groups. Results At the peak of AKI (day 5), Mg sulfate supplementation significantly attenuated the increase of blood urea nitrogen (BUN), and combination of Mg sulfate and DPP-4 inhibitor further suppressed the increase of BUN as compared to rats received only cisplatin. However, DPP-4 inhibitor alone did not attenuate the increase of BUN under Mg deficiency (Fig. 1B). The result of serum creatinine (sCr) was consistent with that of BUN (Fig. 1C). This effect was associated with a reduced renal cell death as evaluated with the terminal uridine nick-end labeling (TUNEL)+ cells (Fig. 1D).The change of eGFR was significantly less in the patients treated with both of DPP-4 inhibitors/Mg supplementation, compared to those without DPP-4 inhibitors/Mg supplementation. The effect was not found in patients with either DPP-4 inhibitor alone or Mg supplementation alone as compared to those without DPP-4 inhibitor/Mg supplementation (Fig. 2). Conclusion Our results suggested that Mg deficiency must be corrected to exert the renoprotective effect of DPP-4 inhibitor on cisplatin nephrotoxicity. The molecular mechanisms underlying this phenomenon remain to be defined.