Shaojun Liu

Ischemia–reperfusion injury (IRI) causes acute kidney injury (AKI) and transplant dysfunction. NKG2D ligands (human MICA and murine RAE-1/H60) drive immune activation, while Roxadustat (FG-4592) is reportedly renoprotective. We hypothesized that Roxadustat modulates these ligands in renal IRI. MICA expression was assessed in biopsies from AKI and post-renal transplantation (PRT) patients versus controls. Male Balb/c mice received Roxadustat or vehicle before unilateral IRI, followed by assessment of kidney injury and HIF-1α, RAE-1, and H60 expression. In vitro, human and murine tubular cells underwent hypoxia/reoxygenation with or without FG-4592 pretreatment, and ligand expression was analyzed. Our results showed that MICA expression was elevated in kidney tissues from individuals with AKI or PRT compared with controls. In mice, FG-4592 pretreatment attenuated renal IRI-induced dysfunction and tubular injury, concurrently stabilizing HIF-1α protein levels. Notably, FG-4592 treatment enhanced the expression of murine NKG2D ligands at the transcriptional and translational levels in renal IRI. This effect was corroborated in vitro, where hypoxia/reoxygenation upregulated MICA in human and RAE-1 in mouse tubular cells, a response potentiated by FG-4592. In conclusion, Roxadustat protects against renal IRI but upregulates NKG2D ligands, warranting further study of its mechanisms and consequences in AKI/PRT.

Membranous nephropathy (MN) is characterized by subepithelial immune complex deposits of IgG, particularly anti-Phospholipase A2 Receptor (anti-Pla2r). However, presence of IgA co-deposition along subepithelial region of the glomerular capillary walls has not been extensively investigated. Five hundred thirty-one biopsy-proven MN patients from Huashan Hospital were screened for capillary IgA deposition. Clinical, biological and histopathological data were collected at biopsy and during follow-ups. A propensity score matched cohort was used to compare treatment response and outcomes between MN patients with capillary co-deposition of IgG and IgA (cIgA-MN) and MN without. Immunofluorescence was used to detect IgA, IgG, Galactose deficient-IgA1 (Gd-IgA1) and Pla2r deposition. ELISA was performed to measure circulating Gd-IgA1 level. IgA and IgG subtypes of sera anti-Pla2r antibodies were investigated by indirect immunofluorescence and validated by ELISA. Fifty-three of 531 MN patients exhibited capillary IgA co-deposition with IgG. Secondary causes were identified in 19 of 53 cIgA-MN patients. The remaining 34 primary cIgA-MN patients had median proteinuria of 6.1 g/day and showed no crescents and mild endocapillary proliferation. 73.5% cIgA-MN patients were positive for Pla2r. Gd-IgA1 was absent in glomeruli of cIgA-MN patients and circulating Gd-IgA1 levels were similar to those in MN patients without IgA deposition. Meanwhile, circulating IgA-type anti-Pla2r antibodies were detected in a subset of cIgA-MN patients. Outcome analysis revealed comparable remission rates and progression to end-stage kideny disease between cIgA-MN and MN without IgA deposition. This study highlights clinical and pathological features of cIgA-MN, suggesting complex immune responses involving IgA in MN. IgA co-deposition did not significantly alter treatment responses or long-term outcomes.

There have been some shifts in the frequency and distribution of biopsy-proven renal diseases in China over recent years. The aim of the study was to investigate the changing spectrum of renal diseases from the view of kidney biopsy data in a single center of China. A total of 10,996 cases of native renal biopsies from patients aged ≥15 years old in Huashan Hospital, Fudan University, between 2008 and 2018 were analyzed retrospectively. The results showed that primary glomerular nephropathy (PGN) remained the most common biopsy-proven renal disease (69.42% of total), with IgA nephropathy (IgAN) accounting for 44.40% of PGN, membranous nephropathy (MN) for 28.55%, minimal change disease (MCD) for 13.26% and focal segmental glomerulosclerosis (FSGS) for 8.00%. During the study period, the proportion of MN in PGN appeared an increasing tendency, while that of IgAN and MCD remained stable and that of FSGS showed a decline. Secondary glomerular nephropathy (SGN) constituted 21.54% of total cases, among which the leading two diseases were lupus nephritis (LN) and Henoch-Schonlein purpura nephritis (HSN) which accounted for 41.08% and 19.11% respectively. The 11-year retrospective study revealed that PGN was the predominant histologic diagnosis among patients undergoing renal biopsy and the most frequent type of PGN remained to be IgAN, followed by MN which increased dramatically.

MRX-8 is a novel polymyxin for carbapenem-resistant Gram-negative infections that has been recently evaluated in Phase I clinical trials. Herein, its pharmacokinetics (PK) and nephrotoxicity in rats are reported for the first time. This study aimed at pre-clinical PK and safety assessments. An LC-MS/MS method was developed to determine concentrations of MRX-8 and its major deacylation metabolite, MRX-8039, in rat plasma. Animals were administered a single dose of MRX-8 (2, 4, 6, and 8 mg/kg) or comparator polymyxin B (PMB) (4 and 8 mg/kg) to compare the kidney injury known for the polymyxin drug class. Nephrotoxicity was evaluated using serum creatinine, blood urea nitrogen (BUN) biomarkers, and renal histopathology. In rats, MRX-8 displayed linear PK within the range of 2–8 mg/kg, with approximately 4% of MRX-8 converted to MRX-8039. MRX-8 induced only mild increases in serum creatinine and BUN levels, with an apparent decrease in nephrotoxicity within 24 h, in contrast to PMB, which exhibited a significant and more persistent toxicity. Additional nephrotoxicity biomarkers (plasma NGAL and urinary NGAL, KIM-1, and TIMP-1) have confirmed attenuated MRX-8 kidney injury. Histopathology has revealed significantly greater cellular/tissue toxicity for PMB as compared to MRX-8 (variances of p = 0.008 and p = 0.048 vs. saline control, respectively). Thus, MRX-8 induces a mild and reversible kidney injury in rats compared to PMB. These data support a continued evaluation of the novel polymyxin in human trials.

The purpose of this study was to analyze the clinical, pathological, prognostic features and treatment response of the coexistence of focal segmental glomerulosclerosis lesions with idiopathic membranous nephropathy.

Objective: Adult immunoglobulin A vasculitis (IgAV) is documented to be associated with more renal involvement and poorer renal outcomes compared to children, but adult IgAV nephritis (IgAV-N) data are rather limited. The present study aimed to describe the characteristics of adult IgAV-N and investigate the long-term prognostic factors.Methods: Clinical and morphological data from 106 adult patients with biopsy-proven IgAV-N and follow-up data from 94 patients in a single Chinese center were analyzed in this retrospective study. Median follow-up time interval was 102 months.Results: The median age of patients with IgAV-N at biopsy was 38 (IQR 24-53) years, and 52.8% were male. The median blood pressure was 126/80 mmHg, and 25.5% of patients were hypertensive at baseline. The median initial proteinuria was 1.4 (IQR 0.7-2.2) g/day and estimated glomerular filtration rate (eGFR) was 103 (IQR 84-121) mL/min/1.73 m². The median time interval of onset to biopsy was 8 (IQR 3-40) weeks. In biopsy, the median percentage of global sclerosis was 5.9% (IQR 0.0-13.8), whereas 45.3% of patients had interstitial fibrosis and tubular atrophy. Further, during follow-up, 7.4% patients died, 4.3% patients progressed to endstage kidney disease (ESKD), and 6.4% patients developed > 30% eGFR reduction from baseline. Multivariate Cox proportional analyses revealed hypertension (HTN) history and > 10% global sclerosis at presentation were independent prognostic factors for poor outcome.Conclusion: The present adult IgAV-N cohort revealed a relatively young onset age, and lower incidence of nephrotic syndrome and ESKD. Moreover, nonimmune factors such as history of HTN and renal chronic histological lesions in biopsy played a crucial role in prognosis of IgAV-N.

Background This study aimed to investigate the role of neurofascin186 (NF186) in the pathogenesis of the concurrent focal segmental glomerulosclerosis (FSGS) in CIDP-like autoimmune nodopathy patients. Methods We presented a case of CIDP-like autoimmune nodopathy complicated with FSGS. We measured NF186 antibodies by cell-binding assay (CBA) method. We performed immunofluorescence analysis in the renal cryosection samples from a patient with minimal nephropathy with rabbit anti-NF186 antibody or NF186 antibody positive human serum. Then we performed western blotting of recombinant NF186 protein and component of NF186 including Ig and FNIII domains incubating with human serum and corresponding rabbit polyclonal antibody. Cases of CIDP complicated with FSGS were searched form PubMed and reviewed. Results We reported a 66-year-old Chinese woman with CIDP-like autoimmune nodopathy and concurrent FSGS. Her NF186 antibody was positive. The fluorescent signal for NF186 was detected in the renal tissue sections of the patient with minimal nephropathy. The staining for NF186 matched the podocyte spatially. In western blotting analysis, patients had antibodies in their serum recognizing the NF186 protein and their antibodies recognized the Ig domain of NF186. 3 cases of CIDP-like autoimmune nodopathy with positive NF186 antibody and FSGS have been reported. All these patients were responsive to corticosteroids rather than the intravenous immunoglobulin, in terms of both the neuropathy and renal disease. Conclusions NF186 was probably a targeted antigen in the pathogenesis of concurrent FSGS in CIDP-like autoimmune nodopathy with positive NF186 antibody. CIDP-like autoimmune nodopathy with positive NF186 antibody and FSGS is a rare entity, which may be responsive to corticosteroids combined with immunosuppressant.