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Sensitization to HLA can result in allograft loss for kidney transplantation (KT) patients. Therefore, it is required to develop an appropriate desensitization (DSZ) technique to remove HLA-donor-specific anti-HLA antibody (DSA) before KT. The aim of this research was to investigate whether combined use of the IL-6 receptor-blocking antibody, tocilizumab (TCZ), and bone-marrow-derived mesenchymal stem cells (BM-MSCs) could attenuate humoral immune responses in an allo-sensitized mouse model developed using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and treated with TCZ, BM-MSC, or both TCZ and BM-MSC. We compared HLA.A2-specific IgG levels and subsets of T cells and B cells using flow cytometry among groups. HLA.A2-specific IgG level was decreased in all treated groups in comparison with that in the allo-sensitized control (Allo-CONT) group. Its decrease was the most significant in the TCZ + BM-MSC group. Regarding the B cell subset, combined use of TCZ and BM-MSC increased proportions of pre-pro B cells but decreased proportions of mature B cells in BM (p < 0.05 vs. control). In the spleen, an increase in transitional memory was observed with a significant decrease in marginal, follicular, and long-lived plasma B cells (p < 0.05 vs. control) in the TCZ + BM-MSC group. In T cell subsets, Th2 and Th17 cells were significantly decreased, but Treg cells were significantly increased in the TCZ+BM-MSC group compared to those in the Allo-CONT group in the spleen. Regarding RNA levels, IL-10 and Foxp3 showed increased expression, whereas IL-23 and IFN-γ showed decreased expression in the TCZ + BM-MSC group. In conclusion, combined use of TCZ and BM-MSC can inhibit B cell maturation and up-regulate Treg cells, finally resulting in the reduction of HLA.A2-specific IgG in a highly sensitized mouse model. This study suggests that the combined use of TCZ and BM-MSC can be proposed as a novel strategy in a desensitization protocol for highly sensitized patients.

We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total eplet, antibody (Ab)-verified eplet mismatch analyses, and Ab-verified single molecular analysis to identify HLA-DR/DQ molecular thresholds for the risk of dnDSA development. A time-weighted tacrolimus trough level (TAC-C0) of 5 ng/mL and a TAC-C0 time-weighted coefficient variability (TWCV) of 20% were applied to find the combined effects on dnDSA development. A high level of mismatch for single molecular eplet (DQ ≥ 10), total eplet (DQ ≥ 12), Ab-verified eplet (DQ ≥ 4), and Ab-verified single molecular eplet (DQ ≥ 4) significantly correlated with HLA class II dnDSA development. Class II dnDSA developed mostly in patients with low TAC-C0 and high eplet mismatch. In the multivariable analyses, low TAC-C0 and high eplet mismatch showed the highest hazard ratio for the development of dnDSA. No significant combined effect was observed in dnDSA development according to TWCV. In conclusion, the determination of HLA class II eplet mismatch may improve the risk stratification for dnDSA development, especially in conjunction with tacrolimus trough levels.

IgA nephropathy (IgAN) is a globally well-known primary glomerular nephropathy. Hypertriglyceridemia (HTG) is one factor contributing to atherosclerosis and is a common complication of renal failure. HTG is a significant risk factor for decreased renal function in patients with IgAN. We evaluated the association of HTG with the histopathological features of IgAN patients. A total of 480 patients diagnosed with IgAN via kidney biopsy from eight university hospitals affiliated with the College of Medicine of the Catholic University of Korea were included in the final cohort. Pathological features were evaluated by eight expert pathologists with hospital consensus. HTG was defined as a serum triglyceride (TG) level of ≥150 mg/dL. In the study population analysis, the HTG group was older, with more males; higher body mass index (BMI), low-density lipoprotein cholesterol (LDL-C) and spot urine protein ratio; and lower estimated glomerular filtration rate (eGFR). In the lipid profile analysis, eGFR was negatively correlated with TGs/ high-density lipoprotein cholesterol (HDL) and triglyceride-glucose index (TyG). Proteinuria positively correlated with TGs/HDL, non-HDL/HDL, LDL/HDL, TyG, TGs and LDL. The percentages of global sclerosis (GS), segmental sclerosis (SS) and capsular adhesion (CA), and the scores for mesangial matrix expansion (MME) and mesangial cell proliferation (MCP), were more elevated in the HTG group compared to the normal TG group. Multivariable linear regression analysis showed that the percentages of global sclerosis, segmental sclerosis and capsular adhesion, as well as the scores for mesangial matrix expansion and mesangial cell proliferation, were positively associated with TG level. In binary logistic regression, the HTG group showed a higher risk for global sclerosis and segmental sclerosis. In conclusion, HTG is a significant risk factor for glomerulosclerosis in IgAN.

Hyperuricemia is a significant risk factor for cardiovascular morbidity and chronic kidney disease progression. IgA nephropathy (IgAN) is a well-known primary glomerular nephropathy. Hyperuricemia is associated with a poor prognosis in IgAN patients. We evaluated the association of hyperuricemia with the histopathological severity of IgAN in male and female patients; 658 patients diagnosed with IgAN via kidney biopsy were initially included. Baseline patient data were collected by eight university hospitals affiliated with the College of Medicine of the Catholic University of Korea. Pathological features were independently evaluated by eight expert pathologists working in the hospitals, and the consensus was reached. Of the initial 658 patients, 517 were finally included (253 males and 264 females). Hyperuricemia was defined as a serum uric acid (UA) level >7.0 mg/dL for males and >5.6 mg/dL for females; 108 (42.7%) males and 95 (35.9%) females exhibited hyperuricemia. Compared to the patients with normal UA levels, the global glomerulosclerosis, segmental sclerosis, mesangial matrix expansion (MME), endocapillary proliferation (ECP), interstitial fibrosis (IF), and tubular atrophy (TA) scores were higher in hyperuricemic males and females. In multivariable linear regression, the serum UA level correlated significantly with the MME, ECP, IF, and TA scores of female IgAN patients only.

B cell activating factor (BAFF) is a cytokine that plays a role in the survival, proliferation and differentiation of B cells. We proposed to observe the effects of BAFF inhibition on the humoral immune responses of an allosensitized mouse model using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and were treated with anti-BAFF monoclonal antibody (mAb) (named Sandy-2) or control IgG1 antibody. HLA.A2-specific IgG was reduced in BAFF-inhibited mice compared to the control group (Δ-13.62 vs. Δ27.07, p < 0.05). BAFF inhibition also resulted in increased pre-pro and immature B cell proportions and decreased mature B cells in the bone marrow (p < 0.05 vs. control). In the spleen, an increase in transitional B cells was observed with a significant decrease in marginal and follicular B cells (p < 0.05 vs. control). There was no significant difference in the proportions of long-lived plasma and memory B cells. Microarray analysis showed that 19 gene probes were significantly up- (>2-fold, p < 0.05) or down-regulated (≤2-fold, p < 0.05) in the BAFF-inhibited group. BAFF inhibition successfully reduced alloimmune responses through the reduction in alloantibody production and suppression of B cell differentiation and maturation. Our data suggest that BAFF suppression may serve as a useful target in desensitization therapy.

Several studies reported the effect of obesity on the progression of IgA nephropathy (IgAN). However, the impact of obesity on the clinicopathologic presentation of IgAN remains uncertain. This is a retrospective cross-sectional study from eight university hospitals in South Korea. Patients were categorized into three groups using the Asia-Pacific obesity classification based on body mass index (BMI). Clinical and histopathologic data at the time of renal biopsy were analyzed. Among 537 patients with IgAN, the obese group was more hypertensive and had lower estimated glomerular filtration rate and more proteinuria than other groups. The histologic scores for mesangial matrix expansion (MME), interstitial fibrosis, tubular atrophy, and mesangial C3 deposition differed significantly between the three groups. Among these histopathologic parameters, BMI was independently positively associated with MME score on multivariable linear regression analysis (p = 0.028). Using multivariable logistic regression analysis, the obese group was independently associated with higher MME scores compared to the normal weight/overweight group (p = 0.020). However, BMI was not independently associated with estimated glomerular filtration rate or proteinuria on multivariable analysis. Obesity was independently associated with severe MME in patients with IgAN. Obesity may play an important pathogenetic role in mesangial lesions seen in IgAN.