Endogenous activation of peroxisome proliferator-activated receptor alpha in proximal tubule cells in counteracting phosphate toxicity.

Increased dietary phosphate consumption intensifies renal phosphate burden. Several mechanisms for phosphate-induced renal tubulointerstitial fibrosis have been reported. Considering the dual nature of phosphate as both a potential renal toxin and an essential nutrient for the body, kidneys may possess inherent protective mechanisms against phosphate overload, rather than succumbing solely to injury. However, there is limited understanding of such mechanisms. To identify these mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) analysis of the kidneys of control (Ctrl) and dietary phosphate-loaded (Phos) mice at a time point when the Phos group had not yet developed tubulointerstitial fibrosis. scRNA-seq analysis identified the highest number of differentially expressed genes (DEGs) in the clusters belonging to proximal tubular epithelial cells (PTECs). Based on these DEGs, in silico analyses suggested that the Phos group activated peroxisome proliferator-activated receptor alpha (PPAR-α) and fatty acid ß-oxidation (FAO) in the PTECs. This activation was further substantiated through various experiments, including the use of an FAO activity visualization probe. Compared to wild-type mice, Ppara knockout mice exhibited exacerbated tubulointerstitial fibrosis in response to phosphate overload. Experiments conducted with cultured PTECs demonstrated that activation of the PPAR-α/FAO pathway leads to improved cellular viability under high phosphate conditions. The Phos group mice showed a decreased serum concentration of free fatty acids, which are endogenous PPAR-α agonists. Instead, experiments using cultured PTECs revealed that phosphate directly activates the PPAR-α/FAO pathway. These findings indicate that noncanonical metabolic reprogramming via endogenous activation of the PPAR-α/FAO pathway in PTECs is essential to counteract phosphate toxicity.

Estimated Effect of Restarting Renin-Angiotensin System Inhibitors after Discontinuation on Kidney Outcomes and Mortality.

BACKGROUND: While renin-angiotensin system inhibitors (RASi) have been the mainstream treatment for patients with CKD, they are often discontinued due to adverse effects such as hyperkalemia and acute kidney injury. It is unknown whether restarting RASi after discontinuation improves clinical outcomes. METHODS: Using the OCKR (Osaka Consortium for Kidney disease Research) database, we performed a target trial emulation study including 6,065 patients with an eGFR of 10-60 mL/min/1.73m2 who were followed up by nephrologists and discontinued RASi between 2005 and 2021. With a clone-censor-weight approach, we compared a treatment strategy for restarting RASi within a year after discontinuation with that for not restarting RASi. Patients were followed up for five years at maximum after RASi discontinuation. The primary outcome was a composite kidney outcome (initiation of kidney replacement therapy, a ≥50% decline in eGFR, or kidney failure [eGFR <5 mL/min/1.73m2]). Secondary outcomes were all-cause death and incidence of hyperkalemia (serum potassium levels ≥5.5 mEq/L). RESULTS: Among those who discontinued RASi (mean [standard deviation (SD)] age 66 [15] years, 62% male, mean [SD] eGFR 40 [26] ml/min/1.73m2), 2,262 (37%) restarted RASi within a year. Restarting RASi was associated with a lower hazard of the composite kidney outcome (hazard ratio 0.85 [95% confidence intervals (CIs) 0.78 to 0.93]) and all-cause death (hazard ratio 0.70 [95% CI 0.61 to 0.80]) compared with not restarting RASi. The incidence of hyperkalemia did not differ significantly between the two strategies (hazard ratio 1.11 [95% CI 0.96 to 1.27]). CONCLUSIONS: Restarting RASi after discontinuation was associated with a lower risk of kidney outcomes and mortality but not related to the incidence of hyperkalemia.

Short sleep duration and smoking initiation in university students: a retrospective cohort study.

PURPOSE: The aim of this study was to clarify an association between short sleep duration and smoking initiation. METHODS: Participants eligible for this retrospective cohort study were university students who were admitted to a single national university in Japan between 2007 and 2015. Baseline sleep duration and smoking status were measured using general questionnaires at health checkups at admission. During a 6-year observation period, smoking initiation was assessed using general questionnaires at annual health checkups. Cox proportional hazards models adjusted for clinically relevant factors were used to assess the association between sleep duration and smoking initiation. RESULTS: Of 17,493 men, including 540, 5,568, 8,458, 2,507, and 420 men with sleep duration of < 5, 5-6, 6-7, 7-8, and ≥ 8 h, respectively, smoking initiation was observed in 16.1%, 12.5%, 11.2%, 10.0%, and 11.7%, respectively, during a median observation period of 3.0 years. Men with shorter sleep duration were at a higher risk of smoking initiation (adjusted hazard ratio 1.49 [95% confidence interval 1.19-1.85], 1.11 [1.01-1.22], 1.00 [reference], 0.92 [0.80-1.06], and 1.00 [0.75-1.34], respectively). Of 8,880 women, including 267, 3,163, 4,220, and 1,230 women with sleep duration of < 5, 5-6, 6-7, and ≥ 7 h, respectively, smoking initiation was observed in 4.9%, 2.3%, 2.0%, and 2.2%, respectively, during a median observation period of 3.0 years. A similar dose dependent association was ascertained in women (2.50 [1.39-4.49], 1.18 [0.86-1.62], 1.00 [reference], and 1.22 [0.79-1.89], respectively). CONCLUSION: This study clarified that university students with short sleep duration were vulnerable to smoking initiation.

Association between urinary uric acid excretion and kidney outcome in patients with CKD.

Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid crystallization, especially in acidified urine, which could be toxic to the kidney. To assess how tubular urate handling affects kidney outcomes, we conducted a retrospective cohort study including 1042 patients with estimated glomerular filtration rates (eGFR) of 15-60 mL/min/1.73 m2. The exposures were fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio (UUCR). The kidney outcome was defined as a halving of eGFR from baseline or initiating kidney replacement therapy. The median FEUA and UUCR were 7.2% and 0.33 g/gCre, respectively. During a median follow-up of 1.9 years, 314 kidney outcomes occurred. In a multivariate Cox model, the lowest FEUA quartile exhibited a 1.68-fold higher rate of kidney outcome than the highest FEUA quartile (95% confidence interval, 1.13-2.50; P = 0.01). Similarly, lower UUCR was associated with a higher rate of kidney outcome. Notably, patients in the highest quartile of FEUA and UUCR were at the lowest risk of kidney outcome even among those with aciduria. In conclusion, lower FEUA and UUCR were associated with a higher risk of kidney failure, suggesting that increased urate reabsorption is harmful to the kidney.

Novel therapeutic strategies targeting abnormal T-cell signaling in systemic lupus erythematosus.

Therapeutic strategies for autoimmune diseases have been based on the use of glucocorticoids and immunosuppressive agents that broadly suppress immune responses. Therefore, organ damage from long-term use and infections due to immunocompromised status have been significant issues. Safer immunosuppressants and biological agents are now available, but there is still an urgent need to develop specific drugs to replace glucocorticoids. T-lymphocytes, central players in immune responses, could be crucial targets in the treatment of autoimmune diseases. Extensive research has been conducted on the phenotypic changes of T-cells in systemic lupus erythematosus, which has led to the discovery of various therapeutic strategies. In this comprehensive review, we discuss novel treatment approaches and target molecules with expected effectiveness in humans and mice, based on research for lymphocytes involved in autoimmune diseases, especially T-cells in SLE.

Development of a three-dimensional HPLC system for the determination of serine, threonine and allo-threonine enantiomers in the plasma of patients with chronic kidney disease.

A highly-selective three-dimensional high-performance liquid chromatographic (3D-HPLC) system was developed for the determination of serine (Ser), threonine (Thr) and allo-threonine (aThr) enantiomers in human plasma to screen the new biomarker of chronic kidney disease (CKD). d-Ser has been reported to be the candidate biomarker of CKD, however, multiple biomarkers are still required. Therefore, Ser analogs of hydroxy amino acids are the focus in the present study. For the sensitive analysis, the amino acids were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole and detected by their fluorescence. The 3D-HPLC system consisted of a reversed-phase column (Singularity RP18, 1.0 × 250 mm), an anion-exchange column (Singularity AX, 1.0 × 150 mm) and a Pirkle-type chiral stationary phase (Singularity CSP-013S, 1.5 × 250 mm). The developed method was validated and applied to the human plasma samples obtained from 15 healthy volunteers and 165 CKD patients. The concentrations of the d-forms were 1.13-2.26 (Ser), 0.01-0.03 (Thr) and 0.04-0.10 µM (aThr) for the healthy volunteers and 0.95-19.0 (Ser), 0-0.57 (Thr) and 0.04-1.02 µM (aThr) for the CKD patients. The concentrations and the %d values of all the target d-amino acids were increased along with the decreasing of renal function and further investigation for clinical applications are expected.

The association between embedded catheter implantation and hospitalization costs for peritoneal dialysis initiation: a retrospective cohort study.

BACKGROUND: Compared with the conventional peritoneal dialysis (PD) catheter insertion, embedding PD catheter implantation is one of the procedures for planned PD initiation. However, facilities where embedded PD catheter implantation is available are limited, and the impact of embedded PD catheter implantation on hospitalization cost and length of hospitalization is unknown. METHODS: This retrospective single-center cohort study included 132 patients with PD initiation between 2005 and 2020. The patients were divided into two groups: 64 patients in the embedding group and 68 patients in the conventional insertion group. We created a multivariable generalized linear model (GLM) with the gamma family and log-link function to evaluate the association among catheter embedding, the duration and medical costs of hospitalization for PD initiation. We also evaluated the effect modification between age and catheter embedding. RESULTS: Catheter embedding (ß coefficient - 0.13 [95% confidence interval - 0.21, - 0.05]) and age (per 10 years 0.08 [0.03, 0.14]) were significantly associated with hospitalization costs. Catheter embedding (- 0.21 [- 0.32, - 0.10]) and age (0.11 [0.03, 0.19]) were also identified as factors significantly associated with length of hospitalization. The difference between the embedding group and the conventional insertion group in hospitalization costs for PD initiation (P for interaction = 0.060) and the length of hospitalization (P for interaction = 0.027) was larger in young-to-middle-aged patients than in elderly patients. CONCLUSIONS: Catheter embedding was associated with lower hospitalization cost and shorter length of hospitalization for PD initiation than conventional PD catheter insertion, especially in young-to-middle-aged patients.

Living Arrangements Predict Frequent Alcohol Consumption Among University Students: A Retrospective Cohort Study.

PURPOSE: This study aimed to confirm the clinical impact of living arrangements on incidence of frequent alcohol consumption in university students. DESIGN: A retrospective cohort study. SETTING: A national university in Japan. SUBJECTS: 17,774 university students. MEASURES: The association between living arrangements on admission and the incidence of frequent alcohol consumption (≥4 days/week) was assessed using multivariable-adjusted Cox proportional-hazards models. RESULTS: Among 5,685, 692, and 5,151 male students living with family, living in the dormitory, and living alone, 5.0%, 6.2%, and 5.8% reported frequent alcohol consumption during the median observational period of 3.0 years, respectively. Living in the dormitory and living alone were identified as significant predictors of frequent alcohol consumption (multivariable-adjusted hazard ratios: 1.00 [reference], 1.39 [1.01-1.92], and 1.21 [1.03-1.42], respectively). On the contrary, living arrangements were not associated with the incidence of frequent alcohol consumption among of 6,091 female students, partly because of low incidence of frequent alcohol consumption (2.3%, 1.4%, and 2.6%, respectively). CONCLUSIONS: Living arrangements predicted frequent alcohol consumption among male university students, whereas not among female university students.

Interstitial Eosinophilic Aggregates and Kidney Outcome in Patients with CKD.

BACKGROUND: Interstitial eosinophilic aggregates are observed in various kidney diseases, but their clinical implications remain unknown. We assessed the association between interstitial eosinophilic aggregates and kidney outcomes and further analyzed the association between blood eosinophil count, as a surrogate for interstitial eosinophilic aggregates, and the risk of kidney failure in patients with advanced CKD. METHODS: We analyzed datasets from two retrospective cohort studies: ( 1 ) the kidney biopsy cohort including 563 patients who underwent native kidney biopsy at Osaka University Hospital between 2009 and 2021 and ( 2 ) the retrospective CKD cohort including 2877 patients with an eGFR of 10-60 ml/min per 1.73 m 2 referred to the nephrology outpatient center at Osaka University Hospital between 2005 and 2018. Interstitial eosinophilic aggregates were defined as ≥5 interstitial eosinophils in the high-power field on hematoxylin and eosin staining. This study outcome was initiation of KRT or ≥40% decline in eGFR. RESULTS: In the kidney biopsy cohort, interstitial eosinophilic aggregates were found in 17% of patients, most frequently in those with diabetic nephropathy (50%). Interstitial eosinophilic aggregates were associated with a higher rate of the composite kidney outcome after adjustment for clinical and histological variables (hazard ratio, 3.61; 95% confidence interval, 2.47 to 5.29; P < 0.001). LASSO revealed that blood eosinophil count was the strongest predictor of interstitial eosinophilic aggregates. In the retrospective CKD cohort, higher baseline and time-updated blood eosinophil counts were significantly associated with a higher rate of KRT initiation in Cox proportional hazards models and marginal structural models. CONCLUSIONS: Interstitial eosinophilic aggregates were associated with a higher risk of a composite of KRT initiation or ≥40% decline in eGFR. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_12_08_CJN0000000000000277.mp3.

Hepatic phosphate uptake and subsequent nerve-mediated phosphaturia are crucial for phosphate homeostasis following portal vein passage of phosphate in rats.

Fibroblast growth factor 23, parathyroid hormone, and 1,25-dihydroxyvitamin D are critical in phosphate homeostasis. Despite these factors' importance, regulators of phosphaturia in the acute postprandial phase remain largely unknown. This study investigated the mechanism of acute phosphate regulation in the postprandial phase in rats. Duodenal administration of radiolabeled phosphate (32P) showed that 32P levels in the inferior vena cava (IVC) blood were lower than those in the portal vein (PV) blood. Serum phosphate concentration transiently increased 5 min after phosphate solution administration through IVC, while it was maintained after the administration through PV. Phosphate administration through both IVC and PV resulted in increased fractional excretion of phosphate (FEPi) at 10 min without elevation of the known circulating factors, but urinary phosphate excretion during the period was 8% of the dose. Experiments using 32P or partial hepatectomy showed that the liver was one of the phosphate reservoirs. The elevation of FEPi and suppression of sodium-phosphate cotransporter 2a in the kidney at 10 min was attenuated in rats with SCH23390, hepatic denervation, or renal denervation, thus indicating that the liver communicated with the kidney via the nervous system to promote phosphaturia. These results revealed previously unknown mechanisms for serum phosphate maintenance.

Preoperative hypomagnesemia as a possible predictive factor for postoperative increase of transvalvular pressure gradient in hemodialysis patients treated with transcatheter aortic valve implantation.

BACKGROUND: Patients undergoing maintenance hemodialysis (HD) with severe aortic stenosis are at a high risk for bioprosthetic valve dysfunction after transcatheter aortic valve implantation (TAVI). Currently, preoperative factors that predict the occurrence of valve dysfunction after TAVI on HD patients remain to be elucidated. The aim of this study is to analyze the association between preoperative clinical factors and valve stenosis after TAVI on HD patients. METHODS: Twenty-four of HD patients who underwent TAVI at our institution between April 2012 and January 2016 were analyzed. The mean aortic transvalvular pressure gradient (MPG) and effective orifice area index (EOAi) were assessed by serial echocardiography. Associations between preoperative clinical factors and time-series changes in MPG were examined using mixed-effects linear regression model for repeated measures. RESULTS: Three patients developed severe structural valve deterioration with calcific valve stenosis requiring reoperation. A multivariate linear mixed-effects model showed that lower serum magnesium (sMg) levels were associated with the increase of MPG after TAVI (beta-coefficient = 0.019, p = 0.03). No correlation was observed with serum calcium, phosphorus, or intact parathyroid hormone. Time-series changes of MPG and EOAi had significant difference between lower and higher sMg group. All 3 of the patients who underwent reoperation showed lower preoperative sMgs. CONCLUSION: Among bone-mineral metabolism markers, preoperative hypomagnesemia was associated with the increase of MPG after TAVI, suggesting that hypomagnesemia could predict post-TAVI valve dysfunction in HD patients. Further studies with larger sample sizes are warranted.

Skipping Breakfast and Incidence of Frequent Alcohol Drinking in University Students in Japan: A Retrospective Cohort Study.

Frequency of alcohol drinking is a potential predictor of binge drinking of alcohol, a serious social problem for university students. Although previous studies have identified skipping breakfast as a predictor of various health-compromising behaviors and cardiometabolic diseases, few studies have assessed the association between skipping breakfast and the incidence of frequent alcohol drinking. This retrospective cohort study included 17,380 male and 8799 female university students aged 18-22 years admitted to Osaka universities between 2004 and 2015. The association between breakfast frequency (eating every day, skipping occasionally, and skipping often/usually) and the incidence of frequent alcohol drinking, defined as drinking ≥4 days/week, was assessed using multivariable-adjusted Cox proportional hazards models. During the median observational period of 3.0 years, 878 (5.1%) men and 190 (2.2%) women engaged in frequent alcohol drinking. Skipping breakfast was significantly associated with the incidence of frequent alcohol drinking (adjusted hazard ratios [95% confidence interval] of eating every day, skipping occasionally, and skipping often/usually: 1.00 [reference], 1.02 [0.84-1.25], and 1.48 [1.17-1.88] in men; 1.00 [reference], 1.60 [1.03-2.49], and 3.14 [1.88-5.24] in women, respectively). University students who skipped breakfast were at a higher risk of frequent alcohol drinking than those who ate breakfast every day.

Reduction of Cell Surface T-Cell Receptor by Non-Mitogenic CD3 Antibody to Mitigate Murine Lupus.

T-cells are critically involved in the pathogenesis of systemic lupus erythematosus. Although treatment with the anti-CD3 antibody has been reported to be effective in several autoimmune disease animal models including lupus, the immunosuppressive mechanisms remain obscure because of its pleiotropic in vivo kinetics. In this study, a conventional anti-CD3 (2C11C) and a non-mitogenic anti-CD3 with a manipulated Fc region (2C11S) were compared to elucidate the underlying mechanism of action. The efficacy and safety of 2C11S in vivo were demonstrated by sustained TCR reduction for a longer period as compared to 2C11C and no induction of cytokine release or T-cell depletion. Anti-CD3s were administered to NZB/W F1 (BWF1) mice at different time points for individual periods. The short-term treatment with 2C11S in the early phase of lupus suppressed the autoantibody associated with the reduction of germinal center B-cells. Treatment in the late phase attenuated lupus nephritis without affecting autoantibodies or differentiation of effector T-cells. The effect of reduced TCR in the development of autoimmunity was examined by CD3ζ heterozygous-deficient mice, in which T-cells had reduced TCR intensity but showed normal TCR signaling response. Autoantibody and lupus nephritis were attenuated significantly in CD3ζ heterozygous-deficient lupus-prone mice. Collectively, the reduction of surface TCR by non-mitogenic anti-CD3 could sufficiently suppress the development of lupus.

Genetic Background and Clinicopathologic Features of Adult-onset Nephronophthisis.

INTRODUCTION: Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH. METHODS: We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes. RESULTS: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-µm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication. CONCLUSIONS: In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients.

Single cell RNA sequencing uncovers cellular developmental sequences and novel potential intercellular communications in embryonic kidney.

Kidney development requires the coordinated growth and differentiation of multiple cells. Despite recent single cell profiles in nephrogenesis research, tools for data analysis are rapidly developing, and offer an opportunity to gain additional insight into kidney development. In this study, single-cell RNA sequencing data obtained from embryonic mouse kidney were re-analyzed. Manifold learning based on partition-based graph-abstraction coordinated cells, reflecting their expected lineage relationships. Consequently, the coordination in combination with ForceAtlas2 enabled the inference of parietal epithelial cells of Bowman's capsule and the inference of cells involved in the developmental process from the S-shaped body to each nephron segment. RNA velocity suggested developmental sequences of proximal tubules and podocytes. In combination with a Markov chain algorithm, RNA velocity suggested the self-renewal processes of nephron progenitors. NicheNet analyses suggested that not only cells belonging to ureteric bud and stroma, but also endothelial cells, macrophages, and pericytes may contribute to the differentiation of cells from nephron progenitors. Organ culture of embryonic mouse kidney demonstrated that nerve growth factor, one of the nephrogenesis-related factors inferred by NicheNet, contributed to mitochondrial biogenesis in developing distal tubules. These approaches suggested previously unrecognized aspects of the underlying mechanisms for kidney development.

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections.

Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

Dynamics of D-serine reflected the recovery course of a patient with rapidly progressive glomerulonephritis.

We experienced a case of a 36-year-old female with rapidly progressive glomerulonephritis (RPGN) due to anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis and systemic lupus erythematosus (SLE) nephritis. Chiral amino acid metabolomics revealed a prominent profile of D-serine in this patient. At the fulminant period of RPGN, the level of plasma D-serine, a potential biomarker in CKD that reflects actual glomerular filtration ratio (GFR), was extremely high. On the other hand, urinary fractional excretion (FE) of D-serine, which was usually much higher than that of L-isoform, was 0% in this patient. These abnormal D-serine profiles normalized in response to the intensive treatment. Normalizations of blood D-serine levels were in parallel with those of blood creatinine levels and potentially reflect the recovery of GFR. FE of D-serine increased transiently before the normalization of D-serine profile, suggesting that kidney promotes urinary excretion of D-serine for the normalization of plasma D-serine level. These unexplored clinical features of D-serine well reflected the clinical course of this patient. Blood D-serine level can also serve as a biomarker in acute kidney injury (AKI) or RPGN, and, in combination with FE of D-serine, may render the clinical practitioners to judge the efficacy of intensive treatments.

Natural and modified IL-2 for the treatment of cancer and autoimmune diseases.

Interleukin-2 (IL-2) is a pleiotropic cytokine required for both effector lymphocyte proliferation/differentiation and regulatory T cell expansion/survival. Ability to receive IL-2 signals is defined by the affinity to distinct IL-2-receptor-complexes expressed on each subset of cells. While IL-2 targets anti-tumor cytotoxic lymphocytes (CTLs) for the treatment of patients with melanoma or renal cell carcinoma, IL-2 directed at regulatory T (Treg) cells could have potential therapeutic value in several immune-related diseases including chronic graft-versus-host disease (cGVHD), type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). A variety of IL-2 alteration has been made to deliver IL-2 to the proper target, including mutant IL-2, IL-2-fusion proteins and anti-IL-2 antibodies. Experimental and clinical trials using IL-2 are expanding to diverse group of diseases including solid organ transplantation. Although the sustainability and efficiency of IL-2-responding cells in controlling disease activity are still not fully understood, the results of clinical trials will provide a basis of the most effective regimen for each disease.

VEGF-A Links Angiolymphoid Hyperplasia With Eosinophilia (ALHE) to THSD7A Membranous Nephropathy: A Report of 2 Cases.

Autoantibodies against thrombospondin type 1 domain-containing 7A (THSD7A) cause membranous nephropathy (MN); however, the mechanisms involved in THSD7A expression and immunization are uncertain. We present 2 cases of THSD7A-associated MN accompanied by angiolymphoid hyperplasia with eosinophilia (ALHE), a benign tumor characterized by proliferation of plump endothelial cells. Prednisolone therapy, but not surgical resection of ALHE tumors, successfully suppressed eosinophilia and proteinuria in both cases. Because ALHE is characterized by the proliferation of plump endothelial cells, we focused on the roles of vascular endothelial growth factor A (VEGF-A) in MN pathogenesis. We found that plump endothelial cells in ALHE modestly expressed THSD7A in both cases. We also found that eosinophils in ALHE expressed VEGF-A, which upregulated THSD7A expression, especially under T-helper type 2-prone conditions in cultured endothelial cells. Furthermore, double-positive cells for THSD7A and CD83 surrounded the proliferated small vessels. Our results suggest that VEGF-A-induced THSD7A expression outside the kidney may be important for MN pathogenesis.