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Introduction:The number of patients with chronic kidney disease (CKD) is increasing worldwide. Cognitive impairment is one of the comorbidities of CKD. With the increased number of aged population, novel biomarkers of impaired cognitive function are required. Intra-body profile of amino acid (AA) is reportedly altered in patients with CKD. Although some AAs act as neurotransmitters in the brain, it is not clear whether altered AA profile are associated with cognitive function in patients with CKD. Therefore, intra-brain and plasma levels of AAs are evaluated with respect to cognitive function in patients with CKD. Methods:Plasma levels of AAs were compared between 14 patients with CKD, including 8 patients with diabetic kidney disease, and 12 healthy controls to identify the alteration of specific AAs in CKD. Then, these AAs were evaluated in the brains of 42 patients with brain tumor using non-tumor lesion of the resected brain. Cognitive function is analyzed with respect to intra-brain levels of AAs and kidney function. Moreover, plasma AAs were analyzed in 32 hemodialyzed patients with/without dementia. Results:In patients with CKD, plasma levels of asparagine (Asn), serine (Ser), alanine (Ala), and proline (Pro) were increased as compared to patients without CKD. Among these AAs, L-Ser, L-Ala, and D-Ser show higher levels than the other AAs in the brain. Intra-brain levels of L-Ser was correlated with cognitive function and kidney function. The number of D-amino acid oxidase or serine racemase-positive cells was not correlated with kidney function. Moreover, the plasma levels of L-Ser are also decreased in patients with declined cognitive function who are treated with chronic hemodialysis. Conclusion:The decreased levels of L-Ser are associated with impaired cognitive function in CKD patients. Especially, plasma L-Ser levels may have a potential for novel biomarker of impaired cognitive function in patients with hemodialysis.

OBJECTIVE--We evaluated the structural-functional relationships and the prognostic factors for renal events, cardiovascular events, and all-cause mortality in type 2 diabetic patients with biopsy-proven diabetic nephropathy. RESEARCH DESIGN AND METHODS--Japanese [...]

Intestinal barrier dysfunction?a ?leaky gut??reportedly contributes to pathological processes in some diseases. In a mouse model, the authors induced diabetic kidney disease, leading to impaired intestinal integrity and inflammation, with IL-17 upregulation. This allowed intestine-derived Klebsiella oxytocaand elevated IL-17 to translocate to the circulation and kidneys, then accelerate kidney injury, especially in diabetic knockout mice lacking mitochondrial antiviral signaling protein (MAVS). Stimulation of tubular epithelial cells with K. oxytocaactivated the MAVS pathway and phosphorylation of Stat3 and ERK1/2, leading to production of kidney injury molecule-1 (KIM-1). Systemic MAVS is renoprotective in diabetic mice by an intestinal protective role and the dominant inhibitory effects on suppressing KIM-1 expression under K. oxytocasupernatant or IL-17 stimulation. Controlling intestinal homeostasis may offer a therapeutic strategy in diabetic kidney disease.

Background: Preclinical left ventricular diastolic dysfunction (LVDD) is a high-risk state for heart failure. Kidney dysfunction is a known risk factor for heart failure, but its association with asymptomatic LVDD is not well-known. Methods: A hospital-based retrospective cohort study was conducted on patients who underwent echocardiogram between 2006 and 2016 to assess the association between baseline kidney function and LVDD on echocardiogram. E/e′ ratio was defined as the ratio of peak velocity of early diastolic left ventricular inflow (E) to mitral annular velocity (e′). The primary outcome was time to development of LVDD, which was defined as E/e′ ratio > 14. The changes in the E/e′ ratio and other echocardiographic parameters were assessed using a mixed effects model. Results: Among 1167 patients, the mean age was 61 years, and the mean baseline E/e′ ratio and ejection fraction were 9.6 and 69%, respectively. During a median follow-up of 3.2 years, 231 (19.8%) people developed LVDD. According to eGFR (mL/min/1.73 m2), the risk for LVDD based on hazard ratio [95% confidence interval (95% CI)] was 1.20 (0.82, 1.75) for 60 to < 90, 1.42 (0.87, 2.31) for 45 to < 60, and 2.57 (1.61, 4.09) for < 45 (Ptrend < 0.001). The adjusted risks (95% CI) for annual change in E/e′ ratio was 0.09 (0.03, 0.14) overall and 0.28 (0.11, 0.45) in the lowest eGFR group; the trend in changes in annual E/e′ ratio by baseline eGFR was significant (Ptrend = 0.01). Conclusions: Relatively low kidney function was related with the risks for LVDD. Long-term cohort studies are warranted to confirm the association between LVDD and symptomatic heart failure in patients with kidney dysfunction. Graphic abstract:

AbstractPurpose:We examined the relationship between autoantibodies to erythropoietin receptor (EPOR) and renal outcome in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).Materials and methods:Sixty-three Japanese patients with AAV were enrolled and followed for a median of 31.4 months. Patients were screened for serum anti-EPOR antibodies using an enzyme-linked immunosorbent assay. Associations of anti-EPOR antibodies with clinical parameters were analyzed using logistic-regression models.Results:Anti-EPOR antibodies were detected in 7 (11%) of the 63 patients, and levels of the antibodies decreased with immunosuppressive therapy. The presence of anti-EPOR antibodies was associated with a higher Birmingham vasculitis activity score. In addition, anti-EPOR antibodies were more frequently observed in patients with renal outcomes, which was defined as a sustained 50% reduction in the estimated glomerular filtration rate from baseline, than in those without. Multiple logistic regression analysis revealed that presence of anti-EPOR antibodies, as well as age at disease onset, were as risk factors for the renal outcome.Conclusion:Anti-EPOR antibodies were associated with the progression of renal dysfunction in patients with AAV.

Carnitine/organic cation transporter 1 (OCTN1) is a specific transporter of the food-derived antioxidant ergothioneine. Ergothioneine is absorbed by intestinal OCTN1, distributed through the bloodstream, and incorporated into each organ by OCTN1. OCTN1 expression is upregulated in injured tissues, and promotes ergothioneine uptake to reduce further damage caused by oxidative stress. However, the role of the OCTN1–ergothioneine axis in kidney–intestine cross-talk and chronic kidney disease (CKD) progression remains unclear. Here we assessed ergothioneine uptake via intestinal OCTN1 and confirmed the expression of OCTN1. The ability of OCTN1 to absorb ergothioneine was diminished in mice with CKD. In combination with OCTN1 dysfunction, OCTN1 localization on the intestinal apical cellular membrane was disturbed in mice with CKD. Proteomic analysis, RT-PCR, Western blotting, and immunohistochemistry revealed that PDZ (PSD95, Dlg, and ZO1), a PDZK1 domain-containing protein that regulates the localization of transporters, was decreased in mice with CKD. Decreased intestinal ergothioneine uptake from food decreased ergothioneine levels in the blood of mice with CKD. Despite increased OCTN1 expression and ergothioneine uptake into the kidneys of mice with CKD, ergothioneine levels did not increase. To identify the role of the OCTN1-ergothioneine axis in CKD, we evaluated kidney damage and oxidative stress in OCTN1-knockout mice with CKD and found that kidney fibrosis worsened. Oxidative stress indicators were increased in OCTN1-knockout mice. Moreover, ergothioneine levels in the blood of patients with CKD decreased, which were restored after kidney transplantation. Thus, a novel inter-organ interaction mediated by transporters is associated with CKD progression.

The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA1expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA1signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA1-deficient (LPA1–/–) or -sufficient (LPA1+/+) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I procollagen promoter (Col-GFP) to identify fibroblasts. Unilateral ureteral obstruction-induced increases in renal collagen were significantly, though not completely, attenuated in LPA1–/–Col-GFP mice, as were the accumulations of both fibroblasts and myofibroblasts. Connective tissue growth factor was detected mainly in tubular epithelial cells, and its levels were suppressed in LPA1–/–Col-GFP mice. LPA-LPA1signaling directly induced connective tissue growth factor expression in primary proximal tubular epithelial cells, through a myocardin-related transcription factor-serum response factor pathway. Proximal tubular epithelial cell–derived connective tissue growth factor mediated renal fibroblast proliferation and myofibroblast differentiation. Administration of an inhibitor of myocardin-related transcription factor/serum response factor suppressed obstruction-induced renal fibrosis. Thus, targeting LPA-LPA1signaling and/or myocardin-related transcription factor/serum response factor-induced transcription could be promising therapeutic strategies for renal fibrosis.

Objective.We examined the clinical significance of autoantibodies to the erythropoietin receptor (EPOR) in patients with systemic lupus erythematosus (SLE) who had biopsy-proven lupus nephritis (LN).Methods.Forty-six Japanese patients with SLE with LN who had undergone renal biopsy during 1993–2014 were enrolled in this study and followed for a mean of 83 months. Sera from those patients were screened for anti-EPOR antibodies using ELISA.Results.Anti-EPOR antibodies were detected in 18 (39%) of the 46 patients with SLE with anemia. Anti-EPOR antibodies were associated with low hemoglobin concentrations and reticulocytopenia. In addition, anti-EPOR antibodies were positively correlated with SLE disease activity, even though serum levels of the complement factors 3 and 4 did not differ between the 2 groups. In patients with International Society of Nephrology/Renal Pathology Society 2003 class IV LN, anti-EPOR antibodies were associated with active lesions including cellular crescents in glomeruli. Decrease in renal function was more frequently observed in patients without complete or partial renal response than in patients with it, and serum levels of the antibodies as well as renal response to treatment were significant risk factors for progression of renal dysfunction.Conclusion.The present study suggests that anti-EPOR antibodies might be involved in overall disease activity and active renal lesions, as well as in the impaired erythropoiesis in patients with SLE with LN. Further, the levels of anti-EPOR antibodies may be an additional predictor for renal injury.

Background Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis, and yet the precise pathogenic mechanisms of peritoneal fibrosis remain unknown. Fibrocytes participate in tissue fibrosis and express chemokine receptors that are necessary for migration. The p38 mitogen-activated protein kinase (MAPK) pathway regulates the production of chemokines and has been demonstrated to contribute to the pathogenesis of various fibrotic conditions. Accordingly, we used an experimental mouse model of peritoneal fibrosis to examine the dependency of fibrocytes on p38MAPK signaling.Methods Peritoneal fibrosis was induced in mice by the injection of 0.1% chlorhexidine gluconate (CG) into the abdominal cavity. Mice were treated with FR167653, a specific inhibitor of p38MAPK, and immunohistochemical studies were performed to detect fibrocytes and cells positive for phosphorylated p38MAPK. The involvement of p38MAPK in the activation of fibrocytes also was also investigated in vitro.Results Fibrocytes infiltrated peritoneum in response to CG, and that response was accompanied by progressive peritoneal fibrosis. The phosphorylation of p38MAPK, as defined by CD45+ spindle-shaped cells, was detected both in peritoneal mesothelial cells and in fibrocytes. The level of peritoneal expression of CCL2, a chemoattractant for fibrocytes, was upregulated by CG injection, and treatment with FR167653 reduced the number of cells positive for phosphorylated p38MAPK, the peritoneal expression of CCL2, and the extent of peritoneal fibrosis. Pretreatment with FR167653 inhibited the expression of procollagen type I α1 induced by transforming growth factor-β1Conclusions Our results suggest that p38MAPK signaling contributes to peritoneal fibrosis by regulating fibrocyte function.

Inflammasomes are important components of innate immunity system. Dysregulation of inflammasomes activation is central to the pathogenesis of inflammatory diseases. The measurement of inflammasomes activity especially in in vivosettings should give us important information to regulate inflammatory events. Ludwig-Portugall et al.clearly visualized the intrarenal activation of inflammasome in a murine model of crystal nephropathy using a proteolytic luciferase-based reporter, and showed that the blockade of NLRP3 inflammasome may prevent renal injuries.

OBJECTIVE: Dendritic cells (DC) contribute to autoimmune disease progression and pathogenesis. Mature DC have been reported to secrete high mobility group box protein (HMGB-1), a novel inflammatory cytokine, via p38 mitogen-activated protein kinase (MAPK) activation. We investigated whether DC are involved in progression of autoimmune diseases followed by secretion of HMGB-1 via p38 MAPK activation in a lupus-prone mouse model. METHODS: FR167653, a specific inhibitor of p38 MAPK, was given orally from 3 months of age in MRL-Fas(lpr) mice. Cultured DC, treated with or without FR167653, were stimulated with tumor necrosis factor-alpha. RESULTS: Inhibition of p38 MAPK led to a reduction in the number of CD11c-positive cells, including those with the mature phenotype, in the diseased kidney and spleen, which resulted in improvement of kidney pathology in MRL-Fas(lpr) mice. The number of CD11c-positive cells in circulation was also reduced. HMGB-1 protein and transcripts detected in the diseased kidney, and the number of cells dual-positive for HMGB-1 and CD11c, were reduced by inhibition of p38 MAPK. Maturation of cultured DC and increased cytokines, including HMGB-1, in the supernatant were inhibited by FR167653 treatment. These results suggest that DC are involved in the progression of autoimmune kidney diseases in MRL-Fas(lpr) mice followed by HMGB-1 secretion via p38 MAPK activation. CONCLUSION: Our results indicated that DC secrete HMGB-1 via p38 MAPK activation to participate in autoimmunity in MRL-Fas(lpr) mice.

Paired box 2 (Pax2) is a transcription factor essential for kidney development and is reactivated in proximal tubular epithelial cells (PTECs) during recovery from kidney injury. However, the role of Pax2 in this process is still unknown. Here the role of Pax2 reactivation during injury was examined in the proliferation of PTECs using an ischemia-reperfusion injury (IRI) mouse model. Kidney proximal tubule-specific Pax2 conditional knockout mice were generated by mating kidney androgen-regulated protein-Cre and Pax2 flox mice. The degree of cell proliferation and fibrosis was assessed and a Pax2 inhibitor (EG1) was used to evaluate the role of Pax2 in the hypoxic condition of cultured PTECs (O25%, 24 hours). The number of Pax2-positive cells and Pax2 mRNA increased after IRI. Sirius red staining indicated that the area of interstitial fibrosis was significantly larger in knockout mice 14 days after IRI. The number of Ki-67-positive cells (an index of proliferation) was significantly lower in knockout than in wild-type mice after IRI, whereas the number of TUNEL-positive cells (an index of apoptotic cells) was significantly higher in knockout mice four days after IRI. Expression analyses of cell cycle-related genes showed that cyclin-dependent kinase 4 (CDK4) was significantly less expressed in the Pax2 knockout mice. In vitrodata showed that the increase in CDK4 mRNA and protein expression induced by hypoxia was attenuated by EG1. Thus, Pax2 reactivation may be involved in PTEC proliferation by activating CDK4, thereby limiting kidney fibrosis.

The renin–angiotensin system is a major pathway in the pathogenesis of cardiovascular and renal diseases. Bone marrow-derived fibrocytes, which are dual positive for CD45 and type I collagen, are now considered to contribute to the pathogenesis of various fibrotic diseases. We hypothesized that fibrocytes might contribute to renal fibrosis by an angiotensin II dependent pathway.

Background. The therapeutic efficacy of the regulation of T helper (Th)-1-predominant immune responses remains to be investigated. Therefore, the effects of the anti-inflammatory compound TAK-603 were investigated in a model of crescentic glomerulonephritis induced by a small dose of nephrotoxic serum in Wistar–Kyoto rats.Methods. TAK-603 (50 mg/kg body weight) was administered orally, starting at the time of induction of glomerulonephritis. In group 1, the drug was administered daily for the initial 6 days. TAK-603 was administered on day 0 only in group 2, and from day 3 to 5 in group 3. In each group, nephritic rats were killed on days 6 and 56.Results. In group 1 consisting of rats treated with TAK-603 daily from day 0 to 5, glomerular damage, including crescent formation, was improved on day 6, with reductions in the numbers of CD4, CD8 and ED-1 positive cells, as well as in urinary protein excretion. Protein and transcript levels of Th1 cytokines in the diseased kidneys were markedly decreased by TAK-603 treatment. Renal pathology, including glomerulosclerosis and interstitial fibrosis, was ameliorated and proteinuria was markedly decreased. Elevated levels of serum creatinine showed concomitant improvement. In group 3, in which treatment was initiated shortly after the appearance of glomerular abnormalities, glomerular damage was also diminished, resulting in a decrease in urinary protein excretion. Treatment only on the first day in group 2, partially rescued renal dysfunction.Conclusions. These results suggest the possible therapeutic application of inhibition of Th1-predominant immune responses in progressive crescentic glomerulosclerosis.

Monocyte/macrophage (Mο) migration to sites of inflammation is a prerequisite cause of organ fibrosis. The recruitment and activation of Mo are regulated by C‐C chemokines, especially monocyte chemoattractant protein‐1 [(MCP‐1)/CC chemokine ligand 2], which interacts with CC chemokine receptor 2 (CCR2). However, the mechanisms leading to fibrosis via MCP‐1/CCR2 signaling in Mo remain to be investigated. The effect of MCP‐1 on the expression of MCP‐1, CCR2, transforming growth factor‐β1(TGF‐β1), and type I collagen in circulating human CD14‐positive Mo was investigated. In addition, the impact of MCP‐1‐specific or TGF‐β1‐specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP‐1 and TGF‐β1by human CD14‐positive Mo. Furthermore, specific CCR2 inhibitors were applied to examine the involvement of CCR2 signaling for the promotion of a fibrogenic response. The stimulation of Mo with MCP‐1 increased mRNA levels of TGF‐β1and a pro‐α1 chain of type I collagen (COL1A1) as well as protein synthesis. Similarly, the expression of MCP‐1 and CCR2 was enhanced by the stimulation with MCP‐1 in dose‐ and time‐dependent manners. This positive loop via MCP‐1 was reduced by pretreatment with MCP‐1‐specific AS‐ODN. It was also noted that pretreatment with TGF‐β1‐specific AS‐ODN partially reduced COL1A1 mRNA levels. Finally, transcripts of these molecules were suppressed by pretreatment with specific CCR2 inhibitors. The present study demonstrated that human peripheral CD14‐positive Mo contribute directly to fibrogenesis by a MCP‐1/CCR2‐dependent amplification loop. These data suggest that fibrogenic processes in Mo regulated by MCP‐1/CCR2 may be novel, therapeutic targets for combating organ fibrosis.

Background:A considerable diversity of prognosis is seen with idiopathic membranous nephropathy (IMN). The initial factors affecting long-term outcome remain unclear. Methods:We studied retrospectively 30 patients with IMN who had been followed up for at least 5 years, or until end-stage renal failure (ESRF). We analyzed the prognostic factors of ESRF in the first renal biopsies; these factors included presence of tubulointerstitial lesions and foam cells, as well as expression of CD68, monocyte chemoattractant protein-1 (MCP-1), its cognate receptor chemokine receptor 2 (CCR2) and α-smooth muscle actin. Results:The patients who developed ESRF showed higher percentages of glomerular segmental sclerosis, interstitial MCP-1 expression, CCR2- or CD68-positive monocyte/macrophages and foam cells in the interstitium, and these proved on multivariate analysis to be independent risk factors for ESRF. Finally, ESRF was characterized by the presence of ten interstitial CD68-positive cells per visual field at 200× magnification (hazard ratio 4.096, CI 1.271–15.029, p < 0.001). Conclusions:Our results suggested that an interstitial infiltration of CD68-positive cells accompanied by MCP-1/CCR2 expression is the most significant indicator of ESRF in IMN.

Cyclosporine A (CsA) has improved short-term results in renal transplantation. However, its toxicities have been serious problems in clinical patients undergoing long-term administration. It is necessary to develop a nonnephrotoxic immunosuppressant that allows reducing doses of CsA. The authors tested the effect of a new pyrazolotriazin compound, FR167653 (FR), that inhibits the production of proinflammatory cytokines, using a rat renal acute-rejection model (Wistar-Lewis).

p38 mitogen-activated protein kinase (p38 MAPK) followed by the activation of NF-kappa B participates in the intracellular signal transduction and production of cytokines and chemokines. The pathophysiological roles of p38 MAPK and NF-kappa B in human glomerulonephritis, however, remain to be investigated.

Various types of chemokines/cytokines play important roles in ischaemia/reperfusion injury in kidneys. However, the roles of p38 mitogen-activated protein kinase (MAPK) in the inflammatory processes of renal ischaemia/reperfusion injury remain to be investigated. We explored the effect of FR167653, a specific inhibitor of p38 MAPK, on renal ischaemia/reperfusion injury in mice.

p38 Mitogen-activated protein kinase (MAPK) is involved in the production and signal transduction of interleukin-1β (IL-1β), tumor necrosis factor-α, and chemokines in vitro. However, the crucial role of p38 MAPK in the inflammatory processes of crescentic glomerulonephritis in vivo remains to be investigated. We showed a dramatic decrease in IL-1β-induced phosphorylation of p38 MAPK, not extracellular signal-regulated kinases 1/2 or jun NH2-terminal kinase, in rat cultured mesangial cells by FR167653. We explored the effects of FR167653 as a specific inhibitor of p38 MAPK on renal injury and subsequent renal expression of chemokines in a progressive experimental crescentic glomerulonephritis model in Wistar-Kyoto rats. Rats developed crescentic glomerulonephritis leading to glomerulosclerosis and interstitial fibrosis by 56 days after the administration of nephrotoxic sera. The number of phosphorylated p38 MAPK-positive cells, detected mainly in crescents, correlated well with the percentage of crescents and number of ED-1-positive cells. Phosphorylated p38 MAPK-positive cells were downregulated in glomeruli in rats with the daily subcutaneous administration of FR167653 for 6 days. Concomitantly, renal expression of macrophage inflammatory protein-1α and monocyte chemoattractant protein-1/monocyte chemotactic and activating factor was markedly reduced by day 6. The severity of glomerulosclerosis and interstitial fibrosis significantly decreased by day 56, and renal function was preserved. These results suggest that p38 MAPK phosphorylation is pivotal for crescentic glomerulonephritis, followed by the subsequent expression of renal chemokines. This study provides evidence that regulation of p38 MAPK is a novel appealing therapeutic target for crescentic glomerulonephritis. © 2001 by the National Kidney Foundation, Inc.

Background/Aim:To evaluate the importance of fractalkine, a novel member of the CX3C chemokine, and natural killer (NK) cells in human crescentic glomerulonephritis, we determined the presence of fractalkine in the diseased kidneys immunohistochemically, and the correlation among fractalkine, NK cells and the degree of renal damage. Methods:Twenty-three patients (13 males and 10 females) with primary or secondary crescentic glomerular disease were evaluated in this study. Fractalkine and CD16-positive cells including NK cells were detected immunohistochemically. Results:Fractalkine-positive cells were detected in the interstitium of 23 patients with crescentic glomerulonephritis, while they were not detected in the glomeruli. In addition, CD16-positive cells were detected in both the glomeruli (1.3 ± 0.2/glomerulus) and interstitium (1.3 ± 0.2/visual field). The number of fractalkine-positive cells in the interstitium correlated with the number of CD16-positive cells before glucocorticoid therapy (r = 0.43, p = 0.047, n = 23). The number of fractalkine-positive cells in the interstitium before glucocorticoid therapy (0.2 ± 0.1/visual field) decreased after therapy (0.1 ± 0.1/visual field, p = 0.050) in 11 cases tested. The number of CD16-positive cells in the diseased kidneys did not change after glucocorticoid therapy. Conclusion:These results suggest that the local production of fractalkine may explain the presence of CD16-positive cells including NK cells, which may participate in the interstitial lesions of human crescentic glomerulonephritis before corticoid therapy.

We investigated the presence of CCR1- and CCR5-positive cells immunohistochemically in the kidneys of 38 patients with several renal diseases, including 13 crescentic glomerulonephritis patients. In addition, we determined cell phenotypes of CCR1- and CCR5-positive cells using a dual immunostaining technique. Urinary levels of their ligands, for CCR1 and CCR5; macrophage inflammatory protein (MIP)-1α, MIP-1β and regulated upon activation in normal T cells expressed and secreted (RANTES) were evaluated by enzyme-linked immunosorbent assay. CCR1- and CCR5-positive cells were detected in both glomeruli and interstitium of the diseased kidneys. Using a dual immunostaining technique, these positive cells were CD68-positive macrophages (MΦ) and CD3-positive T cells. The number of CCR1-positive cells in glomeruli was correlated with urinary levels of MIP-1α. The number of CCR1-positive cells in the interstitium was correlated with both urinary MIP-1α and RANTES levels. CCR1-positive cells in the interstitium remained after glucocorticoid therapy, most of which were MΦ, and were correlated with the intensity of interstitial fibrosis and tubular atrophy. Glomerular CCR5-positive cells were well correlated with extracapillary lesions and urinary MIP-1α levels, while interstitial CCR5-positive cells, mainly CD3-positive T cells, were correlated with interstitial lesions and urinary RANTES levels. Renal CCR5-positive cells were dramatically decreased during convalescence induced by glucocorticoids. These results suggest that chemokine receptor signaling may be pivotal for human renal diseases through the recruitment and activation of MΦ and T cells; CCR5-positive cells may participate in glomerular lesions including extracapillary lesions via MIP-1α and in interstitial lesions via RANTES. CCR1 may be involved in interstitial lesions in resolving phase after glucocorticoid therapy.

We previously reported the glomerular deposition of hepatitis C virus (HCV) core antigen (Ag) in HCV-related nephropathy. In this study, we analyzed 23 HCV-positive subjects with exacerbation of proteinuria and/or hematuria during interferon (IFN) therapy and measured urinary protein selectivity. We also examined the involvement of HCV-related Ag using anti-HCV core (capside) Ag murine monoclonal antibody (Ab) and anti–core2 rabbit polyclonal Abs in nine subjects. Of 17 subjects, 13 (78%) showed low selective proteinuria. We found mesangial proliferative glomerulonephritis in 9 subjects, membranoproliferative glomerulonephritis in 1 subject, and nephrosclerosis in 1 subject. Immunofluorescence study showed the glomerular deposition of immunoglobulin G (IgG) or IgA and complements in all 9 subjects examined. Trace amounts only of HCV core Ag were detected along the glomerular capillary wall in 3 of 9 subjects (33%). Electron microscopy showed subendothelial or mesangial electron-dense deposits and also foot process effacement (20% to 72.5% of glomerular capillary walls) in all subjects and endothelial swelling in 4 subjects. In conclusion, IFN therapy for HCV may exacerbate the underlying glomerulopathies, unrelated to HCV Ags, through direct or indirect effects on glomerular endothelial and epithelial cells. Physicians should carefully distinguish HCV-related nephropathy from other glomerular diseases when they administer IFN therapy to HCV-positive subjects.

We assessed the potential efficacy and safety of propagermanium (PG), an organic compound that inhibits the C–C chemokine receptor type 2, administration in patients with type 2 diabetes and nephropathy. Furthermore, we assessed the feasibility of future studies. We recruited patients from nine medical institutions in Japan for this randomized, open‐label, parallel two‐arm pilot trial. Inclusion criteria were diagnosis of type 2 diabetes, age 30‐75 years, dipstick proteinuria of ≥1+ or urinary albumin‐to‐creatinine ratio (UACR) of ≥30 mg/g and estimated glomerular filtration rate of ≥30 mL/min/1.73 m2. Patients were randomly assigned (1:2) using a minimization algorithm to either continuing usual care or concomitant administration of 30 mg PG per day for 12 months. The primary outcome was the change in UACR from baseline to 12 months. We also collected safety information for all patients who received at least one dose of PG. We enrolled 29 patients, 10 were assigned to continue usual care and 19 to receive PG. Changes in UACR by PG in addition to the usual care were 25.0% (95% CI −20.4%, 96.5%, P= .33). No severe adverse events or renal events were observed during the study. Although the treatment with PG was generally well tolerated, the dosage of 30 mg/d for 12 months did not reduce albuminuria when used in addition to usual care in patients with type 2 diabetes and nephropathy. Efficacy of PG should be verified in future definitive trials. We assessed the potential efficacy and safety of propagermanium (PG), an organic compound that inhibits the C–C chemokine receptor type 2, administration in patients with type 2 diabetes and nephropathy. Changes in albuminuria by PG in addition to the usual care were 25.0% (95% CI −20.4%, 96.5%, P= .33). No severe adverse events or renal events were observed during the study.

Abstract: We describe the upregulation of cytokines in a 45-year-old woman with tubulointerstitial nephritis and membranous nephropathy revealed by renal biopsy. She was treated with a combination of prednisolone and cyclosporin. Histological findings showed appreciable improvement, and urinary protein excretion was decreased from 15 g/day to 1 g/day. Elevated urinary levels of chemokines, interleukin (IL)-8 and monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein (MCP)-1, and serum levels of tumor necrosis factor (TNF)-α decreased during convalescence; 13 other patients with membranous nephropathy did not show elevation of these cytokines. These results suggest that the upregulation of these cytokines may participate in the pathogenesis of tubulointerstitial nephritis and that combination therapy of prednisolone and cyclosporin may be effective, possibly via inducing a decrease in these cytokines.

ABT-263 blocks BCL-XLto induce apoptosis in human dermal fibroblasts from patients with scleroderma and in myofibroblasts in mice, reversing dermal fibrosis.