A retrospective, longitudinal study of rheumatoid arthritis treatment patterns with Janus kinase inhibitors and other disease-modifying antirheumatic drugs in Japan.

OBJECTIVES: There is limited information on the clinical use of Janus kinase inhibitors (JAKis) for rheumatoid arthritis treatment in Japan. The aim of this study was to identify disease-modifying antirheumatic drug (DMARD) treatment patterns in Japan. METHODS: This retrospective, longitudinal study extracted data from the Japan Medical Data Center database. Patients with rheumatoid arthritis diagnosis were enrolled 2016-19, during which patients had a first prescription of a major DMARD, split into six mutually exclusive classes: methotrexate (MTX); other conventional synthetic DMARDs; tumour necrosis factor alpha inhibitors; cytotoxic T-lymphocyte-associated antigen-4-immunoglobulin; anti-interleukin-6 receptor therapies; and JAKis. The primary objective was to describe DMARD treatment patterns, especially for JAKis. RESULTS: Overall, 10,399 patients were included in the analysis. The most common treatments were MTX, other conventional synthetic DMARDs, and tumour necrosis factor alpha inhibitors. The total number of JAKi prescriptions increased approximately 8-fold during 2016-19. Most (61.1%) patients who received JAKis had prior MTX or tumour necrosis factor alpha inhibitor treatment. The duration of JAKi treatment was longer than for biologics and other conventional synthetic DMARDs and comparable to that of MTX. CONCLUSIONS: The sequence of drug class prescriptions for rheumatoid arthritis in Japan during 2016-19 followed clinical guidelines. Over this period, JAKis were increasingly used as a second-line treatment following MTX.

Polyarteritis nodosa with perirenal hematoma due to the rupture of a renal artery aneurysm.

We present the case of a 67-year-old man in good health with perirenal hematoma due to a ruptured arterial aneurysm in the kidney. The patient developed weight loss, muscle weakness, multiple mononeuropathy, hypertension, anemia, renal insufficiency, and multiple lacuna infarctions about a month ago. He was admitted to the hospital due to worsening of his symptom. After admission, severe right-flank pain suddenly occurred; he was then transferred to our hospital. Renal angiography revealed bilateral multiple microaneurysms, and the patient was diagnosed with polyarteritis nodosa based on the clinical, radiographic, and histological findings. We performed selective coil embolization to the ruptured aneurysm and administered oral prednisolone along with intravenous methylprednisolone pulse therapy. Cyclophosphamide pulse therapy was also given. The treatment improved clinical and laboratory findings and achieved clinical remission. Selective coil embolization to the bleeding aneurysm of polyarteritis nodosa was minimally invasive and promptly effective. Immunosuppressants proved useful in the regulation of disease activity and the aneurysm.

Addition of Ipragliflozin to Metformin Treatment in Korean Patients with Type 2 Diabetes Mellitus: Subgroup Analysis of a Phase 3 Trial.

BACKGROUND: This is a subgroup analysis of Korean patients from a phase 3 clinical trial investigating the efficacy and safety of ipragliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin. METHODS: This multicenter, placebo-controlled, double-blind, parallel-group study was carried out between November 2011 and January 2013. Patients entered a 2-week placebo pretreatment period, followed by a 24-week treatment period with either ipragliflozin (50 mg/day) or placebo, while continuing metformin. Efficacy outcomes (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG], and body weight) and safety outcomes (treatment-emergent adverse events [TEAEs]) were measured and compared between the two treatment groups for patients enrolled in all 18 study sites in Korea. RESULTS: Eighty-two Korean patients received ipragliflozin (n=43) or placebo (n=39) during the study period. Mean changes in HbA1c levels from baseline to the end of treatment were -0.97% in the ipragliflozin group and -0.31% in the placebo group, with an adjusted between-group difference of -0.60% (P<0.001). Compared to placebo, FPG and body weight also decreased significantly (both P<0.001) from baseline after treatment in the ipragliflozin group, with between-group differences of -21.4 mg/dL and -1.53 kg, respectively. Decreased weight was the most common TEAE in the ipragliflozin group (7.0%); there were no reports of genital and urinary tract infection. CONCLUSION: Ipragliflozin treatment in addition to metformin led to significant improvement in glycemic outcomes and reduction in body weight in Korean patients with type 2 diabetes mellitus, compared with metformin treatment alone; the safety profile was comparable in both groups.

Efficacy, safety, and tolerability of ipragliflozin in Asian patients with type 2 diabetes mellitus and inadequate glycemic control with metformin: Results of a phase 3 randomized, placebo-controlled, double-blind, multicenter trial.

AIMS/INTRODUCTION: To determine the efficacy and safety of ipragliflozin in combination with metformin in Asian patients with type 2 diabetes mellitus. MATERIALS AND METHODS: This phase 3, multicenter, placebo-controlled, double-blind, parallel-group study was carried out at 18 sites in Korea and 12 sites in Taiwan. After an 8-week washout period for patients using drugs other than metformin and a 2-week run-in period, patients were randomized to either 50 mg ipragliflozin or a placebo for 24 weeks while continuing metformin. Efficacy outcomes included the changes in hemoglobin A1c, fasting plasma glucose (FPG) and bodyweight from baseline to the end of treatment (with last observation carried forward). Safety outcomes included treatment-emergent adverse events. RESULTS: Between November 2011 and January 2013, 171 patients were randomized to and administered ipragliflozin (n = 87) or a placebo (n = 83). The mean changes (standard deviation) in hemoglobin A1c were -0.94% (0.75%) and -0.47% (0.81%) in the ipragliflozin and placebo groups, respectively (between-group difference -0.46%, P < 0.001). The changes in fasting plasma glucose and bodyweight were also significantly greater in the ipragliflozin group, with between-group differences of -14.1 mg/dL and -1.24 kg, respectively (both P < 0.001). The most common treatment-emergent adverse events (ipragliflozin vs placebo) were upper respiratory tract infection (9.2% vs 12.0%) and urinary tract infection (6.9% vs 2.4%). CONCLUSIONS: These results show that ipragliflozin is effective and well tolerated when used in combination with metformin in Asian patients with type 2 diabetes mellitus.

Universal scaling for the dilemma strength in evolutionary games.

Why would natural selection favor the prevalence of cooperation within the groups of selfish individuals? A fruitful framework to address this question is evolutionary game theory, the essence of which is captured in the so-called social dilemmas. Such dilemmas have sparked the development of a variety of mathematical approaches to assess the conditions under which cooperation evolves. Furthermore, borrowing from statistical physics and network science, the research of the evolutionary game dynamics has been enriched with phenomena such as pattern formation, equilibrium selection, and self-organization. Numerous advances in understanding the evolution of cooperative behavior over the last few decades have recently been distilled into five reciprocity mechanisms: direct reciprocity, indirect reciprocity, kin selection, group selection, and network reciprocity. However, when social viscosity is introduced into a population via any of the reciprocity mechanisms, the existing scaling parameters for the dilemma strength do not yield a unique answer as to how the evolutionary dynamics should unfold. Motivated by this problem, we review the developments that led to the present state of affairs, highlight the accompanying pitfalls, and propose new universal scaling parameters for the dilemma strength. We prove universality by showing that the conditions for an ESS and the expressions for the internal equilibriums in an infinite, well-mixed population subjected to any of the five reciprocity mechanisms depend only on the new scaling parameters. A similar result is shown to hold for the fixation probability of the different strategies in a finite, well-mixed population. Furthermore, by means of numerical simulations, the same scaling parameters are shown to be effective even if the evolution of cooperation is considered on the spatial networks (with the exception of highly heterogeneous setups). We close the discussion by suggesting promising directions for future research including (i) how to handle the dilemma strength in the context of co-evolution and (ii) where to seek opportunities for applying the game theoretical approach with meaningful impact.

Insight into the so-called spatial reciprocity.

Up to now, there have been a great number of studies that demonstrate the effect of spatial topology on the promotion of cooperation dynamics (namely, the so-called "spatial reciprocity"). However, most researchers probably attribute it to the positive assortment of strategies supported by spatial arrangement. In this paper, we analyze the time course of cooperation evolution under different evolution rules. Interestingly, a typical evolution process can be divided into two evident periods: the enduring (END) period and the expanding (EXP) period where the former features that cooperators try to endure defectors' invasion and the latter shows that perfect C clusters fast expand their area. We find that the final cooperation level relies on two key factors: the formation of the perfect C cluster at the end of the END period and the expanding fashion of the perfect C cluster during the EXP period. For deterministic rule, the smooth expansion of C cluster boundaries enables cooperators to reach a dominant state, whereas, the rough boundaries for stochastic rule cannot provide a sufficient beneficial environment for the evolution of cooperation. Moreover, we show that expansion of the perfect C cluster is closely related to the cluster coefficient of interaction topology. To some extent, we present a viable method for understanding the spatial reciprocity mechanism in nature and hope that it will inspire further studies to resolve social dilemmas.

Referring to the social performance promotes cooperation in spatial prisoner's dilemma games.

We propose a new pairwise Fermi updating rule by considering a social average payoff when an agent copies a neighbor's strategy. In the update rule, a focal agent compares her payoff with the social average payoff of the same strategy that her pairwise opponent has. This concept might be justified by the fact that people reference global and, somehow, statistical information, not local information when imitating social behaviors. We presume several possible ways for the social average. Simulation results prove that the social average of some limited agents realizes more significant cooperation than that of the entire population.

Fas Ligand Has a Greater Impact than TNF-α on Apoptosis and Inflammation in Ischemic Acute Kidney Injury.

BACKGROUND/AIM: Fas ligand (FasL) and tumor necrosis factor (TNF)-α are major pro-apoptotic molecules and also induce inflammation through cytokine and chemokine production. Although precise intracellular mechanisms of action have been reported for each molecule, the differential impact of these molecules on kidney injury in vivo still requires clarification. METHODS: We explored the differential impact of FasL and TNF-α upon apoptosis and inflammation in ischemic acute kidney injury using neutralizing anti-FasL antibodies and TNF-α receptor 1 (TNFR1)-deficient mice. RESULTS: TNFR1 deficiency was associated with a lesser anti-inflammatory effect upon leukocyte infiltration and tubular necrosis than treatment with anti-FasL antibody. Furthermore, the number of TUNEL-positive cells was significantly reduced in anti-FasL antibody-treated mice, whereas it was only partially diminished in TNFR1-deficient mice. In vitro studies confirmed these findings. FasL administration induced both apoptosis and cytokine/chemokine production from cultured tubular epithelial cells. However, TNF-α had a limited effect upon tubular epithelial cells. CONCLUSION: In ischemic acute kidney injury, FasL has a greater impact than TNF-α on the apoptosis and inflammatory reaction through cytokine/chemokine production from tubular epithelial cells.

How is the equilibrium of continuous strategy game different from that of discrete strategy game?

Cooperation in the prisoner's dilemma (PD) played on various networks has been explained by so-called network reciprocity. Most of the previous studies presumed that players can offer either cooperation (C) or defection (D). This discrete strategy seems unrealistic in the real world, since actual provisions might not be discrete, but rather continuous. This paper studies the differences between continuous and discrete strategies in two aspects under the condition that the payoff function of the former is a linear interpolation of the payoff matrix of the latter. The first part of this paper proves theoretically that for two-player games, continuous and discrete strategies have different equilibria and game dynamics in a well-mixed but finite population. The second part, conducting a series of numerical experiments, reveals that such differences become considerably large in the case of PD games on networks. Furthermore, it shows, using the Wilcoxon sign-rank test, that continuous and discrete strategy games are statistically significantly different in terms of equilibria. Intensive discussion by comparing these two kinds of games elucidates that describing a strategy as a real number blunts D strategy invasion to C clusters on a network in the early stage of evolution. Thus, network reciprocity is enhanced by the continuous strategy.

Activation of p38 mitogen-activated protein kinase promotes peritoneal fibrosis by regulating fibrocytes.

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-ß1. CONCLUSIONS: Our results suggest that p38MAPK signaling contributes to peritoneal fibrosis by regulating fibrocyte function.

Involvement of CD11b+ GR-1 low cells in autoimmune disorder in MRL-Fas lpr mouse.

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) have been identified as immunosuppressive cells in tumor-related inflammation. However, the pathogenesis of MDSCs for autoimmune disease has not been investigated as yet. The aim of this study was to address whether MDSCs contribute to autoimmune organ injury in lupus-prone mice. METHODS: MDSCs were analyzed by flow cytometric staining of CD11b(+) GR-1(+) in MRL-Fas ( lpr ) mice. CD4(+) T-cell proliferation assay was performed by coculture with CD11b(+) GR-1(+) splenocytes. The percentage of immunosuppressive cells was examined during disease progression. Expression of chemokine receptor on immunosuppressive cells was analyzed, and chemotaxis assay was performed. RESULTS: CD11b(+) GR-1(low) cells had a suppressive effect on CD4(+) T-cell proliferation, which was restored by an arginase-1 inhibitor. CD11b(+) GR-1(low) cells increased in percentage during disease progression in kidney and blood. The number of migrated CD11b(+) GR-1(low) cells increased in the presence of monocyte chemoattractant protein-1/CCL2. CONCLUSION: We assessed the involvement of CD11b(+) GR-1(low) cells in autoimmune disorder in MRL-Fas(lpr) mice. These cells regulate immunological responses via CCL2/CCR2 signaling. The regulation of immunosuppressive monocytes may provide novel therapeutic strategy for organ damage in autoimmune diseases.

Fibrocytes are involved in the pathogenesis of human chronic kidney disease.

The presence of chronic kidney disease in humans is associated with a risk of kidney function loss as well as the development of cardiovascular disease. Fibrocytes have been shown to contribute to organ fibrosis. In this study, the presence of fibrocytes was investigated immunohistochemically in kidney biopsy specimens from 100 patients with chronic kidney disease. In addition, 6 patients with thin basement membrane disease were studied as a disease control. In patients with chronic kidney disease, the infiltration of fibrocytes was observed mainly in the interstitium. The number of interstitial fibrocytes in patients with chronic kidney disease was higher than that in patients with thin basement membrane disease. The number of infiltrated fibrocytes in the interstitium correlated well with the severity of tubulointerstitial lesions, such as interstitial fibrosis, in patients with chronic kidney disease. In addition, there were significant correlations between the number of interstitial fibrocytes and the number of CD68-positive macrophages in the interstitium as well as urinary monocyte chemoattractant protein-1/CCL2 levels. In particular, there was an inverse correlation between the number of interstitial fibrocytes and kidney function at the time of biopsy. Finally, the numbers of interstitial fibrocytes and macrophages as well as urinary CCL2 levels were significantly decreased during convalescence induced by glucocorticoid therapy. These results suggest that fibrocytes may be involved in the pathogenesis of chronic kidney disease through the interaction with macrophages as well as CCL2.

Suppression of ripples on ablated Ni surface via a polarization grating.

Gratings were recorded on the surface of nickel by ablation without formation of ripples using an interference of two p-polarized femtosecond laser beams at a pi/4 angle of incidence. The mechanism of ripples' suppression is explained by formation of a polarization grating and by ablation at the locations where the polarization is normal to the Ni surface. The aspect ratio of the ablated grooves was approximately 3 with the period approximately 570 nm at the central wavelength of irradiation of 800 nm. This method is applicable for laser structuring of different materials and a recorded grating structure can be scaled with the irradiation wavelength.

Effect of sevelamer hydrochloride on markers of bone turnover in Japanese dialysis patients with low biointact PTH levels.

BACKGROUND: In hemodialysis patients, adynamic bone disease has been reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. METHODS: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). RESULTS: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31+/-18 pg/mL to 95+/-96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. CONCLUSION: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes.

Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.

OBJECTIVE: Ischemia-reperfusion injury is known to cause organ failure, but the mechanisms of pathogenesis remain unclear. Inflammation is a factor in tissue destruction in ischemia reperfusion injury, and interleukin (IL)-1 is a key promoter of inflammation. DESIGN: Prospective, randomized, and controlled study. SETTING: University laboratory. SUBJECTS: Male mice 6-8 wks of age, in which genes for IL-1alpha and IL-1beta (IL-1alpha/beta deficient) and IL-1 receptor antagonist (IL-1RA deficient) are deleted by homologous recombination, and wild-type controls on a Balb/c background. INTERVENTIONS: In this study, the role of IL-1 on inflammatory cascades, including chemokine expression, inflammatory cell infiltration, and tissue destruction, was investigated in 45 mins of unilateral renal ischemic injury using IL-1alpha/beta-deficient mice and IL-1RA-deficient mice. In addition, the effects of IL-1 on chemokine expression in cultured tubular epithelial cells were investigated. MEASUREMENTS AND MAIN RESULTS: In vivo study revealed that the number of interstitial infiltrated neutrophils and macrophages, which accompanied the increase of the serum levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1alpha, respectively, significantly increased in IL-1RA-deficient mice. The number of interstitial infiltrated neutrophils correlated well with serum levels of KC at 24 hrs after reperfusion, whereas the number of interstitial infiltrated macrophages correlated well with the serum levels of MIP-1alpha and monocyte chemoattractant protein (MCP)-1 at 24 and 48 hrs after reperfusion, respectively. Likewise, in vitro study revealed that stimulation of tubular epithelial cells by IL-1beta and/or H2O2 sequentially induced KC, MIP-1alpha, and MCP-1 in both protein and messenger RNA levels, which is consistent with in vivo results. CONCLUSION: IL-1-dependent inflammatory cascades, followed by inflammatory cell infiltration and subsequent tissue destruction, may affect pathogenesis of renal ischemia-reperfusion injury.

MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes.

Monocyte/macrophage (Momicron) 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-beta1 (TGF-beta1), and type I collagen in circulating human CD14-positive Mo was investigated. In addition, the impact of MCP-1-specific or TGF-beta1-specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP-1 and TGF-beta1 by 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-beta1 and a pro-alpha1 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-beta1-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.

Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy.

BACKGROUND: The involvement of mitogen-activated protein kinase (MAPK) in human diabetic nephropathy has not been fully investigated. METHODS: The presence of cells positive for the phosphorylated MAPK family (phosphorylated extracellular signal-regulated kinase [p-ERK], phosphorylated p38MAPK [p-p38MAPK]) was investigated immunohistochemically in kidneys of 30 patients with diabetic nephropathy. In addition, 10 patients with minimal change nephrotic syndrome, 10 patients with thin basement membrane disease, and 5 patients with benign nephrosclerosis were studied as disease controls. The presence of activated nuclear factor-kappaB (p65)-positive cells also was evaluated in kidney specimens. RESULTS: In patients with diabetic nephropathy, p-ERK, p-p38MAPK, and p65 were observed in mesangial cells, endothelial cells, podocytes, tubular epithelial cells, and mononuclear infiltrates in interstitium. Numbers of p-ERK-, p-p38MAPK-, and p65-positive cells in both glomeruli and interstitium in patients with diabetic nephropathy were higher than those in controls. In particular, the number of glomerular p-ERK-positive cells in patients with diabetic nephropathy increased in accordance with the progression of glomerular lesions and correlated well with the number of glomerular p65-positive cells (r = 0.654; P < 0.01; n = 30). Conversely, the number of p-p38MAPK-positive cells in glomeruli did not correlate with glomerular lesions. However, the number of tubulointerstitial p-p38MAPK-positive cells in patients with diabetic nephropathy reflected the severity of tubulointerstitial lesions, and numbers of those in the interstitium increased with good correlation to numbers of tubulointerstitial p65-positive cells (r = 0.757; P < 0.01; n = 30) and interstitial CD68-positive macrophages (r = 0.647; P < 0.05; n = 30) and urinary monocyte chemoattractant protein-1 levels (r = 0.605; P < 0.05; n = 30). CONCLUSION: These results suggest that MAPK phosphorylation contributes to human diabetic nephropathy. In particular, ERK and p38MAPK may be distinctly involved in glomerular and tubulointerstitial lesions in human diabetic nephropathy.

The outcome and a new ISN/RPS 2003 classification of lupus nephritis in Japanese.

BACKGROUND: A considerable diversity in prognosis is seen with lupus glomerulonephritis (LGN). Hence, the clinical usefulness of a recent International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification to judge the long-term outcome of human LGN has been investigated. METHODS: We studied retrospectively 60 subjects with LGN (7 males, 53 females, mean age of 33 years old) who underwent renal biopsies and were followed from 1 to 366 months, with a mean of 187 months. We diagnosed renal pathology as classes, active and sclerosing lesions, according to the new and WHO1995 classification of LGN, and analyzed the clinicopathologic factors affecting to the prognosis of LGN. RESULTS: New classification got much higher consensus in the judgment of classes (98% vs. 83%, P = 0.0084). The group of Class IV-S (N = 6) or IV-G (N = 17) at initial biopsies showed higher rate of end-stage renal failure (ESRF) compared with that of Class I, II, III or V (40.9% vs. 2.6%, P < 0.001). The mean 50% renal survival time of Class IV was 189 +/- 29 months, and patients with Class IV-S tended to have a poorer prognosis (95 +/- 22 months for IV-S vs. 214 +/- 35 months for IV-G, P = 0.1495). Class IV was also selected as the most significant risk factor for ESRF by stepwise model (P = 0.002). In subanalysis for ESRF in Class IV (-S or -G), treatment including methylprednisolone pulse therapy was only selected as a significant improving factor for primary outcome (P = 0.034). In addition, activity index was the significant risk factor of death and/or ESRF after initial renal biopsies (P = 0.043). As for actuarial patient death during all follow-up periods, complications with anti-phospholipid syndrome or nephrotic syndrome were significant risk factors (P = 0.013, P = 0.041, respectively). CONCLUSION: New ISN/RPS 2003 classification provided beneficial pathologic information relevant to the long-term renal outcome and the optimal therapy preventing ESRF and/or death in patients with LGN.

Effect of incadronate on corticosteroid-induced osteopenia in rats.

The effect of incadronate, a third-generation bisphosphonate, was evaluated in rats with corticosteroid-induced osteopenia. Male Wistar rats were treated with methylprednisolone acetate (1 mg/kg, s.c.) once daily, 3 days a week for 12 weeks. Other groups received simultaneous treatment with methylprednisolone acetate and incadronate (0.03, 0.3 or 3 mg/kg, p.o.); incadronate was given once daily, 6 days a week for 12 weeks. Bone mineral densities (BMDs) of the second lumbar (L2) vertebra as well as the ultimate compressive strength of the fifth lumbar (L5) vertebra decreased. Incadronate dose-dependently inhibited the loss of L2 BMDs and the decrease in strength of the L5 vertebrae. These results suggest that incadronate may be effective in treating osteopenia accompanying corticosteroid therapy.