Tadalafil treatment for preeclampsia (medication in preeclampsia; MIE): a multicenter phase II clinical trial.

PURPOSE: To evaluate the effectiveness and safety of tadalafil treatment for hypertensive disorder of pregnancy (HDP). MATERIALS AND METHODS: In an open-label, randomized clinical trial, singleton pregnancies with HDP between 20 and 33 weeks of gestation were randomized to take 20 mg oral tadalafil every day (tadalafil treatment group) or no drug (conventional treatment group). The primary outcome was prolongation of pregnancy from randomization to delivery. However, this article primarily focuses on the safety assessments performed in the tadalafil treatment for HDP population, because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide. RESULTS: From October 2016 to March 2018, 28 patients were randomized to each group and two cases were excluded (tadalafil treatment group: 12 cases; conventional treatment group: 14 cases). The significant adverse events related to tadalafil did not occur in the tadalafil treatment group. Among maternal adverse events, specifically with regard to headaches, there were significant differences between the two groups (0% in tadalafil group versus 43% in conventional treatment group; p = .02). There was no difference in the prolongation period of pregnancy that served as primary outcomes in both the groups (17.5 d in tadalafil group versus 16.5 d in conventional group, p = .96). The significant adverse events occurred at the same frequency as between the conventional treatment group and the tadalafil treatment group. And, maternal headache decreased significantly in the tadalafil treatment group. CONCLUSIONS: Tadalafil treatment is safe for pregnant women with HDP. Moreover, tadalafil did not prolong the gestational period in pregnant women with HDP.

Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial.

Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor with a long half-life, high selectivity, and rapid onset of action. Because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide, this paper primarily focuses on the safety assessments performed in the Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER) II population. Neonatal and maternal adverse events were analyzed, in addition to fetal, neonatal, and infant death cases, six months after stopping the trial. Eighty-nine pregnant women with FGR were studied between September 2016 and March 2018 (45 and 44 in the tadalafil and conventional treatment groups, respectively). Seven (16%) deaths (four fetal, one neonatal, and two infant) in the control group, whereas only one neonatal death occurred in the tadalafil group. Although headache, facial flushing, and nasal hemorrhage occurred more frequently in the tadalafil group, these symptoms were Grade 1 and transient. In conclusion, this trial showed that tadalafil decreased the fetal and infant deaths associated with FGR. This is thought to be primarily due to pregnancy prolongation. Further studies are warranted to evaluate the efficacy of tadalafil in treating early-onset FGR.

Single versus multiple cervical dilation by osmotic dilator before induction of labor for second-trimester abortion.

AIM: In this study, we aimed to investigate whether there was a significant prognostic difference between single and multiple cervical dilations when inducing second-trimester abortion. METHODS: We conducted a retrospective review of 238 pregnant women who underwent termination of pregnancy at 12-21 weeks of gestation at Osaka University Hospital in Osaka, Japan, between January 2010 and May 2018. Termination of pregnancy was performed by vaginal administration of 1 mg gemeprost every 3 h for up to five doses per day after uterine cervical dilation using lamicel. RESULTS: The women were categorized into two groups: 191 women had a delivery time of <24 h, whereas 47 had delivery times >24 h. Contrasting the groups, there were significant differences with regard to numbers of primiparas (88 [46.1%] and 32 [68.1%], respectively) and lamicel exchanges ± SD (1.9 ± 0.67 for <24 h and 2.4 ± 0.87 for >24 h, respectively). Additionally, we compared the prognosis of primiparas that received just a single lamicel with that of primiparas that had ≥2 exchanged, but no significant differences were noted in the number of patients with a delivery time of >24 h and the number of used gemeprost. CONCLUSION: Primipara is a risk factor for delayed delivery time of induced abortion. However, increasing the number of exchanged lamicel did not significantly reduce the delivery time; therefore, it should be performed as minimally as possible.

Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions.

We have demonstrated that tadalafil facilitates fetal growth in mice with L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia (PE) with fetal growth restriction (FGR). Tadalafil is a selective phosphodiesterase 5 inhibitor that dilates the maternal blood sinuses in the placenta, thereby facilitating the growth of the fetus. The purpose of this study was to investigate the effects of tadalafil treatment for PE and FGR on the developing brain in FGR offspring using an L-NAME-induced mouse model of PE with FGR. A control group of dams received carboxymethylcellulose (CMC). L-NAME-treated groups received L-NAME dissolved in CMC from 11 days post coitum (d.p.c.). The L-NAME-treated dams were divided into two subgroups 14 d.p.c. One subgroup continued to receive L-NAME. The other subgroup received L-NAME with tadalafil suspended in CMC. Tadalafil treatment for PE with FGR reduced the expression of hypoxia-inducible factor-2α in the placenta and in the brain of the FGR fetus. Moreover, tadalafil treatment in utero shows improved synaptogenesis and myelination in FGR offspring on postnatal day 15 (P15) and P30. These results suggest that tadalafil treatment for PE with FGR not only facilitates fetal growth, but also has neuroprotective effects on the developing brain of FGR offspring through modulating prenatal hypoxic conditions.

TADAFER II: Tadalafil treatment for fetal growth restriction - a study protocol for a multicenter randomised controlled phase II trial.

INTRODUCTION: There is no proven therapy to reverse or ameliorate fetal growth restriction (FGR). Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has been reported to potentially play a therapeutic role in FGR, but this has not been established. Tadalafil is also a selective PDE5 inhibitor. We have demonstrated the efficacy of tadalafil against FGR along with short-term outcomes and the feasibility of tadalafil treatment. Based on the hypothesis that tadalafil will safely increase the likelihood of increased fetal growth in FGR, we designed this phase II study to prospectively evaluate the efficacy and safety of tadalafil against FGR. METHODS AND ANALYSIS: This study is a multicentre, randomised controlled phase II trial. A total of 140 fetuses with FGR will be enrolled from medical centres in Japan. Fetuses will be randomised to receive either the conventional management for FGR or a once-daily treatment with 20 mg of tadalafil along with the conventional management until delivery. The primary endpoint is fetal growth velocity from the first day of the protocol-defined treatment to birth (g/day). To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery was established in this study. The investigator will evaluate fetal baseline conditions at enrolment and will decide the timing of delivery based on this fetal indication. Infants will be followed up for development until 1.5 years of age. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of Mie University Hospital and each participating institution. Our findings will be widely disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: UMIN000023778.

Genome-wide association study of IgA nephropathy using 23 465 microsatellite markers in a Japanese population.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis in many parts of the world. Although previous genome-wide association studies (GWAS) identified the major susceptibility loci for IgAN, the causal genes currently remain unknown. We performed a GWAS using 23 465 microsatellite (MS) markers to identify genes related to IgAN in a Japanese population. A pooled sample analysis was conducted in three-stage screenings of three independent case-control populations, and after the final step of individual typing, 11 markers survived. Of these, we focused on two regions on 6p21 and 12q21 because they (i) showed the strongest relationship with IgAN, and (ii) appeared to be highly relevant to IgAN in view of several previous studies. These regions contained the HLA, TSPAN8 and PTPRR genes. This study on GWAS, using >20 000 MS markers, provides a new approach regarding susceptible genes for IgAN for investigators seeking new tools for the prevention and treatment of IgAN.

Kidney Diseases Enhance Expression of Tetraspanin-8: A Possible Protective Effect against Tubular Injury.

BACKGROUND/AIMS: TSPAN8 encoding tetraspanin-8 was identified as a candidate gene for immunoglobulin A nephropathy (IgAN) by a genome-wide association study using microsatellites in the Japanese population. Tetraspanin-8 is a cell surface protein that contributes to the migration and invasion of epithelial cells. METHODS: We performed immunohistochemistry for tetraspanin-8 on human renal biopsy specimens associated with IgAN, antineutrophil cytoplasmic antibody-associated nephropathy and interstitial nephritis, as well as normal renal tissue. Furthermore, to study the potential function of tetraspanin-8, we performed cell migration and invasion assays using human renal tubule cells transfected with tetraspanin-8. RESULTS: Tetraspanin-8 was often expressed in vascular smooth muscle cells and occasionally in tubule cells in normal kidney. In the kidneys of all types of nephropathy, tetraspanin-8 staining in the arteries was unaffected, but that in the tubules was enhanced. The degree of tubular staining negatively correlated with the estimated glomerular filtration rate, independently of the type of nephropathy. Tetraspanin-8-expressing tubule cells were found predominantly in distal and collecting tubules, identified by cytokeratin 7 or aquaporin 2 staining. In vitro studies using cultured tubule cells revealed that tetraspanin-8 promoted migration by 2.7-fold without laminin, by 2.8-fold with laminin and invasion into Matrigel by 3.5-fold, suggesting that enhanced tetraspanin-8 may be involved in the repair of tubules. CONCLUSION: The obtained findings indicate that tetraspanin-8 expression is enhanced in injured distal tubules, which may be involved in the repair of tubules by facilitating migration and invasion.

A 10-year retrospective cohort study on the risk factors for peritoneal dialysis-related peritonitis: a single-center study at Tokai University Hospital.

BACKGROUND: Common outcomes of peritoneal dialysis (PD)-related peritonitis include catheter removal and transition to hemodialysis (HD). According to recent data, the incidence of PD-related peritonitis in Japan is not low, and peritonitis is the most common cause of withdrawal from PD. Against this backdrop, the purpose of this study is to determine the incidence of PD-related peritonitis at the Outpatient Nephrology Clinic of Tokai University Hospital (hereafter "the Clinic") and to examine causative bacteria and the risk factors related to the development of peritonitis. METHODS: We investigated all PD-related peritonitis episodes of 192 PD patients who visited the Clinic during the period from April 1, 2001 to March 31, 2011 and established the incidence of PD-related peritonitis, along with culture-negative peritonitis rates. Regarding the risk factors that are associated with the development of peritonitis, we examined patient backgrounds, whether an automated peritoneal dialysis (APD) device was used, and which type of connection system was employed. RESULTS: The incidence of peritonitis was one episode per 64.5 patient-months, and the culture-negative peritonitis rate was 16.4 %. Of the cultured bacterial isolates 71.3 % were Gram-positive cocci, including 25.0 % of coagulase-negative staphylococci, 13.2 % of methicillin-susceptible Staphylococcus aureus (MSSA), and 6.6 % of methicillin-resistant Staphylococcus aureus (MRSA). Gram-negative rods were 19.1 %. Risk factors associated with the development of peritonitis included age at the start of PD [odds ratio 1.042, 95 % confidence interval (CI) 1.016-1.069, p value = 0.001], diabetes mellitus nephropathy (DMN) (odds ratio 22.003, 95 % CI 2.101-230.452, p value = 0.010), and the use of a sterile tubing welder device (STWD) (odds ratio 2.399, 95 % CI 1.043-5.521, p value = 0.040). CONCLUSIONS: Regarding the situation of peritonitis at a single center during the 10-year period of this study, risk factors associated with the development of peritonitis included age at the start of PD, DMN, and the use of an STWD.

Overestimation of the risk of progression to end-stage renal disease in the poor prognosis' group according to the 2002 Japanese histological classification for immunoglobulin A nephropathy.

BACKGROUND: The current (2012) histological classification of immunoglobulin A nephropathy was established using a case-control study of 287 patients. However, the risk of progression to end-stage renal disease (ESRD) has not been validated for the previous (2002) classification. This study aimed to determine whether the previous classification could identify the risk of long-term renal outcome through re-analysis of the 2012 cohort. METHODS: On the basis of the 2002 classification, namely 'good prognosis', 'relatively good prognosis', 'relatively poor prognosis', and 'poor prognosis', we examined the clinical data at the time of biopsy, the correlation between the 2002 classification and long-term renal outcomes, and a patient-by-patient correlation between the 2002 and 2012 classification systems. This was performed by analyzing samples from the 287 patients used to establish the 2012 classification. RESULTS: The rate of decline of estimated glomerular filtration rate was greater and the odds ratio of progression to ESRD was higher in the 'poor prognosis' group. In contrast, the odds ratio for renal death was comparable between the groups described as 'relatively poor prognosis' and 'relatively good prognosis' in the 2002 classification. Many patients in the 2002 classification were classified with a lower histological grade in the current classification, but none were classified with a higher grade. CONCLUSIONS: The 2002 classification could also identify the risk of progression to ESRD. However, it was overestimated for patients in the 'poor prognosis' group in the 2002 classification, as that group included patients with milder histological damage.

A Retrospectively Diagnosed Case of IgG4-Related Tubulointerstitial Nephritis Showing Good Renal Outcome and Pathological Progress.

A 74-year-old man was hospitalized for diabetic nephropathy evaluation and assessment of the effect of treatment on his tubulointerstitial nephritis (TIN). When he was 62 years old, he developed polyarthralgia and had superficial lymph node swelling, mildly increased serum creatinine concentration, hypergammaglobulinemia, hypocomplementemia, high serum IL-2R level, and positive titer of antinuclear antibody. Several tissues were biopsied. Mild chronic sialadenitis and reactive lymphadenitis were identified. Renal specimen showed mild glomerular ischemia, extensive storiform fibrosis, and abundant infiltrating monocytes and plasma cells. He was treated with oral prednisolone and cyclophosphamide. After the treatment, most of his clinical parameters quickly returned to within the reference range. However, he developed diabetes mellitus soon after steroid therapy. At the time of rebiopsy, a high level of serum IgG4 was detected. The second renal biopsy showed diabetic nephropathy without any tubulointerstitial damage. The first biopsied tissues were retrospectively investigated. Large numbers of IgG4-positive plasma cells were detected in the kidneys and lymph nodes. A retrospective diagnosis of IgG4-related TIN with lymph node involvement was made. In conclusion, this paper describes a retrospectively diagnosed case of IgG4-related TIN with lymph node involvement, showing good clinical and pathological prognosis.

Effects of valsartan on progression of kidney disease in Japanese hypertensive patients with advanced, predialysis, chronic kidney disease: Kanagawa Valsartan Trial (KVT).

Suppression of the renin-angiotensin system is known to slow progression of chronic kidney disease (CKD). However, few trials have been performed with Japanese patients. This study investigated whether the angiotensin receptor blocker (ARB) valsartan would delay the progression of kidney disease more effectively than conventional treatment in Japanese hypertensive patients with advanced, predialysis CKD. In a multicenter, randomized, open-label trial, 303 patients with hypertension and CKD with serum creatinine levels 2.0 mg dl(-1) were assigned to receive either conventional therapy plus valsartan (valsartan add-on group) or conventional therapy without ARB (control group). The primary outcome was a change in serum creatinine levels. Changes in urinary protein levels and time to onset of renal events were analyzed as secondary end points. There were no between-group differences in blood pressure during the study. Changes in serum creatinine and urinary protein levels did not differ between the groups. However, the rate of renal events, including doubling of serum creatinine levels or end-stage renal disease, was significantly lower in the valsartan add-on group than in the control group. The addition of valsartan decreased the risk by 42.6% after adjustment for baseline variables. The addition of valsartan to conventional therapy significantly slowed the rate of renal function decline and delayed the need for renal replacement therapy in Japanese hypertensive patients with advanced CKD.

A histologic classification of IgA nephropathy for predicting long-term prognosis: emphasis on end-stage renal disease.

BACKGROUND: A multicenter case-control study on IgA nephropathy (IgAN) was conducted to develop an evidence-based clinicopathologic classification of IgAN for predicting long-term renal outcome. METHODS: Two hundred and eighty-seven patients including those with isolated hematuria or very mild proteinuria were enrolled. During a median follow-up of 9.3 years after biopsy, 49 patients (17%) progressed to end stage renal disease (ESRD). The associations between pathological variables and the need for chronic dialysis was examined by multivariate logistic regression analysis separately in patients who required dialysis earlier than 5 years (Early Progressors) and those who required dialysis within 5 to 10 years (Late Progressors) after biopsy. RESULTS: Independent pathological variables predicting progression to ESRD were global sclerosis, segmental sclerosis and fibrous crescents for Early Progressors, and global sclerosis and cellular/fibrocellular crescents for Late Progressors. Four histological grades, HG 1, HG 2, HG 3 and HG 4, were established corresponding to <25%, 25-49%, 50-74% and =75% of glomeruli exhibiting cellular or fibrocellular crescents, global sclerosis, segmental sclerosis or fibrous crescents. Eleven (7%) patients in HG 1, 12 (16%) in HG 2, 13 (31%) in HG 3 and 13 (68%) in HG 4 progressed to ESRD. Multivariate logistic analysis revealed that the risk of progression to ESRD was significantly higher in HG 2, 3 and 4 than in HG 1 (odds ratio, 2.4, 5.7 and 27.6 vs. 1.0). CONCLUSIONS: Our evidence-based histologic classification can identify the magnitude of the risk of progression to ESRD and is useful for predicting long-term renal outcome in IgAN.

In vitro silencing of the insulin receptor attenuates cellular accumulation of fibronectin in renal mesangial cells.

BACKGROUND: Insulin receptor (InsR) and insulin signaling proteins are widely distributed throughout the kidney cortex. Insulin signaling can act in the kidney in multiple ways, some of which may be totally independent of its primary role of the maintenance of whole-body glucose homeostasis. However, descriptions of the insulin signaling in renal glomerular mesangial cells (MCs) are quite limited and the roles of insulin signaling in MC functions have not been sufficiently elucidated. RESULTS: InsR silencing induced a unique phenotype of reduced fibronectin (FN) accumulation in renal glomerular MCs. Transcription level of FN was not significantly changed in the InsR silenced cells, suggesting the phenotype switching was caused by post-transcriptional modification. The decreased expression of InsR was associated with enhanced activity of insulin-like growth factor-1 receptor (IGF-1R)/PI3K/Akt signaling pathway which contributed in part to the attenuation of cellular FN accumulation. Formation of IGF-1R homodimer was increased in the InsR silenced cells. The InsR silenced cells also showed increased sensitivity to exogenous IGF-1, and increased PI3K activity was reversed significantly by incubating cells with IGF-1R specific antagonist, AG538. PI3K/Akt dependent activation of cAMP responsive element-binding protein (CREB)-1 induced expression of matrix metalloproteinase (MMP)-9 and suppressing MMP activity by doxycycline partially reversed FN accumulation in the InsR silenced cells. CONCLUSIONS: The effects of InsR silencing on cellular FN accumulation in vitro are, at least partially, mediated by increased degradation of FN by MMPs which is induced by enhanced signaling sequence of IGF-1R/PI3K/Akt/CREB-1.

Characterization and quantification of proliferating cell patterns in endocapillary proliferation.

BACKGROUND: Endocapillary proliferation (EP) is a common pathological finding in proliferative glomerulonephritis (GN). Its appearance indicates the presence of active lesions of GN. In this study, we reinvestigated the pathological features of EP. METHODS: Cell markers that included CD15, CD68, CD45RO, CD31 and alpha-smooth muscle actin (alpha-SMA) were used to identify the intraglomerular cells in renal biopsy tissues collected from patients with post-streptococcal acute GN (PSAGN), methicillin-resistant Staphylococcus aureus-associated GN (MRSAGN) with or without EP, membranoproliferative GN (MPGN) with or without EP, Henoch-Schönlein nephritis, immunoglobulin A nephropathy, membranous nephropathy and minimal change nephrotic syndrome. Proliferating cells and apoptotic cells were investigated simultaneously. RESULTS: The glomerular infiltrating polymorphonuclear leukocytes, macrophages, T cells, mesangial cells and endothelial cells were enumerated. In PSAGN, the glomerulus was enlarged and all cell types were greatly increased. In MRSAGN EP, the glomerulus was slightly enlarged with abundant infiltrating leukocytes and monocyte/macrophages and had moderate mesangial cell proliferation with negligible endothelial cell proliferation. In MPGN, the glomerulus markedly enlarged with multiple monocyte/macrophages and remarkable mesangial proliferation. The mesangial cells in EP glomeruli were highly activated as evidenced by alpha-SMA expression, particularly in PSAGN. CONCLUSIONS: This is the first report to use monoclonal antibodies specific for cell markers to quantitatively analyze and compare the proliferating cell types in EP glomeruli in different forms of GN. The results suggest that identification of the presence of polymorphonuclear leukocytes in the capillary lumen might help in differentiating between glomerular global and segmental EP.

Pasteurella multocida peritonitis associated with a cat in a peritoneal dialysis patient using an automated cycler device.

Pasteurella multocida (P. multocida) is an aerobic Gram-negative coccobacillus, which is found as part of the natural oral flora of many animals, including most healthy cats and dogs. However, it can cause a variety of infections in humans, usually as a result of the patient being bitten or scratched by a cat or dog. There have been 22 reported cases of P. multocida peritonitis in patients undergoing peritoneal dialysis (PD). Of these, 66.7 % occurred within 12 months of the initiation of PD. Only two cases (11.1 %) developed more than 60 months after the commencement of PD. We report a case of P. multocida peritonitis involving a 45-year-old patient who had been undergoing continuous ambulatory peritoneal dialysis (CAPD) for 84 months without a previous history of peritonitis, who developed P. multocida peritonitis associated with a domestic cat on the very night on which he began using an automated cycler device to switch from CAPD to continuous cyclic peritoneal dialysis (CCPD). Patients maintained on PD who keep pets such as cats or dogs at home should be educated about the risk of developing peritonitis related to their domestic pets, and this warning should be repeated when such patients switch from CAPD to CCPD. Physicians should consider using empiric therapy to prevent P. multocida in pet-owning PD patients who present with a history of PD fluid leakage and peritonitis, especially in patients who use cycler devices.

Case of peritoneal dialysis-related acute hydrothorax, which was successfully treated by thoracoscopic surgery, using collagen fleece.

Peritoneal dialysis (PD) is an established renal replacement therapy for patients with end-stage renal disease (ESRD), and it is an effective mean of treatment for maintaining patients' residual renal function and their quality of life (QOL). However, acute hydrothorax is one of the complications of PD that can lead to discontinuation of PD and a switch to hemodialysis. We report a case of a 51-year-old woman with ESRD secondary to chronic glomerulonephritis who was placed on intermittent PD (IPD) and developed right-sided acute hydrothorax one month later. Scintigraphy with technetium-99 m macroaggregated human albumin (Tc-99 m MAA) revealed presence of a pleuroperitoneal communication, and treatment by autologous blood pleurodesis was performed twice. However, the treatment was ineffective, and two months after the onset of the hydrothorax, we performed video-assisted thoracoscopic surgery (VATS), using collagen fleece coated with fibrin glue to seal off the communication. The surgical procedure was followed by complete resolution of the hydrothorax. It was possible to resume the PD about one month postoperatively, and there has been no evidence ofrecurrence of the hydrothorax. VATS with collagen fleece was effective in treating acute hydrothorax secondary to a pleuroperitoneal communication that developed as a complication of PD.

High ambient glucose induces angiotensin-independent AT-1 receptor activation, leading to increases in proliferation and extracellular matrix accumulation in MES-13 mesangial cells.

Diabetic nephropathy is associated with mesangial ECM (extracellular matrix) accumulation. We have shown that AT-1R [Ang II (angiotensin II) type I receptor] signalling induces ECM proteins via transactivation of PI3K (phosphoinositide 3-kinase) in mesangial cells. In the present study, we examined the mechanisms underlying the effect of high ambient glucose on cell proliferation and ECM expansion in a mesangial context. High glucose induced increases in PI3K activity, proliferation and ECM accumulation in mesangial cells. These effects were abrogated by losartan, an AT-1R antagonist, but not by [Sar1,Thr8]-Ang II (Sar is sarcosine), an inactive analogue of Ang II, or by a neutralizing antibody against Ang I/II. Overexpression of a constitutively active PI3Kalpha or AT-1R alone was sufficient to induce similar changes by high glucose. In contrast, overexpression of an inactive AT-1R lowered the basal levels and rendered the cells non-responsive to high glucose. Moreover, cells overexpressing wild-type AT-1R had enhanced sensitivity to acute Ang II stimulation. These cells, however, did not respond to conditioned medium obtained from mesangial cells cultured in high glucose. We further demonstrated that iAng (intracellular Ang II) can be induced by high glucose but only under certain conditions. Efficient suppression of iAng by short hairpin RNA against angiotensinogen, however, did not affect high glucose-induced effects on MES-13 cells. These results suggest that high ambient glucose induces activation of AT-1R in an Ang II-independent manner to transactivate PI3K, resulting in proliferation and ECM accumulation in mesangial cells.

A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis, and a substantial number of patients succumb to end-stage renal disease (ESRD). However, prediction of the renal outcome in individual patients remains difficult. We have already published a scoring system using the data in a prospective cohort of IgAN patients followed up from 1995 to 2002. METHODS: The cohort was further followed up until 2005 in 97 clinical units in Japan. The data from 2283 patients were analysed by Cox regression to determine the predictors of ESRD in IgAN, and their beta-coefficients were converted into scores to estimate ESRD risk within 10 years. RESULTS: During the follow-up (median, 87 months), 252 patients developed ESRD. Male sex, age less than 30 years, family histories of chronic renal failure and chronic glomerulonephritis, hypertension, proteinuria, mild haematuria, hypoalbuminaemia, low glomerular filtration rate and a high histological grade at initial renal biopsy were associated with the risk of ESRD in the multivariable analysis. A scoring system was framed to estimate the 10-year ESRD risk using eight variables significant in both univariable and multivariable models. This prognostic score accurately classified patients by risk: patients with estimates of 0-4.9, 5.0-19.9, 20.0-49.9 and 50.0-100% had an observed incidence of 1.7, 8.3, 36.7 and 85.5%, respectively. The corresponding area under the receiver-operating characteristic curve was 0.942 (95% confidence interval, 0.925-0.958). CONCLUSION: This validated scoring system to quantitatively estimate ESRD risk during the 10-year follow-up of IgAN patients will serve as a useful prognostic tool in clinical practice.

Tonsillectomy and steroid pulse (TSP) therapy for patients with IgA nephropathy: a nationwide survey of TSP therapy in Japan and an analysis of the predictive factors for resistance to TSP therapy.

BACKGROUND: Tonsillectomy and steroid pulse (TSP) therapy was proposed as a curative treatment for IgA nephropathy by Hotta et al. (Am J Kidney Dis 38:736-742, 2001) based on data that about 50% of patients achieved clinical remission (CR) of urinary abnormalities. MATERIALS AND METHODS: As a primary survey, we sent a questionnaire and letter to 848 hospitals in Japan, each of which employed a Fellow of the Japanese Society of Nephrology between October and December of 2006, in order to gather information about the prevalence and efficacy of TSP therapy for patients with IgA nephropathy. As a secondary survey, we collected data from both low- and high-CR-rate groups to determine which factors predicted resistance to TSP therapy. RESULTS: A total of 2,746 patients received TSP therapy between 2000 and 2006. The CR rates, calculated by measuring urinary criteria 6 and 12 months after TSP therapy, were 32.0% (347/1,085) and 45.6% (452/991), respectively. Analysis of the 30 hospitals in which TSP therapy had been performed on at least ten patients revealed that the CR rates varied from below 10% to 100%. A secondary survey of ten hospitals revealed that, after correction of the CR rate from each hospital, patients could be categorized into three groups: those with a low CR rate (122 patients in four hospitals), a middle CR rate (78 patients in four hospitals), and a high CR rate (103 patients in two hospitals). The CR rate of all patients (N = 303) was 54.1%. A comparison of patient data between the low- and high-CR-rate groups showed a significant difference in age at onset (years; P = 0.05), amount of proteinuria (g/day; P = 0.02), total protein (g/dl; P = 0.02), pathological grade (P = 0.009), and prognostic score as described by Wakai et al. [Nephrol Dial Transplant 21:2800-2808, 2006, (P = 0.04)]. Univariate analysis revealed that there was a significant difference between non-CR and CR subgroups in duration from diagnosis until TSP therapy (6.9 +/- 6.8 versus 5.3 +/- 5.2 years; P = 0.02), amount of proteinuria (1.5 +/- 1.6 versus 0.8 +/- 0.8 g/day; P < 0.0001), serum creatinine (0.99 +/- 0.40 versus 0.87 +/- 0.34 mg/dl; P = 0.006), pathological grade (P = 0.0006), and Wakai et al.'s prognostic score (37.4 +/- 17.8 versus 28.1 +/- 15.1; P < 0.0001). A multivariate logistic analysis demonstrated that resistance to TSP therapy depends on age at onset, amount of proteinuria, hematuria grade, and pathological grade, and a score predicting resistance to TSP therapy could be derived by the formula: [(-0.0330) x (age) + (0.4772) x log (amount of proteinuria) - (0.0273) x (hematuria grade: 0, 1, 2, and 3) + (0.7604) x (pathological grade: 1, 2, 3, and 4) - 0.1894]. A receiver operating characteristic (ROC) curve showed that patients with a resistance score of greater than -0.02 easily resist TSP therapy (sensitivity 69%, specificity 75%, positive likelihood ratio 2.76). CONCLUSION: TSP therapy shows promise as a treatment that can bring about CR of urinary abnormalities, but unfortunately the average CR rate is about 50% at 1 year after treatment. Predictive factors for resistance to TSP therapy are age at onset, amount of proteinuria, hematuria grade, and pathological grade. The present study suggests that patients with either early-stage or mild to moderate IgA nephropathy easily achieve CR following TSP therapy, whereas patients with late-stage or severe disease are prone to TSP therapy resistance.