Comparison of anti-peritoneal fibrotic effects between an mTORC1-specific blocker and a PI3K/mTOR dual-blocker.

OBJECTIVE: To compare the anti-peritoneal fibrotic effects between a mammalian target of rapamycin complex 1-specific blocker and a phosphatidyl-inositol 3-kinase/mammalian target of rapamycin dual-blocker. METHODS: A total of 40 male Sprague-Dawley rats were randomly divided into five groups with eight animals per group. The normal group (N group) did not receive any intervention. The normal saline group (NS group) received an intraperitoneal injection of normal saline at 1 ml/100 g daily. The model group (3 W group), rapamycin (RAPA) group and BEZ235 (PI3K/mTOR dual-blocker) group all received an intraperitoneal injection of 0.1% chlorhexidine gluconate at 1 ml/100g daily. And the RAPA and BEZ235 groups also received a 0.5 mg/d RAPA or 2.5 mg/d BEZ235 gavage every day, respectively. Rats in each group were sacrificed after 3 weeks. RESULTS: Immunohistochemistry, real-time PCR and western blotting analysis of fibrosis-related indicators (FN, Col 1, and α-SMA) confirmed that RAPA and BEZ235 significantly inhibited peritoneal fibrosis and that these two drugs had similar effects. The p-Akt, p-mTOR, p-p70S6K expression levels were significantly up-regulated in the 3 W group compared to the NS group, confirming that the mTOR pathway was significantly activated during peritoneal fibrosis. RAPA significantly inhibited the phosphorylation of mTOR and p70S6K but did not have significant effects on p-Akt upstream of mTOR. BEZ235 had significant inhibitory effects on all signaling molecules (p-Akt, p-mTOR, and p-p70S6K) in the mTOR pathway. CONCLUSION: RAPA did not up-regulate p-Akt in a negative feedback fashion. Both drugs effectively inhibited peritoneal fibrosis.

Management of Membranous Nephropathy in Asia.

BACKGROUND: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults, accounting for about 20.0% of all NS cases. With an increasing prevalence, especially in the elderly, it has received great attention in Asia. SUMMARY: Recently, the prevalence of idiopathic MN (IMN) has significantly increased among the elderly people in Asia and other places in the world. Although the exact mechanism of IMN remains unveiled, the identification of new antigens such as PLA2R and THSD7A has greatly enhanced our understanding of its pathogenesis. However, consensus has not yet been reached for the treatment of IMN in Asia. For example, there are many choices of immunosuppressive agents, including corticosteroid monotherapy, corticosteroids combined with cytotoxic agents [such as alkylating agents, calcineurin inhibitors or mycophenolate mofetil (MMF)] or traditional Chinese medicine (triptolide, Shenqi and other Chinese herbal soups). Patients with IMN in Asia often have a favorable prognosis, and progression to end-stage renal disease is relatively uncommon compared to other populations. KEY MESSAGES: The prevalence of MN has significantly increased in the last years. The treatment strategies for IMN have not reached consensus in Asia. Traditional Chinese medicine is generally preferred by the Chinese, and compelling results have been reported recently. FACTS FROM EAST AND WEST: (1) The prevalence of IMN is increasing worldwide, particularly in elderly patients, and has been reported in 20.0-36.8% of adult-onset NS cases. The presence of anti-PLA2R antibodies in serum or PLA2R on renal biopsy is the most predictive feature for the diagnosis of IMN and is used in both the East and West; however, appropriate screening to rule out secondary causes should still be performed. (2) Several observational (nonrandomized) Asian studies indicate a good response to corticosteroids alone in IMN patients, although no randomized controlled trials have been done in Asian membranous patients at high risk of progression. Corticosteroid monotherapy has failed in randomized controlled trial studies in Western countries and is therefore not recommended. (3) Cyclophosphamide is the most commonly prescribed alkylating agent in Europe and China. Also, chlorambucil is still used in some Western countries, particularly in Europe. In North America, calcineurin inhibitors are the more common first-line treatment. (4) Cyclosporine is predominantly used as monotherapy in North America, although KDIGO (Kidney Disease: Improving Global Outcomes) and Japanese guidelines still recommend a combination with low-dose corticosteroids. Clinical studies both in Asia and Europe showed no or little effects of monotherapy with MMF compared to standard therapies. (5) There are encouraging data from nonrandomized Western studies for the use of rituximab and a few small studies using adrenocorticotropic hormone. Clinical trials are ongoing in North America to confirm these observations. These drugs are rarely used in Asia. (6) A Chinese study reported that 36% of IMN patients suffered from venous thromboembolism versus 7.3% in a North American study. Prophylactic anticoagulation therapy is usually added to IMN patients with a low risk of bleeding in both Eastern and Western countries. (7) The Chinese traditional medicine herb triptolide, which might have podocyte-protective properties, is used in China to treat IMN. An open-label, multicenter, randomized controlled trial showed that Shenqi, a mixture of 13 herbs, was superior to corticosteroids plus cyclophosphamide therapy to restore epidermal growth factor receptor in IMN patients, although proteinuria improvement was equal in the two groups. Importantly, Shenqi treatment induced no severe adverse events while standard therapy did.

Diuretics associated acute kidney injury: clinical and pathological analysis.

OBJECTIVE: In order to evaluate the clinical and pathological characteristics of diuretics associated acute kidney injury (AKI) and its management. METHODS: We performed a retrospective study including 131 cases that diagnosed as diuretics associated AKI from 1 January 1999 to 1 January 2010 in Ruijin Hospital affiliated to Shanghai Jiao Tong University. Drug applications and its related clinical, laboratory and histological data were collected. RESULTS: The male to female ratio was 2:1. The proportion of ages <20 years, 20-40 years, 40-60 years and ≥ 60 years were 6.9%, 17.6%, 27.5% and 48.1% respectively. Most patients (96.2%) had at least one complication of which chronic kidney disease (CKD) occurred most frequently (72 in 131, 55.0%). We divided all the patients to diuretic group (N=131) and non-diuretic group (N=185) based on diuretics history. We found patients in diuretic group had higher rates of CVD (38.9% vs. 18.4%), hypertension (42.0% vs. 29.2%), CKD (55.0% vs. 27.0%) and DM (17.6% vs. 4.3%) than non-diuretic group. Of 131 diuretics associated AKI, 36 cases (27.5%) were caused by diuretics only, 39 cases (29.8%) were caused by the combination of diuretics and other drugs like antibiotics, contrast media, ACEI or NSAIDs, and 56 cases (42.7%) had other AKI risk factors such as operation, infection, acute heart failure or hepatorenal syndrome. In addition, our data suggested the severity of RIFLE classification and pathological injury of glomerular basement membrane was higher in large-dosage furosemide group (>=120 mg/d) than in low-dosage group (<120 mg/d). The most common lesion induced by diuretics was vacuolar degeneration of tubular epithelial cell. Logistic regression analysis showed predictors of all-cause mortality were age, gender, RIFLE classification when AKI onset. Age and RIFLE classification were predictive factor of non-complete recovery. CONCLUSION: This article firstly focuses on diuretics associated AKI, whose onset was related to aging, primary diseases and diuretic dosage. The combination of diuretics with other drugs such as antibiotics, contrast media, ACEI, NSAIDs, etc. would synergistically induced AKI. The pathological lesion of diuretics associated AKI may be mostly manifested vacuolar degeneration of tubular epithelial cell. Aging, gender, severity of RIFLE classification may be predictive factors of all-cause mortality of diuretics associated AKI.

Evaluation of anemia and serum iPTH, calcium, and phosphorus in patients with primary glomerulonephritis.

Glomerulonephritis (GN) remains a major cause of morbidity and mortality in chronic kidney disease (CKD). Our study aimed to investigate the prevalence of anemia, abnormal serum intact parathyroid hormone (iPTH), calcium, and phosphorus in a Chinese patient population with primary GN. Medical histories and laboratory test results were collected from 2,924 patients with primary GN hospitalized in Ruijin Hospital of Shanghai between January 2003 and August 2009. The leading cause of CKD was primary glomerular diseases, which were responsible for up to 53.5% of all cases. IgA nephropathy was the most common cause, accounting for 38.7%, followed by focal segmental glomerulosclerosis (FSGS). The anemia rate of GN patients in early stages of CKD (stages 1-2 and 3) was 16-36%, and rapidly accelerated to 65.8 and 80.2% in advanced CKD stage 4 and stage 5, respectively. There was no significant decline observed in the level of serum calcium in patients with CKD stages 1-4 (p > 0.05). However, in patients with CKD stage 5 the prevalence of hypocalcaemia increased significantly (13.7%, p = 0.000). The prevalence of hyperphosphatemia did not significantly increase in patients with CKD stages 1-3 (p < 0.05), but was much higher in patients with CKD stages 4 and 5 (p = 0.001 and p = 0.021, respectively) and showed a negative correlation with renal function. Serum iPTH levels did not increase significantly in GN patients with CKD stages 1-2. The median iPTH levels were 54.7, 88.6, and 289.2 pg/ml (p = 0.000) for CKD stages 3-5, respectively, all of which showed negative correlation with renal function. The proportion of vitamin D insufficiency and deficiency increased to 29.3 and 11.2%, respectively, as the glomerular filtration rate fell below 15 ml/min/1.73 m(2). Primary glomerular disease remains the major cause of CKD in China, and complications such as anemia and metabolic bone disease are frequently present in GN patients.