Efficacy and safety of adding mizoribine to standard treatment in patients with immunoglobulin A nephropathy: A randomized controlled trial.

BACKGROUND: Mizoribine (MZR) is an immunosuppressive drug used in Japan for treating patients with lupus nephritis and nephrotic syndrome and has been also reportedly effective in patients with immunoglobulin A (IgA) nephropathy. However, to date, few randomized control studies of MZR are performed in patients with IgA nephropathy. Therefore, this prospective, open-label, randomized, controlled trial aimed to investigate the efficacy and safety of adding MZR to standard treatment in these patients, and was conducted between April 1, 2009, and March 31, 2016, as a multicenter study. METHODS: Patients were randomly assigned (1:1) to receiving standard treatment plus MZR (MZR group) or standard treatment (control group). MZR was administered orally at a dose of 150 mg once daily for 12 months. RESULTS: Primary outcomes were the percentage reduction in urinary protein excretion from baseline and the rate of patients with hematuria disappearance 36 months after study initiation. Secondary outcomes were the rate of patients with proteinuria disappearance, clinical remission rate, absolute changes in estimated glomerular filtration rate from baseline, and the change in daily dose of prednisolone. Forty-two patients were randomly assigned to MZR (n = 21) and control groups (n = 21). Nine patients in MZR group and 15 patients in the control group completed the study. No significant differences were observed between the two groups with respect to primary and secondary outcomes. CONCLUSION: The addition of MZR to standard treatment has no beneficial effect on reducing urinary protein excretion and hematuria when treating patients with IgA nephropathy.

Prerenal uremia induced by severe diarrhea due to colon adenoma: a case of McKittrick-Wheelock syndrome in an elderly patient.

McKittrick-Wheelock syndrome can be successfully treated by emergent dialysis, prescription of bicarbonate, and endoscopic submucosal dissection, which allow elderly people suffering from this syndrome to maintain their activities of daily living. In patients with this syndrome, a large colonic villous adenoma secretes excessive amounts of mucus and causes severe electrolyte depletion and dehydration. An 81-year-old man who had been suffering from chronic renal failure (creatinine 256.4 µmol/L), hypertension, and arrhythmia presented with frequent mucous diarrhea for a month. He was hospitalized for appetite loss, vomiting, general fatigue, and acute renal failure. His blood tests and blood gas analysis revealed urea nitrogen 58.9 mmol/L, creatinine 954.7 µmol/L, pH 7.13, and a base excess of -20.1 mmol/L. Although his symptoms were improved by the emergent dialysis and rehydration, he suffered a relapse only 4 days after he was discharged. At the second admission, a near-circumferential tumor was found in the rectum by the colonoscopy, which was pathologically confirmed as a villous adenoma. Considering his age and complications, endoscopic submucosal dissection was selected, and internal use of sodium bicarbonate was prescribed. Diarrhea and appetite loss were improved by these treatments, and the creatinine level was also improved to 168.0 µmol/L.

Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway.

BACKGROUND: It is widely acknowledged that the (pro)renin receptor mediates angiotensin (Ang) II-dependent and Ang II-independent effects of prorenin. METHOD: We examined the effect of prorenin on vascular smooth muscle cell (VSMC) signal transduction, proliferation, and hypertrophy. RESULTS: Recombinant rat prorenin dose-dependently increased extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation in rat VSMCs. Prorenin also significantly increased cell number, and [H]-thymidine and [H]-leucine incorporation, which were attenuated by pretreatment with inhibitors for ERK kinase and phosphatidylinositol 3 kinase. Prorenin was also found to stimulate epidermal growth factor (EGF) receptor and Src phosphorylation. Pretreatment of VSMCs with an EGF receptor tyrosine kinase inhibitor and a Src inhibitor significantly attenuated the prorenin-induced increase in ERK 1/2 and Akt phosphorylation, as well as DNA and protein synthesis. Prorenin-induced phosphorylation of the EGF receptor, ERK 1/2, and Akt, as well as DNA and protein synthesis were all blocked by (pro)renin receptor siRNA, but not by an Ang II type 1 receptor blocker, candesartan, nor an Ang-converting enzyme inhibitor, captopril. CONCLUSION: These results reveal that prorenin directly stimulates VSMC proliferative and hypertrophic changes, dependent on the (pro)renin receptor, independent of Ang II. Furthermore, EGF receptor-mediated ERK 1/2 and Akt activation contributes to prorenin-dependent proliferative and hypertrophic effects in VSMCs.

Oxidative stress induced by iron released from transferrin in low pH peritoneal dialysis solution.

BACKGROUND: Transferrin binds extracellular iron and protects tissues from iron-induced oxidative stress. The binding of iron and transferrin is pH dependent and conventional peritoneal dialysis (PD) solutions have unphysiologically low pH values. Herein, we investigated whether conventional PD solution releases iron from transferrin and if the released iron causes oxidative stress. METHODS: Effects of PD solutions on iron binding to transferrin were examined with purified human transferrin and transferrin in dialysates drained from PD patients. Oxidative stress induced by iron released from transferrin was evaluated in terms of the formation of thiobarbituric acid reactive substance (TBARS) and protein carbonylation in the human red blood cell (RBC) membrane. The iron deposition in peritoneal tissue from PD patients was evaluated by Perls' staining with diaminobenzidine intensification. RESULTS: Low pH PD solution released iron from transferrin. This iron release occurred within 1 min. Iron release was not observed in neutralized PD solution. Iron released from transferrin in low pH PD solution increased TBARS formation and protein carbonylation in the human RBC membrane. Iron deposition, which is prominent in the fibrotic area facing the peritoneal cavity, was observed in the peritoneum of PD patients. CONCLUSIONS: Iron released from transferrin in low pH PD solution can produce oxidative stress in the peritoneum of a PD patient. Neutralizing PD solution can avoid this problem. Iron deposition in the peritoneum may participate in the pathogenesis of peritoneal fibrosis in PD patients.

Calcification and osteopontin localization in the peritoneum of patients on long-term continuous ambulatory peritoneal dialysis therapy.

BACKGROUND: Peritoneal calcification is an uncommon complication of continuous ambulatory peritoneal dialysis (CAPD), which is mainly observed in patients on long-term therapy. Although some asymptomatic patients must have microscopic calcification in their peritoneum, little information on this topic has been published. Recent studies have revealed active participation of adhesive/chemotactic protein osteopontin (OPN) in dystrophic calcification. METHODS: Peritoneal tissue was obtained by biopsy or at autopsy from 18 CAPD patients (median duration, 122 months), 5 control haemodialysis (HD) patients, and 3 pre-CAPD patients. The distribution of calcium deposits and OPN protein was determined by von Kossa staining and immunohistochemistry, respectively. Smooth muscle cells and macrophages were identified with anti-alpha smooth muscle actin (alpha-SMA) and anti-CD68 antibodies. RESULTS: Calcium deposits with various configurations were observed in specimens from 12 of the 18 CAPD patients. They included massive calcification facing the peritoneal cavity, scattered granular or crystalloid deposits in the submesothelial stroma, and oval-shaped deposits formed within hyalinized vasa. Most were present in highly sclerosed areas and accompanied by extracellular OPN precipitation. Cytoplasmic OPN was detected in infiltrating leukocytes, granulation tissue cells, fibroblast-like cells and mast cells. Computerized tomography examination also detected peritoneal calcification in seven of the CAPD patients. No calcium deposits or OPN staining was detected in control specimens. CONCLUSIONS: The results of our study suggest that microscopic peritoneal calcification is frequent in patients on CAPD for more than 10 years. Myofibroblast infiltration, OPN expression, calcium deposition, and associated OPN precipitation seem to be components of the peritoneal changes in such patients.

Role of c-SRC and ERK in acid-induced activation of NHE3.

BACKGROUND: In the renal proximal tubule, chronic acidosis causes increases in apical membrane NHE3 activity, which serve to increase transepithelial H+ secretion and return systemic pH to normal levels. Incubation of cultured renal epithelial cells in acid media activates c-Src. METHODS: OKP cells were incubated in control (pH 7.4) or acid (7.0) media, and NHE3 activity measured as cytoplasmic pH (pHi) recovery from an acid load using BCECF. c-Src, ERK, and JNK kinase activities were measured by immune complex kinase assays with enolase, MBP, and GST-c-Jun, respectively, as substrates in the in vitro assays. To determine the role of c-Src in acid-induced NHE3 activation, cells were transfected with vector alone or a dominant negative c-Src (c-SrcK295M). RESULTS: Expression of dominant negative c-srcK295M in OKP cells prevented acid-induced activation of NHE3. Incubation of OKP cells in acid media increased ERK activity and c-fos expression, but did not increase JNK activity. Acidosis in vivo also activated renal cortical c-Src and ERK kinases, whereas incubation of 3T3 cells in acid media activated c-Src but not ERK kinase. Expression of c-srcK295M did not affect ERK or c-fos activation by acid incubation. Inhibition of MEK with PD98059 inhibited activation of NHE3 by acid incubation. CONCLUSIONS: These studies suggest that acidosis activates c-Src and MEK/ERK/c-fos. While both pathways are necessary for activation of NHE3, they are activated independently.