Clinical and experimental studies have shown that sodium glucose co-transporter 2 inhibitors (SGLT2i) contribute to the prevention of diabetic kidney disease progression. In order to clarify its pharmacological effects on the molecular mechanisms underlying the development of diabetic kidney disease, we administered different doses of the SGLT2i, ipragliflozin, to type 2 diabetic mice. A high-dose ipragliflozin treatment for 8 weeks lowered blood glucose levels and reduced urinary albumin excretion. High- and low-dose ipragliflozin both inhibited renal and glomerular hypertrophy, and reduced NADPH oxidase 4 expression and subsequent oxidative stress. Analysis of glomerular phenotypes using glomeruli isolation demonstrated that ipragliflozin preserved podocyte integrity and reduced oxidative stress. Regarding renal tissue hypoxia, a short-term ipragliflozin treatment improved oxygen tension in the kidney cortex, in which SGLT2 is predominantly expressed. We then administered ipragliflozin to type 1 diabetic mice and found that high- and low-dose ipragliflozin both reduced urinary albumin excretion. In conclusion, we confirmed dose-dependent differences in the effects of ipragliflozin on early diabetic nephropathy in vivo. Even low-dose ipragliflozin reduced renal cortical hypoxia and abnormal hemodynamics in early diabetic nephropathy. In addition to these effects, high-dose ipragliflozin exerted renoprotective effects by reducing oxidative stress in tubular epithelia and glomerular podocytes.

BackgroundThe pathophysiological mechanisms of cisplatin nephrotoxicity include the reduction of renal blood flow, as well as tubular epithelial cell toxicity. The objective of this study was to investigate the influence of lower blood pressure and decreased food intake on the incidence of cisplatin nephrotoxicity.MethodsWe conducted a retrospective cohort study at a university hospital between 2011 and 2012. We identified hospitalized adult patients with head and neck cancer, esophageal cancer, or gastric cancer, who received intravenous cisplatin administration. The primary outcome was the incidence of cisplatin nephrotoxicity defined as the increase in serum creatinine after cisplatin administration more than 1.5 times from baseline.ResultsThe study participants included 182 patients, in whom we observed a total of 442 cycles of cisplatin chemotherapy. The incidence of cisplatin nephrotoxicity was observed in 41 of 182 cycles with initial administration. Multivariate logistic regression analysis showed that systolic blood pressure was independently associated with cisplatin nephrotoxicity (adjusted odds ratio 0.75, 95% confidence interval 0.57 to 0.95 for each 10 mmHg). The use of renin-angiotensin system (RAS) inhibitors was also associated with cisplatin nephrotoxicity (3.39, 1.30 to 8.93). Among quartiles of systolic blood pressure in all cycles of chemotherapy, the incidence of nephrotoxicity in the lower blood pressure group was significantly higher than that in the higher blood pressure group for patients taking non-solid food (P = 0.037), while there was no significant difference for patients taking solid food (P = 0.67).ConclusionsLower blood pressure and the use of RAS inhibitors were associated with the incidence of cisplatin nephrotoxicity, and lower blood pressure had a greater influence on nephrotoxicity in patients who could not take solid food. Discontinuation of antihypertensive medication including RAS inhibitors before cisplatin chemotherapy should be considered, which may be beneficial for patients with lower blood pressure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3135-6) contains supplementary material, which is available to authorized users.

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A 69-year-old man was admitted to our hospital with severe hypertension and rapidly worsening renal function. He presented with a 10-year history of chronic renal failure caused by bilateral ureteral obstruction due to retroperitoneal fibrosis. Magnetic resonance angiography and Doppler ultrasonography suggested severe right renal artery stenosis (RAS). Renal angiography revealed 99% stenosis at the ostium of the right renal artery. We performed percutaneous transluminal renal angioplasty (PTRA) with the support of intravascular ultrasound to decrease the amount of contrast agent needed. In addition, to prevent distal atheroembolism, a distal protection device was used. The procedure was completed without any adverse effects. After PTRA, renal function and blood pressure improved remarkably and remained stable for one year. PTRA for RAS remains controversial, especially in patients with renal insufficiency. Use of new devices should be considered to decrease catheterization-related adverse effects.

A 77-year-old woman had been receiving prednisolone (PSL) for 5 months as induction therapy for microscopic polyangiitis. Because of repeated elevation of the antineutrophil cytoplasmic autoantibody titer, we added mizoribine (MZR), and, 2 months later, the patient developed severe hyperglycemia with low serum and urinary C-peptide reactivity (CPR). The MZR was, therefore, withdrawn and insulin therapy was started. One month later, the serum and urinary CPR had increased and postprandial hyperglycemia had improved. Previous in vitro studies have shown that MZR can induce hyperglycemia through at least two mechanisms. One is the alteration of insulin secretion from islet cells, and the other is action via the glucocorticoid receptor (GR). MZR reduces insulin secretion through the depletion of intracellular guanosine triphosphate (GTP), which leads to the inhibition of mitogenesis and induction of beta cell apoptosis. MZR affects insulin resistance by activating the GR through interaction with the 14-3-3 protein, leading to postprandial hyperglycemia. Although postprandial hyperglycemia generally appears between 3 and 7 weeks after PSL administration, that in our patient did not become apparent during 5 months of PSL monotherapy, but was manifested 2 months after the introduction of MZR, and improved after MZR had been withdrawn. We conclude from these findings that MZR had been responsible for the hyperglycemia in our patient.