Toshimi Imai

Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo

Renal fibrosis is the final common pathway leading to end-stage renal disease. Although microRNA (miR) was recently shown to be involved in the development of renal fibrosis, few studies have focused on the effects on renal fibrosis of exogenous miR delivered in an in vivo therapeutic setting. The study reported here investigated the effects of miR-146a delivery using polyethylenimine nanoparticles (PEI-NPs) on renal fibrosis in vivo. PEI-NPs bearing miR-146 or control-miR (nitrogen/phosphate ratio: 6) were injected into the tail vein of a mouse model of renal fibrosis induced by unilateral ureteral obstruction. PEI-NPs bearing miR-146 significantly enhanced miR-146a expression in the obstructed kidney compared with the control group, while inhibiting the renal fibrosis area, expression of alpha-smooth muscle actin, and infiltration of F4/80-positive macrophages into the obstructed kidney. In addition, PEI-NPs bearing miR-146a inhibited the transforming growth factor beta 1–Smad and tumor necrosis factor receptor-associated factor 6–nuclear factor kappa B signaling pathways. Control-miR-PEI-NPs did not show any of these effects. These results suggest that the delivery of miR-146a attenuated renal fibrosis by inhibiting pro-fibrotic and inflammatory signaling pathways and that the delivery of appropriate miRs may be a therapeutic option for preventing renal fibrosis in vivo.

Renal failure caused by plasma cell infiltration in multiple myeloma

We report on a case of severe renal failure in a 61-year-old female with multiple myeloma (MM). Two months prior to admission, the patient was diagnosed to have anemia and progressive renal failure associated with urinary Bence Jones protein and was referred to our hospital. A bone marrow biopsy revealed 40% plasma cells with κ light chain restriction. Thus, she was considered to have MM. A renal biopsy revealed neoplastic plasma cell infiltration within the kidney, moderate interstitial fibrosis, tubular atrophy, and punctate, electron-dense material along the peripheral capillary walls, tubular basement membrane, and in the interstitium of the kidney. This suggested that a combination of compression of the tubules and the microvasculature by the infiltrative process, and local light chain deposition-mediated tissue damage might be implicated in the development of renal failure in this patient. Despite a remission of bone marrow plasmacytosis with a bortezomib-based regimen, her renal function gradually deteriorated and a periodic hemodialysis program was finally required. Although the clinical impact of the direct kidney infiltration of neoplastic plasma cells on the longitudinal changes in renal function remains to be delineated, it is reasonable to consider that the infiltration of neoplastic plasma cells associated with local light chain depositions may result in irreversible renal injuries. Obviously, further studies and accumulation of additional experience with renal biopsy are required to better determine the precise and prognostic relationship between renal outcome and morphological alterations among MM patients with varying degrees of renal impairment.

Management of Diabetes Associated with Nephrotic Syndrome: Therapeutic Potential of Dapagliflozin for Protracted Volume Retention

A 48-year-old female was admitted to our hospital presenting with a chief complaint of progressive swelling because of diabetic nephrotic syndrome. Dapagliflozin seemed to play a role in accelerating the patients urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide. Our experience emphasizes a potential novel approach to overcoming loop diuretic resistance using this agent among some subsets of type 2 diabetic subjects complicated with severe volume accumulation. We believe that combination treatment consisting of dapagliflozin and furosemide may produce diuretic synergy via sequential nephron blockade. The accumulation of more experience with additional cases similar to ours requires continuous and careful attention.

Four consecutive cases of Achilles tendon disorders associated with levofloxacin treatment in hemodialysis patients.

To the Editor Quinolone-induced tendon injury is an uncommon complication with an estimated rate of only 0.14–0.4 % in an otherwise healthy population [1]. However, an epidemiologic study clearly showed that current exposure to quinolone increased the risk of Achilles tendon rupture (adjusted odds ratio 4.3) [2]. Although the mechanism by which quinolones are thought to cause tendon injury has not been established, a number of suggestions, including an ischemic vascular process, direct toxicity to the collagen, oxidative damage, and the structure activity of the quinolone molecule, have been made [1]. Moreover, there is an accumulation of case reports related to quinolone use in patients with renal impairment, including a case described in Clinical and Experimental Nephrology [3]. Renal transplantation, advanced age, renal failure and/or hemodialysis (HD), hyperparathyroidism, rheumatic diseases, gout, and use of corticosteroids have been proposed as predisposing factors [1]. It is of particular interest to nephrologists that patients with end-stage renal diseases are prone to these conditions. We herein report four cases of Achilles tendon disorders following levofloxacin administration in HD patients that occurred in a 2-year period from May 2009 to May 2011 at our hospital. The clinical characteristics of the patients are summarized in Table 1. On careful examinations by an orthopedist, rupture was not evident in any of cases. In consideration of the following clinical courses, bilateral tendonitis was the most likely disorder. All were undergoing thrice-weekly HD and received oral levofloxacin administration: patient 1 at a daily dose of 200 mg (twice a day) and the other three patients at 500 mg on the first day and then 250 mg every 48 h according to the revised dose for patients with severe renal impairment. In Japan, the regimen for levofloxacin was revised in 2009 in this manner, with the intention of enhancing efficacy and avoiding bacterial resistance based on pharmacokinetics and pharmacodynamics [4]. Thus, it is intriguing that we experienced four consecutive cases of Achilles tendon disorders in patients taking a relatively high dose of levofloxacin in this transition period. These observations implicate dose dependency and reduced drug clearance in the development of the tendon disorder, in support of previous reports [1, 2]. Incidentally, levofloxacin was prescribed simply because of the availability at our facility. In fact, other quinolones such as pefloxacin, ciprofloxacin, and norfloxacin accounted for the greater proportions of quinolone-associated tendinopathy in a literature review [1]. Second, the manifestations emerged shortly after administration, within a couple of days in most cases, and completely disappeared 2–4 months later without requiring hospitalization or surgery. Consistent with our experience, Khaliq et al. [1] documented that 50 % of tendonitis cases occurred within 6 days after initiation of fluoroquinolone therapy, during the time when the antimicrobial therapy might still be in effect. Interventions included discontinuation of the drug in the majority of cases [1]. Similarly, levofloxacin was presumptively discontinued in three of our patients, and in patient 1 medication had already ceased at the time of onset because of resolution of the infectious disease. Magnetic resonance imaging was performed only in the latest case (patient 4) with reference to an Images in S. Takeda T. Imai Y. Chaki Dialysis Center, Oyama Municipal Hospital, 1-15 Wakagi-cho, Oyama, Tochigi, Japan

Therapeutic Challenges to End-Stage Kidney Disease in a Patient with Tetralogy of Fallot

In this report, we describe the case of an end-stage kidney disease patient with tetralogy of Fallot (TOF). A 33-year-old female with TOF was admitted to our hospital with complaints of general fatigue and appetite loss probably due to uremic milieu. She was ultimately treated with peritoneal dialysis (PD) with a favorable clinical course. TOF patients with chronic kidney disease are not exceptional, although the currently available information regarding the association between TOF and renal failure severe enough to require dialysis treatment is limited. We also discuss the complex processes of how and why PD was selected as a mode of chronic renal replacement therapy in this case.

Methylglyoxal Induced Basophilic Spindle Cells with Podoplanin at the Surface of Peritoneum in Rat Peritoneal Dialysis Model

Peritoneal dialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS), which is a serious complication of PD. In order to carry out PD safely, it is important to define the mechanism of progression of peritoneal injury and EPS. We prepared rat models of peritoneal injury by intraperitoneal administration of glucose degradation products, such as methylglyoxal (MGO) or formaldehyde (FA), chlorhexidine gluconate (CG), and talc. In rats treated with MGO, peritoneal fibrous thickening with the appearance of basophilic spindle cells with podoplanin, cytokeratin, and α-smooth muscle actin at the surface of the peritoneum was observed. These cells may have been derived from mesothelial cells by epithelial-to-mesenchymal transition. In FA- or CG-treated rats, the peritoneum was thickened, and mesothelial cells were absent at the surface of the peritoneum. The CG- or MGO-treated rats presented with a so-called abdominal cocoon. In the talc-treated rats, extensive peritoneal adhesion and peritoneal thickening were observed. MGO-induced peritoneal injury model may reflect human histopathology and be suitable to analyze the mechanism of progression of peritoneal injury and EPS.

MicroRNA expression profiling in peritoneal fibrosis.

Peritoneal fibrosis (PF) is an intractable complication leading to peritoneal membrane failure in peritoneal dialysis (PD). The aim of this study was to identify microRNAs (miRNAs) involved in PF. Peritoneal tissue from a PF rat model was screened for miRNA expression using microarray analysis. The expression levels of differentially expressed miRNAs were evaluated in serum and drained dialysate and associated with peritoneal membrane functions, as measured by the peritoneal equilibrium test in 33 PD patients. Furthermore, an miRNA inhibitor (anti-miRNA-21-5p locked nucleic acid (LNA): anti-miRNA-21-LNA) was intraperitoneally injected to PF model mice to investigate its effects on PF. The initial profiling study of PF rat peritoneal tissue identified 6 miRNAs (miRNA-142-3p, miRNA-21-5p, miRNA-221-3p, miRNA-223-3p, miRNA-34a-5p, and miRNA-327) whose expression was increased more than 2-fold and no miRNAs whose expression was decreased more than half. Among them, serum levels of miRNA-21-5p, miRNA-221-3p, and miRNA-327 and drained dialysate levels of miRNA-221-3p and miRNA-34a-5p were significantly correlated with peritoneal membrane functions in PD patients. Anti-miRNA-21-LNA significantly inhibited miRNA-21-5p expression in the PF mouse peritoneum, inhibited peritoneal fibrous thickening, and maintained peritoneal membrane functions. These results suggest that several miRNAs are involved in PF and that they may be useful as novel diagnostic biomarkers and therapeutic targets for PF.

Acute Kidney Injury Associated with Renal Cell Carcinoma Complicated by Renal Vein and Inferior Vena Cava Involvement.

Acute kidney injury (AKI) is caused by diverse pathologies, although it may occasionally result from concurrent renal efflux disturbances. We herein describe a case of AKI in a patient complicated by renal cell carcinoma (RCC) with renal vein and inferior vena cava (IVC) involvement. A neoplastic thrombus which disrupted the blood flow in the renal vein appeared to play a role in the rapid decline in the renal function. Such a scenario has rarely been mentioned in the previous literature describing the cases of RCC complicated by AKI. Concerns regarding the diagnostic and therapeutic strategies for RCC are also discussed.

Unexpected observation of glomerular crescents in a patient with diabetes who developed drug-induced acute tubulointerstitial nephritis: A possible feature of diabetic nephropathy?

A 66-year-old man was transferred to our facility in early April 2012 for a renal biopsy. He had been diagnosed with diabetes mellitus accompanied by proteinuria, hypertension, and dyslipidaemia. Also, famotidine was initiated in late February because of abdominal malaise. Shortly afterward, he developed acute kidney injury (AKI) and was hospitalized at a local hospital. Serum creatinine (sCr) was elevated from 1.07 to 10.59 mg/dL in 2 weeks. Thrice-weekly haemodialysis (HD) was immediately started and all drugs were discontinued at the time of hospitalization. Renal biopsy revealed severe infiltration of inflammatory cells in the tubulointerstitial area (Fig. 1a, b), but marked improvement of renal function was observed (sCr, 2.49 mg/dL), eventually resulting in cessation of HD therapy approximately one month later. Famotidine and rosuvastatin were positive in a drug lymphocyte stimulation test. Therefore, drug-induced acute tubulointerstitial nephritis (ATIN) was thought to be the principal cause of AKI. However, along with persistent proteinuria (10.477 g/day) with a low selectivity index (0.54), distinctive features of diabetic nephropathy (DMN) such as nodular lesions and exudative lesions in glomeruli were superposed in kidney specimens (Fig. 1c, d). Of particular note, cellular crescent formation was observed in 3 of 33 glomeruli (Fig. 1d), but otherwise there were no definitive findings of glomerular diseases other than diabetic features.

Effluent Tenascin-C Levels Reflect Peritoneal Deterioration in Peritoneal Dialysis: MAJOR IN PD Study.

Peritoneal deterioration causing structural changes and functional decline is a major complication of peritoneal dialysis (PD). The aim of this study was to explore effluent biomarkers reflecting peritoneal deterioration. In an animal study, rats were intraperitoneally administered with PD fluids adding 20 mM methylglyoxal (MGO) or 20 mM formaldehyde (FA) every day for 21 days. In the MGO-treated rats, tenascin-C (TN-C) levels in the peritoneal effluents were remarkably high and a cluster of TN-C-positive mesothelial cells with epithelial-to-mesenchymal transition- (EMT-) like change excessively proliferated at the peritoneal surface, but not in the FA-treated rats. Effluent matrix metalloproteinase-2 (MMP-2) levels increased in both the MGO- and FA-treated rats. In a clinical study at 18 centers between 2006 and 2013, effluent TN-C and MMP-2 levels were quantified in 182 PD patients with end-stage renal disease. Peritoneal function was estimated using the peritoneal equilibration test (PET). From the PET results, the D/P Cr ratio was correlated with effluent levels of TN-C (ρ = 0.57, p < 0.001) and MMP-2 (ρ = 0.73, p < 0.001). We suggest that TN-C in the effluents may be a diagnostic marker for peritoneal deterioration with EMT-like change in mesothelial cells in PD.