Comparison between the 0- and 30-s balloon dilation time in percutaneous transluminal angioplasty for restenosed arteriovenous fistula among hemodialysis patients: a multicenter, prospective, randomized trial (CARP study).

BACKGROUND: This study aims to compare patency rates of the 0- and 30-s (sec) balloon dilation time in hemodialysis (HD) patients with restenosis after percutaneous transluminal angioplasty (PTA). METHODS: The patients who underwent PTA within 6 months for failed arteriovenous fistula at the forearm were randomly assigned the 0-s or 30-s dilation time group. Effect of dilation time on the 3- and 6-month patency rates after PTA was examined. RESULTS: Fifty patients were enrolled in this study. The 3-month patency rate in the 30-s dilation group was better than that in the 0-s dilation group (P = 0.0050), while the 6-month patency rates did not show a significant difference between the two groups (P = 0.28). Cox's proportional hazard model revealed that 30-s of inflation time (hazard ratio 0.027; P = 0.0072), diameter of the proximal (hazard ratio 0.32; P = 0.031), and dilation pressure (hazard ratio 0.63; P = 0.014) were associated with better 3-month patency. Dilation pressure between previous and present PTA did not differ in the 0-s (P = 0.15) and 30-s dilation groups (P = 0.16). The 6-month patency rate of the present PTA in the 30-s dilation group was higher than that of the previous PTA (P = 0.015). The visual analog scale did not differ between the two groups (P = 0.51). CONCLUSION: The presenting data suggest that 30-s dilation potentially results in a better 3-month patency rate than 0-s dilation in HD patients with restenosis after PTA.

Nephrotic-range proteinuria and membranoproliferative glomerulonephritis-like pattern caused by interferon-ß1b in a patient with multiple sclerosis.

Interferon-beta (IFN-ß) subtypes are widely used as immunomodulatory agents for relapsing-remitting multiple sclerosis (MS). Although generally well tolerated, a growing number of reports have recently shown association of long-term IFN-ß therapy with several types of glomerulonephritis. Here, we present the case of a 42-year-old woman with MS who developed nephrotic-range proteinuria after taking IFN-ß1b for nine years. Initially, due to the presence of histological features consistent with immunoglobulin A (IgA) nephropathy (granular IgA deposits in mesangial lesions), a tonsillectomy plus steroid pulse therapy was performed. However, proteinuria did not significantly decrease after these treatments. Therefore, a second renal biopsy was performed after three years, revealing a membranoproliferative glomerulonephritis-like pattern without immune complex. Further immunofluorescence analysis showed attenuated IgA staining. Consequently, IFN-ß1b was replaced with dimethyl fumarate, resulting in complete remission, with proteinuria decreasing to the level of 0.2 g/day. Although it is a rare adverse effect, physicians should pay careful attention to the symptoms and findings of nephritis during the follow-up of patients under treatment with this agent.

Acute tubulointerstitial nephritis and IgM deposits on glomerular capillary walls after immunotherapy with nivolumab for metastatic renal cell carcinoma.

Nivolumab is an anti-programmed cell death-1 antibody that is utilized as an immune checkpoint inhibitor for several malignancies. However, this agent is associated with immune-related adverse events (irAEs), mainly in the spectrum of autoimmune disease including interstitial pneumonia, colitis, type 1 diabetes, and renal impairment. We herein present the case of a 59-year-old man with renal cell carcinoma who developed worsening renal function approximately 4 months after initiation of nivolumab. Urinalysis showed proteinuria and microscopic hematuria along with increase levels of N-acetyl-ß-D-glucosaminidase. Renal biopsy revealed acute tubulointerstitial nephritis and thickening of the glomerular basement membranes. Immunofluorescence showed granular IgM deposits in capillary loops. We initiated high-dose prednisolone therapy with nivolumab, which improved renal function and achieved complete remission of proteinuria. Although renal irAEs are considered to be rare and glomerulonephropathy is not typical presentation, physicians need the close monitoring of renal function and urinalysis in patients under immunotherapy with this agents. In addition, our case provides a possible link between nivolumab and immune-mediated glomerulonephropathy.

microRNA-200c regulates KLOTHO expression in human kidney cells under oxidative stress.

KLOTHO deficiency is associated with the progression of kidney dysfunction, whereas its overexpression exerts renoprotective effects. Oxidative stress suppresses KLOTHO expression in renal epithelial cells but upregulates microRNA-200c (miR-200c) in human umbilical vein endothelial cells. In this study, we investigated whether oxidative stress-induced miR-200c is implicated in KLOTHO downregulation in human renal tubular epithelium (HK-2) cells. HK-2 cells were stimulated with hydrogen peroxide (H2O2) to examine the effect of oxidative stress. A luciferase reporter containing the KLOTHO 3'-UTR was used to investigate the effect of miR-200c on KLOTHO mRNA metabolism. The expressions of KLOTHO, oxidative stress markers, and miR-200c were determined in human kidney biopsy specimens. H2O2 suppressed KLOTHO expression without a reduction in KLOTHO mRNA levels but upregulated miR-200c expression. Similarly, transfection of a miR-200c mimic reduced KLOTHO levels and luciferase activity without a reduction in KLOTHO mRNA levels. In contrast, transfection of a miR-200c inhibitor maintained KLOTHO expression. Immunofluorescent assay revealed KLOTHO was present in the cytosol and nuclei of HK-2 cells. In human kidney biopsies, KLOTHO expression was inversely correlated with levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine: ρ = -0.38, P = 0.026; 4-hydroxy-2-hexenal: ρ = -0.35, P = 0.038) and miR-200c (ρ = -0.34, P = 0.043). Oxidative stress-induced miR-200c binds to the KLOTHO mRNA 3'-UTR, resulting in reduced KLOTHO expression.

Novel Asp511Thr mutation in McArdle disease with acute kidney injury caused by rhabdomyolysis.

McArdle disease (glycogen storage disease type V) is a rare hereditary metabolic myopathy. It can be overlooked clinically because it often presents as chronic asymptomatic hypercreatine phosphokinasemia (hyperCKemia). However, vigorous exercise or infections can trigger severe rhabdomyolysis. We present the case of a patient with long-term idiopathic hyperCKemia who, after contracting an upper respiratory tract infection, developed severe rhabdomyolysis and acute kidney injury. Upon hemodialysis, his renal function recovered and CK levels fell to below baseline, and maintenance therapy with vitamin B6 was also started. A molecular diagnosis of McArdle disease was subsequently made. Whole-exome sequencing revealed homozygous c1538delG (p.Asp511Thr fs*28) mutations in the PYGM gene, which was a novel mutation. Therefore, when investigating idiopathic hyperCKemia, glycogen storage disorders should also be considered.

Tocilizumab histologically improved AA renal amyloidosis in a patient with multicentric Castleman disease: A case report
.

Multicentric Castleman disease (MCD) is a rare systemic lymphoproliferative disorder and is infrequently associated with renal complications that include amyloid A (AA) amyloidosis. Although it has been reported that patients with MCD and amyloidosis usually have a poor prognosis, recently, tocilizumab, a humanized anti-interleukin-6 receptor antibody, has emerged as an effective and specific treatment for AA amyloidosis secondary to chronic inflammatory disorders. Here we report a case of an MCD patient with secondary AA renal amyloidosis who was successfully treated with tocilizumab. The patient was initially referred to nephrology specialists because of a decline in renal function and proteinuria. Percutaneous renal biopsy revealed the presence of Congo red-positive amorphous depositions and AA protein-positive areas in glomeruli, vessel walls, and interstitium, confirming a diagnosis of renal AA amyloidosis secondary to MCD. At 1 year after starting tocilizumab treatment, a second renal biopsy showed the clearance of amyloid deposits in the interstitium. These observations suggest that tocilizumab may be an effective therapy for AA amyloidosis secondary to MCD.
.

Seasonal variation in hemodialysis initiation: A single-center retrospective analysis.

The number of new dialysis patients has been increasing worldwide, particularly among elderly individuals. However, information on seasonal variation in hemodialysis initiation in recent decades is lacking, and the seasonal distribution of patients' conditions immediately prior to starting dialysis remains unclear. Having this information could help in developing a modifiable approach to improving pre-dialysis care. We retrospectively investigated the records of 297 patients who initiated hemodialysis at Hiroshima Prefectural Hospital from January 1st, 2009 to December 31st, 2013. Seasonal differences were assessed by χ2 or Kruskal-Wallis tests. Multiple comparison analysis was performed with the Steel test. The overall number of patients starting dialysis was greatest in winter (n = 85, 28.6%), followed by spring (n = 74, 24.9%), summer (n = 70, 23.6%), and autumn (n = 68, 22.9%), though the differences were not significant. However, there was a significant winter peak in dialysis initiation among patients aged ≥65 years, but not in those aged <65 years. Fluid overload assessed by clinicians was the most common uremic symptom among all patients, but a winter peak was only detected in patients aged ≥65 years. The body weight gain ratio showed a similar trend to fluid overload assessed by clinicians. Pulmonary edema was most pronounced in winter among patients aged ≥65 years compared with other seasons. The incidences of infection were modestly increased in summer and winter, but not statistically significant. Cardiac complications were similar in all seasons. This study demonstrated the existence of seasonal variation in dialysis initiation, with a winter peak among patients aged ≥65 years. The winter increment in dialysis initiation was mainly attributable to increased fluid overload. These findings suggest that elderly individuals should be monitored particularly closely during the winter.

Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal-induced peritoneal fibrosis.

Activity of H3K9 histone methyltransferase G9a is reportedly induced by transforming growth factor-ß1 (TGF-ß1) and plays an important role in the progression of cancer and fibrosis. In this study, we investigated whether inhibition of G9a-mediated H3K9 methylation attenuates peritoneal fibrosis in mice and human peritoneal mesothelial cells (HPMCs). Nonadherent cells of peritoneal dialysis (PD) patients were isolated from PD effluent to examine expression of G9a. Peritoneal fibrosis was induced by peritoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 3 weeks. BIX01294, a G9a inhibitor, was administered by subcutaneous injection. Effects of BIX01294 on MGO-induced pathological and functional changes in mice were evaluated by immunohistochemistry and a peritoneal equilibration test. HPMCs were isolated from human omentum, and the inhibitory effect of BIX01294 on TGF-ß1-induced fibrotic changes was investigated in the HPMCs by western blotting. G9a was upregulated in nonadherent cells of human PD effluent, the peritoneum of MGO-injected mice, and TGF-ß1-stimulated HPMCs. BIX01294 significantly reduced the submesothelial zone thickness and cell density in MGO-injected mice. Immunohistochemical staining revealed that BIX01294 treatment decreased not only mono-methylation of H3K9 (H3K9me1), but also the number of mesenchymal cells, accumulation of collagen, and infiltration of monocytes. In addition to the pathological changes, BIX01294 reduced the level of TGF-ß1 in peritoneal fluid and improved peritoneal functions. Furthermore, BIX01294 inhibited TGF-ß1-induced fibrotic changes along with suppression of H3K9me1 in HPMCs. Therefore, inhibition of H3K9 methyltransferase G9a suppresses peritoneal fibrosis through a reduction of H3K9me1.

Linagliptin Ameliorates Methylglyoxal-Induced Peritoneal Fibrosis in Mice.

Recent studies have reported increases of methylglyoxal (MGO) in peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of peritoneal fibrosis through production of transforming growth factor-ß1 (TGF-ß1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced peritoneal fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal fibrosis was induced by daily intraperitoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraperitoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of α-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-ß1 concentration in the peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO-injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced peritoneal fibrosis.

Inhibition of SET Domain-Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis.

TGF-ß1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain-containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-ß1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-ß1 neutralizing antibody. TGF-ß1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P<0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-ß1-induced α-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent.

Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression.

H3K9 methyltransferase G9a is reportedly induced by transforming growth factor-ß1 (TGF-ß1) and has an important role in the development of epithelial-mesenchymal transposition in cancer cells. Since the transcriptional activity of the Klotho gene is regulated by H3K9 modification, we investigated the effects of G9a on renal fibrosis and klotho expression. G9a levels were significantly upregulated by day 7 in the kidneys of unilateral ureteral-obstructed mice, but this was inhibited by TGF-ß1-neutralizing antibody. Administration of G9a small interfering RNA not only decreased α-smooth muscle actin and fibronectin but also increased klotho expression in the ureteral-obstructed mice. Similarly, intraperitoneal injection of BIX01294, a specific inhibitor of G9a, showed beneficial effects on renal fibrosis and klotho expression with decreased monomethylation of H3K9 (me1). In in vitro experiments, BIX01294 also inhibited TGF-ß1-induced fibrotic changes and klotho downregulation along with suppressed H3K9me1. In human kidney biopsy specimens, areas of G9a immunostaining correlated positively with H3K9me1 levels, as well as fibrotic markers, but correlated negatively with klotho expression. Thus, TGF-ß1-induced G9a has an important role in the progression of renal fibrosis and reduced klotho expression through H3K9me1.

Hemodialysis immediately after cardiac catheterization is a risk factor for intradialytic hypotension.

Many hemodialysis clinicians have noticed that patients frequently develop intradialytic hypotension (IDH) immediately after cardiac catheterization (CC). However, precise data about the incidence of IDH immediately after CC are scarce. This study involved a single-center, retrospective, cross-sectional design. We reviewed the medical records of all HD patients who underwent CC between January 2009 and March 2012 at Hiroshima Prefectural Hospital. IDH was defined as a fall of systolic blood pressure of more than 20 mm Hg or a fall of mean blood pressure of more than 10 mm Hg, with symptoms according to the K/DOQI criteria. Data on a total of 112 patients were obtained: 64 patients commenced HD immediately after CC (IA group) and 48 patients underwent HD on the day after CC (ND group). The overall incidence of IDH was 34% (38/112). The incidence of IDH was significantly higher in the IA group than in the ND group (27/64, 42% vs. 11/48, 23%; P < 0.05). Multivariate logistic regression analysis showed that IA (odds ratio, 5.39; 95% confidence interval, 1.76 to 16.49; P < 0.01), coronary stenosis (odds ratio, 4.16; 95% confidence interval, 1.49 to 11.64; P < 0.05) were independently associated with IDH. This study revealed that HD immediately after CC is associated with a higher incidence of IDH. Clinicians should consider that HD following CC be scheduled for the next day, especially in patients with coronary stenosis.

Successful treatment with plasma exchange for ANCA-negative pauci-immune crescentic glomerulonephritis with D-negative hemolytic uremic syndrome.

Co-existence of antineutrophil cytoplasmic antibody (ANCA)-negative pauci-immune crescentic glomerulonephritis (CGN) and thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTPHUS) is extremely rare and has a poor renal prognosis. We report a 76-year-old female that had both ANCA and anti-human lysosomal membrane protein 2 (LAMP-2) antibody-negative pauci-immune CGN with D-negative HUS. She was admitted with proteinuria and worsening renal failure with massive crescent formation on renal biopsy specimens. We initiated intravenous methylprednisolone pulse therapy followed by oral prednisolone, but she still developed D-negative HUS. We then initiated plasma exchange, which achieved remission of D-negative HUS and improved renal function. To our knowledge, this is the first report of recovery from renal failure in ANCA-negative pauci-immune CGN with TTP-HUS.