MicroRNA-26a-5p Restoration Ameliorates Unilateral Ureteral Obstruction-Induced Renal Fibrosis in Mice Through Modulating TGF-ß Signaling.

Renal fibrosis is a hallmark of chronic and progressive renal diseases characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and a loss of renal function, eventually leading to end-stage renal diseases. MicroRNA-26a-5p (miR-26a-5p) downregulation has been previously noted in the sera of unilateral ureteral occlusion (UUO)-injured mice, and exosome-mediated miR-26a-5p reportedly attenuated experimental pulmonary and cardiac fibrosis. This study evaluated the expression patterns of miR-26a in a human tissue microarray with kidney fibrosis and in tissues from a mouse model of UUO-induced renal fibrosis. Histologic analyses showed that miR-26a-5p was downregulated in human and mouse tissues with renal interstitial nephritis and fibrosis. Moreover, miR-26a-5p restoration by intravenous injection of a mimic agent prominently suppressed the expression of transforming growth factor ß1 (TGF-ß1) and its cognate receptors, the inflammatory transcription factor NF-κB, epithelial-mesenchymal transition, and inflammatory markers in UUO-injured kidney tissues. In vitro, miR-26a-5p mimic delivery significantly inhibited TGF-ß1-induced activation of cultured normal rat kidney NRK-49F cells, in terms of downregulation of TGF-ß1 receptors, restoration of the epithelial marker E-cadherin, and suppression of mesenchymal markers, including vimentin, fibronectin, and α-smooth muscle actin, as well as TGF-ß1/SMAD3 signaling activity. Our findings identified miR-26a-5p downregulation in kidney tissues with human interstitial nephritis and UUO-induced mouse kidney fibrosis. MiR-26a-5p restoration may exhibit an antifibrotic effect through the blockade of both TGF-ß and NF-κB signaling axes and is considered a novel therapeutic target for treating obstruction-induced renal fibrosis.

WT1: The Hinge Between Anemia Correction and Cancer Development in Chronic Kidney Disease.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) emerge as promising agents to treat anemia in chronic kidney disease (CKD) but the major concern is their correlated risk of cancer development and progression. The Wilms' tumor gene, WT1, is transcriptionally regulated by HIF and is known to play a crucial role in tumorigenesis and invasiveness of certain types of cancers. From the mechanism of action of HIF-PHIs, to cancer hypoxia and the biological significance of WT1, this review will discuss the link between HIF, WT1, anemia correction, and cancer. We aimed to reveal the research gaps and offer a focused strategy to monitor the development and progression of specific types of cancer when using HIF-PHIs to treat anemia in CKD patients. In addition, to facilitate the long-term use of HIF-PHIs in anemic CKD patients, we will discuss the strategy of WT1 inhibition to reduce the development and progression of cancer.

Association between Extreme Values of Markers of Chronic Kidney Disease: Mineral and Bone Disorder and 5-Year Mortality among Prevalent Hemodialysis Patients.

BACKGROUND/AIMS: We examined the association between markers of chronic kidney disease - mineral and bone disorder (CKD-MBD) and mortality in hemodialysis (HD) patients. METHODS: We retrospectively reviewed the association between markers of CKD-MBD and mortality in 1,126 HD patients from 2009 to 2013 with baseline (B), time-average (TA), and time-dependent (TD) Cox regression models. RESULTS: Hypercalcemia (10.9-11.9 mg/dL) indicated an increased risk of all-cause mortality (TA: hazard ratio [HR] 3.49; p = 0.01). Hypophosphatemia (2.0-2.5 mg/dL) was significantly associated with an increased risk of all-cause mortality (TA: HR 5.18; p = 0.01). Hypophosphatemia (<2.0 mg/dL) was significantly associated with an increased risk of cardiovascular mortality in all models. Intact parathyroid hormone levels <60 and >1,500 pg/mL indicated an increased risk of all-cause mortality (TA: HR 1.64; p = 0.02; TD: HR 2.26; p = 0.02). CONCLUSION: Extreme values of CKD-MBD markers are associated with mortality risk in HD patients. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=478972.

Indoxyl Sulfate Downregulates Mas Receptor via Aryl Hydrocarbon Receptor/Nuclear Factor-kappa B, and Induces Cell Proliferation and Tissue Factor Expression in Vascular Smooth Muscle Cells.

BACKGROUND/AIM: Angiotensin converting enzyme-related carboxypeptidase 2/angiotensin (Ang)-(1-7)/Mas receptor axis is protective in the development of chronic kidney disease and cardiovascular disease. This study is aimed at investigating whether indoxyl sulfate (IS) affects Mas receptor expression, cell proliferation and tissue factor expression in vascular smooth muscle cells, and if Ang-(1-7), an activator of Mas receptor, counteracts the IS-induced effects. METHODS: IS was administered to normotensive and hypertensive rats. Human aortic smooth muscle cells (HASMCs) were cultured with IS. RESULTS: IS reduced the expression of Mas receptor in the aorta of normotensive and hypertensive rats. IS downregulated the Mas receptor expression in a time- and dose-dependent manner in HASMCs. Knockdown of aryl hydrocarbon receptor (AhR) and nuclear factor-kappa B (NF-x03BA;B) inhibited IS-induced downregulation of Mas receptor. Further, IS stimulated cell proliferation and tissue factor expression in HASMCs. Ang-(1-7) attenuated IS-induced cell proliferation and tissue factor expression in HASMCs. Ang-(1-7) suppressed phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and NF-x03BA;B in HASMCs. CONCLUSION: IS downregulated the expression of Mas receptor via AhR/NF-x03BA;B, and induced cell proliferation and tissue factor expression in HASMCs. Ang-(1-7) inhibited IS-induced cell proliferation and tissue factor expression by suppressing the phosphorylation of ERK1/2 and NF-x03BA;B p65.

Efficacy and safety of pegylated interferon alfa-2b and ribavirin combination therapy versus pegylated interferon monotherapy in hemodialysis patients: a comparison of 2 sequentially treated cohorts.

BACKGROUND: Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. STUDY DESIGN: 2 prospective observational cohort studies. SETTING & PARTICIPANTS: From 2007-2009, a total of 26 patients received peginterferon alfa-2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. PREDICTORS: Peginterferon alfa-2b monotherapy, 1.0 µg/kg/wk, versus peginterferon alfa-2b, 1.0 µg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. OUTCOMES & MEASUREMENTS: End-of-treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. RESULTS: Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. LIMITATIONS: Comparison of 2 sequential cohorts rather than a randomized control study. CONCLUSIONS: Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa-2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy.

A novel experience of antiviral therapy for chronic hepatitis B in renal transplant recipients.

BACKGROUND: Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B. There is no published data concerning ETV therapy in nucleoside analogue (NUC)-naive hepatitis B surface antigen (HBsAg)-positive renal transplant recipients (RTRs). METHODS: We prospectively treated 27 HBsAg-positive RTRs with ETV since 2007. Serial HBV DNA was assessed at baseline and weeks 12, 24, 52 and 104 after treatment. A cohort of 19 patients who received 2-year lamivudine (3TC) therapy during 2004-2007 was used as a historical control. RESULTS: Of the 27 RTRs, 18 (67%) were NUC-naive patients and 9 (33%) were 3TC-experienced without YMDD mutations. HBV DNA levels became undetectable in 70%, 74%, 96% and 100% of patients after 12, 24, 52 and 104 weeks, respectively, of ETV treatment without viral resistance. There was no change of glomerular filtration rate, and no lactic acidosis or myopathy during treatment. By comparison with the 19 3TC-treated patients, ETV-treated RTRs presented higher rates of undetectable HBV DNA than 3TC-treated RTRs (32%, 37%, 63% and 63% at 12, 24, 52 and 104 weeks; P<0.005). In an analysis excluding 9 patients from the ETV group who were also 3TC-experienced, the remaining 18 ETV-naive RTRs exhibited a better virological response at 52 and 104 weeks than 19 3TC-treated RTRs (P<0.05). Even in the 9 patients who overlapped in two cohorts, ETV exhibited a more rapid virological response than 3TC did, especially at 12 and 24 weeks (P=0.009). CONCLUSIONS: ETV is effective in treating chronic hepatitis B in RTRs. ETV is safe with regards to renal graft function, lactic acidosis, myopathy and virological resistance.

The therapeutic response of antiviral therapy in HBsAg-positive renal transplant recipients and a long-term follow-up.

BACKGROUND: Early prediction of lamivudine (LAM) response by individualized monitoring of serum HBV DNA like roadmap concept, and investigation of the outcome after LAM discontinuation in renal transplant recipients (RTRs) with chronic hepatitis B (CHB). METHODS: We conducted a study on 19 RTRs with HBV infection receiving LAM treatment for 2 years from 2004 to 2007. HBV DNA level was assessed at baseline, 12, 24, 52, and 104 weeks after treatment. Risk factors of tyrosine-methionine-aspartate-aspartate (YMDD) mutation on treatment and relapse rate of HBV after LAM discontinuation were analyzed. RESULTS: HBV DNA levels became undetectable in 32, 37, 63, and 53% of patients after 12, 24, 52, and 104 weeks of LAM treatment, respectively. Overall, three (16%) and five (33%) patients were detected with YMDD mutations at week 52 and 104, respectively. In the concept of roadmap, of the seven patients with inadequate virologic response (IAVR) at week 24, five had YMDD mutations. There was no significant association of YMDD mutations with age, gender, genotype, cirrhosis, HBeAg status, baseline HBV DNA, precore/core promoter mutations, and primary response, except IAVR at week 24 (P = 0.001). The relapse rate of HBV after LAM discontinuation was high (75%) during a median follow-up of 65 weeks. CONCLUSIONS: The rate of LAM resistance in RTRs is similar to immunocompetent CHB patients in a 2-year therapy. By roadmap concept, RTRs with IAVR require a change in therapy to prevent viral resistance. Relapse after LAM withdrawal is frequent. Long-term antiviral therapy is crucial for immunosuppressed patients.

Sex differences in kidney size and clinical features of patients with uremia.

BACKGROUND: Ultrasonographic evaluation of the kidney size is a useful method for assessment of the progression and, in some cases, the type of nephropathy. Ultrasonography (USG) also plays an important role in the evaluation of both acute and chronic renal failure. OBJECTIVE: To investigate the ultrasonographic appearance of the kidneys in patients with uremia, underlying renal diseases and clinical characteristics, including biological sex, were studied. METHODS: This was a retrospective study of data from consecutive adult patients with uremia starting a dialysis program between January 2005 and December 2006 at the nephrology department of a university hospital in Taiwan. Kidney size was determined by USG; demographic and clinical data were obtained prior to initiation of dialysis. RESULTS: Of the patients (167 men, 151 women) included in the analysis, diabetes mellitus (DM) was the leading cause of uremia (127/318; 39.9%). The distribution of DM was similar between male and female patients. In addition to levels of blood urea nitrogen and hemoglobin, body mass index was similar between male and female patients (mean [SD], 22.9 [3.1] vs 22.1 [3.4] kg/m(2), respectively). Female patients had significantly lower serum creatinine levels (P < 0.05) and higher estimated glomerular filtration rates (P < 0.01) than did male patients when they initiated chronic dialysis therapy. Among those with DM, male patients were younger and had larger kidney size on initiation of dialysis therapy than did female patients (age, 59.9 [9.4] vs 64.6 [11.9] years; right renal length, 10.3 [1.4] vs 9.5 [1.5] cm; left renal length, 10.4 [1.5] vs 9.5 [1.4] cm; all, P < 0.05). These sex differences in age and kidney size at the start of dialysis were not observed in patients who did not have DM. Patients with DM had significantly larger kidney size than those without DM (P < 0.05). CONCLUSIONS: The kidney size of these uremic patients varied considerably, depending on sex and the underlying disease. Male patients with DM at the terminal stage of renal failure had larger kidney size and were younger at the start of dialysis therapy than female patients with DM. In uremic patients without DM, no such discrepancy was observed, and both male and female patients started dialysis therapy at a comparable age and kidney size.

Hepatitis B virus infection and renal transplantation.

Although the prevalence of chronic hepatitis B virus (HBV) infection has declined in renal transplant recipients (RTRs), it remains a relevant clinical problem with high morbidity and mortality in long-term follow up. A thorough evaluation, including liver biopsy as well as assessment of HBV replication in serum (i.e. hepatitis B e antigen and/or HBV DNA) is required before transplantation. Interferon should not be used in this setting because of low efficacy and precipitation on acute allograft rejection. The advent of effective antiviral therapies offers the opportunity to prevent the progression of liver disease after renal transplantation. However, as far as we are aware, no studies have compared prophylactic and preemptive strategies. To date, the majority of RTRs with HBV-related liver disease have had a high virological and biochemical response to lamivudine use. However, lamivudine resistance is frequent with a prolonged course of therapy. Considering long-term treatment, antiviral agents with a high genetic barrier to resistance and lack of nephrotoxicity are suggested. The optimal strategy in RTRs with HBV infection remains to be established in the near future.

A longitudinal change of peritoneal equilibration test results in peritoneal dialysis patients aged 60 years and above: a 4-year observation study in comparison with a younger group.

BACKGROUND: The number of elderly people with end-stage renal disease has grown in developed countries and medical teams now face the choice of dialysis therapy in elderly patients. In the present study, we retrospectively analyzed two peritoneal dialysis (PD) patients, of different ages, who were treated at the same unit by the same PD team of doctors and nurses. Our purpose was to study peritoneal membrane changes in elderly and younger PD patients. METHODS: 108 patients above 60 years of age or younger at the start of dialysis, were separated into two cohorts. Diabetic patients were excluded. Peritoneal equilibration test (PET) results taken over 4 continuous years were compared between the two groups. RESULTS: No significant differences were seen between the two groups in peritoneal transport (D/P Cr, D/D0 glucose) during the 4-year observation. Total Kt/V and renal creatinine clearance (Ccr) values in the 4-year period were not significantly different between the two groups. Renal Ccr values showed a longitudinal decline in the two groups but the values of total Kt/V revealed a consistency over the 4-year period. CONCLUSION: Elderly PD patients demonstrated a similar peritoneal permeability to younger PD patients based on a 4-year PET.

Preserved residual kidney function after twelve years' hemodialysis.

Residual kidney function (RKF) contributes significantly to solute clearance and fluid removal for dialysis patients, and the presence of RKF is associated with less morbidity and better long-term outcome. Most studies demonstrate that peritoneal dialysis preserves RKF better than hemodialysis (HD). Herein, we report a 55-year-old man with end stage renal failure who had been on chronic HD for 12 years. His RKF is preserved with very slow decline during the past years. Without specific intervention, delicate fluid management, minimal ultrafiltration, and stable hemodynamics during HD may help maintain his RKF. He is currently normotensive with good nutritional status. Although unexpected, we report this HD patient can preserve his RKF for at least 12 years.

End-stage renal disease in Taiwan: a case-control study.

BACKGROUND: Taiwan has the highest incidence of end-stage renal disease (ESRD) in the world. The epidemiologic features of ESRD, however, have not been investigated. In this case-control study, we evaluated the risk of ESRD associated with a number of putative risk factors. METHODS: We studied 200 patients among whom ESRD had been newly diagnosed between 1 January 2005 and 31 December 2005; 200 controls were selected from among relatives of patients treated in the general surgery unit. Using a structured questionnaire, we collected information related to socioeconomic factors, history of disease, regular blood or urine screening, lifestyle, environmental exposure, consumption of vitamin supplements, and regular drug use at 5 years before disease onset. RESULTS: Our primary multivariate risk models indicated that low socioeconomic status was a strong predictor of ESRD (education: odds ratio [OR], 2.78; 95% confidence interval [CI], 1.49-5.19; income: OR, 2.86, 95% CI, 1.48-5.52), even after adjusting for other risk factors. Other significant predictors for ESRD were a history of hypertension (OR, 3.63-3.90), history of diabetes (OR, 3.85-5.50), and regular intake of folk remedies or over-the-counter Chinese herbs (OR, 10.84-12.51). Regular intake of a multivitamin supplement 5 years before diagnosis was associated with a decreased risk of ESRD (OR, 0.12-0.14). CONCLUSIONS: Our findings indicate that low socioeconomic status, history of hypertension, diabetes, and regular use of folk remedies or over-the-counter Chinese herbs were significant risk factors for ESRD, while regular intake of a multivitamin supplement was associated with a decreased risk of ESRD.

The role of HBV genotype, core promoter and precore mutations in advanced liver disease in renal transplant recipients.

BACKGROUND/AIMS: In renal transplant recipients (RTRs), chronic hepatitis B virus (HBV) infection may lead to poor outcomes. This study aimed to investigate the role of the HBV genotype, core promoter and precore mutations in advanced liver disease in RTRs. METHODS: We retrospectively reviewed 51 RTRs positive for hepatitis B surface antigen (HBsAg). HBV genotype determination and direct sequencing of core promoter and precore regions were performed using the baseline and end-of-follow-up sera post-renal transplantation. RESULTS: Alanine Transaminase (ALT) and HBV DNA levels were elevated after transplantation (66%). HBV genotypes B and C were found in 45 (88%) and 6 (12%) patients, respectively. There was no significant association of cirrhosis development with ALT, and hepatitis B-e antigen (HBeAg) levels, type of immunosuppressant, HBV genotype, T1762/A1764 and A1896 mutations, and duration of follow-up, except endpoint HBV DNA levels (> or =10(5)copies/ml). High T1762/A1764 mutation rates were associated with high HBV DNA levels (P=0.036) at the endpoint. CONCLUSIONS: HBV DNA replication was enhanced in RTRs with T1762/A1764 mutation. Increased serum HBV DNA levels were associated with cirrhosis development. T1762/A1764 mutation and cirrhosis development did not show significant correlation because of small sample size and/or interventional anti-viral therapies during follow-up.

Better sleep quality and less daytime symptoms in patients on evening hemodialysis: a questionnaire-based study.

The aims of this study were to investigate the prevalence of sleep disorders in patients with end-stage renal disease (ESRD), and to assess the effect of dialysis schedule on sleep quality and the presence of daytime symptoms. We prospectively selected 150 long-term hemodialysis (HD) patients in three groups (morning, afternoon, and evening dialysis) and gave them a sleep questionnaire, the Epworth sleepiness scale and the Pittsburgh sleep quality index. Snoring was the most common complaint (56%), followed by insomnia (38%) and restless legs syndrome (22.7%). The evening dialysis group experienced more sleep time in bed (P = 0.02), required less hypnotic medication (P = 0.049), had fewer daytime symptoms (P < 0.01), and experienced less daytime sleepiness (P = 0.034). Our study confirms the high prevalence of sleep disorders in ESRD patients, and indicates a beneficial effect of evening HD on sleep quality and reduction of daytime symptoms.

Expanded-spectrum beta-lactamase producing Klebsiella pneumoniae-related peritonitis in a patient on peritoneal dialysis.

While hospitalized for pneumonia with ventilator-dependent respiratory failure, a 45-year-old man on continuous ambulatory peritoneal dialysis (CAPD) had nosocomial peritonitis secondary to infection by expanded spectrum beta-lactamase producing Klebsiella pneumoniae (ESBL-Kp). He was treated successfully with a 3-week course of intraperitoneal (IP) flomoxef therapy without subsequent relapse, loss of peritoneal catheter, ultrafiltration failure, or dialysis inadequacy. The International Consensus Panel recommends IP ceftazidime as the treatment of choice for CAPD patients suffering Klebsiella species-related peritonitis. However, the most appropriate form of IP antibiotic therapy and the outcomes for expanded-spectrum beta-lactamase (ESBL)-producing bacteria-related peritonitis for CAPD patients have not been established yet. Further, the ability to correctly report minimal inhibitory concentrations (MICs) of ceftazidime for ESBL bacteria in the resistant range varies between laboratories, making the diagnosis of ESBL-Kp-related CAPD peritonitis more complex and difficult. Thus, it appears reasonable to suggest that its incidence is probably underestimated and its significance ignored. The authors suggest that a 3-week IP treatment with flomoxef, a synthesized oxacephem, with loading and maintenance doses of 250 and 125 mg/L, respectively, is effective and safe for ESBL-Kp-related peritonitis in these patients. ESBL producing bacterial infection should be considered as a possible cause of overt CAPD-related peritonitis. Early detection of ESBLB pathogens and institution of effective antibiotic treatment may improve the prognosis.

Longitudinal change in peritoneal membrane function with continuous ambulatory peritoneal dialysis (CAPD) after peritonitis episodes.

BACKGROUND: To assess changes in the peritoneal membrane after peritonitis episodes in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: From 1989 to 2002, CAPD patients who had peritonitis episodes were enrolled. We used the peritoneal equilibration test (PET) and measured plasma creatinine (Cr) levels at 2 hours, and dialysate Cr and glucose levels at 0, 2, and 4 hours. In addition, the dialysate-to-plasma ratio of Cr (D/PCr) at 0, 2, and 4 hours, the ratio of glucose levels in the dialysate effluent and infused dialysate ((D/D0)G), the drained ultrafiltration (UF) volume at 4 hours, and the mass transfer area coefficient of Cr (MTAC) normalized for the body surface area were also calculated. D/PCr, (D/D0)G, UF volume, and MTAC were measured at the baseline and after 2 years, and the results were analyzed and compared. RESULTS: Totally 27 patients were enrolled in the peritonitis group, including 17 males and 10 females. They had received CAPD for 71.23 +/- 28.13 months. Forty-nine peritonitis episodes were noted during the study period. Twenty-four patients were enrolled as controls, including 9 males and 15 females. They had undergone CAPD for 55.83 +/- 25.94 months. The baseline and 2-year levels of D/PCr (0.66 +/- 0.11 vs. 0.62 +/- 0.10, p<0.05), (D/D0)G (0.37 +/- 8.45 vs. 0.43 +/- 7.71, p<0.05), and MTAC (9.36 +/- 3.53 vs. 8.08 +/- 3.41, p<0.05) showed significant changes, but UF volume (253.70 +/- 224.43 vs. 311.54 +/- 186.71 ml, p>0.05) showed no significant change. In the control group, there were no significant changes in D/PCr, (D/D0)G, MTAC, or UF volume. CONCLUSION: Peritonitis episodes affect the peritoneal membrane solute transport function in CAPD patients.