The role(s) of nuclear factor erythroid 2-related factor 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency in type 2 diabetes (T2D) db/db mice (db/dbNrf2 knockout (KO)) attenuates DKD progression through the down-regulation of angiotensinogen (AGT), sodium-glucose cotransporter-2 (SGLT2), scavenger receptor CD36, and fatty -acid-binding protein 4 (FABP4), and lipid accumulation in renal proximal tubular cells (RPTCs). Db/dbNrf2 KO mice were studied at 16 weeks of age. Human RPTCs (HK2) with NRF2 KO via CRISPR-Cas9 genome editing and kidneys from patients with or without T2D were examined. Compared with db/db mice, db/dbNrf2 KO mice had lower systolic blood pressure, fasting blood glucose, kidney hypertrophy, glomerular filtration rate, urinary albumin/creatinine ratio, tubular lipid droplet accumulation, and decreased expression of AGT, SGLT2, CD36, and FABP4 in RPTCs. Male and female mice had similar results. NRF2 KO attenuated the stimulatory effect of the Nrf2 activator, oltipraz, on AGT, SGLT2, and CD36 expression and high-glucose/free fatty acid (FFA)-stimulated lipid accumulation in HK2. Kidneys from T2D patients exhibited markedly higher levels of CD36 and FABP4 in RPTCs than kidneys from non-diabetic patients. These data suggest that NRF2 exacerbates DKD through the stimulation of AGT, SGLT2, CD36, and FABP4 expression and lipid accumulation in RPTCs of T2D.

Purpose: To assess whether angioplasty of hemodialysis access (HA) stenosis with a drug-coated balloon (DCB) would prevent restenosis in comparison with plain-balloon percutaneous transluminal angioplasty (PTA). Materials and Methods: This prospective randomized clinical trial enrolled 120 patients with dysfunctional arteriovenous fistulae (n = 109) and grafts (n = 11), due to a >50% stenosis between March 2014 and April 2018. All patients underwent high-pressure balloon angioplasty and were then randomized to either DCB (n = 60) or PTA (n = 60). Patients were followed-up for 1 year, and angiography was performed 6 months after angioplasty. The primary endpoint was the late lumen loss (LLL) at 6 months. Secondary endpoints included other angiographic parameters at 6 months and HA failures, adverse event, and mortality at 12 months. Continuous variables were compared with a Student t-test, and Kaplan-Meier curves were used for freedom from HA failure and for mortality. Results: LLL in the DCB and in the PTA group were 0.64 mm +/- 1.20 and 1.13 mm +/- 1.51, respectively (P = .082, adjusted P = .0498). DCB was associated with lower percentage stenosis (54.2% +/- 19.3 vs 61.7% +/- 18.2; P = .047) and binary restenosis >= 50% (56.5% vs 81.1%; P = .009) than PTA. The number of HA failures after 12 months was lower for DCB than for PTA (45% vs 66.7%; P = .017). Mortality at 12 months was 10% and 8.3% in the DCB and PTA groups, respectively (P = .75). Conclusions: Despite LLL improvement that failed to reach statistical significance, this study demonstrated decreased incidence and severity of restenosis with DCB compared with PTA to treat dysfunctional HA.

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury and sodium-glucose co-transporter 2 (Sglt2) expression in diabetic Akita Nrf2-/-/Nrf2RPTC transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the SGLT2 promoter, human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial fibrosis and Sglt2 expression in Akita Nrf2-/-/Nrf2RPTC Tg mice compared to their Akita Nrf2-/- littermates. In vitro, oltipraz or transfection of NRF2 cDNA stimulated SGLT2 expression and SGLT2 promoter activity in HK2, and these effects were inhibited by trigonelline or NRF2 small interfering RNA. The deletion of the NRF2-responsive element (NRF2-RE) in the SGLT2 promoter abolished the stimulatory effect of oltipraz on SGLT2 promoter activity. NRF2 binding to the NRF2-RE of the SGLT2 promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia-stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.

Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). In both type 1 (Akita) and type 2 (db/db) DM mice, uHhip is elevated prior to the development of albuminuria, while non-DM controls excrete minimal amount of uHhip. In 87 type 2 DM patients and 39 healthy controls, the uHhip/creatinine (Cr) ratio provides a significant discrimination between non-DM and DM groups; 0 [0-69.5] in non-DM, 9.9 [1.7-39.5] in normoalbuminuric DM, 167.7 [95.7-558.7] in microalbuminuric DM, and 207.9 [0-957.2] in macroalbuminuric DM (median [IQR] ng/mmol, P < 0.0001). The log-uHhip/Cr is positively correlated with urine albumin/Cr ratio (UACR) (spearman correlation coefficient 0.47, P < 0.0001). The log-uHhip/Cr is also associated with eGFR, pulse pressure, and urinary cytokines (IL-1β, IL-6, IL-8, and TGFβ1) independent of UACR. By immunostaining, Hhip is localized in glomeruli and tubules, and is increased in human DM kidneys compared with non-DM kidneys. TGFβ1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation.

Background: Fluid overload leading to pulmonary congestion is an important issue in patients undergoing hemodialysis. This study aimed to determine if a simplified method of extravascular lung water assessment using ultrasound provided clinically relevant information. Methods: This prospective study recruited 47 patients from a single hemodialysis center. Pulmonary ultrasound was performed before and after 2 hemodialysis sessions in 28 regions on the thorax. The B-line score was defined as the percentage regions where B-lines were present. Results: When B-lines were detected before hemodialysis, a significant relationship was found between fluid removal and the change in B-line score. Patients with a B-line score of ≥21.4% (4th quartile) after the second hemodialysis session were more likely to be hospitalized for pulmonary edema or acute coronary syndrome. Conclusions: A simplified pulmonary assessment using ultrasound provides relevant information about pulmonary congestion in hemodialysis patients and identifies patients at risk of hospitalization for heart-related problems.

ABSTRACT In our clinical experience, we have encountered patients who developed hypomagnesemia after the introduction of teriparatide. Some trials have reported hypomagnesemia as an adverse event during teriparatide treatment, but this issue had never been studied specifically. Our objective was twofold: 1) determine the incidence of hypomagnesemia (serum magnesium <0.7 mmol/L) associated with teriparatide in a retrospective cohort and 2) identify the predisposing factors to hypomagnesemia in this cohort. We reviewed the files of 53 patients treated for severe osteoporosis with teriparatide for 6 to 24 months between May 2008 and January 2016. Serum magnesium levels were measured at 0, 3, 6, 12, 18, and 24 months. In the full cohort, we observed an average decrease of serum magnesium of 0.075 mmol/L, 0.069 mmol/L, 0.085 mmol/L, 0.086 mmol/L (p < 0.001) at 3, 6, 12 months, and at the end of the treatment, respectively. The cumulative incidence of hypomagnesemia during treatment with teriparatide was 35.9% (19 patients). Patients’ older age (71.1 versus 65.1 years; p = 0.05) and lower baseline level of magnesium before teriparatide treatment (0.81 mmol/L versus 0.85 mmol/L; p = 0.03) were significant risk factors for teriparatide-induced hypomagnesemia. The average decrease of serum magnesium was greater in the patients who developed hypomagnesemia compared with normomagnesemic patients at 3 months (0.110 mmol/L versus 0.054 mmol/L; p = 0.02), 6 months (0.139 mmol/L versus 0.036 mmol/L; p < 0.001), and 12 months (0.156 mmol/L versus 0.048 mmol/L; p < 0.001). Serum calcium, creatinine, and parathyroid hormone remained normal throughout the treatment period. We observed a statistically significant decrease in the serum magnesium levels in patients treated with teriparatide for severe osteoporosis. Older age and lower baseline magnesium were significant determinants of hypomagnesemia. Closer monitoring of serum magnesium level should be considered in these patients. © 2018 American Society for Bone and Mineral Research.

RATIONALE:Acute kidney injury (AKI) is a frequent complication after liver transplantation. In some patients, prompt intervention targeted at a specific etiology is of paramount importance.PRESENTING CONCERNS OF THE PATIENTS:A 25 years old man with advanced liver cirrhosis caused by sclerosing cholangitis and autoimmune hepatitis underwent orthotopic liver transplantation. One month after surgery, severe AKI developed in conjunction with recurrent ascites and lower extremity edema. Notable clinical findings included a persistently low urinary sodium excretion, a bland urinary sediment, and an abnormally monophasic hepatic vein waveform on Doppler ultrasound.DIAGNOSES:Inferior vena cava stenosis.INTERVENTIONS:Angioplasty with stent installation.OUTCOMES:Rapid improvement of renal function after stent installation.LESSONS LEARNED:The following case illustrates the importance of integrating clinical cues, ultrasound features, and laboratory findings. The combination of AKI associated with lower extremity edema, abnormal monophasic hepatic vein flow on Doppler ultrasound, and a low urinary sodium excretion after liver transplantation should evoke the possibility of inferior vena cava stenosis as the etiologic factor.

We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action in a type 2 diabetes (T2D) mouse model (db/db). Immortalized rat renal proximal tubular cells (IRPTCs) and kidneys from humans with T2D were also studied. The db/db mice developed hyperglycemia, oxidative stress, and nephropathy at age 20 weeks compared with their db/m littermates. These abnormalities, with the exception of hyperglycemia, were attenuated in db/db hnRNP F–transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs. Sirtuin-1, Foxo3α, and catalase expression were significantly decreased in RPTCs from db/db mice and normalized in db/db hnRNP F–Tg mice. In vitro, hnRNP F overexpression stimulated Sirtuin-1 and Foxo3α with downregulation of acetylated p53 expression and prevented downregulation of Sirtuin-1 and Foxo3α expression in IRPTCs by high glucose plus palmitate. Transfection of Sirtuin-1 small interfering RNA prevented hnRNP F stimulation of Foxo3α and downregulation of acetylated p53 expression. hnRNP F stimulated Sirtuin-1 transcription via hnRNP F–responsive element in the Sirtuin-1 promoter. Human T2D kidneys exhibited more RPTC apoptosis and lower expression of hnRNP F, SIRTUIN-1, and FOXO3α than nondiabetic kidneys. Our results demonstrate that hnRNP F protects kidneys against oxidative stress and nephropathy via stimulation of Sirtuin-1 expression and signaling in diabetes.

Because of multiple comorbidities, hemodialysis (HD) patients are prescribed many oral medications, including phosphate binders (PBs), often resulting in a high pill burden. Using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS), we assessed associations between PB pill burden, patient-reported PB non-adherence, and levels of serum phosphorus (SPhos) and parathyroid hormone (PTH) using standard regression analyses. The study included data collected from 5262 HD patients from dialysis units participating in the DOPPS in 12 countries. PB prescription ranged from a mean of 7.4 pills per day in the United States to 3.9 pills per day in France. About half of the patients were prescribed at least 6 PB pills per day, and 13% were prescribed at least 12 PB pills per day. Overall, the proportion of patients who reported skipping PBs at least once in the past month was 45% overall, ranging from 33% in Belgium to 57% in the United States. There was a trend toward greater PB non-adherence and a higher number of prescribed PB pills per day. Non-adherence to PB prescription was associated with high SPhos (>5.5mg/dL) and PTH (>600pg/mL). Adherence to PB is a challenge for many HD patients and may be related to the number of PB pills prescribed. Prescription of a simplified PB regimen could improve patient adherence and perhaps improve SPhos and PTH levels.

It is well known that auditory ability deteriorates with aging, centered on high-frequency hearing loss (4). In addition to aging, diabetes, the most common primary disease of patients on dialysis, is often complicated by hearing loss (5). Additionally, other ESKD patients have hearing loss due to impairment that can be drug-induced or inherited. The present patient had MELAS syndrome, which is a rare inherited disease. There are reports in the literature of adult patients on maintenance hemodialysis for treatment of ESKD due to MELAS syndrome (6). On the other hand, there have been very few reports concerning adult patients with ESKD due to MELAS syndrome who are treated with continuous APD (7,8). Additionally, there have been no previous reports of adult patients introduced to APD. Hameed et al. reported a case of a boy who was introduced to APD due to a mitochondrial disorder with hearing loss (9). However, the boy is 6 years old, and is unlikely to perform APD without assistance from a hearing adult. Various assistive listening devices (ALDs) are available to improve the quality of life of patients with severe hearing loss. For example, methods of converting the auditory signals of doorbells and telephones to optical signals have been developed; these devices are already available in the marketplace. However, it is difficult to detect optical signals during sleep. Kushner et al. reported a hearing-impaired patient who was introduced to APD using ALDs with a vibration function (10). However, the Kushner report contained no patient details, such as age, gender, or underlying disease. The present report is the first to provide detailed background information on the introduction of APD to an ESKD patient with hearing loss. In conclusion, the SilWatch is effective for use in conjunction with APD by ESKD patients with hearing loss. We expect that the quality of life of patients with hearing loss will be improved by this method in the future. This experience suggests that novel techniques can remove hearing-loss as an impediment to the use of APD and that hearing-impaired patients can be considered candidates for APD.

BackgroundA comprehensive analysis of sex-specific differences in the characteristics, treatment, and outcomes of individuals with end-stage renal disease undergoing dialysis might reveal treatment inequalities and targets to improve sex-specific patient care. Here we describe hemodialysis prevalence and patient characteristics by sex, compare the adult male-to-female mortality rate with data from the general population, and evaluate sex interactions with mortality.Methods and findingsWe assessed the Human Mortality Database and 206,374 patients receiving hemodialysis from 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the UK, and the US) participating in the international, prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) between June 1996 and March 2012. Among 35,964 sampled DOPPS patients with full data collection, we studied patient characteristics (descriptively) and mortality (via Cox regression) by sex. In all age groups, more men than women were on hemodialysis (59% versus 41% overall), with large differences observed between countries. The average estimated glomerular filtration rate at hemodialysis initiation was higher in men than women. The male-to-female mortality rate ratio in the general population varied from 1.5 to 2.6 for age groups <75 y, but in hemodialysis patients was close to one. Compared to women, men were younger (mean = 61.9 ± standard deviation 14.6 versus 63.1 ± 14.5 y), were less frequently obese, were more frequently married and recipients of a kidney transplant, more frequently had coronary artery disease, and were less frequently depressed. Interaction analyses showed that the mortality risk associated with several comorbidities and hemodialysis catheter use was lower for men (hazard ratio [HR] = 1.11) than women (HR = 1.33, interaction p<0.001). This study is limited by its inability to establish causality for the observed sex-specific differences and does not provide information about patients not treated with dialysis or dying prior to a planned start of dialysis.ConclusionsWomen's survival advantage was markedly diminished in hemodialysis patients. The finding that fewer women than men were being treated with dialysis for end-stage renal disease merits detailed further study, as the large discrepancies in sex-specific hemodialysis prevalence by country and age group are likely explained by factors beyond biology. Modifiable variables, such as catheter use, showing significant sex interactions suggest interventional targeting. Please see later in the article for the Editors' Summary.

Background: Vascular access (VA) guidelines recommend the native arteriovenous fistula (AVF) as VA of first choice for chronic hemodialysis patients. AVF management is important in hemodialysis patient care. AVF survival is associated with various physical factors, but the effects of dialysis treatment factors upon AVF survival are still not clear. Methods: Study patients were treated at 498 dialysis facilities participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) 2 or 3 (2002-2007). Analyses included 1,183 incident hemodialysis patients (on dialysis ≤7 days and using an AVF at study entry) and 949 prevalent patients (on dialysis >7 days at DOPPS entry and using a new AVF created during study observation). AVF survival was modeled from the study entry date for incident patients and date of first AVF use for prevalent patients. Predictors of primary and final AVF survival were compared across Japan, North America and Europe/Australia/New Zealand (EUR/ANZ) with adjustments for patient characteristics. Results: No meaningful relationship was seen between AVF survival and various physician and staff practices. However, patients with prior catheter use displayed higher rates of primary and final AVF failure. Final AVF failure rates were higher in facilities with higher median blood flow rates (BFR). They were also greater in North America and EUR/ANZ than in Japan, but this difference was substantially attenuated after accounting for regional differences in facility median BFR. Conclusion: AVF longevity differed according to the DOPPS region, and was related to prior patient catheter use and facility BFR practice. Further longitudinal studies may help demonstrate meaningful associations between VA-handling skill and patency.

La présente étude porte sur la gestion des projets de mise en œuvre des systèmes ERP en milieu universitaire. Les systèmes ERP, ou progiciels de gestion intégrée, sont des systèmes informatiques qui tendent à unifier dans une certaine mesure la gestion des activités d'une organisation. Initialement conçus pour le milieu industriel, ces systèmes ont conquis d'autres organisations telles que les administrations publiques et les institutions académiques. Un nombre de plus en plus croissant d'universités se tourne vers les systèmes ERP pour remplacer des systèmes informatiques hétéroclites et vieillissants. Mais cette transition vers les systèmes ERP ne se fait pas sans accroc, comme en témoigne le taux d'échec élevé au niveau de la mise en œuvre de ces systèmes. En effet, l'espace du projet ERP est un environnement d'une extrême complexité qui comprend divers acteurs, diverses technologies et diverses données. Cette complexité représente un défi du point de vue de la gestion du projet de mise en œuvre. La présente thèse analyse la fonction de gestion des projets ERP en milieu universitaire sous trois angles : (i) les défis et les problèmes liés à la mise en œuvre ; (ii) les tactiques d'acquisition et de gestion des ressources humaines ; (iii) le parrainage du projet par un administrateur de l'institution. L'étude a pour objectif d'analyser la gestion de projet en milieu universitaire sous les angles mentionnés ci-dessus afin de faire des suggestions dans le sens de l'amélioration de la gestion de projet. La thèse qui s'est appuyée sur treize projets a permis de collecter des données, de les analyser et de pouvoir relever les aspects positifs et les défis de la gestion des projets ERP afin de tirer des leçons, de faire des suggestions pouvant contribuer à améliorer la gestion des projets ERP en milieu universitaire. À travers l'article (i), l'auteur a analysé les défis majeurs –du point de vue du chef de projet– dans le cadre de chaque projet et l'impact de ces défis sur le processus de mise en œuvre du projet. Cela a permis de dégager des leçons pouvant contribuer à la sélection, à la formation de futurs chefs de projet, à la planification et à la gestion d'autres projets dans le futur. L'article (ii) a donné l'occasion d'analyser les questions liées à l'acquisition et à la gestion des ressources humaines dans le cadre des projets ERP en milieu universitaire. Cette étude a permis de relever les stratégies d'acquisition de ces ressources humaines, les difficultés inhérentes à cette activité et la gestion quotidienne de ces ressources. À travers l'article (iii), l'auteur a analysé le concept et le rôle du parrainage du projet (par un administrateur de l'institution) afin d'en apprécier l'opportunité et la portée sur la réussite du projet. Les leçons tirées de cette étude permettent de traiter cet aspect du projet ERP dans le cadre d'autres projets dans le futur. La présente thèse représente une contribution à la gestion des projets ERP de façon générale et plus particulièrement à la mise en œuvre des projets en milieu universitaire.