Sparsentan is superior to losartan in the gddY mouse model of IgA nephropathy.

BACKGROUND: The mechanism leading to the development of IgA nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation, and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist (DEARA), recently received accelerated approval in United States for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. METHODS: Four-week-old gddY mice were given control chow, chow containing sparsentan, or drinking water containing losartan until 12 or 20 weeks old. RESULTS: Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, ETAR, and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. CONCLUSIONS: The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared to AT1R antagonism alone.

The proteinuria-lowering effects of dapagliflozin are associated with an initial decline in estimated glomerular filtration rate in patients with chronic kidney disease.

AIM: Sodium-glucose co-transporter-2 inhibitor, dapagliflozin (DAPA) reduced albuminuria and slowed down the decline in estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD) in the DAPA-CKD trial. However, proteinuria (albuminuria) does not necessarily decrease in all patients in real-world clinical settings. Therefore, we aimed to identify the clinical characteristics of patients with CKD and decreased proteinuria in response to DAPA treatment. METHODS: Of 106 patients with CKD, 54 patients were finally included who received 10 mg of DAPA once daily. Patients whose urinary protein-to-creatinine ratio (UPCR) decreased by >30% or ≤30% from baseline after 1 month of treatment were defined as responders and non-responders, respectively. RESULTS: At baseline, median eGFR and UPCR were 45.3 mL/min/1.73 m2 (interquartile range [IQR], 29.7, 54.6) and 1.09 g/gCr (IQR, 0.52, 1.91), respectively. After 1 month of treatment, the mean decline in eGFR and reduction in UPCR was 6.5% (standard deviation [SD], 7.2%) and 6.6% (SD, 42.1%) from baseline, respectively. Moreover, the blood pressure, eGFR, and uric acid decreased significantly from baseline, but haemoglobin and serum potassium did not change. The median UPCR decreased significantly in patients with UPCR ≥0.5 g/gCr, but not <0.5 g/gCr at baseline. UPCR responders had a greater initial decline in eGFR at 1 month than non-responders. CONCLUSION: The percent changes in UPCR were positively associated with the initial decline rate in eGFR in patients with CKD with a UPCR ≥0.5 g/gCr at baseline after 1 month of DAPA treatment.

Safety and efficacy of using cereal food (Frugra®) to improve blood pressure and bowel health in patients undergoing chronic hemodialysis: A pilot study.

Hypertension and constipation are major hemodialysis complications. Salt restriction is one of the most important nonpharmacological interventions in managing hypertension. In patients undergoing hemodialysis, nonpharmacological strategies to manage constipation are extremely difficult to develop owing to the presence of excess dietary potassium and fluids. Frugra®, which is a cereal food that has a low salt content of 0.5 g per serving, may help reduce salt intake. Additionally, Frugra is rich in dietary fiber, thereby beneficial for such patients. In this study, we evaluated the safety and efficacy of Frugra in patients undergoing hemodialysis, focusing mainly on blood pressure and bowel health by changing the usual breakfast meal to Frugra for 8 weeks. We enrolled 11 patients undergoing hemodialysis. Despite the absence of changes in the patients' dry weight levels, their systolic blood pressure levels decreased from 155.5 ± 20.9 mmHg to 137.9 ± 10.3 mmHg after 2 months (P < 0.05). All participants reported improvements in bowel movement, and the levels of indoxyl sulfate, a representative gut-derived uremic toxin, were decreased from 49.3 µg/ml to 33.4 µg/ml. Furthermore, adverse events including electrolyte abnormalities were not observed. Therefore, Frugra may be useful to manage the health of patients undergoing hemodialysis.

COVID-19-induced acute renal tubular injury associated with elevation of serum inflammatory cytokine.

BACKGROUND: Severe acute respiratory syndrome Coronavirus 2 has rapidly spread worldwide, with acute kidney injury (AKI) as one of the manifestations with unknown causal mechanisms. We aimed to investigate tubular injury by assessing tubular markers and their association with the severity of Coronavirus disease 2019 (COVID-19). METHODS: We examined the associations between laboratory markers and urinary levels of N-acetyl-ß-D-glucosaminidase (uNAG), ß2-microglobulin (u ß2MG), α1-microglobulin (u α1MG), and liver-type fatty acid binding protein (L-FABP). We studied 18 COVID-19 patients without previous chronic kidney disease and analyzed the relationship between the urinary biomarkers and inflammatory markers in patients with severe (n = 7) or non-severe (n = 11) COVID-19, defined by requirements of supplemental oxygen. RESULTS: Fourteen patients (78%) showed abnormal urinalysis findings and two (11%) developed AKI. Patients with severe COVID-19 had significantly higher levels of proteinuria, uNAG, uß2MG, uα 1MG, and L-FABP than those with non-severe disease. Serum levels of interleukin-6 (IL-6) were significantly higher on admission in all severe COVID-19 cases and correlated with the levels of L-FABP, uß2MG, uα1MG, uNAG, and proteinuria. Moreover, the changes in serum IL-6 (ΔIL-6) levels from baseline to 7 days after admission significantly correlated with ΔL-FABP and Δuß2MG. CONCLUSIONS: Levels of tubular injury markers, especially L-FABP and uß2MG, were significantly associated with IL-6 levels even in patients with no evident AKI. This suggests that L-FABP and uß2MG could be useful as early detective biomarkers for COVID-19 associated renal injury.

Cancer Awareness and Understanding of Students in Japan: What Do Students Having Close Relatives with Cancer Think About the Disease?

Students have become more familiar with cancer because of media, such as television or the Internet, reporting on celebrity cancer cases. Moreover, with Japan's increasing age and cancer rates, the number of students whose parents/relatives develop cancer is likely to increase. This study examined cancer awareness and understanding among students aged 10 to 16 or more. A cross-sectional nationwide survey was conducted using a self-administered questionnaire. Cancer awareness and cancer understanding were assessed using a self-administered questionnaire. We collected a total of 9139 questionnaires and excluded those with missing data. Thus, we analyzed the responses of 8701 students: 2135, 2902, and 3664 from elementary, junior, and high school, respectively. Data were analyzed using a multivariable model adjusted for gender and grade. Approximately 30% of respondents had parents/relatives with cancer. In addition, there was a significant association between having parents/relatives with cancer and cancer awareness; however, students having parents/relatives with cancer had more negative awareness (i.e., "I think cancer is scary," "I think I will get cancer in the future," and "I think cancer is preventable"). Furthermore, there was a significant association between cancer understanding and awareness. These findings suggest that cancer education could have a desirable effect on students whose parents/relatives have cancer. Further, cancer education offers benefits to students who are naive about cancer and ill prepared to cope when a family member discloses a cancer diagnosis.

Analysis of the impact of spinopelvic radiographic parameters on the severity of cervical spondylotic myelopathy.

BACKGROUND: The correlation between spinal radiographic parameters and severity of cervical spondylotic myelopathy (CSM) is controversial. This study aimed to investigate the associations between spinal radiographic parameters and CSM severity, as well as between cervical and other spinopelvic radiographic parameters. METHODS: Patients diagnosed with CSM (N = 118; 77 men) at our hospital from March 2013 to February 2017 were included. The patients' demographic data and the following radiographic parameters were investigated: cervical lordosis (CL), C2-C7 sagittal vertical axis (C2-C7 SVA), T1 slope, thoracic kyphosis, lumbar lordosis, pelvic incidence, sacral slope, pelvic tilt, and sagittal vertical axis (SVA). Cervical cord compression ratio (CCCR) was evaluated on sagittal magnetic resonance imaging. The Japanese Orthopaedic Association (JOA) scoring system was used for clinical evaluation. Correlation analyses were performed among the clinical and radiographic parameters. RESULTS: The JOA score had the strongest correlation with SVA (r = -0.46, p < 0.01), followed by CCCR (r = -0.33, p < 0.01), CL (r = -0.29, p < 0.01), T1 slope (r = -0.29, p = 0.01), and C2-C7 SVA (r = -0.20, p = 0.03). Multivariate linear regression analysis revealed a model predicting the JOA score; JOA = 13.6 - 0.24 × SVA - 4.2 × CCCR (r = 0.51, p < 0.01). Although there was no significant correlation between the cervical and lumbopelvic radiographic parameters, the sequential correlation among the investigated spinopelvic parameters was identified. CONCLUSIONS: CSM severity worsened with spinal malalignment, such as a larger SVA. Though lumbopelvic radiographic parameters did not significantly impact cervical alignment and CSM severity, the sequential correlations among cervical-thoracic-lumbopelvic radiographic parameters were observed. Therefore, SVA is the most relevant radiographic parameter for CSM, but we cannot preclude the possibility that lumbopelvic alignment also affects cervical alignment and CSM severity.

Uremic Toxin-Targeting as a Therapeutic Strategy for Preventing Cardiorenal Syndrome.

Chronic kidney disease (CKD) is a global health problem. CKD patients are at high risk of developing cardiovascular disease (CVD), including coronary artery disease, heart failure and stroke. Several factors invoke a vicious cycle of CKD and CVD, which is referred as to "cardiorenal syndrome". Among these factors, the compounds retained through loss of renal excretion play a pathological role in causing atherosclerosis and CVD. These compounds have been broadly classified as uremic toxins because of their accumulation with declining renal function and cytotoxicity. The major uremic toxins contributing to CVD are asymmetric dimethylarginine (ADMA), advanced glycation endproducts (AGE), and trimethyl amine N-oxide (TMAO). ADMA is linked to CVD through regulation of nitric oxide, reactive oxygen species, and renal anemia. AGE not only directly accumulates in the heart and kidney, but interacts with the receptor for AGE (RAGE), leading to cell damage in CVD. TMAO correlates with a high prevalence of CVD and promotes organ fibrosis by itself. The levels of these and other uremic toxins rise with worsening CKD, inducing multiplicative damage in the heart and kidney. Therefore, a better understanding of uremic toxins has great clinical importance for preventing cardiorenal syndrome. This review highlights the molecular mechanism by which these uremic toxins are implicated in CVD and suggests the possible mutual relationship between them.

Complications after spinal fixation surgery for osteoporotic vertebral collapse with neurological deficits: Japan Association of Spine Surgeons with ambition multicenter study.

BACKGROUND: There have been few reports on the incidence and risk factors of the complications after spinal fixation surgery for osteoporotic vertebral collapse (OVC) with neurological deficits. This study aimed to identify the incidence and risk factors of the complications after OVC surgery. METHODS: In this retrospective multicenter study, a total of 403 patients (314 women and 89 men; mean age 73.8 years) who underwent spinal fixation surgery for OVC with neurological deficits between 2005 and 2014 were enrolled. Data on patient demographics were collected, including age, sex, body mass index, smoking, steroid use, medical comorbidities, and surgical procedures. All postoperative complications that occurred within 6 weeks were recorded. Patients were classified into two groups, namely, complication group and no complication group, and risk factors for postoperative complications were investigated by univariate and multivariate analyses. RESULTS: Postoperative complications occurred in 57 patients (14.1%), and the most common complication was delirium (5.7%). In the univariate analysis, the complication group was found to be older (p = 0.039) and predominantly male (p = 0.049), with higher occurrence rate of liver disease (p = 0.001) and Parkinson's disease (p = 0.039) compared with the no-complication group. In the multivariate analysis, the significant independent risk factors were age (p = 0.021; odds ratio [OR] 1.051, 95% confidence interval [CI] 1.007-1.097), liver disease (p < 0.001; OR 8.993, 95% CI 2.882-28.065), and Parkinson's disease (p = 0.009; OR 3.636, 95% CI 1.378-9.599). CONCLUSIONS: Complications after spinal fixation surgery for OVC with neurological deficits occurred in 14.1%. Age, liver disease, and Parkinson's disease were demonstrated to be independent risk factors for postoperative complications.

Advanced glycation end products evoke inflammatory reactions in proximal tubular cells via autocrine production of dipeptidyl peptidase-4.

We have previously shown that albuminuria and renal levels of advanced glycation end products (AGEs), receptor for AGEs (RAGE), and oxidative stress are suppressed in dipeptidyl peptidase-4 (DPP-4)-deficient diabetic rats, thus suggesting the crosstalk between AGE-RAGE axis and DPP-4 in experimental diabetic nephropathy. Therefore, we examined here the role of DPP-4 in AGE-evoked inflammatory reactions in human proximal tubular cells. Proteins were extracted from proximal tubular cells, and conditioned medium was collected, both of which were subjected to western blot analysis using anti-DPP-4 antibody. RAGE-aptamer was prepared using a systemic evolution of ligands by exponential enrichment. NF-κB p65 and monocyte chemoattractant protein-1 (MCP-1) gene expression was analyzed by reverse transcription-polymerase chain reaction. AGEs significantly increased DPP-4 expression and soluble DPP-4 production by tubular cells, the latter of which was attenuated by RAGE-aptamer or an anti-oxidant, N-acetylcysteine. AGEs or DPP-4 up-regulated NF-κB p65 or MCP-1 mRNA levels in tubular cells, which were suppressed by linagliptin, an inhibitor of DPP-4. AGEs stimulated NF-κB p65 gene expression in tubular cells isolated from control rats, but not from DPP-4-deficient rats. Our present results suggest that the AGE-RAGE-mediated oxidative stress could evoke inflammatory reactions in proximal tubular cells via autocrine production of DPP-4.

Extremely high preoperative C7 slope limits compensatory cervical lordosis after muscle-preserving selective laminectomy.

PURPOSE: A high C7 slope induces C2-C7 lordosis to compensate for cervical sagittal balance adjustments. A muscle-preserving selective laminectomy (SL) can maintain this compensation postoperatively. This study evaluated the effect of an extremely high C7 slope on C2-C7 lordotic compensation following SL. METHODS: This study enrolled 151 cervical compressive myelopathy patients who underwent SL. Lateral cervical spine radiographs were taken before surgery and during final follow-up. Patients were divided into extremely high C7 slope (≥ 30°) (EH) and non-high C7 slope (< 30°) (NH) groups and the influence of a high C7 slope on radiological and surgical outcomes was examined. RESULTS: Mean age was higher in group EH (p < 0.001). Preoperatively, patients in group EH had a larger C2-C7 sagittal vertical axis (SVA) (p = 0.001) and greater cervical lordosis (p < 0.001). Although C2-C7 SVA increased after surgery, mean C2-C7 angle of group EH decreased. Mismatches between C7 slope and C2-C7 angle increased for group EH postoperatively (p = 0.015). Postoperative Japanese Orthopedic Association (JOA) score and recovery rate (RR) were slightly lower in group EH (p = 0.001 and p = 0.006, respectively). Multiple linear regression analyses revealed that extremely high C7 slope, not age, affected the RR of JOA score (p = 0.006). CONCLUSIONS: Patients in group EH were older and had highly compensated cervical sagittal alignment preoperatively. They demonstrated postoperative cervical sagittal balance mismatch increases and slightly worse functional recovery. An extremely high C7 slope limited compensatory cervical lordosis following SL. These slides can be retrieved under Electronic Supplementary Material.

Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia.

Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression.

Effect of Zinc Acetate Dihydrate (NobelzinR) Treatment on Anemia and Taste Disorders in Patients with Chronic Kidney Disease with Hypozincemia.

Some patients with chronic kidney disease (CKD) receiving hemodialysis develop erythropoietin-resistant anemia, possibly due to zinc deficiency. The frequency of zinc deficiency in CKD (stages 1-5 and 5D) and CKD improvement via zinc supplementation are not completely verified. Here 500 CKD patients (Stage 1/2, n=100; Stage 3, n=100; Stage 4, n=100, Stage n=5, 100; Stage 5D, n=100) will be recruited to determine the frequency of serum zinc deficiency at each CKD stage. Patients with serum zinc concentrations <80 µg/dL will be treated with zinc acetate dihydrate (NobelzinR) to evaluate its effects on hypozincemia, taste disturbances, and anemia.

A Cross-sectional Investigation of Cancer-Screening Intentions, Sources of Information, and Understanding of Cancer in Japanese Adolescents.

The purpose of this study was to describe the cancer-screening intention, sources of cancer information, and cancer understanding among Japanese adolescents. A cross-sectional nationwide survey involving a self-administered questionnaire was conducted. Response rates of the target schools were 46.4 % (n = 103) for junior high schools and 55.8 % (n = 116) for high schools. From these, we analyzed the data of 2960 junior high school students (1520 males, 1440 females) and 3703 high school students (1546 males, 2157 females) to examine the association between cancer-screening intention and sources of cancer-related information and understanding. A significant association between cancer-screening intention and sources of cancer information and cancer understanding was observed. The screening intention group identified more sources of cancer information than the no-screening intention group did. Understanding about cancer was reported by a higher proportion of students in the screening intention group compared with the no-screening intention group. Recognition that healthy people must take part in cancer screening was significantly associated with screening intention in both junior high (odds ratio (OR), 1.859; 95 % confidence interval (CI), 1.582-2.185; P < 0.001) and high school (OR, 2.485; 95 % CI, 2.139-2.887; P < 0.001) students. Health education at school was indicated by a high proportion of students as a source of cancer-related information, although the association was not significant. The present survey indicated that those in of our sample who intended to undergo future cancer screening (67.8 %) had more sources of information and understanding regarding cancer. Thus, schools should enrich health education curricula with more information and understanding about cancer to promote cancer-screening intention among Japanese adolescents.

Cervical laminectomy of limited width prevents postoperative C5 palsy: a multivariate analysis of 263 muscle-preserving posterior decompression cases.

PURPOSE: Between 2006 and 2010, we performed wide laminectomy (wide LAM) alone, with decompression performed between the bilateral medial margin of the zygapophyseal joints, or double-door laminoplasty (DL) combined with wide LAM for cervical compressive myelopathy (CCM). From 2010, instead of wide LAM and DL, we began to perform narrow LAM, where the laminectomy width was no more than 2-3 mm wider than the spinal cord width (SW). This study aimed to elucidate the risk factors for C5 palsy by reviewing surgical outcomes. METHODS: The clinical features and radiological findings of 263 CCM patients with or without C5 palsy were compared. Risk factors for C5 palsy were assessed using logistic regression analysis. The decompression width (DW) was defined as the laminectomy width or the width between the bilateral medial margins of the bony gutters in DL. RESULTS: Narrow LAM reduced the incidence of C5 palsy from 9.2 to 1.2%. DL was performed more frequently in the C5 palsy group. The difference between the DW and the SW (DW - SW) was significantly greater in the C5 palsy group. Posterior spinal cord shift, aging, and the number of consecutive laminae surgically treated were significantly higher in the C5 palsy group. The diameter of the foramen (DF) at C4/5 was significantly smaller in the C5 palsy patients. The logistic regression analysis revealed that DL, DW - SW, DF, and aging were risk factors for C5 palsy. CONCLUSIONS: Cervical laminectomy of limited width prevented postoperative C5 palsy without compromising the functional recovery.

The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy.

Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different.

Maternal exposure to high-fat and high-fructose diet evokes hypoadiponectinemia and kidney injury in rat offspring.

BACKGROUND: Maternal exposure to overnutrition during fetal development contributes to metabolic and renal damage in offspring. Adiponectin plays a protective role against obesity-related renal injury. However, role of adiponectin in renal injury of offspring exposed to maternal overnutrition remains unknown. We addressed the issue. METHODS: Female Sprague-Dawley rats were fed either a standard (N) or a high-fat and high-fructose (HFF)-diet for 6 weeks before mating, and kept each diet during the gestation and lactation period. After 4 weeks postpartum, all the offspring were fed N diet, and followed by 12 weeks. Kidney weight, urinary albumin excretion, blood pressure, and blood chemistry, including adiponectin and malondialdehyde, a marker of oxidative stress, were evaluated in the offspring. RESULTS: Compared with N-offspring, serum adiponectin levels of 1-day- and 4-week-old HFF-offspring were significantly lower, the latter of which was inversely associated with malondialdehyde. Kidney weight was significantly decreased in 1-day-old HFF-offspring, whereas increased in 4-week-old HFF-offspring. Urinary albumin excretion levels of HFF-offspring at 8, 12, and 16-week old were significantly higher than those of N-offspring at the same age, whose levels at 16-week old were inversely correlated with plasma adiponectin. Compared with N-offspring, HFF-offspring at 16-week old exhibited glomerulosclerosis, hyperglycemia, and high mean blood pressure associated with reduced podocin and increased transforming growth factor-ß1 expression in the kidneys. CONCLUSIONS: Our present study suggests that exposure to maternal HFF-diet during fetal and early postnatal development induces hypoadiponectinemia in offspring, which might cause renal injury and metabolic derangements later in life.

Oral L-carnitine supplementation increases trimethylamine-N-oxide but reduces markers of vascular injury in hemodialysis patients.

OBJECTIVES: Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in accelerated atherosclerosis in hemodialysis (HD) patients. However, effects of oral L-carnitine supplementation on circulating levels of TMAO and markers of vascular injury and oxidative stress in patients on HD remain unclear. In this study, we addressed the issue. METHODS: Thirty-one HD patients with carnitine deficiency were treated with oral L-carnitine (900 mg/d) for 6 months. At baseline and after treatment, clinical variables including circulating levels of carnitine fractions, TMA, TMAO, advanced glycation end products (AGE), soluble forms of intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) were measured. RESULTS: Oral L-carnitine supplementation significantly increased total, free, acyl carnitine, and plasma TMA and TMAO levels, whereas it decreased markers of vascular injury and oxidative stress such as sICAM-1, sVCAM-1, and MDA levels. TMA and TMAO levels at baseline were correlated with each other, and free carnitine was independently associated with TMAO levels. Furthermore, change in AGE values from baseline ([INCREMENT]AGE) was positively correlated with [INCREMENT]sICAM-1 (P = 0.043) and was a sole independent determinant of [INCREMENT]sICAM-1 (R = 0.133, P = 0.043). CONCLUSIONS: This study demonstrated that although oral L-carnitine supplementation was associated with increased TMAO levels, it might be beneficial on vascular injury in patients on HD. Vasculoprotective properties of L-carnitine supplementation in HD patients might be ascribed partly to its inhibitory actions on AGE.

Elevation of Serum Levels of Advanced Glycation End Products in Patients With Non-B or Non-C Hepatocellular Carcinoma.

BACKGROUND: The prevalence of non-B or non-C hepatocellular carcinoma (NBNC-HCC) has been increasing all over the world. Advanced glycation end products (AGE) play a role in the pathogenesis of alcoholic liver injury or nonalcoholic steatohepatitis (NASH). METHODS: We examined here whether serum levels of AGE were elevated in NBNC-HCC patients compared with NASH subjects without HCC and investigated which anthropometric and clinical variables were independent determinants of AGE. RESULTS: Ninety NBNC-HCC, 56 NASH, and 27 control subjects underwent a complete history and physical examination, determination of blood chemistries, including AGE levels. Serum levels of AGE were significantly higher in NBNC-HCC patients compared with NASH and control subjects [9.1 ± 2.7, 5.2 ± 1.7, 3.5 ± 1.2 (U/ml), respectively, P < 0.05]. Univariate analysis showed that AGE levels were associated with male (P < 0.05), age (P < 0.01), aspartate aminotransferase (P < 0.05), γ-glutamyl transpeptidase (GGT) (P < 0.01), HDL-cholesterol (inversely, P < 0.01), fasting plasma glucose (P < 0.01), and HbA1c (P < 0.05). By the use of multiple stepwise regression analysis, age, GGT, and HDL-cholesterol (inversely) remained significant and were independently related to AGE levels (R(2) = 0.406). CONCLUSION: The present results suggest that AGE might be involved in the pathogenesis of NBNC-HCC, thereby being a biomarker that could discriminate NBNC-HCC from NASH.

Asymmetric dimethylarginine accumulates in the kidney during ischemia/reperfusion injury.

Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury-induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.

Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction.

Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3(+/-) mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3(+/-) mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3(+/-) mice, while it was aggravated by pre-treatment with pyridine6-PGLA. Although there were no differences in renal mRNA levels of TGF-ß and collagens between wild and SOCS3(+/-) mice, MMP-2 activity was enhanced in SOCS3(+/-) UUO mice. Activated MMP-2 was completely suppressed by pyridine6-PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.