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Background: For the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5–1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients. Methods: We analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal. Results: Our analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review. Conclusion: The results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors. [ABSTRACT FROM AUTHOR]

Introduction: Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. Methods: The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. Results: From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. Conclusion: This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies. [ABSTRACT FROM AUTHOR]

Background: Information of short-term prognosis after hemodialysis (HD) introduction is important for elderly patients with chronic kidney disease (CKD) and their families choosing a modality of renal replacement therapy. Therefore, we developed a risk score to predict early mortality in incident elderly Japanese hemodialysis patients. Materials and methods: We analyzed data of incident elderly HD patients from a nationwide cohort study of the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR) to develop a prognostic risk score. Candidate risk factors for early death within 1 year was evaluated using multivariate logistic regression analysis. The risk score was developed by summing up points derived from parameter estimate values of independent risk factors. The association between risk score and early death was tested using Cox proportional hazards models. This risk score was validated twice by using an internal validation cohort derived from the JRDR and an external validation cohort collected for this study. Results: Using the development cohort (n = 2,000), nine risk factors were retained in the risk score: older age (>85), yes = 2, no = 0; sex, male = 2, female = 0; lower body mass index (<20), yes = 2, no = 0; cancer, yes = 1, no = 0; dementia, yes = 3, no = 0; lower creatinine (<6.5 mg/dL), yes = 1, no = 0; lower albumin (<3.0 g/dL), yes = 3, no = 0; normal or high calcium (≥8.5 mg/dL), yes = 1, no = 0; and higher C reactive protein (>2.0 mg/dL), yes = 2, no = 0. In the internal and external validation cohorts (n = 739, 140, respectively), the medium- and high-risk groups (total score, 6 to 10 and 11 or more, respectively) showed significantly higher risk of early death than the low-risk group (total score, 0 to 5) (p<0.001). Conclusion: We developed a prognostic risk score predicting early death within 1 year in incident elderly Japanese HD patients, which may help detect elderly patients with a high-risk of early death after HD introduction. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is an X-linked inherited disease where renal complications are associated with a poor prognosis. However, little is known about the prevalence of Fabry nephropathy (FN) in patients with chronic kidney disease (CKD). We extracted FN data from the Japan Renal Biopsy Registry, analyzed the prevalence of FN, and examined the correlation between clinical characteristics and renal involvement according to sex differences and hemi- and heterozygosity in patients with FD. Methods: A total of 38,351 participants who underwent renal biopsy were retrospectively enrolled, and FN was determined. The clinical characteristics of FD patients were examined based on sex differences. Results: Twenty-nine patients (0.076%) (19 males and 10 females, mean age: 43.7 ± 15.5 years old) were diagnosed with FN. Median estimated urinary protein (UP) and mean eGFR levels were 0.9 [interquartile range (IQR) [0.7–1.6] g/gCr and 67.1 ± 36.8 mL/min/1.73 m2, respectively. Mean systolic blood pressure (SBP) was 126.4 ± 17.1 mmHg and diastolic blood pressure was 76.1 ± 12.6 mmHg. An inverse correlation between eGFR and logarithm UP levels was observed (r2 = 0.23, p = 0.02), SBP was positively associated with logarithm UP (r2 = 0.34, p = 0.004) overall and inversely associated with eGFR (r2 = 0.25, p = 0.007) regardless of sex, and SBP was an independent determinant of proteinuria (p = 0.004) and eGFR (p = 0.007). Conclusions: The prevalence of biopsy-proven FN was 0.076%. Since SBP is associated with eGFR regardless of zygosity, strict SBP control might be necessary to prevent progression to end-stage kidney disease in both male and female patients with FN. [ABSTRACT FROM AUTHOR]

Introduction: To date, the prognosis of patients with sepsis and underlying chronic kidney disease (CKD) had been poor. However, the impact of preseptic renal function on the short-term prognosis of patients with extremely severe septic shock with acute kidney injury (AKI) that requires renal replacement therapy (RRT) is unclear. Methods: Of the septic shock cases treated at the intensive care unit for ≥48 h, 131 adults who were diagnosed as septic AKI and underwent continuous venovenous hemodiafiltration were retrospectively analyzed. The relationships of demographic, clinical, and laboratory data with mortality were evaluated, and the independent risk factors for death were identified. Results: The median age of the subjects was 73 (range, 63–80) years, and 76 (58%) were men. The rate of mortality was significantly higher among patients with CKD (n = 42) than in those without CKD (n = 89) (43% vs. 22%, p < 0.016). On univariate and multivariate logistic regression analyses, the associated factors and independent predictors of death were Sequential Organ Failure Assessment score (odds ratios [ORs] 1.151, 95% confidence intervals [CIs] 1.026–1.293, p = 0.017, and OR 1.129, 95% CI 1.003–1.271, respectively); baseline estimated glomerular filtration rate (OR 0.986, 95% CI 0.975–0.997, p = 0.016, and OR 0.983, 95% CI 0.970–0.996, respectively); and lactic acid (OR 1.094, 95% CI 1.005–1.190, p = 0.038, and OR 1.110 CI 1.015–1.215, respectively). Conclusion: Reduced baseline renal function may be a factor for poor short-term prognosis in severe septic AKI cases requiring RRT. [ABSTRACT FROM AUTHOR]

Background: Dapagliflozin (DAPA), a sodium-glucose transporter 2 inhibitor (SGLT2i), attenuates kidney outcomes in patients with not only diabetes mellitus (DM) but also chronic kidney disease (CKD). SGLT2i-derived initial dip in estimated glomerular filtration rate (eGFR) has been considered to reduce excess glomerular pressure, followed by renal protection in patients with DM. However, whether DAPA confers the eGFR dip and its independent determinants for CKD patients without DM are unclear. Methods: A total of 126 patients with CKD treated with 10 mg DAPA daily was retrospectively registered. After participants with missing data and DM were excluded, 51 participants were enrolled. Results: An initial eGFR dip was observed 1 month after initiation of DAPA, which was sustained until 2 months. DAPA did not affect urinary protein excretion; however, serum uric acid was decreased, while hemoglobin level was increased. Multiple regression analysis revealed that eGFR at baseline was the only independent determinant of the initial dip of eGFR. The patients currently showing exacerbation of glomerular hyperfiltration exhibited the larger initial eGFR dip rather than those showing progressive renal dysfunction. The patients meeting exclusion criteria of DAPA-CKD trial exhibited same degree of the initial eGFR dip as others. Conclusions: DAPA causes an initial dip of eGFR in CKD patients without DM at 1 month after starting DAPA treatment. A higher eGFR at baseline predicts a large initial eGFR dip, which might be linked to the subsequent recovery in eGFR in CKD patients without DM. [ABSTRACT FROM AUTHOR]

The condition of arteriovenous fistula (AVF) blood flow is typically checked by using auscultation; however, auscultation should require a qualitative judgment dependent on the skills of doctors, and further attention to contact infection is required. For these reasons, this study developed a non-contact and non-invasive medical device to measure the pulse wave of AVFs by applying optical imaging technology. As a first step toward realization of the quantification judgment based on non-contact AVF measurement, we experimentally validated the developed system, whereby the hemodynamics of 168 subjects were visually and quantitatively evaluated based on clinical tests. Based on the evaluation results, the fundamental statistical characteristics of the non-contact measurement, including the average and median values, and distribution of measured signal-to-noise power ratio, were demonstrated. The clinical test results contributed to the future construction of quantified criteria for the AVF condition with the non-contact measurement. [ABSTRACT FROM AUTHOR]

Background Fabry disease (FD), an X-linked lysosomal storage disorder caused by a deficiency in alfa-galactosidase A (α-Gal A) activity due to mutations in the GLA gene, has a prevalence of 0–1.69% in patients undergoing haemodialysis; however, its prevalence in patients with chronic kidney disease (CKD) Stages 1–5 is unknown. Methods Serum α-Gal A activity analysis and direct sequencing of GLA were used to screen for FD in 2122 male patients with CKD, including 1703 patients with CKD Stage 5D and 419 with CKD Stages 1–5. The correlation between serum α-Gal A activity and confounding factors in patients with CKD Stages 1–5 was evaluated. Results FD prevalence rates in patients with CKD Stage 5D and CKD Stages 1–5 were 0.06% (1/1703) and 0.48% (2/419), respectively. A patient with CKD Stage 5D exhibited a novel GLA mutation, p.Met208Arg, whereas two patients with CKD Stages 1–5 had c.370delG and p.Met296Ile. p. Met208Arg caused moderate structural changes in the molecular surface region near the substituted amino acid residue but did not affect the catalytic residues Asp170 and Asp231 in α-Gal A. Serum α-Gal A activity in patients with CKD Stages 1–5 was inversely correlated with age (P < 0.0001) but directly correlated with estimated glomerular filtration rate (P < 0.0001). Conclusions FD prevalence was much higher in male patients with CKD Stages 1–5 than in those with CKD Stage 5D. FD screening in patients with CKD Stages 1–5 may improve patient survival, decreasing the number of patients with CKD Stage 5D. [ABSTRACT FROM AUTHOR]

Serum carnitine is decreased in hemodialysis patients, which induces muscle atrophy. Thus, we examined the different effects of l‐carnitine and exercise on exercise activity and muscle status in hemodialysis patients. Twenty patients were divided into l‐carnitine and cycle ergometer groups and were followed for 3 months. Muscle and fat mass, physical activities, and muscle status were evaluated by an impedance, physical function test, and magnetic resonance imaging, respectively. The l‐carnitine significantly increased muscle mass (P =.023) and thigh circumference (P =.027), decreased fat mass (P =.007), and shortened chair stand‐up time (P =.002) and 10‐m walk test (P =.037). The fat fraction was improved by the l‐carnitine (P =.047). Compared with the exercise group, l‐carnitine improved the changes in 10‐m walk test (P =.026), chair stand‐up time (P =.014), and thigh circumference (P =.022). Baseline fibroblast growth factor‐21 and myostatin levels predicted the l‐carnitine‐associated changes in exercise activities. l‐carnitine, rather than exercise, improved physical activity and muscle status in hemodialysis patients. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases (MDs) are occasionally difficult to diagnose. Growth differentiation factor 15 (GDF15) has been reported as a biomarker useful for not only diagnosing MDs, but also evaluating disease severity and therapeutic efficacy. To enable the measurement of serum GDF15 concentrations at medical institutions, we developed a new latex‐enhanced turbidimetric immunoassay (LTIA) as an automated diagnostic indication test for MDs. We also examined the equivalency of specificity and sensitivity in measuring serum GDF15 concentrations between a commercially available enzyme‐linked immunosorbent assay (ELISA) kit and a novel LTIA device in patients with MDs, disease controls, and healthy controls. A clinical performance study used a newly developed LTIA device and an existing ELISA kit to measure the concentrations of GDF15 in 35 MD patients, 111 disease controls, and 86 healthy controls. The median (first quartile‐third quartile) of serum GDF15 concentrations measured with the LTIA device was significantly higher (P <.001) in MD patients (1389.0 U/mL [869.5‐1776.0 U/mL]) than in healthy controls (380.5 U/mL [330.2‐471.8 U/mL]); the interquartile ranges did not overlap between MD patients and healthy controls. The areas under the curve in disease and healthy controls were 0.812 (95% confidence interval [CI]: 0.734‐0.886) and 0.951 (95% CI: 0.910‐0.992), respectively. The automated, high‐throughput technology‐based LTIA device has definite advantages over the ELISA kit in shorter processing time and lower estimated cost per sample measurement. The LTIA device of GDF15 may be a sufficiently reliable, frontline, diagnostic indicator of individuals with suspected MDs in the general population. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in the polycystic kidney disease (PKD) gene. Although tolvaptan has benefits for renal involvement, the different effects depending on the gene mutation type are unknown. Thus, we explore the different effects of tolvaptan on the annual changes in total kidney volume (%TKV) and estimated glomerular filtration rate (eGFR) according to the gene mutation type in ADPKD patients. Methods: In total, 135 ADPKD patients were screened, and 22 patients taking tolvaptan for at least a year were retrospectively studied at the Kurume University Hospital. We examined the decline in renal function and %TKV by computed tomography and analyzed the gene mutation. Patients were classified into the following four groups according to gene mutation type: PKD1-truncated, PKD1-non-truncated, PKD2, and mutation not found. Patients were treated with tolvaptan, and the effects of tolvaptan were analyzed according to the gene mutation type. Results: Patients (age: 52.3 ± 11.2 years) were administered tolvaptan at a dose of 45 or 60 mg. No variation was observed in the annual changes in eGFR (%eGFR) (before: − 10.5% ± 13.9%, after: − 14.4% ± 8.1%, P = 0.139), whereas %TKV was significantly improved after the tolvaptan treatment (before: 14.9% ± 8.0%, after: − 5.4% ± 7.6%, P < 0.001). Unlike %eGFR, tolvaptan treatment significantly improved %TKV, regardless of the type of gene mutation. Conclusions: A year treatment with tolvaptan significantly improved %TKV in patients with ADPKD, regardless of the gene mutation type. [ABSTRACT FROM AUTHOR]

Leukocyte apheresis (LCAP) is a safe and effective treatment for active ulcerative colitis (UC) in Japan. Nevertheless, a limitation of LCAP is its requirement for two puncture sites (double‐needle [DN] apheresis), sometimes leading to problems with needle puncture. Single‐needle (SN) apheresis is useful in hemodialysis and reduces needle puncture pain. If SN apheresis were found to be useful in LCAP for UC, it may reduce patient burden. The aim of this study was to compare the safety and efficacy of SN apheresis with that of DN apheresis. Twenty‐four patients with active UC were retrospectively enrolled. They underwent either SN apheresis (n = 12) or conventional double‐needle (DN) apheresis (n = 12) at the Kurume University Hospital from February 2014 to March 2018. At each session, we recorded access problems defined by the time required to initiate apheresis and the frequency of puncture‐related problems, as well as blood circuit clotting, defined as clotting necessitating interruption of apheresis and changing of the circuit. Efficacy was assessed using partial Mayo scores. The number of apheresis sessions was comparable between SN and DN apheresis (9.0 ± 2.0 times vs 9.6 ± 1.4 times, mean ± SEM). SN significantly reduced the time required to start apheresis (10.0 ± 5.4 minutes vs 19.4 ± 11.9 minutes, P <.05) as well as needle puncture troubles (0.9% vs 11.5%, P <.05). SN had comparable frequency of blood clotting episodes (5.6% vs 8.7%). SN apheresis had similar clinical efficacy (P <.001 in SN and P <.01 in DN). The improvement and remission rates were comparable between groups. SN apheresis may be safe and effective and may reduce patient burden during UC treatment. Nevertheless, further comparative studies are needed. [ABSTRACT FROM AUTHOR]

Background: Diabetic ketoacidosis (DKA) is seen relatively frequently in the emergency department (ED). DKA is characterized by hyperglycemia, acidosis, and ketonemia, and sodium glucose transporter 2 inhibitors (SGLT2i) represent a new diabetes medication that has been associated with euglycemic DKA (eu-DKA). Case presentation: A 71-year-old female who was being treated for type 2 diabetes with canagliflozin, metformin, and saxagliptin orally presented to the ED for evaluation of reduced oral intake, malaise, nausea, and abdominal pain. Although her blood glucose was not severely elevated (259 mg/dL), there was notable ketoacidosis (pH 6.89; CO2, 11.4 mmHg; HCO3, 1.9 mEq/L; base excess, − 31.3 mmol/L; 3-hydroxybutyric acid > 10,000 μmol/L) was observed. The uncontrolled acidosis improved following 3 days of continuous renal replacement therapy, but elevated urinary glucose continued for more than 10 days. Ringer's lactated fluid supplementation was continued for management of polyurea and glucosuria. Urinary glucose turned negative on day 16, and there was improvement in the patient's overall state; hence, she was discharged on day 18. Conclusion: Although it is difficult to diagnose eu-DKA because of the absence of substantial blood glucose abnormalities in the ED, there is a need to consider eu-DKA when evaluating acidosis in a patient treated with SGLT2i. Moreover, even after discontinuing the SGLT2i, attention should be given to the possibility of continuing glucosuria. Regular measurements of urinary glucose should be obtained, and the patient should be monitored for dehydration. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene, followed by deficiency in α-galactosidase A (α-gal) activity. Nephrotic syndrome, as the renal phenotype of FD, is unusual. Here, we report the rare case of a patient with FD with nephrotic syndrome whose proteinuria disappeared by immunotherapy.Case Presentation: A 67-year-old Japanese man was admitted to our hospital because of emesis, abdominal pain, and facial edema due to nephrotic syndrome. The patient was diagnosed with focal segmental glomerulosclerosis (FSGS) by renal biopsy before being diagnosed with FD, and immunotherapy was initiated. After treatment, the kidney biopsy results showed typical glycosphingolipid accumulation in the podocytes of this patient. The white blood cell α-gal activity was very low, and genetic analysis revealed a GLA gene variant (M296I), which is known as a late-onset genetic mutation of FD. Immunotherapy (steroids and cyclosporine A) dramatically improved the massive proteinuria. Currently, he has been undergoing enzyme replacement therapy, and his proteinuria has further decreased. There is the possibility that other nephrotic syndromes, such as minimal change nephrotic syndrome or FSGS, may co-exist in this patient.Conclusions: We experienced the rare case of a FD patient whose nephrotic syndrome disappeared by immunotherapy. These findings suggest that immunosuppressive treatment may be considered if nephrotic syndrome develops, even in patients with FD. [ABSTRACT FROM AUTHOR]

Background: Pulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH. Methods and results: PASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001). Conclusions: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH. [ABSTRACT FROM AUTHOR]

Background: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease.Methods: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD.Results: Low eGFR (<60 mL/min/1.73 m2) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤−50% change and −50 to −30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio.Conclusion: These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Hyperkalemia is prevalent in end-stage renal disease patients, being involved in life-threatening arrhythmias. Although polystyrene sulfonate (PS) is commonly used for the treatment of hyperkalemia, direct comparison of effects between calcium and sodium PS (CPS and SPS) on mineral and bone metabolism has not yet been studied.Methods: In a randomized and crossover design, 20 pre-dialysis patients with hyperkalemia (>5 mmol/l) received either oral CPS or SPS therapy for 4 weeks.Results: After 4-week treatments, there was no significant difference of changes in serum potassium (K) from the baseline (ΔK) between the two groups. However, SPS significantly decreased serum calcium (Ca) and magnesium (Mg) and increased intact parathyroid hormone (iPTH) values, whereas CPS reduced iPTH. ΔiPTH was inversely correlated with ΔCa and ΔMg (r = −0.53 and r = −0.50, respectively). Furthermore, sodium (Na) and atrial natriuretic peptide (ANP) levels were significantly elevated in patients with SPS, but not with CPS, whereas ΔNa and ΔANP were significantly correlated with each other in all the patients. We also found that ΔNa and Δ(Na to chloride ratio) were positively correlated with ΔHCO3−. In artificial colon fluid, CPS increased Ca and decreased Na. Furthermore, SPS greatly reduced K, Mg, and NH3.Conclusion: Compared with SPS, CPS may be safer for the treatment of hyperkalemia in pre-dialysis patients, because it did not induce hyperparathyroidism or volume overload. [ABSTRACT FROM AUTHOR]

Trimethylamine (TMA), an intestinal microflora-dependent metabolite formed from phosphatidylcholine- and L-carnitine-rich food, such as red meat, is further converted to trimethylamine-N-oxide (TMAO), which could play a role in cardiometabolic disease. Red meat-derived products are one of the major environmental sources of advanced glycation end products (AGEs) that may also contribute to the pathogenesis of cardiometabolic disorders through the interaction with receptor for AGEs (RAGE). However, the relationship among AGEs, soluble form of RAGE (sRAGE) and TMAO in humans remains unclear. Non-diabetic subjects underwent a physical examination, determination of blood chemistry and anthropometric variables, including AGEs, sRAGE, TMA and TMAO. Multiple regression analyses revealed that HbA1c, uric acid and AGEs were independently associated with log TMA, whereas log AGEs to sRAGE ratio and statin non-use were independently correlated with log TMAO. Our present findings indicated that AGEs to sRAGE ratio was correlated with log TMAO, a marker of cardiometabolic disorders. [ABSTRACT FROM AUTHOR]

The interaction of advanced glycation end products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy. We screened DNA aptamers directed against RAGE (RAGE-aptamers) in vitro and examined the effects on the development and progression of diabetic nephropathy in streptozotocin-induced diabetic rats. RAGE-aptamer bound to RAGE with a Kd of 5.68 nmol/L and resultantly blocked the binding of AGEs to RAGE. When diabetic rats received continuous intraperitoneal injection of RAGE-aptamer from week 7 to 11 of diabetes, the increases in renal NADPH oxidase activity, oxidative stress generation, AGE, RAGE, inflammatory and fibrotic gene and protein levels, macrophage and extracellular matrix accumulation, and albuminuria were significantly suppressed, which were associated with improvement of podocyte damage. Two-week infusion of RAGE-aptamer just after the induction of diabetes also inhibited the AGE-RAGE-oxidative stress system and MCP-1 levels in the kidneys of 8-week-old diabetic rats and simultaneously ameliorated podocyte injury and albuminuria. Moreover, RAGE-aptamer significantly suppressed the AGE-induced oxidative stress generation and inflammatory and fibrotic reactions in human cultured mesangial cells. The findings suggest that continuous infusion of RAGE-aptamer could attenuate the development and progression of experimental diabetic nephropathy by blocking the AGE-RAGE axis. [ABSTRACT FROM AUTHOR]

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-β1 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. [ABSTRACT FROM AUTHOR]

I R i SP 2 sp = 0.400 I eGFR i estimated glomerular filtration rate, I DM i diabetes mellitus, I CKD i chronic kidney disease, I BUN i blood urea nitrogen, I Cr i creatinine, I UP/UCrea i urinary protein/urinary creatinine ratio, I LDL i low-density lipoprotein * I p i < 0.05, ** I p i < 0.01, *** I p i < 0.001 The original article has been corrected. [Extracted from the article]

A non-enzymatic reaction between sugars or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules, which could impair their structural integrity and function. This process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions, such as rearrangements and dehydration to become irreversibly crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress in a physiological aging process and at an accelerated rate under hyperglycemic, inflammatory and oxidative stress conditions. There is a growing body of evidence that AGEs and their receptor RAGE interaction play a role in the pathogenesis of various devastating disorders, including cardiovascular disease, Alzheimer's disease, insulin resistance, osteoporosis and cancer growth and metastasis. Furthermore, diet has been recently recognized as a major environmental source of AGEs that could also elicit pro-inflammatory reactions, thereby being involved in organ damage in vivo. Therefore, inhibition of AGE formation and/or blockade of the interaction of AGEs with RAGE may be a novel therapeutic target for aging-related disorders. This article discusses a potential utility of DNA-aptamers raised against AGEs for preventing aging and/or diabetes-associated organ damage, especially focusing on diabetic microvascular complications, vascular remodeling, metabolic derangements, and melanoma growth and expansion in animal models. [ABSTRACT FROM AUTHOR]

The article presents a study conducted to monitor the effects of serum albumin-adjusted gylcated albumin on glycaemic control in diabetic patients with end-stage renal diseases like renal anemia and proteinuria, who are not on haemodialysis. The concentration of patient's glycated albumin were calculated by obtaining mean blood glucose concentrations from the diurnal variation.

Late-onset hypogonadism (LOH) and depression contribute to cardiovascular disease (CVD) in male hemodialysis (HD) patients. Carnitine deficiency is frequently observed in HD patients, playing a role in CVD. We examined whether carnitine deficiency was independently associated with LOH and depression in these patients. Twenty-six male HD patients underwent determinations of serum levels of free carnitine and testosterone. Status of LOH and depression were evaluated by questionnaires using aging male symptoms' (AMS) scale and self-rating depression scale (SDS), respectively. Free carnitine and testosterone levels in male HD patients were significantly lower than those in age-matched healthy male subjects. Linear regression analysis showed that AMS scale was positively associated with SDS. Univariate regression analysis revealed that total carnitine (inversely), free carnitine (inversely) and HD duration were correlated with AMS scale. Multiple stepwise regression analysis revealed that free carnitine was an independent determinant of AMS scale. Furthermore, free carnitine was also independently correlated with SDS in male HD patients. This study demonstrated that decreased free carnitine levels were independently associated with AMS scale and SDS in male HD patients. The observations suggest that decreased free carnitine levels could be a marker and therapeutic target of LOH and depression in uremic men with HD. [ABSTRACT FROM AUTHOR]

Peritoneal protein loss due to high peritoneal permeability may contribute to hypoalbuminemia and early withdrawal from peritoneal dialysis ( PD) therapy in end stage renal disease ( ESRD) patients. We have found that pigment epithelium-derived factor ( PEDF) has anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of vascular endothelial growth factor ( VEGF). However, it remains unknown which clinical variables, including dialysate VEGF and PEDF, are associated with decreased serum albumin levels and could predict early withdrawal from the PD in ESRD patients. We address these issues. Twenty-seven ESRD patients undergoing PD were enrolled. Clinical variables were measured at 6 months after commencing PD. We examined the independent correlates of serum albumin in PD patients and then prospectively investigated the predictors of withdrawal from the PD therapy over 4 years. Dialysate VEGF was associated with peritoneal solute transport rate ( P = 0.002), serum albumin (inversely, P < 0.001) and dialysate PEDF levels ( P < 0.001). In multiple stepwise regression analysis, age ( P = 0.002) and dialysate VEGF levels ( P < 0.001) were independent determinants of serum albumin levels. High VEGF (>27 pg/mL), low serum albumin (≤3.31 g/dL) and low hemoglobin (≤11.2 g/dL) were correlated with withdrawal from the PD therapy during the 4 years. The odds ratio of dialysate VEGF for early withdrawal from the PD was 6.310 ( P = 0.035). The present study demonstrated that increased dialysate VEGF was associated with decreased serum albumin and early withdrawal from the PD therapy. Inhibition of peritoneal VEGF production may be a therapeutic target in PD patients. [ABSTRACT FROM AUTHOR]

Background Carnitine deficiency may contribute to cardiovascular disease (CVD) in patients with hemodialysis (HD). Dyslipidemia plays a role in CVD and its prevalence is also high in HD patients. We examined here the effects of switching from oral administration (PO) to intravenous (IV) injection of l-carnitine on lipid metabolism in patients with HD. Methods Nine HD patients who had received l-carnitine orally (900 mg/day) for 1 year were enrolled in this study. We examined whether lipid parameters were improved by switching to IV injection therapy of 1000 mg l-carnitine. Results IV injection of l-carnitine for 1 week significantly increased total, free and acyl carnitine levels both before and after HD. Switching to IV injection therapy for 1 and 4 weeks decreased serum free fatty acid (FFA) (322 ± 104 versus 261 ± 124 µmol/L) and increased high-density lipoprotein-cholesterol levels (1.46 ± 0.49 versus 1.63 ± 0.62 mmol/L), respectively. Change in FFA values from the baseline (ΔFFA) was positively correlated with the Δacyl/free carnitine ratio (r2 = 0.553, P = 0.022). Conclusion This study demonstrated that switching to IV l-carnitine therapy from oral supplementation improved lipid profiles, thus supporting the clinical utility of IV administration of l-carnitine for the treatment of patients on HD. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress and smoking contribute to endothelial dysfunction. Iron might also play a role in oxidative stress generation and endothelial dysfunction. However, the involvement of iron in smoking-induced endothelial dysfunction in healthy smokers remains unclear. Therefore, we examined here whether (1) intravenous iron infusion impaired endothelial function evaluated by flow-mediated vasodilatation (FMD) in non-smokers, and (2) deferoxamine, a potent iron chelator, ameliorated endothelial dysfunction in healthy smokers. Methods: Eight healthy young male non-smokers (23±4 years old) received intravenous injection of saccharated ferric oxide (0.7 mg/kg body weight), while 10 age-matched healthy male smokers received deferoxamine mesylate (8.3 mg/kg body weight). At baseline, 5 and 20 minutes after treatment with iron or deferoxamine, biochemical variables were measured, including serum iron and marondialdehyde (MDA), a marker of lipid oxidation, and endothelial function was simultaneously evaluated by FMD. Results: Compared with non-smokers, FMD was significantly lower in smokers. Iron and MDA levels were significantly increased, whereas FMD was impaired by iron infusion in non-smokers. Conversely, deferoxamine treatment significantly decreased iron and MDA levels and restored the decreased FMD in smokers. Baseline serum iron and MDA levels in all 18 subjects (non-smokers and smokers) were correlated with each other. There was a significant inverse correlation between the changes in MDA values and FMD from baseline in 18 men. Endothelium-independent vasodilation by glyceryl trinitrate was unaltered by either treatment. Conclusions: Our present study suggests that iron-evoked oxidative stress might play a role in endothelial dysfunction in healthy smokers. [ABSTRACT FROM AUTHOR]

Although impaired synthesis and/or bioavailability of nitric oxide are considered to contribute to insulin resistance and the progression of liver disease in nonalcoholic fatty liver disease, role of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, has not been examined. We examined retrospectively which anthropometric and metabolic parameters were independently associated with serum levels of asymmetric dimethylarginine in nonalcoholic fatty liver disease. A total of 194 consecutive biopsy-proven nonalcoholic fatty liver disease patients with or without type 2 diabetes were enrolled. Serum asymmetric dimethylarginine levels in nonalcoholic fatty liver disease patients were significantly higher, irrespective of the presence or absence of diabetes, than those in healthy control. Multiple stepwise regression analysis showed that decreased total protein and procollagen N-terminal peptide levels, markers of advanced liver disease and hepatic fibrosis, respectively, were independently associated with asymmetric dimethylarginine levels in nonalcoholic fatty liver disease subjects without diabetes, whereas soluble form of receptor for advanced glycation end products and density ratio of liver to spleen in computed tomography were independent correlates of asymmetric dimethylarginine in diabetic patients. The present study suggests that asymmetric dimethylarginine may be associated with nonalcoholic fatty liver disease, especially subjects without diabetes. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs-aptamer) in vitro and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight-week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with those in C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2'-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor, and type IV collagen both in the kidney of KKAy/Ta mice and in AGE-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, plays a role in endothelial dysfunction, an initial step of atherosclerosis. Advanced glycation end products (AGEs) also contribute to accelerated atherosclerosis. However, a pathophysiological crosstalk between ADMA and AGEs remains unclear. In this study, we investigated the relationship between ADMA and AGE level in patients with end-stage renal disease (ESRD) due to diabetic nephropathy. We also examined whether and how AGEs increased ADMA generation by cultured endothelial cells (ECs). Plasma ADMA levels were positively associated with serum AGE level and were inversely correlated with endothelial function determined by flow-mediated vasodilatation. AGEs dose dependently increased reactive oxygen species (ROS) generation in ECs, which was blocked by antisense DNA raised against receptor for AGEs (RAGE). Furthermore, AGEs decreased messenger RNA (mRNA) level of dimethylarginine dimethylaminohydrolase (DDAH)-II, an enzyme for ADMA degradation, reduced its total enzymatic activity and resultantly increased ADMA, all of which were completely blocked by an antioxidant, N-acetylcysteine. These results suggest that the AGE-RAGE-mediated ROS generation could be involved in endothelial dysfunction in diabetic ESRD patients partly by increasing the ADMA generation via suppression of DDAH activity in ECs. [ABSTRACT FROM PUBLISHER]

Phosphate binders are useful for the treatment of hyperphosphatemia in hemodialysis ( HD) patients. This study was performed to examine the effects of switching from calcium carbonate ( CC) to lanthanum carbonate ( LC) on bone mineral metabolism and inflammatory markers in HD patients. We conducted 29 stable HD patients receiving CC, which was replaced by LC and followed-up for 12 weeks. Patients underwent determinants of blood chemistries such as serum calcium ( Ca), phosphorus, parathyroid hormone ( PTH) and vitamin D status, and interleukin-6 ( IL-6) mRNA levels in whole blood cells were evaluated by real-time PCR just before and after the treatment with LC. Corrected levels were significantly reduced, but serum phosphorus levels ( P levels) were unchanged after LC treatment. Switching to LC increased whole- PTH, osteocalcin, 1,25 (OH)2D3 levels and 1,25 (OH)2D3/25 (OH)D3 ratio. 1,25 (OH)2D3/25 (OH)D3 ratio was negatively correlated with HD duration. Furthermore, whole blood cell IL-6 mRNA levels were significantly reduced by LC treatment. We provided that the switching from CC to LC improved Ca overload and ameliorated vitamin D and inflammatory status in HD patients. These observations suggest that LC may play a protective role for the progression of atherosclerosis and vascular calcification in these patients. [ABSTRACT FROM AUTHOR]

Background Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. Methods Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. Results Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-d-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. Conclusions Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy. [ABSTRACT FROM PUBLISHER]

ABSTRACT: Aim: There is accumulating evidence that advanced glycation end products (AGE) play a role in cardiovascular disease (CVD) in patients with haemodialysis (HD). Carnitine deficiency is frequently observed in HD patients, which may also contribute to CVD. In this study, we examined whether carnitine deficiency was independently associated with increased tissue accumulation levels of AGE in HD patients. Methods: One hundred and twenty-nine HD patients underwent determinations of blood chemistries including serum level of carnitine. Tissue AGE levels were evaluated by measuring skin autofluorescence with an AGE-reader. Results: Serum carnitine levels were significantly lower, while skin AGE levels were significantly higher in HD patients compared with healthy controls ( P < 0.001). In univariate analysis, β2-microglobulin (β2-MG) and carnitine (inversely) were correlated with skin AGE levels. Multiple stepwise regression analysis revealed that carnitine levels were one of the independent determinants of skin AGE levels ( P = 0.024). When β2-MG-adjusted skin AGE levels were stratified by serum carnitine levels, a statistical significance and dose-response relationship were observed ( P = 0.043). Furthermore, skin AGE levels were one of the independent determinants of serum carnitine levels as well ( P = 0.012). Conclusion: The present study demonstrated that decreased carnitine levels were independently associated with increased skin AGE levels in HD patients. Since carnitine is reported to inhibit the formation of AGE in vitro, our study suggests that supplementation of carnitine may be a therapeutic target for preventing the accumulation of tissue AGE and subsequently reducing the risk of CVD in HD patients. [ABSTRACT FROM AUTHOR]

Background/Aims: Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive microscopic polyangiitis patients with renal involvement have been shown to have a progressive clinical course. In this study, we compared the clinical utility of the Japanese Vasculitis Activity Score (JVAS) with the Birmingham Vasculitis Activity Score (BVAS) for predicting death in patients with MPO-ANCA-associated renal involvement. Methods: Sixty-nine patients with MPO-ANCA-associated vasculitis with renal involvement (22 males and 47 females, age 69.8 ± 8.7 years) were enrolled in this study. We retrospectively investigated which score was better for predicting the poor prognosis of patients. Results: The mortality rate of the patients within 2 years after disease onset was 33% (23/69). JVAS was not correlated with BVAS. Univariate logistic regression analysis for death showed that the odds ratio (OR) of JVAS was statistically significant (OR 1.76, 95% confidence interval, CI, 1.29-2.41, p < 0.001), while that of BVAS was not (OR 1.07, 95% CI 0.98-1.16, p = 0.14). Moreover, a multivariate model showed that JVAS was an independent determinant of death (OR 1.59, 95% CI 1.12-2.25, p = 0.009). The area under the receiver operating characteristic curve for JVAS was 0.778, which was significantly larger (p = 0.02) than that for BVAS (0.586). The estimated optimal cut-off point of JVAS for the prediction of death was 5. At this point, the sensitivity was 82.6% and the specificity was 60.9%. Conclusion: We demonstrated that compared with BVAS, JVAS was a simpler and more reliable measure for predicting death in patients with MPO-ANCA-associated vasculitis with renal involvement. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]