Association between plasma aldosterone concentration and intraglomerular hemodynamics in primary aldosteronism.

BACKGROUND/AIMS: In primary aldosteronism (PA), aldosterone could affect glomerular hemodynamics by elevating renal vascular resistance and glomerular capillary pressure. However, the relationship between plasma aldosterone concentrations (PAC) and glomerular hemodynamics including efferent arteriolar resistance (Re), afferent arteriolar resistance (Ra) in humans is still unclear. The aim of this study was to investigate the relationships of PAC with intraglomerular hemodynamic parameters in patients with PA. METHODS: An observational study of glomerular hemodynamics was performed using simultaneous measurements of plasma clearance of para-aminohippurate and inulin (Cin; glomerular filtration rate (GFR)) in 17 patients with PA. Kidney function was evaluated by Cin, estimated GFR based on serum creatine (eGFRcre) and serum cystatin C (eGFRcys) and creatine clearance (Ccr). Intraglomerular hemodynamic parameters, including Re, Ra, and intraglomerular hydrostatic pressure (Pglo) were calculated using Gomez's formulae. RESULTS: In the 17 PA cases, PAC was significantly correlated with Cin (rho=0.752, p=0.001) and eGFRcys (rho=0.567, p=0.018), but was not correlated witheGFRcreand Ccr. PAC was also significantly correlated with Pglo, Re, and urinary protein/day (rho=0.775, p=0.0004, rho=0.625, p=0.009, and rho=0.625, p=0.007, respectively). Multivariable regression analysis showed that PAC was significantly associated with Cin and Re. In comparing aldosterone producing adenoma (APA) and non-APA cases, Cin was significantly elevated in APA (p=0.037), whereas eGFRcre, eGFRcys, and Ccr were not. Re tended to be higher in APA (p=0.064). CONCLUSIONS: These results suggest high aldosterone cause glomerular hyperfiltration by constricting Re. Cin, but not eGFRcre and Ccr, may be useful for evaluating kidney function in PA.

Differential associations of fetuin-A and calcification propensity with cardiovascular events and subsequent mortality in patients undergoing hemodialysis.

Background: Fetuin-A inhibits precipitation of calcium-phosphate crystals by forming calciprotein particles (CPP). A novel T50 test, which measures transformation time from primary to secondary CPP, is an index for calcification propensity. Both lower fetuin-A and shorter T50 levels were associated with cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD). Extremely high risk for CVD death in advanced CKD patients consists of high-incidental CVD event and high mortality after CVD event. To date, it is unclear whether fetuin-A and/or T50 can equally predict each CVD outcome. Methods: This prospective cohort study examined patients undergoing maintenance hemodialysis. The exposures were fetuin-A and T50. The outcomes of interests were new CVD events and subsequent deaths. The patients were categorized into tertiles of fetuin-A or T50 (T1 to T3). Results: We identified 190 new CVD events during the 5-year follow-up of the 513 patients and 59 deaths subsequent to the CVD events during 2.5-year follow-up. A lower fetuin-A but not T50 was significantly associated with new CVD events [subdistribution hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.15-2.61, P = .009 for T1 vs T3]. In contrast, a shorter T50 but not fetuin-A was a significant predictor of deaths after CVD events (HR 3.31, 95% CI 1.42-7.74, P = .006 for T1 + T2 vs T3). A lower fetuin-A was predictive of new CVD events, whereas a shorter T50 was more preferentially associated with subsequent death. Conclusion: These results indicate that fetuin-A and T50 are involved in cardiovascular risk in different manners.

New-onset Kidney Biopsy-proven Membranous Nephropathy Induced End-stage Kidney Disease in a Living Donor: A Case Report.

Thirteen years after kidney donation, a 70-year-old man was referred to a nephrologist because of proteinuria. The serum creatinine, albumin, and urinary protein levels were 2.39 mg/dL, 3.0 g/dL, and 6.72 g/gCr, respectively. A kidney biopsy revealed thickening of the glomerular basement membrane with sub-epithelial deposits, suggesting membranous nephropathy. Considering the apparent interstitial fibrosis and diffuse glomerulosclerosis, supportive treatment was chosen. However, 11 months after the kidney biopsy, hemodialysis was required. The present case constitutes an important teaching point, as glomerular disease can occur in living donors and require careful and long-term medical checkup examinations.

Novel Digenic Variants in COL4A4 and COL4A5 Causing X-Linked Alport Syndrome: A Case Report.

Introduction: Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS is classified as X-linked, autosomal, and digenic. The number of cases of digenic AS has increased, but the genotype-phenotype correlation of patient with digenic AS is still unclear. Here, we present a case of digenic AS with novel digenic missense variants in COL4A4 (c.827G>C, p.Gly276Ala) and COL4A5 (c.4369G>C, p.Gly1457Arg). Case Presentation: The patient was a 29-year-old Japanese man suffering from persistent microscopic hematuria and proteinuria without kidney function impairment. Kidney biopsy showed focal interstitial foam cell infiltration, global and segmental glomerulosclerosis. Immunofluorescence staining for collagen IV α5 was almost negative in the GBM and Bowman's capsule. Electron microscopy revealed irregular thickening with lamellation and segmental thinning of the GBM. Clinical and pathological findings were consistent with AS. Comprehensive next-generation sequencing revealed a heterozygous missense variant in COL4A4 (c.827G>C, p.Gly276Ala) in exon 1 and a hemizygous missense variant in COL4A5 (c.4369G>C, p.Gly1457Arg) in exon 49 on the patient's paternal and maternal alleles, respectively. The same digenic variants were detected in his sister, and she also showed a similar phenotype. After treatment with angiotensin-converting enzyme inhibitors, proteinuria decreased from 2.3 to 1.1 g/g creatinine, but occult blood persisted. During follow-up, kidney function has been preserved. Conclusion: The novel genotype of our case provides more information on the genotype-phenotype correlation of digenic XLAS, although long-term follow-up is required. The findings in the present case also indicate the importance of genetic tests for family members of a patient diagnosed with digenic AS.

Dapagliflozin administration for 1 year promoted kidney enlargement in patient with ADPKD.

To date, there is insufficient evidence regarding use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with autosomal-dominant polycystic kidney disease (ADPKD), as such cases have been excluded from previous clinical trials exploring the kidney protection effects of such medications. Here, findings of an ADPKD patient who received dapagliflozin, a selective SGLT2 inhibitor, for 1 year are presented. A 38-year-old woman with a family history of ADPKD wished for treatment with dapagliflozin. After starting administration at 10 mg/day, total kidney volume (TKV) continued to increase, from 1641 to 1764 mL after 84 days and then to 2297 mL after 340 days. The estimated glomerular filtration rate (eGFR) was also decreased from 67.3 to 56.2 mL/min/1.73 m2, and then to 51.4 mL/min/1.73 m2 at those times. Immediately after discontinuation of dapagliflozin, TKV and eGFR were slightly improved to 2263 mL and 55.1 mL/min/1.73 m2, respectively. Following a review of basic research studies, we consider that increased intratubular urinary osmotic pressure, compensatory glucose reabsorption by sodium-glucose cotransporter-1 in the late proximal tubule, and hypertrophy shown in collected cells caused by increased vasopressin may be associated with ADPKD disease progression. Caution may be needed when administering dapagliflozin to patients with ADPKD.

Short-Term Dapagliflozin Administration in Autosomal Dominant Polycystic Kidney Disease-A Retrospective Single-Arm Case Series Study.

Treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors may have pleiotropic and beneficial effects in terms of ameliorating of risk factors for the progression of autosomal dominant polycystic kidney disease (ADPKD). However, there is insufficient evidence regarding the use of these drugs in patients with ADPKD, as they were excluded from several clinical trials conducted to explore kidney protection provided by SGLT2 inhibitors. This retrospective single-arm case series study was performed to investigate the effects of dapagliflozin, a selective SGLT2 inhibitor administered at 10 mg/day, on changes in height-adjusted kidney volume (htTKV) and estimated glomerular filtration rate (eGFR) in ADPKD patients. During a period of 102 ± 20 days (range 70-156 days), eGFR was decreased from 47.9 (39.7-56.9) to 40.8 (33.7-44.5) mL/min/1.73 m2 (p < 0.001), while htTKV was increased from 599 (423-707) to 617 (446-827) mL/m (p = 0.002) (n = 20). The annual increase in htTKV rate was significantly promoted, and urinary phosphate change was found to be correlated with the change in htTKV (rs = 0.575, p = 0.020). In the examined patients, eGFR was decreased and htTKV increased during short-term administration of dapagliflozin. To confirm the possibility of the effects of dapagliflozin on ADPKD, additional interventional studies are required.

Serum phosphate as an independent factor associated with cholesterol metabolism in patients undergoing hemodialysis: a cross-sectional analysis of the DREAM cohort.

BACKGROUND: Hyperphosphatemia is a risk factor for cardiovascular outcomes in patients with chronic kidney disease. In an experimental model, hyperphosphatemia promoted atherosclerosis by activating sterol regulatory element-binding protein 2, which controls cholesterol homeostasis. In the present study, we hypothesized that serum phosphate level is associated with cholesterol metabolism in patients with kidney failure. METHODS: We conducted a single-center cross-sectional study including 492 patients undergoing hemodialysis and 100 healthy controls not on statin or ezetimibe treatment. Serum lathosterol and campesterol levels were measured as a marker of cholesterol synthesis and absorption, respectively. As compared with the control group, the hemodialysis patients had higher median phosphate {5.8 mg/dL [interquartile range (IQR 5.0-6.6) versus 3.3 (3.0-3.6); P < .001], lower lathosterol [1.2 µg/mL (IQR 0.8-1.7) versus 2.6 (1.9-3.4); P < .001] and higher campesterol levels [4.5 µg/mL (IQR 3.6-6.0) versus 4.1 (3.2-5.4); P = .02]. Serum phosphate correlated positively to campesterol in the control group (Spearman's r = 0.21, P = .03) and in hemodialysis patients (Spearman's r = 0.19, P < .001). The positive association between phosphate and campesterol levels in the hemodialysis group remained significant in multivariable-adjusted linear regression analysis. There was no significant association between phosphate and lathosterol in either group. CONCLUSIONS: An independent association was found between phosphate and campesterol levels in patients with kidney failure. This study suggests a novel relationship between phosphate and cholesterol metabolism, both of which could affect cardiovascular outcomes in this population.

Seronegative Full-house Nephropathy with Crohn's Disease.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease. Lupus nephritis (LN) is a major risk factor for mortality in SLE, and glomerular "full-house" immunofluorescence staining is a well-known characteristic of LN. However, some cases of non-lupus glomerulonephritis can also present with a "full-house" immunofluorescence pattern. We recently encountered a patient with full-house nephropathy (FHN) during adalimumab administration for Crohn's disease. IgA nephropathy or idiopathic FHN was diagnosed, and treatment with steroids was started, after which there was improvement in proteinuria. The prognosis of FHN has been reported to be poor; therefore, aggressive treatment is required for such patients.

Clinical and histopathological features related to time to complete remission in adult-onset minimal change nephrotic syndrome patients with corticosteroid treatment.

BACKGROUND: Minimal change nephrotic syndrome (MCNS) is a common type of nephrotic syndrome in adults, though evidence regarding its clinical and histopathological features related to time to complete remission (CR) is limited. METHODS: This was a retrospective study of biopsy-proven, first-onset, adult MCNS patients who achieved CR after undergoing corticosteroid treatment. Body weight (BW) change rate was calculated as follows: (BW at admission - BW at discharge)/BW at discharge × 100. Histopathological examinations were performed, with particular attention given to tubulointerstitial lesions. RESULTS: Fifty-seven patients (median 41 years old, range 22-63 years; 37 males) were diagnosed with MCNS from 2007 to 2020. Time to CR was a median 11 (8-21) days. In addition to serum creatinine and urinary protein, BW change rate also showed a positive correlation with time to CR (rs = 0.438, p < 0.001; rs = 0.280, p = 0.035; rs = 0.544, p < 0.001; respectively), while multivariate Cox proportional hazards models also revealed those factors as significant predictors for longer time to CR. In MCNS patients with a higher BW change rate (n = 28), serum creatinine, urinary protein, histopathological score, and time to CR were significantly greater as compared to those with a lower BW change rate (n =29). Also, in those patients, histopathological interstitial edema was significantly associated with longer time to CR after adjustments for serum creatinine and urinary protein. CONCLUSION: The present results indicate that BW change rate can predict time to CR in adult-onset MCNS patients. Histopathologically, interstitial edema is also an important factor for time to CR in MCNS patients with greater BW increase.

Nutritional Disorder Evaluated by the Geriatric Nutritional Risk Index Predicts Death After Hospitalization for Infection in Patients Undergoing Maintenance Hemodialysis.

OBJECTIVE: Infection is related to a higher rate of hospitalization and subsequent death in patients undergoing hemodialysis. Limited data are available about factors associated with death after hospitalization for infection. Nutritional disorder also known as protein energy wasting is profoundly associated with poor consequences. The Geriatric Nutritional Risk Index (GNRI) is a simple but useful nutritional screening tool to predict mortality. We examined whether the GNRI could predict hospitalization for infection and subsequent death. DESIGN AND METHODS: This was a prospective cohort study on patients undergoing hemodialysis. The predictor was the GNRI. The patients were divided into tertiles of the GNRI (T1 to T3), with the highest tertile of T3 as the referent. The outcomes of interest were all-cause mortality, hospitalization for infection, and subsequent death. RESULTS: Of 518 patients, 107 patients died (median follow-up period: 5.0 years; interquartile range: 3.6-5.0) and 169 patients experienced new hospitalization for infection (median follow-up period: 4.5 years; interquartile range: 3.4-5.0) during the follow-up period from December 2004 to December 2009. A lower GNRI was a significant predictor for all-cause mortality in multivariable Cox models (hazard ratio [HR]: 2.9, 95% confidential interval [CI]: 1.5-5.5, P < .001 for T1 vs. T3). However, the GNRI was not associated with hospitalization for infection in multivariable Fine-Gray models with death as a competing risk (subdistributional HR: 1.5, 95% CI: 1.0-2.3, P = .056 for T1 vs. T3). After hospitalization for infection, 38 patients died during the subsequent 2.5-year follow-up period. The GNRI was a significant predictor of death after hospitalization for infection in multivariable Cox models (HR: 2.7, 95% CI: 1.3-5.6, P = .006 for T1 vs. T2+T3). CONCLUSIONS: A lower GNRI predicted a higher risk of all-cause mortality but not hospitalization for infection. However, a lower GNRI was significantly associated with a higher risk of mortality after hospitalization for infection. These findings suggest that long-term mortality after hospitalization for infection was predicted by nutritional disorder evaluated by the GNRI.

New-onset kidney biopsy-proven IgA vasculitis after receiving mRNA-1273 COVID-19 vaccine: case report.

As mRNA COVID-19 vaccines have become widely available, cases of new-onset glomerular disease after receiving COVID-19 vaccination have been reported. Here, we present a case of kidney biopsy-proven new-onset IgA vasculitis after receiving the mRNA-1273 (Moderna) COVID-19 vaccination. A 47-year-old man with a 10-year medical history of hypertension and hyperuricemia visited our hospital 19 days after receiving an initial mRNA-1273 COVID-19 vaccine injection for purpuric eruption on the legs and dorsal regions of the feet. Although the eruptions spontaneously improved within 5 days, they developed again at 15 days after the second injection. A histopathological examination of skin biopsy specimens was reminiscent of leukocytoclastic vasculitis, though direct immunofluorescence did not indicate IgA deposition within small vessel walls. Urinalysis indicated severe proteinuria (3 +) and occult blood (3 +). Thus, a kidney biopsy was performed and light microscopy revealed mild mesangial expansion, hypercellularity, and endocapillary hypercellularity, with cellular and fibrocellular crescents observed in three and one, respectively, of a total of 15 glomeruli. Immunofluorescence also showed diffuse granular mesangial staining (3 +) for IgA. Histopathological features were consistent with IgA vasculitis. Intravenous methylprednisolone at 1000 mg for 3 days was initiated, followed by oral prednisolone (0.6 mg/kg/day). Over the following 2-week period, serum creatinine level improved from 1.24 to 1.06 mg/dL and proteinuria decreased from 2.98 to 0.36 g/g Cr, though occult blood persisted. Findings in the present case indicate that new-onset IgA vasculitis after receiving mRNA-1273 COVID-19 vaccine can be treated with corticosteroid therapy.

Plasma Xanthine Oxidoreductase Activity Associated with Glycemic Control in Patients with Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species, which is associated with cardiovascular disease (CVD) events. Patients with CKD have increased risk of CVD events. In the present study, factors associated with plasma XOR activity in pre-dialysis CKD patients were investigated. METHODS: In this cross-sectional study, plasma XOR activity in 118 pre-dialysis CKD patients (age 68 [57-75] years; 64 males, 26 with diabetes mellitus [DM]) was determined using a newly established highly sensitive assay based on (13C2,15N2) xanthine and liquid chromatography/triple quadrupole mass spectrometry. RESULTS: Plasma glucose, hemoglobin A1c, and estimated glomerular filtration (eGFR) were significantly and positively correlated with plasma logarithmically transformed XOR (ln-XOR) activity. In multiple regression analyses, eGFR and hemoglobin A1c or plasma glucose were significantly, independently, and positively associated with plasma ln-XOR activity after adjusting for several confounders. Plasma XOR activity was significantly higher in CKD patients with (n = 26) than in those without (n = 92) DM (62.7 [32.3-122] vs. 25.7 [13.4-45.8] pmol/h/mL, p < 0.001). A total of 38 patients were taking uric acid-lowering drugs. Multiple regression analysis of CKD patients not administered uric acid-lowering drugs (n = 80) showed no significant association between eGFR and plasma ln-XOR activity. In contrast, association between glycemic control and plasma ln-XOR activity was significant even in CKD patients without uric acid-lowering drug treatment. CONCLUSIONS: These results indicate the importance of glycemic control in CKD patients in regard to decreased XOR, possibly leading to a decrease in CVD events.

Cinacalcet may suppress kidney enlargement in hemodialysis patients with autosomal dominant polycystic kidney disease.

A massively enlarged kidney can impact quality of life of autosomal dominant polycystic kidney disease (ADPKD) patients. A recent in vitro study demonstrated that an allosteric modulator of the calcium sensing receptor decreases adenosine-3',5'-cyclic monophosphate, an important factor for kidney enlargement in ADPKD. Therefore, the present study was performed to determine whether cinacalcet, a calcium sensing receptor agonist, suppresses kidney enlargement in hemodialysis patients with ADPKD. Alteration of total kidney volume together with clinical parameters was retrospectively examined in 12 hemodialysis patients with ADPKD treated at a single institution in Japan. In the non-cinacalcet group with longer hemodialysis duration (n = 5), total kidney volume had an annual increase of 4.19 ± 1.71% during an overall period of 877 ± 494 days. In contrast, the annual rate of increase in total kidney volume in the cinacalcet group (n = 7) was significantly suppressed after cinacalcet treatment, from 3.26 ± 2.87% during a period of 734 ± 352 days before the start of cinacalcet to - 4.71 ± 6.42% during 918 ± 524 days after initiation of treatment (p = 0.047). The present findings showed that cinacalcet could be a novel therapeutic tool for suppression of kidney enlargement in hemodialysis patients with ADPKD.

Effects of fetuin-A-containing calciprotein particles on posttranslational modifications of fetuin-A in HepG2 cells.

Fetuin-A is an inhibitor of ectopic calcification that is expressed mainly in hepatocytes and is secreted into the circulation after posttranslational processing, including glycosylation and phosphorylation. The molecular weight (MW) of fully modified fetuin-A (FM-fetuin-A) is approximately 60 kDa in an immunoblot, which is much higher than the estimated MW by amino acid sequence. Under conditions of calcification stress such as advanced stage chronic kidney disease, fetuin-A prevents calcification by forming colloidal complexes, which are referred to as calciprotein particles (CPP). Since the significance of CPP in this process is unclear, we investigated the effect of synthetic secondary CPP on the level of FM-fetuin-A in HepG2 cells. Secondary CPP increased the level of FM-fetuin-A in dose- and time-dependent manners, but did not affect expression of mRNA for fetuin-A. Treatment with O- and/or N-glycosidase caused a shift of the 60 kDa band of FM-fetuin-A to a lower MW. Preincubation with brefeldin A, an inhibitor of transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi apparatus, completely blocked the secondary CPP-induced increase in FM-fetuin-A. Treatment with BAPTA-AM, an intracellular calcium chelating agent, also inhibited the CPP-induced increase in the FM-fetuin-A level. Secondary CPP accelerate posttranslational processing of fetuin-A in HepG2 cells.

Clinical and histopathological features of acute kidney injury in adult-onset minimal change nephrotic syndrome.

BACKGROUND: Acute kidney injury (AKI) is a common complication of minimal change nephrotic syndrome (MCNS), particularly in adults. To predict development of AKI, as defined by the Kidney Disease Improving Global Outcomes classification, we investigated clinical and histopathological features of adult-onset MCNS patients. METHODS: A retrospective study was conducted with biopsy-proven adult-onset MCNS patients treated with corticosteroids. RESULTS: A total of 58 MCNS patients [49 (24-71) years old, 38 males] were diagnosed using kidney biopsy findings from 2005 to 2018 at Osaka City University Hospital, of whom 24 (41.4%) were found to be complicated with AKI. Age, urinary protein, increased body weight (difference from admission to discharge), and histopathological scores were significantly greater in patients with as compared to without AKI, while urinary protein, increased body weight, and interstitial edema score were significantly associated with AKI development [OR 1.55 (95% CI 1.04-2.31), 1.37 (95% CI 1.03-1.81), 20.7 (95% CI 1.76-243), respectively]. Of the 24 MCNS patients with AKI, 10 underwent transient hemodialysis treatment. Although histopathological features were not different, the time interval between disease onset and kidney biopsy was significantly longer for MCNS patients complicated with AKI requiring hemodialysis as compared to those for whom that was not required [32 (24-46) vs. 13 (10-23) days, p = 0.034]. CONCLUSION: These results indicate that urinary protein, increased body weight, and interstitial edema score are important information for predicting development of AKI in adult-onset MCNS patients.

Increased Glomerular Hydrostatic Pressure is Associated with Tubular Creatinine Reabsorption in Healthy Subjects.

BACKGROUND: Cr is secreted by the proximal tubules and thus Cr clearance (Ccr) can overestimate inulin clearance (Cin). However, in some cases, Ccr can even underestimate Cin. This suggests that Cr could be reabsorbed in the tubuli. We examined the clinical parameters that are associated with tubular Cr reabsorption. METHODS: In 80 kidney donor candidates (53.9 ± 13.2 years, 29 males), Cin and para-aminohippuric acid clearance were measured simultaneously. Intrarenal hemodynamic parameters were calculated by Gomez's formulae. To quantify the secretory component of Ccr (SFcr), it was calculated as follows: SFcr = (Ccr - Cin)/Ccr. RESULTS: Twenty-five subjects (31.3%) showed SFcr values <0. SFcr that correlated significantly and negatively with efferent arteriolar resistance (Re) and glomerular hydrostatic pressure (Pglo) (Re: r = -0.30, p = 0.008; Pglo: r = -0.28, p = 0.025). In multiple regression analyses, Re and Pglo were significantly and negatively associated with SFcr after adjustment for other confounders. CONCLUSIONS: These findings suggest that tubular reabsorption of Cr can occur in some cases. Intrarenal glomerular hemodynamic burden may be related to tubular creatinine reabsorption, which possibly leads to lower Ccr values.

Association between Serum Zinc and Calcification Propensity (T50) in Patients with Type 2 Diabetes Mellitus and In Vitro Effect of Exogenous Zinc on T50.

Zinc inhibits vascular calcification in vivo and in vitro. Patients with type 2 diabetes mellitus show hypozincemia and are at an elevated risk of cardiovascular events. Recently, an in vitro test (T50-test) was developed for determination of serum calcification propensity and a shorter T50 means a higher calcification propensity. This cross-sectional study investigated the association between serum zinc and T50 in 132 type 2 diabetes mellitus patients with various kidney functions. Furthermore, the effect of exogenous zinc on T50 was also investigated in vitro using separately pooled serum samples obtained from healthy volunteers and patients with hemodialysis. We measured T50 levels using the established nephelometric method. The median (interquartile range) levels of T50 and serum zinc were 306 (269 to 332) min, and 80.0 (70.1 to 89.8) µg/dL, respectively. Serum zinc level showed a weak, but positive correlation with T50 (rs = 0.219, p = 0.012). This association remained significant in multivariable-adjusted analysis, and was independent of known factors including phosphate, calcium, and magnesium. Kidney function and glycemic control were not significantly associated with T50. Finally, in vitro experiments showed that addition of a physiological concentration of exogenous zinc chloride significantly increased serum T50. Our results indicate that serum zinc is an independent factor with a potential role in suppressing calcification propensity in serum.

Long-Term Effects of High-Dose Tolvaptan for Autosomal Dominant Polycystic Kidney Disease Patients.

Tolvaptan, a vasopressin V2 receptor antagonist, was initially approved in Japan for treatment of autosomal dominant polycystic kidney disease (ADPKD). Recently, a retrospective study showed that the effect of tolvaptan on kidney function could be sustained for a long period. However, the long-term efficacy and safety of high-dose tolvaptan (120 mg/day) in individual cases remain unknown. We report here 2 Japanese ADPKD patients (males, 36 and 29 years old) treated with tolvaptan (120 mg/day) for 9 years, during which time determinations of estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were performed. In these 2 patients, eGFR prior to therapy was 57.3 and 76.3 mL/min/1.73 m2, respectively, and 30.2 and 43.5 mL/min/1.73 m2, respectively, after 9 years of tolvaptan treatment, for a relatively constant annual decline of -3.01 and -3.64 mL/min/1.73 m2, respectively. As compared to the predicted (calculated) eGFR without tolvaptan treatment, eGFR actually measured was higher by 15.3 and 12.6 mL/min/1.73 m2, respectively, after the 9-year therapy period. In addition, the rate of TKV increase was gradual, 2.4 and 4.7%, respectively, per year during the initial 3-year period, to 6.5 and 12.5%, respectively, per year in the following 6-year period. During the 9 years of treatment, neither patient showed tolvaptan-related adverse events. Our findings suggest that long-term administration of tolvaptan at a high dose is both safe and effective to preserve kidney function, though a gradual increase in TKV was seen in both of the present cases, particularly during the later phase.

Oncostatin M induces C2C12 myotube atrophy by modulating muscle differentiation and degradation.

Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays a role in various disorders such as cancer and inflammatory diseases, which are often accompanied by skeletal muscle atrophy, or sarcopenia. However, the role of OSM in the regulation of skeletal muscle mass remains to be identified. In this study, we investigated the effect of OSM on C2C12 myotube formation in vitro. C2C12 myoblasts were induced to differentiate into myotubes for 3 days and then treated with OSM for 24 or 48 h. The diameter of differentiated C2C12 myotubes were reduced by 18.7% and 23.3% compared to control cells after treatment with OSM for 24 and 48 h, respectively. The expression levels of MyoD and myogenin were decreased, while those of atrogin-1, CCAAT/enhancer binding protein δ, and OSM receptor were increased in C2C12 myotubes treated with OSM for 24 h compared to control cells. Furthermore, the inhibitory effect of OSM on myotube formation was significantly attenuated by pretreatment with an inhibitor of signal transducer and activator of transcription (STAT) 3 or by knockdown of Stat3. Finally, the OSM-induced changes in the expression levels of MyoD, myogenin, and atrogin-1 were reversed by pretreatment with an inhibitor of STAT3 or by Stat3 knockdown in C2C12 myotubes. In conclusion, OSM induces C2C12 myotube atrophy by inhibiting myogenic differentiation and activating muscle degradation in a STAT3-dependent manner.