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BackgroundKnowledge regarding the association between dietary sodium intake and the incidence of masked hypertension is limited.MethodsA total of 193 Japanese type 2 diabetic outpatients who had been treated with antihypertensive agents and with office blood pressures <140/90 mm Hg were recruited. Masked hypertension was defined as having office blood pressure <140/90 mm Hg and 24-h mean ambulatory blood pressure ≥130/80 mm Hg. The dietary sodium intake was estimated by measuring the 24-h urinary sodium excretion.ResultsMasked hypertension was found in 128 (66.3%) patients. An age- and sex-adjusted univariate logistic regression analysis showed that urinary albumin excretion, renin-angiotensin system inhibitor use, office systolic blood pressure, and amount of dietary sodium intake were significantly associated with masked hypertension. A multivariate logistic regression analysis also identified an older age, renin-angiotensin system inhibitor use, an office elevated systolic blood pressure, and high dietary sodium intake to be independently associated with masked hypertension. When compared with those who consumed a low salt diet (sodium <120 mEq/day), the odds ratio for the risk of exhibiting masked hypertension in patients who consumed a medium salt diet (sodium 120 to <200 mEq/day) or a high salt diet (sodium ≥200 mEq/day) were 5.3 (P < 0.001) and 12.6 (P < 0.001), respectively.ConclusionsMasked hypertension is a common feature in type 2 diabetic patients being treated for hypertension. The observed association with sodium intake raised the hypothesis that excessive sodium intake may play a part in the genesis of masked hypertension in these patients.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.102 [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPAR&agr;, &dgr; and &ggr;. It has been demonstrated that PPAR&agr; and &ggr; agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPAR&dgr; agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPAR&dgr; agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(2). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNF&agr;. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNF&agr; is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNF&agr;- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-&bgr; activated kinase 1 (TAK1)-NFkB pathway, a common downstream signaling pathway to TNF&agr; receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Genetic factors have been considered to contribute to the development and progression of diabetic nephropathy. The KCNQ1 gene (potassium voltage-gated channel, KQT-like subfamily, member 1) was originally identified as a strong susceptibility gene for type 2 diabetes in two Japanese genome-wide association studies. In this study, we examined the association of single nucleotide polymorphisms (SNPs) within KCNQ1 with diabetic nephropathy in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS -- We genotyped 33 SNPs in KCNQ1 using 754 type 2 diabetic patients with overt nephropathy and 558 control subjects (an initial study), and we further examined the association of a candidate SNP using three other independent Japanese populations (replications 1-3). RESULTS -- We found that five SNPs were nominally associated with diabetic nephropathy, and the association of rs2237897 was the strongest. We also found that the T allele frequencies of rs2237897 were consistently higher in the nephropathy groups than in the control groups for all study populations (initial study: 0.33 vs. 0.27; replication 1:0.32 vs. 0.30; replication 2:0.33 vs. 0.28; and replication 3:0.32 vs. 0.28), although the individual associations did not reach statistically significant levels. Combined analysis by a meta-analysis revealed that the T allele of rs2237897 was significantly associated with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes (odds ratio 1.22 [95% CI 1.10-1.34], P = 3.1 x 10[sup -4], corrected P = 0.01). CONCLUSIONS -- These results suggest that KCNQ1 is a new candidate gene for conferring susceptibility to diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The renoprotective effects of asialoerythropoietin on acute kidney injury may be mediated through the induction of bcl-2 and BMP-7. Suppression of bcl-2 and BMP-7 could explain the acceleration of renal damage after ischemia-reperfusion injury in the diabetic kidney. Aim: Diabetic patients are at higher risk of failure to recover after acute kidney injury, however, the mechanism and therapeutic strategies remain unclear. Erythropoietin is cytoprotective in a variety of non-haematopoietic cells. The aim of the present study was to clarify the mechanism of diabetes-related acceleration of renal damage after ischaemia–reperfusion injury and to examine the therapeutic potential of asialoerythropoietin, a non-haematopoietic erythropoietin derivative, against ischaemia–reperfusion-induced acute kidney injury in diabetic mice. Methods: C57BL/6J mice with and without streptozotocin-induced diabetes were subjected to 30 min unilateral renal ischaemia–reperfusion injury at 1 week after induction of diabetes. They were divided into four group: (i) non-diabetic plus ischaemia–reperfusion injury; (ii) non-diabetic plus ischaemia–reperfusion injury plus asialoerythropoietin (3000 IU/kg bodyweight); (iii) diabetic plus ischaemia–reperfusion injury; and (iv) diabetic plus ischemia–reperfusion injury plus asialoerythropoietin. Experiments were conducted at the indicated time periods after ischaemia–reperfusion injury. Results: Ischaemia–reperfusion injury of diabetic kidney resulted in significantly low protein expression levels of bcl-2, an anti-apoptotic molecule, and bone morphogenetic protein-7 (BMP-7), an anti-fibrotic and pro-regenerative factor, compared with non-diabetic kidneys. Diabetic kidney subsequently showed severe damage including increased tubular cell apoptosis, tubulointerstitial fibrosis and decreased tubular proliferation, compared with non-diabetic kidney. Treatment with asialoerythropoietin induced bcl-2 and BMP-7 expression in diabetic kidney and decreased tubular cell apoptosis, tubulointerstitial fibrosis and accelerated tubular proliferation. Conclusion: Reduced induction bcl-2 and BMP-7 may play a role in the acceleration of renal damage after ischaemia–reperfusion injury in diabetic kidney. The renoprotective effects of asialoerythropoietin on acute kidney injury may be mediated through the induction of bcl-2 and BMP-7. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Albuminuria in type 2 diabetic patients is a risk factor for cardiovascular disease. We investigated the correlation between albuminuria and spontaneous microaggregation of platelets (SMAP) formed under shear stress. RESEARCH DESIGN AND METHODS -- The study subjects were 401 type 2 diabetic individuals (252 with normoalbuminuria and 149 with albuminuria) who were examined for SMAP under conditions of shear stress only (no agonist stimulation) and the reversibility of platelet microaggregation after stimulation with 1 µmol/l ADP, measured by a laser light-cattering method. Active glycoprotein IIb/IIIa (GPIIb/IIIa) and P-selectin expression levels on platelets as an index of platelet activation were measured by whole-blood flow cytometry. RESULTS -- SMAP formation was noted in 53% of diabetic patients. All patients with SMAP showed an irreversible pattern of platelet microaggregates by a low dose of ADP. SMAP was observed in 75% of diabetic subjects with albuminuria and in 39% of those with normoalbuminuria. Multivariate logistic regression analysis identified urinary albumin excretion rate and brachial-ankle pulse-wave velocity as independent factors associated with SMAP. The degree of SMAP correlated with active GPIIb/IIIa (γ = 0.59, P < 0.001) and P-selectin (γ = 0.55, P < 0.001) expression levels. These early-activated platelet profiles were significantly inhibited in albuminuric patients with aspirin intake, although the effect was incomplete. CONCLUSIONS -- Our study demonstrated an independent association between albuminuria and early changes in activated platelet profiles of type 2 diabetic patients. Further follow-up and intervention studies are needed to establish whether the inhibition of SMAP affects the course of cardiovascular disease in type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

The inhibition of the renin-angiotensin system in the diabetic condition was reported to enhance the sodium sensitivity of blood pressure. In patients with sodium-sensitive hypertension, high sodium intake reduces the nocturnal fall in blood pressure. Therefore, we examined the effects of the amount of sodium intake or diuretics in patients with diabetes treated with an angiotensin receptor blocker. We recruited 32 Japanese type 2 diabetic patients with base line blood pressure ≥130/80 mmHg and treated with valsartan (80 mg daily). At baseline, 24-h ambulatory blood pressure and 24-h urinary excretion of sodium were measured. The patients were then randomly assigned to take either combination therapy with 50 mg of losartan plus 12.5 mg of hydrochlorothiazide or monotherapy with 160 mg of valsartan for 24 weeks. At baseline, 22 of 32 (69%) patients were classified as non-dippers, and the night/day ratio of mean arterial pressure was significantly correlated with 24-h urinary sodium excretion. The combination therapy resulted in a significantly higher fall than the monotherapy in 24-h mean, daytime, night-time and morning blood pressures. The night/day ratio of mean arterial pressure was significantly reduced from the baseline at the end of the study in the combination therapy group, but not in the monotherapy group. In non-dipper patients, the diminished nocturnal fall in blood pressure was restored by the combination therapy. Excessive intake of salt causes non-dipping and diuretics restored nocturnal BP fall in type 2 diabetic patients treated with angiotensin 2 receptor blockers. [ABSTRACT FROM AUTHOR]

Metabolic syndrome has been reported to be associated with chronic kidney disease, but the mechanisms remain unclear. Although feeding of a high-fat diet (HFD) to C57BL/6 mice is reported to induce systemic metabolic abnormalities and subsequent renal injuries, such as albuminuria, similar to human metabolic syndrome, alterations in HFD-induced renal injuries have not been fully elucidated in detail. We therefore investigated the structural and functional changes in the kidneys of C57BL/6 mice on a HFD. Six-week-old mice were fed a low-fat diet (LFD; 10% of total calories from fat) or a HFD (60% fat) for 12 wk. Mice fed a HFD showed significant increases in body weight, systolic blood pressure, plasma insulin, glucose, and triglycerides compared with those on a LFD. Accompanying these systemic changes, mice on a HFD showed albuminuna, an increase in glomerular tuft area, and mesangial expansion. These systemic and renal alterations in mice on a HFD were prevented by body weight control with the dietary restriction of feeding a HFD. Furthermore, mice on a HFD showed renal pathophysiological alterations including renal lipid accumulation, an increased accumulation of type IV collagen in glomeruli, an increase in macrophage infiltration in the renal medulla, an increase in urinary 8-hydroxy-2'-deoxyguanosine excretion, and impaired sodium handling. In conclusion, this study suggests that local metabolic alterations in the kidney play important roles in the development of renal injury associated with metabolic syndrome in addition to systemic metabolic changes and an increase in body weight. [ABSTRACT FROM AUTHOR]

Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin δ ( NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3′ UTR of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27–1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic mRNA corresponding to the disease susceptible haplotype (exon 4 +1340 G, +1307 G, +999 A) was degraded faster than mRNA corresponding to the major haplotype (exon 4 +1340 A, +1307 A, +999 T), and allelic mRNA expression of the disease susceptibility allele was significantly lower than that of the major allele in normal kidney tissues. In an experiment using a short interfering RNA targeting NCALD, we found that silencing of the NCALD led to a considerable enhancement of cell migration, accompanied by a significant reduction in E-cadherin expression, and by an elevation of α smooth muscle actin expression in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07–3.42). These results suggest that the NCALD gene is a likely candidate for conferring susceptibility to diabetic nephropathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study. RESEARCH DESIGN AND METHODS--We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction <50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated. RESULTS--Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI 0.15-0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred. CONCLUSIONS--The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction. Diabetes 56:1727-1730, 2007 [ABSTRACT FROM AUTHOR]

To elucidate the role of the renin–angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the genes that encode angiotensin-converting enzyme ( ACE), angiotensinogen ( AGT) and angiotensin II receptor type 1 ( AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy ( P<0.05), including five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron ( P=0.01, odds ratio =1.34, 95% CI 1.07–1.69). Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59–0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allele in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value =0.00005). We concluded that RAS gene polymorphisms may contribute to the susceptibility to diabetic nephropathy in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: We investigated the contribution of PKC-beta gene (PRKCB1) polymorphisms to diabetic kidney disease in a prospective observational follow-up study.Research Design and Methods: A total of 364 Japanese subjects with type 2 diabetes without overt proteinuria were enrolled during 1996-1998 and followed until 2004. Five single nucleotide polymorphisms (-1504C/T, -546C/G, -348A/G, -278C/T, and -238C/G) in the promoter region of PRKCB1 were genotyped. The end points were transition from stage to stage of diabetic nephropathy as a time-to-event outcome and the annual decline rate of estimated glomerular filtration rate (eGFR) as a slope-based outcome.Results: During the study (median 6 years), 34 of 364 subjects (9.3%) progressed. Kaplan-Meier estimation revealed that subjects with both T allele at -1054 C/T and G allele at -546 C/G polymorphisms frequently showed transition to advanced stages of diabetic nephropathy (P = 0.015). The annual change rate in eGFR in the subjects with both alleles was also significantly higher than in others (-2.96 +/- 0.62 vs. -1.63 +/- 0.15 ml/min per 1.73 m(2)/year, P = 0.02). The estimated frequency of this risk T-G haplotype was significantly higher in the progressors who showed transition to advanced nephropathy stages (12%) than in the nonprogressors (5%) (odds ratio 2.3 [95% CI 1.0-5.2]), and it was also higher in those with accelerated decline of the Delta eGFR (> or =3 ml/min per 1.73 m(2)/year) than in those without (2.1 [1.1-3.9]).Conclusions: Our study indicates that PRKCB1 is a predictor for worsening of kidney disease in Japanese subjects with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Oxidative stress is implicated to play an important role in the development of diabetic vascular complications, including diabetic nephropathy. It is unclear whether oxidative stress is primarily enhanced in the diabetic glomeruli or whether it is merely a consequence of diabetes-induced glomerular injury. To address this issue, we examined diabetic glomeruli to determine whether oxidative stress is enhanced, as well as examined the role of protein kinase C (PKC)-β activation in modulating NADPH oxidase activity. Urinary 8-hydroxydeoxyguanosine excretion and its intense immune-reactive staining in the glomeruli were markedly higher in diabetic than in control rats, and these alterations were ameliorated by a treatment with a selective PKC-β inhibitor, ruboxistaurin (RBX; LY333531) mesylate, without affecting glycemia. NADPH oxidase activity, which was significantly enhanced in diabetic glomeruli and the source of reactive oxygen species (ROS) generation, was also improved by RBX treatment by preventing the membranous translocation of p47phox and p67phox from cytoplasmic fraction without affecting their protein levels. Adenoviral-mediated PKC-β[sub 2] overexpression enhanced ROS generation by modulating the membranous translocation of p47phox and p67phox in cultured mesangial cells. We now demonstrate that oxidative stress is primarily enhanced in the diabetic glomeruli due to a PKC-β-dependent activation of NADPH oxidase resulting in ROS generation. [ABSTRACT FROM AUTHOR]

SGLT2 inhibitors offer strong renoprotection in subjects with diabetic kidney disease (DKD). But the mechanism for such protection is not clear. Here, we report that in damaged proximal tubules of high-fat diet-fed ApoE-knockout mice, a model of non-proteinuric DKD, ATP production shifted from lipolysis to ketolysis dependent due to hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). We further found that empagliflozin raised endogenous ketone body (KB) levels, and thus its use or treatment with 1,3-butanediol, a KB precursor, prevented decreases in renal ATP levels and organ damage in the mice. The renoprotective effect of empagliflozin was abolished by gene deletion of Hmgcs2, a rate-limiting enzyme of ketogenesis. Furthermore, KBs attenuated mTORC1-associated podocyte damage and proteinuria in diabetic db / db mice. Our findings show that SGLT2 inhibition-associated renoprotection is mediated by an elevation of KBs that in turn corrects mTORC1 hyperactivation that occurs in non-proteinuric and proteinuric DKD. • Energy metabolism shifts from lipolysis to ketolysis in damaged kidneys • mTORC1 hyperactivation leads to impaired renal lipolysis and subsequent renal damage • Ketone body supplementation ameliorates renal damage by blocking mTORC1 signaling • SGLT2 inhibitor-mediated renoprotection involves mTORC1 inhibition by ketone bodies SGLT2 inhibitors have been shown to offer potent renoprotection against diabetic kidney disease. But the mechanism for this effect has been unclear. Here, Tomita et al. report that the drugs promote elevation of ketone bodies, which subsequently inhibit mTORC1 in the proximal renal tubules, explaining their protective effects on this organ. [ABSTRACT FROM AUTHOR]

Abstract We carried out impact experiments using cylindrical gypsum targets with various radii and investigated the crater on the top (flat) surface. At a ratio of projectile and target radii ∼1/20, the crater size abruptly increases; the spallation extends to the side surface of the targets. The results are closely similar to the previous ones on the curved surfaces. A shock wave propagation model, introduced by Suzuki et al. (2018, Icarus 301, 1–8), can represent such results as the steep increase of the size of the spallation zone in both cases of spherical and cylindrical targets. Using this model, the maximum fragment size is evaluated and agrees well with the experimental results. We found that the enlargement of the spallation zone is crucial to the transition from cratering to catastrophic disruption. We also carried out numerical calculations with iSALE code capable of simulating impact processes in solid materials. The maximum pressure distribution shows that the most parts of the spallation zone are not metamorphosed by shock waves. Also, the crater depth is represented by iSALE without damage models, while the "spallation" seems not to be well reproduced by iSALE even with the damage models. Highlights • We carried out impact experiments using cylindrical gypsum targets and investigated the crater on the top (flat) surface. • At a ratio of projectile and target radii ~1/20, the spallation extends to the side surface of the targets. • The enlargement of spallation zone is represented by a simple shock propagation model. • The enlargement of spallation zone is crucial to the transition from cratering to catastrophic disruption. • iSALE represents crater depth but seems not to reproduce spallation. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease develop vascular calcification, owing to impaired calcium and phosphate metabolism. The prevention of vascular calcification is important to improve the prognosis of such patients. In this study, we investigated whether treatment with FYB-931, a novel bisphosphonate compound, prevents vascular calcification in rat aortic rings cultured in high-phosphate medium for 9 days, assessed by measurement of the calcium content and the degree of calcium deposition, visualized using von Kossa staining. The effect on the transformation of calciprotein particles (CPPs) from primary to secondary CPPs was assessed using a fluorescent probe-based flow cytometric assay. FYB-931 dose-dependently prevented high phosphate-induced aortic calcification, but failed to rapidly cause the regression of high phosphate-induced vascular calcification once it had developed. Furthermore, the treatment dose-dependently inhibited the high phosphate-induced transformation from primary to secondary CPPs. In addition, the treatment with FYB-931 prevented the transformation from primary to secondary CPPs in vitamin D3-treated rats as a model of ectopic calcification, consistent with the results from rat aortic rings. In conclusion, treatment with FYB-931 prevents high phosphate-induced rat aortic vascular calcification by altering the dynamics of CPP transformation. This finding suggests that inhibition of the transformation from primary to secondary CPPs is an important target for the prevention of vascular calcification in patients with chronic kidney disease. [ABSTRACT FROM AUTHOR]

Abstract: Diabetic nephropathy in type 2 diabetes is a leading cause of end-stage renal disease worldwide. Its early clinical sign is microalbuminuria, which is not only a predictor for progression of nephropathy but also an independent risk factor for cardiovascular disease. A few decades ago, diabetic nephropathy was believed to be progressive and irreversible. Thus, the main therapeutic objective for type 2 diabetic patients with microalbuminuria was to prevent progression to overt proteinuria. However, there is now growing evidence regarding remission/regression of diabetic nephropathy. In recent clinical trials using the renin-angiotensin system blockade drugs, a reduction in microalbuminuria by the use of these drugs has been noted. We also reported that a reduction in microalbuminuria was more frequent than progression to overt proteinuria and that multifactorial control approach was important to the reduction of microalbuminuria. These results for type 2 diabetes are similar to those previously reported for type 1 diabetes. Furthermore, our recent study showed that the 8-year cumulative incidence rate of renal and cardiovascular events was significantly lower in patients with remission than in those without it. The annual decline rate of estimated glomerular filtration rate in patients with remission was also significantly slower. These studies provide clinical evidence implying that the reduction of microalbuminuria in type 2 diabetic patients occurs frequently and brings about renal and cardiovascular risk reduction. Reducing microalbuminuria is therefore considered to be an important therapeutic objective and may be a biomeasure of therapeutic success in type 2 diabetic patients. [Copyright &y& Elsevier]

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown in clinical trials to increase serum Mg2+ levels in patients with type 2 diabetes mellitus. However, it is unclear whether this effect is similarly observed in patients with chronic kidney disease (CKD) and whether such an increase is observed immediately after treatment.Our retrospective observational study included the 62 patients with CKD who started SGLT2 inhibitor therapy at our institution between 2017 and 2022 and who had complete data on serum Mg2+ measurements at baseline and at 1, 3, and 6 months after treatment. Patients were divided into three subgroups, stratified by serum Mg2+ levels at baseline. We evaluated the changes in serum Mg2+ levels from baseline to 6 months after treatment and the factors associated with these changes.Median eGFR and mean serum Mg2+ at baseline were 33.5 mL/min/1.73 m2 and 2.03 mg/dL, respectively. Treatment with SGLT2 inhibitors significantly increased serum Mg2+ levels immediately from 1 month after treatment compared with those at baseline and persisted over 6 months, with an overall mean change of 0.13 mg/dL from baseline to 6 months. This increased effect was observed in the low and middle tertile subgroups, but not in the high tertile subgroup. Multivariate linear regression analysis revealed that baseline serum Mg2+ levels and sodium-chloride differences, as a parameter of acid–base status, were independently associated with these changes.SGLT2 inhibitors increased serum Mg2+ levels in patients with CKD, particularly those with lower baseline Mg2+ levels, potentially improving their prognosis.Methods: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown in clinical trials to increase serum Mg2+ levels in patients with type 2 diabetes mellitus. However, it is unclear whether this effect is similarly observed in patients with chronic kidney disease (CKD) and whether such an increase is observed immediately after treatment.Our retrospective observational study included the 62 patients with CKD who started SGLT2 inhibitor therapy at our institution between 2017 and 2022 and who had complete data on serum Mg2+ measurements at baseline and at 1, 3, and 6 months after treatment. Patients were divided into three subgroups, stratified by serum Mg2+ levels at baseline. We evaluated the changes in serum Mg2+ levels from baseline to 6 months after treatment and the factors associated with these changes.Median eGFR and mean serum Mg2+ at baseline were 33.5 mL/min/1.73 m2 and 2.03 mg/dL, respectively. Treatment with SGLT2 inhibitors significantly increased serum Mg2+ levels immediately from 1 month after treatment compared with those at baseline and persisted over 6 months, with an overall mean change of 0.13 mg/dL from baseline to 6 months. This increased effect was observed in the low and middle tertile subgroups, but not in the high tertile subgroup. Multivariate linear regression analysis revealed that baseline serum Mg2+ levels and sodium-chloride differences, as a parameter of acid–base status, were independently associated with these changes.SGLT2 inhibitors increased serum Mg2+ levels in patients with CKD, particularly those with lower baseline Mg2+ levels, potentially improving their prognosis.Results: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown in clinical trials to increase serum Mg2+ levels in patients with type 2 diabetes mellitus. However, it is unclear whether this effect is similarly observed in patients with chronic kidney disease (CKD) and whether such an increase is observed immediately after treatment.Our retrospective observational study included the 62 patients with CKD who started SGLT2 inhibitor therapy at our institution between 2017 and 2022 and who had complete data on serum Mg2+ measurements at baseline and at 1, 3, and 6 months after treatment. Patients were divided into three subgroups, stratified by serum Mg2+ levels at baseline. We evaluated the changes in serum Mg2+ levels from baseline to 6 months after treatment and the factors associated with these changes.Median eGFR and mean serum Mg2+ at baseline were 33.5 mL/min/1.73 m2 and 2.03 mg/dL, respectively. Treatment with SGLT2 inhibitors significantly increased serum Mg2+ levels immediately from 1 month after treatment compared with those at baseline and persisted over 6 months, with an overall mean change of 0.13 mg/dL from baseline to 6 months. This increased effect was observed in the low and middle tertile subgroups, but not in the high tertile subgroup. Multivariate linear regression analysis revealed that baseline serum Mg2+ levels and sodium-chloride differences, as a parameter of acid–base status, were independently associated with these changes.SGLT2 inhibitors increased serum Mg2+ levels in patients with CKD, particularly those with lower baseline Mg2+ levels, potentially improving their prognosis.Conclusions: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown in clinical trials to increase serum Mg2+ levels in patients with type 2 diabetes mellitus. However, it is unclear whether this effect is similarly observed in patients with chronic kidney disease (CKD) and whether such an increase is observed immediately after treatment.Our retrospective observational study included the 62 patients with CKD who started SGLT2 inhibitor therapy at our institution between 2017 and 2022 and who had complete data on serum Mg2+ measurements at baseline and at 1, 3, and 6 months after treatment. Patients were divided into three subgroups, stratified by serum Mg2+ levels at baseline. We evaluated the changes in serum Mg2+ levels from baseline to 6 months after treatment and the factors associated with these changes.Median eGFR and mean serum Mg2+ at baseline were 33.5 mL/min/1.73 m2 and 2.03 mg/dL, respectively. Treatment with SGLT2 inhibitors significantly increased serum Mg2+ levels immediately from 1 month after treatment compared with those at baseline and persisted over 6 months, with an overall mean change of 0.13 mg/dL from baseline to 6 months. This increased effect was observed in the low and middle tertile subgroups, but not in the high tertile subgroup. Multivariate linear regression analysis revealed that baseline serum Mg2+ levels and sodium-chloride differences, as a parameter of acid–base status, were independently associated with these changes.SGLT2 inhibitors increased serum Mg2+ levels in patients with CKD, particularly those with lower baseline Mg2+ levels, potentially improving their prognosis. [ABSTRACT FROM AUTHOR]

Background: Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy. Methods: We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran-Armitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association. Results: We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy ( P < 0.05), and subsequent haplotype analysis revealed that a haplotype consisting of the 11 SNPs within SIRT1 locus had a stronger association ( P = 0.0028). Conclusion: These results indicate that SIRT1 may play a role in susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. [ABSTRACT FROM AUTHOR]

To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5−/−) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5−/− mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5−/− mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5−/− mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy. • Diabetes causes functional and structural glomerular endothelial damage. • Autophagy protects podocytes against structural glomerular endothelial damage. • Enhanced ER stress is involved in autophagy deficiency-mediated podocyte damage. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the safety, effectiveness, and health-related QOL impact of early rehabilitation in patients with nephrotic syndrome. Methods: Subjects consisted of 23 patients with nephrotic syndrome who had previously received steroid treatment. Patients worked performed quadriceps resistance training and aerobic training 5 days per week for 5 weeks. Urinary protein, albumin (Alb), creatinine (Cre), and blood urea nitrogen (BUN) were monitored once every week over a 5-week period based on medical records. The 36-item short form health survey (SF-36) score was used to evaluate health-related QOL. Results: There was no significant difference in quadriceps force and no significant effect of age as shown by ANCOVA. Anaerobic threshold (AT) and peak oxygen consumption (peak VO2) both increased significantly. AT was affected by the degree of change in body weight according to ANCOVA. Cre and BUN were not significantly altered. Urinary protein showed a significant decrease and Alb was significantly increased. Only physical function (PF) in the SF-36 showed a significant improvement following the intervention. Conclusion: Our data indicate that early rehabilitation involving quadriceps resistance training and aerobic training for nephrotic syndrome is safe and effective. [ABSTRACT FROM AUTHOR]

• Glycemic control was poor in young patients, especially among insulin users. • Dipeptidyl peptidase-4 inhibitors were commonly used in the older patients. • Biguanides are widely prescribed to the younger patients. • Sulfonylurea and insulin use decreased over time, but were used more in older patients. This study aimed to evaluate changes in glycemic control and diabetes treatment by age group in Japanese patients with type 2 diabetes. The study included the results of approximately 40,000 patients/year using cross-sectional and retrospective analyses from 2012 to 2019. There was little change in the glycemic control status in all age groups during the study period. However, by age group, patients aged ≤ 44 years continued to have the highest glycated hemoglobinA1c (HbA1c) values during the study period (7.4 % ± 1.7 % in 2012 and 7.4 % ± 1.5 % in 2019), especially in insulin-treated patients (8.3 % ± 1.9 % in 2012 and 8.4 % ± 1.8 % in 2019). Biguanides and dipeptidyl peptidase-4 inhibitors were widely prescribed. Sulfonylurea and insulin use showed a decreasing trend, but older patients had a higher percentage of prescriptions. Sodium glucose transporter 2 inhibitors were prescribed rapidly, especially in younger patients. There were no obvious changes in glycemic control over time in the study period. The mean HbA1c level was higher in younger patients, which suggested that improvement is required. In older patients, there was a trend toward greater emphasis on management to avoid hypoglycemia. Different treatment strategies based on age showed different drug choices. [ABSTRACT FROM AUTHOR]

Background: The number of patients suffering from diabetic nephropathy resulting in end-stage kidney disease is increasing worldwide. In clinical settings, there are limited data regarding the impact of the urinary albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR) on renal and cardiovascular outcomes and all-cause mortality. Methods: We performed a historical cohort study of 4328 Japanese participants with type 2 diabetes from 10 centers. Risks for renal events (requirement for dialysis or transplantation, or half reduction in eGFR), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), and all-cause mortality were assessed according to UACR and eGFR levels. Results: During follow-up (median 7.0 years, interquartile range 3.0-8.0 years), 419 renal events, 605 cardiovascular events and 236 deaths occurred. The UACR levels increased the risk and the adjusted hazard ratios for these three events. In addition to the effects of UACR levels, eGFR stages significantly increased the adjusted hazard ratios for renal events and all-cause mortality, especially in patients with macroalbuminuria. Diabetic nephropathy score, based on the prognostic factors, well predicted incidence rates per 1000 patient/year for each event. Conclusions: Increased UACR levels were closely related to the increase in risks for renal, cardiovascular events and all-cause mortality in Japanese patients with type 2 diabetes, whereas the association between high levels of UACR and reduced eGFR was a strong predictor for renal events. [ABSTRACT FROM AUTHOR]

Aims/Introduction In Japan, liraglutide was recently approved for patients with type 2 diabetes. To our knowledge, there are no markers predicting successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes and renal impairment. We therefore assessed clinical characteristics predicting successful switching. Materials and Methods We analyzed 21 patients with type 2 diabetes and estimated glomerular filtration rates <60 mL/min/1.73 m2 receiving long-term insulin in Shiga University of Medical Science Hospital, Otsu, Shiga, Japan. Their β-cell function was assessed by measuring urinary C-peptide and C-peptide immunoreactivity ( CPR) index, along with glucagon loading and oral glucose tolerance tests. Blood glucose concentration and blood pressure were measured daily before and after switching from insulin to liraglutide, and glycated hemoglobin ( Hb A1c; National Glycohemoglobin Standardization Program) was assessed 12 weeks after switching to liraglutide. Results Baseline Hb A1c was significantly lower in successfully switched than in unsuccessfully switched patients. CPR index, urinary C-peptide concentration and 6-min post-glucagon increment in CPR (Δ CPR) did not differ significantly in the two groups. Δ CPR 120 min after 75 g oral glucose was significantly higher in successfully than unsuccessfully switched patients. Mean blood glucose concentrations before breakfast, after breakfast, before lunch and after dinner were significantly lower in successfully switched patients. Hb A1c did not change significantly in either group. Conclusions Measurement of oral glucose-stimulated Δ CPR120 min is recommended when considering switching Japanese type 2 diabetes patients with renal impairment from insulin to liraglutide monotherapy. [ABSTRACT FROM AUTHOR]

Background: Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy. Methods: Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations. Results: The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR. Conclusions: Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases. [ABSTRACT FROM AUTHOR]

Identifying the mechanisms that underlie progression from endothelial damage to podocyte damage, which leads to massive proteinuria, is an urgent issue that must be clarified to improve renal outcome in diabetic kidney disease (DKD). We aimed to examine the role of dynamin-related protein 1 (Drp1)-mediated regulation of mitochondrial fission in podocytes in the pathogenesis of massive proteinuria in DKD. Diabetes- or albuminuria-associated changes in mitochondrial morphology in podocytes were examined by electron microscopy. The effects of albumin and other diabetes-related stimuli, including high glucose (HG), on mitochondrial morphology were examined in cultured podocytes. The role of Drp1 in podocyte damage was examined using diabetic podocyte-specific Drp1-deficient mice treated with neuraminidase, which removes endothelial glycocalyx. Neuraminidase-induced removal of glomerular endothelial glycocalyx in nondiabetic mice led to microalbuminuria without podocyte damage, accompanied by reduced Drp1 expression and mitochondrial elongation in podocytes. In contrast, streptozotocin-induced diabetes significantly exacerbated neuraminidase-induced podocyte damage and albuminuria, and was accompanied by increased Drp1 expression and enhanced mitochondrial fission in podocytes. Cell culture experiments showed that albumin stimulation decreased Drp1 expression and elongated mitochondria, although HG inhibited albumin-associated changes in mitochondrial dynamics, resulting in apoptosis. Podocyte-specific Drp1-deficiency in mice prevented diabetes-related exacerbation of podocyte damage and neuraminidase-induced development of albuminuria. Endothelial dysfunction-induced albumin exposure is cytotoxic to podocytes. Inhibition of mitochondrial fission in podocytes is a cytoprotective mechanism against albumin stimulation, which is impaired under diabetic condition. Inhibition of mitochondrial fission in podocytes may represent a new therapeutic strategy for massive proteinuria in DKD. [Display omitted] • Endothelial damage-related albuminuria elongates mitochondria in podocytes. • High glucose inhibits the cytoprotective response of mitochondrial elongation. • Drp1 deficiency prevents albumin-induced podocyte damage in diabetes • Inhibition of Drp1 function may be a novel therapy for proteinuria in diabetes. [ABSTRACT FROM AUTHOR]

Anti-diabetic agent-related hypoglycemia is a serious complication in type 2 diabetic patients on hemodialysis. Therefore, we assessed the efficacy and tolerability of 24 weeks of monotherapy with vildagliptin, a dipeptidyl peptidase four inhibitor, which is a new class of antidiabetic agent. This open-label, single-arm clinical trial was performed on 26 patients on hemodialysis. The primary assessments were changes in postprandial glucose level and glycated albumin (GA). During the study, three patients dropped out, and data from 23 patients were analyzed. Significant reductions were seen in postprandial glucose (−2.60 ± 3.80 mmol/L, P < 0.001) and GA (−2.59 ± 2.33%, P < 0.001) levels. No serious drug-related adverse events were observed. Vildagliptin monotherapy can be recommended for glycemic control in type 2 diabetic patients on hemodialysis. This trial was registered with the University Hospital Medical Information Network (no. UMIN000003661). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00169.x, 2011) [ABSTRACT FROM AUTHOR]

Background: Interleukin-18 (IL-18), a pro-inflammatory cytokine, is a predictor of cardiovascular and renal disease in diabetic patients. Postprandial hyperglycemia is one of the important factors contributing to an increase in the circulating pro-inflammatory cytokine levels. This study investigated the effect of miglitol, an α-glucosidase inhibitor, on postprandial hyperglycemia and IL-18 levels in diabetic patients with nephropathy. Methods: Fifteen Japanese diabetic patients with persistent proteinuria and preserved renal function were recruited. The patients received 50 mg miglitol thrice daily after the baseline examinations and were followed up for 12 weeks. A meal tolerance test was performed on eight patients at baseline and week 12. The fasting miglitol concentration was measured in seven patients just before the meal tolerance test. Results: There were no changes in the body weight, blood pressure, liver and renal function, and proteinuria from baseline to week 12. However, the levels of glycated hemoglobin and interleukin 18 significantly decreased from baseline to week 12. During the meal tolerance test, plasma glucose was significantly decreased 60 min after treatment with miglitol, whereas the serum concentration of insulin was not changed. Fasting and postprandial levels of IL-18 were significantly decreased from baseline to week 12. Serum miglitol concentrations showed a significantly negative correlation with eGFR ( r = −0.82, p = 0.02). However, the serum miglitol concentrations did not changed during the course of this study. Conclusion: Miglitol improved postprandial hyperglycemia and reduced serum IL-18 levels in patients with stage 3 diabetic nephropathy. Miglitol may therefore prevent atherosclerotic diseases and diabetic micro-vascular complications through decreasing glucose swings and/or the circulating IL-18 level. [ABSTRACT FROM AUTHOR]

Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress-induced apoptosis of renal glomerular cells is an important factor for the development of various kidney diseases. Identification of molecules that modulate this process could lead to the development of new strategies for preventing kidney diseases. In this study, we evaluated whether mammalian silent information regulator 2 (SIRT1), which has been recently identified as a cell survival factor countering various stressors, is a key regulator of oxidative stress-induced mesangial cell apoptosis. Morphological features of apoptotic cell death (nuclear condensation) and the expression of biochemical proapoptotic markers [cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP)] were assessed in murine mesangial cells (MMCs) exposed to hydrogen peroxide (H2O2). H2O2 increased mesangial cell apoptosis, predominantly through p53 activation by acetylation, which is a posttranscriptional modification for p53 activation. H2O2-induced apoptosis was significantly attenuated in SIRT1-overexpressing MMCs, but enhanced in SIRT1-knockdown MMCs. Although SIRT1 did not affect H2O2-mediated phosphorylation of mitogen-activated protein (MAP) kinase, it interacted with p53 and inhibited H2O2-mediated p53 acetylation but not phosphorylation in MMCs. Our results indicate that SIRT1 can prevent oxidative stress-induced apoptosis through p53 deacetylation in mesangial cells. Upregulation of SIRT1 may provide a new strategy for preventing kidney glomerular diseases. [Copyright &y& Elsevier]

A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.

TAFRO syndrome is a rare systemic inflammatory disease. Its pathogenesis mainly involves excessive cytokine secretion and autoimmune dysfunction. Although its etiology is unclear, some viral infections have been reported to cause it. Here, we report a case of severe systemic inflammation mimicking TAFRO syndrome that arose after COVID-19. A 61-years-old woman suffered from a continuous fever, ascites, and edema after contracting COVID-19. She developed progressive thrombocytopenia, renal failure, and elevated C-reactive protein levels. She was tentatively diagnosed with multisystem inflammatory syndrome in adults (MIS-A) and received steroid pulse therapy. However, she exhibited worsening fluid retention and progressive renal failure, which are not typical of MIS-A. A bone marrow examination showed reticulin myelofibrosis and an increased number of megakaryocytes. Although a definitive diagnosis of TAFRO syndrome was not made according to current diagnostic criteria, we determined that her symptoms were clinically consistent with those of TAFRO syndrome. Combination therapy, including steroid pulse therapy, plasma exchange, rituximab, and cyclosporine, improved her symptoms. There are pathological similarities between hyperinflammation that arises after COVID-19 and TAFRO syndrome in terms of the associated cytokine storms. COVID-19 may have triggered the development of systemic inflammation mimicking TAFRO syndrome in this case., (© 2023. Japanese Society of Hematology.)

Aim: To investigate whether any reduction in all-cause mortality and cardiovascular disease morbidity was found over the decade in type 2 diabetes on real-world practice., Methods: A prospective observational study was performed by following two independent cohorts recruited in 2004 (n = 3286, Cohort 1) and 2014 (n = 3919, Cohort 2). The primary outcome was a composite of onset of cardiovascular disease and death. Cox proportional hazards analysis was used to explore any difference between Cohort 2 and Cohort 1 for the composite endpoints and cardiovascular disease after adjustment for covariates and accumulation of five risks (smoking, HbA1c, blood pressure, lipids, and albuminuria) outside target ranges., Results: During the 8-year follow-up, 391 (11.9%) and 270 (6.9%) primary outcomes, and 270 (8.2%) and 161 (4.1%) cardiovascular diseases occurred in Cohort 1 and Cohort 2, respectively. Cohort 2 (vs. Cohort 1) exhibited a significant risk reduction for composite endpoints (HR 0.73, 95% CI 0.62 to 0.86) and cardiovascular disease (HR 0.64, 95% CI 0.52 to 0.79), and similarly exhibited a significant reduction independent of the accumulation of the five risks., Conclusions: The significant reduction of Cohort 2 for cardiovascular disease independent of the baseline covariates suggests an integrated effect delivered by the recent treatment advances., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aging is a major risk factor for the leading causes of mortality, and the incidence of age-related diseases including cardiovascular disease, kidney disease and metabolic disease increases with age. NAD + is a classic coenzyme that exists in all species, and that plays a crucial role in oxidation-reduction reactions. It is also involved in the regulation of many cellular functions including inflammation, oxidative stress and differentiation. NAD + declines with aging in various organs, and the reduction in NAD + is possibly involved in the development of age-related cellular dysfunction in cardiorenal metabolic organs through the accumulation of inflammation and oxidative stress. Levels of NAD + are regulated by the balance between its synthesis and degradation. CD38 is the main NAD + -degrading enzyme, and CD38 is activated in response to inflammation with aging, which is associated with the reduction in NAD + levels. In this review, focusing on CD38, we discuss the role of CD38 in aging and the pathogenesis of age-related diseases, including cardiorenal metabolic disease.

Aims: The roles of urinary albumin, eGFRcystatin (eGFRcys), and eGFRcreatinine (eGFRcre) in the progression of coronary artery calcification (CAC) remain unclear. Therefore, the present study investigated the relationship between kidney function and CAC progression., Methods: A total of 760 Japanese men aged 40-79 years were enrolled in this population-based study. Kidney function was measured using eGFRcre, eGFRcys, and the urine albumin-to-creatinine ratio. CAC scores were calculated using the Agatston method. CAC progression was defined as an annual increase of ＞10 Agatston units (AU) among men with 0＜CAC＜100 AU at baseline, that of ＞10% among those with CAC ≥ 100 AU, and any progression for those with CAC=0 at baseline. The relative risk (RR) of CAC progression based on kidney function was assessed using a robust Poisson regression model., Results: The mean follow-up period was 4.9 years. CAC progression was detected in 45.8% of participants. Positive associations between CAC progression and albuminuria (＞30mg/g) (RR: 1.29; 1.09 to 1.53; p=0.004) and low eGFRcys (＜60ml/min/1.73m 2 ) (RR: 1.27; 1.05 to 1.53; p=0.012) remained significant after adjustments for age, the follow-up time, and computerized tomography type. Following further adjustments for hypertension, diabetes mellitus, dyslipidemia, C-reactive protein, and lifestyle factors, CAC progression was associated with albuminuria (RR: 1.20; 1.01 to 1.43; p=0.04) and low eGFRcys (RR: 1.19; 0.99 to 1.43; p=0.066), but not with eGFRcre., Conclusion: CAC progression was associated with albuminuria; however, its relationship with eGFRcys was weakened by adjustments for risk factors.

Introduction: We investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with type 2 diabetes., Research Design and Methods: A serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model., Results: The proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin., Conclusions: During the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective Evaluating the rate of decline in the estimated glomerular filtration rate (eGFR) may help identify patients with occult chronic kidney disease (CKD). We herein report that eGFR fluctuation complicates the assessment of the rate of decline and propose a long-term eGFR plot analysis as a solution. Methods In 142 patients with persistent eGFR decline in a single hospital, we evaluated the factors influencing the rate of eGFR decline, calculated over the long term (≥3 years) and short term (<3 years) using eGFR plots, taking into account eGFR fluctuation between visits. Results The difference between the rate of eGFR decline calculated using short- and long-term plots increased as the time period considered in the short-term plots became shorter. A regression analysis revealed that eGFR fluctuation was the only factor that explained the difference and that the fluctuation exceeded the annual eGFR decline in all participants. Furthermore, the larger the eGFR fluctuation, the more difficult it became to detect eGFR decline using a short-term eGFR analysis. Obesity, a high eGFR at baseline, and faster eGFR decline were associated with larger eGFR fluctuations. To circumvent the issue of eGFR fluctuation in the assessment of the rate of eGFR decline, we developed a system that generates a long-term eGFR plot using all eGFR values for a participant, which enabled the detection of occult CKD, facilitating early therapeutic intervention. Conclusion The construction of long-term eGFR plots is useful for identifying patients with progressive eGFR decline, as it minimizes the effect of eGFR fluctuation.

Introduction: Changes in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether the combined changes in albuminuria and eGFR are more strongly associated with future risk of ESKD., Research Design and Methods: Using data from a multicenter observational cohort study of people with type 2 diabetes, we evaluated the association of percentage change in urine albumin to creatinine ratio (UACR) and/or annual change in eGFR over 2 years with subsequent ESKD risk., Results: Among 1417 patients with repeated albuminuria and eGFR over 2 years, 129 (9.1%) developed ESKD. Patients with >30% UACR decline had lower ESKD risk (HR 0.47; 95% CI 0.29 to 0.77), whereas those with >30% UACR increase had higher ESKD risk (HR 2.31; 95% CI 1.52 to 3.51), compared with those with minor UACR change. Patients with greater eGFR decline had an increased ESKD risk than those with minor eGFR change (a decline of <2.5 mL/min/1.73 m 2 /year): HR 4.19 (95% CI 1.87 to 9.38) and 2.89 (95% CI 1.32 to 6.33) for those with a decline of >5 and 2.5-5 mL/min/1.73 m 2 /year, respectively. When the combined changes in UACR and eGFR were used, the highest ESKD risk (HR 5.60; 95% CI 2.08 to 15.09) was observed among patients with >30% UACR increase and an eGFR decline of >5 mL/min/1.73 m 2 /year compared with those with a minor change in UACR and eGFR., Conclusions: Combined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Progression of muscle strength weakening will lead to a poor physical performance and disability. While this is particularly important in patients with diabetes, the associations of reduced muscle strength measured by grip strength with clinical features and physical performance remain unclear. We investigated clinical features and physical performance measures in association with grip strength in elderly people with diabetes in a primary care setting., Research Design and Methods: A cross-sectional study was conducted enrolling 634 male and 323 female Japanese patients with type 2 diabetes aged 60 years or older. First, grip strength was measured and the associations of gender-specific grip strength with clinical features were evaluated. Second, in patients with a grip strength below the gender-specific median, physical performance measures, including gait speed, timed chair stand speed, knee extension strength, standing balance, and short physical performance battery scores, were investigated. Patients with and without a low performance defined by Asian Working Group for Sarcopenia were compared in terms of clinical features and physical performance measures., Results: Grip strength decreased according to aging and longer duration of diabetes and was independently related to body mass index, glycated hemoglobin A1c (HbA1c), serum albumin, albuminuria, neuropathy, and stroke in male patients, and to body mass index and albuminuria in female patients. The physical performance measures became worse proportionally to a decrease in the grip strength. Patients with a low performance exhibited a significantly older age, lower grip strength and serum albumin, higher albuminuria, and poorer physical performance measures than those without., Conclusions: Reduced grip strength was associated with glycemic exposure indicators of age-related duration, HbA1c, and vascular complications. The physical performance measures became worse with decreasing grip strength. Measurements of grip strength and physical performance in patients with diabetes may help promote intervention to prevent frailty in future studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A 43-year-old male patient on maintenance hemodialysis had an enhanced computed tomography scan examination with iohexol for the first time 10 min before regular hemodialysis therapy. At the start of hemodialysis, no symptoms were observed, and the platelet count was 148,000/μl. Approximately 1 h after starting hemodialysis, dyspnea and chest discomfort appeared. Since oxygen saturation of the peripheral artery decreased to 87%, oxygen administration was immediately started while continuing hemodialysis therapy. Furthermore, gingival hemorrhage was observed, and the platelet count decreased to 5000/μl. We were carefully monitoring his conditions while continuing hemodialysis and oxygen administration, but no further deterioration was observed. Thereafter, these symptoms and severe thrombocytopenia gradually improved without additional treatment. At the end of hemodialysis, these symptoms completely disappeared. As well, the platelet count recovered to 35,000/μl at the end of hemodialysis and increased to 92,000/μl the next morning. From the clinical course, we diagnosed with contrast medium-induced thrombocytopenia. Acute thrombocytopenia is a rare complication induced by the contrast medium. Until now, 16 cases on contrast medium-induced thrombocytopenia have been reported. Our case spontaneously recovered from severe thrombocytopenia relatively earlier than previous reports. Our patient started hemodialysis therapy 10 min after an enhanced computed tomography examination. Early removal of contrast medium by hemodialysis might be associated with early improvement. We should acknowledge that contrast media have potential to induce severe thrombocytopenia, even in patients on maintenance hemodialysis.