Two acute kidney injury episodes after ICI therapy: a case report.

A 74-year-old Japanese male with lung squamous cell carcinoma received his first dose of immune checkpoint inhibitors (ICIs): ipilimumab and nivolumab. He developed acute kidney injury (AKI) and was admitted to our department. We diagnosed kidney immune-related adverse effects (irAE), and a kidney biopsy revealed acute tubulointerstitial nephritis. We started oral prednisolone (PSL) and his AKI immediately improved. The patient maintained stable findings after PSL was tapered off. However, seven months after the ICI administration, he developed rapid progressive glomerular nephritis and was admitted to our department again. The second kidney biopsy showed findings consistent with anti-glomerular basement membrane glomerulonephritis. Although the patient was treated with pulse methylprednisolone followed by oral PSL and plasma exchange, he became dependent on maintenance hemodialysis. To our knowledge, no case report has described two different types of biopsy-proven nephritis. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome presenting as recurrent aseptic peritonitis in a patient receiving peritoneal dialysis: a case report.

BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by mutations in the ubiquitin-activating enzyme1 (UBA1) gene and characterised by an overlap between autoinflammatory and haematologic disorders. CASE PRESENTATION: We reported a case of a 67-year-Japanese man receiving peritoneal dialysis (PD) who had recurrent aseptic peritonitis caused by the VEXAS syndrome. He presented with unexplained fevers, headache, abdominal pain, conjunctival hyperaemia, ocular pain, auricular pain, arthralgia, and inflammatory skin lesions. Laboratory investigations showed high serum C-reactive protein concentration and increased cell count in PD effluent. He was treated with antibiotics for PD-related peritonitis, but this was unsuccessful. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography images demonstrated intense FDG uptake in his left superficial temporal artery, nasal septum, and bilateral auricles. The working diagnosis was giant cell arteritis, and he was treated with oral prednisolone (PSL) 15 mg daily with good response. However, he was unable to taper the dose to less than 10 mg daily because his symptoms flared up. Since Tocilizumab was initiated, he could taper PSL dose to 2 mg daily. Sanger sequencing of his peripheral blood sample showed a mutation of the UBA1 gene (c.122 T > C; p.Met41Thr). We made a final diagnosis of VEXAS syndrome. He suffered from flare of VEXAS syndrome at PSL of 1 mg daily with his cloudy PD effluent. PSL dose of 11 mg daily relieved the symptom within a few days. CONCLUSIONS: It is crucial to recognise aseptic peritonitis as one of the symptoms of VEXAS syndrome and pay attention to the systemic findings in the patients.

Effect of tirzepatide on glycaemic control and weight loss compared with other glucagon-like peptide-1 receptor agonists in Japanese patients with type 2 diabetes mellitus.

AIM: To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). RESULTS: A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. CONCLUSIONS: Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.

Effects of a High-Protein Diet on Kidney Injury under Conditions of Non-CKD or CKD in Mice.

Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects.

Updates for Cardio-Kidney Protective Effects by Angiotensin Receptor-Neprilysin Inhibitor: Requirement for Additional Evidence of Kidney Protection.

The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor-neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin-angiotensin system inhibitors (RAS-Is) in large clinical trials such as the PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS-Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM-HF trial, ARNI was associated with more albuminuria compared with RAS-I; thus, it is unclear whether long-term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS-I in patients with chronic kidney disease in the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS-I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

Clinical impact of left ventricular systolic dysfunction in patients undergoing dialysis access surgery.

BACKGROUND: An arteriovenous fistula (AVF) is the most frequently used dialysis access for haemodialysis. However, it can cause volume loading for the heart and may induce circulatory failure when performed in patients with low cardiac function. This study aimed to characterise patients with low cardiac function when initiating dialysis and determine how cardiac function changes after the dialysis access surgery. METHODS: We conducted a retrospective observational study at two centres incorporating 356 patients with end-stage kidney disease who underwent echocardiography before the dialysis access surgery. RESULTS: An AVF and a subcutaneously fixed superficial artery were selected in 70.4% and 23.5% of 81 patients with reduced/mildly reduced (< 50%) left ventricular ejection fraction (LVEF), respectively, and in 94.2% and 1.1% of 275 patients with preserved (≥ 50%) LVEF (p < 0.001), respectively. Follow-up echocardiography was performed in 70.4% and 38.2% of patients with reduced/mildly reduced and preserved LVEF, respectively, which showed a significant increase in LVEF (41 ± 9-44 ± 12%, p = 0.038) in patients with reduced/mildly reduced LVEF. LVEF remained unchanged in 12 patients with reduced/mildly reduced LVEF who underwent subcutaneously fixed superficial artery (30 ± 10-32 ± 15%, p = 0.527). Patients with reduced/mildly reduced LVEF had lower survival rates after surgery than those with preserved LVEF (p = 0.021 for log-rank). CONCLUSION: The LVEF subcategory was associated with dialysis access selection. After the dialysis access surgery, LVEF was increased in patients with reduced/mildly reduced LVEF. These results may help select dialysis access for patients initiating dialysis.

Deficiency of the kidney tubular angiotensin II type1 receptor-associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization.

Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.

Clinical significance of a novel reticulocyte-based erythropoietin resistance index in HD patients: A retrospective study.

INTRODUCTION: The erythropoietin resistance index (ERI) is an indicator of erythropoiesis-stimulating agent (ESA) responsiveness and is typically calculated using Hb. However, Hb does not directly reflect ESA-induced erythropoiesis because of its long-term nature. We thus designed a novel ERI calculated with reticulocyte Hb (RetHb), a real-time index, and investigated its association with mortality in HD patients. METHODS: We calculated the ERI using the change in RetHb before and after ESA administration (ERIΔRetHb ) and retrospectively analyzed its association with 3-year all-cause mortality using Kaplan-Meier survival curves and Cox regression analyses. RESULTS: A total of 102 patients were included. Patients with the highest ERIΔRetHb had the worst prognosis according to the Kaplan-Meier survival curves (Log-rank p = 0.02). Multivariate Cox regression analysis showed that the ERIΔRetHb was significantly and independently associated with all-cause mortality (hazard ratio: 9.82, 95% CI [1.50, 64.41], p = 0.02). CONCLUSION: The ERIΔRetHb was significantly and independently associated with all-cause mortality in HD patients.

LPIN1 is a new target gene for essential hypertension.

BACKGROUND: We previously showed Lipin1 (LPIN1) to be a candidate gene for essential hypertension by genome-wide association studies. LPIN1 encodes the Lipin 1 protein, which contributes to the maintenance of lipid metabolism and glucose homeostasis. However, little is known about the association between LPIN1 and blood pressure (BP). METHODS: We evaluated the BP of LPIN1-deficient [fatty liver dystrophy (fld)] mice and explored related mechanisms. RESULTS: Fld mice have very low expression of LPIN1 and exhibit fatty liver, hypertriglyceridemia, insulin resistance and peripheral neuropathy. Fld mice had significantly elevated SBP and heart rate (HR) throughout the day as measured by a radiotelemetric method. Diurnal variation of SBP and HR was also absent in fld mice. Furthermore, urinary excretion of adrenaline and noradrenaline by fld mice was significantly higher compared with that of control mice. The BP response of fld mice to clonidine (a centrally acting α2-adrenergic receptor agonist) was greater than that of control mice. However, levels of Angiotensinogen and Renin 1 mRNA and urinary nitric oxide excretion were comparable between the two groups. The decrease in SBP at 8 weeks after fat grafting surgery was significantly greater in the transplant group compared with the sham operated group. CONCLUSION: The elevated BP in fld mice may result from activation of the sympathetic nervous system through decreased levels of adipose cytokines. These results indicate that LPIN1 plays a crucial role in blood pressure regulation and that LPIN1 is a new target gene for essential hypertension.

Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy.

Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1ß, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.

Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice.

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated ß-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

Potential effective treatment of shortening continuous erythropoietin receptor activator treatment interval combined with iron supplementation in hemodialysis patients.

Our previous randomized controlled trial comparing the total dose of weekly versus biweekly continuous erythropoietin receptor activator (CERA) therapy to maintain optimal hemoglobin (Hb) levels showed no significant differences between the two therapies. This post-hoc analysis assessed whether the total dose of weekly versus biweekly CERA therapy to maintain Hb levels among HD patients differed among groups with or without iron supplementation. Of 107 patients, 40 received intravenous iron supplementation due to iron deficiency (iron group) and 67 did not (non-iron group). In the iron group, the weekly therapy tended to require a lower total CERA dose compared with the biweekly therapy (274 ± 274 vs 381 ± 223 µg/12 weeks, P = 0.051). Changes in circulating hepcidin levels, a negative regulator of intestinal iron uptake, after 2 weeks of CERA treatment were significantly lower in the weekly therapy compared with the biweekly therapy (-4.2 ± 6.3 vs 11.1 ± 7.3 ng/mL, P = 0.015). In the non-iron group, there were no significant differences in total CERA dose or changes in hepcidin levels between the two therapies. Shortening the CERA treatment interval combined with iron supplementation may lead to the more efficient treatment of HD patients with iron deficiency.

Systematic review and meta-analysis for prevention of cardiovascular complications using GLP-1 receptor agonists and SGLT-2 inhibitors in obese diabetic patients.

Patients with type 2 diabetes mellitus (T2DM) and obesity are at high risk of developing cardiovascular disease (CVD). Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors have been shown to prevent CVD in T2DM patients. Additionally, the two drugs reduce body mass. However, it is unknown which drug is more effective at reducing the risk of CVD in such patients. We searched Medline, EMBASE, and Cochrane Library records to February 20, 2021 and performed a network meta-analysis to compare the efficacy with which the drugs reduced the risk of major adverse cardiovascular events (MACE). We included 102,728 patients in 12 studies containing data of obesity subgroup analyses. In T2DM patients with obesity, GLP-1 RAs significantly reduced the risk of MACE versus placebo (relative risk, RR [95% confidence interval, CI]: 0.88 [0.81-0.96]), whereas SGLT-2 inhibitors showed a tendency (RR [95% CI]: 0.91 [0.83-1.00]). In an indirect comparison, GLP-1 RAs were not associated with a significant difference in MACE compared with SGLT-2 inhibitors (RR [95% CI]: 0.97 [0.85-1.09]). Thus, GLP-1 RAs are effective at preventing MACE than placebo in T2DM patients with obesity, although further studies are warranted to conclude their superiority to SGLT-2 inhibitors.

Comparison of the effects of weekly and biweekly intravenous CERA administration on erythropoiesis: A randomized controlled trial.

Although continuous erythropoietin receptor activators (CERAs) are widely used erythropoiesis-stimulating agents for correcting renal anemia in patients undergoing hemodialysis (HD), few reports have examined weekly CERA administration. In this randomized controlled trial, we compared the efficacy and changes in the parameters of iron metabolism and erythropoiesis between weekly and biweekly CERA administration. In total, 120 patients undergoing maintenance HD were randomized to the weekly or biweekly group. The primary end point was the total CERA dose needed to maintain the target hemoglobin (Hb) levels during a 12-week evaluation period. There was no significant difference in the total dose between the weekly and biweekly groups (median 175.0 [interquartile range (IQR) 93.8-337.5] µg/12 weeks vs. 300.0 [IQR 125.0-375.0] µg/12 weeks, P = .18). The mean Hb levels during the evaluation period were 10.9 ± 0.8 g/dL in the weekly group and 10.7 ± 0.8 g/dL in the biweekly group (P = .25). Weekly CERA administration was well tolerated. Weekly CERA administration similarly managed anemia as biweekly administration in patients undergoing HD.

A case of minimal change nephrotic syndrome with pregnancy.

A 32-year-old Japanese woman at 8 weeks of gestation was admitted to our hospital for systemic edema, hypoalbuminemia, and severe proteinuria. The patient had a history of generalized alopecia and migraine. We diagnosed nephrotic syndrome, and renal biopsy revealed minimal change nephrotic syndrome (MCNS). We administered 1000 mg/day of methylprednisolone for 3 days. Oral corticosteroid therapy was followed by 40 mg of prednisolone daily. We carefully selected concomitant medication after considering organogenesis. Before and after renal biopsy, we administered heparin, antithrombin III, and immunoglobulin agents as appropriate. The patient achieved complete remission on day 8 of treatment and gave birth to a boy at 37 weeks of gestation without recurrence. MCNS during pregnancy is rare, and there is no established treatment. In conclusion, we present a case of a pregnant woman with MCNS during organogenesis. Early treatment initiation can provide a good prognosis for both mother and child.

Relationship between basal sodium intake and the effects of dapagliflozin in albuminuric diabetic kidney disease.

We investigated the impact of basal dietary sodium intake on the dapagliflozin-induced changes in albuminuria and blood pressure (BP) measured at home in patients with diabetic kidney disease (DKD).This was a secondary analysis of the Y-AIDA Study, in which DKD patients with estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine were administered dapagliflozin for 24 weeks, and dapagliflozin significantly improved albuminuria levels and home BP profiles. The effects on UACR, home-measured BP, and eGFR were compared between high- and low-sodium intake groups (HS and LS groups), which were created using baseline urinary sodium-to-creatinine ratio of 84 participants with available basal sodium-to-creatinine ratios. At baseline, clinic-/home-measured BPs, UACR, and eGFR, were comparable in the two groups. After 24 weeks, the reductions from baseline in ln-UACR were comparable in the two groups. In contrast, the reductions in evening home systolic BP and eGFR from baseline were larger in HS than in LS (BP: - 13 ± 2.08 vs. - 6 ± 1.88, P = 0.020; eGFR: - 3.33 ± 1.32 vs. 0.37 ± 1.29, P = 0.049). The home BP-lowering effects of dapagliflozin are larger in HS than LS, concomitant with a larger reduction in eGFR, suggesting a dapagliflozin-induced improvement in glomerular relative hyperfiltration in HS.

Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice.

Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.

Preliminary Report: The Relevance of Tumor Necrosis Factor-α in Acquired Primary Lymphedema-A Histopathological Investigation.

Background: Lymphedema includes primary lymphedema (P-LE) and secondary lymphedema (S-LE), which is a chronic progressive disease. The former group is further classified as congenital and acquired P-LE (AP-LE); its etiology is unclear, and only a few studies on its pathophysiology exist. We hypothesized that an autoimmune disease or self-inflammatory mechanism occurs in lymphatic vessels, leading to obstruction. Methods and Results: We enrolled 46 patients with lymphedema who underwent lymphaticovenous anastomosis (LVA) from January to October 2015. Collecting lymph ducts were obtained during LVA. We performed hematoxylin/eosin staining and immunostaining for LYVE-1, IL-1ß, IL-6, and TNF-α. There were no substantial histological differences between the two types of lymphedema, whereas some differences in expression of inflammatory cytokines, including interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, were observed. Only a few inflammatory cells could be seen around the vessels. Although no significant differences in expression of IL-1ß were found between AP-LE and S-LE, TNF-α was more highly expressed in the smooth muscle layer in AP-LE patients than in S-LE patients. There were no significant morphological differences in the collecting ducts of lymphatic vessels between S-LE and P-LE. Nevertheless, higher levels of TNF-α accumulation were found in the thick smooth muscle layer of P-LE patients than in that of S-LE patients. Conclusion: TNF-α-related inflammation in collecting ducts of lymphatic vessels is an important characteristic of the pathology of P-LE. TNF-α inhibitors might improve symptoms of AP-LE.

Angiotensin II type 1 receptor-associated protein deficiency attenuates sirtuin1 expression in an immortalised human renal proximal tubule cell line.

The proximal tubule is a particularly important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. However, the mechanisms of SIRT1 regulation remain to be elucidated. We recently reported that angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP)-deficient mice displayed age-associated renal function decline and tubulointerstitial fibrosis. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, although the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, therefore, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageing-associated kidney dysfunction. Here, since ageing studies are inherently lengthy, we used an ex vivo model of the proximal tubule to determine the role of ATRAP in SIRT1 protein expression. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP. Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Thus, ATRAP likely mediates SIRT1 protein abundance in ciRPTEC.

Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study).

BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.