Kouichi Tamura’s research while affiliated with Yokohama City University and other places

Aim The favor effect on liver disease by odium‐glucose cotransporter inhibitor (SGLT2i) and GLP‐1 receptor agonist (GLP1Ra) was reported; however, the effect of the combination treatment of these drugs was not well known. Methods We retrospectively analyzed data for 643 patients with type 2 diabetes receiving SGLT2i + GLP1Ra combination treatment for at least 1 year (331 and 312 patients in the GLP1Ra‐ and SGLT2i‐preceding groups, respectively). Propensity score (PS) matching was used to compare the effects of the preceding drugs on liver function. Results The mean AST and ALT values at baseline, at the initiation of combination treatment, and at final observation were 29.8 ± 20.0 and 37.7 ± 29.5, 28.7 ± 17.3 and 35.3 ± 6.0, 26.0 ± 14.6 and 30.1 ± 21.6 IU/L, respectively, indicative of significant improvements in liver function (P < 0.001). Conversely, significant progress in the fibrosis‐4 (FIB‐4) index category was observed even after the combination treatment (P = 0.03). Subgroup analysis revealed that a significant decrease in ALT was observed only in patients with a baseline ALT ≥30 IU/L after the combination treatment (P = 0.005). Improvement of the FIB‐4 index category was observed in patients in the baseline FIB‐4 index ≥2.6 group and in the 1.3 ≤FIB‐4 index <2.6 group (46% and 19%, respectively). The matched model showed no significant differences in liver function after combination treatment between the SGLT2i‐ and GLP1Ra‐preceding groups. Conclusions SGLT2i + GLP1Ra combination treatment significantly improved liver dysfunction and prevented the progression of FIB‐4 index category among patients with an FIB‐4 index ≥1.3.

Objective: We report that the effect of combination therapy with SGLT2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1Ra) on renal composite outcomes is not affected by the preceding drug in patients with type 2 diabetes (T2D). In this study, we performed a post-hoc analysis of dulaglutide and liraglutide users and investigated the differences between GLP1Ra. Methods: We analyzed 266 patients treated with an SGLT2i followed by dulaglutide or liraglutide and 194 treated with dulaglutide or liraglutide followed by an SGLT2i. In addition, we analyzed dulaglutide users (n = 246) and liraglutide users (n = 214). Renal composite outcome was defined as the progression of albuminuria and/or a ≥ 30% eGFR decline. Results: The incidence of renal composite outcomes in the SGLT2i-preceding and GLP1Ra (dulaglutide or liraglutide)-preceding groups was not significantly different. It also did not differ between the dulaglutide and liraglutide users. The incidence of ≥ 30% eGFR decline was more frequent in liraglutide users, with an odds ratio of 2.63 (95% confidence interval: 1.07-6.45, p = 0.04), with a significantly larger decrease in albuminuria in liraglutide users, with an odds ratio of 0.44 (95% confidence interval: 0.04-0.85, p = 0.03). Conclusions: Dulaglutide and liraglutide may have different effects on albuminuria and the kidney function in combination with SGLT2i.

Background: Patients with both heart failure (HF) and chronic kidney disease (CKD) are often treated with renin-angiotensin-aldosterone system inhibitors (RAASi), but these drugs can cause hyperkalemia, which may lead to their reduction or discontinuation, resulting in the loss of their beneficial effects. Approaches to managing RAASi-induced hyperkalemia are discordant, so in this study we aimed to establish a cross-specialty consensus on the optimal approach to managing hyperkalemia in patients with HF and CKD. Methods and Results: The study used a modified Delphi methodology. A steering committee of Japanese cardiologists and nephrologists drafted 26 consensus statements, which were used to create a survey, distributed across Japan. A total of 250 responses were received. Consensus, defined as 75% agreement, was achieved for 21/26 (81%) statements. Respondents agreed on the importance of effective hyperkalemia management based on serum potassium levels and supported the use of potassium binders (PBs), particularly novel PBs such as sodium zirconium cyclosilicate, to treat hyperkalemia while maintaining RAASi therapy. However, when potassium levels exceed 6.0 mEq/L, reduction or discontinuation of RAASi may be considered based on individual risk factors. Conclusions: This consensus provides proposals that may help support the optimal management of RAASi-induced hyperkalemia in Japanese patients with HF and CKD. It highlights the importance of treating hyperkalemia alongside optimal RAASi therapy.

BACKGROUND We investigated the effects of sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), on 24-hour blood pressure (BP) and safety for 12 weeks in Japanese patients with non-dialysis advanced chronic kidney disease (CKD). METHODS We conducted a prospective, single-arm exploratory study. Patients with non-dialysis CKD stage G4-5 (estimated glomerular filtration (eGFR) <30 mL/min/1.73 m2) who did not achieve their BP goals with angiotensin receptor blocker (ARB) administration, were enrolled and switched to sacubitril/valsartan. Primary and key secondary endpoints were changes from baseline in the 24-hour systolic BP (SBP) measured via ambulatory BP monitoring (ABPM) over 12 weeks and the safety, especially incidence of serum creatinine (Cr) increase (≥ 30% increase from baseline) and hyperkalemia. RESULTS Thirty patients were enrolled, and 29 patients were switched to sacubitril/valsartan. Efficacy analysis was conducted on 26 patients. Baseline mean eGFR and office BP were 21.1 ± 5.0 mL/min/1.73m2 and 149.4 ± 23.7/80.7 ± 11.9 mmHg, respectively. Baseline 24-hour, daytime, and nighttime BP were 139.6 ± 17.7/77.0 ± 7.8 mmHg, 143.5 ± 18.5/79.6 ± 8.7 mmHg, and 131.0 ± 20.4/71.1 ± 8.8 mmHg, respectively. After 12 weeks, changes in 24-hour, daytime, and nighttime SBP from baseline were -7.1 ± 12.4 mmHg (P < 0.01), -7.7 ± 12.9 mmHg (P < 0.01), and -5.8 ± 15.8 mmHg (P = 0.07), respectively. No incidences of potassium values > 6.0 mmol/L or serum Cr ≥ 30% increase from baseline were reported after sacubitril/valsartan initiation. CONCLUSIONS Switching from ARB to sacubitril/valsartan can safely enhance 24-hour antihypertensive treatment in patients with non-dialysis CKD G4-5 who do not achieve BP goals with ARBs. CLINICAL TRIALS REGISTRATION: Trial Number jRCT1031220149. CLINICAL TRIALS REGISTRATION Trial Number jRCT1031220149.

Haptoglobin (Hp) is required for the metabolism of hemoglobin into bilirubin after hemolysis. Herein, we report a case of thrombotic microangiopathy (TMA) in a person with permanently low expression of Hp. The patient was an 80‒year‒old man. He was referred to our hospital because of rapid deterioration of renal function within a few days. The patient had thrombocytopenia, anemia with schistocytes, elevated LDH, and his serum Hp level was below detection sensitivity. During the course of blood transfusion and hemodialysis as supportive care, TMA subsided. The patient was weaned from hemodialysis. Two years after discharge, plasma Hp concentration remained below the detection sensitivity of conventional nephelometry and was barely detectable by high‒sensitivity ELISA. The absence of jaundice during the acute phase of TMA was likely due to low Hp expression. When such an atypical sign is observed in TMA in the future, congenital Hp deficiency should be considered. Special precautions against anaphylaxis are recommended during transfusion and plasma exchange, which may become the preferred treatment options.

A 69-year-old Japanese man developed abdominal pain, purpura, proteinuria, and hematuria while receiving treatment for pulmonary tuberculosis. A skin biopsy revealed IgA-positive leukocytoclastic vasculitis, and a renal biopsy showed IgA-positive mesangial proliferative glomerulonephritis with crescent formation. Based on these findings, we diagnosed IgA vasculitis with nephritis (IgAVN) and initiated treatment. The patient’s abdominal symptoms improved following factor XIII supplementation and corticosteroids. Corticosteroids were administered, and after 5 months, the proteinuria was in complete remission. Although IgAVN often follows a prior infection, it is rarely complicated by tuberculosis. In this case, staining for galactose-deficient IgA1, which is specifically positive in IgA nephropathy and IgAVN, was positive. Nephritis-associated plasmin receptor staining was also positive, suggesting some involvement of infectious glomerulonephritis. Therefore, the patient was considered to have IgAVN associated with pulmonary tuberculosis. In adult-onset cases, IgAVN is often severe. This patient was presented with adult-onset nephrosis and International Study of Kidney Disease in Children grade IIIb IgAVN, suggesting a poor prognosis. Therefore, we immediately initiated treatment with corticosteroids, factor XIII supplementation, a renin-aldosterone-system inhibitor, and a sodium–glucose cotransporter 2 inhibitor. The patient recovered uneventfully with no worsening of tuberculosis.

Ischemia reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and ultimately leads to renal fibrosis, primarily via the transforming growth factor-β (TGF-β) pathway. Leucine-rich alpha-2-glycoprotein 1 (LRG1), a novel modulator of the TGF-β pathway, has been implicated in the modulation of renal fibrosis by affecting the TGF-β/Smad3 signaling axis. However, the role of LRG1 in the transition from AKI to chronic kidney disease (CKD) remains unclear. This study aimed to investigate the functional role of LRG1 during the remodeling phase post-IRI. Unilateral IRI was induced in C57BL/6J wild-type (WT) mice and systemic LRG1 knockout (KO) mice. In C57BL/6J WT mice, renal LRG1 mRNA expression was significantly elevated on the ischemia/reperfusion side compared to the sham side over a 28-day period. In contrast, LRG1 KO mice demonstrated significantly reduced renal fibrosis compared to WT mice on postoperative day 28. Additionally, renal mRNA expression of TGF-β and associated pro-fibrotic genes was diminished in LRG1 KO mice compared to WT mice. Consequently, LRG1 KO mice exhibited attenuated IRI-induced chronic fibrosis. These findings indicate that LRG1 is involved in the pathogenesis of the transition from AKI to CKD and may be a potential therapeutic target.

Introduction The efficacy of lipoprotein apheresis (LA) in peripheral arterial disease (PAD) has been primarily attributed to its anti‐atherosclerotic effects through the adsorption of lipoproteins. However, the other potential effects of LA remain unknown. We evaluated changes in serum profiles before and after LA using a comprehensive analysis to explore the underlying mechanism. Methods Ten patients with leg ulcers were included from the LETS‐PAD study, in which patients with lipoprotein‐controlled PAD underwent LA. Serum samples collected at baseline and 1 month after LA were analyzed for proteomic changes. Results Six patients exhibited ulcer epithelialization and skin perfusion pressure improvement. Proteomic analysis identified 2033 proteins. Fifty‐five proteins showed significant differences. B‐cell lymphoma protein‐2 associated X (BAX) and C‐X‐C motif chemokine 10 (CXCL10) were downregulated. Conclusion Serum BAX and CXCL10 levels significantly decreased after LA, which may be involved in the ulcer epithelialization mechanism of LA, which potentially acts through angiogenesis promotion.