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Background: We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients., Methods: This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0 mg/dL and < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL and < 7.0 mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment., Results: Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23 mg/dL at baseline and 6.13 mg/dL at 52 weeks. In the Intensive therapy group, mean serum UA was 8.15 mg/dL at baseline and 5.25 mg/dL at 52 weeks. There was no significant difference in changes in log ACR at 52 weeks between the Intensive therapy and the Standard therapy groups., Conclusion: This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146)., (© 2024. The Author(s).)

Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1 -KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1 -KO mice. CD206 + expression was upregulated, and β-catenin expression was downregulated in Sult1a1 -KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1 -KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1 -KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis., Competing Interests: The authors declare no conflict of interest.

Background: Practice facilitation program by multidisciplinary care for primary care physicians (PCPs) is expected to improve chronic kidney disease (CKD) outcomes, but there is no clear evidence of its long-term effectiveness. We have previously performed a cluster-randomized controlled trial for 3.5 years (the Frontier of Renal Outcome Modifications in Japan (FROM-J) study) with two arms-group A without the program and group B with the program. We aimed to assess the long-term effectiveness of the practice facilitation program on CKD outcomes via an extended 10-year follow-up of the FROM-J study., Methods: We enrolled patients who were in the FROM-J study. The primary composite endpoint comprised cardiovascular disease (CVD), renal replacement therapy initiation and a 50% decrease in the estimated glomerular filtration rate (eGFR). The secondary endpoints were survival rate, eGFR decline rate and collaboration rate between PCPs and nephrologists., Results: The occurrence of the primary composite endpoint tended to be lower in group B (group A: 27.1% versus group B: 22.1%, P = 0.051). Furthermore, CVD incidence was remarkably lower in group B (group A: 10.5% versus group B: 6.4%, P = 0.001). Although both mortality and the rate of eGFR decline were identical between both groups, the eGFR decline rate was significantly better in group B than in group A only in patients with stage G3a at enrollment (group A: 2.35 ± 3.87 mL/min/1.73 m2/year versus group B: 1.68 ± 2.98 mL/min/1.73 m2/year, P = 0.02). The collaboration rate was higher in group B., Conclusions: The CKD practice facilitation program for PCPs reliably decreases CVD events and may reduce the progression of cases to end-stage kidney disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Osteocrin (OSTN), a bone-derived humoral factor, was reported to act on heart and bone by potentiating the natriuretic peptide (NP) system. Ostn gene polymorphisms have been associated with renal function decline, but its pathophysiological role in the kidney remains unclear., Methods: The role of endogenous OSTN was investigated using systemic Ostn-knockout (KO) mice. As a model for OSTN administration, liver-specific Ostn-overexpressing mice crossed with KO (KO-Tg) were generated. These mice were subjected to unilateral ischemia-reperfusion injury (IRI) and renal lesions after 21 days of insult were evaluated. A comprehensive analysis of the Wnt/β-catenin pathway was performed using a polymerase chain reaction (PCR) array. Reporter plasmid-transfected proximal tubular cells (NRK52E) were used to investigate the mechanism by which OSTN affects the pathway., Results: After injury, KO mice showed marginal worsening of renal fibrosis compared with wild-type mice, with comparable renal atrophy. KO-Tg mice showed significantly ameliorated renal atrophy, fibrosis and tubular injury, together with reduced expressions of fibrosis- and inflammation-related genes. The PCR array showed that the activation of the Wnt/β-catenin pathway was attenuated in KO-Tg mice. The downstream targets Mmp7, Myc and Axin2 showed similar results. MMP7 and Wnt2 were induced in corticomedullary proximal tubules after injury, but not in KO-Tg. In NRK52E, OSTN significantly potentiated the inhibitory effects of NP on transforming growth factor β1-induced activation of the Wnt/β-catenin pathway, which was reproduced by a cyclic guanosine monophosphate analog., Conclusions: Ectopic Ostn overexpression ameliorated subsequent renal injury following ischemia-reperfusion. OSTN could represent possible renoprotection in acute to chronic kidney disease transition, thus serving as a potential therapeutic strategy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Background: The dipstick urinalysis for proteinuria has been used for chronic kidney disease (CKD) screening at community-based health checkups; however, it has major drawbacks in that the result is only semi-quantitative and is influenced by urine concentration., Methods: We conducted urine protein/creatinine ratio (UPCR) measurements of 590 participants who showed a result of more than trace proteinuria on a dipstick analysis and evaluated the usefulness of UPCR measurements in community-based health checkups., Results: The UPCR values increased in accordance with the severity of the dipstick test findings, but statistical significance was only obtained between (±) and (1+), between (±) and (2+), and between (±) and (3+) groups. When the participants with (±) proteinuria were subjected to CGA classification (a classification of CKD by cause, glomerular filtration rate category, and albuminuria category) according to their UPCR data, a significant proportion of subjects (277, 77.0%) moved from the A2 category into A1, which is a less severe category. Conversely, 21 subjects (5.8%) were reclassified into a more severe category (A3). Thus, a dipstick test may produce a non-negligible number of false negatives as well as a large number of false positives. Similarly, the classifications of more than half of the subjects with (1+) or more severe proteinuria were changed based on their UPCR results., Conclusion: The dipstick urinalysis for proteinuria appears less reliable than expected, suggesting that the quantitative measurement of urine protein should be performed even during mass health checkups to ensure the early detection and prevention of CKD.

Aim: Metabolic acidosis occurs due to insufficient urinary ammonium excretion as chronic kidney disease (CKD) advances. Because obese subjects tend to have excessive consumption of protein and sodium chloride, they are prone to chronic acid loading and may therefore be predisposed to acid-induced kidney injury. We investigated the involvement of obesity in ammoniagenesis within damaged kidneys., Methods: In the clinical study, urinary ammonium excretion was compared between 13 normal-weight and 15 overweight/obese CKD outpatients whose creatinine clearance was higher than 25 mL/min. For animal experiments, NH 4 Cl was loaded to KKAy/TaJcl (KKAy), a metabolic syndrome model, and control BALB/c mice for 20 weeks. Kidney injury was evaluated through histological analysis and the expression of proinflammatory markers., Results: Urinary ammonium excretion was lower in overweight/obese patients than in normal-weight patients, while intakes of protein and sodium chloride were higher in overweight/obese patients, implying that subclinical metabolic acidosis occurs in overweight/obese patients. The increase in urinary ammonium excretion induced by NH 4 Cl loading was attenuated in KKAy mice after 16 weeks, whereas the increase was maintained in BALB/c mice throughout the study period. Histological study and real-time polymerase chain reaction analysis showed proximal tubular injury and enhanced expression levels of neutrophil gelatinase-associated lipocalin (NGAL) protein and messenger RNA, respectively, in KKAy mice but not in BALB/c mice. Finally, urinary NGAL concentration was higher in overweight/obese patients than in normal-weight patients in the early stage of CKD., Conclusion: Obesity could facilitate the induction of subclinical metabolic acidosis and acid accumulation in the kidney, which may potentially exacerbate kidney injury in CKD patients., (© 2018 Asian Pacific Society of Nephrology.)

Metabolic acidosis often results from chronic kidney disease; in turn, metabolic acidosis accelerates the progression of kidney injury. The mechanisms for how acidosis facilitates kidney injury are not fully understood. To investigate whether low pH directly affects the expression of genes controlling local homeostasis in renal tubules, we performed transcription start site sequencing (TSS-Seq) using IN-IC cells, a cell line derived from rat renal collecting duct intercalated cells, with acid loading for 24 h. Peak calling identified 651 up-regulated and 128 down-regulated TSSs at pH 7.0 compared with those at pH 7.4. Among them, 424 and 38 TSSs were ≥ 1.0 and ≤ -1.0 in Log2 fold change, which were annotated to 193 up-regulated and 34 down-regulated genes, respectively. We used gene ontology analysis and manual curation to profile the up-regulated genes. The analysis revealed that many up-regulated genes are involved in renal fibrosis, implying potential molecular mechanisms induced by metabolic acidosis. To verify the activity of the ubiquitin-proteasome system (UPS), a candidate pathway activated by acidosis, we examined the expression of proteins from cells treated with a proteasome inhibitor, MG132. The expression of ubiquitinated proteins was greater at pH 7.0 than at pH 7.4, suggesting that low pH activates the UPS. The in vivo study demonstrated that acid loading increased the expression of ubiquitin proteins in the collecting duct cells in mouse kidneys. Motif analysis revealed Egr1, the mRNA expression of which was increased at low pH, as a candidate factor that possibly stimulates gene expression in response to low pH. In conclusion, metabolic acidosis can facilitate renal injury and fibrosis during kidney disease by locally activating various pathways in the renal tubules.

Thermal therapy has become a nonpharmacological therapy in clinical settings, especially for cardiovascular diseases. However, the practical role of thermal therapy on chronic kidney disease remains elusive. We performed the present study to investigate whether a modified thermal protocol, repeated mild thermal stimulation (MTS), could affect renal damages in chronic kidney disease using a mouse renal ablation model. Mice were subjected to MTS or room temperature (RT) treatment once daily for 4 wk after subtotal nephrectomy (Nx) or sham operation (Sh). We revealed that MTS alleviated renal impairment as indicated by serum creatinine and albuminuria in Nx groups. In addition, the Nx + MTS group showed attenuated tubular histological changes and reduced urinary neutrophil gelatinase-associated lipocalin excretion approximately by half compared with the Nx + RT group. Increased apoptotic signaling, such as TUNEL-positive cell count and cleavage of caspase 3, as well as enhanced oxidative stress were significantly reduced in the Nx + MTS group compared with the Nx + RT group. These changes were accompanied with the restoration of kidney Mn-SOD levels by MTS. Heat shock protein 27, a key molecular chaperone, was phosphorylated by MTS only in Nx kidneys rather than in Sh kidneys. MTS also tended to increase the phosphorylation of p38 MAPK and Akt in Nx kidneys, possibly associated with the activation of heat shock protein 27. Taken together, these results suggest that modified MTS can protect against renal injury in a rodent model of chronic kidney disease., (Copyright © 2016 the American Physiological Society.)

Renal fibrosis is a common pathological consequence of chronic kidney disease (CKD) with tissue fibrosis closely associated with chronic inflammation in numerous pathologies. However, molecular mechanisms underlying that association, particularly in the kidney, remain unclear. Here, we determine whether there is a molecular link between chronic inflammation and tissue fibrosis in CKD progression. Histological analysis of human kidneys indicated abundant expression of angiopoietin-like protein 2 (ANGPTL2) in renal tubule epithelial cells during progression of renal fibrosis. Numerous ANGPTL2-positive renal tubule epithelial cells colocalized with cells positive for transforming growth factor (TGF)-β1, a critical mediator of tissue fibrosis. Analysis of M1 collecting duct cells in culture showed that TGF-β1 increases ANGPTL2 expression by attenuating its repression through microRNA-221. Conversely, ANGPTL2 increased TGF-β1 expression through α5β1 integrin-mediated activation of extracellular signal-regulated kinase. Furthermore, ANGPTL2 deficiency in a mouse unilateral ureteral obstruction model significantly reduced renal fibrosis by decreasing TGF-β1 signal amplification in kidney. Thus, ANGPTL2 and TGF-β1 positively regulate each other as renal fibrosis progresses. Our study provides insight into molecular mechanisms underlying chronic inflammation and tissue fibrosis and identifies potential therapeutic targets for CKD treatment., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors., (Copyright © 2016 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)

Background/aims: We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model., Methods: In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy., Results: CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro., Conclusion: Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.

Chronic kidney disease (CKD) is not merely a disorder featuring renal dysfunction, but also accelerates the progression of cardiovascular disease. Recently, the prevalence of CKD has been increasing in parallel with that of metabolic syndrome, suggesting that these two disorders are closely related. Metabolic syndrome is generally characterized by several metabolic and cardiovascular features, including obesity, insulin resistance and hypertension, all of which are known to cause renal impairment. Hence, it is likely that metabolic syndrome could be a key factor in the development of renal disease. Among several factors associated with metabolic syndrome, lipid abnormality, in particular a high level of serum low-density lipoprotein, has been emerging as a cause of kidney injury. Accumulating evidence has demonstrated that statin therapy for treating hyperlipidemia could slow the progression of renal disease, indicating that a treatment for lipid abnormality might prevent the progression of renal disease. In other words, statin therapy might be renoprotective in addition to its beneficial effect on the cardiovascular system. We are carrying out a clinical trial, the ASUCA trial, in which we examine whether statins might slow the progression of CKD in the Japanese population. We organized the multi-center clinical trial to investigate the effect of atorvastatin on estimated glomerular filtration rate in patients with CKD and lipid abnormality. In this paper, we discuss the outline and significance of this trial.