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Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min −1 per 1.73 m 2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R 2 ) = 0.97 (95% Bayesian credible interval (BCI) 0.82–1.00)) and moderately associated with those on chronic slope (R 2  = 0.55 (95% BCI 0.25–0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression. A meta-analysis of individual-level patient data from 66 clinical studies supports the utility of glomerular filtration rate as a surrogate endpoint in clinical trials for chronic kidney disease, with potential to enable detection of events earlier in the disease course.

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic β-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-β, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, β-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

Reduced methylation at key transcription factor binding sites might contribute to the progression of diabetic nephropathy in type 1 diabetes through the activation of insulin signaling and other pathways.

Key Points The innate immune system consists of several classes of pattern recognition receptors, including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response TLR2 and TLR4 are the predominant TLRs expressed on pancreatic β cells which trigger an inflammatory response that results in insulitis during type 1 diabetes mellitus TLR2 and TLR4 signalling, and activation of NLRP3 inflammasomes result in the production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy Pattern recognition receptors and danger-associated molecular patterns of the innate immune system contribute to the initiation of an inflammatory response in diabetes mellitus and diabetic nephropathy. In this Review, Jun Wada and Hirofumi Makino discuss how these components of the innate immune system can lead to insulin resistance, diabetes mellitus, and renal failure and describe signalling mediators and pathways that could be targeted for treatment. The innate immune system includes several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL-1β, and IL-18 thereby initiating an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome can induce the production of various proinflammatory cytokines and are critically involved in inflammatory responses in pancreatic islets, and in adipose, liver and kidney tissues. This Review describes how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction resulting in insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways could be beneficial for the treatment of diabetes mellitus and diabetic nephropathy.

Objectives\\nOwing to recent changes in our understanding of the underlying cause of chronic kidney disease (CKD), the importance of lifestyle modification for preventing the progression of kidney dysfunction and complications has become obvious. In addition, effective cooperation between general physicians (GPs) and nephrologists is essential to ensure a better care system for CKD treatment. In this cluster-randomized study, we studied the effect of behavior modification on the outcome of early- to moderate-stage CKD.\\n\\nDesign\\nStratified open cluster-randomized trial.\\n\\nSetting\\nA total of 489 GPs belonging to 49 local medical associations (clusters) in Japan.\\n\\nParticipants\\nA total of 2,379 patients (1,195 in group A (standard intervention) and 1,184 in group B (advanced intervention)) aged between 40 and 74 years, who had CKD and were under consultation with GPs.\\n\\nIntervention\\nAll patients were managed in accordance with the current CKD guidelines. The group B clusters received three additional interventions: patients received both educational intervention for lifestyle modification and a CKD status letter, attempting to prevent their withdrawal from treatment, and the group B GPs received data sheets to facilitate reducing the gap between target and practice.\\n\\nMain outcome measure\\nThe primary outcome measures were 1) the non-adherence rate of accepting continuous medical follow-up of the patients, 2) the collaboration rate between GPs and nephrologists, and 3) the progression of CKD.\\n\\nResults\\nThe rate of discontinuous clinical visits was significantly lower in group B (16.2% in group A vs. 11.5% in group B, p = 0.01). Significantly higher referral and co-treatment rates were observed in group B (p<0.01). The average eGFR deterioration rate tended to be lower in group B (group A: 2.6±5.8 ml/min/1.73 m2/year, group B: 2.4±5.1 ml/min/1.73 m2/year, p = 0.07). A significant difference in eGFR deterioration rate was observed in subjects with Stage 3 CKD (group A: 2.4±5.9 ml/min/1.73 m2/year, group B: 1.9±4.4 ml/min/1.73 m2/year, p = 0.03).\\n\\nConclusion\\nOur care system achieved behavior modification of CKD patients, namely, significantly lower discontinuous clinical visits, and behavior modification of both GPs and nephrologists, namely significantly higher referral and co-treatment rates, resulting in the retardation of CKD progression, especially in patients with proteinuric Stage 3 CKD.

Background IgG4-related disease has attracted wide attention recently. It is characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive plasma cells into multiple organs, with the kidney being one representative target. Although several sets of diagnostic criteria for autoimmune pancreatitis (AIP) are available and renal lesion is recognized as an extra-pancreatic manifestation of AIP, it is difficult to differentiate IgG4-related tubulointerstitial nephritis (TIN) without AIP from other types of TIN. To clarify the entity of IgG4-related kidney disease (IgG4-RKD) and support in-depth studies, the Japanese Society of Nephrology has established a working group to prepare diagnostic criteria for IgG4-RKD. Method The working group analyzed 41 patients with IgG4-RKD, and collected the following data to devise a diagnostic algorithm and diagnostic criteria for IgG4-RKD: clinical features including extra-renal organ involvement, urinalysis and serological features including serum IgG4 levels, imaging findings demonstrated by computed tomography (CT), renal histology with IgG4 immunostaining, and response to steroid therapy. Results The conditions for criteria are as follows. (1) Presence of some kidney damage, as manifested by abnormal urinalysis or urine marker(s) and/or decreased kidney function with either elevated serum IgG level, hypocomplementemia, or elevated serum IgE level. (2) Kidney imaging studies showing abnormal renal imaging findings, i.e., multiple low density lesions on enhanced CT, diffuse kidney enlargement, hypovascular solitary mass in the kidney, and hypertrophic lesion of the renal pelvic wall without irregularity of the renal pelvic surface. (3) Serum IgG4 level exceeding 135 mg/dl. (4) Renal histology showing two abnormal findings: (a) dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/high power field (HPF) and/or ratio of IgG4-positive plasma cells/IgG positive plasma cells >40%. (b) Characteristic ‘storiform’ fibrosis surrounding nests of lymphocytes and/or plasma cells. (5) Extra-renal histology showing dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/HPF and/or ratio of IgG4-positive plasma cells/IgG-positive plasma cells >40%. The diagnosis is classified into 3 stages of definite, probable and possible according to the combinations of the above conditions. Thirty-nine cases (95.1%) were diagnosed with IgG4-RKD according to the criteria. Conclusion The provisional criteria and algorithm appear to be useful for clarifying the entity of IgG4-RKD and seeking underlying IgG4-RKD cases; however, further experience is needed to confirm the validity of these criteria.

Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD). We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification. The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075). Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.

Background We previously estimated the prevalence of chronic kidney disease (CKD) stages 3–5 at 19.1 million based on data from the Japanese annual health check program for 2000–2004 using the Modification of Diet in Renal Disease (MDRD) equation multiplied by the coefficient 0.881 for the Japanese population. However, this equation underestimates the GFR, particularly for glomerular filtration rates (GFRs) of over 60 ml/min/1.73 m 2 . We did not classify the participants as CKD stages 1 and 2 because we did not obtain proteinuria data for all of the participants. We re-estimated the prevalence of CKD by measuring proteinuria using a dipstick test and by calculating the GFR using a new equation that estimates GFR based on data from the Japanese annual health check program in 2005. Methods Data were obtained for 574,024 (male 240,594, female 333,430) participants over 20 years old taken from the general adult population, who were from 11 different prefectures in Japan (Hokkaido, Yamagata, Fukushima, Tochigi, Ibaraki, Tokyo, Kanazawa, Osaka, Fukuoka, Miyazaki and Okinawa) and took part in the annual health check program in 2005. The glomerular filtration rate (GFR) of each participant was computed from the serum creatinine value using a new equation: GFR (ml/min/1.73 m 2 ) = 194 × Age −0.287  × S-Cr −1.094  (if female × 0.739). The CKD population nationwide was calculated using census data from 2005. We also recalculated the prevalence of CKD in Japan assuming that the age composition of the population was same as that in the USA. Results The prevalence of CKD stages 1, 2, 3, and 4 + 5 were 0.6, 1.7, 10.4 and 0.2% in the study population, which resulted in predictions of 0.6, 1.7, 10.7 and 0.2 million patients, respectively, nationwide. The prevalence of low GFR was significantly higher in the hypertensive and proteinuric populations than it was in the populations without proteinuria or hypertension. The prevalence rate of CKD in Japan was similar to that in the USA when the Japanese general population was age adjusted to the US 2005 population estimate. Conclusion About 13% of the Japanese adult population—approximately 13.3 million people—were predicted to have CKD in 2005.

It is well-known that hypertension exacerbates chronic kidney disease (CKD) progression, however, the optimal target blood pressure (BP) level in patients with CKD remains unclear. This study aimed to assess the optimal BP level for preventing CKD progression. The risk of renal outcome among different BP categories at baseline as well as 1 year after, were evaluated using individual CKD patient data aged between 40 and 74 years from FROM-J [Frontier of Renal Outcome Modifications in Japan] study. The renal outcome was defined as ≥ 40% reduction in estimated glomerular filtration rate to < 60 mL/min/1.73 m 2 , or a diagnosis of end stage renal disease. Regarding baseline BP, the group of systolic BP (SBP) 120–129 mmHg had the lowest risk of the renal outcome, which increased more than 60% in SBP ≥ 130 mmHg group. A significant increase in the renal outcome was found only in the group of diastolic BP ≥ 90 mmHg. The group of BP < 130/80 mmHg had a benefit for lowering the risk regardless of the presence of proteinuria, and it significantly reduced the risk in patients with proteinuria. Achieving SBP level < 130 mmHg after one year resulted in a 42% risk reduction in patients with SBP level ≥ 130 mmHg at baseline. Targeting SBP level < 130 mmHg would be associated with the preferable renal outcome. Clinical Trial Registration-URL: https://www.umin.ac.jp/ctr/ . Unique identifier: UMIN000001159 (16/05/2008).

Aim/Introduction Senescence is a key driver of age‐related kidney dysfunction, including diabetic kidney disease. Oxidative stress activates cellular senescence, induces abnormal glycolysis, and is associated with pyruvate kinase muscle isoform 2 (PKM2) dysfunction; however, the mechanisms linking PK activation to cellular senescence have not been elucidated. We hypothesized that PKM2 activation by TEPP‐46 could suppress oxidative stress‐induced renal tubular cell injury and cellular senescence. Materials and Methods To investigate the effects of PKM2 activation on oxidative stress‐induced cellular senescence, we conducted β‐galactosidase staining and western blot analysis on human primary renal tubular cells (pRPTECs) treated with hydrogen peroxide with or without TEPP‐46. IL‐6 levels and glycolytic flux were measured. Cell viability and apoptosis were assessed via the MTS assay and caspase 3 cleavage. For in vivo experiments, we utilized CD‐1db/db mice, a fibrotic type 2 diabetes model, which exhibit kidney fibrosis. After 4 weeks of TEPP‐46 intervention, kidney fibrosis and the expression of senescence markers were analyzed. Results In pRPTECs, hydrogen peroxide increased the number of β‐galactosidase‐positive cells, the expression of senescence markers (p16, p21, p53), and p38 phosphorylation; co‐incubation with TEPP‐46 suppressed these alterations. Hydrogen peroxide reduced cell viability, induced apoptosis, mesenchymal alterations, and increased lactate production and IL‐6 secretion; co‐incubation with TEPP‐46 or a p38 inhibitor mitigated these effects. In CD‐1db/db mice, TEPP‐46 intervention suppressed apoptosis, fibrosis, and tended to reduce the levels of senescence‐associated molecules in the kidney. Conclusions PKM2 activation could be a molecular target for protection against senescence‐associated organ damage, including diabetic kidney disease. PKM2 activator TEPP46 inhibited hydrogen peroxide‐induced cellular senescence in proximal tubular cells and suppressed kidney fibrosis in CD‐1 db/db mice with a trend toward suppression of certain senescence markers. But, hydrogen peroxide‐stimulated apoptosis and reduction in cell viability were both inhibited by TEPP46. This article provides that deficiency in PK enzyme activity contributes to the induction of cellular senescence in proximal tubule cells.