A multi-trait GWAS identifies novel genes influencing albuminuria.

BACKGROUND: Albuminuria is common and associated with increased risks of end-stage kidney disease and cardiovascular diseases, yet its underlying mechanism remains obscure. Previous genome-wide association studies (GWAS) for albuminuria did not consider gene pleiotropy and primarily focused on European ancestry populations. This study adopted a multi-trait analysis of GWAS (MTAG) approach to jointly analyze two vital kidney traits, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) to identify and prioritize the genes associated with UACR. METHODS: Data from the Taiwan Biobank from 2012 to 2023 were analyzed. GWAS of UACR and eGFR were performed separately and the summary statistics from these GWAS were jointly analyzed using MTAG. The polygenic risk scores (PRS) of UACR were constructed for validation. The UACR-associated loci were further fine-mapped and prioritized based on their deleteriousness, eQTL associations, and relatedness to Mendelian kidney diseases. RESULTS: MTAG analysis of the UACR revealed 15 genetic loci, including 12 novel loci. The PRS for UACR was significantly associated with urinary albumin level (P < 0.001) and microalbuminuria (P = 0.001 ∼ 0.045). A list of priority genes was generated. Twelve genes with high priority included the albumin endocytic receptor gene LRP2 and ciliary genes  IFT172. CONCLUSIONS: The findings of this multi-trait GWAS suggest that primary cilia play a role in sensing mechanical stimuli, leading to albumin endocytosis. The priority list of genes warrants further translational investigation to reduce albuminuria.

Update of pericytes function and their roles in kidney diseases.

Studies have highlighted the significant involvement of kidney pericytes in renal fibrosis. Kidney pericytes, classified as interstitial mesenchymal cells, are extensively branched, collagen-producing cells that closely interact with endothelial cells. This article aims to provide an overview of the recent advancements in understanding the physiological functions of pericytes and their roles in kidney diseases. In a healthy kidney, pericytes have essential physiological function in angiogenesis, erythropoietin (EPO) production, and the regulation of renal blood flow. Nevertheless, pericyte-myofibroblast transition has been identified as the primary cause of disease progression in acute kidney injury (AKI)-to-chronic kidney disease (CKD) continuum. Our recent research has demonstrated that hypoxia-inducible factor-2α (HIF-2α) regulates erythropoietin production in pericytes. However, this production is repressed by EPO gene hypermethylation and HIF-2α downregulation which were induced by transforming growth factor-ß1-activated DNA methyltransferase and activin receptor-like kinase-5 signaling pathway during renal fibrosis, respectively. Additionally, AKI induces epigenetic modifications in pericytes, rendering them more prone to extracellular matrix production, cell migration and proliferation, thereby contributing to subsequent capillary rarefaction and renal fibrosis. Further investigation into the specific functions and roles of different subpopulations of pericytes may contribute for the development of targeted therapies aimed at attenuating kidney disease and mitigating their adverse effects.

Comparative clinical significance and biological roles of PFKFB family members in oral squamous cell carcinoma.

BACKGROUND: Cancer cells promote glycolysis, which supports rapid cell growth and proliferation. Phosphofructokinase-fructose bisphosphatases (PFKFBs), a family of bidirectional glycolytic enzymes, play key roles in the regulation of glycolysis in many types of cancer. However, their roles in oral squamous cell carcinoma (OSCC), the most common type of oral cancer, are still unknown. METHODS: We compared the gene expression levels of PFKFB family members and analyzed their clinical significance in oral cancer patients, whose clinical data were obtained the Cancer Genome Atlas database. Moreover, real-time quantitative polymerase chain reaction, western blotting, assays for cell viability, cell cycle, cell migration and viability of cell spheroid were performed in scramble and PFKFB-silenced cells. RESULTS: We discovered that PFKFB3 expression in tumor tissues was slightly higher than that in tumor adjacent normal tissues but that PFKFB4 expression was significantly higher in the tumor tissues of oral cancer patients. High PFKFB3 and PFKFB4 expression had different effects on the prognosis of oral cancer patients with different clinicopathological outcomes. Our data showed that PFKFB3 and PFKFB4 play different roles; PFKFB3 is involved in cell viability, G2/M cell cycle progression, invasion, and migration, whereas PFKFB4 is involved in the drug resistance and cancer stemness of OSCC cells. Furthermore, oral cancer patients with co-expressions of PFKFB3/cell cycle or EMT markers and PFKFB4/stemness markers had poor prognosis. CONCLUSIONS: PFKFB3 and PFKFB4 play different biological roles in OSCC cells, which implying that they might be potential prognostic biomarkers for OSCC patients with certain clinicopathological outcomes.

A competing risk predictive model for kidney failure in patients with advanced chronic kidney disease.

BACKGROUND/PURPOSE: Predictive modeling aids in identifying patients at high risk of adverse events. Using routinely collected data, we report a competing risk prediction model for kidney failure. METHODS: A total of 5138 patients with CKD stages 3b-5 were included and randomized into the development and validation cohorts at a ratio of 7:3. The outcome was end-stage kidney disease, defined as the initiation of dialysis or kidney transplantation. All patients were followed-up until December 31, 2020. A Fine and Gray model was applied to estimate the sub-hazard ratio of kidney failure, with death as a competing event. RESULTS: In the development cohort, the mean age was 67.6 ± 13.9 years and 60 % were male. The mean index eGFR and median urinary protein-creatinine ratio (UPCR) were 26.5 ± 12.8 mL/min/1.73 m2 and 1051 mg/g, respectively. The median follow-up duration was 1051 days. The proportion of patients with kidney failure and death was 25.4 % and 14.1 %, respectively. Four models were applied, including eGFR, age, sex, UPCR, systolic and diastolic blood pressure, serum albumin, phosphate, uric acid, haemoglobin, and potassium levels had the best goodness of fit. All models had good discrimination with time-to-event c statistics of 0.89-0.95 in the development cohort and 0.86-0.95 in the validation cohort. The prediction models showed excellent and fairly good calibration at 2 and 5-year risk, respectively. CONCLUSION: Using real-world data, our competing risk model can accurately predict progression to kidney failure over 2 years in patients with advanced CKD.

Subgingival Microbiome in Rheumatoid Arthritis Patients with Periodontitis.

Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched age, gender, and diabetes statuses: group AM (all of the matched participants), group PD (periodontally diseased), and group PH (periodontally healthy). Their subgingival microbial composition was determined by V3-V4 16S rRNA gene sequencing. Significant differences in subgingival microbial clustering between the RA patients and controls were observed in groups AM and PD. Among the taxa enriched in RA, Aminipila butyrica and Peptococcus simiae were the only two species displaying positive correlation to the level of anti-citrullinated protein antibodies (ACPAs) in both of the groups. Surprisingly, the median of relative abundances of A. butyrica and P. simiae were 0% in the controls of group PD. Furthermore, a gene encoding arginine deiminase with the capability to produce citrulline was addressed in the complete genome sequence of A. butyrica. This is the first study to elucidate the important roles of A. butyrica and P. simiae as periodontal bacteria leading to RA possibly through the induction of ACPA production.

Highly educated patients have lower dental compliance during the COVID-19 pandemic: an observational study.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) is rapidly changed medical habits, and dental clinics have been forced to adapt. This study explored the pandemic-induced changes in patient utilization of dental services to assist practitioners in responding efficiently to similar public crises as references in the future. METHODS: We retrospectively analyzed the correlation between patient profiles and dental visits attendance within 2 months before and during the outbreak. RESULTS: A total of 332 patients, 210 women and 122 men (total number of visits: 1068) were enrolled in this study. A significantly lower attendance rate was noted during the COVID-19 period (70.3%) than prior to the pandemic (83.4%). The rate of return visits for patients with a high education level during the COVID-19 period was significantly reduced from 96.5 to 93.1%. In addition, the number of days between two visits significantly increased during the pandemic. CONCLUSIONS: Our results indicate that, during the pandemic period, the attendance rates of return dental appointments decreased, and the rate of missed appointments for patients with a high educational levels was higher than that of patients with a low educational level. CLINICAL RELEVANCE: Preventive management of these patients who are easy to miss dental appointments may enable more effective use of medical resources.

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis.

Prolyl hydroxylase domain enzyme (PHD) inhibitors are effective in the treatment of chronic kidney disease (CKD)-associated anemia by stabilizing hypoxia inducible factor (HIF), thereby increasing erythropoietin and consequently erythropoiesis. However, concern for CKD progression needs to be addressed in clinical trials. Although pre-clinical studies showed an anti-inflammatory effect in kidney disease models, the effect of PHD inhibitors on kidney fibrosis was inconsistent probably because the effects of HIF are cell type and context dependent. The major kidney erythropoietin-producing cells are pericytes that produce erythropoietin through HIF-2α-dependent gene transcription. The concern for the impact of HIF in pericytes on kidney fibrosis arises from the fact that pericytes are the major precursor cells of myofibroblasts in CKD. Since cells expressing Gli1 fulfill the morphologic and anatomic criteria for pericytes, we induced Gli1+ cell-specific HIF stabilization or knockout to study the impact of HIF in pericytes on kidney pathology of mice with or without fibrotic injury induced by unilateral ureteral obstruction. Compared with the littermate controls, mice with pericyte-specific HIF stabilization due to von Hippel-Lindau protein or PHD2 knockout showed increased serum erythropoietin and polycythemia rather than a discernible difference in kidney fibrosis. Compared with Gli1+ pericytes sorted from littermate controls, Gli1+ pericytes sorted from PHD2 knockout mice showed increased erythropoietin gene expression rather than discernible changes in Col1a1 or Acta2 expression. Furthermore, pericyte-specific knockout of HIF-1α or HIF-2α did not affect kidney fibrosis. Thus, our study supports the absence of negative effects of PHD inhibitors on kidney fibrosis of mice despite HIF stabilization in pericytes.

Completion and Adverse Drug Events of Latent Tuberculosis Infection Treatment in Patients Receiving Dialysis: Predictors and Impacts of Different Regimens in a Prospective Cohort Study.

Although patients with end-stage renal disease receiving maintenance hemodialysis are at high risk for tuberculosis, the optimal treatment regimen for latent tuberculosis infection (LTBI) in this group has scarcely been studied for predictors of completion rate and adverse drug events (ADE). We prospectively enrolled dialysis patients for LTBI intervention from three medical centers in Taiwan. LTBI treatments were 3 months of weekly rifapentine plus isoniazid (3HP) and 9 months of daily isoniazid (9H). Completion rate, ADE, and reasons for treatment termination were recorded. Factors associated with treatment termination and ADE were analyzed using multivariate logistic regression. In all, 91 treatment courses (41 9H and 50 3HP) were surveyed. The completion rates were 61% for 9H and 82% for 3HP (P = 0.046). Use of 9H and development of ADE with a grade of ≥2 (≥grade 2 ADE) were associated with treatment termination. Hypersensitivity occurred in 29.2% of subjects in the 3HP group and 10.8% in the 9H group (P = 0.035) and independently correlated with 3HP regimen, diabetes mellitus (DM), and peritoneal dialysis (PD). Similarly, the independent predictors of ≥grade 2 ADE were use of 3HP regimen, presence of DM, and use of PD, whereas ≥grade 3 ADE were associated with eosinophil counts of >700/mm3 after 2 weeks of LTBI treatment even after adjustment for age and gender. In conclusion, for patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk factors for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE.

Transforming growth factor-ß1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells.

BACKGROUND: Renal erythropoietin (EPO)-producing (REP) cells produce EPO through hypoxia-inducible factor (HIF) 2α-activated gene transcription. Insufficient EPO production leads to anemia in patients with chronic kidney disease. Although recombinant EPO is effective to improve anemia, no reliable REP cell lines limit further progress of research and development of novel treatment. METHODS: We screened Epo mRNA expression in mouse fibroblast cell lines. Small interfering RNA specific for HIF1α or HIF2α was transfected to study Epo expression in C3H10T1/2 cells. The effect of transforming growth factor-ß1 (TGF-ß1) on HIF-EPO axis was studied in C3H10T1/2 cells and mice. RESULTS: Similar to mouse REP pericytes, C3H10T1/2 cells differentiated to α-smooth muscle actin+ myofibroblasts after exposure to TGF-ß1. Specific HIF knockdown demonstrated the role of HIF2α in hypoxia-induced Epo expression. Sustained TGF-ß1 exposure increased neither DNA methyltransferase nor methylation of Epas1 and Epo genes. However, TGF-ß1 repressed HIF2α-encoding Epas1 promptly through activating activin receptor-like kinase-5 (ALK5), thereby decreasing Epo induction by hypoxia and prolyl hydroxylase domain inhibitor roxadustat. In mice with pro-fibrotic injury induced by ureteral obstruction, upregulation of Tgfb1 was accompanied with downregulation of Epas1 and Epo in injured kidneys and myofibroblasts, which were reversed by ALK5 inhibitor SB431542. CONCLUSION: C3H10T1/2 cells possessed the property of HIF2α-dependent Epo expression in REP pericytes. TGF-ß1 induced not only the transition to myofibroblasts but also a repressive effect on Epas1-Epo axis in C3H10T1/2 cells. The repressive effect of TGF-ß1 on Epas1-Epo axis was confirmed in REP pericytes in vivo. Inhibition of TGF-ß1-ALK5 signaling might provide a novel treatment to rescue EPO expression in REP pericytes of injured kidney.

A retrospective cohort study of how alveolar ridge preservation affects the need of alveolar ridge augmentation at posterior tooth implant sites.

OBJECTIVES: The aim of this study was to assess whether alveolar ridge preservation (ARP) can reduce the need of ridge augmentation at posterior tooth sites. MATERIAL AND METHODS: This study enrolled patients who received dental implants at posterior tooth sites during 2013-2019. Demographic data and dental treatment histories were collected. Based on healing patterns after tooth extraction, patients were divided into ARP and spontaneous healing (SH) groups. Three surgical treatment plans were devised according to the alveolar bone volume on cone-beam computed tomography (CBCT). The three treatment plans were to perform implant alone, simultaneous guided bone regeneration (GBR) and implantation, and staged GBR before implantation. Statistical analyses were performed to determine relationships. RESULTS: There were 92 implant records in the ARP group and 249 implant records in the SH group. A significant intergroup difference was observed regarding the frequency distribution of the treatment modality of staged GBR before implant (χ 2 = 15.07, p = 0.0005). Based on the implant alone treatment modality and simple logistic regression, the SH pattern was related to staged GBR before implant (SH vs. ARP: crude odds ratio (OR) = 4.65, 95% confidence interval (CI) = 2.15-11.61, p = 0.0003). After adjusting confounding factors, the risk was still significant (adjusted OR = 5.02, 95% CI = 2.26-12.85, p = 0.0002). CONCLUSIONS: The study results suggested that ARP is more likely to lead to the treatment modality of implant alone and reduce the need for staged GBR before implantation. CLINICAL RELEVANCE: This study describes ARP capable of minimizing the need for staged GBR before implantation and shortening the treatment duration.

Recommendations for treating stage I-III periodontitis in the Taiwanese population: A consensus report from the Taiwan Academy of Periodontology.

BACKGROUND/PURPOSE: Based on the fundamental of the S3-level clinical practice guideline (CPG) for treating stage I-III periodontitis developed by the European Federation of Periodontology (EFP), this consensus report aimed to develop treatment recommendations for treating periodontitis in the Taiwanese population. METHODS: The report was constructed by experts from the Taiwan Academy of Periodontology. The following topics were reviewed: (a) the prevalence of periodontitis in Asia and current status of treatment in Taiwan; (b) specific anatomical considerations for treating periodontitis in Asians; (d) educational and preventive interventions and supragingival plaque control; (d) subgingival instrumentation and adjunctive treatment; (e) surgical periodontal therapy; and (f) maintenance and supportive periodontal care. Recommendations were made according to the evidences from the EFP CPG, the published literature and clinical studies in Asians, and the expert opinions. RESULTS: The treatment recommendations for the Taiwanese population were generally in parallel with the EFP CPG, and extra cautions during treatment and maintenance phases were advised due to the anatomical variations, such as shorter root trunk, higher prevalence of supernumerary distolingual root and lingual bony concavity in mandibular posteriors, and thinner anterior labial plate, of the Asian population. CONCLUSION: The EFP CPG could be adopted for treating periodontitis and maintaining periodontal health of the Taiwanese population, and anatomical variations should be cautious when the treatment is delivered.

Heart rate variability as a predictor of rapid renal function deterioration in chronic kidney disease patients.

AIM: Autonomic dysfunction contributes to cardiovascular morbidity/mortality and can be evaluated with heart rate variability (HRV). This study is to evaluate the prognostic significance of HRV on renal function in non-dialysis chronic kidney disease (CKD) patients. METHODS: We enrolled 326 non-dialysis CKD patients in this prospective observational study. The median follow-up period was 2.02 years. Five-minutes of electrocardiography recordings obtained at enrolment were reprocessed to assess HRV. Five frequency-domain measures and one time-domain measures were obtained. Rapid CKD progression was defined as annual estimated glomerular filtration rate (eGFR) loss over 30% per year or eGFR decline rate over 3 mL/min per 1.73 m2 per year. The prevalence of abnormal HRV, associated factors of HRV and impact of HRV on the risk of CKD progression were analyzed. RESULTS: The abnormality of HRV increased along with the severity of CKD. In patients with stage 5 CKD, the proportion of abnormal ln(low frequency power) (LF), ln(high frequency power) (HF), lnLF/HF were 69.5, 52.8 and 50%, respectively. Associated factors of HRV included advanced CKD, diabetes mellitus, serum albumin, severe proteinuria, Beck Anxiety Inventory score, erythropoietin use, renin-angiotensin system inhibitors and heart failure. Multivariate logistic regression model analysis revealed lower lnLF/HF, hypertension and severe proteinuria were the risk factors of rapid CKD progression. CONCLUSION: The prevalence of autonomic dysfunction measured by HRV among each stage CKD patients is different. Most patients in advanced CKD stage have reduced values of HRV parameters. The estimation of lnLF/HF also provided prognostic information on CKD progression in addition to classical risk factors.

Old age is a positive modifier of renal outcome in Taiwanese patients with stages 3-5 chronic kidney disease.

BACKGROUND: The incidence of end-stage renal disease (ESRD) is increasing in elderly patients with chronic kidney disease (CKD). This contradicts the general notion that elderly people are more likely to die than to ever reach ESRD. And racial disparity in relation to age on kidney disease outcomes has always been a subject of research interest. AIMS: We investigated the effect of age on outcome in a cohort with stages 3-5 CKD patients by age category. METHODS: A total of 430 patients with a mean age of 65.6 years were enrolled and followed till death, ESRD, or end of 2015. Multivariable Cox regression was used to identify predictors of all-cause mortality. Competing risk-adjusted Cox regression was used to identify determinants of ESRD. The median follow-up was 7.3 (interquartile range 8.8) years. RESULTS: Cox regression showed old age and low mean arterial pressure were predictors of mortality before and after onset of ESRD. Competing risk analysis revealed patients aged 20-39 years and 40-64 years exhibited greater risks of ESRD, compared to those aged over 75 years. These effects of age on outcomes occurred independently of traditional risk factors such as low estimated glomerular filtration rate and high proteinuria. CONCLUSIONS: Age over 75 years is associated with decreased risk for ESRD even after adjustment for competing mortality. Given the global trends in population aging, there is a need to develop age-specific strategies, on top of the existing stage-based measures, to optimize the management of CKD in the elderly.

Sleep and emotional disturbance in patients with non-dialysis chronic kidney disease.

BACKGROUND/PURPOSE: Sleep disorder and depression are prevalent in patients on dialysis but less investigated in earlier-stage chronic kidney disease (CKD) patients. We aimed to evaluate the prevalence of depression, anxiety, health anxiety, and sleep disturbance and explore the association between CKD stage, psychological symptoms and sleep quality. METHODS: We recruited 326 patients with CKD (stage 1-5) not on dialysis from the nephrology clinic. All participants completed the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), Health Anxiety Questionnaire (HAQ), and Pittsburgh Sleep Quality Index (PSQI). Chi-square tests were used to assess the difference in psychological symptoms between CKD stages. Multiple linear regression was employed to assess relationships among selected variables and sleep/emotional disturbance. RESULTS: Clinically significant depression, anxiety, health anxiety, and sleep disturbance were found in 3.1%, 3.1%, 18%, and 36.2% of the patients, respectively. BDI-II, BAI, HAQ, and PSQI scores did not significantly differ across CKD stages. In a multiple linear regression model that included psychological variables, BDI-II score had a statistically significant association with PSQI score (ß = 0.418, p < 0.001). CONCLUSION: Depressive symptoms were associated with sleep quality of patients with earlier-stage CKD. However, there was no significant association between CKD stage and sleep disturbance or other psychological symptoms.

The relationship of anti-phospholipase A2 receptor antibody and C5a complement with disease activity and short-term outcome in idiopathic membranous nephropathy.

BACKGROUND: The binding of anti-phospholipase A2 receptor (anti-PLA2R) antibody to podocyte and complement activation is the mechanisms of idiopathic membranous nephropathy (IMN). C5a, a complement activation end product, is a strong inflammatory cell stimulator and can influence the behavior of T cells and dendritic cells. This study examined the etiology-disease relationship and significance of auto-antibody and C5a with short-term remission. METHOD: Plasma anti-PLA2R antibody and C5a were measured with the blood samples that were collected when patients were admitted for renal biopsy. The deposition of IgA, IgG, IgM, C1q and C3c in glomerulus was graded according to immunofluorescence staining. The relationship of anti-PLA2R antibody with C5a, glomerular immunoglobulin and complement deposition was examined. Antibody and C5a levels as predictors of short-term remission were also examined. RESULTS: In 72 IMN patients, 50 patients had positive plasma anti-PLA2R antibody. The antibody had positive correlation to proteinuria. Patients with high grade IgG or C3c, but not IgA/IgM/C1q, deposition had higher anti-PLA2R antibody titers. C5a was increased in IMN patients, but had no correlation with anti-PLA2R antibody or proteinuria. The analysis revealed that C5a, not initial anti-PLA2R antibody, was a predictor associated with 12-month remission in patients receiving immunosuppression with multivariate-adjusted OR 0.74 (95% CI, 0.58-0.94, P = 0.01). CONCLUSION: This study provides indirect evidences of etiology-disease relationship of anti-PLA2R antibody in IMN patients. The role of C5a, a predictor of remission, in the disease course of MN and the influences on inflammatory cells in MN patients is worth to be clarified.

Erythropoietin modulates macrophages but not post-ischemic acute kidney injury in mice.

BACKGROUND/PURPOSE: Substantial progress was made in acute kidney injury (AKI) over the past 10 years, but no therapeutic interventions have been shown to prevent AKI or accelerate functional recovery after injury. A large number of preclinical studies supports the use of recombinant human erythropoietin (rHuEPO) to prevent AKI, but the clinical trial data are inconclusive. To address concerns about preclinical study design and reporting in AKI, we here presented our rigorous experiments on the use of rHuEPO in a mouse model simulating the most common post-ischemic AKI in patients. METHODS: Use of saline vehicle or rHuEPO (100 or 1000 U/KgBW) in mice subjected to AKI induced by ischemia-reperfusion injury of left kidney 2 weeks after right nephrectomy (NX + IRI). RESULTS: NX + IRI resulted in a reproducible AKI model. Use of rHuEPO as a pretreatment or posttreatment did not affect AKI severity, functional recovery, and mouse survival regardless of gender, injury severity, or doses of rHuEPO. Administering rHuEPO with 1000 U/KgBW did increase hematocrit and modulate AKI kidney macrophages by Nos2 downregulation and Ccl17 upregulation. Active expression of erythropoietin receptor (EPOR) was not identified in renal cells by lineage tracing study, whereas expression of colony-stimulating factor 2 receptor ß (CSF2Rß) was identified in kidney macrophages and upregulated after AKI. Both EPOR and CSF2Rß were identified in cultured bone marrow derived macrophages, possibly mediated the robust inhibition of cytokine-induced phenotype switching by rHuEPO. CONCLUSION: Use of rHuEPO can modulate macrophage function but not the post-ischemic AKI severity, functional recovery and survival in mice.

Role of renin-angiotensin system in acute kidney injury-chronic kidney disease transition.

Acute kidney injury (AKI) can increase the risk of developing incident chronic kidney disease (CKD). The severity, frequency and duration of AKI are crucial predictors of poor renal outcome. A repair process after AKI can be adaptive and kidney recovers completely after a mild injury. However, severe injury will lead to a maladaptive repair, which frequently progresses to nephron loss, vascular rarefaction, chronic inflammation and fibrosis. Although different mechanisms underlying AKI-CKD transition have been extensively discussed, no definite intervention has been proved effective to block or to retard the transition until recently. In CKD, renin-angiotensin system (RAS) inhibitor has been proved effective to slow down disease progression. Furthermore, RAS needs to be highlighted again in AKI-CKD transition because recent animal studies have shown the activation of intra-renal RAS after AKI, and RAS blockade can reduce the ensuing CKD and mortality. In patients with the complete renal recovery after AKI, administration of RAS inhibitor is associated with reduced risk of subsequent CKD as well. In this article, we will demonstrate the role of RAS in AKI-CKD transition comprehensively. We will then emphasize the promising effect of RAS inhibitor on CKD prevention in patients recovering from AKI based on evidence from the bench to clinical research. All of these discussions will contribute to the establishment of reliable monitoring and therapeutic strategies for patients with functional recovery from AKI who can be most easily ignored.

Novel insights into acute kidney injury-chronic kidney disease continuum and the role of renin-angiotensin system.

Acute kidney injury (AKI) is an independent risk factor for chronic kidney disease (CKD). If injury is mild, a repair process can be adaptive and lead to complete renal recovery. However, severe injury will be accompanied by a maladaptive repair which usually leads to nephron loss, fibrosis, vascular rarefaction, and chronic inflammation. Although various mechanisms underlying AKI-CKD transition have been explored, no intervention has been proved effective to block the transition until very recently. A lack of consensus for monitoring renal function and defining renal recovery after AKI should be the reasons for the slow advance in the discovery of a timely pharmacologic treatment to block AKI-CKD transition. Recently, animal studies have shown the activation of renin-angiotensin system (RAS) after AKI. In patients with complete renal recovery after AKI defined as the decrease of serum creatinine level to within 0.3 mg/dL above the baseline, administration of RAS inhibitor can prevent the ensuing CKD. In this review, we will discuss the renal recovery after AKI and the mechanisms underlying AKI-CKD transition. We will then highlight the promising effect of RAS inhibitor on CKD prevention in patients with complete renal recovery from AKI based on the recent clinical evidence.

Early initiation of immunosuppressive treatment in membranous nephropathy patients.

BACKGROUND/PURPOSE: Suggestion for the management of idiopathic membranous nephropathy (IMN) includes 6 months of observation, followed with steroid plus alkylating agent. However, delayed immunosuppression exposes the kidneys to persistent damage. This study aimed to examine the benefit of early immunosuppression in IMN patients. METHODS: A retrospective study was performed. From 1993 to 2013, 161 IMN patients were enrolled. Patients receiving immunosuppression within 6 months after diagnosis were classified as initial-treatment group, whereas other patients as initial-no-treatment group. The clinical outcomes and complication were examined. RESULT: Patients in the initial-treatment group had lower serum albumin concentration, less diabetes, and were younger. Steroid monotherapy is the main immunosuppression (64.5%) in this group. The initial-treatment group had a higher complete and partial remission rate than the initial-no-treatment group 6 months (52.9% vs. 35.0%, p=0.05) and 12 months (71.1% vs. 45.0%, p=0.003) after diagnosis. A similar result was seen between initial-steroid monotherapy and initial-no-treatment patients. Early immunosuppression is an independent predictor of remission within 1 year [hazard ratio (HR)=2.09; 95% confidence interval (CI)=1.25-3.49; p=0.005] and estimated glomerular filtration rate (eGFR) decline over 50% during the follow-up. (HR=0.33; 95% CI=0.13-0.86; p=0.02). The initial-treatment group also had a low frequency of eGFR decline over 50% (p=0.001) and low combined end-stage renal disease/mortality (p=0.001) compared with the initial-no-treatment group, but without more immunosuppression-related complication. CONCLUSION: In contrast to Western countries, early immunosuppression (even steroid monotherapy) in our patients is associated with better remission in the 1st year and renal preserve. Further randomized controlled trials are needed to clarify the benefit of early immunosuppression in IMN patients, especially with oriental ethnic background.