Delay Chronic Kidney Disease Progression Research Articles

#1373 Effect of Astragalus membranaceus normalized acute kidney injury-induced renal conditions corelated with serum carnosine

Abstract Background and Aims Astragalus membranaceus (AM) exhibits various pharmacological effects against several diseases, including chronic kidney disease (CKD) (see http://nccih.nih.gov/health/astragalus). We have previously investigated the correlation between AM and acute kidney injury (AKI), which is an important factor causing CKD pathogenesis or progression. Recently, we demonstrated that old mice showed lethality in response to 20 mg/kg cis-diamminedichloroplatinum (CDDP), which is a general dose used to generate AKI in young mice. AKI also occurred in response to a reduced dose of cisplatin, which was completely reversible in young mice. The administration of AM to mice (20 mg/kg) significantly improved AKI pathology, especially in old mice treated with a reduced dose of cisplatin, thereby demonstrating the therapeutic effect of AM against age-dependent AKI pathogenicity. More recently, we found that serum carnosine levels correlated with renal conditions in AM. Here, we examined the effects associated with serum carnosine levels to prevent AKI and delay CKD progression [1]. Methods Female C57BL/6 mice (52 weeks old) were orally administered either an AM powder mixed with sterilized 0.5% methylcellulose 400 (w/v) (AM group) or only 0.5% methylcellulose 400 (control). Four hours after the most recent dose (20 mg/kg of AM twice a day), 0.5 mg/ml CDDP (reduced dose: 10 mg/kg or 0.9% NaCl for the CG) was injected intraperitoneally into old mice. Subsequently, we measured the blood serum urea nitrogen (BUN) and creatinine (CRE) levels, which are biomarkers of AKI, and assessed histochemical changes in kidney sections stained with anti-CD3 and anti-CD68 antibodies 20 h and 3 d after CDDP injection (n = 6 per group). Thereafter, serum carnosine levels in the samples collected from each sample (n = 6 per group) were determined using a carnosine ELISA kit (Novus, NBP2-75013). Data were analyzed statistically using PRISM software, and statistical significance was set at P = 0.05. Results Higher susceptibility to a half CDDP dose in old mice was indicated by increased BUN levels and the histological damage caused to renal tubule epithelial cells and glomeruli; however, no pathological change was observed in younger mice. Histochemical analysis of old mice showed a significant increase in the number of CD3-positive cells following AKI induction; however, AM pretreatment ameliorated these inflammatory conditions. Our recent findings suggest that a correlation exists between the effects of AM and serum carnosine levels. Fig. 1 shows that different serum carnosine levels were observed in old control mice (white box), probably because of age-dependent pathogenesis. However, serum carnosine was concentrated to lower levels after AM administration (orange box), suggesting an age-dependent AM effect. Moreover, owing to the effect of AM on CDDP-AKI, serum carnosine levels changed transiently but significantly in old mice (blue and yellow boxes) within 20 h; this indicates that age-dependent renal conditions were improved by the AM effect and correlated with serum carnosine levels. Conclusion AM administration normalizes the renal pathology caused by age-dependent susceptibility to CDDP-AKI; this is particularly true for older mice, wherein serum carnosine is downregulated but concentrated. Serum carnosine can be effective in preventing AKI pathology in old mice, regardless of the AM effects. We believe that AM can prevent age-dependent accumulation of AKI pathology, thereby facilitating CKD progression.

#837 Information needs and emotional impact when receiving a diagnosis of chronic kidney disease: insights from DISCOVER CKD

Abstract Background and Aims Chronic kidney disease (CKD) is often a silent condition, with symptoms typically not appearing until a large proportion of kidney function has been lost. Therapeutic interventions, e.g., disease-modifying medications, blood pressure and diabetes control, and lifestyle changes, can delay CKD progression, particularly if instigated early. However, psychological distress can reduce adherence to interventions. It is important patients are adequately informed about their diagnosis to improve adherence and reduce the impact of distress. Multinational, real-world data on patient experiences with CKD, particularly about clinical management, treatment patterns and quality of life, are limited. This DISCOVER CKD sub-study aimed to capture the emotions elicited by patients at CKD diagnosis and their perceptions of the information received. Method DISCOVER CKD (NCT04034992) is a multinational cohort study that aims tocharacterise the epidemiology of CKD and describe patient characteristics, CKD progression, clinical outcomes, the patient journey, practice patterns, and clinical management. The current analysis includes a subset of patients from the USA, UK, Japan, and Spain, who participated in 1-2-1 telephone interviews about their CKD experience, including their disease journey and interactions with the healthcare system. Interview topics in DISCOVER CKD were informed by a pilot study that utilised data from PatientsLikeMe, an online network for patients to share personal stories and health data. Qualitative interviews, conducted in the local language by trained interviewers, January–June 2023, lasted ∼60–90 minutes. Transcribed interviews were translated into English for coding (MAXQDA Plus 2022 v22.3.0) and analysis. The study received research ethics board approval and all participants provided written informed consent. Results 103 patients (mean age 63.1 years; 42.7% female; 51.5% with type 2 diabetes) were interviewed. Most had CKD stage 3A (22.3%) or 3B (28.2%); 26.2% had stage 4 or 5 no dialysis and 9.7% were stage 4 (n = 1) or 5 on dialysis. Average time since diagnosis was 9.5 years. Over one-third (38.8%; n = 40/103) of participants did not recall any specific symptoms or signs of CKD prior to diagnosis. Of the pre-diagnosis symptoms reported, the most common was fatigue (21.4%; n = 22/103), then high blood pressure (15.5%; n = 16/103) and swelling (11.7%; n = 12/103). With respect to patient experiences, 55.2% (n = 32/58) said they did not feel sufficient information about CKD was provided at diagnosis and 59.2% (n = 45/76) said no information about their CKD stage was shared. Participants felt overwhelmed and confused about the diagnostic process and struggled to understand the information provided to them, including information about kidney function and symptoms. To supplement their understanding, participants reported using additional sources of information, including the internet (52.9%; n = 36/68), other healthcare professionals (HCPs) (19.1%; n = 13/68), books/printed information (11.8%; n = 8/68) and patient support groups (8.8%; n = 6/68). The most common emotions experienced at the time of diagnosis were worry and fear (28.2%; n = 29/103), then shock/surprise (25.2%; n = 26/103) (Figure). For those reporting no reaction (27.2%; n = 28/103), many stated the condition had no discernible effect on their daily lives. Reasons for fear or worry were related to the potential for disease progression. Conclusion Many patients expressed dissatisfaction with the information they received at their CKD diagnosis. This suggests that HCPs could dedicate more time to explaining the diagnosis, the characteristics and severity of CKD, likelihood of progression, and the benefits of self-management and adherence to intervention. This could be particularly important for those without symptoms at the time of diagnosis, and patients who rely on HCPs as their primary source of information. Patients should be asked what information they want to receive and be directed to trusted sources. The diagnostic process was a highly emotional experience for many patients and counselling or psychological therapy should be considered.

Sodium-Glucose Cotransporter 2 Inhibitors' Mechanism of Action and Use in Kidney Transplantation Recipients: Extended Review and Update

AbstractFive sodium-glucose cotransporters (SGLTs) protein family members are important for regulating blood glucose levels. The essential cotransporters for glucose reabsorption by proximal convoluted tubule are SGLT1 and 2. The newest recommendations advocate GLT2 inhibitors as first-line treatment for type 2 diabetes (T2D) with and without chronic kidney disease (CKD), improving CKD and cardiovascular outcomes.SGLT2 inhibitors enhance kidney transplant patients' life quality, delay CKD progression, have renoprotective effects, and reduce cardiovascular disease in CKD patients, despite minimal published evidence on the usage of SGLT2 inhibitors in kidney transplantation recipients (KTxRs) with T2D or new-onset T2D. They preserve and improve renal function and cardiovascular outcomes in KTxRs. SGLT2 inhibitors' safety issues have prevented KTxRs from participating in major randomized studies, leaving doctors and patients unsure whether these extraordinary drugs outweigh the risks.This extended review analyzes the established mechanisms through which SGLT2 inhibitors exert their positive effects, evaluate the potential advantages and drawbacks of these agents in KTx, and examine the current research findings on using SGLT2 inhibitors in KTxRs. Additionally, potential avenues for future research will be suggested. Different phrases were used to search for recent original and review articles published between January 2020 and November 2023 in PubMed, Google Scholar, Scopus, EMBASE, and Google to achieve the review objectives.

The Etiology of Advanced Chronic Kidney Disease in Southeast Asia: A Meta-analysis.

Chronic kidney disease (CKD) etiology varies greatly between developed and developing countries. In addition, differences in underlying pathogenesis and therapeutic options affect the progression towards advanced-CKD. This meta-analysis aims to identify the etiology of advanced-CKD in Southeast Asia. A systematic search in four electronic-databases and complementary search on national kidney registries and repository libraries was conducted until July 20, 2023. The risk of bias was assessed using Newcastle-Ottawa Scale for observational studies and Version-2 of Cochrane for intervention studies. A random-effects model was used to estimate pooled prevalence. The protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO; Registration ID:CRD42022300786. We analyzed 81 studies involving 32,834 subjects. The pooled prevalence of advanced-CKD etiologies are diabetic kidney disease (DKD) 29.2% (95%CI 23.88-34.78), glomerulonephritis 20.0% (95%CI 16.84-23.38), hypertension 16.8% (95%CI 14.05-19.70), other 8.6% (95%CI 6.97-10.47), unknown 7.5% (95%CI 4.32-11.50), and polycystic kidney disease 0.7% (95%CI 0.40-1.16). We found a significant increase in DKD prevalence from21% (9.2%, 95%CI 0.00-33.01) to 30% (95%CI 24.59-35.97) before and after the year 2000. Among upper-middle-income and high-income countries, DKD is the most prevalent (26.8%, 95%CI 21.42-32.60 and 38.9%, 95%CI 29.33-48.79, respectively), while glomerulonephritis is common in lower-middle-income countries (33.8%, 95%CI 15.62-54.81). The leading cause of advanced-CKD in Southeast Asia is DKD, with a substantial proportion of glomerulonephritis. An efficient screening program targeting high-risk populations (diabetes mellitus and glomerulonephritis) is needed, with the aim to delay CKD progression.

Recovery of Water Homeostasis in Adenine-Induced Kidney Disease Is Mediated by Increased AQP2 Membrane Targeting.

Chronic kidney disease (CKD) represents a major public health burden with increasing prevalence. Current therapies focus on delaying CKD progression, underscoring the need for innovative treatments. This necessitates animal models that accurately reflect human kidney pathologies, particularly for studying potential reversibility and regenerative mechanisms, which are often hindered by the progressive and irreversible nature of most CKD models. In this study, CKD was induced in mice using a 0.2% adenine-enriched diet for 4 weeks, followed by a recovery period of 1 or 2 weeks. The aim was to characterize the impact of adenine feeding on kidney function and injury as well as water and salt homeostasis throughout disease progression and recovery. The adenine diet induced CKD is characterized by impaired renal function, tubular injury, inflammation, and fibrosis. A significant decrease in urine osmolality, coupled with diminished aquaporin-2 (AQP2) expression and membrane targeting, was observed after adenine treatment. Intriguingly, these parameters exhibited a substantial increase after a two-week recovery period. Despite these functional improvements, only partial reversal of inflammation, tubular damage, and fibrosis were observed after the recovery period, indicating that the inclusion of the molecular and structural parameters is needed for a more complete monitoring of kidney status.

Anemia and Hypoxia Impact on Chronic Kidney Disease Onset and Progression: Review and Updates.

Chronic kidney disease (CKD) is caused by hypoxia in the renal tissue, leading to inflammation and increased migration of pathogenic cells. Studies showed that leukocytes directly sense hypoxia and respond by initiating gene transcription, encoding the 2-integrin adhesion molecules. Moreover, other mechanisms participate in hypoxia, including anemia. CKD-associated anemia is common, which induces and worsens hypoxia, contributing to CKD progression. Anemia correction can slow CKD progression, but it should be cautiously approached. In this comprehensive review, the underlying pathophysiology mechanisms and the impact of renal tissue hypoxia and anemia in CKD onset and progression will be reviewed and discussed in detail. Searching for the latest updates in PubMed Central, Medline, PubMed database, Google Scholar, and Google search engines were conducted for original studies, including cross-sectional studies, cohort studies, clinical trials, and review articles using different keywords, phrases, and texts such as "CKD progression, anemia in CKD, CKD, anemia effect on CKD progression, anemia effect on CKD progression, and hypoxia and CKD progression". Kidney tissue hypoxia and anemia have an impact on CKD onset and progression. Hypoxia causes nephron cell death, enhancing fibrosis by increasing interstitium protein deposition, inflammatory cell activation, and apoptosis. Severe anemia correction improves life quality and may delay CKD progression. Detection and avoidance of the risk factors of hypoxia prevent recurrent acute kidney injury (AKI) and reduce the CKD rate. A better understanding of kidney hypoxia would prevent AKI and CKD and leadto new therapeutic strategies.

Venous bicarbonate and CKD progression: a longitudinal analysis by the group-based trajectory model.

Metabolic acidosis accelerates chronic kidney disease (CKD) progression towards kidney failure in animal models. Clinical trials testing the effect of bicarbonate on kidney outcomes are underpowered and/or of suboptimal quality. On the other hand, observational studies testing the same hypothesis are generally based on bicarbonate measured at a single time point. We studied the longitudinal relationship between repeated venous bicarbonate levels and a predefined composite renal outcome (a ≥30% estimated glomerular filtration rate reduction, dialysis or transplantation) by using group-based trajectory model (GBTM) analysis. The GBTM analysis was used to classify patients based on individual bicarbonate levels over time. The relationship between trajectory groups and renal outcomes was investigated using crude and adjusted Cox regression models. A total of 528 patients with stage 2-5 CKD were included in the analysis. The GBTM analysis identified four distinct trajectories of bicarbonate levels: low, moderate, moderate-high and high. During the follow-up period, 126 patients experienced the combined renal endpoint. The hazard rate of renal events decreased dose-dependently from the lowest to the highest bicarbonate trajectory. After adjusting for potential confounders, there was a 63% risk reduction for the composite renal endpoint for patients in the high trajectory category compared with those in the low trajectory category. The study found that higher bicarbonate trajectories were associated with a lower risk of adverse renal outcomes in CKD patients. These results suggest that strategies to maintain higher bicarbonate levels may benefit patients with CKD. However, further high-quality randomised trials are needed to confirm these findings and recommend bicarbonate supplementation as a strategy to delay CKD progression.

The Microbiome and Protein Carbamylation: Potential Targets for Protein-Restricted Diets Supplemented with Ketoanalogues in Predialysis Chronic Kidney Disease.

In chronic kidney disease (CKD), metabolic derangements resulting from the interplay between decreasing renal excretory capacity and impaired gut function contribute to accelerating disease progression and enhancing the risk of complications. To protect residual kidney function and improve quality of life in conservatively managed predialysis CKD patients, current guidelines recommend protein-restricted diets supplemented with essential amino acids (EAAs) and their ketoanalogues (KAs). In clinical studies, such an approach improved nitrogen balance and other secondary metabolic disturbances, translating to clinical benefits, mainly the delayed initiation of dialysis. There is also increasing evidence that a protein-restricted diet supplemented with KAs slows down disease progression. In the present review article, recent insights into the role of KA/EAA-supplemented protein-restricted diets in delaying CKD progression are summarized, and possible mechanistic underpinnings, such as protein carbamylation and gut dysbiosis, are elucidated. Emerging evidence suggests that lowering urea levels may reduce protein carbamylation, which might contribute to decreased morbidity and mortality. Protein restriction, alone or in combination with KA/EAA supplementation, modulates gut dysbiosis and decreases the generation of gut-derived uremic toxins associated, e.g., with cardiovascular disease, inflammation, protein energy wasting, and disease progression. Future studies are warranted to assess the effects on the gut microbiome, the generation of uremic toxins, as well as markers of carbamylation.

Probiotics and Fecal Transplant: An Intervention in Delaying Chronic Kidney Disease Progression?

Chronic kidney disease (CKD) is a global health challenge affecting nearly 700 million people worldwide. In the United States alone, the Medicare costs for CKD management has reached nearly USD 80 billion per year. While reversing CKD may be possible in the future, current strategies aim to slow its progression. For the most part, current management strategies have focused on employing Renin Angiotensin Aldosterone (RAS) inhibitors and optimizing blood pressure and diabetes mellitus control. Emerging data are showing that a disruption of the gut-kidney axis has a significant impact on delaying CKD progression. Recent investigations have documented promising results in using microbiota-based interventions to better manage CKD. This review will summarize the current evidence and explore future possibilities on the use of probiotics, prebiotics, synbiotics, and fecal microbial transplant to reduce CKD progression.

Strategies to Prevent and Delay Chronic Kidney Disease Progression: A Pathway to Sustainability and Green Nephrology

Chronic kidney disease prevalence is increasing worldwide and is responsible for important morbidity, mortality and poor quality of life. Progression to end stage renal disease leads to major sustainability burden with high consumption of human and material resources. Hemodialysis particularly is associated with high rates of water consumption, waste production and greenhouse gas emissions. The nephrology community is gaining environmental awareness and several international societies are creating specific groups focusing on green nephrology. The first concerns are centered in the impact of hemodialysis, but it is unanimous that chronic kidney disease prevention and delayed progression are the most important measures to sustainability. New drug classes such as SGLT-2 inhibitors, selective mineralocorticoid receptors antagonists and GLP-1 analogues are revolutionizing the treatment of proteinuric and non-proteinuric chronic kidney disease. Large randomized clinical trials have proved strong and sustained benefits in renal and cardiovascular outcomes, and these drugs are now first and second-line therapy for the treatment of diabetic and non-diabetic kidney disease. In this mini-review article we explore the prevalence of chronic kidney disease, its environmental impact and resume the major strategies to prevent and delay its progression, including recent evidence on pharmacotherapy. Implementing prevention strategies and adopting environmentally-friendly practices, is the key to a better patient care and a greener nephrology.

Probiotic Formula Ameliorates Renal Dysfunction Indicators, Glycemic Levels, and Blood Pressure in a Diabetic Nephropathy Mouse Model.

One-third of patients with end-stage chronic kidney disease (CKD) experience diabetic nephropathy (DN), which worsens the progression of renal dysfunction. However, preventive measures for DN are lacking. Lactobacillus acidophilus TYCA06, Bifidobacterium longum subsp. infantis BLI-02, and Bifidobacterium bifidum VDD088 probiotic strains have been demonstrated to delay CKD progression. This study evaluated their biological functions to stabilize blood-glucose fluctuations and delay the deterioration of renal function. The db/db mice were used to establish a DN animal model. This was supplemented with 5.125 × 109 CFU/kg/day (high dose) or 1.025 × 109 CFU/kg/day (low dose) mixed with probiotics containing TYCA06, BLI-02, and VDD088 for 8 weeks. Blood urea nitrogen (BUN), serum creatinine, blood glucose, and urine protein were analyzed. Possible mechanisms underlying the alleviation of DN symptoms by probiotic strains were evaluated through in vitro tests. Animal experiments revealed that BUN, serum creatinine, and blood glucose upon probiotic administration were significantly lower than in the control group. The rate of change of urine protein decreased significantly, and blood pressure, glucose tolerance, and renal fibrosis were improved. In vitro testing indicated that TYCA06 and BLI-02 significantly increased acetic acid concentration. TYCA06, BLI-02, and VDD088 were associated with better antioxidation, anti-inflammation, and glucose consumption activities relative to the control. A combination of the probiotics TYCA06, BLI-02, and VDD088 attenuated renal function deterioration and improved blood-glucose fluctuation in a diabetes-induced CKD mouse model.

#6562 ITGAM PROMOTES MACROPHAGE ALTERNATIVE ACTIVATION IN HYPERURICEMIA-RELATED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD progression is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney injury, repair, and fibrosis. Here, we aim to investigate whether and how macrophage ITGAM contributes to hyperuricemia-related CKD. Method In vivo, we explored dynamic characteristics of renal tissue in hyperuricemia-related CKD. By incorporating mRNA and protein sequencing data, we analyzed gene expression profile, hub genes and potential pathways responsible for disease development, which was further confirmed using qPCR, western blotting, and immunofluorescent stainings. In vitro, we validated bioinformatic findings under different conditions of macrophages with interventions corresponding to core nodes in pathway. Results Hyperuricemia-related CKD was characterized by the rise in serum uric acid, decline in renal function, macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed ITGAM as the potential core gene mediating disease progression which was associated with FAK/Akt1/β-catenin signaling. Notably, we confirmed the upregulated macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys and Raw 264.7 macrophages. In vitro, we verified ITGAM/FAK/Akt1/β-catenin pathway participated in promoting macrophage M2 polarization through silencing Itgam and inhibiting FAK or Akt1 phosphorylation, where the expression of M2 phenotype macrophage markers and downstream molecules in pathway were down-regulated. Conclusion In hyperuricemia-related CKD, ITGAM promotes macrophage M2 polarization contributing to renal fibrosis through FAK/Akt1/β-catenin signaling pathway. Targeting macrophage ITGAM might be a promising therapeutic approach for preventing or delaying CKD.

#4598 ADMINISTRATION OF ASTRAGALUS MEMBRANACEUS IMPROVES RENAL CONDITIONS AND SERUM CARNOSINE LEVELS IN AN ACUTE KIDNEY INJURY MODEL

Abstract Background and Aims Astragalus membranaceus (AM) exhibits various pharmacological effects against many diseases, including chronic kidney disease (CKD) (see http://nccih.nih.gov/health/astragalus). Acute kidney injury (AKI) is a sudden episode of kidney failure. AKI occurs frequently but is believed to heal completely and is likely an important factor causing CKD pathogenesis or progression. Previously, we demonstrated the lethal dose in old mice is 20 mg/kg cis-diamminedichloroplatinum (CDDP), and the dosage that will cause AKI in young mice is 14 mg/kg of CDDP. Low doses of CDDP caused AKI in old mice. However, the same dosage in young mice would manifest AKI that was subsequently completely reversible. On administration of AM, old mice (50 mg/kg) showed significantly improved AKI pathology, suggesting the therapeutic effect of AM is age-dependent with regard to AKI pathogenicity. Here, we further examined the possible effect of AM in preventing AKI and delaying CKD progression. Method Female C57BL/6 mice were separated into three groups based on age: young, 10 weeks; middle-aged, 35 weeks; and old, 52 weeks. The mice received oral administered of either AM powder mixed with sterilized 0.5% methylcellulose 400 (w/v) (AM group) or 0.5% methylcellulose 400 alone in the control group (CG). Four hours after most recent dose (twice a day at 20 mg/kg AM), 0.5 mg/ml CDDP (reduced dose: 14 mg/kg or 0.9% NaCl for the CG) was injected intraperitoneally. We measured blood serum urea nitrogen (BUN) and creatinine (CRE) levels, which are biomarkers of AKI. Additionally, we assessed histochemical changes in kidney sections stained with anti-CD3 and anti-CD68 antibodies after the mice were sacrificed on day x. Thereafter, serum carnosine levels in the samples collected 4 hours after AM administration (n = 6 per group) were determined using a carnosine ELISA kit (Novus, NBP2-75013). Data were analyzed statistically with PRISM software. Significance was considered P = 0.05. Results The 14 mg/kg CDDP dose in old mice significantly increased BUN and CRE levels and caused histological damage in renal tubule epithelial cells and glomeruli. However, these pathological changes were not observed in young and middle-aged mice receiving the same CDDP dose. Histochemical analysis of the old mice showed a significant increase in the number of CD3- and CD68-positive cells following AKI induction (Fig. 1). However, the increase of these inflammatory markers was clearly ameliorated by the AM pretreatment in the experimental group. Serum carnosine levels were markedly increased in young and middle-aged mice following AM administration (Fig. 2). Moreover, the serum carnosine concentration in old mice was upregulated at levels corresponding to those in young mice with AM administration. However, serum carnosine levels showed no additional increase after AM administration in old mice and remained stable. Our findings suggest that normal renal conditions show a simple upregulation of serum carnosine level after AM administration. Furthermore, AM administration improves renal conditions in old mice with high levels of CD-3 positive cells in particular (Fig. 1, arrow). Figure 2 shows the increased and then subsequent stabilizing of the serum carnosine levels (Fig. 2, arrow). Conclusion AM administration can upregulate serum carnosine in younger mice and shows at least some effectiveness in older mice, where serum carnosine is downregulated but concentrated. Serum carnosine might not be necessary for reducing the pathogenesis of AKI in younger mice, but it becomes important to prevent AKI in old mice. This indicates the effect of AM is probably age-dependent because AKI sequelae manifested spontaneously in all mice but were specifically ameliorated when administered to old mice as opposed to younger mice who recovered completely irrespective of AM administration.

#5309 MODELLING LONG-TERM OUTCOMES FOR PATIENTS WITH IMMUNOGLOBULIN A NEPHROPATHY (IGAN) FROM SHORT-TERM PROTEINURIA DATA

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is rare kidney disease that leads to glomerular injury, progressive loss of kidney function and progression to kidney failure. Pre-specified interim proteinuria data from ongoing clinical trials is being used as the basis of regulatory approval of new therapies but little is known about the translation of these results to long-term patient outcomes; a topic of particular interest to heath technology assessment (HTA) groups looking to inform decisions on reimbursement before final renal outcome data are available. The objective of this study was to model long-term outcomes for patients with IgAN based on short-term proteinuria data. Method We developed a de novo model including a short-term (36-week) decision tree and a long-term Markov model to capture expected lifetime outcomes associated with treatment for IgAN. We used achievement of proteinuria <1 g/day as a clinically relevant treatment target. The short-term model included data on proteinuria level and distribution of chronic kidney disease (CKD) health states (CKD 1/2, 3, 4, and 5). At the end of 36 weeks of treatment, patients were categorized into groups based on their proteinuria level (<1g/day and ≥1 g/day) and CKD stage before transitioning to the long-term Markov model. In the long-term model, proteinuria level-based, CKD health state transition matrices derived from analysis of UK National Registry of Rare Kidney Disease (RaDaR) data, and transition matrices to dialysis and transplant derived from the US Renal Data System (USRDS) were used. Other included clinical inputs of complications and mortality were derived from extension of US Optum data analyses and literature. Health-related quality of life (HRQoL) was assessed as health state utilities and disutility associated with complications. Hypothetic scenarios of improvement in short-term proteinuria and impact on long term outcomes were tested. Model outputs included life years (LYs) and quality-adjusted life years (QALYs). Effectiveness was discounted at 3% annually. Deterministic sensitivity analysis was conducted. Results Over a lifetime, patients receiving treatment that increased the probability of achieving proteinuria <1 g/day by 10% in the short-term, were modelled to have gained an additional 0.388 LYs from reduced CKD/transplant/dialysis-related mortality and 0.633 QALYs from delaying CKD progression to kidney failure. As expected, results improved when the probability of achieving proteinuria <1 g/day increased; with a 30% increase in the probability of achieving proteinuria <1 g/day, LYs gained were 0.562 (Figure 1) and QALYs 0.968 (Figure 2). Results were most sensitive to time horizon and long-term extrapolation of CKD health state transition matrices. Conclusion Despite challenges inherent in the translation of surrogate endpoints to long-term outcomes, combining short-term proteinuria from clinical trials and long-term CKD data from real-world registry and claims-based data provides a solution. Based on modelling, treatments that increase the probability of achieving <1 g/day in the short-term, are expected to provide benefits to patients with IgAN in the long-term including less time with advanced kidney disease, less time on dialysis and avoiding the need for kidney transplant resulting in improved survival, and better quality of life. Refinement and customization of country-specific model inputs will help ensure outputs are relevant for different jurisdictions and as representative of anticipated real-world outcomes as possible.

Metabolomics profiling distinctively identified end-stage renal disease patients from chronic kidney disease patients

Chronic kidney disease (CKD) is a serious public health problem characterized by progressive kidney function loss leading to end-stage renal disease (ESRD) that demands dialysis or kidney transplantation. Early detection can prevent or delay progression to ESRD. The study aimed to gain new insights into the perturbed biochemical reactions and to identify novel distinct biomarkers between ESRD and CKD. Serum samples of 32 patients with ESRD (n = 13) and CKD (n = 19) were analyzed using chemical isotope labeling liquid chromatography-mass spectrometry metabolomics approach. A total of 193 metabolites were significantly altered in ESRD compared to CKD and were mainly involved in aminoacyl-tRNA biosynthesis, branched-chain amino acid (BCAA) biosynthesis, taurine metabolism, and tryptophan metabolism. Three kynurenine derivatives, namely, 2-aminobenzoic acid, xanthurenic acid, and hydroxypicolinic acid were upregulated in ESRD compared to CKD due to the significant decrease in glomerular filtration rate with the progression of CKD to ESRD. N-Hydroxy-isoleucine, 2-aminobenzoic acid, and picolinic acid yielded AUC > 0.99 when analyzed using Receiver Operating Characteristic (ROC) analysis. Our findings suggest that inhibiting the kynurenine pathway might be a promising target to delay CKD progression and that metabolites with high discriminative ability might serve as potential prognostic biomarkers to monitor the progression of CKD to ESRD or used in combination with current markers to indicate the status of kidney damage better.

The level of serum albumin is associated with renal prognosis and renal function decline in patients with chronic kidney disease

ObjectiveThe study’s purpose is to explore the link of serum albumin on renal progression in patients with chronic kidney disease (CKD).MethodsThis study was a secondary analysis of a prospective cohort study in which a total of 954 participants were non-selectively and consecutively collected from the research of CKD-ROUTE in Japan between November 2010 and December 2011. We evaluated the association between baseline ALB and renal prognosis (initiation of dialysis or 50% decline in eGFR from baseline) and renal function decline (annual eGFR decline) using the Cox proportional-hazards and linear regression models, respectively. We performed a number of sensitivity analyses to ensure the validity of the results. In addition, we performed subgroup analyses.ResultsThe included patients had a mean age of (66.86 ± 13.41) years, and 522 (69.23%) were male. The mean baseline ALB and eGFR were (3.89 ± 0.59) g/dL and (33.43 ± 17.97) ml/min/1.73 m2. The annual decline in eGFR was 2.65 mL/min/1.73 m2/year. 218 (28.9%) individuals experienced renal prognosis during a median follow-up period of 36.0 months. The baseline ALB was inversely linked with renal prognosis (HR = 0.61, 95%CI: 0.45, 0.81) and renal function decline (β = -1.41, 95%CI: -2.11, -0.72) after controlling for covariates. The renal prognosis and ALB had a non-linear connection, with ALB’s inflection point occurring at 4.3 g/dL. Effect sizes (HR) were 0.42 (0.32, 0.56) and 6.11 (0.98, 38.22) on the left and right sides of the inflection point, respectively. There was also a non-linear relationship between ALB and renal function decline, and the inflection point of ALB was 4.1 g/dL. The effect sizes(β) on the left and right sides of the inflection point were -2.79(-3.62, -1.96) and 0.02 (-1.97, 1.84), respectively.ConclusionThis study shows a negative and non-linear association between ALB and renal function decline as well as renal prognosis in Japanese CKD patients. When ALB is lower than 4.1 g/dL, ALB decline was closely related to poor renal prognosis and renal function decline. From a therapeutic point of view, reducing the decline in ALB makes sense for delaying CKD progression.

Role of hypertension in progression of pediatric CKD.

Hypertension is frequent in children with chronic kidney disease (CKD). Its prevalence varies according to CKD stage and cause. It is relatively uncommon in children with congenital kidney disease, while acquired kidney disease is associated with a higher prevalence of hypertension. Studies in children with CKD utilizing ambulatory blood pressure monitoring also showed a high prevalence of masked hypertension. Uncontrolled and longstanding hypertension in children is associated with progression of CKD. Aggressive treatment of high blood pressure should be an essential part of care to delay CKD progression in children.

Mechanisms underlying acupuncture therapy in chronic kidney disease: A narrative overview of preclinical studies and clinical trials.

Chronic kidney disease (CKD) is associated with high incidence, low awareness, and high disability rates among the population. Moreover, the disease significantly affects the physical and mental health of patients. Approximately 25% of patients with CKD develop end-stage renal disease (ESRD) within 20 years of diagnosis and have to rely on renal replacement therapy, which is associated with high mortality, heavy economic burden, and symptoms including fatigue, pain, insomnia, uremia pruritus, and restless leg syndrome. Currently, the means to delay the progress of CKD are insufficient; therefore, developing strategies for delaying CKD progression has important practical implications. In recent years, more and more people are accepting the traditional Chinese medical technique "acupuncture." Acupuncture has been shown to improve the uncomfortable symptoms of various diseases through stimulation (needling, medicinal moxibustion, infrared radiation, and acupressure) of acupoints. Its application has been known for thousands of years, and its safety and efficacy have been verified. As a convenient and inexpensive complementary therapy for CKD, acupuncture has recently been gaining interest among clinicians and scientists. Nevertheless, although clinical trials and meta-analysis findings have demonstrated the efficacy of acupuncture in reducing albuminuria, improving glomerular filtration rate, relieving symptoms, and improving the quality of life of patients with CKD, the underlying mechanisms involved are still not completely understood. Few studies explored the correlation between acupuncture and renal pathological diagnosis. The aim of this study was to conduct a literature review summarizing the currently known mechanisms by which acupuncture could delay the progress of CKD and improve symptoms in patients with ESRD. This review help provide a theoretical basis for further research regarding the influence of acupuncture on renal pathology in patients with CKD, as well as the differences between specific therapeutic mechanisms of acupuncture in different renal pathological diagnosis. The evidence in this review indicates that acupuncture may produce marked effects on blocking and reversing the critical risk factors of CKD progression (e.g., hyperglycemia, hypertension, hyperlipidemia, obesity, aging, and anemia) to improve the survival of patients with CKD via mechanisms including oxidative stress inhibition, reducing inflammatory effects, improving hemodynamics, maintaining podocyte structure, and increasing energy metabolism.

Nocturnal Hypertension in Children With Chronic Kidney Disease Is Common and Associated With Progression to Kidney Replacement Therapy.

Nocturnal hypertension is a risk factor for chronic kidney disease (CKD) progression among adults. In children, effects of nocturnal hypertension on CKD progression is less studied. We investigated the relationships between nocturnal, daytime, or sustained hypertension and progression to kidney replacement therapy in children using Cox proportional hazards models. Nocturnal and diurnal hypertension respectively defined as: mean blood pressure >95th percentile and/or load >25% for either systolic or diastolic blood pressure within sleep or wake periods. One thousand five hundred seventy-seven ambulatory blood pressure monitoring studies from 701 CKiD participants were reviewed. Nighttime, daytime, and both types of hypertension were 19%, 7%, and 33%, respectively. Participants with both daytime and nocturnal hypertension had the highest risk of kidney replacement therapy. Among children with CKD, compared with those who were normotensive, those with isolated nocturnal hypertension had a hazard ratio of 1.49 ([CI, 0.97-2.28]; P=0.068) while those with both daytime and nocturnal hypertension had a HR of 2.23 ([CI, 1.60-3.11]; P<0.001) when adjusted for age, race, sex, and baseline proteinuria and glomerular filtration. Estimates for risk were similar among glomerular and nonglomerular participants but not significant in glomerular due to smaller sample size. The presence of both daytime and nocturnal hypertension is significantly associated with risk of kidney replacement therapy. Our study confirms the utility of ambulatory blood pressure monitoring in children with CKD. Identifying and controlling both daytime and nocturnal hypertension using ambulatory blood pressure monitoring may improve outcomes and delay CKD progression in this population.

Possible protective role of probiotic and symbiotic to limit the progression of chronic kidney disease in 5/6th nephrectomized albino rats

BackgroundThe unbalanced gut microbiota, poorly ingested enriched fiber foods, leaky gut is connected to the progression of chronic kidney disease (CKD). The leaky gut translocates uremic toxins to the systemic circulation, promote systemic inflammation, worsen CKD. Decreasing the uremic toxins influx from the gut may decrease the progression of CKD. So, we aimed to evaluate the effect of probiotic and symbiotic supplementation on the leaky gut and their role to prevent CKD progression.Methods48 white albino rats were randomly allocated into 6 groups: sham group; CKD rats; probiotic treated and symbiotic treated rats. Treatment started either immediately or 2 weeks after the operation for each treated group. Blood pressure, body weight changes, serum level of urea, creatinine, indoxyl sulphate and CRP were determined. Histological studies of kidney remnants and intestine and renal fibrosis index were calculated. SPSS program was used for statistics.ResultsSerum urea, creatinine, indoxyl sulphate, CRP, fibrosis index and blood pressure significantly increased in CKD rats. Probiotic treatment decreased serum level of urea, creatinine and CRP and fibrosis index. Symbiotic treatment decreased the serum level of urea, creatinine, indoxyl sulphate and CRP compared to CKD rats. Blood pressure and fibrosis index were decreased significantly upon symbiotic treatment.ConclusionsA strong correlation between the gut microbial ecosystem and CKD has been proved. The use of probiotics and symbiotic to modulate an unhealthy gut microbiome is a promising intervention to delay CKD progression specially in early stages. Symbiotic results were better than probiotic alone.