Kidney Research and Clinical Practice最新文献

Background: Posttransplantation diabetes mellitus (PTDM) is a crucial problem after kidney transplantation. We aimed to determine whether metformin affects cardiovascular and graft outcomes in patients with PTDM.

Methods: This retrospective cohort study included 1,663 kidney transplant recipients without preexisting diabetes mellitus. The patients were divided into metformin and non-metformin groups, with matched propensity scores. We also estimated metformin's effect on percutaneous coronary intervention (PCI), major adverse cardiovascular events (MACEs), acute rejection, and graft failure.

Results: Of 634 recipients with PTDM, 406 recipients were treated with metformin. The incidence of PCI was 2.4% and 7.1% in the metformin and non-metformin groups, respectively (p = 0.04). The metformin group exhibited a lower risk of PCI in Cox regression analyses (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.10-0.77; p = 0.014), especially in subgroups with male sex, age over 49 years (median), long-term metformin use (mean of ≥1,729 days), and simultaneous tacrolimus administration. Long-term metformin use was also associated with lower incidence of MACEs (HR, 0.09; 95% CI, 0.01-0.67; p = 0.02). Incidence of graft failure was 9.9% and 17.0% in the metformin and non-metformin groups, respectively (p = 0.046). Both long-term use and higher dose of metformin, as well as tacrolimus administration with metformin, were associated with a lower risk of graft failure (HR, 0.29; 95% CI, 0.11-0.75; p = 0.01; HR, 0.39; 95% CI, 0.18-0.85; p = 0.02; and HR, 0.39; 95% CI, 0.19-0.79; p = 0.009, respectively).

Conclusion: Metformin use is associated with a decreased risk of developing coronary artery disease and better graft outcomes in PTDM.

Background: The association between body mass index (BMI) and risk of kidney replacement therapy (KRT) initiation in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) remains uncertain. Furthermore, controversies remain around baseline BMI as the only exposure in the analysis.

Methods: A total of 2,136 patients enrolled in the KoreaN Cohort Study for Outcome in Patients With CKD were included in this study. The exposure was baseline and time-updated BMI. The outcome was initiation of KRT including dialysis or kidney transplantation during follow-up. A multivariable Cox proportional hazards model, a time-dependent Cox model without inverse probability weights, and a marginal structural Cox model were fitted, adjusting for both time-fixed and time-varying covariates including various clinicodemographic characteristics.

Results: During the median follow-up of 8.3 years, KRT initiation occurred in 723 patients (34%). In patients with BMI ≥25.0 kg/m2, a higher time-updated BMI was significantly associated with a lower risk of KRT initiation compared to the reference group with normal BMI of 18.5-22.9 kg/m2, and a gradual decrease in risk of KRT initiation was observed with increasing BMI. The groups with BMI 25.0-29.9 kg/m2 (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.61-0.87) and BMI ≥30.0 kg/m2 (HR, 0.69; 95% CI, 0.53-0.88) exhibited a significantly lower risk of KRT initiation in the results of the marginal structural Cox model.

Conclusion: A higher time-updated BMI has a lower risk of KRT initiation in obese patients with NDD-CKD. Therefore, aggressive reduction of body weight in patients with both obesity and CKD may not always be beneficial for adverse kidney events.

Diabetic acute kidney disease (AKD) represents a pivotal transitional phase between acute kidney injury (AKI) and chronic kidney disease (CKD), carrying a high risk of progression to end-stage kidney disease. Effective medical management is crucial during this phase. Renin-angiotensin-aldosterone system inhibitors remain the foundation of therapy, and newer agents have expanded the armamentarium. Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to confer significant nephroprotective and cardioprotective effects, including decreased risks of AKD progression, heart failure, and mortality. Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, has also been shown to reduce kidney disease progression and cardiovascular events in patients with established diabetic CKD, although its role in AKD remains uncertain. However, real-world data indicate the suboptimal utilization of these therapies, highlighting barriers related to clinical inertia, safety concerns after AKI, and socioeconomic disparities. Future strategies should emphasize the timely initiation and combination of treatments to maximize renoprotection, while exploring emerging agents such as endothelin receptor antagonists and aldosterone synthase inhibitors. Integrating evidence-based therapies, improving adherence to guideline-directed care, and leveraging real-world data to inform clinical practice are necessary to optimize kidney and cardiovascular outcomes in patients with diabetic AKD.

Background: This study aims to investigate the effects of complete SLC12A3 gene knock-in using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) in human-induced pluripotent stem cells (hiPSCs), focusing on cellular characteristics and functional implications in the context of Gitelman syndrome.

Methods: Employing CRISPR/Cas9 gene-editing technology, the SLC12A3 gene was integrated into WTC-11 hiPSCs, resulting in the creation of the WTC-11SLC12A3-KI cell line. Successful integration was confirmed through green fluorescence protein (GFP) reporter gene expression, and SLC12A3 expression was verified via polymerase chain reaction, flow cytometry, immunoblotting, and immunofluorescence in kidney organoids. Functional analysis with the intracellular sodium indicator CoroNa Green dye (Invitrogen) assessed the impact of SLC12A3 gene knock-in and thiazides.

Results: The WTC-11SLC12A3-KI hiPSCs exhibited successful integration of the SLC12A3 gene, with enhanced SLC12A3 expression evidenced by GFP and SLC12A3 proteins compared to WTC-11 hiPSCs. Upon differentiation into kidney organoids, the WTC-11SLC12A3-KI organoids displayed increased GFP, SLC12A3 expression, and the associated WNK-SPAK/OSR1 signaling cascade relative to WTC- 11 organoids. The intracellular sodium flux was stimulated by angiotensin II treatment in kidney organoid cells and attenuated by thiazides in both WTC-11 and WTC-11SLC12A3-KI groups.

Conclusion: This study indicates that the knock-in of the SLC12A3 gene could serve as a therapeutic strategy for Gitelman syndrome.

Background: Ferric citrate (FC) can replenish iron stores in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) and iron deficiency anemia (IDA). This study evaluated the efficacy and safety of FC (PBF-1681, Panion & BF Biotech Inc.) in NDD-CKD Taiwanese patients.

Methods: In this double-blind, placebo-controlled, randomized Phase III trial, patients were assigned 1:1 to receive either PBF-1681 or placebo for 16 weeks, followed by an 8-week open-label extension in which all participants received PBF-1681. The starting dose was 2 g/day, with an additional 2 g/day titration based on hemoglobin and serum phosphate levels.

Results: A total of 141 patients were randomized to either the PBF-1681 or placebo group. Of these, 114 completed the 16-week randomized period and 106 completed the full 24-week study. The primary endpoint was met, with the PBF-1681 group showing a significantly greater increase in hemoglobin from baseline to Week 16 compared to the placebo group (intergroup difference: 0.62 ± 0.15 g/dL, p < 0.0001). Significant between-group differences were also observed for all secondary and several exploratory endpoints, including the proportion with hemoglobin increase ≥1.0 g/dL, a sustained effect (hemoglobin increase of ≥0.75 g/dL from baseline over any 4-week time period), and changes in iron-related parameters, serum phosphate, intact parathyroid hormone, and fibroblast growth factor 23 levels (all p < 0.05). The most common treatment-related adverse events were gastrointestinal disorders, including diarrhea, discolored feces, abdominal discomfort, constipation, and abdominal pain.

Conclusion: PBF-1681 was effective for treating IDA in Taiwanese NDD-CKD patients and had a favorable safety profile.

Background: Multidrug-resistant organisms (MDROs) present significant challenges in the treatment of peritoneal dialysis (PD)-related peritonitis. This study aimed to describe the incidence, risk factors, and outcomes of MDRO-peritonitis in a national cohort from the PDOPPS (Peritoneal Dialysis Outcomes and Practice Patterns Study)-Korea.

Methods: Between July 2019 and December 2021, 147 of 292 peritonitis episodes had available data on organism sensitivity and resistance. Episodes were categorized as MDRO-defined as resistance to three or more classes of antibiotics-or non-MDRO. Multivariate logistic regression analysis identified factors associated with MDRO versus non-MDRO peritonitis and predictors of peritonitis cure.

Results: Forty-one of the total 292 peritonitis episodes (14.0%) were identified as MDRO. Prior hospitalization (odds ratio [OR], 32.9; 95% confidence interval [CI], 3.5-313.1), diabetes mellitus (OR, 4.1; 95% CI, 1.2-14.2), and recurrent peritonitis (OR, 48.3; 95% CI, 3.2-735.8) were independent risk factors for MDRO-peritonitis. In the analysis of factors associated with peritonitis cure, longer PD vintage (OR, 0.8; 95% CI, 0.7-1.0) and Gram-negative organisms (OR, 0.1; 95% CI, 0.0-0.4) were associated with lower cure rates, while higher serum albumin level (OR, 1.2; 95% CI, 1.1-1.4) and management at a tertiary referral hospital (OR, 8.8; 95% CI, 1.6-48.0) were associated with higher cure rates. MDRO status itself was not significantly associated with peritonitis cure.

Conclusion: Nearly one in seven peritonitis episodes (14.0%) was caused by MDROs. Prior hospitalization, diabetes mellitus, and recurrent peritonitis were independent risk factors for MDRO-peritonitis. Regarding peritonitis cure, characteristics of causative organisms tended to have a greater impact than did MDRO status itself.

Renal fibrosis (RF) is a prevalent clinical symptom of numerous chronic kidney illnesses and a significant pathological alteration in end-stage renal disease resulting from various mechanisms, such as abnormally activated signaling pathways, microRNAs, aging, autophagy disorders, and fibrotic ecological niches, all of which contribute to RF development. Inhibiting, blocking, or delaying the aforementioned mechanisms may yield novel approaches for treating RF. This article explores advancements in the comprehension of the mechanisms and therapeutic approaches for RF.

Background: The heterogeneity of chronic kidney disease (CKD) and fragmented analysis methods hinder the precise identification of novel biomarkers. We addressed this challenge using two independent cohorts to integrate genomics and metabolomics, aiming to identify cause-specific biomarkers for CKD in the Korean population.

Methods: A longitudinal genome-wide association study using the Cox proportional hazards model was conducted using the Ansan and Ansung cohort. To validate these genomic biomarkers and integrate them with plasma metabolomics biomarkers, we utilized a hospital-based biopsy cohort to identify cause-specific CKD biomarkers. Within the biopsy cohort, we analyzed four disease subsets, including type 2 diabetic kidney disease (DKD), hypertensive nephropathy (HN), immunoglobulin A nephropathy (IgAN), and membranous nephropathy (MN), and compared them with healthy individuals. Significant single nucleotide polymorphisms(SNPs) and metabolites for each CKD subset were identified through logistic regression and correlation-based network analyses. Subsequently, we analyzed the risk of disease progression associated with the identified pairs.

Results: A total of 448 variants associated with CKD occurrence were identified, with significant differences in several genetic variants and metabolites observed among patients with DKD, HN, IgAN, and MN compared to healthy individuals. Among 36 SNP-metabolite pairs, those involing FOXB1 and ZFP42 were associated with DKD, whereas pairs involving MMRN1 and SYNJ2 were linked to MN. Notably, the rs1025170 variant in FOXB1 and tyrosine pair was correlated with DKD progression.

Conclusion: Integrating genomics and metabolomics across independent cohorts enables the discovery of cause-specific biomarkers for the occurrence and progression of CKD in the Korean population.

Extracellular vesicles (EVs) are nanosized membranous particles released by nearly all cell types, playing a crucial role in mediating cell-to-cell communication. The molecular profile of EVs often reflects that of their originating cells, rendering them valuable for therapeutic and diagnostic purposes. The kidney comprises various cell types, and urinary EVs are predominantly produced from tubular, glomerular, and urinary bladder cells. Within the nephron, EVs produced from the upper segments, such as glomerular tufts and proximal tubules, can be taken up by their downstream counterparts, thereby altering the physiology of recipient cells. Recent studies have demonstrated that this proximal-distal intra-nephron crosstalk via EVs is crucial for normal kidney physiology. Additionally, EVs from interstitial cells (e.g., fibroblasts and macrophages) have been demonstrated to mediate the exacerbation of kidney damage. This review provides up-to-date findings on the function of renal EVs during the progression of renal diseases. Furthermore, we discussed future directions to use the clinical potential of renal EVs as an early biomarker for renal disorders.