Clinical and Experimental Nephrology最新文献

Chronic kidney disease (CKD) is a global health burden associated with increasing mortality rates. Aging populations and declining fertility rates exacerbate this issue, particularly in countries such as Japan. Acute kidney injury (AKI) was previously considered temporary and reversible condition. However, in recent years, multiple studies on kidney diseases have shown that AKI survivors are at an increased risk of developing CKD. During the AKI-to-CKD transition, a subset of AKI-induced epigenetic alterations persists in cells, potentially driving the progression of tubulointerstitial fibrosis. Therefore, targeting epigenetic mechanisms may represent a promising therapeutic approach for preventing AKI-to-CKD transition. Among the epigenetic mechnisms involved, "hypoxic memory" plays a crucial role in this transition by inducing persistent epigenetic changes. Hypoxic memory induces DNA methylation, histone modification, changes in chromatin conformation, and long non-codingRNA (lncRNA) expression. Herein, we review the latest evidence on epigenetic memory in the AKI-to-CKD transition, identifying that the detailed mechanisms of epigenetic memory and temporal specificity are crucial for developing effective treatments.

Background: Maintenance therapy using immunosuppressive agents after rituximab can be effective for sustaining remission in childhood-onset refractory frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS). We evaluated the long-term outcome of mycophenolate mofetil (MMF) after rituximab.

Methods: We conducted a multicenter, retrospective cohort study of patients with childhood-onset refractory FRNS/SDNS who received MMF as maintenance therapy after a single dose of rituximab and were followed up ≥ 2 years at three pediatric renal centers. Relapses, additional treatment, risk factors for relapse, and adverse events were analyzed.

Results: We enrolled 106 patients, and the median follow-up was 7.2 years. Forty-seven (44%) patients had no relapse under MMF, and the 50% relapse-free survival was 3.2 years during MMF administration. Sixty-one (58%) patients required additional rituximab during the observation period. The mean annual number of relapses before the first rituximab treatment versus 1 year after rituximab initiation was 3.7 (standard deviation: 1.3) versus 0.4 (standard deviation: 0.8) times (p < 0.0001). Sixty-six of 74 (89%) patients could discontinue calcineurin inhibitors within 1 year after rituximab. MMF < 1000 mg/m² was an independent significant risk factor for the first relapse (p = 0.03). No fatal adverse events and 23 episodes of infection requiring hospitalization were observed during the study period.

Conclusions: MMF after a single dose of rituximab is safe and effective in achieving a long relapse-free period and discontinuing a calcineurin inhibitor in patients with refractory FRNS/SDNS.

Background: Patients undergoing hemodialysis have decreased skeletal muscle mass which is associated with higher mortality and lower physical functioning. Since these patients frequently experience hospitalizations, we hypothesized that hospital admissions could be a cause of loss of skeletal muscle mass.

Methods: This was a longitudinal observational study among patients on hemodialysis (N = 132). The outcome was the change in thigh muscle cross-sectional area (TMCSA) measured by computed tomography and standardized by squared height (cm²/m²) per year. The exposures were the presence or absence of hospital admissions, the total number of hospital admissions (times), and the total length of hospital stays (nights) between the TMCSA measurements. Association was analyzed by multivariable-adjusted linear regression analysis.

Results: During a median follow-up period of 3.95 years, 104 patients were hospitalized (hospitalization group), whereas 28 patients were not (non-hospitalization group). Both groups showed a significant decrease in TMCSA, and it was more rapid in the hospitalization group than the non-hospitalization group (P = 0.023). Multivariable-adjusted linear regression analysis showed that the total number of hospital admissions and the total length of hospital stays were the independent factors associated with the decrease in TMCSA.

Conclusion: This study showed for the first time that hospital admissions were independently associated with the longitudinal decrease in TMCSA in patients undergoing hemodialysis.

Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. We aimed to explore the role of RNA binding motif protein 15 (RBM15) in high glucose (HG)-induced pyroptosis of renal tubular epithelial cell, thus providing theoretical knowledge and new targets for DN treatment.

Methods: HG-induced HK-2 cells were used to establish DN cell models. RBM15 expression was inhibited in HK-2 and detected. Cell viability was detected by cell counting kit-8. The levels of NLR family pyrin domain containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4), gasdermin D (GSDMD)-N, and cleaved Caspase-1 were detected by Western blot assay. The levels of IL-1β and IL-18 were detected by enzyme linked immunosorbent assay. The enrichment of insulin-like growth factor 2 mRNA binding protein (IGF2BP2) and N6-methyladenosine (m6A) on NLRP3 and NLRC4 were analyzed by methylated RNA immunoprecipitation (MeRIP) and RIP. The stability of NLRP3 and NLRC4 mRNA was analyzed. The mechanism was verified by interfering NLRP3 and NLRC4 expression.

Results: RBM15 was highly expressed in HG-induced HK-2 cells. Inhibition of RBM15 reversed cell viability, inhibited inflammation, and alleviated pyroptosis. RBM15 promoted the expression of inflammasomes NLRP3 and NLRC4 through IGF2BP2-dependent m6A modification.

Conclusion: RBM15 promoted the expression of inflammasomes NLRP3 and NLRC4 through IGF2BP2-dependent m6A modification, thereby promoting pyroptosis.

Background: Renal fibrosis is key histopathological lesion in chronic kidney disease progression. This study explored pyroptosis-related gene signatures, potential molecular pathways and chemicals, as well as immune infiltration in renal fibrosis.

Methods: Renal fibrosis datasets and pyroptosis-related genes were obtained and differentially expressed pyroptosis-related genes (DEPGs) were identified. Then functional enrichment analysis was performed and core DEPGs were screened by WGCNA and LASSO regression analysis. Subsequently, miRNA-core DEPG interactions and potential chemicals were established. Finally, immune cell subtype distribution was evaluated and the core DEPGs were externally validated.

Results: A total of 38 DEPGs were identified which were enriched in inflammatory- and immune-related pathways. Nine core DEPGs were identified and the risk core = (0.1003 × Bak1) + (0.0944 × Zbp1) + (0.0882 × Tlr2) + (0.0585 × Il18) + (0.0497 × Adora2b) + (0.0418 × Stat3) + (0.0325 × Icam1) + (0.0272 × Pycard) + (0.0132 × Epha2). Nine core DEPGs exhibited high sensitivity and specificity for predicting UUO occurrence. A total of 444 miRNA-core DEPG interactions were obtained and miR-124-3p, miR-92a-3p, and miR-6807-5p were identified as core miRNAs. Adenosine served as a potential chemical that directly bound to Adora2b. Immune cells, including naïve B cells, CD4⁺ effector memory T cells, (plasmacytoid) dendritic cells, monocytes, and neutrophils were significantly enriched in fibrotic kidneys. Finally, the differential expression, temporal expression patterns, and clinical correlation with renal function of core DEPGs were externally validated.

Conclusions: This study sheds light on the novel pyroptosis-related gene signatures in renal fibrosis.

Background: The study aims to investigate the impact of immunosuppressive therapy on clinical outcomes in patients with baseline negative PLA2R antibody, providing new therapeutic insights for this patient population.

Methods: This study included 133 patients with positive histological PLA2R antigen and baseline serum anti-PLA2R antibody data. ELISA (enzyme-linked immunosorbent assay) was used to measure serum anti-PLA2R antibody levels. Renal biopsy specimens were analyzed by light microscopy, immunofluorescence, and electron microscopy.

Results: Among the 133 patients, 84 (63.2%) were positive for serum antibodies (SAb +) and glomerular antigen (GAg +), while 49 (36.8%) were negative for serum antibodies (SAb-) but positive for glomerular antigen (GAg +). Compared with the Sab-/GAg + group, the SAb + /GAg + group exhibited more severe clinical features compared to the SAb-/GAg + group; however, there was no significant difference in the pathological characteristics between the two groups of patients. The complete remission (CR) rate was significantly higher in the SAb-/GAg + group (67.35% vs. 33.33%, P < 0.001), with higher CR rates at 12, 24, and 36 months. The SAb-/GAg + group also had a lower relapse rate than Sab + /GAg + (12.24% vs. 36.90%, P = 0.002). In the SAb-/GAg + group, 67.3% received conservative treatment, while 32.7% underwent immunotherapy. Patients receiving immunosuppressive therapy in the SAb-/GAg + group exhibited more severe proteinuria, more impaired renal function, and higher hyperlipidemia at baseline. Compared with conservative treatment, immunotherapy improved overall remission rates (100.00% vs. 75.76%, P = 0.041) in the SAb-/GAg + group. Cox regression analysis showed that immunotherapy significantly predicted urinary protein remission (HR 3.92, 95% CI 1.58-9.70, P = 0.003).

Conclusion: Immunosuppressive therapy in PLA2R-related membranous nephropathy patients with severe baseline clinical manifestations may help predict urine protein remission, even if they are serum anti-PLA2R antibody negative.

Background: This study aims to investigate the bidirectional causal relationship between chronic kidney disease (CKD) and sarcopenia using two-sample Mendelian randomization (MR) analysis.

Methods: A bidirectional MR analysis was performed using genetic data for CKD from the MEGASTROKE consortium and sarcopenia traits from the UK Biobank. SNPs associated with CKD and sarcopenia were used as instrumental variables. MR analysis was conducted with inverse variance weighting (IVW), weighted median, and MR-Egger methods. Sensitivity analyses included Cochran's Q test, MR-Egger intercept, and the leave-one-out method. Enrichment analysis was performed using GO and KEGG pathways.

Results: The results indicate a positive association between CKD and both left-hand grip strength (OR = 1.03, 95% CI 1.01-1.04, P < 0.001) and right-hand grip strength (OR = 1.03, 95% CI 1.02-1.04, P < 0.001) for both sides. In addition, appendicular lean mass (ALM) was found to be positively associated with an increased risk of CKD (OR = 1.35, 95% CI 1.19-1.53, P < 0.001). However, no significant causal relationships were observed between CKD and ALM or usual walking pace. Enrichment analysis identified several relevant biological processes and pathways, such as DNA transcription regulation, protein degradation, and immune response pathways, that may mediate the relationship between CKD and sarcopenia.

Conclusions: This study provides evidence for a bidirectional causal relationship between CKD and sarcopenia, with CKD contributing to decreased hand grip strength and ALM being associated with an increased risk of CKD.

Background: Acute hyperglycaemia is often accompanied by acid-base and electrolyte disorders as well as changes in serum osmolality which have a significant clinical impact. This study explores the prevalence of complex acid-base disorders in patients with hyperglycaemia, focusing on the limitations of current diagnostic criteria which primarily rely on pH, serum bicarbonate and anion gap.

Methods: A retrospective analysis of 1159 episodes of severe hyperglycaemia was performed. Arterial blood gas analysis, serum osmolality and electrolyte levels were measured at admission to hospital and patient's outcome was observed until day seven. Patients were evaluated for acid-base and electrolyte disorders as well as for changes in measured or calculated serum osmolality.

Results: Our findings reveal that 90.7% of patients exhibited some form of acid-base disorder, mixed acid-base disorders were the most prevalent (75%). Patients with an accompanying respiratory acidosis showed higher mortality rates (12%) than patients with respiratory alkalosis (6%, p = 0.006) or no respiratory disorder (5%, p = 0.003). An elevated serum osmolality was associated with higher mortality when using the calculated, effective osmolality (19% vs 4%, p < 0.001) as well as the measured osmolality (10% vs 4%, p = 0.001). Only 20% of our population had no electrolyte disorder. This group had a significantly lower mortality rate (2%) compared to patients with elevated or decreased sodium, potassium and phosphate levels.

Conclusion: Patients with severe hyperglycaemia often had complex acid-base and electrolyte disorders but current criteria for diagnosing diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS) ignore combined disorders of acid-base homeostasis, potentially influencing patient management and outcomes.

Background: Cancer is one of the most common complications after kidney transplantation and an important cause of mortality. However, no large, nationally representative study has investigated cancer incidence post-kidney transplantation. This study aimed to determine the standardized incidence ratio (SIR) for cancer after kidney transplantation using the National Database of Health Insurance Claims (NDB).

Methods: We used NDB from April 2013 to March 2022; patients were included if they had been on dialysis for at least one year, were diagnosed with cancer related to post-kidney transplantation, and were prescribed immunosuppressant drugs in FY2014 or FY2015. We defined patients with cancer as those who were coded as ICD-10 for cancer in FY2016 or later. The number of patients and SIRs were tabulated according to the duration after kidney transplantation and cancer type.

Results: The total number of patients was 4484 (males: 2879; females: 1605). The SIRs of all cancers from the first to the seventh year after kidney transplantation were 232/291/235/248/257/187/149, respectively, showing a gradual downward trend over time. The predilection sites of cancer in both men and women were post-transplant lymphoproliferative disease, Kaposi sarcoma, and the kidney.

Conclusion: This observational study, which followed over 100 million people, is the first large-scale research to track kidney transplant recipients for under 10 years. It incorporates an unprecedented sample size and uniquely identified short-term cancer risk trends following kidney transplantation.

Background: Hyperparathyroidism (HPT) is a potential risk factor for graft loss after kidney transplantation (KTx). However, the effects of HPT management on graft outcomes remain unclear. This retrospective study aimed to investigate the impact of HPT status and its management on graft outcomes.

Methods: Patients who underwent KTx were categorized based on their HPT status and treatment at 1-year post-KTx into four groups: normal (no HPT), normocalcemic HPT, hypercalcemic HPT, or intervention (parathyroidectomy or calcimimetics within 1 year after KTx). Patients treated for HPT beyond the first year post-KTx were censored. The primary outcome was death-censored graft survival and the secondary outcome was the progression of interstitial fibrosis and tubular atrophy (IFTA) at 1-year post KTx.

Results: Among 1264 patients, the 10-year death-censored graft-survival rate was lowest in the hypercalcemic HPT group (79.7%), whereas the intervention group had a survival rate of 100.0%. In the multivariate Cox regression analysis, hypercalcemic HPT was associated with an increased risk of graft loss (fully adjusted hazard ratio [HR] = 4.25, P = 0.001, compared to the normal group). Contrarily, the intervention group did not show an increased risk of graft loss (fully adjusted HR = 0.28, P = 0.239). Additionally, hypercalcemia during the first year after KTx was significantly associated with IFTA progression (fully adjusted odds ratio = 1.91, P = 0.038).

Conclusion: Hypercalcemic HPT was associated with inferior graft survival and IFTA progression. Proactive management of HPT may reduce the risk of graft loss and mitigate IFTA progression.