Clinical and Experimental Nephrology最新文献

Background: Improved renal function (IRF) observed in acute heart failure (AHF) is associated with poor prognosis. Since IRF is linked to renal congestion resulting from inadequate decongestion, predicting IRF could enhance management strategies. The Fibrosis-4 (Fib-4) index, originally developed as a marker for liver fibrosis, correlates with hepatic congestion, which is associated with renal congestion, making it a potential predictor of IRF. This study aims to investigate whether the Fib-4 index can predict IRF in patients with AHF and preserved ejection fraction (AHFpEF).

Methods: We analyzed 389 patients hospitalized for AHF between April 2004 and March 2022 at Yamanashi University Hospital. All-cause mortality was monitored for 1 year. IRF was defined as a ≥ 20% increase in the estimated glomerular filtration rate (eGFR) compared to admission levels. Preserved ejection fraction was defined as an ejection fraction ≥ 40%.

Results: IRF was observed in approximately 21% of patients with AHFpEF. Kaplan-Meier analysis showed that patients with IRF had higher mortality rates than those without IRF (p = 0.03, log-rank test). Multivariable analysis for IRF revealed that the eGFR, albumin level, and a Fib-4 index ≥ 3.24 (determined by receiver-operating characteristic curve) on admission were independent predictors of IRF in patients with AHFpEF.

Conclusion: IRF in patients with AHFpEF is associated with poor prognosis. A higher Fib-4 index at admission in AHFpEF can serve as a predictor of IRF.

Background: IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis. Elevation in the blood levels of aberrantly glycosylated IgA1 is a crucial initial step in IgAN pathogenesis. Here, we aimed to determine the longitudinal changes in the serum levels of IgA1 O- and N-glycoforms in patients with IgAN receiving different treatments.

Methods: We enrolled Japanese patients diagnosed with primary IgAN: 10 patients who underwent tonsillectomy and corticosteroid therapy (T-CST), 7 who received corticosteroid therapy (CST), 8 who received conservative therapy (CO), and 5 with other renal diseases who received corticosteroid therapy (ORD) as disease controls. IgA was purified from patient sera collected at diagnosis and post-treatment. After sample preparation, O-glycoforms of the hinge region (HR) and N-glycoforms of the fragment crystallizable region were analyzed using high-resolution mass spectrometry (MS).

Results: The MS analysis of O-glycoforms of IgA1 showed that the relative abundance of IgA1 with 3GalNAc3Gal, which we previously identified as a characteristic IgA1 O-glycoform in IgAN, decreased post-treatment only in the T-CST group (P = 0.0195). Regarding N-glycoforms, the relative abundance of fucosylated N-glycan at asparagine (Asn)³⁴⁰ increased in the IgAN group compared with that in the ORD group (P = 0.0189) and decreased post-treatment only in the T-CST group (P = 0.0195).

Conclusion: The MS analysis of O- and N-glycoforms of IgA1 revealed substantial changes in their abundance in the T-CST group but not in the CST, CO, and ORD groups. Our study provides new insights into how specific treatments alter the IgA1 glycoform abundance.

Background: Acute kidney injury (AKI) following cardiac surgery is common and is associated with poor outcomes. The combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) is a strong predictor of AKI after cardiac surgery. However, most studies have focused on non-Asian populations, and comparisons with other AKI biomarkers or the optimal timing for measurement have yet to be explored.

Methods: We prospectively enrolled adult patients at Kochi Medical School Hospital in Kochi, Japan, to assess the predictive values of [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, neutrophil gelatinase-associated lipocalin (NGAL), and liver fatty acid-binding protein (L-FABP) measured preoperatively and at 2, 4, 6, and 8 h, as well as on day 1 and day 2 after postoperative intensive care unit (ICU) admission, using receiver operating characteristic curve (ROC) analysis.

Results: Of the 38 patients, 13 (34.2%) developed AKI: seven (18.4%) with stage 1, four (10.5%) with stage 2, and two (5.2%) with stage 3. ROC analysis showed that the area under the curve (AUC) for predicting any stage of AKI peaked at 0-4 h, with the highest value at 2 h after ICU admission. Among the biomarkers, [TIMP-2]•[IGFBP7] showed the best AUC at 2 h after ICU admission, followed by TIMP-2, IGFBP7, L-FABP, and NGAL.

Conclusions: Our study demonstrated the good predictive performance of urine biomarkers, including [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, NGAL, and L-FABP, for any stage of cardiac surgery-associated AKI (CSA-AKI). The combination of TIMP-2 and IGFBP7 measured 2 h after postoperative ICU admission effectively predicted CSA-AKI, identifying patients at higher risk.

Urinary presepsin (uPSEP) is a marker of tubular interstitial injury. For patients who have undergone kidney transplantation, the early diagnosis of rejection is important to early treatment and preservation of the transplanted kidney function. We investigated whether uPSEP is useful for predicting T-cell-mediated rejection (TCMR). Patients who underwent graft biopsy in 2020 and 2023 after kidney transplantation at our hospital were included. We excluded protocol biopsy samples obtained at 1 h. We measured uPSEP and divided the patients into groups based on the presence or absence of TCMR; then, group comparisons were performed. A total of 39 patients (17 female and 22 male patients) with a median age of 57 years (interquartile range [IQR], 46.5-63 years) at the time of biopsy were included. Thirty-one patients underwent protocol biopsies and eight underwent episode biopsies. TCMR occurred in three patients. The uPSEP value of the TCMR group was 6788.63 ng/gCr (IQR, 5374.57-9931.87 ng/gCr), and that of the non-TCMR group was 777.61 ng/gCr (IQR, 321.57-1299.63 ng/gCr) (P < 0.01). The receiver-operating characteristic curve for predicting TCMR had a cutoff value of 3961 ng/gCr and an area under the curve of 0.982 (95% confidence interval [CI], 0.942-1). The odds ratio of TCMR based on uPSEP (per 1000-ng/gCr increase in uPSEP) was 1.90 (95% CI, 1.10-3.28; P = 0.02). uPSEP levels may predict TCMR with high accuracy.

Background: Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, are influenced by environmental factors and play a central role in the progression and therapeutic targeting of kidney diseases, such as diabetic kidney disease (DKD), chronic kidney disease (CKD), and hypertension. These epigenetic changes are also preserved as cellular memory, with this "epigenetic memory" known to have long-term effects on such chronic diseases. Histone modifications are readily reversible epigenetic changes that regulate gene expression by altering chromatin structure or providing docking sites for transcriptional regulators. From a disease perspective, the involvement of epigenetics and "epigenetic memory" in DKD, CKD, senescence, and hypertension has been increasingly studied in recent years. Targeting epigenetic mechanisms is, thus, expected to offer novel therapeutic strategies for these diseases. Advances in treatment include histone deacetylase inhibitors and methyltransferase inhibitors, their applications of which have expanded from oncology to nephrology. However, challenges such as long-term toxicity and off-target effects remain significant. Further elucidation of kidney-specific epigenetic pathways and memory mechanisms may pave the way for precision epigenetic therapies, enabling the reversal of pathological epigenetic signatures and the mitigation of disease progression.

Conclusion: This review integrates recent advancements, highlighting functional evidence that histone modifications, particularly histone tail methylation, are involved in the pathogenesis of kidney diseases. It also emphasizes the translational significance of these findings, underlining the potential of epigenetics-based therapies to transform the management of kidney diseases.

Background: The prognosis of Japanese dialysis patients diagnosed with latent tuberculosis infection (LTBI) at the time of starting dialysis remains unclear. The purpose of this study was to examine whether there is a difference in prognosis between incident dialysis patients with and without LTBI.

Methods: A retrospective study of incident dialysis patients who underwent an interferon-gamma release assay (T-SPOT test) within 1 year before or after dialysis initiation at our hospital between May 1, 2013, and December 31, 2021 was conducted. Using propensity score matching (PSM), survival of the non-LTBI and LTBI groups was compared after adjusting for patient background characteristics.

Results: Of the 737 incident dialysis patients, 276 (37.4%) underwent the T-SPOT test, of whom 23 (8.3%) were diagnosed with LTBI. After matching for age, sex, activities of daily living (ADL), estimated glomerular filtration rate (eGFR), Charlson comorbidity index (CCI), and serum albumin level, 23 patients were selected for each group. Kaplan-Meier analysis showed a significantly lower cumulative survival rate in the LTBI group (p = 0.048, log-rank test). In the LTBI group, the cumulative survival rate tended to be higher in the LTBI-treated group (n = 13) than in the untreated group (n = 10) (p = 0.089).

Conclusion: Patients with LTBI at dialysis initiation have a poorer prognosis than those without LTBI, and LTBI treatment may improve their prognosis. This study emphasizes the clinical importance and necessity of managing LTBI in dialysis patients.

Background: Massive proteinuria, dyslipidemia, and hypoalbuminemia induced by nephrotic syndrome (NS) secondarily affect tubular cells. We conducted an RNA sequencing (RNA-seq) analysis using a mouse model of focal segmental glomerulosclerosis to clarify the impact of NS on tubular cells.

Methods: We used transgenic mice expressing hCD25 in podocytes (Nep25) to induce NS by injecting human CD25-specific immunotoxin (LMB2) at a dose of 0.625 ng/g body weight. Seven days after LMB2 injection, we extracted RNA from the whole kidney and conducted an RNA-seq analysis. Subsequently, we conducted multiple immunostaining and in situ hybridization (ISH) of differentially expressed genes (DEGs) to identify their locations and associated cell types. We also investigated the expression levels of DEGs in an additional mouse model of NS induced by adriamycin.

Results: After NS induction, 562 upregulated and 430 downregulated DEGs were identified using RNA-seq. An enrichment analysis revealed the upregulation of cell proliferation-related genes. We observed significant upregulation of Foxm1, a transcription factor linked to cell proliferation. Immunostaining and ISH showed that various tubular cells expressed Mki67 and Foxm1 during NS development. The adriamycin-induced NS model also demonstrated the upregulation of Mki67 and Foxm1 in tubular cells.

Conclusions: NS induced the upregulation of cell proliferation-related genes in tubular cells without detectable renal dysfunction. Our findings may contribute to understanding the pathological effects of nephrotic syndrome on tubular cells.

Background: Debate continues regarding the potential of the ultrasonic renal length to serve as an indicator for evaluating the advancement of renal fibrosis in chronic kidney disease (CKD). This study investigates the independent association between renal length and renal fibrosis in non-diabetic CKD patients and assesses its diagnostic performance.

Methods: From April 2019 to December 2021, 144 non-diabetic patients diagnosed with CKD who underwent a renal ultrasound examination and kidney biopsy were prospectively enrolled. Patients were categorized into the mild fibrosis group (n = 70) and the moderate-severe group (n = 74) based on the extent of fibrotic involvement. Ultrasonic renal length was measured from pole-to-pole in the coronal plane. A receiver operating characteristic (ROC) curve, multivariable logistic regression analysis, and a generalized additive model were performed.

Results: A negative linear correlation was found between renal length and moderate-severe renal fibrosis risk. Each centimeter increase in renal length decreased the odds of moderate-severe fibrosis by 38% (OR: 0.62; 95% CI 0.41-0.93; P = 0.020). After adjusting for confounders, the relationship persisted (OR: 0.58; 95% CI 0.33-1.00; P = 0.048). However, renal length presented limited discrimination ability in distinguishing degrees of renal fibrosis while controlling the key confounding factors, yielding an area under the ROC curve of only 0.58 (95% CI 0.45-0.70).

Conclusion: While an inverse relationship exists between renal length and risk of having moderate-severe renal fibrosis in non-diabetic CKD patients, renal length alone is insufficient for diagnosing fibrosis severity, underscoring the need for additional diagnostic parameters in CKD assessment.

Background: We investigated the roles of renal volumetry and histological features in the assessment of preoperative and postoperative renal function in living kidney donors (LKDs) including high-risk marginal donors (MDs).

Methods: We included 128 LKDs who underwent donor nephrectomy at our institution between 2006 and 2022. Clinical and radiographic data were retrospectively obtained from medical charts. Renal volume parameters were calculated using preoperative computed tomography images. Tissues obtained from allograft biopsies were examined. MDs were defined according to the Japanese guidelines and compared with standard donors (SDs).

Results: LKDs were divided into 89 SDs and 39 MDs. Renal volumetry parameters did not differ significantly between the two groups, while interstitial inflammation and interstitial fibrosis/tubular atrophy were significantly higher in MDs (P = 0.031 and P = 0.041). In the multivariate analysis, age < 60 years (P = 0.036), body mass index > 25 (P = 0.031), and residual kidney volume/body surface area (RKV/BSA; P = 0.002) were independent factors for poor preservation of renal function. Subgroup analysis of the MDs revealed that RKV/BSA (P = 0.0096), residual measured glomerular filtration rate (GFR) (P = 0.0005), and arteriosclerosis (P = 0.045) were associated with poor preservation of renal function. Furthermore, the risk of graft loss was significantly higher for kidneys donated from MDs (P = 0.0019).

Conclusions: RKV/BSA can be a reliable screening and prognostic tool for selection of LKDs, including MDs, and RKV/BSA, measured GFR, and histological findings such as arteriosclerosis can be used to establish clearer MD criteria for optimal personalized follow-up after surgery.