American Journal of Nephrology最新文献

Introduction: Rituximab has proven effective and safe in pediatric and adult minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) patients with frequently relapsing nephrotic syndrome. However, its efficacy diminishes in several patients who experience nephrotic syndrome relapsing in short durations or failing to achieve remission. We aimed to explore the efficacy and safety of obinutuzumab, a novel anti-CD20 antibody, in these patients.

Methods: A retrospective case series study at our center included 11 adult MCD or FSGS patients who presented with nephrotic syndrome characterized by short-duration relapses or lack of remission after multitarget therapy, including rituximab. Primary outcomes included the first relapse-free time, relapse rate during follow-up, and the use of immunosuppressants after obinutuzumab. All adverse events were recorded.

Results: Eleven adult patients (median age 26.0 years, 81.9% males) received an average obinutuzumab dose of 2.0 (1.0, 2.0) g during a median follow-up period of 17.0 (12.0, 22.0) months. The first relapse-free time was 12.1 (10.8, 18.9) months. Two patients with FSGS experienced relapses, while the remaining maintained remission by the end of follow-up. Six patients (54.5%) achieved cessation of corticosteroids and immunosuppressants within 3 months after obinutuzumab. Adverse events were mostly mild.

Conclusion: Obinutuzumab may be an efficient and safe option for inducing remission in adult MCD and FSGS patients who presented with nephrotic syndrome relapsing in short durations or failed to achieve remission after multitarget therapy, including rituximab. It was effective in maintaining remission in MCD patients, while its efficacy in maintaining remission in FSGS patients remained uncertain.

Introduction: The aim of the study was to investigate the potential of diffusion kurtosis imaging (DKI) in monitoring the improvement of liver and kidney injury in cirrhotic rats after bone marrow-derived mesenchymal stem cell (BMSCs) treatment.

Methods: Thirty rats were induced with liver cirrhosis via subcutaneous injection of carbon tetrachloride. Six rats were randomly selected for DKI scanning and subsequently euthanized for biochemical and histological analysis. The remaining 24 rats were randomly divided into a BMSC group (n = 12) and a control group (n = 12). In the BMSC group, six rats underwent dynamic DKI scans and were sacrificed after 13, 14, 15, and 16 weeks, while the other 6 rats were sacrificed after being scanned in the 14th week. The control group followed the same protocol as the BMSC group. Additionally, six normal rats were euthanized after undergoing DKI scanning to provide baseline data. Liver and kidney DKI parameters, biochemical markers, liver fibers, kidney hematoxylin and eosin (HE) score, and alpha smooth muscle actin (α-SMA) were analyzed.

Results: Compared to baseline, there was a significant increase in liver fibers and kidney HE scores by week 12. At weeks 13, 14, 15, and 16, the mean kurtosis (MK) of the liver in the BMSC group was significantly lower than that at week 12 and in the control group. At week 16, the mean diffusion in the BMSC group was significantly higher than that at week 12 and in the control group. The apparent diffusivity coefficient (ADC) values in the BMSC group were higher than those at week 12 and in the control group at weeks 13, 14, and 16. All regions of kidney showed decreased MK values from weeks 14-16 compared to week 12 and the control group. Liver fiber was moderately or highly correlated with all DKI parameters. MK and ADC of the renal cortex and outer stripe of the outer medulla showed moderate correlation with HE scores and α-SMA.

Conclusion: DKI can serve as a non-invasive means to effectively monitor the process of liver and kidney injury improvement in cirrhotic rats treated with BMSCs.

Introduction: Angiotensin II may reduce muscle ischemia during intermittent hemodialysis (IHD) and thereby decrease the incidence and/or intensity of intradialytic muscle cramps. We aimed to test whether angiotensin II infusion during IHD is safe, feasible, and effective in the attenuation of muscle cramps.

Methods: We performed a pilot, single-blinded, randomized crossover trial of patients receiving IHD who frequently experience intradialytic muscle cramps. Patients were randomly allocated to receive either intravenous angiotensin II or placebo for the duration of their first dialysis session of the week. They crossed over to the alternate arm each week for 4 weeks. The primary outcome was safety. Secondary outcomes included cramp-related symptoms, hemodynamic parameters, dialysis prescription alterations, and biomarkers.

Results: We studied 24 sessions in 6 patients. Intradialytic hypertension (systolic blood pressure >180 mm Hg) occurred more often with angiotensin II than with placebo (4/12 sessions, 33% vs. 2/12 sessions, 17% sessions, p = 0.64). There were no other adverse events. Compared with placebo, muscle cramps were less frequent (4/12 sessions, 33% vs. 11/12 sessions, 92% sessions, p = 0.009) and of lower intensity with angiotensin II (median Brief Pain Inventory score 1.4 vs. 5.3; p < 0.001; maximal Brief Pain Inventory score 1.2 vs. 6.0; p < 0.001). Fluid bolus administration for cramps was less common during angiotensin II infusion than placebo (0/12 sessions, 0% vs. 5/12 sessions, 42% sessions, p = 0.037).

Conclusion: Angiotensin II increased blood pressure and heart rate but not cardiac output or levels of troponin, creatine kinase, or renin. Angiotensin II infusion during IHD appears safe and effective at reducing intradialytic muscle cramps. These observations justify further investigation in larger controlled studies.

Introduction: Zinc, an essential trace element, plays an important role in various cellular processes, and zinc deficiency is common in patients undergoing hemodialysis. Zinc has been shown to stimulate osteoblastic bone formation and mineralization and inhibit osteoclastic bone resorption. Although osteoporosis is highly prevalent among patients undergoing hemodialysis, the utility of areal bone mineral density (aBMD) measured using dual-energy X-ray absorptiometry (DXA) is limited because DXA cannot reveal bone microarchitectural alterations. The trabecular bone score (TBS) extracted from DXA images is a new texture measurement used to assess the bone microarchitecture. However, whether zinc status is associated with TBS in patients undergoing hemodialysis remains unclear. Therefore, we investigated the association between serum zinc levels and osteoporosis parameters (aBMD and TBS) in patients undergoing chronic hemodialysis.

Methods: This cross-sectional study included 316 outpatients undergoing hemodialysis at the Masuko Memorial Hospital in Japan. Serum zinc levels were measured, and aBMD and TBS were assessed using DXA.

Results: In total, 139 (41.0%) patients had zinc deficiency, defined as serum zinc levels <60 µg/dL. In multivariate linear regression analyses, high serum zinc levels were associated with high TBS (β = 0.146, p = 0.004) but not aBMD values (total hip aBMD: β = -0.0200, p = 0.63; lumbar spine aBMD: β = 0.0478, p = 0.34). In multiple logistic regression analysis, zinc deficiency was associated with degraded bone microarchitecture according to the TBS (odds ratio, 2.27; 95% confidence interval, 1.22-4.22; p = 0.009). No association was found between the serum zinc status and aBMD thresholds for osteoporosis.

Conclusion: These results suggest that zinc plays a protective role in bone metabolism by inhibiting chronic kidney disease-induced changes in the bone microarchitecture.

Introduction: CD24+/CD133+ scattered tubular-like cells (STCs) are surviving renal cells that acquire progenitor-like characteristics to repair other damaged kidney cells. Renal artery stenosis (RAS) impairs the reparative capacity of STCs, but the underlying mechanisms remain unknown. STCs contain abundant endoplasmic reticulum (ER), but its capacity to fold proteins could become saturated (ER stress), leading to STC dysfunction. We hypothesized that RAS alters the expression of genes implicated in ER stress in swine STCs.

Methods: STCs were harvested from pig kidneys after 10 weeks of RAS or sham (n = 6 each) and expression of ER stress genes was assessed using mRNA-seq (n = 3 each). To elucidate mechanisms regulating ER stress genes in RAS-STCs, integrated mRNA-seq/microRNA (miRNA)-seq and transcription factor (TF) prediction analysis were performed. STC ER stress was assessed in vitro using Western blotting, serial block-face electron microscopy, and mass spectrometry. The involvement of ER stress in regulating the STC-protective effects was also assessed in vitro by their capacity to improve viability of injured human tubular epithelial cells.

Results: RAS pigs developed significant renal dysfunction. mRNA-seq identified 25 ER stress genes upregulated and 30 downregulated in RAS-STCs versus normal-STCs. miRNAs were found to target over a third of all differentially expressed ER stress genes, and almost half of genes encoding for the top 50 TFs involved in regulation of ER stress genes were dysregulated in RAS-STCs. RAS-STCs exhibited higher ER stress compared to normal-STCs, reflected in significant ER dilation and formation of ER-mitochondria contacts and increased levels of ER stress-related amino acids. Importantly, ER stress inhibition improved the reparative capacity of RAS-STCs in vitro.

Conclusion: Renal ischemia alters expression of ER stress-related genes in swine STCs, likely through post-transcriptional- and TF-regulatory mechanisms, which induces ER stress and impairs their reparative potency. These alterations may limit the potential of STCs to repair damaged kidneys in subjects with RAS.

Introduction: Idiopathic membranous nephropathy (iMN) has become one of the most prevalent primary glomerular diseases, with a marked increase in prevalence over the past two decades in northern China. Fine particulate matter (PM2.5) is considered to be associated with this rising prevalence. In this study, we aimed to evaluate the trends of iMN in relation to improved air quality and conduct a cross-sectional study in Hebei province (northern China, near Beijing) to investigate the role of gene-environment interactions in its development.

Methods: This study established two cohorts. Cohort 1 included 22,937 pathology reports from Peking University First Hospital (2002-2021) to assess iMN prevalence. Cohort 2 comprised 5,635 iMN patients from 11 cities in Hebei province (2009-2013). DNA samples from 374 iMN patients and 1,259 controls were genotyped for SNPs rs4664608 (PLA2R1) and rs2187668 (HLA-DQA1). Patients were stratified by air pollution risk levels. The annual percentage change (APC) and average annual percentage change were estimated using a joinpoint regression model. Gene-environment interactions were analyzed using logistic regression and epinet calculation.

Results: In cohort 1, 5,586 patients with iMN were identified, representing 24.3% of the 22,937 patients from 2002 to 2021. The general population showed a significant increase in iMN proportion with an APC of +12.7% per year from 2002 to 2014 (95% CI: 10.3-17.5, p < 0.001), followed by a decline with an APC of -5.6% per year from 2014 to 2021 (95% CI: -9.6 to -2.6, p < 0.001). In Hebei province, the iMN frequency rose significantly with an APC of +17.6% per year from 2002 to 2016 (95% CI: 14.5-28.6, p < 0.001), peaking at 60%, and then declined with an APC of -5.5% per year from 2016 to 2021 (95% CI: -13.1 to -1.2, p = 0.02). Cohort 2 highlighted significant regional variation in iMN incidence across Hebei province. Geographic exposure to pollution was identified as an independent risk factor for iMN (RR: 1.49, 95% CI: 1.38-1.56, p < 0.001). Gene-environment interaction analysis revealed that patients with risk alleles in the PLA2R1 gene and exposure to risk environments had a markedly increased risk of developing iMN (odds ratio = 38.72, 95% CI: 11.95-125.46, p < 0.01).

Conclusion: The annual growth rate of iMN in northern China appears to be slowing down. Gene-environment interactions may have contributed to the previously observed increase in prevalence.

Introduction: This study aimed to investigate the effects of cumulative exposure to plasma aldosterone concentration (PAC) and its time course on chronic kidney disease (CKD) in hypertensive patients, with the goal of providing insights into preventing future CKD events, especially in younger hypertensive patients.

Methods: This study enrolled a total of 7,142 hypertensive participants, each of whom had undergone at least two PAC measurements before the age of 60. We calculated the annual PAC area under the curve (AUC) and used Cox regression analyses to examine the association between annual PAC_AUC and CKD risk. We also explored how the timing course of PAC accumulation affected CKD risk, as different stages of PAC accumulation, even with the same annual PAC_AUC, may lead to varying risks. Additionally, we conducted a comparative analysis to assess the predictive performance of annual PAC_AUC versus single PAC measurements.

Results: During a median follow-up of 5.83 years, 754 participants developed CKD. The results showed a progressive increase in CKD risk with higher annual PAC_AUC (hazard ratio: 1.19; 95% confidence interval: 1.17, 1.21). Moreover, the timing course of PAC accumulation modulates this risk; Kaplan-Meier curves indicated that participants with similar annual PAC_AUC, but earlier PAC exposure had a higher CKD risk compared to those exposed later (Log-rank test, p < 0.001). Furthermore, annual PAC_AUC outperformed single PAC measurements in predictive accuracy.

Conclusion: CKD risk is influenced by both annual PAC_AUC and the time course of PAC exposure. Participants exposed to elevated PAC earlier had a higher CKD risk than those exposed later, even at the same annual PAC_AUC. This highlights the importance of early PAC control to prevent CKD.

Introduction: In primary membranous nephropathy (MN), 80% of patients harbor antibodies (Abs) against phospholipase A2 receptor 1 (PLA2R1), closely linked to disease prognosis. Prior research has validated the correlation between Abs directed toward the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 and outcomes in MN.

Methods: In a prospective cohort of 52 patients with newly diagnosed PLA2R1-MN, with urine protein ≥ 3.5 g/24 h and estimated glomerular filtration rate ≥30 mL/min/1.73 m2, we studied epitope spreading patterns and domain-specific PLA2R1-Ab clinically using Western blot and ELISA. The primary outcome was a combination of remission at 12 months. Kaplan-Meier curves and multivariable Cox regression were employed to compare the single and multiple epitope patients.

Results: All patients had anti-CysR-Abs. 26 (50.0%) exhibited multi-domain recognition, with 1 patient specifically recognizing the CTLD8 domain. A significant association was observed between PLA2R1-Ab and CysR-Ab (r = 0.869, p < 0.001), as well as with anti-CTLD1 Ab (r = 0.803, p < 0.001). During a median follow-up of 11 months (IQR, 6.0-17.0), 27 patients (65.9%) experienced complete or partial nephrotic syndrome remission. Notably, the multi-domain recognition exhibited a reduced remission rate compared to the single-domain (44.44% vs. 82.61%, p = 0.011, alongside higher concentrations of anti-PLA2R1-Abs. A higher baseline level of anti-CTLD1 was notably linked to a lower likelihood of remission. In a univariate analysis, multi-domain recognition decreases the probability of remission (HR, 0.38 [95% CI, 0.16-0.87], p = 0.022). After the Kaplan-Meier analysis, the multi-domain group showed lower remission rates than the single-domain group at various time points.

Conclusion: The PLA2R1 epitope spreading (ES) is a potent tool for monitoring disease severity and stratifying patients based on renal outcomes for prognostic purposes. Hence, we advocate evaluating ES at the baseline stage when determining early therapeutic interventions for individuals diagnosed with MN.

Introduction: Little is known about the biofluid specificity of microRNAs (miRNAs) in systemic lupus erythematosus (SLE) and the biofluid influence on miRNA diagnosis and prognosis accuracy. Our aim was to analyze the effect of biofluid on miRNA expression and to identify a specific miRNA profile in plasma exosomes related to SLE activity, renal damage, and disease flares over a 60-month follow-up period.

Methods: Noncoding RNA-sequencing analysis was used to determine miRNA in plasma and plasma exosomes in a discovery cohort of SLE patients and controls. Potential miRNAs were selected based on the differential expression between biofluids and were validated by quantitative polymerase chain reaction in a higher validation cohort.

Results: From the small RNA sequencing, the 25 miRNAs with the highest fold-change expression between biofluids were identified. Nine miRNAs were validated in a larger cohort (n = 115, of whom 30 had nephritis) and were found to be increased in exosomal fraction and patient groups. Further analysis revealed a panel combining three miRNAs for lupus nephritis diagnosis (miR-101-3p, miR-144-5p, and miR-15a-5p) gave an area under the curve that improves the readout of the single miRNAs (0.964, p < 0.0001). However, only miR-15a-5p had a strong discriminatory power of renal injury between patients (0.81, p < 0.0001). Finally, exosomal miR-15a-5p was associated with histological features, chronicity index and flares (odds ratio 4.24, p < 0.001), high levels being a strong independent predictor of 60-month follow-up flares (hazard ratio 4.24, p < 0.001).

Conclusion: This novelty study demonstrated a biofluid exosome specificity of miRNA profile related to SLE with nephritis, highlighting exosomal miR-15a-5p levels with a strong association with proteinuria, renal histological features, and high accuracy in the diagnosis of renal damage and detection of lupus flares. The detection of altered miRNAs levels in exosome-enriched fraction improved the diagnostic accuracy of renal damage in SLE.

Introduction: IgA nephropathy (IgAN), a leading cause of kidney failure worldwide, is one of the most common forms of primary glomerulonephropathy with variability by race and ethnicity. Using a diverse cohort within a large integrated health system in the United States (US), we identified and characterized patients with biopsy-proven IgAN and report annual incidence rates across racial/ethnic groups and standardized to the US nationally.

Methods: A cross-sectional study between January 1, 2010, and December 31, 2021 within Kaiser Permanente Southern California was performed. Patients (age >/=18 years) who underwent a native kidney biopsy and identified as having primary IgAN comprised the study population. Laboratory, demographic, and comorbidity information were obtained from the electronic health records. Annual incidence rates were calculated for biopsy-proven IgAN (per 100,000 person-years) and standardized to 2020 US Census.

Results: Of 9,392 individuals who underwent kidney biopsy, 606 adult patients were identified with primary IgAN. Crude annual IgAN incidence rates ranged from 1.3 to 2.2 (per 100,000 person-years). US census standardized incidence rate (CI) of IgAN was 1.4 (0.8, 2.0) per 100,000 person-years in the 12-year period. Incidence rate (per 100,000 person-years) was highest among Asian/Pacific Islander (4.5) and Hispanic (1.7) patients and lowest among White (1.2) and Black (0.6) patients. Median estimated glomerular filtration rate (eGFR) was 51 mL/min with median urine protein creatinine ratio (uPCR) 1.8 g/g.

Conclusion: Among a large diverse US population within Southern California, we observed an IgAN incidence rate of 1.7 which estimated to a standardized US incidence of 1.4 (per 100,000 person-years) within a 12-year period. Patients appear to be diagnosed at more advanced disease given kidney function and proteinuria at biopsy.