American Journal of Nephrology最新文献

Introduction: The early diagnosis and appropriate treatment of monogenic glomerular diseases can reduce kidney failure, avoid unnecessary investigations such as kidney biopsies and ineffective treatment with immunosuppressants, guide transplant decisions, and inform the genetic risks of their family members. Yet, genetic testing for kidney disease is underutilized in Singapore. We aimed to implement a nephrologist-led genetic service and evaluate the acceptance, adoption, utility, and cost-effectiveness of genetic testing for monogenic glomerular disease in Singapore.

Methods: We will perform a prospective, multi-centre, type II hybrid effectiveness-implementation study with a post-design to evaluate both implementation and clinical outcomes of nephrologist-led genetic testing for suspected genetic glomerular kidney diseases. The multi-disciplinary implementation team will train "genetic nephrologists" to provide pre- and post-test counselling, order targeted exome panel sequencing for suspected glomerular kidney diseases (persistent microscopic haematuria and/or albuminuria or proteinuria in the absence of known causes, steroid-resistant primary nephrotic syndrome, apparent familial IgA nephropathy, or chronic kidney disease with no apparent cause), and interpret genetic test results; create workflows for patient referral, evaluation and management, and discuss genetic results at regular genomic board meetings. The outcomes are acceptance, appropriateness and adoption among patients and nephrologists, utility (proportion of patients who received genetic testing and have a confirmed diagnosis of genetic glomerular disease), and cost-effectiveness.

Conclusion: This study will create and evaluate a nephrologist-led genetic service, develop an efficient variant curation process, and inform future recommendations on the optimal referral and genetic testing strategy for monogenic glomerular disease in Singapore. This will facilitate the future mainstreaming of genetic testing that will enable precision medicine in kidney care.

Introduction: Peritoneal dialysis (PD) is an effective home therapy for end-stage kidney disease. However, continuous exposure to PD fluids with high glucose concentration and recurrent peritonitis may lead to the activation of cellular and molecular processes of peritoneal damage, including inflammation and fibrosis. In particular, recent studies have highlighted the role of neutrophils in chronic inflammation. This study explores how neutrophil extracellular traps (NETs) affect peritoneal membrane function and contribute to technical failures in PD patients.

Methods: We conducted a prospective observational study involving 250 noninfectious and 30 acute peritonitis patients. NETs were measured using nucleosome and myeloperoxidase DNA levels in PD fluids. Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-8 (MMP-8) were also measured to assess peritoneal inflammation and damage.

Results: A significant increase in peritoneal NETs, as determined by nucleosome and myeloperoxidase DNA levels, was observed in patients with acute peritonitis compared to patients without peritonitis. Even in noninfectious samples, NET levels were widely distributed and closely correlated with levels of MCP-1 and MMP-8. Higher levels of peritoneal NETs were closely associated with increased 4-h dialyzate/peritoneal (D/P) creatinine ratio and 1-h D/P sodium levels, indicating a higher prevalence of fast transport and limited free water transport. These factors were associated with a higher risk of technical failure. During a mean follow-up of 34 months, 39.2% (98 patients) switched from PD to hemodialysis, with higher NET levels significantly increasing the risk by 1.9 times (95% confidence interval: 1.27-2.83, p = 0.020).

Conclusion: This study suggests the importance of peritoneal NETs not only as markers of acute inflammation but also as significant immunological predictors of chronic peritoneal membrane inflammation and dysfunction and as potential risk factors for technical failure.

Introduction: Moderate vitamin A levels during pregnancy are strongly related to normal embryonic development in both animal models and population studies. Abnormal development of urinary tract system is linked to either an excess or a shortage of vitamin A. The relationships among maternal vitamin A deficiency prior to conception, moderate vitamin A supplementation during pregnancy, and abnormal urinary system development in offspring are unclear.

Methods: By creating preconception and preconception + pregnancy vitamin A insufficiency mouse models, we investigated whether moderate vitamin A treatment during pregnancy may reduce the prevalence of CAKUT and increase distant vitamin A levels in offspring, as well as any potential pathways involved.

Results: We effectively established a prepregnancy vitamin A-deficient mouse model by providing a particular diet with or without vitamin A for 4 weeks. The offspring of the hypovitaminosis A model group presented a greater proportion of neonatal urinary tract developmental malformations. Abnormalities in ureteral bud emergence and key molecules during renal development, such as p-Plcγ and Ret, may be the primary causes of offspring development of CAKUT as a result of mothers' hypovitaminosis A. Normal vitamin A diets, on the other hand, may help mitigate the teratogenic consequences of prepregnancy hypovitaminosis A, as well as defects produced by ureteral budding and major molecular changes.

Conclusion: In contrast, the administration of normal vitamin A feeds during pregnancy may ameliorate the teratogenic effects of prepregnancy hypovitaminosis A to a certain extent and may also ameliorate the abnormalities associated with ureteral budding and key molecular changes.

Introduction: Understanding the molecular signals associated with the progression of kidney disease is vital for risk stratification and targeted treatment. Recent advances in RNA-sequencing technique have enabled us to characterize extracellular transcriptome profiles for precision diagnostics.

Method: We evaluated the plasma mRNA profile of participants exhibiting slow (n = 119) and fast (n = 119) decline in estimated glomerular filtration rate (eGFR) among the Chronic Renal Insufficiency Cohort (CRIC) in a nested case control study. The two groups were matched for age, sex, race, baseline eGFR, proteinuria, and diabetes status. The next-generation sequencing data were analyzed using edgeR to identify differentially expressed genes (DEGs) and ingenuity pathway analysis was done to identify the associated pathways. We also compared the top plasma DEGs with gene expression in microdissected human chronic kidney disease (CKD) kidney.

Results: We identified fragments from ∼28,000 annotated genes, of which 783 transcripts exhibited differential expression between slow and fast CKD progressors. Among 629 protein coding genes, 469 were overexpressed in slow progressors, while 157 showed increased expression in fast progressors. Expression of GLI2, CUX1, NOTCH1, and LRP1 transcripts were amplified in slow progressors. Pathway analysis linked these DEG to WNT/β-catenin signaling, IL-12 signaling and production in macrophages, Netrin-1 Signaling and Epithelial-Mesenchymal Transition pathways. Many of the plasma DEGs were also upregulated in microdissected human CKD kidney.

Conclusion: Warranting further validation, circulating levels of aberrantly expressed transcripts hold potential to be used as biomarkers for fast CKD progression.

Introduction: Mycophenolate mofetil (MMF) is widely used off-label in patients with immunoglobulin A nephropathy (IgAN), although the literature does not consistently agree on its efficacy and safety.

Methods: We systematically searched PubMed, Embase, CENTRAL, CNKI, VIP, Wanfang Data, and SinoMed from their inception to August 2023. We included randomized controlled trials that enrolled patients of IgAN who received MMF treatment and compared effects with placebo or as an add-on therapy to usual care. Literature screening, risk of bias assessment, and data extraction were independently conducted in duplicate. Fixed-effects or random-effects meta-analyses were performed for pooling data where eligible. The primary outcomes were the composite kidney outcomes of major adverse kidney events (MAKDE) defined as doubling of serum creatinine, end-stage renal disease (ESRD), or death from a kidney disease-related or cardiovascular cause.

Results: Of 13 studies identified, 918 participants (463 [50.4%] treated with MMF) with IgAN were included in the analysis. MMF treatment in IgAN was associated with decreasing the occurrence of MAKDE (relative risk [RR], 0.32; 95% confidence interval [CI], 0.13-0.77), reducing proteinuria (RR, 1.41; 95% CI, 1.22-1.64), and lessening the probability of doubling blood creatinine (RR, 0.32, 95% CI, 0.14-0.72). No significant differences were detected in the incidence of ESRD (RR, 0.87, 95% CI, 0.38-2.03), or progression of chronic kidney disease (RR, 1.01; 95% CI, 0.22-4.57). Patients receiving MMF had a higher risk of infection (RR, 2.20; 95% CI, 1.21-4.00).

Conclusion: MMF administration in IgAN indicates promising in decreasing the occurrence of MAKDE, reducing proteinuria level, and lessening the probability of doubling blood creatinine, but also comes with the risk of infection. These findings tend to be introduced to non-Caucasian population. The long-term favorable effects that MMF improved kidney outcomes still need further cross-regional and cross-ethnical verification.

Introduction: Individuals with end-stage kidney disease face barriers and delays in access to kidney transplantation, but little is known about access before waitlisting due to the lack of national data on pre-waitlisting measures. The Early Steps to Transplant Access Registry (E-STAR) captures referral and evaluation data in four US regions, including the Ohio River Valley, and this study utilizes E-STAR data to describe sociodemographic factors associated with starting the transplant evaluation and waitlisting in this region.

Methods: Adults referred to a transplant center for evaluation within the Ohio River Valley during 2015-2021 and captured within E-STAR were included. Linked E-STAR, US Renal Data System, and American Community Survey data were used to assess the association between sociodemographic (age, sex, race or ethnicity, insurance status), clinical, and neighborhood factors and time from referral to evaluation start and time from evaluation start to waitlisting by Cox proportional hazards analyses.

Results: Among 15,673 referred adults, the mean age was 55 years, and the majority were male (61.4%) and had public insurance (56.6%), while 21.3% were preemptively referred. Compared to individuals aged 18-29, all other age groups had a lower likelihood of starting the evaluation in the adjusted model. Black adults (vs. White; adjusted hazard ratio: 0.89 [95% CI: 0.81-0.98]), and those with Medicaid or Medicare were less likely to start the evaluation (vs. employer-sponsored, 0.58 [0.50-0.66]; 0.66 [0.66-0.82], respectively). Among individuals who started the evaluation, those with Black (vs. White) race, and Medicaid or Medicare (vs. employer-sponsored) were less likely to be waitlisted in the adjusted analysis.

Conclusion: Associations between age, sex, race, and economic characteristics and access to evaluation start and waitlisting were observed. Future research investigating underlying causes and points of intervention in this region is warranted.

Introduction: Multimorbidity, defined as the presence of two or more chronic conditions, is associated with poor outcomes and increased cardiovascular risk in the general population. However, the effect of multimorbidity on patients with chronic kidney disease (CKD), a group of patients already at high risk for cardiovascular disease, is not well understood.

Methods: We analyzed data from 4,420 patients with non-dialysis CKD enrolled in the Fukuoka Kidney disease Registry Study. We identified 23 comorbidities, including cardiometabolic and non-cardiometabolic conditions. The patients were categorized into four groups according to the number of comorbidities: Group 1 (0-1 comorbidities), Group 2 (2 comorbidities), Group 3 (3 comorbidities), and Group 4 (≥4 comorbidities). We examined the associations between the number of comorbidities and the incidence of major adverse cardiovascular events (MACE) and all-cause mortality using Cox proportional hazards models.

Results: Over a 5-year follow-up, 229 patients experienced MACE and 456 died. The risk of MACE increased with the number of comorbidities. The multivariable-adjusted hazard ratios (95% confidence intervals) for MACE were 1.40 (0.80-2.44) for Group 2, 2.27 (1.33-3.88) for Group 3, and 3.53 (2.11-5.91) for Group 4 compared with Group 1. The all-cause mortality risk also increased with the number of comorbidities, with adjusted hazard ratios of 1.13 (0.77-1.66), 1.75 (1.22-2.51), and 2.53 (1.80-3.54) for Groups 2, 3, and 4, respectively.

Conclusion: In patients with CKD, multimorbidity is associated with an increased risk of MACE and all-cause mortality.

Introduction: Previous studies have shown that there is a higher incidence of men initiating kidney replacement therapy (KRT) in comparison to women. However, the contribution of gender disparity may well differ among the different types of kidney disease, and over time. Utilising a Nationwide Registry, we examined disease- and gender-specific trends in incident kidney failure requiring KRT.

Methods: Registry-based analysis of all incident patients commencing KRT in Australia using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. All patients who initiated dialysis in Australia from January 1971 to 31 December 2021 were included. Confidence intervals around rates were calculated and compared using Poisson distributions.

Results: During the study period, a total of 31,834 women and 47,718 men were recorded in ANZDATA to have commenced KRT in Australia, a male-to-female ratio of 1.51 (1.49-1.53). The male-to-female ratio increased over time from 1.05 (0.83-1.34) in 1971 to 1.78 (1.66-1.92) in 2021. There was a progressive increase in the male:female ratio with age; for those starting in 2017-21, this rose from 1.37 (95% CI: 1.26-1.50) among 25-44-year-olds to 4.38 (2.47-5.53) among those ≥85 years at KRT start.

Conclusion: Men had a significantly higher rate of starting KRT in Australia compared with women, and this difference is increasing over time. This disparity also varied between types of primary kidney disease but was higher among older age groups. It is still seen for causes (such as polycystic kidney disease) that have theoretically equal gender disease distribution, suggesting differences in propensity to commence KRT as well as differences in underlying disease processes.

Introduction: There are conflicting reports about the effect or rapamycin on the kidneys. Rapamycin is known to promote phosphaturia that may be associated to renal injury.

Methods: Detailed histopathological studies were performed on the kidneys of rats with normal (control) and reduced (Nx) renal mass that were treated with rapamycin (1.3 mg/kg for 22 days) or placebo. The effect of rapamycin was also evaluated in control and Nx rats fed different amounts of phosphorus: 0.6% P (NP), 1.2% P (HP), and 0.2% P (LP). Quantitative scores of kidney lesions were obtained for interstitial nephritis (IN), tubular damage (TD), and nephrocalcinosis (NC).

Results: When compared with placebo, rapamycin administration to Nx rats resulted in significant increases in IN (4.17 ± 0.74 vs. 1.51 ± 0.53%) and TD (14.45 ± 1.51 vs. 8.61 ± 1.83%). Rapamycin also increased NC both in control (0.86 ± 0.23 vs. 0.14 ± 0.06%) and Nx (0.86 ± 0.32 vs. 0.15 ± 0.14%) rats. In control rats receiving rapamycin, feeding HP aggravated IN (3.25 ± 0.48%), TD (22.47 ± 4.56%), and NC (3.66 ± 0.75%), while feeding LP prevented development of any renal lesions. In Nx rats treated with rapamycin, HP intake also increased IN (8.95 ± 1.94%), TD (26.86 ± 3.95%), and NC (2.77 ± 0.60%), whereas feeding LP reduced all lesions to lower levels than in rats fed NP. Rapamycin treatment increased fractional excretion of P (FEP), and an excellent correlation between scores for renal lesions and FEP was found.

Conclusion: Rapamycin has deleterious effects on kidney pathology causing lesions that are located mainly at tubular and tubulointerstitial level. Rapamycin-induced kidney damage is more evident in rats that already have decreased renal function and seems to be related to the phosphaturic effect of the drug. Dietary P restriction prevents kidney damage in rats treated with rapamycin.