Hyperhomocysteinemia occurs in chronic- and end-stage kidney disease at the time when dialysis or transplant becomes indispensable for survival. Excessive accumulation of homocysteine (Hcy) aggravates conditions associated with imbalanced homeostasis and cellular redox thereby resulting in severe oxidative stress leading to oxidation of reduced free and protein-bound thiols. Thiol modifications such as N-homocysteinylation, sulfination, cysteinylation, glutathionylation, and sulfhydration control cellular responses that direct complex metabolic pathways. Although cysteinyl modifications are kept low, under Hcy-induced stress, thiol modifications persist thus surpassing cellular proteostasis. Here, we review mechanisms of redox regulation and show how cysteinyl modifications triggered by excess Hcy contribute development and progression of chronic kidney disease. We discuss different signaling events resulting from aberrant cysteinyl modification with a focus on transsulfuration.

Homocysteine in Chronic Kidney Disease

Sex differences in brain physiology and by inference various pathologies are generally recognized, however frequently ignored in epidemiological and experimental studies, leading to numerous data gaps. As a consequence, the mechanisms underlying sexual dimorphism of neurological diseases remain largely unknown. Several cellular and molecular pathways linked to the etiology and pathogenesis of various brain disorders have been recently described as sex-specific. Here, we review the evidence for sex differences in brain redox homeostasis, which is an important factor in brain physiology and disease. First, we focus on sex-specific differences in the healthy brain regarding popular redox balance markers, including reactive oxygen and nitrogen species, oxidative damage, and antioxidant status. We also review the modulatory effect of steroid sex hormones on these markers. Lastly, we approach the sex-specific changes in brain redox homeostasis in disease and discuss the possibility that differential redox response contributes to the sexual dimorphism of neurological disorders.

Sex-Specific Differences in Redox Homeostasis in Brain Norm and Disease.

Aims: Thioredoxin interacting protein (TXNIP), an inhibitor of antioxidant thioredoxin (Trx), is upregulated by hyperglycemia and implicated in pathogenesis of diabetes complications. We evaluated mRNA expressions of genes encoding TXNIP and Trx (TXN) in urinary sediment and peripheral blood mononuclear cells (PBMC) of type 1 diabetes (T1D) patients with different degrees of chronic complications. Methods: qPCR was employed to quantify target genes in urinary sediment (n = 55) and PBMC (n = 161) from patients sorted by presence or absence of diabetic nephropathy (DN), retinopathy, peripheral and cardiovascular neuropathy; 26 healthy controls and 13 patients presenting non-diabetic nephropathy (focal and segmental glomerulosclerosis, FSGS) were also included. Results: Regarding the urinary sediment, TXNIP (but not TXN) expression was higher in T1D (p = 0.0023) and FSGS (p = 0.0027) patients versus controls. Expressions of TXNIP and TXN were higher, respectively, in T1D patients with versus without ...

Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes.

The transradial approach (TRA) for coronary angiography and percutaneous coronary intervention is associated with lower rates of vascular complications and acute kidney injury when compared to the transfemoral approach (TFA). Urine metabolites and proteins may be useful in identifying the dynamic changes at the vascular endothelial cell level. We attempted to explore the changes in the measurable signals of endothelial and nephron injury within 60 to 90 minutes after catheterization among those with the TRA and TFA approaches. Consecutive patients of a single interventionist who underwent coronary angiography between June 2015 and May 2016 were included. Of the 60 patients included in the analysis, the baseline characteristics were similar between those with a TRA (n = 30) and TFA (n = 30) approach. The values of the biomarkers were natural log transformed for the analysis. We found that the mean values of heat shock protein 27, taurine, and sulfuric acid did not significantly change after the procedure. However, the median value of thioredoxin decreased (P = 0.002) and that of talose increased (P = 0.01) after the procedure. None of the patients in our cohort experienced vascular complications or acute kidney injury. No differences in the values of urinary metabolites (pre, post, and delta) were found between TRA and TFA except for postprocedural thioredoxin. In conclusion, this exploratory study showed no difference in the patterns of acute vascular/renal injury metabolic markers before and after catheterization irrespective of the arterial access site.

Urinary metabolites in patients undergoing coronary catheterization via the radial versus femoral artery approach

Significance: The development and progression of renal diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), are the result of heterogeneous pathophysiology that reflects ...

Urinary thioredoxin as a biomarker of renal redox dysregulation and a companion diagnostic to identify responders to redox-modulating therapeutics

Aim

The role of urinary (U-) thioredoxin (Trx), a class of small redox proteins, in physiological and pathological conditions, in addition to its gender specificity, has been insufficiently determined in chronic kidney disease (CKD) patients, especially in diabetes mellitus (DM) nephropathy.



Methods

U-Trx was measured cross-sectionally in 110 CKD outpatients with estimated glomerular filtration rate (eGFR) of >15 mL/min per 1.73 m2, namely, in 57 type 2 DM patients (male: n = 41, female: n = 16) and 53 non-DM patients (M: n = 33, F: n = 20), as well as 30 healthy controls (M: n = 11, F: n = 19). Comparisons were made among controls, DM and non-DM, and between M and F, with clinical parameters compared in each group. In addition, a comparison between average U-Trx level and the changes of renal function during a one-year period was performed.



Results

U-Trx was significantly higher in females than in males in controls (P < 0.05) and in non-DM patients (P < 0.05). Multiple regression analysis revealed that urinary protein (UP)/creatinine (Cr) ratio, female sex and HbA1c were independent factors affecting U-Trx among all subjects (adjusted R2 = 0.468). In DM patients, U-Trx was negatively correlated with eGFR, especially in males, and positively correlated with UP/Cr and NAG in both sexes (all P < 0.01), as well as with systolic blood pressure in all (P < 0.05). Average U-Trx was positively correlated with the rate of annual eGFR decline of male (P < 0.01) but not female DM patients.



Conclusion

U-Trx might have a gender-specific physiological and pathological role and be a potent marker of renal damage in DM nephropathy.

Gender- and disease-specific urinary thioredoxin in chronic kidney disease patients with or without type 2 diabetic nephropathy.

Background: Japanese COPD patients tend to have lower CAT scores than Western patients. A previous 1-year study showed wide variation in change in CAT score over time (Rassouli et al. Int J COPD 2017;12:3103). Aims: Identify whether change in health status over time was associated with exacerbations in Japanese patients with COPD. Methods: Patients were studied in routine practice. CAT data were collected weekly for 1 year using a smartphone app (YaDoc, Integrity Healthcare Co. Ltd. Japan). Patients were categorized as improved, stable and worsened, based on linear regression analysis of change in weekly CAT scores. Association between CAT progression group and occurrence of a COPD exacerbation was tested using a Cox regression model including a time-varying variable. Results: 84 COPD patients were enrolled; mean age: 68.7 years and mean±SD CAT and % predicted FEV1 at baseline: 8.3±6.6 and 72.9±22.0. Median compliance of weekly record was 81%. Median CAT slope was 0.6 units/year (IQR -1.0 to +3.8). 28% of patients had a significant negative slope (improved); 22% had a slope not significantly different from 0 (stable); 50% had a significant positive slope (worsened). A significant positive association was found between CAT change category and occurrence of a single exacerbation during the study (HR: 1.15, 95% CI: 1.06–1.26; p&lt;0.001). Conclusions: Weekly telemedicine CAT measurements provide useful information in individual patients with COPD. Occurrence of a single exacerbation was associated with progressive worsening of CAT compared to no exacerbation, suggesting that worsening health status is a risk factor for exacerbation. Funding: GSK (212648).

Health status progression measured using weekly COPD Assessment Test (CAT) scores over 1 year and its association with COPD exacerbations

Background: The disease behavior in cases of newly diagnosed IIPs has rarely been investigated prospectively. Methods: In JIPS registry, progression-free survival (PFS) and the percentage of cases meeting progressive fibrosing interstitial lung disease (PF-ILD) criteria were longitudinally investigated. PFS was defined as duration without any event of death, an absolute decline of forced vital capacity (FVC) ≥10%, onset of acute exacerbation, or a decline of &gt;50 meters in the 6-minute walk distance. The PF-ILD criteria were defined as: 1) relative annual decline of FVC ≥5%, 2) FVC decline ≥2.5% and worsening of mMRC or CT findings, or 3) worsening of mMRC and CT findings. Results: In 866 cases with IIPs, mean age was 70 years, and mean FVC %predicted was 80%. The most common was IPF (469 cases), followed by unclassifiable IIP. Median PFS of IPF and unclassifiable IIP were 24.2 and 24.6 months, respectively (HR = 0.91 (95%CI: 0.76–1.10), log-rank test: p = 0.345). Three-year progression-free rates for IIPs, IPF, and unclassifiable IIP were 40%, 36%, and 40%, respectively. After 1 and 2 years, 23% and 37% met the PF-ILD criteria for IIPs: 24% and 42% for IPF, and 23% and 39% for unclassifiable IIP. Conclusions: Among newly diagnosed IIP cases, the prognosis of unclassifiable IIP was similar to that of IPF within 3 years. (NCT03041623)&nbsp;

Nationwide prospective registry of idiopathic interstitial pneumonias with central multidisciplinary diagnosis in Japan (JIPS Registry): Analysis of disease progression

Kyoko Tobino

Papers

Gender- and disease-specific urinary thioredoxin in chronic kidney disease patients with or without type 2 diabetic nephropathy.

Health status progression measured using weekly COPD Assessment Test (CAT) scores over 1 year and its association with COPD exacerbations

Nationwide prospective registry of idiopathic interstitial pneumonias with central multidisciplinary diagnosis in Japan (JIPS Registry): Analysis of disease progression