Different administration schedules of darbepoetin alfa affect oxidized and reduced glutathione levels to a similar extent in 5/6 nephrectomized rats

Background

The development of erythropoiesis-stimulating agents (ESAs) with extended serum half-lives has allowed marked prolongation of the administration intervals. The level of oxidative stress is increased in chronic kidney disease, and is reportedly decreased after long-term ESA treatment. However, the effect of different dosing regimens of ESAs on oxidative stress has not been elucidated.

Methods

Five-sixths nephrectomized (NX) rats received either 0.4 μg/kg darbepoetin alfa (DA) weekly or 0.8 μg/kg DA fortnightly between weeks 4 and 10. NX animals receiving saline and a sham-operated (SHAM) group served as controls. The levels of oxidized and reduced glutathione (GSSG, GSH) were followed from blood samples drawn fortnightly.

Results

During the follow-up, the ratios GSSG/GSH showed similar trends in both DA groups, levels being significantly lower than those in the SHAM group at weeks 8 and 10. GSSG levels were lower than the baseline throughout the study in all groups except for NX controls. The GSH levels were increased in all three NX groups (weeks 6–10) compared with both the baseline and the SHAM group

Conclusion

Our results suggest that the extent of oxidative stress is similar in response to different dosing regimens of DA in 5/6 NX rats when comparable hemoglobin levels are maintained. These findings remain to be confirmed in chronic kidney disease patients.     

Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension

Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood–brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation.     

ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor–Induced Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor–related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor–related TMA. ADAMTS13^−/− mice overexpressing sFlt-1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor–related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13^−/− mice overexpressing sFlt-1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition.     

Alpha-synuclein pathology in the olfactory pathways of dementia patients

Lewy-type pathology is a characteristic of a number of neurodegenerative disorders, including Parkinson's disease and dementia with Lewy bodies. Thus far, the definitive diagnosis of these dementias can only be confirmed at post-mortem. However, it is known that the loss of smell (anosmia) is an early symptom in patients who develop dementia, and the use of the smell test has been proposed as an early diagnostic procedure. The aim of this study was to understand further the extent of Lewy pathology in the olfactory system of patients with neurodegenerative disorders. Post-mortem tissue from 250 subjects was obtained from the OPTIMA brain bank. Five areas of the olfactory pathway were examined by immunolabelling for alpha-synuclein - a major component of Lewy pathology: the olfactory tract/bulb (n = 79), the anterior olfactory nucleus in the lateral olfactory gyrus (n = 193), the region of olfactory projection to the orbito-frontal cortex (n = 225), the hippocampus (n = 236) and the amygdala (n = 201). Results show that Lewy pathology affects different parts of the olfactory pathways differentially, suggesting a specific pattern of development of pathology. Clinical Parkinson's disease is most likely to be identified if the orbito-frontal cortex is affected, while the diagnosis is less likely if the pathology is restricted to the olfactory bulb or tract. These results suggest that pathology in the olfactory bulb and tract occurs prior to clinical signs of Parkinson's disease. Furthermore, the results presented here provide further evidence supporting the possible value of a smell test to aid the clinical diagnosis of neurodegenerative diseases.     

Effect of tonsillectomy and its timing on renal outcomes in Caucasian IgA nephropathy patients

Purpose

The role of tonsillectomy in the treatment of IgA nephropathy in Caucasian patients is controversial.

Methods

A retrospective cohort study was conducted in 264 patients with biopsy-proven primary IgA nephropathy to examine the association between tonsillectomy and long-term renal survival, defined as the incidence of estimated glomerular filtration rates (eGFRs) of ≤30 ml/min/1.73 m² or end-stage renal disease (the composite of initiation of dialysis treatment or renal transplantation). The association of tonsillectomy with renal end-points was examined using the Kaplan–Meier method and Cox models.

Results

One-hundred and sixty-six patients did not undergo tonsillectomy (Group I, follow-up 130 ± 101 months) and 98 patients underwent tonsillectomy (Group II, follow-up 170 ± 124 months). The mean renal survival time was significantly longer for both end-points between those patients who underwent tonsillectomy (Group II) versus patients without tonsillectomy (Group I) (p < 0.001 and p = 0.005). The mean renal survival time was significantly longer for both end-points between those patients who had macrohaematuric episodes versus patients who had no macrohaematuric episodes (p = 0.035 and p = 0.019). Tonsillectomy, baseline eGFR and 24-h proteinuria were independent risk factors for both renal end-points.

Conclusion

Tonsillectomy may delay the progression of IgA nephropathy mainly in IgA nephropathy patients with macrohaematuria. Prospective investigation of the protective role of tonsillectomy in Caucasian patients is needed.