GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile.

Glycosphingolipids (GSL) are plasma membrane components that influence molecular processes involved in cancer initiation, progression, and therapeutic responses. They also modulate receptor tyrosine kinases involved in EMT. Therefore, understanding the mechanisms that regulate GSLs in cancer has important therapeutic potential. One critical regulator of GSLs is the lysosomal glucosylceramidase ß1 (GBA) that catalyzes the last step in GSL degradation. We show that, in cancer, GBA copy number amplifications and increased expression are widespread. We show that depleting GBA in squamous cell carcinoma cell lines results in a mesenchymal-to-epithelial shift, decreased invasion and migration, increased chemotherapeutic sensitivity, and decreased activation of receptor tyrosine kinases that are involved in regulating EMT. Untargeted lipidomics shows that GBA depletion had significant effects on sphingolipids and GSLs, suggesting that increased GBA activity in cancer sustains EMT and chemoresistance by modulating receptor tyrosine kinase activity and signaling via effects on the cellular lipid profile.

Approaches to ascertaining comorbidity information: validation of routine hospital episode data with clinician-based case note review.

BACKGROUND: In clinical practice, research, and increasingly health surveillance, planning and costing, there is a need for high quality information to determine comorbidity information about patients. Electronic, routinely collected healthcare data is capturing increasing amounts of clinical information as part of routine care. The aim of this study was to assess the validity of routine hospital administrative data to determine comorbidity, as compared with clinician-based case note review, in a large cohort of patients with chronic kidney disease. METHODS: A validation study using record linkage. Routine hospital administrative data were compared with clinician-based case note review comorbidity data in a cohort of 3219 patients with chronic kidney disease. To assess agreement, we calculated prevalence, kappa statistic, sensitivity, specificity, positive predictive value and negative predictive value. Subgroup analyses were also performed. RESULTS: Median age at index date was 76.3 years, 44% were male, 67% had stage 3 chronic kidney disease and 31% had at least three comorbidities. For most comorbidities, we found a higher prevalence recorded from case notes compared with administrative data. The best agreement was found for cerebrovascular disease (κ = 0.80) ischaemic heart disease (κ = 0.63) and diabetes (κ = 0.65). Hypertension, peripheral vascular disease and dementia showed only fair agreement (κ = 0.28, 0.39, 0.38 respectively) and smoking status was found to be poorly recorded in administrative data. The patterns of prevalence across subgroups were as expected and for most comorbidities, agreement between case note and administrative data was similar. Agreement was less, however, in older ages and for those with three or more comorbidities for some conditions. CONCLUSIONS: This study demonstrates that hospital administrative comorbidity data compared moderately well with case note review data for cerebrovascular disease, ischaemic heart disease and diabetes, however there was significant under-recording of some other comorbid conditions, and particularly common risk factors.

Chronic kidney disease, a useful trigger for proactive primary care? Mortality results from a large U.K. cohort.

BACKGROUND: Much of the emphasis for primary care management of chronic kidney disease (CKD) has focused on cardiovascular risk; however, many patients die of other causes. Aim. In order to guide future primary care management of CKD, we report the causes of death from a large U.K. CKD cohort linked to health care administrative data. DESIGN, SETTING AND METHODS: The Grampian Laboratory Outcomes Mortality and Morbidity Study (GLOMMS-1) is a community cohort of people with established CKD, identified in 2003 and followed up for 6 years. Causes of death were available from death certificates. The relative likelihood of different causes of death was compared to the general population. RESULTS: When standardized for age and sex, mortality was 4.7 (95% confidence interval 4.5-4.9) times higher in GLOMMS-1 than the general population. Non-cardiovascular diseases accounted for 1076 (50.9%) of deaths, 3.7 times more common than in the age- and sex-matched general population. For those with stages 3 and 4 CKD, without cardiovascular disease at baseline, a non-cardiovascular cause accounted for almost two-thirds of deaths. In those 75 years and older, dementia and falls were among the main non-cardiovascular causes of death. CONCLUSIONS: Mortality in those with CKD is high, with non-cardiovascular diseases accounting for more than half of all deaths. While there is evidence that intervention may benefit those at risk of cardiovascular death, most of the non-cardiovascular causes of death identified were not readily amenable to prevention. A mechanism to identify which patients may benefit from intervention to prevent cardiovascular disease or renal disease progression is needed.

Translating chronic kidney disease epidemiology into patient care--the individual/public health risk paradox.

BACKGROUND: Applying the Kidney Disease Outcomes Quality Initiative definitions of chronic kidney disease (CKD), it appears that CKD is common. The increased recognition of CKD has brought with it the clinical challenge of translating into practice the implications for the patient and for service planning. To understand the clinical relevance and translate that into information to support individual patient care and service planning, we explored clinical outcomes in a large British CKD cohort, identified through routine opportunistic testing, with a 6-year follow-up (≈ 13,000 patient-years). METHODS: A cohort had previously been identified with CKD-sustained reduced eGFR over at least 3 months and case note review. Six-year (13,339 patient-years) follow-up for renal replacement therapy (RRT) initiation and death was achieved through data linkage. Age- and sex-specific mortality rates were compared to the general population. RESULTS: Of 3414 individuals (most Stage 3b-5), median age 78.6 years, followed for 13 339 patient-years, 170 (5%) initiated RRT and 2024 (59%) died without initiating RRT. RRT initiation rates decreased with age from 14.33 to 0.65 per 100 patient-years among those aged 15-25 and 75-85 years at baseline but the actual numbers initiating RRT increased from 6 to 34, respectively. RRT initiation rates were lower for female sex, absence of macroalbuminuria and less advanced CKD stage. Mortality rates increased with age from 2 to 34 per 100 patient-years for those aged 15-45 and > 85 years at baseline, an excess of 2 and 17 per 100 patient-years over that of the general population, respectively. However, the increase in relative risk was 19-fold for those aged 15-45 years and just 2-fold in those > 85 years. These data have been converted into simple tools for considering individual patients' risk and informing service planning. CONCLUSIONS: The contrast between relative and absolute risk for both RRT initiation and mortality by age group illustrates the difficulties for planning services. The challenge that now faces clinicians is how to appropriately identify which elderly patients with CKD are at high risk of poor outcome.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Outcomes in CKD: what we know and what we need to know.

Chronic kidney disease (CKD) is a major public health concern. The high prevalence of reduced estimated glomerular filtration (eGFR) in the elderly has led to speculation as to whether it should really be regarded as a disease in all. Patients with CKD exhibit considerable cardiovascular morbidity and mortality but until recently data regarding the natural history of CKD, particularly in the elderly, has been somewhat lacking. As such the clinical significance of K/DOQI's CKD definition in terms of additional morbidity, mortality and progression to end-stage renal disease (ESRD) remains uncertain. Data have shown that death from cardiovascular disease is far more common than progression to renal replacement therapy in the elderly. Factors which increase the risks of progression to ESRD include younger age, proteinuria and diabetes. Although the elderly have high rates of cardiovascular death, comparatively younger patients with CKD have substantially increased relative risks of death. Specialist renal review should be targeted towards these high-risk patients while the majority of elderly patients can be safely monitored in primary care. It remains doubtful whether labelling all elderly CKD patients with a 'disease' confers any additional benefit.