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Patient selection from the Salford Kidney Study (SKS)

Patient selection from the Salford Kidney Study (SKS)

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Background Risk factors predictive of rapid linear chronic kidney disease (CKD) progression and its associations with end-stage renal disease (ESRD) and mortality requires further exploration, particularly as patients with linear eGFR trajectory represent a clear paradigm for understanding true CKD progression. Methods A linear regression slope wa...

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... selection into this study was performed retrospectively and involved 2 stages (Fig. 1). First, linear regression was applied to all outpatient eGFR values for patients with at least 4 eGFR measurements and 2 years follow-up [12,13] in order to obtain a delta () eGFR slope (ml/min/1.73m 2 /yr). The outpatient eGFR values used to calculate the eGFR for each patient represent all the tests performed in clinic as part of a ...

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... However, changes in HDL-C levels may have different impacts on the outcomes of patients on the maintenance of CKD, HD, and PD patients. In a study of CKD patients, TC/HDL-C was independently associated with rapid CKD progression but could not predict mortality [29]. A study of HD patients found that low TC/HDL-C was associated with higher mortality. ...
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This study evaluated the association of the serum total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C) with mortality in incident peritoneal dialysis (PD) patients. We performed a multi-center, prospective cohort study of 630 incident PD patients from 2008 to 2015 in Korea. Participants were stratified into quintiles according to baseline TC, HDL-C, LDL-C and TC/HDL-C. The association between mortality and each lipid profile was evaluated using multivariate Cox regression analysis. During a median follow-up period of 70.3 ± 25.2 months, 185 deaths were recorded. The highest TC/HDL-C group had the highest body mass index, percentage of diabetes and serum albumin level. Multivariate analysis demonstrated that the highest quintile of TC/HDL-C was associated with increased risk of all-cause mortality (hazard ratio 1.69, 95% confidence interval 1.04–2.76; p = 0.036), whereas TC, HDL-C and LDL-C were not associated with mortality. Linear regression analysis showed a positive correlation between TC/HDL-C and body mass index. Increased serum TC/HDL-C was an independent risk factor for mortality in the subgroup of old age, female, cardiovascular disease and low HDL-C. The single lipid marker of TC or HDL-C was not able to predict mortality in PD patients. However, increased serum TC/HDL-C was independently associated with all-cause mortality in PD patients.
... According to a survey, CRF and its end-stage renal disease have a high incidence with poor prognosis but high medical expenses. CRF is also considered as an independent risk factor of cardiovascular events, intimately associated with cardiovascular events, and cardiovascular mortality, and all-cause mortality- [2] . The number of end-stage renal disease patients requiring renal replacement is growing rapidly. ...
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Chronic renal failure (CRF) threatens human health greatly and attracts worldwide concerns of health professionals in the public health sector. In our preliminary study, we found that Compound capsule (Shengqing Jiangzhuo Capsule, SQJZJN) had a significant therapeutic effect on CRF. Quercetin is one of the main components of this Compound capsule. In this study, we investigated the effect of Quercetin monomer on CRF and the regulation of PI3k/Akt pathway. Network pharmacology analysis methods were employed to analyze the SQJZJN/Quercetin/PIK3R1 network relationships. In this study, a CRF rat model was prepared using the gavage adenine solution method and detected the indicators of Creatinine (Cr), Blood Urea Nitrogen (BUN), and Uric Acid (UA). After treating the rat model with Quercetin and PIK3R1-interfering lentivirus, respectively, we observed the changes on the histological morphology of the kidney and detected apoptosis using TUNEL staining. Gene and protein expression associated with renal function were detected using qPCR, WB and immunofluorescence. Quercetin was identified as the main ingredient of SQJZJN by the network pharmacological screening and Quercetin at 1.5 and 3 g/(kg.d) concentrations could effectively alleviate the CRF symptoms, reduce the levels of Cr, BUN, and UA, and markedly inhibit cell apoptosis demonstrated by the intragastric administration. Furthermore, the protein expression of p-PI3K, p-AKT, NLRP3, caspase1, AQP1, and AQP2 in all groups was detected by immunofluorescence and western blot assays, indicating that Quercetin could reduce the expression of NLRP3, caspase1, p-PI3k, and p-Akt, and increase the expression of AQP1 and AQP2 in the renal tissues of CRF rats. Being labeled with biotin and incubated with the total protein extracted from kidney tissues, Quercetin could bind to PIK3R1. Following the PIK3R1 interference lentivirus was injected into the CRF model rats by tail vein, the CRF symptoms were effectively alleviated in the PIK3R1 interference group, consistent with the effect of Quercetin. Taken together, Quercetin, a major component of SQJZJN, might minimize renal fibrosis and apoptosis in CRF rats by inhibiting the PI3k/Akt pathway through targeting PIK3R1. By regulating AQP1 and AQP2, both water retention and toxin accumulation were reduced.
... However, with respect to calibration, all the KFREs consistently underestimated the risk of ESRD in this patient group, which is of particular relevance given that patients with ADPKD had the highest proportion of ESRD at 2-and 5years (Table 2). Renal progression in ADPKD is notably different to other disease aetiologies in that it can be characterised by rapid rates of decline, often in a linear fashion [17], and this reflects the genetically pre-determined expansion of renal cysts that destroy healthy parenchyma over time, and which is not influenced by modification of risk factors such as uACR. This disease mechanism is evidently not well predicted through the variables within the KFRE alone. ...
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Background: The Kidney Failure Risk Equation (KFRE) predicts the 2- and 5-year risk of end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD) stages 3a-5. Its predictive performance in advanced CKD and in specific disease aetiologies requires further exploration. This study validates the 4- and 8-variable KFREs in an advanced CKD population in the United Kingdom by evaluating discrimination, calibration and clinical utility. Methods: Patients enrolled in the Salford Kidney Study who were referred to the Advanced Kidney Care Service (AKCS) clinic at Salford Royal NHS Foundation Trust between 2011 and 2018 were included. The 4- and 8-variable KFREs were calculated on the first AKCS visit and the observed events of ESRD (dialysis or pre-emptive transplantation) within 2- and 5-years were the primary outcome. The area under the receiver operator characteristic curve (AUC) and calibration plots were used to evaluate discrimination and calibration respectively in the whole cohort and in specific disease aetiologies: diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, autosomal dominant polycystic kidney disease (ADPKD) and other diseases. Clinical utility was assessed with decision curve analyses, comparing the net benefit of using the KFREs against estimated glomerular filtration rate (eGFR) cut-offs of < 20 ml/min/1.73m2 and < 15 ml/min/1.73m2 to guide further treatment. Results: A total of 743 patients comprised the 2-year analysis and 613 patients were in the 5-year analysis. Discrimination was good in the whole cohort: the 4-variable KFRE had an AUC of 0.796 (95% confidence interval [CI] 0.762-0.831) for predicting ESRD at 2-years and 0.773 (95% CI 0.736-0.810) at 5-years, and there was good-to-excellent discrimination across disease aetiologies. Calibration plots revealed underestimation of risk at 2-years and overestimation of risk at 5-years, especially in high-risk patients. There was, however, underestimation of risk in patients with ADPKD for all KFRE calculations. The predictive accuracy was similar between the 4- and 8-variable KFREs. Finally, compared to eGFR-based thresholds, the KFRE was the optimal tool to guide further care based on decision curve analyses. Conclusions: The 4- and 8-variable KFREs demonstrate adequate discrimination and calibration for predicting ESRD in an advanced CKD population and, importantly, can provide better clinical utility than using an eGFR-based strategy to inform decision-making.
... Younger age and dyslipidaemia were also found to be associated with rapid CKD progression, in line with findings from previous studies on rapid CKD progression [32,33]. It is believed that the CKD aetiology is different in older patients, with more aggressive disease found among younger patients, while in adults some decline of eGFR is believed to occur as part of aging, rather than from deteriorating CKD [34]. ...
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Personalised medicine is potentially useful to delay the progression of chronic kidney disease (CKD). The aim of this study was to determine the effects of CYP3A5 polymorphism in rapid CKD progression. This multicentre, observational, prospective cohort study was performed among adult CKD patients (≥18 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, who had ≥4 outpatient, non-emergency eGFR values during the three-year study period. The blood samples collected were analysed for CYP3A5*3 polymorphism. Rapid CKD progression was defined as eGFR decline of >5 mL/min/1.73 m2/year. Multiple logistic regression was then performed to identify the factors associated with rapid CKD progression. A total of 124 subjects consented to participate. The distribution of the genotypes adhered to the Hardy–Weinberg equilibrium (X2 = 0.237, p = 0.626). After adjusting for potential confounding factors via multiple logistic regression, the factors associated with rapid CKD progression were CYP3A5*3/*3 polymorphism (adjusted Odds Ratio [aOR] 4.190, 95% confidence interval [CI]: 1.268, 13.852), adjustments to antihypertensives, young age, dyslipidaemia, smoking and use of traditional/complementary medicine. CKD patients should be monitored closely for possible factors associated with rapid CKD progression to optimise clinical outcomes. The CYP3A5*3/*3 genotype could potentially be screened among CKD patients to offer more individualised management among these patients.
... Patients with chronic kidney disease (CKD) that experience rapidly declining renal function are at increased risk of adverse outcomes, including increased risk of end-stage renal disease (ESRD) as well as increased risk of mortality prior to ESRD [1]. Over the past decade, there has been growing attention to not only considering the slope of renal function change, as defined by annual changes in estimated glomerular filtration rate (eGFR) [2], but also the pattern of the eGFR trajectory on patient outcomes [3,4], especially given that patients with CKD progress in ways other than in a simply linear manner [5]. ...
... losing more than 3ml/min/1.73m 2 /yr), a threshold associated with worse outcomes [2], were defined as a rapid progressor, and they had to have baseline CKD G3a-4 (eGFR 15 to < 60 ml/min/1.73m 2 ) for study inclusion. To differentiate linear versus non-linear progression, the eGFR-time graphs were visually inspected independently by two clinicians, an approach that has been successfully utilised in previous studies [1,8], and also quantitively assessed with the coefficient of determination (R 2 ). ...
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Background Patients with rapidly declining renal function face the dual threat of end-stage renal disease (ESRD) and mortality prior to ESRD. What is less well characterised is whether the pattern of the renal trajectory, linear or non-linear, unmasks subgroups of rapidly progressing patients that face adverse outcomes in a differential manner. Methods An individual eGFR slope was applied to all outpatient estimated glomerular filtration rate (eGFR) values for each patient in the Salford Kidney Study from 2002 to 2018 who had at least 2 years follow-up, ≥4 eGFR values and baseline eGFR 15 to < 60 ml/min/1.73m². Rapid progression was defined as an annual eGFR slope of ≤ − 3 ml/min/1.73m²/yr and patients were categorised as linear or non-linear progressors based on the nature of their eGFR-time graphs. A Fine-Gray competing risk hazard model was used to determine factors associated with progression to ESRD and with mortality prior to ESRD. Cumulative incidence function curves highlighted differences in outcomes between linear and non-linear patients. Results There were 211 rapidly deteriorating patients with linear eGFR trajectories and 61 rapid non-linear patients in the study cohort. Factors associated with ESRD included younger age, male gender, lower baseline eGFR and higher serum phosphate, whilst older age, history of myocardial infarction and anaemia predicted mortality prior to ESRD. Over a median follow-up of 3.7 years, linear progressors reached ESRD sooner whilst those with non-linear progression faced significantly higher rates of mortality prior to ESRD. Conclusions Patients with rapid eGFR decline have high rates of adverse outcomes that are differentially expressed in those progressing linearly and non-linearly as a result of differing phenotypic profiles. Consequently, addressing individual risk factor profiles is important to deliver optimal personalised patient care.
... This latter step can be supplemented further by determining the 95% confidence interval (CI) of the ΔeGFR calculation, which can help indicate linearity -the smaller the CI, by definition, the greater the degree of linearity. 22 Fundamentally, having the ΔeGFR calculated using a robust methodological approach provides the foundations to meaningfully evaluate whether or not a distinct biomarker pattern exists in specific forms of CKD progression, and such information may provide insight into pathophysiological mechanisms driving progression. Patterns of progression could be defined by a combination of descriptive terms such as linear or non-linear, slow progressive or exponential decline (in parallel with patterns described by O'Hare et al) or simply rapid progressors, stable non-progressors or those with positively improving eGFR. ...
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Biomarker discovery in the field of risk prediction in chronic kidney disease (CKD) embraces the prospect of improving our ability to risk stratify future adverse outcomes and thereby guide patient care in a new era of personalised medicine. However, many studies that report biomarkers predictive of CKD progression share a key methodological limitation: failure to characterise patients’ renal progression precisely. This weakens any observable association between a biomarker and an outcome poorly defined by a patient’s change in renal function over time. In this commentary, we discuss the need for a better approach in this research arena and describe a compelling strategy that has the advantage of offering robust and meaningful biomarker exploration relevant to CKD progression.