Abstract Background The early identification of patients at high-risk for end-stage renal disease (ESRD) is essential for providing optimal care and implementing targeted prevention strategies. While the Kidney Failure Risk Equation (KFRE) offers a more accurate prediction of ESRD risk compared to static eGFR-based thresholds, it does not provide insights into the patient-specific biological mechanisms that drive ESRD. This study focused on evaluating the effectiveness of KFRE in a UK-based advanced chronic kidney disease (CKD) cohort and investigating whether the integration of a proteomic signature could enhance 5-year ESRD prediction. Methods Using the Salford Kidney Study biobank, a UK-based prospective cohort of over 3000 non-dialysis CKD patients, 433 patients met our inclusion criteria: a minimum of four eGFR measurements over a two-year period and a linear eGFR trajectory. Plasma samples were obtained and analysed for novel proteomic signals using SWATH-Mass-Spectrometry. The 4-variable UK-calibrated KFRE was calculated for each patient based on their baseline clinical characteristics. Boruta machine learning algorithm was used for the selection of proteins most contributing to differentiation between patient groups. Logistic regression was employed for estimation of ESRD prediction by (1) proteomic features; (2) KFRE; and (3) proteomic features alongside KFRE. Results SWATH maps with 943 quantified proteins were generated and investigated in tandem with available clinical data to identify potential progression biomarkers. We identified a set of proteins (SPTA1, MYL6 and C6) that, when used alongside the 4-variable UK-KFRE, improved the prediction of 5-year risk of ESRD (AUC = 0.75 vs AUC = 0.70). Functional enrichment analysis revealed Rho GTPases and regulation of the actin cytoskeleton pathways to be statistically significant, inferring their role in kidney function and the pathogenesis of renal disease. Conclusions Proteins SPTA1, MYL6 and C6, when used alongside the 4-variable UK-KFRE achieve an improved performance when predicting a 5-year risk of ESRD. Specific pathways implicated in the pathogenesis of podocyte dysfunction were also identified, which could serve as potential therapeutic targets. The findings of our study carry implications for comprehending the involvement of the Rho family GTPases in the pathophysiology of kidney disease, advancing our understanding of the proteomic factors influencing susceptibility to renal damage.
Abstract BACKGROUND AND AIMS Obesity is a major global problem affecting more than 1.9 billion adults [1]. The aetiological factors of obesity are complex and consist of genetic, social and environmental elements. Obesity can lead to chronic kidney disease (CKD) via both direct and indirect pathways. However, the effect of obesity on the progression of CKD remains unclear. This study aimed to investigate the impact of higher body mass index (BMI) on clinical outcomes in a large UK cohort of patients with non-dialysis dependent (NDD)-CKD. METHOD The Salford Kidney Study is a longitudinal prospective cohort of more than 3000 patients with NDD-CKD. All patients with available BMI at baseline from October 2002 to December 2016 were included in this study. Patients were grouped according to their BMI into underweight [(BMI < 18.5 kg/m2), n = 35], healthy weight [(BMI 18.5–24.9 kg/m2), n = 628], overweight [(BMI 25–29.9 kg/m2), n = 860] and obese [(BMI > 30 kg/m2), n = 897]. Cox-regression analysis was performed to study the strength of association between BMI groups and major clinical outcomes [all-cause mortality, end-stage kidney disease (ESKD) and annual rate of progression of CKD (delta eGFR)] by using the healthy weight BMI group as a reference. The outcomes were also analysed in a 1:1 propensity score-matched analysis between patients in the healthy weight and obese groups (414 in each). RESULTS A total of 2420 patients with a median follow-up of 44.3 months were available for analysis. The median age of the cohort was 67 years and 58% were male. The prevalence of hypertension and diabetes increased with a higher BMI (84.0% and 18.8% in healthy weight, 91.7% and 31.0% in overweight and 94.2% and 46.8% in the obese groups, respectively). There was no significant difference in the baseline eGFR between the groups with a median of 29.3 mL/min/1.73 m2. There was an inverse association between a higher BMI and all-cause mortality [obese versus healthy weight: hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.81–0.96; P = 0.004] but there was no association observed with ESKD (HR 0.96; 95% CI: 0.87–1.06; P = 0.422). The delta eGFR was not significantly different between the different BMI groups (Table 1). A similar observation with all-cause mortality being better in the obese group was noted in the propensity-matched analysis (HR:0.88; CI:0.81–0.96; P = 0.004) (Table 2). CONCLUSION In our large cohort of patients, a higher BMI was seen to be protective against all-cause mortality. Furthermore, the annual rate of decline in eGFR was similar among the BMI groups. Patients with normal BMI had significantly higher all-cause mortality compared with the obese group.
Abstract Background and Aims Obesity is a major issue with an estimated prevalence of 1.9 billion adults worldwide. Obesity is an important risk factor for premature death and the development of non-communicable diseases such as diabetes mellitus (DM), heart diseases, and chronic kidney disease (CKD). However, mounting evidence in the literature describes a reverse association whereby obesity may have a protective effect on mortality; this is sometimes referred to as the “obesity paradox”. Several reports question the concept of obesity paradox claiming methodology flaws such as collider stratification bias. In this study, we aimed to examine the effects of obesity on the combined outcomes of all-cause mortality (ACM) and renal replacement therapy (RRT) incidence in a cohort of patients with non-dialysis dependent CKD (NDD-CKD) by correcting for major risk factors to reduce the risk of bias. Method This retrospective study was undertaken on all patients with a documented body mass index (BMI) in the Salford Kidney Study database from October 2002 until December 2016. Patients were grouped according to their BMI into normal weight [BMI 18.5-24.9 kg/m2], overweight [BMI 25–29.9 kg/m2 and obese [BMI> 30 kg/m2]. Patients were also grouped according to their level of co-morbidity into 4 groups: group 1 had CKD only; group 2 had CKD and heart failure (HF); group 3 had CKD and DM; and group 4 had CKD, DM, and HF. Univariate Cox regression as well as three stepwise models of multivariate analysis were performed to study the strength of association between BMI categories and combined outcomes (incidence of RRT and ACM) across the 4 groups of different clusters of co-morbidity. Results A total of 2416 patients were included in the analysis. The median age of the cohort was 67.3 years [IQR 55.9-75.6], 61.8% were male, and 96.4% were of white ethnicity. The median BMI was 28.1 kg/m2 [IQR 24.7-32.6] and the median estimated glomerular filtration rate (eGFR) was 30.7 ml/min/1.73m2 [IQR 20.4-43.5]. At baseline, patients with increasing level of co-morbidity tended to be older with higher prevalence of hypertension (HTN), angina, myocardial infarction (MI), and stroke with lower baseline eGFR. The risk of combined outcomes followed the same trend in the three BMI groups, risk is higher with higher index of co-morbidity (p <0.001). Further analysis of four subgroups of co-morbidity was undertaken. A univariate Cox regression analysis for group 1 [CKD only, n = 1351], and group 2 [CKD and HF, n = 227] showed that patients with obesity had significant lower rates of combined outcomes compared to patients with normal BMI (HR 0.75; 95%CI = 0.63-0.89; p = 0.001 and HR 0.56; 95%CI = 0.38-0.82; p = 0.003 for group 1 and group 2 respectively). In multivariate models, obesity consistently proved to be a strong protective factor against combined outcomes (HR 0.77; 95%CI = 0.65-0.92; p = 0.005 for group 1 and HR 0.53; 95%CI = 0.34-0.83; p = 0.005 for group 2). This was independent of age, gender, HTN, angina, stroke, MI, and prescription of statins and angiotensin converting enzyme inhibitors. For group 3 [CKD and DM, n = 614], and group 4 [CKD, DM, and HF, n = 190], there was no significant difference in the combined outcomes between the different BMI groups when using univariate Cox regression analysis (for patients with obesity: HR 0.78; 95%CI = 0.61-1.01; p = 0.060 and HR 0.70; 95%CI = 0.43-1.16; p = 0.166 for both groups respectively). There was no significant difference in the incidence of RRT in any of the four groups. Conclusion In our largely white NDD-CKD cohort of patients, there was evidence of increasing risk of RRT or ACM as comorbidity increased irrespective of BMI. This is not surprising as ACM would be expected to increase as the burden of disease increases. However, when comparing the effect of BMI within groups, obesity was protective against combined outcomes in group 1 (CKD only) and group 2 (CKD+HF). This ‘protective’ effect was not seen in patients who had concomitant diabetes. These data suggest that diabetes is a potent predictor of outcomes irrespective of BMI, however, in patients without diabetes, obesity may play a protective role.
Abstract Background In people living with polycystic kidney disease (PKD), physical inactivity may contribute to poor health-related quality of life (HRQoL). To date, no research has elucidated the impact of a PKD-specific physical activity programme on HRQoL and physical health. This sub-study of the Kidney BEAM Trial evaluated the impact of a PKD-specific 12-week educational and physical activity digital health intervention for people living with PKD. Methods This study was a mixed-methods, single-blind, randomised waitlist-controlled trial. Sixty adults with a diagnosis of PKD, were randomised 1:1 to the intervention or a wait-list control group. Primary outcome was difference in the Kidney Disease QoL Short Form 1.3 Mental Component Summary (KDQoL MCS) between baseline and 12 weeks. Six participants completed individualised semi-structured interviews. Results All 60 individuals (mean 53 years, 37% male) were included in the intention-to-treat analysis. At 12 weeks, there was a significant difference in mean adjusted change in KDQoL MCS score between the intervention group and waitlist control (4.2 [95% confidence interval, CI: 1.0–7.4] arbitrary units [AU], p = 0.012). Significant between-group differences in KDQoL sub-scales; burden of kidney disease (p = 0.034), emotional wellbeing (p = 0.001), and energy/fatigue (p = 0.001) were also achieved. There was no significant between-group difference in KDQoL PCS scores (p = 0.505). Per protocol analyses revealed significant between group differences in the PAM-13 patient activation score (p = 0.010) and body mass (p = 0.027). Mixed-methods analyses revealed key influences of the programme, including opportunities for peer support and to build on new skills and knowledge, as well as the empowerment and self-management. Conclusion A PKD-specific digital health educational and physical activity intervention is acceptable and has the potential to improve HRQoL. Further research is needed to better understand how specific education and lifestyle management may help to support self-management behaviour.
Importance Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m 2 (SD, 22 mL/min/1.73 m 2 ) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m 2 (SD, 22 mL/min/1.73 m 2 ) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m 2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m 2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.
IntroductionThe Kidney BEAM randomised controlled trial reported clinically meaningful and statistically significant improvements in mental health-related quality of life (HRQoL), physical function (sit-to-stand-60, but not the physical component of HRQoL) and patient activation following a 12-week physical activity digital health intervention (DHI). This study explores factors that contributed to the effectiveness of Kidney BEAM through mixed methods analyses.MethodsQuantitative data analysis was taken from the recently published primary manuscript. Participants from the Kidney BEAM trial intervention group (n=30) completed individualized semi-structured interviews after the 12-week DHI. Interviews were analysed using the framework method with inductive and deductive coding. Quantitative and qualitative data collection and analyses occurred concurrently, and independently, before combining using a mixed methods analysis with joint displays to triangulate datasets and further explore the primary findings.ResultsThe integrated mixed methods analyses facilitated explanation of the primary findings. The Kidney BEAM intervention was shown to have mental and physical wellbeing benefits and enhanced self-management in this cohort of people living with CKD. Elements that contributed to the effectiveness of the intervention were reported, including the different functional levels and gradual progression of the program, shared lived experiences with other participants, self-monitoring, the sense of achievement, taking back control of their health, moving beyond medications and feeling safe and confident to exercise.ConclusionElements of the Kidney BEAM intervention that contributed to the main quantitative trial findings were identified. This will allow researchers and practitioners to maximize the effectiveness of DHI's to enhance healthy behaviours in people living with CKD.
Iron deficiency (ID) is common in patients with chronic kidney disease (CKD). Intravenous (IV) iron in heart failure leads to improvement in exercise capacity and improvement in quality-of-life measurements; however, data in patients with CKD are lacking.The Iron and the Heart Study was a prospective double blinded randomised study in non-anaemic CKD stages 3b-5 patients with ID which investigated whether 1000 mg of IV iron (ferric derisomaltose (FDI)) could improve exercise capacity in comparison to placebo measured at 1 and 3 months post infusion. Secondary objectives included effects on haematinic profiles and haemoglobin, safety analysis and quality of life questionnaires (QoL).We randomly assigned 54 patients mean (SD) age for FDI (n = 26) 61.6 (10.1) years vs placebo (n = 28; 57.8 (12.9) years) and mean eGFR (33.2 (9.3) vs. 29.1 (9.6) ml/min/1.73m2) at baseline, respectively. Adjusting for baseline measurements, six-minute walk test (6MWT) showed no statistically significant difference between arms at 1 month (p = 0.736), or 3 months (p = 0.741). There were non-significant increases in 6MWT from baseline to 1 and 3 months in the FDI arm. Haemoglobin (Hb) at 1 and 3 months remained stable. There were statistically significant increases in ferritin (SF) and transferrin saturation (TSAT) at 1 and 3 months (p < 0.001). There was a modest numerical improvement in QoL parameters. There were no adverse events attributable to IV iron.This study demonstrated a short-term beneficial effect of FDI on exercise capacity, but it was not significant despite improvements in parameters of iron status, maintenance of Hb concentration, and numerical increases in functional capacity and quality of life scores. A larger study will be required to confirm if intravenous iron is beneficial in iron deficient non-anaemic non-dialysis CKD patients without heart failure to improve the 6MWT.European Clinical Trials Database (EudraCT) No: 2014-004133-16 REC no: 14/YH/1209 Date First Registered: 2015-02-17 and date of end of trail 2015-05-23 Sponsor ref R1766 and Protocol No: IHI 141.