Paul Cockwell

Multiple long-term conditions (MLTC) are common in people with chronic kidney disease (CKD). This study examined the impact of MLTC on mortality, CKD progression, and health-related quality of life (HRQoL) in a referred CKD population. Adults with non-kidney replacement therapy (KRT)-dependent CKD (stages G1 to G5) were recruited to the prospective NURTuRE-CKD cohort across 16 UK nephrology centres. MLTC was defined as ≥2 conditions (including CKD) and comorbidities categorised into 19 groups. Depression and anxiety were defined using the Hospital Anxiety and Depression Scale, and Cognitive impairment using the Six-item Cognitive Impairment Test. Outcomes were all-cause mortality, CKD progression (eGFR 2 or KRT), and HRQoL (EQ-5D-5L, at two time points). Participants with eGFR < 15 at baseline were excluded from progression analyses. All 2996 participants had comorbidities at baseline, and therefore MLTC. Mean age was 62.7 (SD ± 14.7) years, mean eGFR 37.3 mL/min/1.73m² (SD ± 17.9), and 41% were female. Median baseline comorbidity count was 3 (IQR 2 to 5; range 1 to 19). The commonest baseline comorbidities were hypertension, pain, obesity, hyperuricaemia, diabetes, sarcopenia, and cardiovascular disease. Over a median 1.42 years between baseline and first follow up, the most frequent new comorbidities were pain (285 people (14%)), anxiety and depression (226 (11%)), cognitive impairment (115 (6%)), obesity (98 (5%)), and anaemia (82 (4%)). Increasing comorbidity count was associated with higher mortality (adjusted hazard ratios (vs. 1 comorbidity): 1.37 (2), 1.45 (3), 1.54 (4), and 1.80 (≥5)), with statistical significance at ≥4 comorbidities). Comorbidity number was not associated with CKD progression. Greater number and certain specific comorbidities were associated with worse HRQoL. Greater comorbidity burden was associated with mortality and worse HRQoL but not CKD progression in this cohort. CKD management should target prevention of additional conditions, prioritise holistic care and focus on MLTC as much as kidney protection.

Key Points: A higher risk of kidney failure and mortality persisted in men with CKD, despite adjusting for sociodemographic, clinical, and treatment factors. Differences in biomarkers linked to CKD progression and cardiovascular stress were observed between men and women after adjusting for eGFR and urine albumin-to-creatinine ratio. When adjusting for the differences in the biomarkers, the excess risk of kidney failure and mortality seen in men was eliminated. Background: Men with CKD experience worse outcomes than women, a difference not fully explained by comorbidities or sociocultural factors. We explored whether sex-based differences in biomarkers could account for this difference in risk. Methods: Our study included 1680 male and 1204 female participants with non–dialysis-dependent CKD and 84 controls from National Unified Renal Translational Research Enterprise-CKD, a prospective multicenter cohort study. Twenty-one biomarkers relating to kidney injury and fibrosis, inflammation, and cardiovascular stress were measured. Outcomes were kidney failure (eGFR 2 or kidney replacement therapy) and all-cause mortality. Multivariable Cox and Fine and Gray models assessed outcomes by sex. Analysis of covariance compared biomarker values between men and women adjusted for eGFR and urine albumin-to-creatinine ratio. Results: Sex differences in biomarker concentrations were observed in both controls and CKD participants. In male controls, higher levels of urinary vascular endothelial growth factor, tissue inhibitor of metalloproteinases-1 and blood neutrophil gelatinase-associated lipocalin, soluble cluster of differentiation 40, soluble cluster of differentiation 40 ligand, soluble tumor necrosis factor receptor 1, monocyte chemoattractant protein-1, and high-sensitivity cardiac troponin T were observed. In men with CKD, additionally higher levels of urine collagen type 1 α 1, blood kidney injury molecule-1, Growth Differentiation Factor-15, and N -terminal pro-B-type natriuretic peptide were noted, while women with CKD showed higher urinary osteoactivin, kidney injury molecule-1, Matrix Metalloproteinase-9, and blood Fibroblast Growth Factor-23 concentrations. In Cox proportional hazards models adjusted for demographics, kidney function, comorbidities, social factors, and medications, male sex was associated with a higher risk of kidney failure (hazard ratio [HR] 1.28; 95% confidence interval, 1.09 to 1.50) and mortality (HR, 1.29; 95% CI, 1.05 to 1.60). Male sex was no longer associated with higher risk after adjustment for biomarker differences, kidney failure (HR, 1.18; 95% CI, 0.97 to 1.43), and mortality (HR, 1.17; 95% CI, 0.98 to 1.58). Conclusions: Male sex was associated with a higher risk of kidney failure and mortality, despite adjustment for demographic, clinical, and treatment factors. Men had higher levels of inflammatory and extracellular matrix deposition biomarkers. By contrast, women showed higher levels of matrix turnover and degradation markers. After adjustment for these biomarker differences, the elevated risk associated with male sex was eliminated, suggesting a biologic basis for the observed sex difference in outcomes. Clinical Trial registry name and registration number: NCT04084145.

Objective: To study the performance of two contemporary sets of estimating equations for glomerular filtration rate, published by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) and EKFC (European Kidney Function Consortium) that include one (creatinine or cystatin C only) and combined (creatinine and cystatin C) biomarkers, to assess their accuracy in a population with moderate chronic kidney disease. Design: Prospective cohort study. Setting: Primary, secondary, and tertiary care in six centres in England. Participants were recruited from April 2014 to January 2017. Participants: 1167 adults, aged ≥18 years, with moderate chronic kidney disease (estimated glomerular filtration rate 30-59 mL/min/1.73 m ² sustained over at least three months before recruitment). Main outcome measures: Accuracy of estimating equations CKD-EPI _creatinine , CKD-EPI _cystatin , CKD-EPI _{creatinine-cystatin} , EKFC _creatinine , EKFC _cystatin , and EKFC _{creatinine-cystatin} compared with measured glomerular filtration rate (iohexol clearance). Remodelled 2021 versions of the CKD-EPI equations were also studied. Accuracy was expressed as P30 (percentage of estimates within 30% of measured glomerular filtration rate). Results: Median age was 67.5 years, 58.3% of patients were men, 86.9% were white participants, and 27.8% had diabetes. Median measured glomerular filtration rate was 47.0 mL/min/1.73 m ² ; 57.0% of participants had albuminuria. Test calibration critically affected measurement of cystatin C. After recalibration of cystatin C, P30 values were 90.2% (CKD-EPI _creatinine ), 89.5% (CKD-EPI _cystatin ), 94.9% (CKD-EPI _{creatinine-cystatin} ), 88.0% (CKD-EPI(2021) _creatinine ), 94.9% (CKD-EPI(2021) _{creatinine-cystatin} ), 89.4% (EKFC _creatinine ), 91.0% (EKFC _cystatin ), and 94.9% (EKFC _{creatinine-cystatin} ). Creatinine based equations showed varying bias depending on the glomerular filtration rate level; inclusion of cystatin C in the equations improved this effect. Differences in accuracy in age, sex, and glomerular filtration rate level subgroups varied by equation. Equations combining creatinine and cystatin performed equally across age, sex, diabetes status, albuminuria status, and body mass index categories. Conclusions: The CKD-EPI _creatinine equation had acceptable accuracy in a white population in England with moderate chronic kidney disease. Combined dual biomarker equations showed higher accuracy than the CKD-EPI _creatinine equation and their equivalent creatinine only equations. Further research is needed to determine the most accurate equation to use in people of black and South Asian origin living in England.

Background: In the STOP-ACEi trial, patients with advanced CKD were randomised to continue or stop renin–angiotensin system inhibitors (RASi) and showed no difference in kidney outcomes. This post-hoc analysis investigates interactions with loop diuretic use. Methods: Patients with eGFR2 and progressive CKD were randomized, to stop or continue RASi. Primary outcome was eGFR over 3-years using repeated-measures, mixed-effects linear regression, random-slope models. Cox models were used to calculate hazard ratios for time-to-event outcomes, including ESKD and KRT. Results: At baseline, eGFR, arterial pressure and proteinuria were similar for 133 patients taking loop diuretics and 278 who were not. Those receiving loop diuretics at randomization, least-squares mean (±SE) eGFR at 3-years was 12.3 (±1.1) for those stopping compared to 10.1 (±1.2) for those continuing RASi, trend favouring stopping RASi (+2.2; 95% CI, –0.9 to +5.4), but eGFR slope over 3-years was similar (-7.2 vs -7.7 ml/min/1.73m ² ). Those not receiving loop diuretics, eGFR at 3-years was 8.8 (±0.8) and 11.6 (±0.8) (discontinue and continue RASi groups), a difference favouring continuing RASi (–2.8; 95% CI, –4.9 to -0.8), and a steeper eGFR slope for those discontinuing RASi (-9.9 vs -7.6 ml/min/1.73m ² ). The interaction between loop diuretic use and the effect of RASi on eGFR at 3-years and the three-way interaction between diuretic subgroup, effect of RASi and time were both statistically significant (p=0.01 and p=0.04 respectively). Of patients taking loop diuretics, 73 (55%) developed ESKD/KRT, and 23 (17%) died. Of patients not taking loop diuretics, 170 (61%) developed ESKD/KRT and 19 (7%) died. Conclusions: Withdrawal of RASi was associated with a steeper decline in eGFR over 3-years in those not receiving loop diuretics but this was not observed in those who were taking loop diuretics. Patients receiving loop diuretics had a high mortality. These data support the need for randomised trials investigating the efficacy and safety of loop diuretics in patients with advanced CKD.

Key Points: Established risk factor models demonstrate excellent discrimination for CKD outcomes but do not adequately reflect disease activity or mechanisms. We have developed models solely from novel biomarkers that reflect key disease pathways driving CKD progression with equivalent discrimination. Although biomarkers offer limited incremental gains in risk prediction, they may provide critical insights into disease mechanisms and treatment response. Background: CKD carries a variable risk for multiple adverse outcomes, highlighting the need for a personalized approach. This study evaluated several novel biomarkers linked to key disease mechanisms to predict the risk of kidney failure (first event of eGFR 2 or KRT), all-cause mortality, and a composite of both. Methods: We included 2884 adults with nondialysis CKD from 16 nephrology centers across the United Kingdom. Twenty-one biomarkers associated with kidney damage, fibrosis, inflammation, and cardiovascular disease were analyzed in urine, plasma, or serum. Cox proportional hazards models were used to assess biomarker associations and develop risk prediction models. Results: Participants had mean age 63 (15) years; 58% were male and 87% White. Median eGFR was 35 (25–47) ml/min per 1.73 m ² , and the median urinary albumin-to-creatinine ratio was 197 (32–895) mg/g. During median 48 (33–55) months of follow-up, 680 kidney failure events and 414 all-cause mortality events occurred. For kidney failure, a model combining three biomarkers (soluble TNF receptor 1, soluble cluster of differentiation 40, and urinary collagen type 1 α 1 chain) showed good discrimination (C-index, 0.86; 95% confidence interval [CI], 0.83 to 0.89) but was outperformed by a model using established risk factors (age, sex, ethnicity, eGFR, and urinary albumin-to-creatinine ratio; C-index, 0.90; 95% CI, 0.88 to 0.92). For all-cause mortality, a model using three biomarkers (high-sensitivity cardiac troponin T, N -terminal pro-brain natriuretic peptide, and soluble urokinase plasminogen activator receptor) demonstrated equivalent discrimination (C-index, 0.80; 95% CI, 0.75 to 0.84) to an established risk factor model (C-index, 0.80; 95% CI, 0.76 to 0.84). For the composite outcome, the biomarker model discrimination (C-index, 0.78; 95% CI, 0.76 to 0.81) was numerically higher than for established risk factors (C-index, 0.77; 95% CI, 0.74 to 0.80), and the addition of biomarkers to the established risk factors led to a small but statistically significant improvement in discrimination (C-index, 0.80; 95% CI, 0.77 to 0.82; P value <0.01). Conclusions: Risk prediction models incorporating novel biomarkers showed comparable discrimination to established risk factors of kidney failure and all-cause mortality. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT04084145.

Background: Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS. Objectives: Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies. Design: A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline (n = 1167) and their ability to detect change over 3 years (n = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components (n = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs (n = 875). Setting: Primary, secondary and tertiary care. Participants: Adults (≥ 18 years) with stage 3 chronic kidney disease. Interventions: Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Main outcome measures: Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated. Results: Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine–cystatin equation (94.9%) was superior (p < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/−17.7, with lower reference change values for estimated glomerular filtration rate. Limitations: Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target. Future work: Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken. Conclusions: Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease. Trial registration: This trial is registered as ISRCTN42955626. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

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Point of care testing (POCT) devices have been developed to facilitate immediate results with the potential to aid screening for new disease and enable patients to self-monitor their disease. Non-communicable diseases (NCDs) are the major cause of mortality globally and are increasing in prevalence as the population ages. Allied health care professionals (AHPs) are skilled in undertaking risk assessment and delivering preventative advice, providing opportunities to access large proportions of the population who may not visit their doctor, within non-traditional community settings. There is evidence of high levels of support from public, patients and health professionals for engaging AHPs in risk-targeted early case detection of certain NCDs. Thus, POCT devices offer a potential alternative to traditional venous blood collection, as novel care pathways for increasing early case detection and access to preventative care. The objectives of this study were to: (i) determine the concordance of the specific POCT devices with laboratory-based standard assays employed within clinical biochemistry laboratories. (ii) compare the sampling experience of both methods via patient-reported experiences. A prospective, two-centre study was undertaken involving 158 participants who provided informed consent. Venous blood was collected for traditional assays of HbA1c, creatinine/ estimated Glomerular-Filtration-Rate (eGFR) and vitamin-D. Capillary blood was collected by finger prick test and also assayed for the same biochemical indices (Nova StatSensor (creatinine/eGFR); Siemens DCA-Vantage (HbA1C); CityAssays (vitamin-D)). All users were provided with device training. Participants reported any discomfort experienced by each simultaneously applied method (randomised in order) via a 100 mm Visual-Analogue-Scale. Results for each POCT device and the laboratory standard were analysed by Bland-Altman plots to determine assay concordance. POCT devices demonstrated good concordance with laboratory testing, with at least 95% of all samples being within two standard deviations, for each of the devices tested. The majority of participants reported less discomfort with POCT than venepuncture, with the average reported discomfort being 17/100 mm less for POCT compared to venous blood sample collection on the visual analogue scale. The POCT devices demonstrated acceptable concordance with laboratory-based assays, and patients reported lower levels of discomfort compared to traditional means of blood collection. This study demonstrates the potential of using these devices as acceptable methods for opportunistic testing of “at-risk” individuals within non-traditional community care settings.