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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 5%/year difference between mGFR and eGFR. Ability of equations to detect change was studied based on whether or not eGFR detected overall change, or decline only, in mGFR over 3 years against threshold changes variously defined as (1) > 10 ml/minute/1.73 m2; (2) > reference change value (RCV) (a > 21.5% increase or a > 17.7% decrease); (3) > 25% change; and (4) > 25% change and a change in disease stage. Sensitivity and specificity of eGFRs to identify progressive disease were evaluated. Estimated GFRs, in addition to urinary ACR, were also tested as predictors of progression and mortality. In the substudy of disease progression the change in mGFR, and the difference between mGFRs and eGFRs (bias), assessed every 12 months, were modelled over time using a longitudinal linear random coefficients regression model, to estimate average and variability in disease progression and bias. A model of disease progression based on mGFR was developed and differences in progression for risk factors estimated. In the biological variation substudy, analytical (CVA) and individual (CVI) components of variation were calculated and used to derive the RCV for significant changes in serial results for both mGFR and eGFR. Results from the main study informed a measurement model analysis. The trajectory of participants mGFR and eGFR over 10 years was used to estimate the proportion meeting the National Institute for Health and Care Excellence (NICE) definition of accelerated progression or of progression to CKD stage G4, assuming an annual testing schedule, and the number of participants expected to be incorrectly managed at each of the evaluated monitoring time points using different estimating equations. Based on the findings, the comparative costs of monitoring with GFR-estimating equations were calculated. Sample size Main study. Complete baseline data n = 1167. Three-year follow-up GFR data n = 875. Disease progression substudy. n = 278. Biological variation substudy. n = 20. Results All estimates of GFR relating to the primary study objectives were negatively biased compared to mGFR. There was no difference in median bias (ml/minute/1.73 m2) against mGFR between the MDRD (−3.7), CKD-EPIcreatinine (−2.8), CKD-EPIcystatin (−4.1) and CKD-EPIcreatinine-cystatin (−3.9) equations. Accuracy (P30) of the CKD-EPIcystatin equation (89.5%) did not differ from that of the MDRD (89.5%) and CKD-EPIcreatinine (90.2%) equations: accuracy of the CKD-EPIcreatinine-cystatin equation (94.9%) was superior (p 70% concordance. The CKD-EPIcreatinine-cystatin equation had better concordance than the other three primary study equations (p 83% in all cases), sensitivity for detecting change was < 63% in all cases. There was no clear difference in sensitivity or specificity between the four main study equations. For all equations and all thresholds, there was no clear evidence of improved performance of cystatin-containing equations compared to their matched creatinine-only equation. In the substudy of disease progression, modelling data showed a strong association between albuminuria status and rate of progression in mGFR and CKD-EPIcreatinine eGFR, with those with albuminuria having faster progression (steeper decline). Higher baseline mGFR values were associated with faster progression rate for mGFR. African-Caribbean ethnicity increased (slower decline) and South Asian ethnicity decreased (faster decline) the estimate of progression slope for mGFR and CKD-EPIcreatinine GFR. However, recruitment of ethnic minority participants in particular to the substudy fell short of target, limiting the strength of any conclusions. Within-subject biological variation of mGFR was 6.7%, with similar, although in some cases significantly lower, biological variation of eGFR (5.0, 5.3, 5.3 and 5.0% for MDRD, CKD-EPIcreatinine, CKD-EPIcystatin and CKD-EPIcreatinine-cystatin equations, respectively). Derived RCVs (%, positive/negative) were 21.5/−17.7 (mGFR), 15.1/−13.1 (MDRD), 15.9/−13.7 (CKD-EPIcreatinine), 15.9/−13.8 (CKD-EPIcystatin) and 15.1/−13.1 (CKD-EPIcreatinine-cystatin). We observed 62 deaths during the 3-year follow-up period. The study was not powered for hard end points. However, in agreement with earlier studies, regression models including each GFR-estimating equation separately demonstrated mortality was associated with lower eGFR, increasing age and male gender. An association with categorical albuminuria was not observed. There was no evidence of superiority of CKD-EPI equations, including the cystatin C-containing equations, as predictors of death compared to the MDRD equation. A measurement model analysis found no evidence to suggest that any of the estimating equations were superior for identifying CKD progression based on NICE-defined clinical end points. The average incremental per patient costs (compared to MDRD) of monitoring over a 10-year period using the cystatin C-based equations were estimated (CKD-EPIcystatin £42.20; CKD-EPIcreatinine-cystatin £43.32). Conclusions Most GFR equations achieved acceptable accuracy as judged by P30. There was little difference between the equations in accuracy, with evidence of superior accuracy for the CKD-EPIcreatinine-cystatin equation. Across several important characteristics (age, gender, diabetes, albuminuria, BMI, GFR level) we found no difference in accuracy of GFR-estimating equations. In relation to GFR estimation in African-Caribbean individuals, there was evidence to suggest caution should be exercised before advocating simple removal of the black race factor from the original CKD-EPI equations. In the longitudinal study, the CKD-EPIcreatinine-cystatin displayed slightly better concordance with mGFR than the other main study equations when tracking patients, but all study equations underestimated the mGFR decline. The sensitivity of GFR equations to detect clinically relevant threshold changes in mGFR, either overall or when considering decline in GFR only, was ≤ 63% for all equations. This is of concern given that such thresholds, including the NICE definition of accelerated progression and the change recognised as being true as determined by biological variation (RCV), were studied. Overall, data comparing the accuracy of different GFR-estimating equations demonstrated no notable benefit of using a cystatin C-containing equation in detecting GFR change. The measurement model underpinning the health economic analysis focused on the comparative accuracy of the estimating equations to detect accelerated progression. The analysis estimated accuracy over a longer trajectory than the main study and factored in measurement error, but found no clear benefit of using a cystatin C-based estimating equation. There was therefore no evidence to suggest that adding cystatin C measurement to current GFR monitoring protocols would be cost-effective. The disease progression modelling of the substudy data noted faster progression associated with higher baseline GFR and albuminuria; the latter consistent with other studies. Any conclusions relating to the influence of ethnicity were tempered by poor recruitment of ethnic minority individuals. The biological variability data have implications for monitoring of patients with CKD and clinical ability to understand CKD progression, both in clinical practice and research. The information presented provides an evidence base allowing clinicians to have meaningful discussions with their patients about the implications of changes in their GFR results. Inclusion of cystatin C in GFR-estimating equations was associated with marginal improvements in accuracy, but no clear advantages in terms of detecting GFR change over time. Problems of standardisation of cystatin C assays remain, despite the introduction of an international standard. The use of cystatin C increases the economic cost of CKD monitoring with little apparent gain. These data do not support the use of cystatin C for the routine monitoring of GFR in people with stage 3 CKD. Further research is warranted to investigate specific patient groups that may benefit from cystatin C use. Trial registration This trial is registered as ISRCTN42955626 www.controlled-trials.com/ISRCTN42955626 (accessed 26 July 2023). 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.

Background Chronic kidney disease (CKD) is estimated to affect more than 2.5 million adults in England, and this is expected to rise to 4.2 million by 2036 (1). Population-level digital healthcare systems have the potential to enable earlier detection of CKD providing an opportunity to introduce interventions that attenuate progression and reduce the risk of end-stage kidney disease (ESKD) and cardiovascular diseases (CVD). Services that can support patients with CKD, CVD, and diabetes mellitus (DM) have the potential to reduce fragmented clinical care and optimise pharmaceutical management.Methods and results The Salford renal service has established an outpatient improvement programme which aims to address these issues via two projects. Firstly, the development of a CKD dashboard that can stratify patients by their kidney failure risk equation (KFRE) risk. High-risk patients would be invited to attend an outpatient clinic if appropriate. Specialist advice and guidance would be offered to primary care providers looking after patients with medium risk. Patients with lower risk would continue with standard care via their primary care provider unless there was another indication for a nephrology referral. The CKD dashboard identified 11546 patients (4.4% of the total adult population in Salford) with T2DM and CKD. The second project is the establishment of the Metabolic CardioRenal (MRC) clinic. It provided care for 209 patients in the first 8 months of its establishment with a total of 450 patient visits. Initial analysis showed clustering of cardiorenal metabolic diseases with 85% having CKD stages 3 and 4 and 73.2% having DM. In addition, patients had a significant burden of CVD with 50.2% having hypertension and 47.8% having heart failure.Conclusion There is a pressing need to create new outpatient models of care to tackle the rising epidemic of cardio-renal metabolic diseases. This model of service has potential benefits at both organisational and patient levels including improving patient management via risk stratification, increased care capacity and reduction of variation of care. Patients will benefit from earlier intervention, appropriate referral for care, reduction in CKD-related complications, and reduction in hospital visits and cardiovascular events. In addition, this combined digital and patient-facing model of care will allow rapid translation of advances in cardio-renal metabolic diseases into clinical practice.

Objectives To describe prevalence of chronic kidney disease (CKD), demographic and clinical characteristics, treatment patterns and rates of cardiovascular and renal complications for patients with type 2 diabetes (T2D) treated in routine clinical care.Design Repeat cross-sectional study (6 monthly cross-sections) and cohort study from 1 January 2017 to 31 December 2019.Setting Primary care data from English practices contributing to the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data.Participants Patients with T2D aged >18 years, at least one year of registration data.Primary and secondary outcomes Primary outcome was prevalence of CKD defined as chronic kidney disease epidemiology collaboration (CKD-EPI) estimated glomerular filtration rate

BackgroundDepression is common amongst patients receiving haemodialysis (HD). Assessment and intervention when faced with language and cultural barriers is challenging. To support clinician decisions, we conducted a cross-sectional study to assess the use of culturally adapted and translated versions of commonly-used depression screening questionnaires with South Asian patients receiving HD in England.MethodsPatients completed adapted versions of the Patient Health Questionnaire (PHQ-9), the Centre for Epidemiological Studies Depression Scale Revised (CESD-R), and the Beck Depression Inventory II (BDI-II). All questionnaires were available in Gujarati, Punjabi, Urdu, and Bengali. A comparative sample of white-Europeans completed the questionnaires in English. The research was based across 9 National Health Service (NHS) Trusts in England. Structural validity of translated questionnaires was assessed using confirmatory factor analysis. Diagnostic accuracy was explored in a subgroup of South Asians against ICD-10 categories using the Clinical Interview Schedule Revised (CIS-R) with receiver operating curve (ROC) analysis.Results229 South Asian and 120 white-European HD patients participated. A single latent depression factor largely accounted for the correlations between items of the PHQ-9, CESD-R and BDI-II. Issues with measurement equivalence implied that scores on the translations may not be comparable with the English language versions. Against CIS-R based ICD-10 diagnosis of depression, sensitivity was modest across scales (50-66.7%). Specificity was higher (81.3-93.8%). Alternative screening cut-offs did not improve positive predictive values.ConclusionsCulturally adapted translations of depression screening questionnaires are useful to explore symptom endorsement amongst South Asian patients. However, data indicate that standard cut-off scores may not be appropriate to classify symptom severity. Use of the CIS-R algorithms for optimal case identification requires further exploration in this setting. Strategies to encourage recruitment of under-represented groups in renal research are also warranted, especially for in-depth discussions related to psychological care needs.

Abstract Background Acute kidney injury (AKI) is a recognised complication of coronavirus disease 2019 (COVID-19), yet the reported incidence varies widely and the associated risk factors are poorly understood. Methods Data was collected on all adult patients who returned a positive COVID-19 swab while hospitalised at a large UK teaching hospital between 1st March 2020 and 3rd June 2020. Patients were stratified into community- and hospital-acquired AKI based on the timing of AKI onset. Results Out of the 448 eligible patients with COVID-19, 118 (26.3 %) recorded an AKI during their admission. Significant independent risk factors for community-acquired AKI were chronic kidney disease (CKD), diabetes, clinical frailty score and admission C-reactive protein (CRP), systolic blood pressure and respiratory rate. Similar risk factors were significant for hospital-acquired AKI including CKD and trough systolic blood pressure, peak heart rate, peak CRP and trough lymphocytes during admission. In addition, invasive mechanical ventilation was the most significant risk factor for hospital-acquired AKI (adjusted odds ratio 9.1, p

Abstract Background Renal ischemia reperfusion injury (R‐IRI) can cause acute kidney injury (AKI) and chronic kidney disease (CKD), resulting in significant morbidity and mortality. To understand the underlying mechanisms, reproducible small‐animal models of AKI and CKD are needed. We describe how innovative technologies for measuring kidney function noninvasively in small rodents allow successful refinement of the R‐IRI models, and offer the unique opportunity to monitor longitudinally in individual animals the transition from AKI to CKD. Methods Male BALB/c mice underwent bilateral renal pedicle clamping (AKI) or unilateral renal pedicle clamping with delayed contralateral nephrectomy (CKD) under isoflurane anesthetic. Transdermal GFR monitoring and multispectral optoacoustic tomography (MSOT) in combination with statistical analysis were used to identify and standardize variables within these models. Results Pre‐clamping anesthetic time was one of the most important predictors of AKI severity after R‐IRI. Standardizing pre‐clamping time resulted in a more predictably severe AKI model. In the CKD model, MSOT demonstrated initial improvement in renal function, followed by significant progressive reduction in function between weeks 2 and 4. Performing contralateral nephrectomy on day 14 enabled the development of CKD with minimal mortality. Conclusions Noninvasive monitoring of global and individual renal function after R‐IRI is feasible and reproducible. These techniques can facilitate refinement of kidney injury models and enable the degree of injury seen in preclinical models to be translated to those seen in the clinical setting. Thus, future therapies can be tested in a clinically relevant, noninvasive manner.

IntroductionMembranous nephropathy is the commonest cause of nephrotic syndrome in non-diabetic Caucasian adults over the age of 40 years. Primary membranous nephropathy is limited to the kidneys. Clinical management aims to induce remission, either spontaneously with supportive care, or with immunosuppression. Here, we describe the natural history of this condition in a large tertiary centre in the UK.Methods178 patients with primary membranous nephropathy were identified over 2 decades. We collected data on demographics, baseline laboratory values, treatment received and outcomes including progression to renal replacement therapy and death. Analysis was performed on the whole cohort and specific subgroups. Univariate and multivariate Cox regression was also performed.ResultsMedian age was 58.3 years with 63.5% male. Median baseline creatinine was 90μmol/L and urine protein-creatinine ratio 664g/mol. Remission (partial or complete) was achieved in 134 (75.3%), either spontaneous in 60 (33.7%) or after treatment with immunosuppression in 74 (41.6%), and of these 57 (42.5%) relapsed. Progression to renal replacement therapy was seen in 10.1% (much lower than classically reported) with mortality in 29.8%. Amongst the whole cohort, those who went into remission had improved outcomes compared to those who did not go into remission (less progression to renal replacement therapy [4.5% vs 28%] and death [20.1% vs 67%]. Those classified as high-risk (based on parameters including eGFR, proteinuria, serum albumin, PLA2R antibody level, rate of renal function decline) also had worse outcomes than those at low-risk (mortality seen in 52.6% vs 10.8%, pConclusionWe provide a comprehensive epidemiologic analysis of primary membranous nephropathy at a large tertiary UK centre. Only 10.1% progressed to renal replacement therapy. For novelty, the KDIGO risk classification was linked to outcomes, highlighting the utility of this classification system for identifying patients most likely to progress.

Background and objectivesIgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, with an incidence of 2.5 per 100,000 population per year. The 10-year risk of progression to end stage kidney disease (ESKD) or halving of eGFR is 26%. Here we aimed to collect a comprehensive dataset of IgAN patients at our centre over 2 decades to provide real world data, describe outcomes and determine the effects of immunosuppression use.Design, setting, participants and measurementsAll patients diagnosed with biopsy-proven IgAN at our centre over 2 decades were identified. After exclusions, the total cohort size was 401. Data relating to (i) baseline demographics, (ii) laboratory and urine results, (iii) histological data, and (iv) outcomes of initiation of renal replacement therapy (RRT) and mortality were collected.ResultsThe median age was 45.0 years, with 69.6% male and 57.6% hypertensive; 20.4% received immunosuppression, 29.7% progressed to RRT and 19.7% died, over a median follow up period of 51 months. Baseline eGFR was 46.7ml/min/1.73m2 and baseline uPCR was 183mg/mmol. Median rate of eGFR decline was -1.31ml/min/1.73m2/year. Those with a higher MEST-C score had worse outcomes. Immunosuppression use was associated with an increased rate of improvement in proteinuria, but not with a reduction in RRT or mortality. Factors favouring improved outcomes with immunosuppression use included female gender; lower age, blood pressure and T-score; higher eGFR; and ACEi/ARB use.ConclusionsA variety of clinical and histological factors are important in determining risk of progression in IgAN. Therapeutic interventions, particularly use of immunosuppression, should be individualised and guided by these factors.

Background: Whether or not clinically implementable exercise interventions in haemodialysis patients improve quality of life remains unknown. Objectives: The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial evaluated the clinical effectiveness and cost-effectiveness of a 6-month intradialytic exercise programme on quality of life compared with usual care for haemodialysis patients. Design: We conducted a prospective, multicentre randomised controlled trial of haemodialysis patients from five haemodialysis centres in the UK and randomly assigned them (1 : 1) using a web-based system to (1) intradialytic exercise training plus usual-care maintenance haemodialysis or (2) usual-care maintenance haemodialysis. Setting: The setting was five dialysis units across the UK from 2015 to 2019. Participants: The participants were adult patients with end-stage kidney disease who had been receiving haemodialysis therapy for > 1 year. Interventions: Participants were randomised to receive usual-care maintenance haemodialysis or usual-care maintenance haemodialysis plus intradialytic exercise training. Main outcome measures: The primary outcome of the study was change in Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score (from baseline to 6 months). Cost-effectiveness was determined using health economic analysis and the EuroQol-5 Dimensions, five-level version. Additional secondary outcomes included quality of life (Kidney Disease Quality of Life Short Form, version 1.3, generic multi-item and burden of kidney disease scales), functional capacity (sit-to-stand 60 and 10-metre Timed Up and Go tests), physiological measures (peak oxygen uptake and arterial stiffness), habitual physical activity levels (measured by the International Physical Activity Questionnaire and Duke Activity Status Index), fear of falling (measured by the Tinetti Falls Efficacy Scale), anthropometric measures (body mass index and waist circumference), clinical measures (including medication use, resting blood pressure, routine biochemistry, hospitalisations) and harms associated with intervention. A nested qualitative study was conducted. Results: We randomised 379 participants; 335 patients completed baseline assessments and 243 patients (intervention, n = 127; control, n = 116) completed 6-month assessments. The mean difference in change in physical component summary score from baseline to 6 months between the intervention group and control group was 2.4 arbitrary units (95% confidence interval –0.1 to 4.8 arbitrary units; p = 0.055). Participants in the intervention group had poor compliance (49%) and very poor adherence (18%) to the exercise prescription. The cost of delivering the intervention ranged from £463 to £848 per participant per year. The number of participants with harms was similar in the intervention (n = 69) and control (n = 56) groups. Limitations: Participants could not be blinded to the intervention; however, outcome assessors were blinded to group allocation. Conclusions: On trial completion the primary outcome (Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score) was not statistically improved compared with usual care. The findings suggest that implementation of an intradialytic cycling programme is not an effective intervention to enhance health-related quality of life, as delivered to this cohort of deconditioned patients receiving haemodialysis. Future work: The benefits of longer interventions, including progressive resistance training, should be confirmed even if extradialytic delivery is required. Future studies also need to evaluate whether or not there are subgroups of patients who may benefit from this type of intervention, and whether or not there is scope to optimise the exercise intervention to improve compliance and clinical effectiveness. Trial registration: Current Controlled Trials ISRCTN83508514. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 40. See the NIHR Journals Library website for further project information.

BackgroundMissing values are a key issue in the statistical analysis of proteomic data. Defining the strategy to address missing values is a complex task in each study, potentially affecting the quality of statistical analyses.ResultsWe have developed OptiMissP, a dashboard to visually and qualitatively evaluate missingness and guide decision making in the handling of missing values in proteomics studies that use data-independent acquisition mass spectrometry. It provides a set of visual tools to retrieve information about missingness through protein densities and topology-based approaches, and facilitates exploration of different imputation methods and missingness thresholds.ConclusionsOptiMissP provides support for researchers' and clinicians' qualitative assessment of missingness in proteomic datasets in order to define study-specific strategies for the handling of missing values. OptiMissP considers biases in protein distributions related to the choice of imputation method and helps analysts to balance the information loss caused by low missingness thresholds and the noise introduced by selecting high missingness thresholds. This is complemented by topological data analysis which provides additional insight to the structure of the data and their missingness. We use an example in Chronic Kidney Disease to illustrate the main functionalities of OptiMissP.

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.

Background: Advanced chronic kidney disease is common in older people and is frequently accompanied by metabolic acidosis. Oral sodium bicarbonate is used to treat this acidosis, but evidence is lacking on whether or not this provides a net gain in health or quality of life for older people. Objectives: The objectives were to determine whether or not oral bicarbonate therapy improves physical function, quality of life, markers of renal function, bone turnover and vascular health compared with placebo in older people with chronic kidney disease and mild acidosis; to assess the safety of oral bicarbonate; and to establish whether or not oral bicarbonate therapy is cost-effective in this setting. Design: A parallel-group, double-blind, placebo-controlled randomised trial. Setting: The setting was nephrology and geriatric medicine outpatient departments in 27 UK hospitals. Participants: Participants were adults aged ≥ 60 years with advanced chronic kidney disease (glomerular filtration rate category 4 or 5, not on dialysis) with a serum bicarbonate concentration of

BACKGROUND:In studies including the general population, the presence of non-malignant monoclonal gammopathy (MG) can be causally associated with kidney damage and shorter survival. We assessed whether the presence of an MG is associated with a higher risk of kidney failure or death in individuals with chronic kidney disease (CKD). METHODS AND FINDINGS:Data were used from 3 prospective cohorts of individuals with CKD (not on dialysis or with a kidney transplant): (1) Renal Impairment in Secondary Care (RIISC, Queen Elizabeth Hospital and Heartlands Hospital, Birmingham, UK, N = 878), (2) Salford Kidney Study (SKS, Salford Royal Hospital, Salford, UK, N = 861), and (3) Renal Risk in Derby (RRID, Derby, UK, N = 1,739). Participants were excluded if they had multiple myeloma or any other B cell lymphoproliferative disorder with end-organ damage. Median age was 71.0 years, 50.6% were male, median estimated glomerular filtration rate was 42.3 ml/min/1.73 m2, and median urine albumin-to-creatinine ratio was 3.4 mg/mmol. All non-malignant MG was identified in the baseline serum of participants of RIISC. Further, light chain MG (LC-MG) was identified and studied in participants of RIISC, SKS, and RRID. Participants were followed up for kidney failure (defined as the initiation of dialysis or kidney transplantation) and death. Associations with the risk of kidney failure were estimated by competing-risks regression (handling death as a competing risk), and associations with death were estimated by Cox proportional hazards regression. In total, 102 (11.6%) of the 878 RIISC participants had an MG. During a median follow-up time of 74.0 months, there were 327 kidney failure events and 202 deaths. The presence of MG was not associated with risk of kidney failure (univariable subhazard ratio [SHR] 0.97 [95% CI 0.68 to 1.38], P = 0.85; multivariable SHR 1.16 [95% CI 0.80 to 1.69], P = 0.43), and although there was a higher risk of death in univariable analysis (hazard ratio [HR] 2.13 [95% CI 1.49 to 3.02], P < 0.001), this was not significant in multivariable analysis (HR 1.37 [95% CI 0.93 to 2.00], P = 0.11). Fifty-five (1.6%) of the 3,478 participants from all 3 studies had LC-MG. During a median follow-up time of 62.5 months, 564 of the 3,478 participants progressed to kidney failure, and 803 died. LC-MG was not associated with risk of kidney failure (univariable SHR 1.07 [95% CI 0.58 to 1.96], P = 0.82; multivariable SHR 1.42 [95% CI 0.78 to 2.57], P = 0.26). There was a higher risk of death in those with LC-MG in the univariable model (HR 2.51 [95% CI 1.59 to 3.96], P < 0.001), but not in the multivariable model (HR 1.49 [95% CI 0.93 to 2.39], P = 0.10). An important limitation of this work was that only LC-MG, rather than any MG, could be identified in participants from SKS and RRID. CONCLUSIONS:The prevalence of MG was higher in this CKD cohort than that reported in the general population. However, the presence of an MG was not independently associated with a significantly higher risk of kidney failure or, unlike in the general population, risk of death.

OBJECTIVES:The R102G variant in complement 3 (C3) results in two allotypic variants: C3 fast (C3F) and C3 slow (C3S). C3F presents at increased frequency in patients with chronic kidney disease (CKD), our aim is to explore its role in CKD progression and mortality. METHODS:Delta (Δ) eGFR for 2038 patients in the Salford Kidney Study (SKS) was calculated by linear regression; those with ≤-3ml/min/1.73m2/yr were defined as rapid progressors (RP) and those with ΔeGFR between -0.5 and +1ml/min/1.73m2/yr, labelled stable CKD patients (SP).A group of 454 volunteers was used as a control group. In addition, all biopsy-proven glomerulonephritis (GN) patients were studied regardless of their ΔeGFR. R102G was analysed by real-time PCR, and genotypic and allelic frequencies were compared between RP and SP along with the healthy control group. RESULTS:There were 255 SP and 259 RP in the final cohort. Median ΔeGFR was 0.07 vs. -4.7 ml/min/1.73m2/yr in SP vs. RP. C3F allele frequency was found to be significantly higher in our CKD cohort (25.7%) compared with the healthy control group (20.6%); p = 0.008.However, there was no significant difference in C3F allele frequency between the RP and SP groups. In a subgroup analysis of 37 patients with IgA nephropathy in the CKD cohort (21 RP and 16 SP), there was a significantly higher frequency of C3F in RP 40.5% vs. 9.4% in SP; p = 0.003. In the GN group, Cox regression showed an association between C3F and progression only in those with IgA nephropathy (n = 114);HR = 1.9 (95% CI 1.1-3.1; p = 0.018) for individuals heterozygous for the C3F variant, increased further for individuals homozygous for the variant, HR = 2.8 (95% CI 1.2-6.2; p = 0.014). CONCLUSION:The C3 variant R102G is associated with progression of CKD in patients with IgA nephropathy.

BackgroundScreening with cardiac non-invasive stress studies (NISS) prior to listing for kidney transplantation can help in identifying treatable coronary disease and is considered an integral part of pre-kidney transplant evaluation. However, few studies assessed their effectiveness in all patients evaluated for transplantation in clinical practice. To evaluate the role of NISS in pre-kidney transplant evaluation we analyzed their impact prior to waitlisting in 1053 adult CKD-5 patients consecutively evaluated in Greater Manchester, UK during a 6-year period.Methods918 waitlisted patients were grouped based on presence or absence of Diabetes or Cardio-Vascular Disease (CVD): Group-1 (255 DM-/CVD-/NISS-), Group-2 (368 DM-/CVD-/NISS+) and Group-3 (295 with DM or CVD).ResultsGroup-2 patients had longer 'time-to-listing' (5.5months in Group-1 vs 6.9months in 'Normal-NISS' vs 9.9months in 'Abnormal-NISS', pConclusionsPre-kidney transplant evaluation with NISS influenced clinical management in 19 of 1053 (2%) patients. Screening with NISS added limited benefit but contributes to significant delays in listing and adding resource implications. Further studies are needed to assess clinical and cost effectiveness of NISS in pretransplant evaluation to optimize outcomes and resources.

ObjectivesThe first phase of the published OPAL-HK study was a single-group treatment phase, which showed that patiromer normalised serum potassium at 4weeks in patients with chronic kidney disease stages 3-4 who were receiving renin-angiotensin-aldosterone inhibitors. We utilised real-world data to provide a control comparison to evaluate patiromer's efficacy in lowering serum potassium.Materials and methodsThe Salford Kidney Study (SKS) in the United Kingdom provided a matched cohort. After applying OPAL-HK inclusion and exclusion criteria, patients with an outpatient potassium level between 5.1mmol/L to ResultsThe study comprised 87 precisely matched patients. The mean follow-up in the 87 SKS patients was 31±5 days. At baseline, matched patients had a mean potassium of 5.5±0.3mmol/L. At follow-up, the mean level was unchanged in SKS patients but was 4.5±0.5mmol/L in the OPAL-HK group (pConclusionsUsing real-world data as a matched control arm for the first phase of the OPAL-HK study, we highlight a potential role for patiromer in lowering potassium levels in patients with CKD 3-4 receiving renin-angiotensin-aldosterone inhibitors.

BackgroundAcute kidney injury (AKI) and chronic kidney disease (CKD) are common syndromes associated with significant morbidity, mortality and cost. The extent to which repeated AKI episodes may cumulatively affect the rate of progression of all-cause CKD has not previously been investigated. In this study, we explored the hypothesis that repeated episodes of AKI increase the rate of renal functional deterioration loss in patients recruited to a large, all-cause CKD cohort.MethodsPatients from the Salford Kidney Study (SKS) were considered. Application of KDIGO criteria to all available laboratory measurements of renal function identified episodes of AKI. A competing risks model was specified for four survival events: Stage 1 AKI; stage 2 or 3 AKI; dialysis initiation or transplant before AKI event; death before AKI event. The model was adjusted for patient age, gender, smoking status, alcohol intake, diabetic status, cardiovascular co-morbidities, and primary renal disease. Analyses were performed for patients' first, second, and third or more AKI episodes.ResultsA total of 48,338 creatinine measurements were available for 2287 patients (median 13 measures per patient [IQR 6-26]). There was a median age of 66.8years, median eGFR of 28.4 and 31.6% had type 1 or 2 diabetes. Six hundred and forty three (28.1%) patients suffered one or more AKI events; 1000 AKI events (58% AKI 1) in total were observed over a median follow-up of 2.6 years [IQR 1.1-3.2]. In patients who suffered an AKI, a second AKI was more likely to be a stage 2 or 3 AKI than stage 1 [HR 2.04, p 0.01]. AKI events were associated with progression to RRT, with multiple episodes of AKI progressively increasing likelihood of progression to RRT [HR 14.4 after 1 episode of AKI, HR 28.4 after 2 episodes of AKI]. However, suffering one or more AKI events was not associated with an increased risk of mortality.ConclusionsAKI events are associated with more rapid CKD deterioration as hypothesised, and also with a greater severity of subsequent AKI. However, our study did not find an association of AKI with increased mortality risk in this CKD cohort.

BackgroundMost sepsis and acute kidney injury (AKI) cases are community acquired (CA). The aim of this study was to evaluate the characteristics of suspected community acquired infection (sCA-I) and CA-AKI and their impact upon patient outcomes.MethodsAll adult creatinine blood tests from non-elective, non-dialysis attendances to a single centre over a 29-month period were analysed retrospectively. We defined sCA-I and CA-AKI cases as antibiotic prescription and AKI alert within 48 hours of attendance respectively. Binary logistic regression models were created to determine associations with 30-day mortality, intensive care unit (ICU) admission and length of stay (LOS) dichotomised at median.ResultsOf 61,471 attendances 28.1% and 5.7% suffered sCA-I or CA-AKI in isolation respectively, 3.4% suffered both. sCA-I was present in 58.8% of CA-AKI cases and CA-AKI was present in 11.9% of CA-I cases. The combination of sCA-I and CA-AKI was associated with a higher risk for all outcomes compared to sCA-I or CA-AKI in isolation. The 30-day mortality was 8.1%, 11.8% and 26.2% in patients with sCA-I, CA-AKI and when sCA-I and CA-AKI occurred in combination respectively. The adjusted odds ratios (OR) and 95% confidence intervals (CI) for 30-day mortality, ICU admission and LOS for sCA-I combined with CA-AKI stage 1 were OR 6.09:CI: 5.21-7.12, OR 12.52 CI: 10.54-14.88 and OR 8.97 CI: 7.62-10.56, respectively, and for combined sCA-I and CA-AKI stage 3 were OR 9.23 CI: 6.91-12.33, OR 29.26 CI: 22.46-38.18 and OR 9.48 CI: 6.82-13.18 respectively.ConclusionThe combination of sCA-I and CA-AKI is associated with worse outcomes.

BackgroundAcute Kidney Injury (AKI) is common and associated with increased morbidity and mortality. This retrospective analysis quantified and compared the association between AKI and the risk of death and admission to critical care in acute admissions of different aetiology.MethodsData were extracted anonymously from the Trust 'data warehouse' for admissions between 2011and 2017. We applied KDIGO AKI criteria to establish AKI stage. Odds ratios (OR) for death and critical care admission were calculated for patients with AKI stage 3 (compared to all other patients), and patients with any stage AKI (compared to non-AKI admissions). Analyses were performed using logistic regression, adjusted for age, pre-existing CKD, co-morbid index, and gender.ResultsThere were 26,052 medical and 12,560 surgical patient episodes within sixteen common diagnoses with 3823 medical and 1520 surgical patients with AKI events. The likelihood of AKI was highest in sepsis (31.8%), and the likelihood of death in AKI 3 highest in femoral neck fracture (54.5%). AKI 3 has a OR for death for acute coronary syndrome of 12.8 and a OR of 24.6 in femoral neck fracture. Admission to critical care for any AKI in medical patients has a OR of 9.6, but increases to OR 37.2 for heart failure.ConclusionThe clinical impact of AKI differs across medical and surgical diagnoses, but is a significant contributor to the risk for death and critical care admission. This body of work may indicate a benefit to a more diagnosis-specific stratified approach to AKI care.

BackgroundVascular calcification is associated with increased cardiovascular morbidity and mortality in patients with atherosclerosis, diabetes and chronic kidney disease. However, no viable treatments for this condition have been identified. This study aimed to determine whether farnesyl transferase inhibitors (FTIs) can reduce vascular calcification and the mechanism by which this reduction occurs.ResultsWe demonstrate that FTI-277 significantly inhibits phosphate-induced mineral deposition by vascular smooth muscle cells (VSMC) in vitro, prevents VSMC osteogenic differentiation, and increases mRNA expression of matrix Gla protein (MGP), an inhibitor of mineralization. FTI-277 increases Akt signaling in VSMC in short-term serum-stimulation assays and in long-term mineralization assays. In contrast, manumycin A has no effect on Akt signaling or mineralization. Co-incubation of VSMC with FTI-277 and SH6 (an Akt inhibitor) significantly reduces the inhibitory effect of FTI-277 on mineralization, demonstrating that FTI-277 inhibits calcification by activating Akt signaling. Over-expression of the constitutively active p110 sub-unit of PI3K in VSMC using adenovirus activates Akt, inhibits mineralization, suppresses VSMC differentiation and significantly enhances MGP mRNA expression. FTI-277 also inhibits phosphate-induced activation of caspase 3 and apoptosis of VSMC, and these effects are negated by co-incubation with SH6. Finally, using an ex vivo model of vascular calcification, we demonstrate that FTI-277 inhibits high phosphate-induced mineralization in aortic rings derived from rats with end-stage renal failure.ConclusionsTogether, these results demonstrate that FTI-277 inhibits VSMC mineral deposition by up-regulating PI3K/Akt signaling and preventing apoptosis, suggesting that targeting farnesylation, or Akt specifically, may have therapeutic potential for the prevention of vascular calcification.

BACKGROUND:The benefits of dialysis in older people with ESKD are not clear. We prospectively evaluated whether dialysis has survival advantage compared to conservative care (CC) in older people who were medically suitable for dialysis therapy. METHODS:This was a prospective observational study of CKD patients aged ≥75 years when eGFR first reached ≤15ml/min/1.73m2. Hazard ratios (HR) for death were compared between patients who chose dialysis versus conservative care (CC) from when first seen in pre-dialysis clinic (eGFR ≤15ml/min/1.73m2), and when initiation of dialysis was first considered (eGFR ≤10ml/min/1.73m2). Patients with co-morbidities likely to significantly reduce life expectancy such as advanced heart failure, advanced dementia, and malignancy, were excluded. RESULTS:There were 204 patients (123 dialysis, 81 CC). 115 went on to record eGFR of ≤10ml/min/1.73m2 (73 dialysis, 42 CC). The median survival from eGFR first ≤15ml/min/1.73m2 for the dialysis and CC groups were 42 (33-50) months and 31 (21-41) months. The adjusted hazard ratio (HR) for death in the dialysis group compared to CC was 0.61 (0.41-0.61, p = 0.01). The median survival from eGFR first ≤10ml/min/1.73m2 for dialysis and CC group were 36 (25-47) months and 12 (0-5) months. The adjusted HR for death in the dialysis group compared to CC was 0.36 (0.21-0.62, p

INTRODUCTION:It has been suggested that sudden cardiac death (SCD) contributes around 50% of cardiovascular and 27% of all-cause mortality in hemodialysis patients. The true burden of arrhythmias and arrhythmic deaths in this population, however, remains poorly characterised. Cardio Renal Arrhythmia Study in Hemodialysis (CRASH-ILR) is a prospective, implantable loop recorder single centre study of 30 established hemodialysis patients and one of the first to provide long-term ambulatory ECG monitoring. METHODS:30 patients (60% male) aged 68±12 years receiving hemodialysis for 45±40 months with varied etiology (diabetes 37%, hypertension 23%) and left ventricular ejection fraction (LVEF) 55±8% received a Reveal XT implantable loop recorder (Medtronic, USA) between August 2011 and October 2014. ECG data from loop recorders were transmitted at each hemodialysis session using a remote monitoring system. Primary outcome was SCD or implantation of a (tachy or bradyarrhythmia controlling) device and secondary outcome, the development of arrhythmia necessitating medical intervention. RESULTS:During 379,512 hours of continuous ECG monitoring (mean 12,648±9,024 hours/patient), there were 8 deaths-2 SCD and 6 due to generalised deterioration/sepsis. 5 (20%) patients had a primary outcome event (2 SCD, 3 pacemaker implantations for bradyarrhythmia). 10 (33%) patients reached an arrhythmic primary or secondary end point. Median event free survival for any arrhythmia was 2.6 years (95% confidence intervals 1.6-3.6 years). CONCLUSIONS:The findings confirm the high mortality rate seen in hemodialysis populations and contrary to initial expectations, bradyarrhythmias emerged as a common and potentially significant arrhythmic event.

BACKGROUND:Randomized controlled trials (RCT) have shown no overall benefit of renal revascularization in atherosclerotic renovascular disease (ARVD). However, 25% of patients demonstrate improvement in renal function. We used the ratio of magnetic resonance parenchymal volume (PV) to isotopic single kidney glomerular filtration rate (isoSKGFR) ratio as our method to prospectively identify "improvers" before revascularization. METHODS:Patients with renal artery stenosis who were due revascularization were recruited alongside non-ARVD hypertensive CKD controls. Using the controls, 95% CI were calculated for expected PV:isoSK-GFR at given renal volumes. For ARVD patients, "improvers" were defined as having both >15% and >1ml/min increase in isoSK-GFR at 4 months after revascularization. Sensitivity and specificity of PV:isoSK-GFR for predicting improvers was calculated. RESULTS:30 patients (mean age 68 ±8 years), underwent revascularization, of whom 10 patients had intervention for bilateral RAS. Stented kidneys which manifested >15% improvement in function had larger PV:isoSK-GFR compared to controls (19±16 vs. 6±4ml/ml/min, p = 0.002). The sensitivity and specificity of this equation in predicting a positive renal functional outcome were 64% and 88% respectively. Use of PV:isoSK-GFR increased prediction of functional improvement (area under curve 0.93). Of note, non-RAS contralateral kidneys which improved (n = 5) also demonstrated larger PV:isoSK-GFR (15.2±16.2 ml/ml/min, p = 0.006). CONCLUSION:This study offers early indicators that the ratio of PV:isoSK-GFR may help identify patients with kidneys suitable for renal revascularization which could improve patient selection for a procedure associated with risks. Calculation of the PV:isoSK-GFR ratio is easy, does not require MRI contrast agent.

To assess the frequency of chronic kidney disease (CKD), define the associated demographics, and evaluate its association with use of evidence-based drug therapy in a contemporary global study of patients with stable coronary artery disease.22,272 patients from the ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease (CLARIFY) were included. Baseline estimated glomerular filtration rate (eGFR) was calculated (CKD-Epidemiology Collaboration formula) and patients categorised according to CKD stage: >89, 60-89, 45-59 and