Publications by authors named "Philip A Kalra"

221 Publications

Longitudinal change in c-terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease.

BMC Nephrol 2021 Oct 2;22(1):329. Epub 2021 Oct 2.

Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK.

Background: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes.

Methods: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis.

Results: Across our population, median baseline eGFR was 32.3mls/min/1.73m, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events.

Conclusion: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02528-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487581PMC
October 2021

Randomized Trial-PrEscription of intraDialytic exercise to improve quAlity of Life in Patients Receiving Hemodialysis.

Kidney Int Rep 2021 Aug 30;6(8):2159-2170. Epub 2021 May 30.

School of Health Sciences, Queen Margaret University, Edinburgh, UK.

Introduction: Whether clinically implementable exercise interventions in people receiving hemodialysis (HD) therapy improve health-related quality of life (HRQoL) remains unknown. The PrEscription of intraDialytic exercise to improve quAlity of Life PEDAL) study evaluated the clinical benefit and cost-effectiveness of a 6-month intradialytic exercise program.

Methods: In a multicenter, single-blinded, randomized, controlled trial, people receiving HD were randomly assigned to (i) intradialytic exercise training (exercise intervention group [EX]) and (ii) usual care (control group [CON]). Primary outcome was change in Kidney Disease Quality of Life Short-Form Physical Component Summary (KDQOL-SF 1.3 PCS) from baseline to 6 months. Cost-effectiveness was determined using health economic analysis; physiological impairment was evaluated by peak oxygen uptake; and harms were recorded.

Results: We randomized 379 participants; 335 and 243 patients (EX  = 127; CON  = 116) completed baseline and 6-month assessments, respectively. Mean difference in change PCS from baseline to 6 months between EX and CON was 2.4 (95% confidence interval [CI]: -0.1 to 4.8) arbitrary units ( = 0.055); no improvements were observed in peak oxygen uptake or secondary outcome measures. Participants in the intervention group had poor compliance (47%) and poor adherence (18%) to the exercise prescription. Cost of delivering intervention ranged from US$598 to US$1092 per participant per year. The number of participants with harms was similar between EX ( = 69) and CON ( = 56). A primary limitation was the lack of an attention CON. Many patients also withdrew from the study or were too unwell to complete all physiological outcome assessments.

Conclusions: A 6-month intradialytic aerobic exercise program was not clinically beneficial in improving HRQoL as delivered to this cohort of deconditioned patients on HD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2021.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343798PMC
August 2021

Artherosclerotic Renovascular Disease: A KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference.

Am J Kidney Dis 2021 Aug 9. Epub 2021 Aug 9.

Department of Renal Medicine, Salford Royal Hospital, Salford, United Kingdom. Electronic address:

The diagnosis and management of atherosclerotic renovascular disease (ARVD) is complex and controversial. Despite evidence from the ASTRAL (2009) and CORAL (2013) randomized controlled trials showing that percutaneous renal artery revascularization did not improve major outcomes compared to best medical therapy alone over 3-5 years, several areas of uncertainty remain. Medical therapy, including statin and antihypertensive medications, has evolved in recent years, and the use of renin angiotensin aldosterone system (RAAS) blockers is now considered the primary means for treating hypertension in the setting of ARVD. However, the criteria to identify kidneys with renal artery stenosis that have potentially salvageable function are evolving. There are also data suggesting that certain high-risk populations with specific clinical manifestations may benefit from revascularization. Here, we provide an overview of the epidemiology, diagnosis, and treatment of ARVD based on consensus recommendations from a panel of physician experts who attended the recent KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference on Central & Peripheral Arterial Diseases in Chronic Kidney Diseases. Most focus is provided for contentious issues and we also outline aspects of investigation and management of ARVD that require further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2021.06.025DOI Listing
August 2021

Community- versus hospital-acquired acute kidney injury in hospitalised COVID-19 patients.

BMC Nephrol 2021 07 23;22(1):269. Epub 2021 Jul 23.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK.

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 < 0.0001) while atrial fibrillation conferred a protective effect (adjusted odds ratio 0.29, p < 0.0209). Mortality was significantly higher for patients who had an AKI compared to those who didn't have an AKI (54.3 % vs. 29.4 % respectively, p < 0.0001). On Cox regression, hospital-acquired AKI was significantly associated with mortality (adjusted hazard ratio 4.64, p < 0.0001) while community-acquired AKI was not.

Conclusions: AKI occurred in over a quarter of our hospitalised COVID-19 patients. Community- and hospital-acquired AKI have many shared risk factors which appear to converge on a pre-renal mechanism of injury. Hospital- but not community acquired AKI was a significant risk factor for death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02471-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299737PMC
July 2021

A Predictive Model for Progression of CKD to Kidney Failure Based on Routine Laboratory Tests.

Am J Kidney Dis 2021 Jul 20. Epub 2021 Jul 20.

Chair and Institute of Functional Genomics, University of Regensburg, Regensburg, Germany. Electronic address:

Rationale & Objective: Stratification of chronic kidney disease (CKD) patients at risk for progressing to kidney failure requiring kidney replacement therapy (KFRT) is important for clinical decision-making and trial enrollment.

Study Design: Four independent prospective observational cohort studies.

Setting & Participants: The development cohort comprised 4,915 CKD patients, and 3 independent validation cohorts comprised a total of 3,063. Patients were observed for approximately 5 years.

Exposure: 22 demographic, anthropometric, and laboratory variables commonly assessed in CKD patients.

Outcome: Progression to KFRT.

Analytical Approach: A least absolute shrinkage and selection operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for KFRT. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation both in a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs.

Results: The newly derived 6-variable risk score (Z6) included serum creatinine, albumin, cystatin C, and urea, as well as hemoglobin and the urinary albumin-creatinine ratio. In the the resampling approach, Z6 achieved a median C statistic of 0.909 (95% CI, 0.868-0.937) at 2 years after the baseline visit, whereas the T4 achieved a median C statistic of 0.855 (95% CI, 0.799-0.915). In the 3 independent validation cohorts, the Z6C statistics were 0.894, 0.921, and 0.891, whereas the T4C statistics were 0.882, 0.913, and 0.862.

Limitations: The Z6 was both derived and tested only in White European cohorts.

Conclusions: A new risk equation based on 6 routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to KFRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2021.05.018DOI Listing
July 2021

Real-world safety and effectiveness of sucroferric oxyhydroxide for treatment of hyperphosphataemia in dialysis patients: a prospective observational study.

Clin Kidney J 2021 Jul 5;14(7):1770-1779. Epub 2021 Feb 5.

Department of Nephrology, UCBL, CarMeN, Centre Hospitalier Lyon-Sud, University of Lyon, Lyon, France.

Background: The iron-based phosphate binder (PB), sucroferric oxyhydroxide (SFOH), is indicated to control serum phosphorus levels in patients with chronic kidney disease on dialysis.

Methods: This non-interventional, prospective, multicentre, cohort study conducted in seven European countries evaluated the safety and effectiveness of SFOH in dialysis patients with hyperphosphataemia in routine practice. Safety outcomes included adverse drug reactions (ADRs) and changes in iron-related parameters. SFOH effectiveness was evaluated by changes-from-baseline (BL) in serum phosphorus and percentage of patients achieving in-target phosphorus levels.

Results: The safety analysis set included 1365 patients (mean observation: 420.3 ± 239.3 days). Overall, 682 (50.0%) patients discontinued the study. Mean SFOH dose during the observation period was 1172.7 ± 539.9 mg (2.3 pills/day). Overall, 617 (45.2%) patients received concomitant PB(s) during SFOH treatment. ADRs and serious ADRs were observed for 531 (38.9%) and 26 (1.9%) patients. Most frequent ADRs were diarrhoea (194 patients, 14.2%) and discoloured faeces (128 patients, 9.4%). Diarrhoea generally occurred early during SFOH treatment and was mostly mild and transient. Small increases from BL in serum ferritin were observed (ranging from +12 to +75 µg/L). SFOH treatment was associated with serum phosphorus reductions (6.3 ± 1.6 mg/dL at BL versus 5.3 ± 1.8 mg/dL at Month 30; ΔBL: -1.0 mg/dL, P < 0.01). Percentage of patients achieving serum phosphorus ≤4.5 mg/dL increased from 12.0% at BL to 34.8% at Month 30, while the percentage achieving serum phosphorus ≤5.5 mg/dL increased from 29.9% to 63.0%.

Conclusions: SFOH has a favourable safety and tolerability profile in a real-world setting, consistent with results of the Phase 3 study. Moreover, SFOH improved serum phosphorus control with a low daily pill burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243278PMC
July 2021

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

N Engl J Med 2021 09 30;385(13):1172-1183. Epub 2021 Jun 30.

From the Vaccine Institute, St. George's, University of London, and St. George's University Hospitals NHS Foundation Trust (P.T.H., E.P.G., C.C., A.S.F.R.), Chelsea, Westminster Hospital NHS Foundation Trust and Imperial College London (M.B.), the Institute for Global Health, University College London, and Royal Free London NHS Foundation Trust (F.B.), the Centre for Rheumatic Disease, Kings College London (J.G.), the Department of Infectious Diseases, Guy's and St. Thomas' NHS Foundation Trust, MRC Clinical Trials Unit at University College London (A.L.G.), and Renal Services, Epsom and St. Helier University Hospitals NHS Trust (P.A.S.), London, Stockport NHS Foundation Trust, Stepping Hill Hospital, Stockport (D.N.B.), Royal Cornwall Hospitals NHS Trust, Truro (D.B.), Centre for Clinical Infection, South Tees Hospitals NHS Foundation Trust, James Cook University Hospital, Middlesbrough (D.R.C.), Layton Medical Centre, Blackpool (R.C.), Lakeside Healthcare Research, Lakeside Surgeries, Corby (A. Heer), University Hospitals of Morecambe Bay NHS Foundation Trust, Kendal (A. Higham), Accelerated Enrollment Solutions, Synexus Hexham Dedicated Research Site, Hexham General Hospital, Hexham (S.I.), Accelerated Enrollment Solutions, Synexus Thames Valley Dedicated Research Site, Reading (A.J.), Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich (C.J., J.T.), Salford Royal NHS Foundation Trust, Northern Care Alliance, Salford (P.A.K.), Accelerated Enrollment Solutions, Synexus Midlands Dedicated Research Site, Birmingham (C.K.), Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast and Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast (D.F.M.), Accelerated Enrollment Solutions, Synexus Merseyside Dedicated Research Site, Liverpool (A.M.), Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, and Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford (A.M.M.), St. James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds (J.M.), the Adam Practice, Poole (P.M.), University Hospital Southampton NHS Foundation Trust, Southampton (P.M.), Accelerated Enrollment Solutions, Synexus Glasgow Dedicated Research Site (I.M.), and MRC-University of Glasgow Centre for Virus Research and Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde (E.C.T.), Glasgow, Accelerated Enrollment Solutions, Synexus Wales Dedicated Research Site, Cardiff (H.N.), the School of Medical Sciences, Bangor University, and Betsi Cadwaladr University Health Board, Bangor (O.O.), the Division of Epidemiology and Public Health, University of Nottingham, Nottingham (J.P.), Haywood Hospital, Midlands Partnership NHS Foundation Trust, Stafford (J.P.), Accelerated Enrollment Solutions, Synexus Lancashire Dedicated Research Site, Chorley (C.H.P.), the National Institute for Health Research Patient Recruitment Centre and Bradford Teaching Hospitals NHS Foundation Trust, Bradford (D.S.), Royal Devon and Exeter Hospital, Exeter (R.P.S.), East Suffolk, North Essex NHS Foundation Trust and University of Essex, Colchester (R.S.), Aberdeen Royal Infirmary, NHS Grampian, and Aging Clinical and Experimental Research Group, University of Aberdeen, Aberdeen (R.L.S.), and Accelerated Enrollment Solutions, Synexus Manchester Dedicated Research Site, Manchester (M.E.V.) - all in the United Kingdom; and Novavax, Gaithersburg, MD (G.A., I.C., F.D., G.G., J.R., A.R., K.S., S.T.).

Background: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population.

Methods: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.

Results: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.

Conclusions: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2107659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262625PMC
September 2021

Motion correction of free-breathing magnetic resonance renography using model-driven registration.

MAGMA 2021 Jun 23. Epub 2021 Jun 23.

Department of Biomedical Imaging Sciences, University of Leeds, Leeds, UK.

Introduction: Model-driven registration (MDR) is a general approach to remove patient motion in quantitative imaging. In this study, we investigate whether MDR can effectively correct the motion in free-breathing MR renography (MRR).

Materials And Methods: MDR was generalised to linear tracer-kinetic models and implemented using 2D or 3D free-form deformations (FFD) with multi-resolution and gradient descent optimization. MDR was evaluated using a kidney-mimicking digital reference object (DRO) and free-breathing patient data acquired at high temporal resolution in multi-slice 2D (5 patients) and 3D acquisitions (8 patients). Registration accuracy was assessed using comparison to ground truth DRO, calculating the Hausdorff distance (HD) between ground truth masks with segmentations and visual evaluation of dynamic images, signal-time courses and parametric maps (all data).

Results: DRO data showed that the bias and precision of parameter maps after MDR are indistinguishable from motion-free data. MDR led to reduction in HD (HD = 9.98 ± 9.76, HD = 1.63 ± 0.49). Visual inspection showed that MDR effectively removed motion effects in the dynamic data, leading to a clear improvement in anatomical delineation on parametric maps and a reduction in motion-induced oscillations on signal-time courses.

Discussion: MDR provides effective motion correction of MRR in synthetic and patient data. Future work is needed to compare the performance against other more established methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10334-021-00936-xDOI Listing
June 2021

Exercise programme to improve quality of life for patients with end-stage kidney disease receiving haemodialysis: the PEDAL RCT.

Health Technol Assess 2021 06;25(40):1-52

School of Health Sciences, Queen Margaret University, Edinburgh, UK.

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,  = 127; control,  = 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;  = 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 ( = 69) and control ( = 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 ; Vol. 25, No. 40. See the NIHR Journals Library website for further project information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3310/hta25400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256322PMC
June 2021

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy.

JACC Heart Fail 2021 Jul 9;9(7):518-527. Epub 2021 Jun 9.

Department of Renal Medicine, King's College Hospital, London, United Kingdom.

Objectives: This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients.

Background: Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat.

Methods: The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial.

Results: Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event.

Conclusions: Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchf.2021.04.005DOI Listing
July 2021

Diabetic kidney disease: update on clinical management and non-glycaemic effects of newer medications for type 2 diabetes.

Ther Adv Endocrinol Metab 2021 29;12:20420188211020664. Epub 2021 May 29.

Department of Nephrology, Salford Royal NHS Foundation Trust, Salford, UK.

Type 2 diabetes is a leading cause of chronic kidney disease worldwide and continues to increase in prevalence. This in turn has significant implications for healthcare provision and the economy. In recent years there have been multiple advances in the glucose-lowering agents available for the treatment of diabetes, which not only modify the disease itself but also have important benefits in terms of the associated cardiovascular outcomes. The cardiovascular outcome trials of agents such as glucagon-like peptide-1 receptor agonists (GLP-RAs) and sodium glucose cotransporter 2 inhibitors (SGLT-2) have demonstrated significant benefits in reducing major adverse cardiovascular events, admissions for heart failure and in some cases mortality. Secondary analysis of these trials has also indicated significant renoprotective benefit. Canagliflozin and Renal Outcomes in Type 2 Diabetes Mellitus and Nephropathy (CREDENCE) a renal-specific trial, has shown major benefits with canagliflozin for renal outcomes in diabetic kidney disease, and similar trials with other SGLT-2 inhibitors are either underway or awaiting analysis. In this article we review current goals of treatment of diabetes and the implications of advancing renal impairment on choice of treatments. Areas discussed include the diagnosis of diabetic kidney disease and current treatment strategies for diabetic kidney disease ranging from lifestyle modifications to glycaemic control. This review focuses on the role of GLP-RAs and SGLT-2 inhibitors in treating those with diabetes and chronic kidney disease with some illustrative cases. It is clear that these agents should now be considered first choice in combination with metformin in those with diabetes and increased cardiovascular risk and/or reduced renal function, and in preference to other classes such as dipeptidyl peptidase-4 (DPP-4) inhibitors or sulphonylureas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/20420188211020664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165820PMC
May 2021

Cognitive impairment in patients with moderate to severe chronic kidney disease: the Salford kidney cohort study.

Clin Kidney J 2021 Jun 3;14(6):1639-1648. Epub 2020 Nov 3.

Renal Department, Salford Royal NHS Trust, Salford, UK.

Background: Cognitive impairment in chronic kidney disease (CKD) is common and underrecognized [1, 2]. Determining risk factors for cognitive impairment and whether speed of CKD progression is an important consideration may help identify cognitive impairment by nephrologists. Vascular disease is thought to underpin cognitive impairment in CKD and by segregating CKD patients with proven vascular disease, we may also be able to discover other important associations with cognitive impairment in CKD patients.

Method: A total of 250 patients in a UK prospective cohort of CKD patients underwent two cognitive assessments: Montreal Cognitive Assessment test and Trail Making Test. Cognitive impairment was defined using validated population cut-offs (cognitive impairment) and relative cognitive impairment. Relative cognitive impairment was defined by <1 standard deviation below the mean -score on any completed test. Two multivariable logistical regression models identified variables associated with cognitive impairment and realtive cognitive impairment.

Results: About 44 and 24.8% of patients suffered cognitive impairment and relative cognitive impairment, respectively. Depression, previous stroke and older age were significantly associated with cognitive impairment. Older age was significantly associated with relative cognitive impairment (P ≤ 0.05) and higher proteinuria and the use of psychodynamic medications were also significantly associated with relative cognitive impairment (P = 0.05). Delta estimated glomerular filtration rate (eGFR) in patients with cognitive impairment and relative cognitive impairment compared with those having normal cognition was similar (-0.77 versus -1.35 mL/min/1.73 m/year, P = 0.34 for cognitive impairment and -1.12 versus -1.02 mL/min/1.73 m/year, P = 0.89 for relative cognitive impairment).

Conclusion: Risk factors for cognitive impairment in CKD include previous stroke, depression or anxiety, higher proteinuria and prescription of psychodynamic medications. Patients with a faster eGFR decline do not represent a group of patients at increased risk of cognitive impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162857PMC
June 2021

Inflammation and Oxidative Damage in Ischaemic Renal Disease.

Antioxidants (Basel) 2021 May 25;10(6). Epub 2021 May 25.

Department of Nephrology, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.

Ischaemic renal disease as result of atherosclerotic renovascular disease activates a complex biological response that ultimately leads to fibrosis and chronic kidney disease. Large randomised control trials have shown that renal revascularisation in patients with atherosclerotic renal artery disease does not confer any additional benefit to medical therapy alone. This is likely related to the activation of complex pathways of oxidative stress, inflammatory cytokines and fibrosis due to atherosclerotic disease and hypoxic injury due to reduced renal blood flow. New evidence from pre-clinical trials now indicates a role for specific targeted therapeutic interventions to counteract this complex pathogenesis. This evidence now suggests that the focus for those with atherosclerotic renovascular disease should be a combination of revascularisation and renoprotective therapies that target the renal tissue response to ischaemia, reduce the inflammatory infiltrate and prevent or reduce the fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox10060845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227971PMC
May 2021

A validation study of the kidney failure risk equation in advanced chronic kidney disease according to disease aetiology with evaluation of discrimination, calibration and clinical utility.

BMC Nephrol 2021 May 24;22(1):194. Epub 2021 May 24.

Department of renal medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK.

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/1.73m and < 15 ml/min/1.73m 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02402-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147075PMC
May 2021

Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety.

Expert Opin Drug Saf 2021 Jul 15;20(7):757-769. Epub 2021 May 15.

Department of Medicine, Division of Hematology and Thromboembolism, St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada.

: The newest intravenous (IV) iron products show an improved safety profile over predecessors, allowing for the rapid administration of relatively high doses. Ferric derisomaltose (FDI; also known as iron isomaltoside), ferric carboxymaltose (FCM), and ferumoxytol (FER), are successful treatments for iron deficiency (Europe; FDI and FCM) and iron deficiency anemia (US; FDI, FCM, and FER).: This review focusses on the chemistry and structure of FDI, FCM, and FER, and on three key aspects of IV iron safety: (1) hypersensitivity; (2) hypophosphatemia and sequelae; (3) cardiovascular safety.: Although the safety of modern IV iron has improved, immediate infusion reactions and the development of hypophosphatemia must be appreciated and recognized by those who prescribe and administer IV iron. Immediate infusion reactions can occur with any IV iron and are usually mild; severe reactions - particularly anaphylaxis - are extremely rare. The recognition and appropriate management of infusion reactions is an important consideration to the successful administration of IV iron. Severe, persistent, hypophosphatemia is a specific side effect of FCM. No cardiovascular safety signal has been identified for IV iron. Ongoing trials in heart failure will provide additional long-term efficacy and safety data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14740338.2021.1912010DOI Listing
July 2021

Central and peripheral arterial diseases in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2021 07 5;100(1):35-48. Epub 2021 May 5.

Department of Cardiology I: Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Münster, Germany. Electronic address:

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, vascular biology, epidemiology, and health economics attended. The objective was to identify key issues related to the optimal detection, management, and treatment of cerebrovascular diseases, central aortic disease, renovascular disease, and peripheral artery disease in the setting of CKD. This report outlines the common pathophysiology of these vascular processes in the setting of CKD, describes best practices for their diagnosis and management, summarizes areas of uncertainty, addresses ongoing controversial issues, and proposes a research agenda to address key gaps in knowledge that, when addressed, could improve patient care and outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2021.04.029DOI Listing
July 2021

The PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease trial: study design and baseline data for a multicentre randomized controlled trial.

Clin Kidney J 2021 May 10;14(5):1345-1355. Epub 2020 Sep 10.

School of Health Sciences, Centre for Health, Activity and Rehabilitation Research, Queen Margaret University, Edinburgh, UK.

Background: Exercise interventions designed to improve physical function and reduce sedentary behaviour in haemodialysis (HD) patients might improve exercise capacity, reduce fatigue and lead to improved quality of life (QOL). The PrEscription of intraDialytic exercise to improve quAlity of Life study aimed to evaluate the effectiveness of a 6-month intradialytic exercise programme on QOL and physical function, compared with usual care for patients on HD in the UK.

Methods: We conducted a prospective, pragmatic multicentre randomized controlled trial in 335 HD patients and randomly (1:1) assigned them to either (i) intradialytic exercise training plus usual care maintenance HD or (ii) usual care maintenance HD. The primary outcome of the study was the change in Kidney Disease Quality of Life Short Form (KDQOL-SF 1.3) Physical Component Score between baseline and 6 months. Additional secondary outcomes included changes in peak aerobic capacity, physical fitness, habitual physical activity levels and falls (International Physical Activity Questionnaire, Duke's Activity Status Index and Tinetti Falls Efficacy Scale), QOL and symptom burden assessments (EQ5D), arterial stiffness (pulse wave velocity), anthropometric measures, resting blood pressure, clinical chemistry, safety and harms associated with the intervention, hospitalizations and cost-effectiveness. A nested qualitative study investigated the experience and acceptability of the intervention for both participants and members of the renal health care team.

Results: At baseline assessment, 62.4% of the randomized cohort were male, the median age was 59.3 years and 50.4% were white. Prior cerebrovascular events and myocardial infarction were present in 8 and 12% of the cohort, respectively, 77.9% of patients had hypertension and 39.4% had diabetes. Baseline clinical characteristics and laboratory data for the randomized cohort were generally concordant with data from the UK Renal Registry.

Conclusion: The results from this study will address a significant knowledge gap in the prescription of exercise interventions for patients receiving maintenance HD therapy and inform the development of intradialytic exercise programmes both nationally and internationally.

Trial Registration: ISRCTN N83508514; registered on 17 December 2014.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087141PMC
May 2021

Investigating the utility of COVID-19 antibody testing in end-stage renal disease patients receiving haemodialysis: a cohort study in the United Kingdom.

BMC Nephrol 2021 04 27;22(1):154. Epub 2021 Apr 27.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, M6 8HD, UK.

Background: End-stage renal disease (ESRD) patients receiving haemodialysis (HD) are a vulnerable group of patients with increased mortality from COVID-19. Despite improved understanding, the duration of host immunity following COVID-19 infection and role of serological testing alone or in addition to real-time reverse transcription polymerase chain reaction (rRT-PCR) testing in the HD population is not fully understood, which this study aimed to investigate.

Methods: There were two parts to this study. Between 15th March 2020 to 15th July 2020, patients receiving HD who tested positive on rRT-PCR for SARS-CoV-2 were recruited into the COVID-19 arm, whilst asymptomatic patients without a previous diagnosis of COVID-19 were recruited to the epidemiological arm of the Salford Kidney Study (SKS). All patients underwent monthly testing for anti-SARS-CoV-2 antibodies as per routine clinical practice since August 2020. The aims were twofold: firstly, to determine seroprevalence and COVID-19 exposure in the epidemiological arm; secondly, to assess duration of the antibody response in the COVID-19 arm. Baseline characteristics were reviewed between groups. Statistical analysis was performed using SPSS. Mann-Whitney U and Chi-squared tests were used for testing significance of difference between groups.

Results: In our total HD population of 411 patients, 32 were PCR-positive for COVID-19. Of the remaining patients, 237 were recruited into the SKS study, of whom 12 (5.1%) had detectable anti-SARS-CoV-2 antibodies. Of the 32 PCR-positive patients, 27 (84.4%) were symptomatic and 25 patients admitted to hospital due to their symptoms. Of the 22 patients in COVID-19 arm that underwent testing for anti-SARS-CoV-2 IgG antibodies beyond 7 months, all had detectable antibodies. A higher proportion of the patients with COVID-19 were frail compared to patients without a diagnosis of COVID-19 (64.3% vs 34.1%, p = 0.003). Other characteristics were similar between the groups. Over a median follow up of 7 months, a higher number of deaths were recorded in patients with a diagnosis of COVID-19 compared to those without (18.7% vs 5.9%, p = 0.003).

Conclusions: Serological testing in the HD population is a valuable tool to determine seroprevalence, monitor exposure, and guide improvements for infection prevention and control (IPC) measures to help prevent local outbreaks. This study revealed HD patients mount a humoral response detectable until at least 7 months after COVID-19 infection and provides hope of similar protection with the vaccines recently approved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02366-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075608PMC
April 2021

OptiMissP: A dashboard to assess missingness in proteomic data-independent acquisition mass spectrometry.

PLoS One 2021 15;16(4):e0249771. Epub 2021 Apr 15.

Division of Informatics, Imaging, and Data Science, School of Health Sciences, The University of Manchester, Manchester, United Kingdom.

Background: Missing 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.

Results: We 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.

Conclusions: OptiMissP 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249771PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049317PMC
October 2021

A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism.

BMC Nephrol 2021 Mar 23;22(1):106. Epub 2021 Mar 23.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, M6 8HD, UK.

Background: Secondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control.

Methods: This is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months.

Results: There was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses.

Conclusions: With a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02312-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989372PMC
March 2021

Adverse outcomes associated with rapid linear and non-linear patterns of chronic kidney disease progression.

BMC Nephrol 2021 03 6;22(1):82. Epub 2021 Mar 6.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK.

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/1.73m. Rapid progression was defined as an annual eGFR slope of ≤ - 3 ml/min/1.73m/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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02282-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937251PMC
March 2021

SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function.

Sci Signal 2021 Mar 2;14(672). Epub 2021 Mar 2.

Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health and Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

Renal fibrosis is a common end point for kidney injury and many chronic kidney diseases. Fibrogenesis depends on the sustained activation of myofibroblasts, which deposit the extracellular matrix that causes progressive scarring and organ failure. Here, we showed that the transcription factor SOX9 was associated with kidney fibrosis in humans and required for experimentally induced kidney fibrosis in mice. From genome-wide analysis, we identified Neuron navigator 3 (NAV3) as acting downstream of SOX9 in kidney fibrosis. NAV3 increased in abundance and colocalized with SOX9 after renal injury in mice, and both SOX9 and NAV3 were present in diseased human kidneys. In an in vitro model of renal pericyte transdifferentiation into myofibroblasts, we demonstrated that NAV3 was required for multiple aspects of fibrogenesis, including actin polymerization linked to cell migration and sustained activation of the mechanosensitive transcription factor YAP1. In summary, our work identifies a SOX9-NAV3-YAP1 axis involved in the progression of kidney fibrosis and points to NAV3 as a potential target for pharmacological intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scisignal.abb4282DOI Listing
March 2021

A validation study of the 4-variable and 8-variable kidney failure risk equation in transplant recipients in the United Kingdom.

BMC Nephrol 2021 02 9;22(1):57. Epub 2021 Feb 9.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK.

Background: There is emerging evidence that the 4-variable Kidney Failure Risk Equation (KFRE) can be used for risk prediction of graft failure in transplant recipients. However, geographical validation of the 4-variable KFRE in transplant patients is lacking, as is whether the more extensive 8-variable KFRE improves predictive accuracy. This study aimed to validate the 4- and 8-variable KFRE predictions of the 5-year death-censored risk of graft failure in patients in the United Kingdom.

Methods: A retrospective cohort study involved 415 transplant recipients who had their first renal transplant between 2003 and 2015 and were under follow-up at Salford Royal NHS Foundation Trust. The KFRE risk scores were calculated on variables taken 1-year post-transplant. The area under the receiver operating characteristic curves (AUC) and calibration plots were evaluated to determine discrimination and calibration of the 4- and 8-variable KFREs in the whole cohort as well as in a subgroup analysis of living and deceased donor recipients and in patients with an eGFR< 45 ml/min/1.73m.

Results: There were 16 graft failure events (4%) in the whole cohort. The 4- and 8-variable KFREs showed good discrimination with AUC of 0.743 (95% confidence interval [CI] 0.610-0.876) and 0.751 (95% CI 0.629-0.872) respectively. In patients with an eGFR< 45 ml/min/1.73m, the 8-variable KFRE had good discrimination with an AUC of 0.785 (95% CI 0.558-0.982) but the 4-variable provided excellent discrimination in this group with an AUC of 0.817 (0.646-0.988). Calibration plots however showed poor calibration with risk scores tending to underestimate risk of graft failure in low-risk patients and overestimate risk in high-risk patients, which was seen in the primary and subgroup analyses.

Conclusions: Despite adequate discrimination, the 4- and 8-variable KFREs are imprecise in predicting graft failure in transplant recipients using data 1-year post-transplant. Larger, international studies involving diverse patient populations should be considered to corroborate these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02259-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874608PMC
February 2021

Calciphylaxis in end-stage kidney disease: outcome data from the United Kingdom Calciphylaxis Study.

J Nephrol 2021 10 6;34(5):1537-1545. Epub 2021 Feb 6.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, M6 8HD, UK.

Background And Aims: Calciphylaxis is a rare condition associated with very high mortality in patients with end-stage kidney disease. Data from country-based registries have been an invaluable resource for a better understanding of the natural history and management for this condition. This study aimed to investigate the current management strategies and outcomes of patients enrolled in the United Kingdom Calciphylaxis study (UKCS).

Methods: The study was conducted on 89 patients registered in the UKCS since 2012. The initial analysis included a description of the baseline characteristics, management strategies and outcomes on follow-up until May 2020. Further analysis included a comparison of the mortality outcome of the UKCS patients who were receiving haemodialysis with a propensity score matched cohort of haemodialysis patients from the Chronic Renal Insufficiency Standards Implementation Study- Haemodialysis (CRISIS-HD).

Results: Median age of the cohort was 59 years, with a predominance of females (61%) and Caucasian (95%) ethnicity. About 54% of the patients were diabetic and 70% were receiving haemodialysis at study entry. The skin lesions were mostly distributed in the lower extremities (48%). Sodium thiosulphate and calcimimetic were the most widely used management strategies. The mortality rate was 72 deaths per hundred patient-years (50 deaths observed in 69.5 patient years). Complete wound healing was noted in 17% and bacteraemia was reported in 26% of patients. In a comparative analysis of the matched haemodialysis patients, the presence of calciphylaxis in 62 patients showed a strong association with all-cause mortality (HR 6.96; p < 0.001), with annual mortality 67% versus 10.2% in haemodialysis patients without calciphylaxis.

Conclusions: This UK wide study strengthens the evidence that calciphylaxis is a strong and independent risk factor associated with all-cause mortality; no significant benefit was shown with any individual treatment modality. Until further evidence becomes available, a multifaceted approach would be the appropriate treatment strategy in the management of this extremely serious condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40620-020-00908-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494680PMC
October 2021

Rubrometabolic syndrome.

Minerva Endocrinol 2020 Dec 17. Epub 2020 Dec 17.

Clinical Associate Professor, University of Melbourne VIC, Launceston, Australia.

Metabolic syndrome (MS), a conglomeration of several conditions including obesity, type 2 diabetes mellitus (T2DM), insulin resistance, elevated blood pressure, and dyslipidemia is reaching epidemic proportions. Anemia is caused by iron deficiency or dysregulation of iron homeostasis, leading to tissue hypoxia. Coexistence of anemia and MS or its components has been reported in the literature. The term "rubrometabolic syndrome" acts as a unifying entity linking the importance of blood in health and anemia in MS; it justifies two principles-redness of blood and low-grade inflammation. Chronic low-grade inflammation in MSaffects iron metabolism leading to anemia. Tissue hypoxia that results from the anemic condition seems to be a major causative factor for the exacerbation of several microvascular and macrovascular components of T2DM, which include diabetic neuropathy, nephropathy, retinopathy, and cardiovascular complications. In obesity, anemia leads to malabsorption of micronutrients and can complicate the management of the condition by bariatric surgery. Anemia interferes with the diagnosis and management of T2DM, obesity, dyslipidemia, or hypertension due to its effect on pathological tests as well as medications. Since anemia in MS is multifaceted, the management of anemia is challenging as overcorrection of anemia with erythropoietin-stimulating agents can cause detrimental effects. These limitations necessitate availability of an effective and safe therapy that can maintain and elevate the hemoglobin levels along with maintaining the physiological balance of other systems. This review discusses the physiological links between anemia and MS along with diagnosis and management strategies in patients with coexistence of anemia and MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S0391-1977.20.03353-2DOI Listing
December 2020

A Paradigm to Discover Biomarkers Associated With Chronic Kidney Disease Progression.

Biomark Insights 2020 1;15:1177271920976146. Epub 2020 Dec 1.

Department of Renal Medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1177271920976146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716058PMC
December 2020

NIMO-CKD-UK: a real-world, observational study of iron isomaltoside in patients with iron deficiency anaemia and chronic kidney disease.

BMC Nephrol 2020 12 10;21(1):539. Epub 2020 Dec 10.

Royal Devon and Exeter University Hospital, Exeter, UK.

Background: Intravenous iron is often used to treat iron deficiency anaemia in non-dialysis chronic kidney disease (ND-CKD), but the optimal dosing regimen remains unclear. We evaluated the impact of high- versus low-dose intravenous iron isomaltoside on the probability of retreatment with intravenous iron in iron-deficient ND-CKD patients.

Methods: This real-world, prospective, observational study collected data from 256 ND-CKD patients treated for anaemia in the UK. Following an initial course of iron isomaltoside, patients were followed for ≥12 months. Iron dose and the need for retreatment were determined at the investigators' discretion. The primary study outcome was the need for retreatment at 52 weeks compared between patients who received >1000 mg of iron during Course 1 and those who received ≤1000 mg. Safety was evaluated through adverse drug reactions.

Results: The probability of retreatment at Week 52 was significantly lower in the >1000 mg iron group (n = 58) versus the ≤1000 mg group (n = 198); hazard ratio (95% confidence interval [CI]): 0.46 (0.20, 0.91); p = 0.012. Mean (95% CI) haemoglobin increased by 6.58 (4.94, 8.21) g/L in the ≤1000 mg group and by 10.59 (7.52, 13.66) g/L in the >1000 mg group (p = 0.024). Changes in other blood and iron parameters were not significantly different between the two groups. Administering >1000 mg of iron isomaltoside saved 8.6 appointments per 100 patients compared to ≤1000 mg. No serious adverse drug reactions were reported. Of the patients who received ≤1000 mg of iron in this study, 82.3% were eligible for a dose >1000 mg.

Conclusions: The >1000 mg iron isomaltoside regimen reduced the probability of retreatment, achieved a greater haemoglobin response irrespective of erythropoiesis-stimulating agent treatment, and reduced the total number of appointments required, compared to the ≤1000 mg regimen. Many of the patients who received ≤1000 mg of iron were eligible for >1000 mg, indicating that there was considerable underdosing in this study.

Trial Registration: ClinicalTrials.gov NCT02546154 , 10 September 2015.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-020-02180-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726614PMC
December 2020

Safely reducing haemodialysis frequency during the COVID-19 pandemic.

BMC Nephrol 2020 12 7;21(1):532. Epub 2020 Dec 7.

Department of Renal Medicine, Salford Royal NHS Trust, Stott Lane, Salford, M68HD, UK.

Background: Patients undergoing haemodialysis (HD) are at higher risk of developing worse outcomes if they contract COVID-19. In our renal service we reduced HD frequency from thrice to twice-weekly in selected patients with the primary aim of reducing COVID 19 exposure and transmission between HD patients.

Methods: Dialysis unit nephrologists identified 166 suitable patients (38.4% of our HD population) to temporarily convert to twice-weekly haemodialysis immediately prior to the peak of the COVID-19 pandemic in our area. Changes in pre-dialysis weight, systolic blood pressure (SBP) and biochemistry were recorded weekly throughout the 4-week project. Hyperkalaemic patients (serum potassium > 6.0 mmol/L) were treated with a potassium binder, sodium bicarbonate and received responsive dietary advice.

Results: There were 12 deaths (5 due to COVID-19) in the HD population, 6 of which were in the twice weekly HD group; no deaths were definitively associated with change of dialysis protocol. A further 19 patients were either hospitalised and/or developed COVID-19 and thus transferred back to thrice weekly dialysis as per protocol. 113 (68.1%) were still receiving twice-weekly HD by the end of the 4-week project. Indications for transfer back to thrice weekly were; fluid overload (19), persistent hyperkalaemia (4), patient request (4) and compliance (1). There were statistically significant increases in SBP and pre-dialysis potassium during the project.

Conclusions: Short term conversion of a large but selected HD population to twice-weekly dialysis sessions was possible and safe. This approach could help mitigate COVID-19 transmission amongst dialysis patients in centres with similar organisational pressures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-020-02172-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720264PMC
December 2020

Recent advances in treatment of haemodialysis.

J R Soc Med 2021 01 3;114(1):30-37. Epub 2020 Dec 3.

Department of Nephrology, Colchester General Hospital, East Suffolk and North Essex NHS Foundation Trust, Colchester CO4 5JL, UK.

Haemodialysis remains the most widely used treatment for patients with end-stage renal disease. Despite the progress that has occurred in the treatment of end-stage renal disease over the last six decades, there has been a failure to translate this into the desired clinical benefits, with morbidity and mortality rates among patients on haemodialysis remaining unacceptably high. Recently, however, there have been expectations that the significant advances that took place over the last few years may result in improved outcomes. New medications for the treatment of anaemia and secondary hyperparathyroidism, as well as novel trends in the areas of iron therapy, diabetes management and physical exercise are among the most important advances which, taken together, are changing the standards of care for patients on haemodialysis. The latest advances, of relevance not only to specialists in Renal Medicine but also to general practitioners caring for these patients, are reviewed in this collaborative paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0141076820972669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173362PMC
January 2021
-->