Recent Submissions

  • Development and validation of prediction models of adverse kidney outcomes in the population with and without diabetes mellitus

    Brunskill, Nigel; Major, Rupert; Medcalf, James (2022-07)
    Objective: To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. Research design and methods: In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; ≥60 or <60 mL/min/1.73 m2) to predict a composite of ≥40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years. Results: There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting ≥40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. Conclusions: Novel prediction equations for a decline of ≥40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR.
  • Immunosuppressive regimens and outcomes of inflammatory bowel disease patients requiring kidney transplantation

    Singh, Baljit (2022-02)
    Patients with inflammatory bowel disease (IBD) can develop extra-renal complications and as a result, suffer from end stage renal failure requiring kidney transplantation (KT). A brief review of available literature revealed that IBD patients undergoing KT have shorter overall survival rates compared to their controls. Literature reporting steroid regimens and survival outcomes specific to IBD and post kidney transplant are scarce and these studies have small sample sizes thus making it difficult to draw accurate conclusions. Further research is required in the form of a randomized controlled study to clarify the effect and mechanism of steroid immunosuppression on the prognosis of renal transplant recipients and explore new treatment schemes.
  • Intradialytic cycling does not exacerbate microparticles or circulating markers of systemic inflammation in haemodialysis patients

    March, Daniel; Young, Hannah; Graham-Brown, Matthew; Brunskill, Nigel; Smith, Alice; Burton, James (2022-03)
    Purpose: Patients receiving haemodialysis (HD) display elevated circulating microparticle (MP) concentration, tissue factor (TF) expression and markers of systemic inflammation, though regular intradialytic cycling (IDC) may have a therapeutic effect. This study investigated the impact of regular, moderate-intensity IDC on circulating MPs and inflammatory markers in unit-based HD patients. Methods: Patients were cluster-randomised to intervention (n = 20, age: 51.4 ± 18.1 years, body mass: 77.6 ± 18.3 kg, mean ± SD) or no-exercise control (n = 20, 56.8 ± 14.0 years, 80.5 ± 26.5 kg). Intervention participants completed 30 min of moderate intensity (rating of perceived exertion [RPE] of 12-14) IDC, thrice weekly for 6 months. Pre-dialysis venous blood samples were obtained at 0, 3 and 6 months. Circulating MP phenotypes, cytokines, chemokine and MP TF expression were quantified using flow cytometry and cytometric bead array assays. Results: Despite high exercise compliance (82%), no IDC-dependent effects were observed for any MP, cytokine or chemokine measure (p ≥ 0.051, ηρ2 ≤ 0.399) other than TNF-α (p = 0.001, ηρ2 = 0.186), though no significance was revealed upon post hoc analysis. Conclusion: Six months of regular, moderate-intensity IDC had no effect on MPs, cytokines or chemokines. This suggests that the exercise did not exacerbate thrombotic or inflammatory status, though further functional assays are required to confirm this.
  • A multicenter feasibility randomized controlled trial to assess the impact of incremental versus conventional initiation of hemodialysis on residual kidney function

    Burton, James (2022)
    Twice-weekly hemodialysis, as part of incremental initiation, has reported benefits including preservation of residual kidney function (RKF). To explore this, we initiated a randomized controlled feasibility trial examining 55 incident hemodialysis patients with urea clearance of 3 ml/min/1.73 m2 or more across four centers in the United Kingdom randomized to standard or incremental schedules for 12 months. Incremental hemodialysis involved twice-weekly sessions, upwardly adjusting hemodialysis dose as RKF was lost, maintaining total (Dialysis+Renal) Std Kt/V above 2. Standard hemodialysis was thrice weekly for 3.5-4 hours, minimum Dialysis Std Kt/V of 2. Primary outcomes were feasibility parameters and effect size of group differences in rate of loss of RKF at six months. Health care cost impact and patient-reported outcomes were explored. Around one-third of patients met eligibility criteria. Half agreed to randomization; 26 received standard hemodialysis and 29 incremental. At 12 months, 21 incremental patients remained in the study vs 12 in the standard arm with no group differences in the urea clearance slope. Ninety-two percent of incremental and 75% of standard arm patients had a urea clearance of 2 ml/min/1.73 m2 or more at six months. Serious adverse events were less frequent in incremental patients (Incidence Rate Ratio 0.47, confidence interval 0.27-0.81). Serum bicarbonate was significantly lower in incremental patients indicating supplementation may be required. There were three deaths in each arm. Blood pressure, extracellular fluid and patient-reported outcomes were similar. There was no signal of benefit of incremental hemodialysis in terms of protection of RKF or Quality of Life score. Median incremental hemodialysis costs were significantly lower compared to standard hemodialysis. Thus, incremental hemodialysis appears safe and cost-saving in incident patients with adequate RKF, justifying a definitive trial.
  • Commentary on the NICE guideline on renal replacement therapy and conservative management

    Iyasere, Osasuyi (2021)
    NICE Guideline NG107, "Renal replacement therapy and conservative management" (Renal replacement therapy and conservative management (NG107); 2018:1-33) was published in October 2018 and replaced the existing NICE guideline CG125, "Chronic Kidney Disease (Stage 5): peritoneal dialysis" (Chronic kidney disease (stage 5): peritoneal dialysis | Guidance | NICE; 2011) and NICE Technology Appraisal TA48, "Guidance on home compared with hospital haemodialysis for patients with end-stage renal failure"(Guidance on home compared with hospital haemodialysis for patients with end-stage renal failure (Technology appraisal guideline TA48); 2002) The aim of the NICE guideline (NG107) was to provide guidance on renal replacement therapy (RRT), including dialysis, transplant and conservative care, for adults and children with CKD Stages 4 and 5. The guideline is extremely welcomed by the Renal Association and it offers huge value to patients, clinicians, commissioners and key stakeholders. It overlaps and enhances current guidance published by the Renal Association including "Haemodialysis" (Clinical practice guideline: Haemodialysis; 2019) which was updated in 2019 after the publication of the NICE guideline, "Peritoneal Dialysis in Adults and Children" (Clinical practice guideline: peritoneal Dialysis in adults and children; 2017) and "Planning, Initiation & withdrawal of Renal Replacement Therapy" (Clinical practice guideline: planning, initiation and withdrawal of renal replacement therapy; 2014) (at present there are no plans to update this guideline). There are several strengths to NICE guideline NG107 and we agree with and support the vast majority of recommendation statements in the guideline. This summary from the Renal Association discusses some of the key highlights, controversies, gaps in knowledge and challenges in implementation. Where there is disagreement with a NICE guideline statement, we have highlighted this and a new suggested statement has been written.
  • The role of macrophage polarization and interaction with renal tubular epithelial cells in ischemia-reperfusion induced acute kidney injury

    Yang, Bin (2022)
    Acute kidney injury (AKI) is a common critical clinical disease characterized by a sharp decline of renal function. Ischemia-reperfusion (IR) is one of the main causes of AKI. The mortality of AKI remains high due to the lack of early diagnosis and cause specific treatment. IR rapidly initiates innate immune responses, activates complement and innate immune cells, releasing a large number of injury-related molecules such as high mobility group box-1 (HMGB1), inflammatory mediators such as caspase-3, and then recruits immune inflammatory cells including M1 macrophages (Mϕ) to the microenvironment of injury, causing apoptosis and necrosis of renal tubular epithelial cells (TECs). Dead cells and associated inflammation further activate the adaptive immune system, which not only aggravates tissue damage, but also initiates M2 Mϕ participated inflammatory clearance, tissue repair and regeneration. Mϕ, professional phagocytes, and TECs, semi-professional phagocytes, can phagocytose around damaged cells including apoptotic Mϕ and TECs, which are key innate immune cells to regulate the outcome of injury, repair or fibrosis. In recent years, it has been found that erythropoietin (EPO) not only binds to the homodimeric receptor (EPOR)2 to induce erythropoiesis, but also binds to the heterodimeric receptor EPOR/βcR, also known as innate repair receptor, which plays renoprotective roles. Properdin is the only positive regulator in the complement activation of alternative pathway. It also can effectively identify and bind to early apoptotic T cells and facilitate phagocytic clearing by Mϕ through a non-complement activation-dependent mechanism. Our previous studies have shown that Mϕ and TECs associated with EPO and its receptors and properdin are involved in IR injury and repair, but the underlying mechanism needs to be further explored. As an important carrier of cell-to-cell signal transmission, exosomes participate in the occurrence and development of a variety of renal diseases. The role of exosomes involved in the interaction between Mϕ and TECs in IR-induced AKI is not fully defined. Based on the available results in the role of Mϕ and TECs in renal IR-induced AKI, this review discussed the role of Mϕ polarization and interaction with TECs in renal IR injury, as well as the participation of EPO and its receptors, properdin and exosomes.
  • Demographics, distribution and experiences of UK clinical academic trainees using GMC NTS Survey data

    Graham-Brown, Matthew; Carr, Sue (2022)
    Involvement in research plays an integral role in the delivery of high-quality patient care, benefitting doctors, patients and employers. It is important that access to clinical academic training opportunities are inclusive and equitable. To better understand the academic trainee population, distribution of academic posts and their reported experience of clinical training, we analysed 53 477 anonymous responses from General Medical Council databases and the 2019 National Training Survey. Academic trainees are more likely to be men, and the gender divide begins prior to graduation. There are very low numbers of international medical graduates and less than full-time academic trainees. A small number of UK universities produce a greater prevalence of doctors successfully appointed to academic posts; subsequent academic training also clusters around these institutions. At more senior levels, academic trainees are significantly more likely to be of white ethnicity, although among UK graduates, no ethnicity differences were seen. Foundation academic trainees report a poorer experience of some aspects of their clinical training placements, with high workloads reported by all academic trainees. Our work highlights important disparities in the demographics of the UK clinical academic trainee population and raises concerns that certain groups of doctors face barriers accessing and progressing in UK academic training pathways.
  • Impact of changing medical workforce demographics in renal medicine over 7 years: Analysis of GMC national trainee survey data

    Graham-Brown, Matthew; Carr, Sue (2021)
    Increasing numbers of doctors in training are taking career breaks, with burnout cited as a potential cause. This study analysed General Medical Council (GMC) national training survey data (renal medicine) to understand the impacts of changing workforce demographics on trainee outcomes and wellbeing. Increasing proportions of female, Black, Asian and minority ethnic (BAME), and international medical graduates are entering the workforce. Specialty exam pass rates have fallen and are lower for BAME and international medical graduates in renal medicine. Time to complete higher specialty training has increased for female trainees. Self-reported burnout rates for renal trainees were higher than other medical specialties and highest for male BAME trainees. Burnout was only partially mitigated by less-than-full-time working, but had no impact on progression, sick-leave or time out of training. It is important to recognise changes to the workforce and proactively plan to effectively support a more diverse group of trainees, to enable them to succeed and reduce differential attainment.
  • Clinical practice guideline exercise and lifestyle in chronic kidney disease

    March, Daniel; Wilkinson, Thomas; Billany, Roseanne; Graham-Brown, Matthew; Kanavaki, Archontissa; Lightfoot, Courtney; Smith, Alice; Burton, James (2022)
    No abstract available.
  • Patient and staff experiences of remote kidney healthcare: lessons learnt from COVID-19

    Lightfoot, Courtney; Wilkinson, Thomas; Palmer, Jared; Smith, Alice; Kanavaki, Archontissa (2022)
    No abstract available.
  • The impact of chronic kidney disease Stages 3-5 on pregnancy outcomes

    Brunskill, Nigel; Carr, Sue (2021-11)
    Background: Contemporaneous data are required for women with chronic kidney disease (CKD) Stages 3-5 to inform pre-pregnancy counselling and institute appropriate antenatal surveillance. Methods: A retrospective cohort study in women with CKD Stages 3-5 after 20 weeks' gestation was undertaken in six UK tertiary renal centres in the UK between 2003 and 2017. Factors predicting adverse outcomes and the impact of pregnancy in accelerating the need for renal replacement therapy (RRT) were assessed. Results: There were 178 pregnancies in 159 women, including 43 women with renal transplants. The live birth rate was 98%, but 56% of babies were born preterm (before 37 weeks' gestation). Chronic hypertension was the strongest predictor of delivery before 34 weeks' gestation. Of 121 women with known pre-pregnancy hypertension status, the incidence of delivery before 34 weeks was 32% (31/96) in women with confirmed chronic hypertension compared with 0% (0/25) in normotensive women. The risk of delivery before 34 weeks doubled in women with chronic hypertension from 20% [95% confidence interval (CI) 9-36%] to 40% (95% CI 26-56%) if the gestational fall in serum creatinine was <10% of pre-pregnancy concentrations. Women with a urinary protein:creatinine ratio >100 mg/mmol prior to pregnancy or before 20 weeks' gestation had an increased risk for birthweight below the 10th centile (odds ratio 2.57, 95% CI 1.20-5.53). There was a measurable drop in estimated glomerular filtration rate (eGFR) between pre-pregnancy and post-partum values (4.5 mL/min/1.73 m2), which was greater than the annual decline in eGFR prior to pregnancy (1.8 mL/min/1.73 m2/year). The effect of pregnancy was, therefore, equivalent to 1.7, 2.1 and 4.9 years of pre-pregnancy renal disease in CKD Stages 3a, 3b and 4-5, respectively. The pregnancy-associated decline in renal function was greater in women with chronic hypertension and in those with a gestational fall in serum creatinine of <10% of pre-pregnancy concentrations. At 1 year post-partum, 46% (58/126) of women had lost ≥25% of their pre-pregnancy eGFR or required RRT. Most women with renal transplants had CKD Stage 3 and more stable renal function prior to pregnancy. Renal transplantation was not independently associated with adverse obstetric or renal outcomes. Conclusions: Contemporary pregnancies in women with CKD Stages 3-5 are complicated by preterm delivery, low birthweight and loss of maternal renal function. Chronic hypertension, pre- or early pregnancy proteinuria and a gestational fall in serum creatinine of <10% of pre-pregnancy values are more important predictors of adverse obstetric and renal outcome than CKD Stages 3-5. Pregnancy in women with CKD Stages 3-5 advances the need for dialysis or transplantation by 2.5 years.
  • Novel approach to unpleasant symptom clusters surrounding pruritus in patients with chronic kidney disease and on dialysis therapy

    Burton, James (2022)
    Purpose of review: Chronic kidney disease-associated-pruritus (CKD-aP) is a common symptom in patients with end-stage kidney disease (ESKD) undergoing dialysis. CKD-aP typically occurs alongside other debilitating symptoms and may comprise so-called 'symptom clusters' which have synergistic effects that adversely impact patient health-related quality of life (HRQoL). Importantly, symptoms in a cluster may share a common biological mechanism. Here we review the clinical impact of CKD-aP and its association with other symptoms reported by dialysis patients. The clinical benefits of treating pruritus and its potential impact on other symptoms are also addressed. Recent findings: Studies have shown CKD-aP significantly impairs HRQoL in patients with ESKD undergoing dialysis and is associated with adverse clinical outcomes, including increased risk of infections, hospitalizations, and mortality. Despite these negative effects, CKD-aP remains underrecognized and undertreated in clinical practice. CKD-aP is frequently associated with other symptoms, including disturbed sleep/poor sleep quality, anxiety, depression, and pain. Clinical studies of antipruritic therapies show that reduction of itch intensity may also alleviate other associated symptoms, such as poor sleep quality. Summary: CKD-aP and its associated symptoms are inadequately managed in clinical practice. Greater understanding and awareness of CKD-aP and its surrounding symptom clusters in dialysis patients may improve their overall symptom management and HRQoL.
  • Inflammation and physical dysfunction: responses to moderate intensity exercise in chronic kidney disease

    Watson, Emma L; Wilkinson, Thomas; Graham-Brown, Matthew; Major, Rupert; Ashford, Robert; Smith, Alice (2021)
    Background: People with chronic kidney disease (CKD) experience skeletal muscle wasting, reduced levels of physical function and performance, and chronic systemic inflammation. While it is known that a relationship exists between inflammation and muscle wasting, the association between inflammation and physical function or performance in CKD has not been well studied. Exercise has anti-inflammatory effects, but little is known regarding the effect of moderate intensity exercise. This study aimed to (i) compare systemic and intramuscular inflammation between CKD stage G3b-5 and non-CKD controls; (ii) establish whether a relationship exists between physical performance, exercise capacity and inflammation in CKD; (iii) determine changes in systemic and intramuscular inflammation following 12 weeks of exercise; and (iv) investigate whether improving inflammatory status via training contributes to improvements in physical performance and muscle mass. Methods: This is a secondary analysis of previously collected data. CKD patients stages G3b-5 (n = 84, n = 43 males) and non-CKD controls (n = 26, n = 17 males) underwent tests of physical performance, exercise capacity, muscle strength and muscle size. In addition, a subgroup of CKD participants underwent 12 weeks of exercise training, randomized to aerobic (AE, n = 21) or combined (CE, n = 20) training. Plasma and intramuscular inflammation and myostatin were measured at rest and following exercise. Results: Tumour necrosis factor-α was negatively associated with lower $^{^{^{.}}}{\rm V}$O2Peak (P = 0.01), Rectus femoris-cross sectional area (P = 0.002) and incremental shuttle walk test performance (P < 0.001). Interleukin-6 was negatively associated with sit-to-stand 60 performances (P = 0.006) and hand grip strength (P = 0.001). Unaccustomed exercise created an intramuscular inflammatory response that was attenuated following 12 weeks of training. Exercise training did not reduce systemic inflammation, but AE training did significantly reduce mature myostatin levels (P = 0.02). Changes in inflammation were not associated with changes in physical performance. Conclusions: Systemic inflammation may contribute to reduced physical function in CKD. Twelve weeks of exercise training was unable to reduce the level of chronic systemic inflammation in these patients, but did reduce plasma myostatin concentrations. Further research is required to further investigate this.
  • Omicron neutralising antibodies after COVID-19 vaccination in haemodialysis patients

    Billany, Roseanne; Graham-Brown, Matthew (2022)
    No abstract available.
  • The novel allele HLA-DQA1*05:05:10 was detected in a Nigerian who also lacks the DRB5 gene in the DRB1*16 haplotype

    Bradshaw, Robert; Dunn, Paul (2022)
    One synonymous nucleotide substitution in exon 2 of DQA1*05:05:01:13 results in a novel allele, HLA-DQA1*05:05:10.
  • Primary skeletal muscle cells from chronic kidney disease patients retain hallmarks of cachexia in vitro

    Graham-Brown, Matthew; Major, Rupert; Ashford, Robert; Smith, Alice; Watson, Emma L (2022)
    Background: Skeletal muscle wasting and dysfunction are common characteristics noted in people who suffer from chronic kidney disease (CKD). The mechanisms by which this occurs are complex, and although progress has been made, the key underpinning mechanisms are not yet fully elucidated. With work to date primarily conducted in nephrectomy-based animal models, translational capacity to our patient population has been challenging. This could be overcome if rationale developing work could be conducted in human based models with greater translational capacity. This could be achieved using cells derived from patient biopsies, if they retain phenotypic traits noted in vivo. Methods: Here, we performed a systematic characterization of CKD derived muscle cells (CKD; n = 10; age: 54.40 ± 15.53 years; eGFR: 22.25 ± 13.22 ml/min/1.73 m2 ) in comparison with matched controls (CON; n = 10; age: 58.66 ± 14.74 years; eGFR: 85.81 ± 8.09 ml/min/1.73 m2 ). Harvested human derived muscle cells (HDMCs) were taken through proliferative and differentiation phases and investigated in the context of myogenic progression, inflammation, protein synthesis, and protein breakdown. Follow up investigations exposed HDMC myotubes from each donor type to 0, 0.4, and 100 nM of IGF-1 in order to investigate any differences in anabolic resistance. Results: Harvested human derived muscle cells isolated from CKD patients displayed higher rates of protein degradation (P = 0.044) alongside elevated expression of both TRIM63 (2.28-fold higher, P = 0.054) and fbox32 (6.4-fold higher, P < 0.001) in comparison with CONs. No differences were noted in rates of protein synthesis under basal conditions (P > 0.05); however, CKD derived cells displayed a significant degree of anabolic resistance in response to IGF-1 stimulation (both doses) in comparison with matched CONs (0.4 nm: P < 0.001; 100 nM: P < 0.001). Conclusions: In summary, we report for the first time that HDMCs isolated from people suffering from CKD display key hallmarks of the well documented in vivo phenotype. Not only do these findings provide further mechanistic insight into CKD specific cachexia, but they also demonstrate this is a reliable and suitable model in which to perform targeted experiments to begin to develop novel therapeutic strategies targeting the CKD associated decline in skeletal muscle mass and function.
  • Persistent hesitancy for SARS-CoV-2 vaccines among healthcare workers in the United Kingdom: analysis of longitudinal data from the UK-REACH cohort study

    Martin, Christopher; Carr, Sue; Nazareth, Joshua; Tobin, Martin; Pan, Daniel; Pareek, Manish (2022)
    No abstract available.
  • Rapidly progressive iga nephropathy: clinicopathological characteristics and outcomes assessed according to the revised definition of the KDIGO 2021 guideline

    Barratt, Jonathan (2022)
    Background: Rapidly progressive IgA nephropathy (RPIgAN) is a severe clinical phenotype of IgAN, associated with a poor outcome. The recently published KDIGO 2021 Guideline for the Management of Glomerular Diseases has proposed a new definition for RPIgAN, which is based simply on a ≥ 50% decline in eGFR ≤ 3 months. Methods: In 1,677 IgAN patients followed at a single centre in China, we evaluated the utility of this new definition to identify the highest risk IgAN patients who might be suitable for combination immunosuppressive therapy. Results: The proportion of a ≥ 50% decline in eGFR ≤ 3 months was 5.2%. The majority of these patients had reversible causes, only 2.3% (39/1,677) meeting the KDIGO 2021 criteria for RPIgAN. These patients had a significantly higher risk for ESKD than non-RPIgAN patients (log rank P < 0.001). RPIgAN was an independent risk factor for ESKD (hazard ratio [HR] 3.99; 95% confidence interval [CI] 2.25 - 7.09; P < 0.001). A minority of the RPIgAN patients (25.6%) had ≥ 50% crescents. There was no significant difference in the risk for ESKD between patients in the RPIgAN group with ≥ 50% crescents and ˂ 50% crescents (log rank P = 0.27). Patients with RPIgAN and ≥ 50% crescents had a higher risk for ESKD than patients with non-RPIgAN and ≥ 50% crescents (log rank P = 0.04). Conclusions: These data support the validity of the KDIGO 2021 definition but require independent validation in other non-Chinese cohorts.

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