The effect of a novel, digital physical activity and emotional well-being intervention on health-related quality of life in people with chronic kidney disease: trial design and baseline data from a multicentre prospective, wait-list randomised controlled trial (kidney BEAM).

BACKGROUND: Physical activity and emotional self-management has the potential to enhance health-related quality of life (HRQoL), but few people with chronic kidney disease (CKD) have access to resources and support. The Kidney BEAM trial aims to evaluate whether an evidence-based physical activity and emotional wellbeing self-management programme (Kidney BEAM) leads to improvements in HRQoL in people with CKD. METHODS: This was a prospective, multicentre, randomised waitlist-controlled trial, with health economic analysis and nested qualitative studies. In total, three hundred and four adults with established CKD were recruited from 11 UK kidney units. Participants were randomly assigned to the intervention (Kidney BEAM) or a wait list control group (1:1). The primary outcome was the between-group difference in Kidney Disease Quality of Life (KDQoL) mental component summary score (MCS) at 12 weeks. Secondary outcomes included the KDQoL physical component summary score, kidney-specific scores, fatigue, life participation, depression and anxiety, physical function, clinical chemistry, healthcare utilisation and harms. All outcomes were measured at baseline and 12 weeks, with long-term HRQoL and adherence also collected at six months follow-up. A nested qualitative study explored experience and impact of using Kidney BEAM. RESULTS: 340 participants were randomised to Kidney BEAM (n = 173) and waiting list (n = 167) groups. There were 96 (55%) and 89 (53%) males in the intervention and waiting list groups respectively, and the mean (SD) age was 53 (14) years in both groups. Ethnicity, body mass, CKD stage, and history of diabetes and hypertension were comparable across groups. The mean (SD) of the MCS was similar in both groups, 44.7 (10.8) and 45.9 (10.6) in the intervention and waiting list groups respectively. CONCLUSION: Results from this trial will establish whether the Kidney BEAM self management programme is a cost-effective method of enhancing mental and physical wellbeing of people with CKD. TRIAL REGISTRATION: NCT04872933. Registered 5th May 2021.

A multicentre prospective double blinded randomised controlled trial of intravenous iron (ferric Derisomaltose (FDI)) in Iron deficient but not anaemic patients with chronic kidney disease on functional status.

BACKGROUND: Iron deficiency (ID) is common in patients with chronic kidney disease (CKD). Intravenous (IV) iron in heart failure leads to improvement in exercise capacity and improvement in quality-of-life measurements; however, data in patients with CKD are lacking. METHODS: The Iron and the Heart Study was a prospective double blinded randomised study in non-anaemic CKD stages 3b-5 patients with ID which investigated whether 1000 mg of IV iron (ferric derisomaltose (FDI)) could improve exercise capacity in comparison to placebo measured at 1 and 3 months post infusion. Secondary objectives included effects on haematinic profiles and haemoglobin, safety analysis and quality of life questionnaires (QoL). RESULTS: We randomly assigned 54 patients mean (SD) age for FDI (n = 26) 61.6 (10.1) years vs placebo (n = 28; 57.8 (12.9) years) and mean eGFR (33.2 (9.3) vs. 29.1 (9.6) ml/min/1.73m2) at baseline, respectively. Adjusting for baseline measurements, six-minute walk test (6MWT) showed no statistically significant difference between arms at 1 month (p = 0.736), or 3 months (p = 0.741). There were non-significant increases in 6MWT from baseline to 1 and 3 months in the FDI arm. Haemoglobin (Hb) at 1 and 3 months remained stable. There were statistically significant increases in ferritin (SF) and transferrin saturation (TSAT) at 1 and 3 months (p < 0.001). There was a modest numerical improvement in QoL parameters. There were no adverse events attributable to IV iron. CONCLUSION: This study demonstrated a short-term beneficial effect of FDI on exercise capacity, but it was not significant despite improvements in parameters of iron status, maintenance of Hb concentration, and numerical increases in functional capacity and quality of life scores. A larger study will be required to confirm if intravenous iron is beneficial in iron deficient non-anaemic non-dialysis CKD patients without heart failure to improve the 6MWT. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT) No: 2014-004133-16 REC no: 14/YH/1209 Date First Registered: 2015-02-17 and date of end of trail 2015-05-23 Sponsor ref R1766 and Protocol No: IHI 141.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell-related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group-namely, the tolerant recipients-were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross-validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Potential for biomarkers of chronic kidney disease-mineral bone disorder to improve patient care.

Chronic kidney disease (CKD) is a growing public health problem. Cardiovascular disease is common in CKD, but standard risk assessment tools perform poorly in this population. Equally, despite CKD being associated with an increased risk for death and dialysis, standard biochemical measurements have limited prognostic value. Novel serum biomarkers may aid risk assessment; however, studies have shown varying clinical utility in relation to progression of CKD, incident cardiovascular disease and death. This inconsistency may relate to limitations in our understanding of the biological actions and interactions of these biomarkers. This review discusses a range of biomarkers in relation to these clinical endpoints in CKD-mineral bone disorder. We consider where biomarkers may enhance risk stratification and improve clinical management, but also highlight where they fall short of achieving this objective.

Associations of baseline characteristics with evolution of eGFR in a referred chronic kidney disease cohort.

BACKGROUND: Currently, most chronic kidney disease (CKD) classifications identify patients at different stages of CKD but do not identify risk of progression or adverse outcome. This analysis aims to describe associations between baseline characteristics and the evolution of estimated glomerular filtration rate (eGFR) and identify threshold values for clinical parameters that maximally discriminate progression to renal replacement therapy (RRT) in a referred cohort of patients with CKD stages 3-5. DESIGN AND METHODS: A longitudinal mixed-effect model was used to determine annualized estimated change in eGFR and classification tree analysis to identify threshold values that maximally discriminate progression to RRT. RESULTS: A total of 1316 patients were available for analysis with median follow-up of 33 months (interquartile range 20-60). Mixed model analysis suggested that the underlying diagnoses of autosomal dominant polycystic kidney disease and diabetic nephropathy exhibited on average a 2.7 (0.3) and 0.7 (0.3) ml/min/year faster rate of decline in eGFR, respectively, compared to those patients with biopsy-proven glomerulonephritis. In the regression tree analysis, we attempted to identify threshold values for clinical parameters that maximally discriminate progression to RRT. eGFR ≤24 ml/min was the first ranked discriminator, diastolic blood pressure appeared in the second and fourth rounds, eGFR appeared again in the third round together with cholesterol and systolic blood pressure, with basal metabolic index in the fourth. CONCLUSION: This analysis highlights risk factors for progressive kidney disease and demonstrates the variability in evolution of eGFR across the cohort as well as the importance of underlying renal disease type on the progression of CKD.

Accelerated total dose infusion of low molecular weight iron dextran is safe and efficacious in chronic kidney disease patients.

BACKGROUND: Low molecular weight iron dextran (LMWID) is licensed for use as a total dose infusion (TDI) over 4-6 h. In order to improve patient convenience and cost-effectiveness of therapy, we investigated the safety and efficacy of adopting accelerated dosing regimens and compared this with a standard rate LMWID infusion. METHODS: A retrospective study of patients undergoing accelerated and standard rate TDI of LMWID was conducted across three centres. A total of 1904 doses of LMWID were administered at an accelerated rate of 1 g over 1 h 40 min. This was compared with 395 patients who had standard rate infusion of 1 g LMWID over 3-4 h. RESULTS: There were eight minor adverse events in patients receiving accelerated dose LMWID (8/1904, 0.42%) in comparison to one adverse event in patients receiving a standard regimen (1/395, 0.25%). No serious adverse events occurred. Serum haemoglobin and ferritin significantly improved in both groups. CONCLUSION: TDI LMWID is a safe and efficacious method of iron replacement. Accelerated infusion regimen is safe and compares well with standard rate infusion regimen. Furthermore, accelerated TDI of LMWID enables greater numbers of patients to be treated and consequently there appear to be advantages for both patient and health resources.

Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA): a randomized double-blind placebo-controlled trial of high- vs. low-dose atorvastatin(1).

AIMS: To compare the renal effects of low- vs. high-dose atorvastatin in patients with Type 2 diabetes mellitus and optimally managed early renal disease. METHODS: We compared the 2-year progression of nephropathy in a double-blind randomized controlled trial of atorvastatin 80 mg/day (n = 60) vs. 10 mg/day (n = 59) in patients with Type 2 diabetes with microalbuminuria or proteinuria [mean (sd): age 64 years (10 years); HbA(1c) 7.7% (1.3%), 61 mmol/mol (10 mmol/mol); blood pressure 131/73 mmHg; renin-angiotensin system blocker use > 80%; dual blockade > 67%] recruited from diabetes clinics in Greater Manchester. RESULTS: Over (mean) 2.1 years of follow-up, the Modification of Diet in Renal Disease estimated glomerular filtration rate declined by 3 ml min(-1) 1.73 m(-2) in the combined group. The mean (95% CI) between-group difference during follow-up was not significant [2.2 ml min(-1) 1.73 m(-2) (-1.1 to 5.4 ml min(-1) 1.73: m(-2) ), P = 0.20] after adjusting for baseline differences in renal function; positive difference favours 80 mg dose. Similarly, there was no significant difference in creatinine clearance by Cockcroft and Gault [2.5 ml/min (-2.4 to 7.3 ml/min), P = 0.32]; serum creatinine/24-h urine collections [4.0 ml/min (-4.8 to 12.7 ml/min), P = 0.38]; cystatin C (P = 0.69); or 24-h urine protein or albumin excretion (P = 0.92; P = 0.93). We recorded no significant between-group differences in deaths or adverse events. CONCLUSIONS: In patients with Type 2 diabetes with early renal disease, we found no statistical difference in renal function between those taking high- or low-dose atorvastatin over 2 years. We cannot exclude a beneficial effect of < 1.6 ml min(-1) 1.73 m(-2) year(-1) on Modification of Diet in Renal Disease estimated glomerular filtration rate, or if blood pressure management or if renin-angiotensin system blocker use had not been optimized.

Proteinuria as a predictor of renal functional outcome after revascularization in atherosclerotic renovascular disease (ARVD).

BACKGROUND: Renal revascularization is performed in 16% of newly diagnosed patients with atherosclerotic renovascular disease (ARVD). Although there may be some improvement in hypertension control as a result of intervention, renal functional outcomes are known to vary. Pre-existing renal parenchymal injury, as manifested by proteinuria, is associated with poor functional outcome in conservatively managed ARVD patients, but this association has not been investigated in patients undergoing revascularization. METHODS: Retrospective case note review of 83 ARVD patients who underwent renal revascularization in four centres within a renal network between 1998 and 2003 was undertaken. Amongst other parameters, baseline proteinuria was correlated with renal functional outcome post revascularization. Renal functional outcome was determined over a mean follow up of 22 months by rate of change of estimated glomerular filtration rate (eGFR) over time. RESULTS: Univariate analysis showed that proteinuria >0.6 g/day was the only significant predictor of poor outcome after revascularization. The relationship persisted with multivariate analysis, and linear regression showed a correlation between baseline proteinuria and decline in eGFR with time (r(2) = 0.058, P = 0.039). CONCLUSION: This study confirms that prior renal parenchymal injury, here reflected by proteinuria at baseline, is a major arbiter of renal functional outcome after renal revascularization in ARVD.

Magnetic resonance imaging: advances in the investigation of atheromatous renovascular disease.

Prediction of renal functional outcome following revascularization procedures in atheromatous renovascular disease (ARVD) has remained a challenge. In considering the etiology of renal impairment, researchers have shifted their focus now from the influence of degree of renal artery stenosis (RAS) to the importance of intrinsic parenchymal damage caused by hypertension, atheroemboli, downstream cytokine and/or cholesterol crystal release, as well as indicators of tissue viability. Magnetic resonance (MR) imaging techniques and MR-based indices are able to provide a detailed assessment of the morphologic and functional aspects of the ARVD kidney. These indices look beyond "lumenology" and enable a better understanding of the parenchyma's physiology which may provide insight into predictors of outcome. This review summarizes the multipurpose benefits of MR in the assessment of ARVD.

Importance of checking anti-glomerular basement membrane antibody status in patients with anti-neutrophil cytoplasmic antibody-positive vasculitis.

The case is reported of a 68-year-old man with perinuclear anti-neutrophil cytoplasmic antibody (pANCA)-associated glomerulonephritis who developed antibodies to glomerular basement membrane (anti-GBM) resulting in end stage renal failure. His pANCA titre on admission was 1:1024 IgG and he was anti-myeloperoxidase positive. A renal biopsy showed advanced sclerosing necrotising glomerulonephritis consistent with a pauci-immune ANCA-positive glomerulonephritis. He was treated with steroids and cyclophosphamide. His serum creatinine profile improved. He had a relapse of disease 16 months later, which was successfully treated. After a further 16 months, he presented with acute renal failure (creatinine 1060 micromol/l). His pANCA titre on admission was 1:64 IgG. This was treated as a further relapse of ANCA-positive vasculitis. He became oliguric and his haemoglobin concentration fell. Eight days after admission, he was found to be strongly positive for anti-GBM (138 U/ml). Despite receiving cyclophosphamide, steroids and plasma exchange, he remained dialysis-dependent.

Renal specific secondary hypertension.

Chronic kidney disease (CKD) is now understood to affect over 5% of all adult patients and it conveys a risk of reduced survival in those affected. At least 80% of those patients with stages 3-5 CKD (i.e. GFR <60 ml/min) suffer with hypertension, and in most the major cause is due to pertubation of an important renal endocrine system, the renin-angiotensin-aldosterone (RAA) axis. In this article the epidemiology of renal-related hypertension and its importance in pre-disposing to the increased cardiovascular risk in renal disease are discussed. Hypertension is known to be a major cause of progressive loss of renal function in CKD, particularly because of activation of the RAA, and hence the case for blockade of this system with ACE inhibitors and Angiotensin receptor blockers is highlighted.

Angioplasty and STent for Renal Artery Lesions (ASTRAL trial): rationale, methods and results so far.

Atherosclerotic renovascular disease (ARVD) is a relatively common condition which may lead to progressive renal dysfunction, and eventually to end-stage renal failure. Revascularization has been used in an attempt to prevent progression of ARVD, despite a lack of evidence for a benefit on kidney function. Therefore, large-scale randomized trials are needed to determine reliably whether or not there is any worthwhile benefit. The Angioplasty and STent for Renal Artery Lesions (ASTRAL) trial comparing renal function in ARVD patients randomized to either revascularization or medical management alone was designed to provide this evidence. ASTRAL started recruiting in November 2000 and, as of the end of 2006, 731 patients have been randomized into the trial (19 patients short of its minimum target of 750 patients). A pooled analysis (not split by treatment arm) of all patients shows that serum creatinine increased in the first 6 months then remained relatively steady, whereas blood pressure has decreased from baseline. The trial is due to close to recruitment in April 2007, with the first presentation of the results of the randomized treatment comparison planned for the spring of 2008. To date ASTRAL is by far the largest randomized trial in ARVD, and will provide the most reliable and timely evidence on the role, if any, of revascularization in ARVD with which to guide the treatment of future patients.

Prevalence of hypogonadism in male patients with renal failure.

BACKGROUND: Hypogonadism in men may be secondary to renal failure and is well recognised in patients with end-stage renal disease. It is thought to contribute to the sexual dysfunction and osteoporosis experienced by these patients. However, the association between hypogonadism and lesser degrees of renal dysfunction is not well characterised. METHODS: The gonadal status of 214 male patients (mean age 56 (SD 18) years) attending a renal centre was studied; 62 of them were receiving haemodialysis and 22 continuous ambulatory peritoneal dialysis for end-stage renal disease, whereas 34 patients had functioning renal transplants and 96 patients were in the low-clearance phase. Non-fasting plasma was analysed for testosterone, follicle-stimulating hormone, luteinising hormone, sex hormone-binding globulin, parathyroid hormone and haemoglobin. Creatinine clearance was estimated in patients not on dialysis, and Kt/V and urea reduction ratio were assessed in patients on dialysis. Testosterone concentrations were classified as normal (>14 nmol/l), low-normal (10-14 nmol/l) or low (<10 nmol/l). RESULTS: 56 (26.2%) patients had significantly low testosterone levels and another 65 (30.3%) had low-normal levels. No significant changes were seen in sex hormone-binding globulin or gonadotrophin levels. Gonadal status was not correlated with haemoglobin level, parathyroid hormone level, creatinine clearance, or dialysis duration or adequacy. CONCLUSION: Over half of patients with renal failure, even in the pre-dialysis phase, have low or low-normal levels of testosterone, which may be a potentially reversible risk factor for osteoporosis and sexual dysfunction. These patients may be candidates for testosterone-replacement therapy, which has been shown to improve bone mineral-density and libido in men with low and low-normal testosterone levels.

MR-derived renal morphology and renal function in patients with atherosclerotic renovascular disease.

Appropriate selection of patients with atherosclerotic renovascular disease (ARVD) for revascularization might be improved if accurate non-invasive investigations were used to assess severity of pre-existing parenchymal damage. The purpose of this study was to evaluate the associations between magnetic resonance imaging (MRI)-measured renal morphological parameters and single-kidney glomerular filtration rate (GFR) in ARVD. Three-dimensional (3D)-MRI was performed on 35 ARVD patients. Renal bipolar length (BL), parenchymal volume, parenchymal (PT), and cortical thicknesses (CT) were measured in 65 kidneys. Thirteen kidneys were supplied by normal vessels, 13 had insignificant (<50%) renal artery stenosis (RAS), 33 significant (>or=50%) RAS, and six complete vessel occlusion. All patients underwent radioisotopic measurement of single-kidney GFR (isoSK-GFR). Overall, 3D parameters such as parenchymal volume were better correlates of isoSK-GFR (r=0.86, P<0.001) than BL (r=0.78, P<0.001), PT (r=0.63, P<0.001) or CT (r=0.60, P<0.001). Kidneys with >or=50% RAS did show significant reduction in mean CT compared to those supplied by normal vessel (5.67+/-1.63 vs 7.28+/-1.80 mm, P=0.002; 22.1% reduction) and an even greater loss of parenchymal volume (120.65+/-47.15 vs 179.24+/-86.90 ml, P<0.001; 32.7% reduction) with no significant reduction in BL. In a proportion of >or=50% RAS kidneys, a disproportionately high parenchymal volume to isoSK-GFR was observed supporting a concept of 'hibernating parenchyma'. 3D parameters of parenchymal volume are stronger correlates of isoSK-GFR than two-dimensional measures of BL, PT or CT. 3D morphological evaluation together with isoSK-GFR might be useful in aiding patient selection for renal revascularization. Kidneys with increased parenchymal volume to SK-GFR might represent a subgroup with the potential to respond beneficially to angioplasty.

Severe acute renal failure in adults: place of care, incidence and outcomes.

BACKGROUND: Department of Health guidelines recommend specialist critical care facilities for patients with severe single-organ failure such as acute renal failure (ARF). Prospective studies examining incidence, causes and outcomes of ARF outside of intensive care settings are lacking. AIM: To determine the incidence, causes, place of care and outcomes of severe single-organ ARF. DESIGN: Prospective observational study. METHODS: For 6 weeks in June-July 2003, renal physicians were contacted daily, and ICUs on alternate days, to identify cases of severe single-organ ARF in the Greater Manchester area. All patients with serum creatinine >or=500 micromol/l and not requiring other organ support were included. Patients with end-stage renal disease were excluded. Survivors were followed up at 90 days and 1 year from admission. Two independent consultant nephrologists assessed each case using anonymized summaries. RESULTS: Eighty-five patients had multi-organ ARF and 28 had severe single-organ ARF (380 and 125 pmp/year, respectively). Of those with single-organ ARF, 10 (36%) had known pre-existing chronic kidney disease. Renal replacement therapy (RRT) was required in 15 (54%). Total bed occupancy on ICUs relating to single-organ ARF was 59 days (range per patient 1-21). At 90 days, 18 (64%) were alive, and 17 (94%) had independent renal function. At 1 year, 4/18 had died, none receiving RRT at the time of death. Survivors all had independent renal function. In 13 (46%) cases there was an unacceptable delay in patient transfer and in 7 (25%), delays in assessment or commencement of RRT may have adversely affected patient outcome. DISCUSSION: The incidence of ARF treated with RRT is rising. Delays in transfer to renal services may result in inappropriate ICU bed use, and may adversely affect patient outcomes. There are serious problems regarding the appropriate use of expensive and limited medical resources in the critical care area, and in providing safe and effective treatment of patients with ARF.

The importance of associated extra-renal vascular disease on the outcome of patients with atherosclerotic renovascular disease.

Atherosclerotic renovascular disease (ARVD) is a disease of ageing. It is usually a manifestation of widespread vascular disease and although it may be symptomless, many patients with ARVD present with the effects of extra-renal vascular disease, such as peripheral vascular (PVD), coronary heart (CHD) and cerebrovascular disease. ARVD is a common cause of hypertension and chronic renal failure (CRF), and it is one of the most common renal diagnoses in elderly patients accepted on to dialysis programmes with end-stage renal failure (ESRF). The cause of renal impairment in these patients is still a matter of debate. Patients with ARVD have a high mortality, especially those with renal failure. In this review we examine the relationships between ARVD and co-morbid extra-renal vascular disease, and the impact of these associated vascular pathologies upon renal functional and mortality outcomes is considered. The latest evidence concerning the likely pathogenesis of renal dysfunction in patients with ARVD is also reviewed.