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.

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.

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.

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.

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.

New insights into the epidemiologic and clinical manifestations of atherosclerotic renovascular disease.

Atherosclerotic renovascular disease (ARVD) continues to challenge the clinician as we enter the third millenium. ARVD frequently complicates patients with other vascular pathological states, and it is an increasingly common cause of end-stage renal failure. Although renovascular interventional procedures are now widely available and are of benefit to some patients with ARVD, a large proportion still progress to dialysis. Recent epidemiological investigations have emphasized the relationship between ARVD and other vascular diseases, and these are notable in patients with coronary artery disease and/or cardiac failure. Increased awareness of the possible coexistence of ARVD in patients with these latter conditions may allow earlier diagnosis and a minimization of complications (eg, angiotensin-converting enzyme inhibitor-related uremia or flash pulmonary edema). Contemporary studies also highlight the importance of intrarenal vascular and parenchymal injury in the cause of chronic renal failure in many patients with ARVD. Severe renal structural damage often coexists with proximal renal arterial narrowing, and this can explain the variability of renal functional outcomes known to accompany revascularization procedures. More appropriate selection of those patients likely to benefit from renovascular revascularization is now required. Large-scale trials that will identify the optimal approach to improving renal functional and survival outcomes in this high-risk group of patients are now long overdue.

Proteinuria in atherosclerotic renovascular disease.

Proteinuria is well described in atherosclerotic renovascular disease (ARVD), but the prevalence is unknown, and the pathogenesis may vary between patients. Substantial proteinuria (> 2 g/day) however, would be regarded by many as atypical of ARVD. We studied 94 patients (52 male) with ARVD, median age 67 years (range 49-87). Digital subtraction angiography was performed on all patients. Protein was assayed in 24-h urine samples and GFR derived using the Cockroft-Gault formula. Forty-nine patients (52%) had proteinuria < 0.5 g/24 h. Proteinuria increased with worsening renal function. Biopsies from seven non-diabetic patients with substantial proteinuria showed: minimal changes (1); glomerular sclerosis with marked ischaemic changes (3); focal glomerulosclerosis (2); and athero-emboli (1). Proteinuria, rather than being indicative of other pathology, is often a marker of severity of parenchymal disorder in atherosclerotic nephropathy, which itself is the major determinant of renal dysfunction in patients with ARVD.

Prostacyclin and iloprost do not affect action of standard dose heparin on haemostatic function during haemodialysis.

The actions of prostacyclin and iloprost, as supplements to heparin therapy, were examined by measuring indices of blood coagulation and platelet activation during the first two hours of haemodialysis in six patients with stable chronic renal failure. Patients received either prostacyclin 5 ng kg-1 min-1, iloprost 2 ng kg-1 min-1 or placebo at random on three separate occasions as a supplement to standard therapy with heparin 50 I.U. kg-1 loading dose and 30 I.U. kg-1 hr-1 infusion. Neither prostacyclin nor iloprost significantly affected dialysis induced changes in whole blood platelet count and plasma concentrations of beta thromboglobulin, (beta TG) platelet factor 4 (PF4), fibrinogen and fibrinopeptide A. Thus platelet count still fell by 12 +/- 8% within 15 min of the start of dialysis, slowly returning to the initial count over the study period and plasma PF4 increased nearly 10 fold over the same time. In addition, serial measurements of KCCT failed to indicate any sparing effect of the prostanoids on this dose of heparin.

Mesangioproliferative glomerulonephritis associated with retinitis pigmentosa.

Two patients with retinitis pigmentosa and glomerulonephritis are described. The patients were unrelated and had identical renal lesions, mesangioproliferative glomerulonephritis. This may not be a chance association, and simple dip-stick urine analysis in patients with primary retinal degenerations may lead to earlier identification of renal disease.

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.

Carbamazepine-induced acute granulomatous interstitial nephritis.

A 79-year-old man, newly started on carbamazepine, presented with rash, eosinophilia and liver dysfunction progressing to acute renal failure despite discontinuation of the anti-epileptic agent. Percutaneous renal biopsy revealed acute granulomatous interstitial nephritis, which responded successfully to high-dose oral steroid therapy.

Nephrotic-range proteinuria associated with right atrial myxoma.

A case of right atrial myxoma presenting with right heart failure and proteinuria is described. Proteinuria was variable and this corresponded with the degree of systemic venous congestion. On one occasion the proteinuria was within the nephrotic range. There was no evidence of intrinsic renal pathology. The right heart failure and proteinuria resolved after tumour removal, suggesting that the etiology of urinary protein loss was a reversible increase in glomerular permeability.

Isolated sarcoid granulomatous interstitial nephritis: review of five cases at one center.

AIMS: To identify any clinical or biochemical parameters which determine prognostic outcome in isolated sarcoid granulomatous interstitial nephritis presenting with renal failure. METHODS: A review of five cases of renal failure due to isolated sarcoid granulomatous interstitial nephritis, which presented to Hope Hospital over the 7-year period 1994 to 2000. Follow-up averaged 35 months with a range of 11 to 73 months. RESULTS: Only one patient had an elevated serum ACE at presentation, reflecting the suboptimal sensitivity of this test as a marker in sarcoidosis and the limited extent of disease in these patients. Four of the five cases had a marked improvement in creatinine clearance within 10 days of starting oral prednisolone. Two patients required acute hemodialysis on presentation. Their renal failure responded to treatment with steroids, enabling withdrawal of dialysis within 10 days. All patients remained dialysis-independent although serum creatinine levels rose during follow-up. One patient experienced a relapse that responded to an increased dose of steroid. CONCLUSIONS: Serum ACE is not reliable in the diagnosis of renal failure due to sarcoid interstitial nephritis and the diagnosis can only be made on renal biopsy. First-line treatment with oral prednisolone results in a rapid improvement in creatinine clearance although prolonged treatment may be needed to prevent a relapse.

Increasing the diagnostic yield of renal angiography for the diagnosis of atheromatous renovascular disease.

Atheromatous renovascular disease (ARVD) is a common cause of hypertension and chronic renal failure (CRF). In this unit, intravenous digital subtraction angiography (DSA) (or intraarterial DSA if indicated) is used as a screening angiographic study when ARVD is suspected. However, increased use of these investigations has resulted in a longer waiting time for angiography. As the majority of studies are negative for ARVD, clinical features and results of investigations of patients undergoing angiography were reviewed to identify those having the greatest likelihood of ARVD. The clinical notes were reviewed for all 249 patients undergoing angiography over an 18-month period. Primary indications for investigation were: hypertension 71 (28.5%), CRF 156 (62.7%) and CRF with severe hypertension 22 (8.8%). 12 of the CRF patients had end-stage renal failure. 166 (66.7%) patients had no evidence of ARVD, while only 83 (33.3%) patients showed some degree of ARVD, 29 (35%) of which had bilateral renal artery disease. There was no significant difference between the ARVD group and the non-ARVD group for mean age (69.0 years vs 63.3 years), male to female ratio, history of smoking (68.7% vs 55.4%), severe hypertension (10.8% vs 9.0%), hypercholesterolaemia (61.4% vs 47.0%), diabetes mellitus (28.6% vs 25.3%) or angiotensin converting enzyme inhibitor-related renal dysfunction (9.6% vs 6.1%). More patients in the ARVD group were investigated for CRF than in the non-ARVD group, as reflected by the higher serum creatinine level and the lower creatinine clearance in the ARVD group. 55 (33.1%) of the non-ARVD patients had no comorbid vascular disease, vascular bruits or ultrasound discrepancy in the size of the two kidneys, whereas all ARVD patients had at least one of these features (negative predictive value 100%). All three features were present in 19.3% of ARVD patients but in only 3.0% of the non-ARVD patients (positive predictive value 76.2%, specificity 97%). We plan to rationalize the criteria for angiography in the light of these findings, anticipating an increase in the diagnostic yield of renal angiography from its current 33.3% to above 42%.