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.

Time-dependent lipid profile inversely associates with mortality in hemodialysis patients - independent of inflammation/malnutrition.

BACKGROUND: Patients with end-stage kidney disease have an extremely high cardiovascular mortality rate, but there is a paradoxical relationship between lipid profile and survival in haemodialysis patients. To investigate whether inflammation/malnutrition confounds the associations between lipids and mortality, we studied a full lipid profile comprising of five clinically well-established lipid parameters and its associations with mortality in a large, multinational European cohort with a median follow-up >3 years. METHODS: The association between quartiles of total, high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL) cholesterol, as well as triglyceride, levels and the end-points of all-cause, cardiovascular and non-cardiovascular mortality was assessed in a cohort of 5,382 incident, adult haemodialysis patients from >250 Fresenius Medical Care dialysis centres out of 14 participating countries using baseline and time-dependent Cox models. Analyses were fully adjusted and stratified for inflammation/malnutrition status and other patient-level variables. RESULTS: Time-dependent quartiles of total, HDL, non-HDL and LDL cholesterol were inversely associated with the hazard for all-cause, cardiovascular and non-cardiovascular mortality. Compared with the lowest quartile of the respective lipid parameter, hazard ratios of other quartiles were <0.86. Similar, albeit weaker, associations were found with baseline lipid profile and mortality. Neither time-dependent nor baseline associations between lipid profile and mortality were affected by inflammation/malnutrition, statin use or geography. CONCLUSIONS: Baseline and time-dependent lipid profile are inversely associated with mortality in a large, multicentre cohort of incident haemodialysis patients. Inflammation/malnutrition is not a confounder nor effect modificator of the associations between lipid profile and mortality in European haemodialysis patients.

The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure?

BACKGROUND: Considerable evidence suggests that hyperhomocysteinemia is an independent vascular risk factor that promotes atherosclerosis by inducing endothelial dysfunction. Although folic acid reduces hyperhomocysteinemia, the effect on adverse vascular events is unknown. We hypothesized that in patients with chronic renal failure, a condition associated with both hyperhomocysteinemia and atherosclerosis, treatment with folic acid would improve endothelial function. METHODS AND RESULTS: In a prospective, double-blind protocol, 100 patients (mean age 62 years, 67 men) with predialysis chronic renal failure were randomized to 5 mg folic acid or placebo daily for 12 weeks. Endothelial function was assessed by measuring (1) endothelium-dependent dilation of the brachial artery, (2) combined serum nitrite/nitrate concentrations, and (3) plasma von Willebrand factor concentration. Baseline characteristics of the 2 groups were similar. At the end of the study, both serum and red cell folate concentrations were greater in the folic acid group than the placebo group [mean (95% CI) 39.0 (29.8 to 51.0) versus 7.7 (6.6 to 8.9) microg/L and 739 (613 to 891) versus 220 (184 to 262) microg/L, respectively; both P<0.001]. Despite a reduction in hyperhomocysteinemia in the folic acid group compared with the placebo group [15.1 (14.1 to 16.2) versus 20.1 (18.2 to 22.2) micromol/L; P<0.001], there were no significant differences in endothelium-dependent dilation, combined serum nitrite/nitrate concentrations, or plasma von Willebrand factor concentration between the 2 groups. CONCLUSIONS: High-dose folic acid lowers but fails to normalize hyperhomocysteinemia in patients with predialysis chronic renal failure. This was not accompanied by an improvement of endothelial function and suggests that treatment with folic acid may not reduce the burden of vascular disease in uremia.

A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease.

OBJECTIVES: This study was designed to determine the effects of folic acid therapy on endothelial function in patients with coronary artery disease (CAD). BACKGROUND: Hyperhomocysteinemia, a risk factor for CAD, may cause atherosderosis by oxidative endothelial injury. Folic acid reduces plasma homocysteine, but the effect on adverse vascular events is unknown. METHODS: In a double-blind placebo-controlled trial, 90 patients (mean age [range] 63 [46 to 79] years, 79 men) with CAD were randomized to either folic acid 5 mg or placebo daily for 12 weeks. Endothelial function was assessed by measuring: 1) flow-mediated endothelium-dependent dilation (EDD) of the brachial artery; 2) combined serum nitrite/nitrate (NOx) concentrations and; 3) plasma von Willebrand factor (vWF) concentration. RESULTS: At the end of the study, plasma homocysteine was lower in the folic acid group compared with the placebo group (mean [95% confidence interval] 9.3 (8.5 to 10.1) vs. 12.3 [11.3 to 13.4] micromol/l, p < 0.001). Although there were no significant differences in EDD, serum NOx or plasma vWF between the two groups, there was a greater increase in EDD from baseline in the folic acid group compared to placebo (1.2 [0.7 to 1.8] vs. 0.4 [-0.3 to 1.1]%, p = 0.07). CONCLUSIONS: Folic acid reduced plasma homocysteine and was associated with a trend toward improved endothelial function in patients with CAD. The absence of an unequivocally positive result may have been due to inadequate sample size or chance. This reinforces the need for the results of large randomized controlled trials before the implementation of routine folic acid supplementation.

Glomerular structures and lipids in progressive renal disease.

In the last few years, remarkable advances have been made in the understanding of lipoprotein metabolism in the pathogenesis of renal disease in animal models and in vitro cell culture. Central to this work is the problem of the progression of renal disease in humans. This review recapitulates the theory (Lancet 1982; II: 1309-1312) that the progression of disease depends in part on the damage inflicted on the glomerulus by lipoproteins. The glomerular environment of high or low pressure, basement membrane damage, and destruction or damage of the mesangial and epithelial cells permits the filtration of protein, the consequence of which is hyperlipidemia. Whatever the therapeutic measures employed, if proteinuria persists, hyperlipidemia will follow. This suggest that lipoprotein toxicity may contribute to the final common path of renal damage in progressive renal disease. "Lipoprotein toxicity" in arteries is called atherosclerosis, but this term ignores the complexity of the glomerulus and the possible tubular damage that might be caused by filtered lipoprotein. It is clear there is insufficient knowledge of the metabolism of the damaged kidney to confidently attribute the pathology of progression of disease to any single process.

Evolution and etiology of cardiovascular diseases in renal transplant recipients.

The mortality rates for CVDs in transplant recipients are greater than those in the general population (13). CVDs are a major cause of both patient and graft loss in renal transplant recipients, and improving cardiovascular health may help to extend both patient and graft survival. A complication of chronic renal failure, CVDs are frequently present in patients being considered for transplantation. Pretransplant screening, based on risk stratification, may detect pre-existing disease and identify patients likely to benefit from therapeutic strategies designed to reduce CVDs prevalence. Further studies are needed to better define the risk factors for CVDs in the renal transplant population and to evaluate the effectiveness of risk modification on the related morbidity and mortality. Risk-factor management initiated early in the course of chronic renal failure might reduce the burden of CVDs in both dialysis and transplant populations.

Are there potential non-lipid-lowering uses of statins?

Recent clinical trials have demonstrated beyond doubt that statins are effective in the prevention of acute coronary events. Critical analysis of these studies suggests that the benefits of statin therapy cannot be fully explained on the basis of reductions in plasma cholesterol levels. Accumulating knowledge of the actions of these drugs shows that they may prevent several processes that eventually lead to plaque rupture and the development of occlusive thrombosis, the basis of acute coronary events. Hence, statins may correct endothelial dysfunction (thus protecting against ischaemic injury), stabilise existing plaques and modify the coagulation pathway, thereby reducing the likelihood of a sudden vascular event. At a cellular level, these drugs inhibit the synthesis not just of cholesterol, but of other compounds important in cell proliferation. Antiproliferative effects have been demonstrated in vitro and may broaden the applications of statins to the treatment of noncardiovascular diseases. Finally, preliminary clinical studies indicate that as a result of immunosuppressive actions, statins may reduce the incidence of rejection following organ transplantation.

Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment.

Patients with chronic renal impairment (CRI) are at greatly increased risk for premature vascular disease; however, little is known about its evolution. This paper describes a cohort of patients with CRI and reports study design, baseline demographic and biochemical data, and comparisons with two contemporaneous age- and sex-matched control groups, one with established coronary artery disease and the other without overt vascular disease. Among 369 individuals (median age, 63 years; range, 18 to 88 years; 67% men) with CRI, 34% had a history of vascular disease and 21% had electrocardiographic left ventricular hypertrophy (LVH). Even in those with mild renal impairment (serum creatinine < 2.1 mg/dL), approximately one third had vascular disease and 12% had LVH. A history of hypertension was present in 76% of the CRI group, but as compared with controls, systolic and diastolic blood pressures were not elevated. Low-density lipoprotein (LDL) cholesterol concentration also was not elevated, but CRI was associated with elevated serum triglyceride and plasma homocysteine levels and reduced high-density lipoprotein (HDL) cholesterol, hemoglobin, and serum albumin concentrations. Across the spectrum of CRI, more severe renal dysfunction was associated with lower levels of diastolic blood pressure, LDL and HDL cholesterol, albumin, and hemoglobin, but increased levels of plasma homocysteine. This cross-sectional analysis shows that vascular disease is common in individuals with mild CRI attending a nephrology program and also suggests trends in the levels of a number of potential vascular risk factors with respect to severity of renal dysfunction. These results will be further quantified in a prospective biennial follow-up.

Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis.

We report ten patients with rheumatoid arthritis (RA) who developed a focal segmental necrotizing glomerulonephritis (FSNGN) and extracapillary proliferation typical of vasculitic glomerulonephritis. Five patients also had extrarenal vasculitis. Renal presentation was with renal impairment (n = 9) (median creatinine 726 mumol/l, range 230-1592 mumol/l), microscopic haematuria (n = 8) and proteinuria (n = 10). Nine patients were seropositive for rheumatoid factor and nine had bone erosions. Serum from four of five patients tested by indirect immunofluorescence was positive for antineutrophil cytoplasmic antibody (ANCA) with perinuclear staining. Only three patients had penicillamine or gold therapy. Treatment was with prednisolone and cyclophosphamide (six patients, two of whom were also plasma-exchanged), prednisolone and azathioprine (two patients) and prednisolone alone (two patients). There was a marked improvement in renal function in eight patients. Two patients with dialysis-dependent renal failure recovered renal function, although in one patient this was transient and she required further dialysis 4 months later. Two other patients progressed to dialysis at 3 months and 1 year respectively. Four patients died, one remains dialysis-dependent, and four continue to have good renal function at 5 year follow-up (median creatinine 148.5 mumol/l, range 120-193 mumol/l). One patient was lost to follow-up at 5 years. FSNGN should be considered in all patients with RA and renal impairment, proteinuria and/or microscopic haematuria. This diagnosis appears to be more likely in patients with clinical extrarenal vasculitis, bone erosions or who are seropositive. In these cases, an urgent renal biopsy is indicated.

Abnormalities of endothelial function in patients with predialysis renal failure.

BACKGROUND: Endothelial dysfunction plays an important role in the development of atherosclerotic vascular disease, which is the leading cause of mortality in patients with chronic renal failure. OBJECTIVE: To examine the relation between predialysis renal failure and endothelial function. DESIGN: Two groups were studied: 80 patients with non-diabetic chronic renal failure and 26 healthy controls, with similar age and sex distributions. Two indices of endothelial function were assessed: high resolution ultrasonography to measure flow mediated endothelium dependent dilatation of the brachial artery following reactive hyperaemia, and plasma concentration of von Willebrand factor. Endothelium independent dilatation was also assessed following sublingual glyceryl trinitrate. The patients were divided into those with and without overt atherosclerotic vascular disease. RESULTS: Although patients with chronic renal failure had significantly impaired endothelium dependent dilatation compared with controls (median (interquartile range), 2.6% (0.7% to 4.8%) v 6.5% (4.8% to 8.3%); p < 0.001) and increased von Willebrand factor (254 (207 to 294) v 106 (87 to 138) iu/dl; p < 0.001), there was no difference between renal failure patients with and without atherosclerotic vascular disease. Within the chronic renal failure group, endothelium dependent dilatation and von Willebrand factor were similar in patients in the upper and lower quartiles of glomerular filtration rate (2.7% (0.7% to 6.7%) v 2.8% (1.1% to 5.0%); and 255 (205 to 291) v 254 (209 to 292) iu/dl, respectively). Endothelium independent dilatation did not differ between the renal failure or control groups and was also similar in patients with renal failure irrespective of the degree of renal failure or the presence of atherosclerotic vascular disease. CONCLUSIONS: Endothelial function is abnormal in chronic renal failure, even in patients with mild renal insufficiency and those without atherosclerotic vascular disease, suggesting that uraemia may directly promote the development of atherosclerosis early in the progression of chronic renal failure.

Audiometric configuration in patients being treated for alcoholism.

The auditory acuity of 52 alcoholic subjects showed a consistent bilateral high frequency loss. Presence of this loss was found to be related to drinking time, but independent of age, suggesting a definite relationship between length of heavy drinking time and loss of auditory acuity in the high frequencies.

Lipid abnormalities in the nephrotic syndrome: the therapeutic role of statins.

Hyperlipidaemia complicating the nephrotic syndrome is characterised by elevated levels of total and LDL cholesterol, often with hypertriglyceridaemia and low HDL cholesterol levels. The underlying mechanisms are complex but involve abnormalities of both lipoprotein synthesis and catabolism. Experience to date suggests that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or "statins" offer the most effective therapy and are relatively safe, at least in short term studies. The benefits of treatment remain unproven but may include a reduction in cardiovascular risk and preservation of residual renal function. Newly defined actions of statins, some of which may be unrelated to lipid lowering, are likely to extend the application of these drugs in patients with glomerular disease.

Measurement of renal functional reserve of the single kidney in man.

The renal functional reserve capacity (RFRC) and response of the single kidney to a low protein diet (LPD) were investigated. Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured using a single injection of I125 Hippuran and Cr51 EDTA during a dopamine infusion (3 micrograms/kg/min) and after 2 weeks on a LPD (0.6 g/kg/day). Dopamine increased ERPF but the associated rise in GFR was not significant. There was a significant decrease in both ERPF and GFR on LPD. The change in GFR during dopamine infusion, but not during LPD, correlated inversely with baseline GFR. Dopamine and LPD had no effect on heart rate or blood pressure and LPD did not alter urinary sodium excretion. These results suggest that the single kidney lacks functional reserve capacity and that protein restriction may be useful in preserving long term function.

Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

Statins and the kidney.

Experience to date suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins can be used relatively safely and effectively to treat dyslipidaemia complicating renal disease. Recent studies suggest that in addition to lowering plasma lipid levels, these drugs modify other factors that contribute to vascular injury. Furthermore, statins could slow the progression of chronic renal failure and may augment the action of immunosuppressive therapy after renal transplantation. Such newly defined actions, some of which could be unrelated to lipid lowering, are likely to extend the applications of statins in nephrology.