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.

Symptom-burden in people living with frailty and chronic kidney disease.

BACKGROUND: Frailty is independently associated with worse health-related quality of life (HRQOL) in chronic kidney disease (CKD). However, the relationship between frailty and symptom experience is not well described in people living with CKD. This study's aim was to evaluate the relationship between frailty and symptom-burden in CKD. METHODS: This study is a secondary analysis of a cross-sectional observational study, the QCKD study (ISRCTN87066351), in which participants completed physical activity, cardiopulmonary fitness, symptom-burden and HRQOL questionnaires. A modified version of the Frailty Phenotype, comprising 3 self-report components, was created to assess frailty status. Multiple linear regression was performed to assess the association between symptom-burden/HRQOL and frailty. Logistic regression was performed to assess the association between experiencing symptoms frequently and frailty. Principal Component Analysis was used to assess the experienced symptom clusters. RESULTS: A total of 353 patients with CKD were recruited with 225 (64%) participants categorised as frail. Frail participants reported more symptoms, had higher symptom scores and worse HRQOL scores. Frailty was independently associated with higher total symptom score and lower HRQOL scores. Frailty was also independently associated with higher odds of frequently experiencing 9 out of 12 reported symptoms. Finally, frail participants experienced an additional symptom cluster that included loss of appetite, tiredness, feeling cold and poor concentration. CONCLUSIONS: Frailty is independently associated with high symptom-burden and poor HRQOL in CKD. Moreover, people living with frailty and CKD have a distinctive symptom experience. Proactive interventions are needed that can effectively identify and address problematic symptoms to mitigate their impact on HRQOL.

The epidemiology of hospitalised acute kidney injury not requiring dialysis in England from 1998 to 2013: retrospective analysis of hospital episode statistics.

AIMS: Epidemiology studies of acute kidney injury (AKI) have focused on cases requiring dialysis but those not requiring dialysis represent the majority. To address this gap, we interrogated hospital episode statistics (HES) to investigate population trends in temporal epidemiology of AKI not requiring dialysis between 1998 and 2013. METHODOLOGY: In this retrospective observational study of HES data covering the entire English National Health Service, we identified 1,136,167 AKI events, not requiring dialysis, diagnosed between 1998 and 2013. We explored the effect of age, gender, ethnicity, Charlson's comorbidity score (CCS), method of admission, diagnosis period and AKI in diagnosis codes on temporal changes in the incidence and case-fatality of AKI with specific examination of its predictors. RESULT: The incidence of AKI increased from 15,463 cases (317 pmp) in 1998-1999 to 213,700 cases (3995 pmp) in 2012-2013. There was increase in proportion of people over 75 years from 51.1% in 1998-1999 to 63.4% in 2012-2013. Overall unadjusted case-fatality decreased from 42.3% in 1998-2003 to 27.1% in 2008-2013, p < 0.001. Compared with 1998-2003, the multivariable adjusted odds ratio for death was 0.64 in 2003-2008 (95% CI 0.63-0.65) and 0.35 in 2008-2013 (95% CI 0.34-0.35). Odds for death were higher for patients over 85 years (2.93; 95% CI 2.89-2.97), CCS of more than five (2.75; 95% CI 2.71-2.79), emergency admissions (2.14; 95% CI 2.09-2.18) and AKI in the secondary diagnosis code (1.35; 95% CI 1.33-1.36) and AKI in other diagnoses codes (2.17; 95% CI 2.15-2.20). CONCLUSIONS: In England, the incidence of AKI not requiring dialysis has increased and case-fatality has decreased over last 15 years. Efforts to reduce the incidence of AKI and improve survival should focus on elderly people, emergency admissions and those with multi-morbidity.

High sodium intake is associated with important risk factors in a large cohort of chronic kidney disease patients.

BACKGROUND/OBJECTIVES: An increased risk of mortality and cardiovascular disease (CVD) is observed in people with chronic kidney disease (CKD) even in early stages. Dietary sodium intake has been associated with important CVD and CKD progression risk factors such as hypertension and proteinuria in this population. We aimed to investigate the relationship between sodium intake and CVD or CKD progression risk factors in a large cohort of patients with CKD stage 3 recruited from primary care. SUBJECTS/METHODS: A total of 1733 patients with previous estimated glomerular filtration rate (eGFR) of 30-59 ml/min/1.73m(2), with a mean age 72.9±9.0 years, were recruited from 32 general practices in primary care in England. Medical history was obtained and participants underwent clinical assessment, urine and serum biochemistry testing. Sodium intake was estimated from three early-morning urine specimens using an equation validated for this study population. RESULTS: Sixty percent of participants who had estimated sodium intake above recommendation (>100 mmol/day or 6 g salt/day) also had higher diastolic blood pressure, mean arterial pressure (MAP), urinary albumin-to-creatinine ratio, high-sensitive C-reactive protein and uric acid and used a greater number of anti-hypertensive drugs. In multivariable regression analysis, excessive sodium intake was an independent predictor of MAP (B=1.57, 95% confidence interval (CI) 0.41-2.72; P=0.008) and albuminuria (B=1.35, 95% CI 1.02-1.79; P=0.03). CONCLUSIONS: High sodium intake was associated with CVD and CKD progression risk factors in patients with predominantly early stages of CKD followed up in primary care. This suggests that dietary sodium intake could afffect CVD risk even in early or mild CKD. Intervention studies are warranted to investigate the potential benefit of dietary advice to reduce sodium intake in this population.

Renal risk scores: progress and prospects.

Worldwide adoption of the Kidney Disease Outcomes Quality Initiative classification for chronic kidney disease (CKD) and widespread use of the estimated glomerular filtration rate to assess renal function have identified large numbers of patients with previously undiagnosed CKD. It is clear, however, that this is a heterogeneous group and that only a small minority of such patients ever progress to end-stage renal disease. There is thus an urgent need for a simple method of risk assessment that can be applied to all patients with CKD to identify those few at greatest risk. The magnitude of baseline proteinuria has long been recognized as an important predictor of renal prognosis. Furthermore, several studies have found that change in proteinuria after initiation of antihypertensive treatment as well as achieved level of proteinuria correlate with prognosis. Thus, proteinuria has emerged as the single most important marker of renal risk. Many other factors have been identified as risk factors for CKD progression. Several attempts have been made to combine a relatively small number of risk factors into a risk score to predict renal outcomes in specific groups of patients. Validation of these risk scores as well as further studies are now required to develop a renal risk score applicable to a more general population of patients with CKD. Similar methodology could be applied to assess the important issue of the cardiovascular risk associated with CKD.

Predicting initiation and progression of chronic kidney disease: Developing renal risk scores.

Epidemiological studies have raised awareness of the problem of undiagnosed chronic kidney disease (CKD) and suggest that early identification and treatment will reduce the global burden of patients requiring dialysis. This has highlighted the twin problems of how to identify subjects for screening and target intervention to those with CKD most likely to progress to end-stage renal disease. Prospective studies have identified risk factors for CKD in the general population as well as risk factors for progression in patients with established CKD. Risk factors may thus be divided into initiating factors and perpetuating factors, with some overlap between the groups. In this paper, we review current data regarding CKD risk factors and illustrate how each may impact upon the mechanisms underlying CKD progression to accelerate loss of renal function. We propose that these risk factors should be used as a basis for developing a renal risk score, analogous to the Framingham risk score for ischemic heart disease, which will allow accurate determination of renal risk in the general population and among CKD patients.

Achieving maximal renal protection in nondiabetic chronic renal disease.

A rapid global increase in the number of patients requiring renal replacement therapy necessitates that effective strategies for renal protection are developed and applied widely. We review the experimental and clinical evidence in support of individual renoprotective interventions, including angiotensin-converting enzyme therapy, control of systemic hypertension, dietary protein restriction, reduction of proteinuria, treatment of hyperlipidemia, and smoking cessation. We also consider potential future renoprotective therapies. To achieve maximal renal protection, a comprehensive strategy employing all of these elements is required. This strategy should be directed at normalizing clinical markers of renal disease to induce a state of remission.

Pathogenesis of diabetic nephropathy: focus on transforming growth factor-beta and connective tissue growth factor.

Although considerable improvement in the prognosis of diabetic nephropathy has been achieved in recent years due to intensive insulin and angiotensin-converting enzyme inhibitor treatment, these approaches do not provide complete protection against progression of diabetic nephropathy. An urgent need for additional novel therapies to prevent or further slow the progression of diabetic nephropathy motivated us to provide an up-to-date review with particular emphasis on the potential role of two growth factors--transforming growth factor-beta and connective tissue growth factor--in the pathogenesis of diabetic nephropathy. The most intensively studied to date, transforming growth factor-beta appears to play a central role in the pathogenesis of diabetic nephropathy. Recently, attention has focused on connective tissue growth factor, which mimics the biological activity of transforming growth factor-beta in profibrotic tissue formation. Thus, acting as a downstream mediator of the profibrotic activity of transforming growth factor-beta, connective tissue growth factor may constitute a more specific target for future antifibrotic therapies.

Evolving strategies for renoprotection: non-diabetic chronic renal disease.

Experimental and clinical studies over the past two decades have identified several interventions for slowing the progression of chronic renal disease towards end-stage renal failure. In this paper we review the experimental and clinical evidence in support of dietary protein restriction, angiotensin-converting enzyme inhibitor therapy, control of systemic hypertension, reduction of proteinuria, treatment of hyperlipidemia and smoking cessation. We also consider potential future renoprotective therapies. Finally we propose a comprehensive strategy for achieving maximal renoprotection with available interventions and monitoring.

Cost-effectiveness of hepatitis B vaccination in haemodialysis patients.

BACKGROUND: Vaccination against hepatitis B virus is an important means of controlling the infection, but its role in haemodialysis patients has been questioned due to the latter's impaired immune response. METHODS: Forty-eight of 79 haemodialysis patients who were negative for antibodies to both hepatitis B surface and core antigens were entered into a vaccination programme. Standard doses of a plasma-derived vaccine were administered into the deltoid muscle at 0, 1, 2 and 4 months, and the antibody response was measured at 1 and 2 months after the third and fourth doses. RESULTS: The peak mean antibody titre of 372 IU/l was recorded at 1 month after the fourth dose, and the maximum response rate was achieved at 2 months after the final dose. Seroconversion occurred in 26 of 36 patients (72%) who completed the programme, and protective levels of antibody above 10 IU/l were found in 25 of 36 patients (69%). Cost analysis of the project revealed a net saving of +/- R90/patient entered at the end of the first year, due to the reduced number of patients requiring monthly surveillance tests for hepatitis B surface antigen. After that, an annual saving of +/- R380/patient is projected. CONCLUSION: In view of the high prevalence of chronic hepatitis B carriers in the South African population, the reduction in the number of patients at risk of infection, combined with a net cost saving, makes it reasonable to recommend vaccination in all non-immune haemodialysis patients despite a reduced response rate.

Mechanisms underlying renoprotection during renin-angiotensin system blockade.

Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.

Angiotensin-converting enzyme gene polymorphisms in renal disease: clinically relevant?

The most recent studies of the effect of polymorphisms of the angiotensin-converting enzyme gene on the pathogenesis of renal diseases and the response to treatment with angiotensin-converting enzyme inhibitors continue to produce conflicting results. Large prospective studies are required before angiotensin-converting enzyme genotyping will provide information that will assist in the assessment of prognosis and response to angiotensin-converting enzyme inhibitor treatment in individual patients. Until such studies are performed, all patients with chronic renal disease, regardless of angiotensin-converting enzyme genotype, should be considered candidates for angiotensin-converting enzyme inhibitor therapy.

Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney.

BACKGROUND: Macrophage (Mphi) infiltration may contribute to chronic renal injury. We therefore sought to examine the expression of genes associated with Mphi recruitment in the rat remnant kidney model. METHODS: Male Munich Wistar rats underwent 5/6 nephrectomy or sham operation (SHM, N = 18) and received no treatment (VEH, N = 18), enalapril 100 mg/L (ENA, N = 18), or candesartan 70 mg/L (CSN, N = 24) in drinking water. Competitive, quantitative reverse transcription-polymerase chain reaction was used to determine renal cortex mRNA levels for cell adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), the Mphi chemoattractant monocyte chemoattractant protein-1 (MCP-1), Mphi products interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), and the profibrotic cytokine transforming growth factor-beta1 (TGF-beta1), at intervals post-nephrectomy. RESULTS: Glomerular and interstitial Mphi infiltration in VEH rats was associated with an early (4 week) and sustained rise in MCP-1 and TGF-beta1 mRNA levels. Progressive increases in ICAM-1, VCAM-1, IL-1beta, and TNF-alpha expression followed at 8 and 12 weeks. Immunostaining in VEH rats localized TGF-beta1 to glomeruli, tubules, and interstitium; MCP-1 to tubules and interstitial cells; ICAM-1 to glomeruli; and IL-1beta and TNF-alpha to tubules and interstitial cells. At 12 weeks, both treatments normalized systolic blood pressure (ENA, 105 +/- 6; CSN, 97 +/- 3 mm Hg) and the urinary protein excretion rate (ENA, 8.4 +/- 0.9; CSN, 5.7 +/- 0.8 mg/day), prevented renal injury (focal and segmental glomerulosclerosis: ENA, 3.3 +/- 0.9; CSN, 1.3 +/- 0.4%), and suppressed Mphi infiltration and cytokine expression (with the exception of TNF-alpha) to near SHM levels. CONCLUSIONS: These findings support the hypothesis that the coordinated up-regulation of several molecules regulating Mphi recruitment and activation is a fundamental response to renal mass ablation and is dependent on an intact renin-angiotensin system. We speculate that these responses may play a role in the pathogenesis of the ensuing glomerulosclerosis and tubulointerstitial fibrosis.

Hepatitis C virus infection in chronic haemodialysis patients--relationship to blood transfusions and dialyser re-use.

BACKGROUND: A high prevalence of hepatitis C virus (HCV) infection has been observed in haemodialysis units. Many studies have demonstrated an association with blood transfusions, but other data suggest that nosocomial transmission also occurs. There is disagreement as to what measures are necessary to prevent nosocomial spread. METHODS: In 1992 we commenced screening of patients for antibodies to HCV (anti-HCV) using a second-generation enzyme-linked immunosorbent assay (ELISA) test. Positive patients were not confined to special machines or units and all dialysers were re-used. RESULTS: The prevalence of anti-HCV declined from 16.4% in 1992 to 5.3% in 1995 (P = 0.04). At both times, anti-HCV-positive patients, when compared with negative patients, had a longer mean time on haemodialysis (1992: 101.6 (standard deviation (SD) = 57.4) months v. 30.3 (32.4); 1995: 105.5 (23.9) v. 30.2 (32.8) months) and a greater mean number of blood transfusions (1992: 22.6 (18) v. 6.8 (9.4) units; 1995: 14.8 (3.6) v. 4.5 (7.1) units). When the 1992 and 1995 groups were compared there was no difference in time on haemodialysis (mean 42 months v. 34.2 months), but there was a significant reduction in the mean number of blood transfusions (mean 9.4 (12.5) v. 5.0 (7.2), P = 0.03). CONCLUSIONS: We attribute the decline in prevalence of HCV seropositivity mainly to the introduction of screening of blood donations and a decline in the number of blood transfusions. The reduction in prevalence occurred despite routine re-use of dialysers and lack of isolation of seropositive patients, suggesting that in the setting of low overall prevalence, neither factor contributed significantly to the transmission of HCV. Clearly the possibility of some nosocomial transmission could not be totally excluded.

Cellular and molecular mediators in common pathway mechanisms of chronic renal disease progression.

Injury mechanisms activated by the hemodynamic adaptations to nephron loss are considered to represent a final common pathway that underlies the progressive nature of chronic renal disease. In this article, we review experimental evidence that the induction of cell adhesion molecule, cytokine and profibrotic growth factor gene expression and the resultant renal infiltration by inflammatory cells, especially macrophages, are important components of these common pathway mechanisms. Interventions aimed at inhibiting these mechanisms may offer new treatments for slowing or arresting the progression of chronic renal disease.

Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists.

In landmark clinical trials, pharmacological inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEIs) attenuated the decline in renal function associated with chronic renal disease (CRD). Hemodynamic and nonhemodynamic effects of angiotensin II (Ang II) attest to its central role in the pathogenesis of CRD. Angiotensin II subtype 1 receptor antagonists (AT1RA) differ from ACEI in their effects on the RAS and on bradykinin metabolism. Elevations in bradykinin levels associated with ACEI and stimulation of angiotensin subtype 2 receptors resulting from AT1RA may produce therapeutic effects unique to each class of drug. Nevertheless, in animal models of CRD, ACEI and AT1RA exert equivalent renoprotection, implying that their renoprotective effects result primarily from inhibition of Ang II-mediated stimulation of angiotensin subtype 1 receptors. Clinical data comparing ACEI and AT1RA therapy in renal disease are limited to short-term studies, which indicate that AT1RAs have equivalent effects to ACEI on the major determinants of CRD progression, namely blood pressure and proteinuria. AT1RAs were well tolerated, with side-effect profiles similar to placebo. Taken together, available evidence suggests that AT1RAs will share the renoprotective properties of ACEI in human CRD. Nevertheless, the results of long-term clinical trials are required before AT1RA can be recommended as an alternative to ACEI in renoprotective therapy.

Risk factors for reduced bone density in haemodialysis patients.

BACKGROUND: Renal osteodystrophy may result in considerable morbidity for patients with end-stage renal disease. Secondary hyperparathyroidism, adynamic bone disease and osteomalacia, the main bony problems in chronic renal failure, may all be responsible for a reduction in bone mineral density (BMD). This can result in an increased fracture risk. By virtue of their age, post-menopausal status (in women), sedentary life-style and treatment (including previous corticosteroids), haemodialysis patients may be expected also to be at risk for developing osteoporosis, but little is known about the relative importance of these factors. METHODS: We report a prospective study examining the prevalence of reduced bone mineral density (BMD) and its association with a wide range of factors, in a heterogenous group of 88 chronic haemodialysis patients. Femoral neck and lumbar BMD were measured by dual-energy X-ray absorptiometry (DXA). Stepwise multiple linear regression analysis was used to identify risk factors associated with low bone mass. RESULTS: Forty three patients (48.9%) had reduced BMD, and in 17 (19.3%) BMD was below the fracture threshold as defined on DXA measurements by the World Health Organization (WHO). The BMD had significant negative associations with age, serum parathyroid hormone (PTH) levels, current gastric acid suppression therapy, female gender, age at menarche and history of previous fracture. Positive associations were found with weight, haemoglobin concentration, average serum phosphate, weekly heparin dose, oral calcium supplementation and history of parathyroidectomy. CONCLUSIONS: We have confirmed the importance of PTH-related bone disease in affecting BMD in haemodialysis patients, but have found that some other factors, which are known to be risk factors for osteoporosis, are also important.

Usefulness of quantitative heel ultrasound compared with dual-energy X-ray absorptiometry in determining bone mineral density in chronic haemodialysis patients.

BACKGROUND: Reduced bone mineral density (BMD) is associated with renal osteodystrophy and osteoporosis in end-stage renal failure patients. Dual-energy X-ray absorptiometry (DXA) is the standard non-invasive method to assess BMD, but is not always widely available. Quantitative heel ultrasound (QUS) is a mobile, relatively inexpensive, easy to perform and radiation-free method which can predict fractures to the same extent as DXA. This study assessed the usefulness of QUS vs DXA in determining BMD in chronic haemodialysis patients. METHODS: Patients had their BMD at the hip and spine measured by DXA (Lunar Expert). QUS of the left heel (McCue CubaClinical II machine) measured broadband ultrasound attenuation (BUA) and velocity of sound (VOS). Correlations between DXA and QUS parameters were calculated. Receiver operator characteristic (ROC) curves were plotted for BUA and VOS and used to define cut-off points for calculating sensitivities and specificities for BUA and VOS. Femoral neck BMD was applied as the standard for diagnosing osteoporosis (T< or =-2.5) and osteopaenia (T>-2.5 and < or =-1) by WHO criteria. RESULTS: Eighty eight patients (45.5% women), mean age 58+/-17 years, were studied. A total of 19% and 49% had femoral neck BMDs in the 'osteoporosis' and 'osteopaenia' ranges, respectively. There were good correlations between hip BMD and QUS parameters (r=0.68-0.79, P<0.001). Areas under the ROC curves for BUA and VOS in diagnosing 'osteoporosis' were 0.86 and 0.80, respectively. BUA and VOS had sensitivities of 76 and 71% and specificities of 80 and 69%, respectively, for diagnosing 'osteoporosis'. The positive predictive values for BUA and VOS were 48 and 35%, respectively, and the negative predictive values were 93 and 91% respectively. CONCLUSIONS: DXA and QUS parameters were significantly correlated. However, sensitivities and specificities of QUS parameters were not sufficiently high for QUS to be used simply as an alternative to DXA. The relatively high negative predictive values suggest that QUS may reliably screen out patients unlikely to have a BMD in the osteoporotic range. The relatively low positive predictive values, however, mean that subjects classified as osteoporotic using QUS require further investigations such as DXA to confirm the diagnosis.