Health-related quality of life, functional impairment and comorbidity in people with mild-to-moderate chronic kidney disease: a cross-sectional study.

OBJECTIVES: To determine the associations between comorbidities, health-related quality of life (HRQoL) and functional impairment in people with mild-to-moderate chronic kidney disease (CKD) in primary care. DESIGN: Cross-sectional analysis at 5-year follow-up in a prospective cohort study. SETTING: Thirty-two general practitioner surgeries in England. PARTICIPANTS: 1008 participants with CKD stage 3 (of 1741 people recruited at baseline in the Renal Risk in Derby study) who survived to 5 years and had complete follow-up data for HRQoL and functional status (FS). PRIMARY AND SECONDARY OUTCOME MEASURES: HRQoL assessed using the 5-level EQ-5D version (EQ-5D-5L, with domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression and index value using utility scores calculated from the English general population), and FS using the Karnofsky Performance Status scale (functional impairment defined as Karnofksy score ≤70). Comorbidity was defined by self-reported or doctor-diagnosed condition, disease-specific medication or blood result. RESULTS: Mean age was 75.8 years. The numbers reporting some problems in EQ-5D-5L domains were: 582 (57.7%) for mobility, 166 (16.5%) for self-care, 466 (46.2%) for usual activities, 712 (70.6%) for pain/discomfort and 319 (31.6%) for anxiety/depression. Only 191 (18.9%) reported no problems in any domain. HRQoL index values showed greater variation among those with lower FS (eg, for those with Karnofsky score of 60, the median (IQR) EQ-5D index value was 0.45 (0.24 to 0.68) compared with 0.94 (0.86 to 1) for those with Karnofsky score of 90). Overall, 234 (23.2%) had functional impairment.In multivariable logistic regression models, functional impairment was independently associated with experiencing problems for all EQ-5D-5L domains (mobility: OR 16.87 (95% CI 8.70 to 32.79, p<0.001, self-care: OR 13.08 (95% CI 8.46 to 20.22), p<0.001, usual activities: OR 8.27 (95% CI 5.43 to 12.58), p<0.001, pain/discomfort: OR 2.94 (95% CI 1.86 to 4.67), p<0.001, anxiety/depression: 3.08 (95% CI 2.23 to 4.27), p<0.001). Higher comorbidity count and obesity were independently associated with problems in mobility, self-care, usual activities and pain/discomfort: for three or more comorbidities versus none: (mobility: OR 2.10 (95% CI 1.08 to 4.10, p for trend 0.002), self-care: OR 2.64 (95% CI 0.72 to 9.67, p for trend 0.05), usual activities: OR 4.20 (95% CI 2.02 to 8.74, p for trend <0.001), pain/discomfort: OR 3.06 (95% CI 1.63 to 5.73, p for trend <0.001)), and for obese (body mass index (BMI) ≥30 kg/m2) versus BMI <25 kg/m2: (mobility: OR 2.44 (95% CI 1.61 to 3.69, p for trend <0.001), self-care: OR 1.98 (95% CI 1.06 to 3.71, p for trend 0.003), usual activities: OR 1.82 (95% CI 1.19 to 2.76, p for trend 0.019), pain/discomfort: OR 2.37 (95% CI 1.58 to 3.55, p for trend <0.001)). Female sex, lower FS and lower educational attainment were independently associated with anxiety/depression (ORs 1.60 (95% CI 1.18 to 2.16, p 0.002), 3.08 (95% CI 2.23 to 4.27, p<0.001) and 1.67 (95% CI 1.10 to 2.52, p 0.009), respectively). Older age, higher comorbidity count, albuminuria (≥30 mg/mmol vs <3 mg/mmol), lower educational attainment (no formal qualifications vs degree level) and obesity were independently associated with functional impairment (ORs 1.07 (95% CI 1.04 to 1.09, p<0.001), 2.18 (95% CI 0.80 to 5.96, p for trend <0.001), 1.74 (95% CI 0.82 to 3.68, p for trend 0.005), 2.08 (95% CI 1.26 to 3.41, p for trend <0.001) and 4.23 (95% CI 2.48 to 7.20), respectively). CONCLUSIONS: The majority of persons with mild-to-moderate CKD reported reductions in at least one HRQoL domain, which were independently associated with comorbidities, obesity and functional impairment. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632.

Hepato-splanchnic circulatory stress: An important effect of hemodialysis.

The gastro-intestinal tract is being increasingly recognized as the site of key pathophysiological processes in the hemodialysis patient. Intestinal dysbiosis, increased intraluminal toxin production, and increased intestinal permeability are commonly observed processes which contribute to the pathogenesis of cardiovascular disease and thus elevated mortality. The acute circulatory effects of dialysis itself may contribute significantly to the development of gastrointestinal dysfunction as a result of both local and distant effects. Additionally, the liver, a relatively unknown entity in this process, has a substantial role as a functional barrier between the portal and systemic circulation and in the metabolism of pathogenic gut-derived uremic toxins. Here we summarize the evidence for acute gastro-intestinal and hepatic effects of hemodialysis and identify gaps in knowledge to date which require further study.

Intradialytic Cardiac Magnetic Resonance Imaging to Assess Cardiovascular Responses in a Short-Term Trial of Hemodiafiltration and Hemodialysis.

Hemodynamic stress during hemodialysis (HD) results in recurrent segmental ischemic injury (myocardial stunning) that drives cumulative cardiac damage. We performed a fully comprehensive study of the cardiovascular effect of dialysis sessions using intradialytic cardiac magnetic resonance imaging (MRI) to examine the comparative acute effects of standard HD versus hemodiafiltration (HDF) in stable patients. We randomly allocated 12 patients on HD (ages 32-72 years old) to either HD or HDF. Patients were stabilized on a modality for 2 weeks before undergoing serial cardiac MRI assessment during dialysis. Patients then crossed over to the other modality and were rescanned after 2 weeks. Cardiac MRI measurements included cardiac index, stroke volume index, global and regional contractile function (myocardial strain), coronary artery flow, and myocardial perfusion. Patients had mean±SEM ultrafiltration rates of 3.8±2.9 ml/kg per hour during HD and 4.4±2.5 ml/kg per hour during HDF (P=0.29), and both modalities provided a similar degree of cooling. All measures of systolic contractile function fell during HD and HDF, with partial recovery after dialysis. All patients experienced some degree of segmental left ventricular dysfunction, with severity proportional to ultrafiltration rate and BP reduction. Myocardial perfusion decreased significantly during HD and HDF. Treatment modality did not influence any of the cardiovascular responses to dialysis. In conclusion, in this randomized, crossover study, there was no significant difference in the cardiovascular response to HDF or HD with cooled dialysate as assessed with intradialytic MRI.

Collection of daily patient reported outcomes is feasible and demonstrates differential patient experience in chronic kidney disease.

INTRODUCTION: Patient reported outcomes (PROs) are a critical metric documenting the impact of disease and treatment from the patient's perspective. A variety of generic and disease specific PRO measures (PROMs) are used in chronic kidney disease (CKD) but studies are primarily cross-sectional. None of the available PROMs are designed for frequent iterative application. METHODS: An online PROM for daily use in dialysis and CKD 4/5 patients was developed. The custom website utilised visual analogue scales to capture 6 PROs (general well being (GWB), pain, sleep, breathing, energy, and appetite). Outcomes of interest were uptake, response rates, intermodality variation, and change in PRO corresponding to predefined events. FINDINGS: Forty-three patients submitted at least once and 34 submitted beyond 30 days. Median follow-up was 247 days, 64% male, age 62 ± 12 years. In individuals submitting for >30 days, dialysis patients had significantly worse median scores compared to CKD for sleep (47[32-80], 97[76-99], P = 0.003), appetite (66[50-96], 97[88-100], P = 0.008), energy (47[40-89], 84[67-96], P = 0.031), and GWB (63[49-94], 93[71-98], P = 0.026). Patients demonstrated a variety of stable bandwidths of response, deviations from this were associated with specific events e.g., acute admission, vascular procedures, disturbed fluid status, and dialysis start. DISCUSSION: We successfully introduced an online, patient acceptable, iterative PROM that discriminates symptom burden, cross-sectionally, and longitudinally. Further work will prospectively examine the predictive power of changes in PRO and more rigorously investigate the potential use of these methods to optimise patient care.

The Association between Polyclonal Combined Serum Free Light Chain Concentration and Mortality in Individuals with Early Chronic Kidney Disease.

A major component of increased mortality risk in people with chronic kidney disease (CKD) is associated with non-traditional cardiovascular risk factors including markers of inflammation. We studied whether a novel marker of systemic inflammation, elevated serum combined polyclonal immunoglobulin free light chains (cFLC), was an independent risk factor for increased all-cause mortality in people with CKD stage 3. In a prospective community based cohort study, 1695 participants with stage 3 CKD and no cases of monoclonal gammopathy had cFLC concentrations measured. cFLC levels were determined using the summation of Freelite kappa and lambda assays. All other bioclinical variables were collected at the time of sample collection. Kaplan-Meier plots and Cox proportional hazards analysis was used to assess the relationship between high cFLC levels (>43.3 mg/L) and mortality. There were 167 deaths (10%) after a median of 1375 days. cFLC levels at recruitment were higher in participants who died compared with those who were alive at the end of the study; median: 46.5 mg/L (IQR: 36.1-65.4 mg/L) and 35.4 mg/L (28.1-46.6 mg/L) respectively, P <0.001. Kaplan-Meier survival analysis demonstrated participants with cFLC >43.3 mg/L levels had an increased risk of mortality compared to people with normal cFLC levels (P <0.001). Elevated cFLC levels were independently associated with worse survival (Hazard ratio: 1.50; 95% confidence interval: 1.04-2.16; P=0.03). Other independent risk factors for worse survival were: older age, male gender, previous cardiovascular event, lower eGFR and higher high sensitivity C-reactive protein (hsCRP). To conclude, high cFLC levels predict increased mortality in people with stage 3 CKD, independent of established risk factors and other markers of inflammation.

Euvolemia in hemodialysis patients: a potentially dangerous goal?

Dialysis patients have high mortality rate and the leading cause of death is cardiovascular disease. Uremic cardiomyopathy differs from that due to conventional atherosclerosis, where cardiovascular changes result in ineffective circulation and lead to tissue ischemia. Modern dialysis has significant limitations with fluid management probably the most challenging. Current evidence suggests that both volume overload and aggressive fluid removal can induce circulatory stress and multi-organ injury. Furthermore, we do not have accurate volume assessment tools. As a result, targeting euvolemia might result in more harm than benefit with conventional hemodialysis therapy. Therefore, it might be time to consider a degree of permissive over-hydration until we have better tools to both determine ideal weight and improve current renal replacement therapy so that the process of achieving it is not so fraught with the current dangers.

Defining uremic arterial functional abnormalities in patients recently started on haemodialysis: combined in vivo and ex vivo assessment.

Endothelial dysfunction is a key initiating event in vascular disease in chronic kidney disease (CKD) patients and haemodialysis (HD) patients exhibit significant vascular abnormalities. To understand this further, we examined how ex vivo intrinsic function in isolated arteries correlates with in vivo assessments of cardiovascular status in HD patients. Abdominal fat biopsies were obtained from 11 HD patients and 26 non-uremic controls. Subcutaneous arteries were dissected and mounted on a wire myograph, and cumulative concentration-response curves to noradrenalin, endothelin-1, a thromboxane A2 agonist (U46619), angiotensin II, vasopressin, bradykinin (BK), acetylcholine (ACh) and sodium nitroprusside (SNP) were constructed. Pulse wave velocity and blood pressure were measured in HD patients. Enhanced (P<0.05-0.0001) maximal contractile responses (Rmax) to all spasmogens (particularly vasopressin) were observed in arteries from HD patients compared to controls, and this effect was more pronounced in arteries with an internal diameter>600 µm. The potency (pEC50) of U46619 (P<0.01) and vasopressin (P<0.001) was also increased in arteries>600 µm of HD patients. The maximal relaxant response to the endothelium-dependent dilators ACh and BK were lower in HD patients (P<0.01-P<0.0001) (worse for ACh than BK); however the endothelium-independent dilator SNP was similar in both groups. PWV was significantly correlated with the vasoconstrictor response to vasopressin (P = 0.042) in HD patients. HD patients are primed for hypertension and end organ demand ischaemia by a highly sensitised pressor response. The failure of arterial relaxation is mediated by endothelial dysfunction. Intrinsic vascular abnormalities may be important in sensitising HD patients to recurrent cumulative ischaemic end organ injury.

The impact of hemodialysis on segmental and global longitudinal myocardial strain.

BACKGROUND: Strain analysis derived from the analysis of speckle tracked imaging echocardiography can be used to examine ventricular contractile functions. In this study, we examined the relationship of hemodialysis (HD)-induced circulatory stress with overall ventricular function assessed according to global longitudinal strain (GLS) and segmental distribution of strain. METHODS: This prospective observational study included 104 conventional HD patients at Royal Derby Hospital. Averaged values of segmental and GLS were determined from the echocardiography of these patients before and at peak dialysis. These values were compared with the reference values of healthy individuals, correlated with their demographic characteristics, and the effect on survival was assessed. RESULTS: The global strain value was -11.5% ± 4.42, and the segmental strain values were significantly greater in HD patients than in healthy individuals by 2.7%-9.8% (P < 0.001). The strain values were not significantly different before dialysis and at peak dialysis (P > 0.05), except within the basal lateral segment (P = 0.01). The adjusted hazard ratio for mortality was 4.3 (95% confidence interval, 1.2-14.9; P = 0.021) when > 80% of the segments exhibited more than the mean of segmental strain values. For the 46 patients who died, there were statistically significant negative correlations between survival time and GLS (r = -0.30; P = 0.04). CONCLUSIONS: Global and segmental strain measured using speckle tracked imaging provides information relating to the effects of HD-induced cardiac injury. The segmental strain abnormalities in the watershed area of the left ventricle suggest a higher degree of vulnerability to HD-induced demand ischemia.

Acute kidney injury is independently associated with death in patients with cirrhosis.

BACKGROUND AND AIMS: Current creatine-based criteria for defining acute kidney injury (AKI) are validated in general hospitalised patients but their application to cirrhotics (who are younger and have reduced muscle mass) is less certain. We aimed to evaluate current definitions of AKI (acute kidney injury network (AKIN) criteria) in a population of cirrhotic patients and correlate this with outcomes. METHODS: We prospectively identified patients with AKI and clinical, radiological or histological evidence of cirrhosis. We compared them with a control group with evidence of cirrhosis and no AKI. RESULTS: 162 cirrhotic patients were studied with a mean age of 56.8±14 years. They were predominantly male (65.4%) with alcoholic liver disease (78.4%). 110 patients had AKI: 44 stage 1, 32 stage 2 and 34 stage 3. They were well matched in age, sex and liver disease severity with 52 cirrhotics without AKI. AKI was associated with increased mortality (31.8% vs 3.8%, p<0.001). Mortality increased with each AKI stage; 3.8% in cirrhotics without AKI, 13.5% stage 1, 37.8% stage 2 and 43.2% stage 3 (p<0.001 for trend). Worsening liver disease (Child-Pugh class) correlated with increased mortality: 3.1% class A, 23.6% class B and 32.8% class C (p=0.006 for trend). AKI was associated with increased length of stay: median 6.0 days (IQR 4.0-8.75) versus 16.0 days (IQR 6.0-27.5), p<0.001. Multivariate analysis identified AKI and Child-Pugh classes B and C as independent factors associated with mortality. CONCLUSIONS: The utility of AKIN criteria is maintained in cirrhotic patients. Decompensated liver disease and AKI appear to be independent variables predicting death in cirrhotics.

Haemodialysis-induced myocardial stunning in chronic kidney disease - a new aspect of cardiovascular disease.

Chronic haemodialysis (HD) patients are already primed by a large number of structural and functional peripheral vascular and cardiac abnormalities to experience demand myocardial ischaemia. Transient myocardial ischaemia may lead to left ventricular (LV) dysfunction that can persist after the return of normal perfusion. This prolonged dysfunction is known as myocardial stunning. Repetitive episodes of ischaemia can be cumulative and have been shown to lead to prolonged LV dysfunction (in patients with ischaemic heart disease). Conventional HD itself is a sufficient cardiovascular functional stressor to precipitate such recurrent ischaemic insults, leading to myocardial functional and structural changes, eventually resulting in fixed systolic dysfunction and heart failure (conferring a dismal prognosis for patients undergoing dialysis). Furthermore these same haemodynamic insults may also adversely affect other vascular beds in other vulnerable organ systems, driving an even wider range of pathophysiological processes. A variety of therapeutic manoeuvres aimed at improving the haemodynamic tolerability of treatment have been shown to reduce acute dialysis-induced myocardial ischaemia. This article aims to give an appreciation of the possibility that modification of the dialysis treatment to improve tolerability of therapy may have the potential to provide us with additional therapeutic targets, to reduce currently excessive rates of cardiovascular morbidity and mortality.

Categorization of the hemodynamic response to hemodialysis: the importance of baroreflex sensitivity.

Intradialytic hypotension (IDH) remains an important cause of morbidity and mortality in hemodialysis (HD) patients. The baroreflex arc is under autonomic control and regulates blood pressure. This study aimed to investigate the contribution of impaired baroreflex sensitivity (BRS) to the pathophysiology of IDH. Thirty-four chronic HD (12 IDH-prone, 22 IDH-resistant) patients underwent BRS measurement during HD with relative blood volume monitoring. During analysis, patients were separated into four age-matched groups according to resting BRS>or=4.5 ms/mmHg and hemodynamic stability. Resting BRS was extremely heterogenous (geometric mean BRS 5.78+/-1.41 [range 1.76-41.41] ms/mmHg). Relative blood volume reduction was well matched in all groups (mean reduction in relative blood volume for all patients -6.74%+/-0.86%, P>0.05). Thirty-seven episodes of IDH occurred in the IDH prone, reduced BRS group. Patients with impaired resting BRS and prone to IDH had markedly different responses to HD as compared to the preserved BRS group, but the total peripheral resistance response was significantly lower than in the IDH-resistant patients (15.9%+/-2.1% vs. 42.4%+/-3.0%, respectively, P<0.001). In those patients prone to IDH and with impaired resting BRS, percentage reduction in cardiac output at the end of HD highly correlated with reduction in relative blood volume (r=0.94, P=0.006). Hypotension during dialysis may be an important source of recurrent cardiac injury and early recognition of those patients prone to relative symptomatic and asymptomatic hypotension remains important. Impaired resting BRS and recognition of a suboptimal peripheral pressor response, appear to predict those patients most likely to undergo hemodynamic instability and may assist in the pursuit of this elusive goal.

Cardiac assessment in chronic kidney disease.

Patients with chronic kidney disease are well recognized to develop a wide range of cardiac structural and functional abnormalities. These changes may be progressive and relate directly to a grossly aggravated risk of cardiovascular events and reduced survival. Although conventional methods of cardiac assessment have been shown to be useful, they are limited by insufficient sensitivity and specificity, to fully appreciate the overall degree of myocardial distress that is common in these patients. This article aims to review the use of established and emerging cardiac imaging tools and, in particular, their application in patients with chronic kidney disease.

Elevated osteoprotegerin is associated with all-cause mortality in CKD stage 4 and 5 patients in addition to vascular calcification.

BACKGROUND: Cardiovascular disease is the leading cause of death in the chronic kidney disease (CKD) population. The mechanisms of vascular damage are not fully understood. The objective of this study was to prospectively investigate the importance of novel mediators of vascular damage, in conjunction with vascular calcification (VC), on survival. METHODS: A total of 134 subjects [60 haemodialysis (HD), 28 peritoneal dialysis (PD) and 46 CKD stage 4] were studied. All survivors completed 40 months of follow-up. VC was measured using multi-slice spiral CT of the superficial femoral artery. Circulating osteoprotegerin (OPG), Fetuin-A and high sensitivity C-reactive protein (hs-CRP) were measured in addition to standard clinical biochemical analysis. RESULTS: After a 40-month follow-up, 31 patients had died (27 men and 4 women). Of 31 subjects, 31 had evidence of significant VC. The majority of deaths were in the HD group (48%), 36% were PD subjects and 16% were CKD subjects. The outcome of interest was survival at the end of follow-up. Multivariate logistical regression analysis revealed male gender [OR 8.06 (1.34-48.450) P = 0.02], OPG >25 pmol/L [OR 5.31(1.35-20.88) P = 0.02] and hypoalbuminaemia [OR 0.26 (0.12-0.56) P < 0.01], were associated with increased odds of death. CONCLUSION: We have previously reported that VC and low albumin predict death in CKD stages 4 and 5 over a 2-year follow-up period. These data show that OPG, independent of CRP, is also associated with a negative outcome. The mechanisms remain to be elucidated; however, it is likely that they are associated with vascular damage through mechanisms in addition to VC.

Cool dialysate reduces asymptomatic intradialytic hypotension and increases baroreflex variability.

Intradialytic hypotension (IDH) remains an important cause of morbidity and mortality in chronic hemodialysis (HD) patients and can be ameliorated by cool temperature HD. The baroreflex arc is under autonomic control and is essential in the short-term regulation of blood pressure (BP). This study aimed to investigate if the baroreflex sensitivity (BRS) response to HD differed between standard and cool-temperature dialysate. Ten patients (mean age 67+/-2 years) prone to IDH were recruited into a randomized, crossover study to compare BRS variation at dialysate temperatures of 37 degrees C (HD(37)) and 35 degrees C (HD(35)). Each patient underwent continuous beat-to-beat BP monitoring during a dialysis session of HD(37) and HD(35). During HD(37) 2 patients developed symptomatic IDH, as opposed to 1 with HD(35). However, asymptomatic IDH occurred with a frequency of 0.4 episodes per session with HD(35) and 6.2 episodes per session during HD(37) (odds ratio15.5; 95%CI 5.6-14.2). Although absolute BRS measurements did not differ between the 2 modalities, BRS variability increased during HD(35). Our study has demonstrated that in IDH-prone patients, cool HD resulted in a reduction in heart rate and a greater reduction in cardiac output and stroke volume. Mean arterial pressure was maintained through a significantly greater increase in total peripheral resistance. Furthermore, although absolute BRS values during HD were not significantly altered by a reduction in dialysate temperature, there was a greater percentage increase in BRS values during cool HD. Understanding the varied causes of, and categorizing impaired hemodynamic responses to HD will enable further individualization of HD prescriptions according to patient need.

Advances in the cardiovascular assessment of patients with chronic kidney disease.

Cardiovascular mortality is grossly elevated in patients with chronic kidney disease (CKD), and is associated with a wide variety of structural and functional abnormalities. These issues have driven additional attempts to further characterise these abnormalities to elucidate the pathophysiology involved, assess individual risk and/or target and monitor therapies specifically directed at the cardiovascular (CV) system. This review aims to assess the techniques that are currently available for the study of the CV system. This includes conventional assessments of the whole CV system from heart to peripheral microcirculation (although not deal with VC assessment), as well as the key functional consequences relating to stress induced cardiovascular reserve, perfusion and vasoregulation. In addition this review will introduce a variety of techniques aiming to expand the envelope of conventional measurements.