Kirsten A. Armstrong

OBESITY IS ASSOCIATED WITH WORSENING CARDIOVASCULAR RISK FACTOR PROFILES AND PROTEINURIA PROGRESSION IN RENAL TRANSPLANT RECIPIENTS

Obesity is associated with adverse cardiovascular (CV) parameters and may be involved in the pathogenesis of allograft dysfunction in renal transplant recipients (RTR). We sought the spectrum of body mass index (BMI) and the relationships between BMI, CV parameters and allograft function in prevalent RTR. Data were collected at baseline and 2 years on 90 RTR (mean age 51 years, 53% male, median transplant duration 7 years), categorized by BMI (normal, BMI ≤ 24.9 kg/m2; pre‐obese, BMI 25–29.9 kg/m2; obese, BMI ≥ 30 kg/m2). Proteinuria and glomerular filtration rate (eGFRMDRD) were determined.

Metabolic syndrome in severe chronic kidney disease: Prevalence, predictors, prognostic significance and effects of risk factor modification

Background:  Metabolic syndrome (MS) is a significant risk factor for cardiovascular disease, mortality and chronic kidney disease (CKD) in the general population. However, the prevalence, predictors, prognostic value and treatment of MS in the CKD population have not been rigorously studied.

Impact of obesity on renal transplant outcomes

SUMMARY:  Obesity is a frequent and important consideration to be taken into account when assessing patient suitability for renal transplantation. In addition, posttransplant obesity continues to represent a significant challenge to health care professionals caring for renal transplant recipients. Despite the vast amount of evidence that exists on the effect of pretransplant obesity on renal transplant outcomes, there are still conflicting views regarding whether obese renal transplant recipients have a worse outcome, in terms of short‐ and long‐term graft survival and patient survival, compared with their non‐obese counterparts. It is well established that any association of obesity with reduced patient survival in renal transplant recipients is mediated in part by its clustering with traditional cardiovascular risk factors such as hypertension, dyslipidaemia, insulin resistance and posttransplant diabetes mellitus, but what is not understood is what mediates the association of obesity with graft failure. Whether it is the higher incidence of cardiovascular comorbidities jeopardising the graft or factors specific to obesity, such as hyperfiltration and glomerulopathy, that might be implicated, currently remains unknown. It can be concluded, however, that pre‐ and posttransplant obesity should be targeted as aggressively as the more well‐established cardiovascular risk factors in order to optimize long‐term renal transplant outcomes.

Does uric acid have a pathogenetic role in graft dysfunction and hypertension in renal transplant recipients

Background. Uric acid (UA) may play a pathogenetic role in hypertension and kidney disease. We explored the prevalence of hyperuricemia and the relationship of UA to graft function and hypertension in prevalent renal transplant recipients (RTR). Methods. Baseline and follow-up data were collected on 90 RTR (mean age 51 yrs, 53% male, median transplant duration 7 years). Graft function was estimated using MDRD Study Equation 7. Results. At baseline, 70% RTR had hyperuricemia (UA >7.0 mg/dl (0.42mmol/L) in men and >6.0 mg/dl (0.36 mmol/L) in women) compared to 80% after 2.2 years (P=0.06). UA was not associated with blood pressure (BP) level but was higher in RTR with a history of hypertension compared to those without (8.6±1.8 vs. 7.3±2.2 mg/dl, [0.51±0.11 vs. 0.43±0.13 mmol/L], P=0.003) and in RTR on ≥3 antihypertensive medications compared to those taking less (9.1±1.6 vs. 7.6±1.8 mg/dL, [0.54±0.1 vs. 0.45±0.11 mmol/L], P<0.001). A history of hypertension was independently predictive of UA (&bgr; 0.06, [95% CI 0.02 to 0.10], P=0.007) in addition to sex, cyclosporine dose, prednisolone dose, estimated glomerular filtration rate (eGFRMDRD) and beta-blocker therapy. UA was independently predictive of follow-up eGFRMDRD (&bgr; −22.2 [95% CI −41.2 to −3.2], P=0.02) but did not predict change in eGFRMDRD over time. UA was independently associated with requirement for antihypertensive therapy (&bgr; 0.34, [95% CI 1.05 to 1.90], P=0.02). Conclusions. Hyperuricemia is common in RTR and is associated with need for antihypertensive therapy and level of graft function.

Effect of aggressive risk factor modification on cardiac events and myocardial ischaemia in patients with chronic kidney disease

Objective: To examine whether aggressive risk factor modification in chronic kidney disease (CKD) can limit the development of new ischaemia or reduce cardiac events. Methods: Patients with CKD were randomly assigned to either an aggressive risk factor modification strategy (targeted treatment of hypertension, dyslipidaemia, homocysteine, haemoglobin and phosphate) or standard care. An intention to treat analysis was performed on 152 patients who had baseline dobutamine stress echocardiography (DSE), including 107 who had follow-up DSE. Biochemical parameters, cardiac risk factors and investigations (ECG, two-dimensional echocardiography) were recorded at baseline. New ischaemia was classed as new or worsening stress wall motion abnormality between follow-up and baseline DSE. Patients were followed up for the development of new ischaemia or cardiac death, acute coronary syndrome and non-fatal myocardial infarction over 1.8 years. Results: The development of new ischaemia was common but not different between the standard and aggressively treated groups (15 (21%) v 18 (23%), p  =  0.8). Independent predictors of new ischaemia were older age, abnormal ECG, higher systolic blood pressure and lower serum high density lipoprotein cholesterol, but not treatment arm. The standard and aggressively treated groups did not differ in cardiac event rate (10% v 13%, p  =  0.6) or all-cause mortality (10% v 19%, p  =  0.2). In patients with an abnormal baseline DSE (non-diagnostic, scar or ischaemia), the event rate was similar (22% v 20%, p  =  0.9). Conclusion: Aggressive risk factor modification in CKD does not limit the development of new ischaemia or reduce cardiac events in patients with an abnormal DSE.

Free fatty acids are associated with obesity, insulin resistance, and atherosclerosis in renal transplant recipients.

Background. Insulin resistance (IR) may be implicated in the pathogenesis of atherosclerosis in renal transplant recipients (RTRs) and be contributed to, in part, by free fatty acids (FFAs), produced in excess in centrally obese individuals. The aim of this study was to determine the prevalence of IR and the relationships between FFAs, central obesity, and atherosclerosis in a cohort of prevalent RTRs. Methods. Observational data were collected on 85 RTRs (mean age 54 years; 49% male, 87% Caucasian). Fasting serum was analyzed for FFAs, glucose, and insulin; IR was calculated using the homeostasis model assessment (HOMA-IR) score. Vascular structure was assessed by carotid intima-media thickness (IMT) measurement. Linear regression analyses were performed to determine the factors associated with IR and atherosclerosis. Results. IR occurred in 75% of RTRs, and FFA levels were independently associated with its occurrence (β: –0.55, 95% CI: –1.02 to –0.07, P = 0.02). Other variables independently associated with IR were male sex, body mass index, central obesity, diabetes, systolic blood pressure and corticosteroid use. There was a significant correlation between FFA levels and IMT (r = 0.3, P=0.01). On multivariate analysis, IMT correlated with elevated FFA (β: 0.07, 95% CI: 0.02–0.12, P = 0.007), diabetes mellitus (P = 0.05), older age (P < 0.002), and a body mass index >25 kg/m2 (P = 0.002). Conclusions. FFAs are associated with the development of IR and may be involved in the pathogenesis of atherosclerosis in RTRs. Additional studies are required to explore these associations further before considering whether an interventional trial aimed at lowering FFA would be a worthwhile undertaking.

Should an Oral Glucose Tolerance Test Be Performed Routinely in All Renal Transplant Recipients

Posttransplantation diabetes (PTD) contributes to cardiovascular disease and graft loss in renal transplant recipients (RTR). Current recommendations advise fasting blood glucose (FBG) as the screening and diagnostic test of choice for PTD. This study sought to determine (1) the predictive power of FBG with respect to 2-h blood glucose (2HBG) and (2) the prevalence of PTD using FBG and 2HBG compared with that using FBG alone, in prevalent RTR. A total of 200 RTR (mean age 52 yr; 59% male; median transplant duration 6.6 yr) who were > 6 mo posttransplantation and had no known history of diabetes were studied. Patients with FBG < 126 mg/dl (7.0 mmol/L; n = 188) underwent an oral glucose tolerance test (OGTT). Receiver operating characteristic analyses evaluated the optimal level of FBG predictive of PTD (2HBG > or = 200 mg/dl [11.1 mmol/L]) and impaired glucose tolerance (IGT; 2HBG 140 to 200 mg/dl [7.8 to 11.0 mmol/L]). An abnormal OGTT was reported in 79 (42%) nondiabetic RTR: PTD (n = 22) and IGT (n = 57). The optimal FBG that was predictive of PTD was 101 mg/dl (5.6 mmol/L; area under the curve 0.70; sensitivity 64%, specificity 67%, positive predictive value 20%, negative predictive value 93%). The optimal FBG that was predictive of IGT was less well defined (area under the curve 0.54). The prevalence of PTD was higher by OGTT than by FBG alone (17 versus 6%; P < 0.001). FBG may not be the optimal screening or diagnostic tool for PTD or IGT in RTR. Consideration should be given to introducing the OGTT as a routine posttransplantation investigation, although the implications of a pathologic OGTT are still to be determined in this population.

Cardiorespiratory Fitness Is Related to Physical Inactivity, Metabolic Risk Factors, and Atherosclerotic Burden in Glucose-Intolerant Renal Transplant Recipients

The mechanisms of reduced cardiorespiratory fitness (CF) in renal transplant recipients (RTR) have not been studied closely. This study evaluated the relationships between CF and specific cardiovascular risk factors (metabolic syndrome [MS], physical inactivity, myocardial ischemia, and atherosclerotic burden) in glucose-intolerant RTR. Data were recorded on 71 glucose-intolerant RTR (mean age 55 yr; 55% male; median transplant duration 5.7 yr). MS was defined using National Cholesterol Education Programme Adult Treatment Panel III criteria. Resting and exercise stress echocardiography were performed, and myocardial ischemia was identified by new or worsening wall motion abnormalities. Cardiorespiratory fitness was determined using peak oxygen uptake (VO(2)) by expired gas analysis. Atherosclerotic burden was assessed by carotid intima-media thickness (IMT). Mean peak VO(2) was 19 +/- 7 ml/kg per min and was significantly lower than predicted peak VO(2) (29 +/- 6 ml/kg per min; P < 0.001). Patients with MS (63%) had reduced CF (17 +/- 6 versus 22 +/- 8 ml/kg per min; P = 0.001) and were more likely to be physically inactive (76 versus 48%; P = 0.02). CF was reduced in 14 patients with myocardial ischemia (15 +/- 3 versus 20 +/- 7 ml/kg per min; P = 0.05). CF was positively correlated with male gender, height, and physical activity and inversely correlated with number of MS risk factors and IMT (adjusted R(2) = 0.66). Carotid IMT added incremental value to clinical variables in determining VO(2) (adjusted R(2) = 0.65 versus 0.63; P = 0.04). Reduced CF is associated with physical inactivity, MS, and atherosclerotic burden in glucose-intolerant RTR. Further studies should address whether increasing exercise and modifying MS risk factors improve CF in RTR.

Evaluation of Dietetic Advice for Modification of Cardiovascular Disease Risk Factors in Renal Transplant Recipients

OBJECTIVE To investigate the effect of dietitian involvement in a multidisciplinary lifestyle intervention comparing risk factor modification for cardiovascular disease with standard posttransplant care in renal transplant recipients (RTR) with abnormal glucose tolerance (AGT). DESIGN Randomized controlled trial. SETTING Hospital outpatient department. PATIENTS Adult RTR with AGT. INTERVENTION RTR with AGT were randomized to a lifestyle intervention that consisted of either regular consultations with the dietitian and multidisciplinary team or standard care. MAIN OUTCOME MEASURES Dietary intake, physical activity (PA) levels, cardiorespiratory fitness (CF), and anthropometry. RESULTS Total fat and percent saturated fat intake rates were significantly lower in the intervention group as compared with the control group at 2-year follow-up, 54 g (16 to 105 g) versus 65 g (34 to 118 g), P = .01 and 10% (5% to 17%) versus 13% (4% to 20%), P = .05., respectively. There was a trend for an overweight (but not obese) individual to lose more weight in the intervention group (4% loss vs. a gain of 0.25% at the 2-year follow-up). Overall, RTR were significantly less fit than age- and gender-matched controls, mean peak oxygen uptake was 19.42 ± 7.09 mL/kg per minute versus 28.35 ± 8.80 mL/kg per minute, P = .000. Simple exercise advice was not associated with any improvement in total PA or CF in either group at the 2-year follow-up. CONCLUSION Dietary advice can contribute to healthier eating habits and a trend for weight loss in RTR with AGT. These improvements in conjunction with multidisciplinary care and pharmacological treatment can lead to improvements in cardiovascular risk factors such as lipid profile. Simple advice to increase PA was not effective in improving CF and other measures are needed.

Higher Levels of Physical Activity Are Associated With a Lower Risk of Abnormal Glucose Tolerance in Renal Transplant Recipients

OBJECTIVE We investigated and compared diets and physical activity levels of renal transplant recipients (RTRs) with normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT), and we identified clinical risk factors for AGT. DESIGN This study was cross-sectional and observational. SETTING This study took place in a hospitals renal outpatient department. PATIENTS Patients included adult RTRs with NGT and AGT. MAIN OUTCOME MEASURE All patients were assessed regarding age, body mass index (BMI), waist circumference (WC), waist/hip ratio (WHR), percent body fat (measured using dual-energy x-ray absorptiometry), dietary intake (3-day diet diary), and physical activity (PA) levels (total minutes/week, using the Physical Activity Statewide Questionnaire). RESULTS The RTRs with AGT (n = 47) were significantly more obese (P = .04) and more centrally obese (P = .05) than RTRs with NGT (n = 35). The mean self-reported dietary macronutrient and energy intake was not significantly different between groups. However, the total amount of PA (median) was significantly lower in RTRs with AGT versus RTRs with NGT (255 [median, range 0 to 1940] versus 580 [median, 75 to 1095] minutes/week, respectively, P = .03), particularly in female RTRs (P = .007). After logistic regression analysis, total PA was identified as an independent predictor of AGT in all RTRs (beta = 0.940, R(2) = 0.090, P = .04). Percent body fat according to dual-energy x-ray absorptiometry was inversely associated with a high level of PA (>300 minutes/week) (beta = 0.906, R(2) = 0.211, P = .003). CONCLUSIONS A higher amount of PA is associated with a lower risk of AGT in RTRs (particularly in females). An emphasis on increasing PA should be encouraged for all RTRs.