J.P. Kooman

Undercarboxylated Matrix GLA Protein Levels Are Decreased in Dialysis Patients and Related to Parameters of Calcium-Phosphate Metabolism and Aortic Augmentation Index

Background: Vascular calcifications are related to cardiovascular mortality and morbidity in dialysis patients. Limited data exist on the role of calcification inhibitors, such as matrix-carboxyglutamic acid protein (MGP) in dialysis patients. Methods: In 120 dialysis patients and 41 age-matched healthy controls, circulating undercarboxylated (uc) MGP levels were measured with a novel ELISA-based competitive assay. The association between ucMGP levels and determinants of bone mineral metabolism, including the calcification inhibitor fetuin-A, was studied. Moreover, the relation between ucMGP levels and arterial stiffness was investigated. Results: The ucMGP level was significantly lower in dialysis patients compared to controls (173 ± 70 vs. 424 ± 126 nmol/l; p < 0.0001). After adjustment for age, sex and duration of dialysis an independent negative association between time-averaged phosphate levels [regression coefficient β with 95% confidence interval = –64 (–107 to –21)] and a positive association between serum ucMGP and fetuin-A [131 (55–208)] was observed. Duration of dialysis was inversely correlated with ucMGP (r = –0.24, p = 0.007). ucMGP levels were not related to high-sensitivity C-reactive protein or time-averaged calcium levels. After adjustment for age, sex, cardiovascular disease, diabetes, height and mean arterial pressure, ucMGP level was negatively associated with the aortic augmentation index [–0.036 (–0.061 to –0.010)] but not with pulse wave velocity or pulse pressure. Conclusion: Significantly lower serum ucMGP levels were observed in dialysis patients compared to healthy controls. ucMGP levels were inversely associated with phosphate and positively associated with serum fetuin-A levels. Furthermore, ucMGP levels were inversely associated with the aortic augmentation index. These data suggest that low ucMGP levels may be a marker of active calcification.

The functional, metabolic, and anabolic responses to exercise training in renal transplant and hemodialysis patients.

Background. Exercise intolerance is common in hemodialysis (HD) and renal transplant (RTx) patients and is related to muscle weakness. Its pathogenesis may vary between these groups leading to a different response to exercise. The aim of the study was to compare intrinsic muscular parameters between HD and RTx patients and controls, and to assess the response to exercise training on exercise capacity and muscular structure and function in these groups. Methods. Quadriceps function (isokinetic dynamometry), body composition (dual-energy x-ray absorptiometry), and vastus lateralis muscle biopsies were analyzed before and after a 12-week lasting training-program in 35 RTx patients, 16 HD patients, and 21 healthy controls. Results. At baseline, myosin heavy chain (MyHC) isoform composition and enzyme activities were not different between the groups. VO2peak and muscle strength improved significantly and comparably over the training-period in RTx, HD patients and controls (ptime<0.05). The proportion of MyHC type I isoforms decreased (ptime<0.001) and type IIa MyHC isoforms increased (ptime<0.05). The 3-hydroxyacyl-CoA-dehydrogenase activity increased (ptime=0.052). Intrinsic muscular changes were not significantly different between groups. In the HD group, changes in lean body mass were significantly related to changes in muscle insulin-like growth factor (IGF)-II and IGF binding protein-3. Conclusions. Abnormalities in metabolic enzyme activities or muscle fiber redistribution do not appear to be involved in muscle dysfunction in RTx and HD patients. Exercise training has comparable beneficial effects on functional and intrinsic muscular parameters in RTx patients, HD patients, and controls. In HD patients, the anabolic response to exercise training is related to changes in the muscle IGF system.

RELATION BETWEEN STEROID DOSE, BODY COMPOSITION AND PHYSICAL ACTIVITY IN RENAL TRANSPLANT PATIENTS

BACKGROUND Fat mass is increased in renal transplant (RTx) patients, which may have untoward metabolic and cardiovascular effects. The influence of steroids on body composition (BC), resting energy expenditure (REE), and substrate oxidation rates was assessed in stable RTx patients in a cross-sectional design. Also, the relation between physical activity and nutrient intake, respectively, and body composition was studied. METHODS 77 RTx patients (42 males, 35 females) were studied. Twenty-one patients were on 10 mg and 27 patients on 5 mg maintenance steroid dose; 29 patients were receiving steroid-free immunosuppression. Assessed were BC (DEXA, anthropometry), REE and substrate oxidation (indirect calorimetry), physical activity (Baecke questionnaire), and nutrient intake (dietary records). RESULTS BC was not different between the 0-, 5-, and 10-mg steroid group, and no relationship existed between cumulative dose of steroids and BC. REE and substrate oxidation also did not differ between the various groups, apart from a small increase in glucose and decrease in lipid oxidation in female patients using 5-mg steroids. Especially in females, leisure time physical activity was positively related with the percentage lean body mass (r=0.571, P=0.004) and inversely related with fat mass (r= -0.588, P=0.003). Nutrient intake and BC (corrected for physical activity) were not related. CONCLUSIONS No relation was observed between daily and cumulative steroid dosage and BC and between daily steroid dose and REE and substrate oxidation in RTx patients. Especially in female patients, physical activity level and the percentage of lean body mass concluded and body fat were significantly related.

Comparison of Outcomes on Continuous Ambulatory Peritoneal Dialysis Versus Automated Peritoneal Dialysis: Results from a USA Database

♦ Background and Objective: Automated peritoneal dialysis (APD) is being increasingly used as an alternative to continuous ambulatory peritoneal dialysis (CAPD). However, there has been concern regarding reduced sodium removal leading to hypertension and resulting in a faster decline in residual renal function (RRF). The objective of the present study was to compare patient and technique survival and other relevant parameters between patients treated with APD and patients treated with CAPD. ♦ Methods: Data for incident patients were retrieved from the database of the Renal Research Institute, New York. Treatment modality was defined 90 days after the start of dialysis treatment. In addition to technique and patient survival, RRF, blood pressure, and laboratory parameters were also compared. ♦ Results: 179 CAPD and 441 APD patients were studied. Mean as-treated survival was 1407 days [95% confidence interval (CI) 1211 – 1601] in CAPD patients and 1616 days (95% CI 1478 – 1764) in APD patients. Adjusted hazard ratio (HR) for mortality was 1.31 in CAPD compared to APD (95% CI 0.76 – 2.25, p = NS). Unadjusted as-treated technique survival was lower in CAPD compared to APD, with HR 2.84 (95% CI 1.65 – 4.88, p = 0.002); adjusted HR was 1.81 (95% CI 0.94 – 3.57, p = 0.08). Peritonitis rate was 0.3 episodes/patient-year for CAPD and APD; exit-site/tunnel infection rate was 0.1 and 0.3 episodes/patient-year for CAPD and APD respectively (p = NS). ♦ Conclusions: Patient survival was not significantly different between APD and CAPD patients, whereas technique survival appeared to be higher in APD patients and could not be explained by differences in infectious complications. No difference in blood pressure control or decline in RRF was observed between the 2 modalities. Based on these results, APD appears to be an acceptable alternative to CAPD, although technique prescription should always follow individual judgment.

Seasonal Variations in Mortality, Clinical, and Laboratory Parameters in Hemodialysis Patients: A 5-Year Cohort Study

BACKGROUND AND OBJECTIVES Mortality varies seasonally in the general population, but it is unknown whether this phenomenon is also present in hemodialysis patients with known higher background mortality and emphasis on cardiovascular causes of death. This study aimed to assess seasonal variations in mortality, in relation to clinical and laboratory variables in a large cohort of chronic hemodialysis patients over a 5-year period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study included 15,056 patients of 51 Renal Research Institute clinics from six states of varying climates in the United States. Seasonal differences were assessed by chi-squared tests and univariate and multivariate cosinor analyses. RESULTS Mortality, both all-cause and cardiovascular, was significantly higher during winter compared with other seasons (14.2 deaths per 100 patient-years in winter, 13.1 in spring, 12.3 in autumn, and 11.9 in summer). The increase in mortality in winter was more pronounced in younger patients, as well as in whites and in men. Seasonal variations were similar across climatologically different regions. Seasonal variations were also observed in neutrophil/lymphocyte ratio and serum calcium, potassium, and platelet values. Differences in mortality disappeared when adjusted for seasonally variable clinical parameters. CONCLUSIONS In a large cohort of dialysis patients, significant seasonal variations in overall and cardiovascular mortality were observed, which were consistent over different climatic regions. Other physiologic and laboratory parameters were also seasonally different. Results showed that mortality differences were related to seasonality of physiologic and laboratory parameters. Seasonal variations should be taken into account when designing and interpreting longitudinal studies in dialysis patients.

Peritoneal Dialysis in Patients with Primary Cardiac Failure Complicated by Renal Failure

Background/Aims: Clinical outcome in cardiorenal syndrome type II and treated with peritoneal dialysis (PD). Methods: Retrospective analysis over a period of 10 years. Results: Twenty-four patients with mean age at start of dialysis of 67 ± 10 years had mean survival on dialysis of 1.03 ± 0.84 years (median survival 1.0 year). The number of hospitalizations for cardiovascular causes were reduced (13.7 ± 26.5 predialysis vs. 3.5 ± 8.8 days/patient/month postdialysis, p = 0.001). Patients who survived longer than the median survival time (n = 12) also had a reduced number of hospitalizations for all causes (3.7 ± 3.8 predialysis vs. 1.4 ± 2.1 days/patient/month postdialysis, p = 0.041), a lower age (62 ± 10 vs. 71 ± 8 years, p = 0.013) and fewer had diabetes (2 vs. 7 patients, p = 0.039), but left ventricular ejection fraction was not different. Conclusion: After starting PD for cardiorenal syndrome, hospitalizations for cardiovascular causes were reduced for all patients. Survival after starting PD is highly variable. Age and diabetes seem to be significant prognostic factors, but not left ventricular ejection fraction.

Salt and Hypertension in End-Stage Renal Disease

Salt and fluid overload play an important role in the pathogenesis of hypertension in patients with end-stage renal disease. However, in the individual patient, the relation between salt loading and blood pressure response is variable and appears to be influenced by various neurohumoral regulatory mechanisms. This may also have implications for the pathogenesis of structural cardiovascular abnormalities in patients with end-stage renal disease.

The Predictive Value of C-Reactive Protein in End-Stage Renal Disease: Is It Clinically Significant?

Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Besides traditional risk factors, disturbances in mineral and bone metabolism and inflammation are thought to be responsible for the increased risk of death. In the last years C-reactive protein (CRP) has gained a lot of attention in the general population, especially with regard to its link with atherosclerosis. Although several studies suggest that CRP may be useful as a parameter in predicting future cardiovascular events in both the general population and in patients with end-stage renal disease, there is doubt about the clinical evidence of this assumption. A statistical association between CRP and cardiovascular disease was observed in various studies, but the predictive power of this association is markedly diminished when adjusted for other risk factors. The relative contributions of CRP as a marker, as a causative agent, or as a consequence of atherosclerotic vascular disease are unclear, both in the general population and in the dialysis population. The CRP levels are highly variable and influenced by intercurrent events in dialysis patients. In dialysis patients, it is possible to reduce the CRP levels by statins, although these agents do not reduce the cardiovascular mortality in diabetic dialysis patients.

Hypotension and Ultrafiltration Physiology in Dialysis

One of the main goals of dialysis therapy in patients with end-stage renal failure is removal of excess fluid that has accumulated during the interdialytic period. In this respect, hemodynamic instability with symptomatic hypotension will remain one of the most important complications in dialysis therapy especially as the number of elderly, cardiovascular-compromised patients on dialysis is still increasing. Although recent data are lacking, the incidence of hypotensive episodes is still reported to be around 20%. Symptomatic hypotension is not only a burden for the patient it also implicates expensive interventions leading to less effective treatment. Furthermore, recent data showed that also low preand postdialysis systolic blood pressures are increasing the relative risk for mortality in dialysis patients [1]. Moreover, blood pressure is even decreasing further as compared to the postdialysis blood pressure in some patients in the first 5–6 h after dialysis, as could be shown by Battle et al. [2]. Therefore, it is of utmost importance to optimize dialysis therapy with respect to blood pressure stability. Already in the late 1970s, Bergström [3] and Quellhorst et al. [4] showed that blood pressure was better maintained when fluid was withdrawn during either isolated ultrafiltration or hemofiltration as compared to combined ultrafiltration hemodialysis. Differences in blood volume preservation due to osmotic changes as well as differences in vascular reactivity due to differences in increase of sympathetic tone has been held responsible for the disparity in blood pressure stability [5, 6]. A theoretical analysis of the pathophysiology of intradialytic hypotension reveals 3 important factors: the fall in blood volume, a reduced vascular reactivity, which will even enhance the effect of structural cardiovascular abnormalities like decreased left-ventricular compliance [7].

Morphological changes of the venous system in uremic patients. A histopathologic study.

UNLABELLED Because of the decreased venous compliance in hypertensive dialysis patients, it was investigated whether their venous system exhibited structural abnormalities. Venous samples were taken during transplantation from the common and external iliac vein in 12 hypertensive and 6 normotensive uremic patients and from the distal inferior caval vein and the common iliac vein in 7 kidney donors and 5 autopsy patients without history of cardiovascular disease. The thickness of the venous media was significantly increased in hypertensive uremic patients as compared to controls, but did not differ between normotensive patients and controls. The quantity of medial collagen did not differ among the various groups. The smooth muscle content of the media was increased in 5 uremic patients (2 normotensive and 3 hypertensive patients), whereas almost no smooth muscle was observed in the media of controls. Intimal thickening was observed neither in uremic patients nor in controls. IN CONCLUSION increased medial thickness in hypertensive dialysis patients could be an explanation for the decreased venous compliance previously found in these patients.