Resistance Exercise in People With Stage-3 Chronic Kidney Disease: Effects of Training Frequency (Weekly Volume) on Measures of Muscle Wasting and Function.

Background: Resistance training (RT) is a proven anabolic intervention in people living with and without chronic kidney disease (CKD). To date, there is a dearth of knowledge regarding the dose-response relationship of RT in the non-dialysis dependent CKD population. Therefore, we aimed to explore the effects of RT frequency (weekly volume) on established measures of muscle wasting and function in CKD. Methods: Twenty people with stage-3 CKD (CKD-3) were allocated to either a low frequency (one-session per week, RT1) or higher frequency (three-sessions per week, RT3) 12-week RT programme consisting of lower extremity strengthening exercises. The two RT programmes were not volume matched. Assessment outcomes before and after the intervention included measures of total and regional body composition, muscle size and architecture, strength, physical function, and uraemic symptoms. Results: Significant improvements over time in muscle size and architecture, strength, physical function, and uraemic symptoms were observed for both RT1 and RT3. Compared to RT1, participants who performed RT3 showed greater increases in vastus lateralis (VL) anatomical cross-sectional area (30.8% vs. 13.2%, p < 0.001) and pennation angle (36.3% vs. 17.5%, p = 0.008) after 12 weeks. In either group, there were no significant changes over time in mid-VL fascicle length, nor in measures of total body composition and upper arm muscle strength. Conclusion: Despite the group differences observed in the VL physiological adaptations, the strength and physical function responses, as well as the reductions of uraemic symptoms, were similar whether training once or thrice weekly. Therefore, performing RT just once per week may be an effective pre-habilitation strategy for people with CKD-3.

Validity and reliability of high-resolution ultrasound imaging for the assessment of regional body composition in stage 5 chronic kidney disease patients undergoing continuous ambulatory peritoneal dialysis.

BACKGROUND: Accurate measurement of muscle mass is an important research and clinical tool. High-resolution ultrasound (US) has shown potential as a method to assess muscle and fat mass at specific anatomical sites. However, there is limited evidence for the reliability of US to measure muscle size in patients receiving continuous ambulatory peritoneal dialysis (CAPD). Therefore, we examined the validity and reliability of an US method compared to a gold standard comparison for the assessment of a quadriceps muscle in this clinical population. METHODS: Twenty people receiving CAPD (mean age = 56.5 ± 16.7 years) at a single dialysis unit were assessed on two occasions, 7 days apart. Measures of the mid-thigh, such as vastus lateralis (VL) anatomical cross-sectional area (ACSA), VL muscle thickness and subcutaneous fat thickness were compared for US reliability and validity compared to magnetic resonance imaging (MRI) measures. RESULTS: US had high validity against gold standard MRI measures, with intraclass correlation coefficients (ICC) equating to VL ACSA of 0.95, VL thickness of 0.99 and fat thickness of 0.98. The US measurements also exhibited high intra-rater reliability (ICCs: VL thickness = 0.98, total muscle thickness = 0.97 and fat thickness = 0.99) in measuring body composition at the mid-VL site in the study population. CONCLUSIONS: Valid assessment of regional body composition can be achieved via high-resolution US in patients receiving CAPD. The validity and reliability of the US in repeated measures (in comparison to the gold standard MRI) warrant further investigation in the wider chronic kidney disease population.

Patients receiving maintenance dialysis have more severe functionally significant skeletal muscle wasting than patients with dialysis-independent chronic kidney disease.

BACKGROUND: Chronic renal replacement therapy patients exhibit reduction in skeletal muscle function as a result of a combination of metabolic effects and muscle fibre size reduction. The aim of this study was to compare muscle mass with function in patients with chronic kidney disease (CKD) at stages 4 and 5 on haemodialysis (HD) and peritoneal dialysis (PD), and investigate the associations of muscle wasting in a cross-sectional cohort. METHODS: We studied 134 patients (60 HD, 28 PD and 46 CKD 4). The three groups were well matched for age, sex, diabetes and dialysis vintage. Cross-sectional area (CSA) of muscle and fat was measured from a standardized multi-slice CT scan of a 6 cm long section of thigh. CSA of soft tissue was taken from appropriate fat and muscle densities. Functional assessment was by the sit-to-stand 60 test, assessing both the number of sit-to-stands possible under controlled conditions in 60 s (STS 60), and the time taken to perform five sit-to-stand movements (STS 5). Data were collected on a wide range of potential determinants of muscle CSA. RESULTS: There were no significant differences in haemoglobin between males or females or between any of the groups studied. Serum phosphate and calcium-phosphate product were higher in HD patients as compared to CKD4 patients, but there were no differences in these variables when comparing PD patients with either CKD4 or HD patients. Muscle CSA correlated well with objective functional assessments in males (STS 60 R = 0.52, P<0.0001) and females (R = 0.41, P = 0.004), and STS performance was reduced in dialysed patients as compared with CKD 4. Univariate analysis demonstrated that muscle CSA was associated with serum albumin concentration (R = 0.49, P<0.0001), age (R = -0.35, P = 0.005) and C-reactive protein (R = -0.34, P = 0.004). Creatinine clearance, dialysis adequacy, dialysis vintage and time-averaged serum bicarbonate, calcium and phosphate concentrations were not correlated with muscle CSA. CONCLUSION: In conclusion, patients with dialysis-treated CKD 5 exhibited more functionally significant muscle wasting than patients with CKD 4. This may be amenable to modification with targeted exercise or amelioration of factors associated with observed differences in muscle mass.

Influence of recombinant human erythropoietin treatment on pulmonary O2 uptake kinetics during exercise in humans.

We hypothesized that 4 weeks of recombinant human erythropoietin (RhEPO) treatment would result in a significant increase in haemoglobin concentration ([Hb]) and arterial blood O(2)-carrying capacity and that this would (1) increase peak pulmonary oxygen uptake during ramp incremental exercise, and (2) speed kinetics during 'severe'-, but not 'moderate'- or 'heavy'-intensity, step exercise. Fifteen subjects (mean +/- s.d. age 25 +/- 4 years) were randomly assigned to either an experimental group which received a weekly subcutaneous injection of RhEPO (150 IU kg(-1); n = 8), or a control group (CON) which received a weekly subcutaneous injection of sterile saline (10 ml; n = 7) as a placebo, for four weeks. The subjects and the principal researchers were both blind with respect to the group assignment. Before and after the intervention period, all subjects completed a ramp test for determination of the gas exchange threshold (GET) and , and a number of identical 'step' transitions from 'unloaded' cycling to work rates requiring 80% GET (moderate), 70% of the difference between the GET and (heavy), and 105% (severe) as determined from the initial ramp test. Pulmonary gas exchange was measured breath-by-breath. There were no significant differences between the RhEPO and CON groups for any of the measurements of interest ([Hb], kinetics) before the intervention. Four weeks of RhEPO treatment resulted in a 7% increase both in [Hb] (from 15.8 +/- 1.0 to 16.9 +/- 0.7 g dl(-1); P < 0.01) and (from 47.5 +/- 4.2 to 50.8 +/- 10.7 ml kg(-1).min(-1); P < 0.05), with no significant change in CON. RhEPO had no significant effect on kinetics for moderate (Phase II time constant, from 28 +/- 8 to 28 +/- 7 s), heavy (from 37 +/- 12 to 35 +/- 11 s), or severe (from 33 +/- 15 to 35 +/- 15 s) step exercise. Our results indicate that enhancing blood O(2)-carrying capacity and thus the potential for muscle O(2) delivery with RhEPO treatment enhanced the peak but did not influence kinetics, suggesting that the latter is principally regulated by intracellular (metabolic) factors, even during exercise where the requirement is greater than the , at least in young subjects performing upright cycle exercise.

Skeletal muscle morphology and capillarization of renal failure patients receiving different dialysis therapies.

The morphology of gastrocnemius muscles was examined in RFPs (renal failure patients) being treated using HD (haemodialysis) and CAPD (continuous ambulatory peritoneal dialysis). RFPs (n=24) volunteered to participate in the present study. Twelve RFPs (five women and seven men; mean age, 55 years) were undergoing CAPD treatment and 12 RFPs (two women and ten men; mean age, 62 years) were undergoing HD treatment. Muscle biopsies from gastrocnemius muscles were found not to differ (P>0.05) in fibre type distribution, MyHC (myosin heavy chain) expression or fibre CSA (cross-sectional area) between the two groups. There were, however, significant differences (P<0.05) in CC/F (capillary contact/fibre), C/F (capillary to fibre ratio) and cytochrome c oxidase activity. The HD group had 33% more CC/F, with a 19% higher C/F and 33% greater cytochrome c activity in glycolytic fibres (II) than the CAPD group. There were no apparent differences in age, gender, co-morbidity, self-reported physical activity or physical functioning between the two groups, which could account for the difference in muscle capillarity between the groups. The HD patients were, however, administered heparin as a routine part of the dialysis therapy. The possibility is discussed that heparin in combination with mild anaemia and acidosis may have augmented angiogenesis in the HD patients.

Atrophy of non-locomotor muscle in patients with end-stage renal failure.

BACKGROUND: All previous histological studies of skeletal muscles of patients with renal failure have used locomotor muscle biopsies. It is thus unclear to what degree the observed abnormalities are due to the uraemic state and how much is due to disuse. The present study was undertaken to attempt to investigate this question by examining a non-locomotor muscle (rectus abdominis) in patients with end-stage renal failure. METHODS: Biopsies from rectus abdominis were obtained from 22 renal failure patients (RFPs) undergoing surgical Tenchkoff catheter implantation for peritoneal dialysis and 20 control subjects undergoing elective abdominal surgery. Histochemical staining of frozen sections and morphometric analysis was used to estimate the proportion of each fibre type, muscle fibre area and capillary density. Myosin heavy chain composition was examined by SDS-PAGE. RESULTS: There were no differences in fibre type distribution between RFPs and controls. All RFPs showed fibre atrophy [mean cross-sectional area (CSA) 3300 +/- 1100 microm2, compared to 4100 +/- 1100 microm2 in controls (P < 0.05)]. All fibre types were smaller in mean CSA in RFPs than in controls (15, 26 and 28% for types I, IIa and IIx, respectively). These differences could not be accounted for by differences in age, gender or cardiovascular or diabetic comorbidity. Muscle fibre capillarization, expressed as capillaries per fibre or capillary contacts per fibre, was significantly less in RFPs. CONCLUSIONS: Since a non-locomotor muscle was examined, the effects of disuse as a cause of atrophy have been minimized. It is likely, therefore, that the decreased muscle fibre CSA and capillary density of RFPs compared to controls were due predominantly to uraemia itself.

Changes in muscle morphology in dialysis patients after 6 months of aerobic exercise training.

BACKGROUND: In the present study we investigated the effect of a 6-month aerobic exercise programme on the morphology of the gastrocnemius muscle of end-stage renal disease (ESRD) patients. METHODS: Twenty-four ESRD patients volunteered to participate in the training programme and underwent muscle biopsy before training. Eighteen patients completed the training programme of whom nine agreed to a post-training biopsy (one woman and eight men, mean age 56 +/- 15 years). Data are presented for the nine subjects who were biopsied before (PRE) and after training (POST) and separately for the 15 subjects for whom we only have a biopsy before training (cross-sectional group). RESULTS: There were no significant differences (P > 0.05) in fibre type distribution or myosin heavy chain (MyHC) expression between the cross-sectional and PRE/POST groups. The mean cross-section fibre area after training (POST) increased by 46% compared with the PRE training status (P < 0.01). The proportion of atrophic fibres decreased significantly after training in type I, IIa and IIx fibre populations (from 51 to 15%, 58 to 21% and 62 to 32%, respectively). Significant differences were also found in capillary contact per fibre (CC/F), with the muscle having 24% (P < 0.05) more CC/F compared with the PRE training status. No significant differences in cytochrome c oxidase concentration were found between the groups. CONCLUSIONS: In conclusion, exercise appeared to be beneficial in renal rehabilitation by correcting the fibre atrophy, increasing the cross-section fibre area and improving the capillarization in the skeletal muscle of renal failure patients.

An alternative histochemical method to simultaneously demonstrate muscle nuclei and muscle fibre type.

We present a modified histochemical method to examine, simultaneously, nuclei and fibre type in human skeletal muscle. The new procedure (Haem-ATPase) is based on two previously used histochemical protocols. Biopsies were obtained from the rectus abdominis muscle of patients undergoing elective abdominal surgery. Fibre type composition, cross-sectional area (CSA) and nuclei to fibre ratio (N:F) were determined from frozen sections of each biopsy. To test the validity of the new method, serial sections of each biopsy were stained separately using the standard and modified methods. No differences were found in fibre type distribution, mean-weighted CSA and N:F when comparing the modified method with the standard methods. The Haem-ATPase method was found to shrink fibre size by at least 3% ( P>0.05) compared with the established myosin acid labile method. We propose that this modified technique is suitable for initial examination of both the nuclei and fibre type in the same frozen sections of human skeletal muscle.

Quantifying comorbidity in peritoneal dialysis patients and its relationship to other predictors of survival.

BACKGROUND: Comorbidity is the single most important determinant of outcome in patients on renal replacement therapy. The aims of this study were to evaluate a semi-quantitative approach to comorbidity scoring in predicting survival of patients commencing peritoneal dialysis (PD), and to establish the interaction between this and other known predictors of patient outcome, in particular membrane function, residual renal function (RRF) and plasma albumin. METHODS: Comorbidity was recorded in a prospective, single centre cohort study of 303 patients commencing on PD. Using seven disease domains, chosen to reflect the dominance of cardiovascular morbidity in the end-stage renal failure population, comorbidity was graded as '0' when absent, '1' when one or two, and '2' when three or more conditions were present. The Wright comorbidity index, which includes age within the scoring method, was also evaluated. RRF, plasma albumin and peritoneal solute transport were measured every 6 months. Patients were censored at death. RESULTS: Median survival according to grade of comorbidity was 105, 42 and 29 months, respectively (P<0.0001), with good separation of the actuarial survival curves. Using Cox regression, the addition of age and the grade of comorbidity to Kt/V(urea), solute transport and plasma albumin increased the predictive power of the model. All were independent predictors of outcome with the exception of albumin. The Wright comorbidity index also enhanced the Cox model, although was not as powerful as when age and comorbidity were considered independently. At baseline, RRF was not different according to comorbidity unless diabetes was considered separately. Diabetics started with higher RRF, but after 6 months on PD this was the same as non-diabetic patients. Otherwise, initial rate of decline of RRF was similar across the comorbid grades, although the impact of higher drop-out due to earlier loss in patients with more comorbidity may have disguised earlier loss in these patients. Peritoneal solute transport tended to be higher in patients with increased comorbidity at baseline, chi(2) 13.8, P=0.032, and this was sustained with time on treatment. CONCLUSION: Comorbidity has a quantitative effect on survival that is independent of age, RRF and membrane function in PD patients. Comorbidity also appears to be associated with increased solute transport at the start of treatment, which is sustained. With the exception of diabetes, grade of comorbidity does not have a profound effect on loss of RRF.

Effects of exercise training on aerobic and functional capacity of end-stage renal disease patients.

The aim was to assess the effects of exercise training on aerobic and fuctional capacity of patients with end-stage renal disease (ESRD). Patients completed an incremental exercise test on a cycle ergometer to determine VO2 peak and VO2 at ventilatory threshold (VT; V-slope). On a separate day they performed two constant load exercise tests on a cycle ergometer at 90% of VT and at a workload of 33 W, to determine VO2 kinetics. Functional capacity was assessed using measurements of sit-to-stands (STS-5, STS-60) and a walk test. Dialysis patients were randomly allocated to an exercise (ET: n = 18, age = 57.3 years) or control (C: n = 15, age = 50.5 - 5 years) group. The ET group participated in an exercise training programme involving cycling for 3 months. Repeated measures ANOVA revealed significant time by group interactions (P < 0.05) following training for VO2 peak (ET: 17 +/- 6.1 versus 19.9 +/- 6-3, C: 19.5 +/- 4.7 versus 188 +/- 4.9 ml kg min(-1)) and VO2-VT (ET: 10.7 +/- 3.5 versus 11.8 +/- 3.3, C:12.9 +/- 3.2 versus 119 +/- 3.5 ml kg min(-10). VO2 kinetics remained unchanged in both groups at 90% -VT, but a trend (P = 0.059) towards faster kinetics at the 33 W was observed (ET: 49.6 +/- 19.5 versus 37.8 +/- 12.7, C: 42.8 +/- 13 versus 49.4 +/- 20.2 s). Significant time by group interactions (P < 0.05) were also observed for STS-5 (ET: 14.7 +/- 6.2 versus 11.0 +/- 3.3, C: 12.8 +/- 4.4 versus 12.7 +/- 4.8 s) and STS-60 measurements (ET: 21.2 + 7.2 versus 26.9 +/- 6.2, C: 23.7 +/- 6.8 versus 24.1 +/- 7.2). Three months of exercise rehabilitation significantly improves peak exercise capacity of patients with ESRD. Measurements of VO2 kinetics and functional capacity suggest that longer time might be needed to induce peripheral adaptations.

Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis.

Peritoneal solute transport increases with time on treatment in a proportion of peritoneal dialysis (PD) patients, contributing to ultrafiltration failure. Continuous exposure of the peritoneum to hypertonic glucose solutions results in morphologic damage that may have a causative role in changes in peritoneal function. The purpose of this analysis was to establish whether increased exposure to glucose preceded changes in solute transport in a selected group of long-term PD patients. Peritoneal solute transport, residual renal function, peritonitis rate, and peritoneal exposure to glucose were recorded prospectively in a cohort of 303 patients at a single dialysis center. A subgroup of individuals, treated continuously for 5 yr, were identified and defined retrospectively as having either stable or increasing transport status. Of the 22 patients who were treated continuously for 5 yr, 13 had stable solute transport (solute transport at start, 0.67 [+/-0.1]; at 5 yr, 0.67 [+/-0.1]), whereas 9 had a sustained increase (solute transport at start, 0.56 [+/-0.08]; at 5 yr, 0.77 [+/-0.09]). Compared with the stable patients, those with increasing transport had earlier loss in residual renal function and were exposed to significantly more hypertonic glucose during the first 2 yr of treatment that preceded the increase in solute transport. This was associated with greater achieved ultrafiltration compensating for the reduced urinary volumes in these patients. Further increases in glucose exposure were observed as solute transport continued to rise. Peritonitis, including severity of infection and causative organism, was similar in both groups. In this selected group of long-term survivors on PD, an increase in solute transport with time was preceded by increased peritoneal exposure to hypertonic glucose. This is supportive evidence that hypertonic glucose may play a causative role in alterations in peritoneal membrane function.