De la discriminación inversa de Dworkin

Despite evidence from cross sectional and longitudinal studies in healthy populations indicating that physical activity can decrease CRP levels (Plaisance &

Grandjean 2006) and coupled with the knowledge that CRP is a strong predictor of outcome in HD patients (Yeun et al 2000), very few exercise studies have examined or reported the influence of exercise on CRP. To date two studies employing 12 week intradialytic resistance interventions have reported a reduction in CRP (Nindl et al 2004, Cheema et al 2007). One was a small, uncontrolled study (Nindl et al 2004) and whilst reporting reductions in CRP, it was unclear whether they were statistically significant. In contrast to these results, two controlled studies, one intradialytic aerobic intervention of 12 weeks duration (Toussaint, Polkinghorne &

Kerr 2008) and one interdialytic combined aerobic/resistance intervention of 5 months, demonstrated no significant change in CRP (Kopple et al 2007). Therefore, whether exercise in HD patients can positively influence CRP requires further study.

Furthermore, exploring the impact of exercise on CRP in the wider context would also provide information on whether exercise can positively influence the management of anaemia.

There is some evidence from studies conducted in the pre ESA era that long term (at least 12 months duration) interdialytic high intensity (75-85% HR_max) aerobic interventions in young HD patients with little comorbidity can increase haemoglobin

and haematocrit levels over time (Goldberg et al 1983, Goldberg et al 1986).

However, the relevance of these findings in a post ESA era where patients are older and with a greater degree of comorbidity is questionable. In the post ESA era, one controlled study (Miller et al 2002) of intradialytic aerobic exercise has suggested positive changes may occur. In this study of intradialytic aerobic exercise a significant reduction in ESA dose and an increased haematocrit were observed at 6 months. Another uncontrolled 6 month study of intradialytic aerobic exercise (Anderson, Boivin & Hatchett 2004) also found that a reduction in ESA dose, coupled with an increased haematocrit occurred as a result of the intervention, but these changes were not statistically significant. CRP was not measured in either study, which would have aided the interpretation of these findings. Conversely, the majority of the available evidence in the post ESA era suggests that neither resistance interventions nor aerobic interventions can positively influence haemoglobin or haematocrit levels (Cappy, Jablonka & Schroeder 1999, Koufaki, Mercer & Naish 2002a, Van Vilsteren, de Greef & Huisman 2004, Mustata et al 2004, Parsons, Toffelmire & VanVlack 2004, Parsons, Toffelmire & King-VanVlack 2006, Kopple et al 2007, Toussaint, Polkinghorne & Kerr 2008). However, as haemoglobin levels are being constantly titrated to therapeutic targets (Singh 2008), examining haemoglobin without examining changes in ESA doses could be misleading. In addition as inflammation can affect responsiveness to ESA’s, the omission of inflammatory markers such as CRP could be misleading. Only two of the above studies (Kopple et al 2007, Toussaint, Polkinghorne & Kerr 2008) measured CRP levels and only one study examined changes in ESA doses, but they did not report the significance of their findings (Cappy, Jablonka & Schroeder 1999). Due to these omissions in methodology the effect of exercise and, in particular, the effects of longer term interventions on the management of anaemia remain inconclusive.

Further to the changes overleaf, there is a small body of evidence in hypertensive HD patients, that suggests positive improvements in systolic blood pressure (SBP) are possible as a consequence of either combined intradialytic resistance and aerobic interventions (Deligiannis et al 1999, Ouzouni et al 2009), interdialytic aerobic (Hagberg et al 1983) or intradialytic aerobic exercise interventions (Painter et al 1986, Anderson, Boivin & Hatchett 2004, Macdonald et al 2005). However, this evidence is not consistent, with a number of other studies failing to report significant improvements in blood pressure (Shalom et al 1984, Ross et al 1989, Cappy, Jablonka & Schroeder 1999, De Paul et al 2002, Van Vilsteren, de Greef & Huisman 2004, Molsted et al 2004, Parsons, Toffelmire & King-VanVlack 2004, Toussaint, Polkinghorne & Kerr 2008).

Doses of antihypertensive drugs are constantly being titrated to maintain therapeutic blood pressure targets (Mactier 2007); therefore it is possible that decreases in prescribed antihypertensives may occur in the absence of changes in SBP. This aspect however has been ignored in all but two of the studies reporting no significant changes in blood pressure (Shalom et al 1984, Molsted et al 2004).

Decreases in antihypertensives have been seen in other studies of either interdialytic (Goldberg et al 1983, Hagberg et al 1983, Goldberg et al 1986) or intradialytic aerobic interventions (Miller et al 2002, Macdonald et al 2005). Changes in interdialytic weight gains and ECW volumes may also influence blood pressure (Lopez-Gomez et al 2005, Charra 2007).These aspects have also been ignored with the exception of one study which reported a significant decrease in ECW which could have contributed to the observed decrease in systolic blood pressure (Macdonald et al 2005).

It is equally possible that, in studies reporting no significant changes in blood pressure, the mode of exercise or the frequency, intensity or duration of the exercise intervention was insufficient to derive such changes. In comparison the majority of studies demonstrating positive effects have been of at least 6 months duration (Goldberg et al 1983, Hagberg et al 1983, Goldberg et al 1986, Painter et al 1986, Deligiannis et al 1999, Miller et al 2002, Anderson, Boivin & Hatchett 2004, Ouzoni et al 2009). Furthermore, the patients recruited to these particular studies were younger with arguably a lower level of comorbidities due to their age and the recruitment process (VO₂max/peak) which may have been influenced the results.

Four of the studies demonstrating positive effects were conducted in the pre ESA era (Goldberg et al 1983, Hagberg et al 1983, Goldberg et al 1986, Painter et al 1986) and as it is known that ESAs have a dose dependent effect on blood pressure, potentially aggravating hypertension (van de Borne et al 1992) these studies are perhaps less relevant now. If these studies are excluded then the body of evidence suggesting a beneficial effect of exercise on blood pressure diminishes and is limited to five studies. Two of these studies were combined resistance and aerobic interventions (Deligiannis et al 1999, Ouzoni et al 2009) and three were intradialytic aerobic interventions (Miller et al 2002, Anderson, Boivin & Hatchett 2004, Macdonald et al 2005). This suggests that further work is required to confirm such findings, particularly in older patients and those with a greater degree of comorbidity.

It has been hypothesised that intradialytic aerobic exercise interventions, via what is assumed to be an increase in the perfusion of skeletal muscles, may have the added advantage of increasing solute removal and thereby improving dialysis efficiency and uraemia (Cappy, Jablonka & Schroeder 1999, Kong et al in 1999, Daul et al 2004, Parsons, Toffelmire & King-VanVlack 2006). It is therefore

possible that this affect may act as a contributory mechanism to improvements seen in these types of exercise intervention studies.

One of the first studies to report a possible effect of intradialytic exercise on dialysis adequacy was a study of 11 HD patients, in which, by means of paired dialysis sessions, the effects of a single 60 minute session of intradialytic aerobic exercise versus no exercise was examined (Kong et al 1999). In this study, exercise was shown to significantly reduce the rebound of urea, creatinine and potassium and significantly increase the dialysis efficiency (Kt/v and URR) of that session. A subsequent study, demonstrated by means of two separate studies conducted over a week, that either an extended dialysis time or an unaltered dialysis time plus 30-60 minutes of intradialytic aerobic exercise resulted in improved removal of phosphate, with the latter considered to be more favourable from a patients perspective (Vaithilingham et al 2004).

Two exercise intervention studies, (Cappy, Jablonka & Schroeder 1999, Parsons, Toffelmire & King-VanVlack 2006) have reported improvements in dialysis efficiency attributed to the exercise intervention. Both studies were of a longer duration (12 months and 5 months respectively) with one involving at least 30 minutes of aerobic exercise during dialysis (Parsons, Toffelmire & King-VanVlack 2006) and the other involving 30 minutes of aerobic exercise immediately prior to dialysis (Cappy, Jablonka & Schroeder 1999). In contrast, studies of shorter duration (3 months or less) involving less than 30 minutes of intradialytic aerobic exercise or resistance exercise have failed to show any improvement in URR or Kt/v (Frey, Mir & Lucas 1999, Kopple et al 2007, De Paul et al 2002, Van Vilsteren, de Greef & Huisman 2004, Parsons, Toffelmire & King-VanVlack 2004, Cheema et al 2007). However, none of these studies report having controlled for the factors known to influence

URR and Kt/v such as dialyser size, type, effective blood flow, treatment time and muscle mass. Moreover, whilst it would be reasonable to postulate that the improved efficiency in dialysis could contribute to positive changes in function, nutritional and clinical status, the limited outcome measures used in the above studies make this difficult to confirm.