Blog entry by Meguid El Nahas
A recent paper in the Journal of the American Soceity of Nephrology has linked physical exercise with a slower rate of eGFR decline in patients with CKD3.
Physical activity may counteract metabolic disturbances that promote the progression of CKD. To address this concept, we performed a longitudinal cohort study of 256 participants in the Seattle Kidney Study, a clinic-based study of CKD. Participants with an estimated GFR (eGFR) of 15-59 ml/min per 1.73 m(2) at baseline were eligible for the study. Physical activity was quantified using the Four-Week Physical Activity History Questionnaire. We used generalized estimating equations to test associations of physical activity with change in eGFR determined by longitudinal measurements of serum cystatin C. Mean baseline eGFR was 42 ml/min per 1.73 m(2). During a median 3.7 years of follow-up, the mean change in eGFRcystatin C was -7.6% per year (interquartile range, -16.8%, 4.9% per year). Participants who reported >150 minutes of physical activity per week had the lowest rate of eGFRcystatin C loss (mean -6.2% per year compared with -9.6% per year among inactive participants). In adjusted analyses, each 60-minute increment in weekly physical activity duration associated with a 0.5% slower decline per year in eGFR (95% confidence interval, 0.02 to 0.98; P=0.04). Results were similar in sensitivity analyses restricted to participants without cardiovascular disease or diabetes, or to participants with moderate/high physical function. After adjustment for eGFR at the time of questionnaire completion, physical activity did not associate with the incidence of ESRD (n=34 events). In summary, higher physical activity levels associated with slower rates of eGFR loss in persons with established CKD.
This is an interesting observation that falls within the usual trap of eGFR calculation and measurement.
The authors used eGFR Cystatin C to estimate changes in GFR, thus equating once more changes in a surrogate marker, in this instance CystatinC, as an indicator of changes in Glomerular Filtration Rate; that wasnt measured!
As with studies relying on eGFR Creatinine (MDRD or CKD-EPI equations), the use of such surrogate markers (serum creatinine or cystatin C) needs to take into considerations the non-GFR confounders associated with such a marker:
So for serum creatinine:
Dietary protein/creatine/creatinine intake
Creatine/creatinine metabolism and muscle mass
Tubular secretion of creatinine
For serum Cystatin C:
Obesity, smoking as well as inflammation have been associated with increased circulating levels of this bioamrker.
Therefore, when considering changes in the calculated eGFR based on these biomarkers, it is essential that the intervention under study doesnt affect the variable in other ways, independently, from changes in GFR.
So for example a low protein diet would improve the eGFR (creatinine) decline rate by decreasing serum creatinine/increasing eGFR through a reduction in dietary protein, changes in creatinine meatbolism as well as the possibility muscle wasting.
Now, in the publications under discussion the biomarker used to measure and calculate eGFR is Cystatin C, thus claiming that improved eGFR Cyst takes place in those undergoing regular physical exercise.
So we have to ask ourselves is Cystatin C affected by exercise through non-GFR pathways?
And the answer is possibly. Cystatin C is know to be raised in chronic inflammation. CKD is known to be associated with chronic inflammation. And...exercise is known to reduce inflammation in CKD patients. In a recent publication in JASN (April 2014), investigators in Leicester (UK) showed that acute exercise induced a systemic anti-inflammatory environment most likely mediated by increased plasma IL-6 levels. Furthermore, they noted that 6 months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation.
So once more one has to question whether the changes observed in the under discussion publication are directly related to changes in the rate of progression of CKD OR instead in the rate of progression of inflammatory changes associated with CKD and reflected in the changes in an inflammtory marker namely serum Cystatin C; possibly wrongly assumed in this study to reflect changes in GFR.
Increasingly the literature is overloaded with publications using eGFR as a synonym for measured GFR; this is a grave error and open to considerable misinterpretation whether serum creatinine measurement is used to estimate eGFR or whether it is Cystatin C as in the publication under discussion.
It is high time Nephrologists learn that if they want to study CKD progression they need to measure CKD progression and not rely on dubious and confounded surrogate biomarkers!