Effects of a Structured Physical Activity Program on Serum Adipokines and Markers of Inflammation and Volume Overload in Kidney Transplant Recipients

Background

As in the general population, low physical activity level has been associated with increased risk of all-cause and cardiovascular mortality in patients with chronic kidney disease (CKD) [1] and in patients after kidney transplantation (KTx) [2].

Recent studies have shown that KTx recipients have on average 4 times higher risk of cardiovascular complications compared to the healthy population [3,4], but their risk is still much lower than in patients with chronic kidney disease on the waiting list for kidney transplantation [4].

A significant deterioration of general condition of patients with CKD, especially those with end-stage renal disease, causes a gradual decline in physical activity observed in this group of patients, and their sedentary lifestyle frequently persists after KTx [5]. Decreased physical activity not reduces quality of life and mental state, but is also associated with a number of detrimental consequences such as worsening of already existing inflammation and altered metabolic and heart conditions. These changes lead to a progressive injury to the cardiovascular system and other organs and systems, resulting in a number of complications [6].

Early introduction of modifications in daily lifestyle can significantly reduce the metabolic disturbances and extend the survival of patients and grafts [7]. Fat tissue has been found to be hormonally active, with the expression of several adipokines that regulate energy metabolism. Adiponectin and leptin are mostly expressed in adipocytes [8,9]. Adiponectin increases insulin sensitivity without influencing insulin levels [9] and has strong anti-atherosclerotic and anti-inflammatory effects. Leptin, in turn, reduces the synthesis of insulin, decreases lipogenesis, increases lipolysis in adipose tissue, and increases the activity of the sympathetic nervous system [10].

Wolf et al. found that increased leptin concentrations in obese patients can play a role in the pathogenesis of diabetic changes in the kidneys, mainly through the binding of leptin to its receptors expressed in the proximal kidney tubules [11]. This shows that the kidney is not only the location of leptin metabolism but is also its target organ [11].

C-reactive protein is a marker of inflammation and has also been used as a marker of cardiovascular risk [12]. There is a tight inverse relationship between serum CRP and physical activity [13], but this relation is ambiguous because physical activity can lead to higher CRP concentrations [14].

Brain natriuretic peptide (BNP) is a natriuretic hormone secreted by cardiomyocytes, and its concentration reflects the volume of load on the cardiovascular system. Its serum concentration has been recognized as an independent cardiovascular risk factor in patients with impaired kidney function [15].

Most of the recent studies related to physical activity in CKD and KTx patients have focused on the dialysis population, and only a few included patients after kidney transplantation and compared them to the patients with CKD without a history of kidney transplantation. One recent study, conducted in a group of 32 subjects, revealed that physical activity increased by 30% in the first year after transplantation. Despite the increase, the level of physical activity in these patients was still comparable to the population of elderly people without renal insufficiency [16].

Another study revealed that an increase in habitual activity levels in CKD patients led to reduced systemic inflammation. The patients with highest baseline concentration of serum inflammation markers had the greatest benefits from physical training [13].

The aim of the present study was to compare the effects of a structured physical activity program on the biomarkers of inflammation and volume overload in patients after renal transplantation and in subjects with stage 3 and 4 chronic kidney disease.

Material and Methods

STATISTICAL ANALYSIS:

The results are presented as mean±SD. P value <0.05 was considered statistically significant. Data distribution was checked with the Kolmogorov-Smirnov test. Within-group comparisons were made using ANOVA for repeated measurements. The unpaired t test or Mann-Whitney test were used to test the differences between the 2 study groups. For dependency analysis between 2 variables, Pearson’s r correlation coefficient was calculated. The statistical analysis was performed using Statistica (v. 10PL, StatSoft, Tulsa, OK, USA).

Results

Active energy expenditure increased significantly compared with baseline after completion of the 3-month physical training program in both KTx and CKD patients, (by 47%, p<0.001 and 20%, p=0.01, respectively). The time spent daily on physical activity followed the same pattern of changes (129±83 vs. 194±142 and 81±56.7 vs. 124±57.3 min, respectively, p<0.001). Adipose tissue mass decreased significantly only in KTx recipients (from 40.8±1.6 to 38.5±10.3 kg, p=0.01).

Serum leptin decreased significantly in both KTx and CKD patients (from 11.5±7.0 to 10.0±5.6, p=0.03 and from 14.1±8.3 to 12.2±6.1 ng/mL, p=0.01, respectively). Serum adiponectin increased in KTx patients (from 1900±953 to 2015±1133 ng/L, p=0.004) but not in CKD patients (1881±909 and 1905±925 ng/L, respectively).

Adiponectin expressed per body fat mass (ATM) increased significantly after 3 months of physical activity only in the KTx group (from 484.6±185.3 to 548.6±234.3 ng/lxkg, respectively, p=0.002). A significant decrease of leptin/ATM after 3 months of training was observed only in the KTx group (0.36±0.3 to 0.34±0.3 ng/lxkg, p=0.022). The changes in adiponectin/ATM and leptin/ATM in the CKD group were not significant (p=0.10). These results are shown in Table 2.

The percentage changes of active energy expenditure, physical activity, serum adiponectin, serum leptin, and adipose tissue mass are presented in Figure 1.

Serum CRP decreased in both groups – from 15.1±5.2 to 14.0±5.6 mg/L (p=0.01) in KTx patients and from 16.5±3.9 to 15.4±4.3 mg/L (p=0.05) in CKD patients). A significant positive linear correlation between serum leptin and CRP in KTx group was found at baseline (r=0.59, p=0.007) and after 3 months of exercise training (r=0.72, p=0.0004, respectively). No significant correlations between serum leptin and CRP were found in the CKD group.

In the KTx group, we also found a significant negative correlation between CRP and adiponectin at baseline and at 3 months (r=−0.69, p=0.001; r=−0.77, p=0.001).

NT-proBNP at 3 months did not significantly change in either group (544±294 vs. 537±317 and 514±170 pg/mL vs. 512±161 pg/mL, respectively).

Discussion

The main finding of the study was the observation that the significant increase in physical activity in both KTx and CKD patients led to a simultaneous decrease of adipose tissue mass and increase of serum adiponectin concentration.

Although adiponectin is secreted by adipose cells, its concentration is inversely related to BMI [17], and this was also seen in our study. Our study showed that the changes in adiposity and serum adiponectin were inversely correlated in KTx patients. However, Boudou et al. found that serum adiponectin concentration remained unchanged despite a reduced adipose tissue mass and increased insulin sensitivity after 8 weeks of physical exercises in 16 middle-aged men with type 2 diabetes and without significant impairment of kidney function [18].

It has been recently shown that serum adiponectin levels are higher in patients with CKD and in patients receiving renal replacement therapy including hemodialysis and peritoneal dialysis [19], most probably due to reduced clearance of adiponectin by the kidneys [19,20]. We observed higher concentrations of adiponectin after the training program, both in TX and CKD patients.

Taherimahmoudi et al. found that the level of adiponectin was higher in kidney transplant candidates than in healthy subjects, and remained increased even after kidney transplantation [21]. In this context, it would be worth analyzing to what extent our findings were the result of increased physical activity, and to what extent they were caused by the kidney function impairment itself.

It is noteworthy that the higher beneficial effect in the group of kidney transplant patients may be related with the difference in psychological status between the 2 groups.

In CKD patients, there was decreased leptin concentration at the end of the study, despite the fact that adipose tissue mass did not change in these patients. Recent studies reported that leptin level is correlated with high CRP level [22,23]. At the end of our study, CRP levels in both groups were significantly lower than at baseline, which might be influenced by the significant reduction of adipose tissue mass in both groups.

Scotece et al. [24] showed that despite the important role played by leptin in the initiation of inflammation processes, the use of agents that inhibit inflammatory cytokines did not affect its serum concentration.

We showed a significant reduction of serum C-reactive protein in both groups, which may be indirect evidence of a potentially beneficial effect of physical activity on chronic inflammation in patients with CKD and in KTx patients. It is important to mention that CRP can increase immediately as a response to exercise, but in our study the long-term effect was assessed [25]. However, CKD patients are a sedentary population with physical activity levels that are significantly lower than recommended by national guidelines [26,27]. Physical capacity is markedly lower in CKD stages 3–5 compared to healthy subjects, and higher CRP directly after exercise might not occur or might be lower than would be expected due to the much less strenuous exercise performed [28–30]. Moreover, in our study, we did not measure serum CRP immediately after exercise [26].

NTpro-BNP has been recognized as a serum marker of overhydration. Booth et al. showed that NT-pro BNP expression is modulated not only by volume overload, but is also affected by malnutrition [31]. It was demonstrated that high fluid status and high fat tissue index were associated with impaired upper and lower extremity muscle endurance in CKD patients [32].

In our study, NTpro-BNP concentration was unchanged despite the changes in ATM and adipokines in CKD and KTx patients. Our results contrast with some previous studies. Neeland et al. [33] showed that higher concentrations of BNP were independently associated with reduced visceral and hepatic adipose tissue mass and increased adipose tissue mass of the lower body parts, suggesting a direct relationship between adipose tissue mass and its hormonal activity and the production of the natriuretic peptides.

Our patients were encouraged to undertake physical activity through short text message reminders. Sarabi et al. confirmed the role of mobile technologies in patient compliance [34], but it has not been confirmed by other studies [35].

Our study has several limitations. We did not measure interleukin-6, which is directly secreted from visceral fat to the portal circulation and reaches the liver in high concentrations [36]. Another important issue is the lack of a thoroughly conducted assessment of the effect of medicines taken by the patients during the study, especially renin-angiotensin-aldosterone system blocking drugs, but it is noteworthy that the dose of all the concomitant drugs was unchanged for at least 3 months before and, more importantly, during the study. Another limitation of our study is that much of the biologically active adiponectin molecule is thought to arise from high molecular weight forms, and total levels may be only be a surrogate indicator of this [37].

Conclusions

In summary, the beneficial impact of physical activity on adipokines in both groups was demonstrated, with more pronounced effect in patients after kidney transplantation. This physical activity program benefit KTx recipients.