Background
The worldwide prevalence of chronic kidney disease (CKD) continues to increase [
1]. CKD patients develop many complications, which lead to a high risk of co-morbidities and mortality [
2‐
4].Therefore, two issues are important for healthcare professionals caring for CKD patients: (1) prolonging the life span and (2) improved quality of life of patients.
CKD patients have a poor quality of life [
5]. This may be attributed to the underlying disease or to the complications associated to CKD. The Dialysis Outcomes and Practice Patterns Study (DOPPS), a large, international, observational study, demonstrated that quality-of-life indicators from SF-36 were associated with differential survival and morbidity [
6]. Body pain is one of the most important qualitative parameters for evaluating patients’ quality of life [
7]. To improve quality of care provided to CKD patients, it is important to understand and relieve body pain.
It has been reported that 82% of CKD patients undergoing dialysis had chronic pain, [
8] and 35-70% of patients had moderate to severe chronic pain [
9]. Chronic pain is common in CKD patients [
10], especially in patients with end-stage renal disease (ESRD) [
11]. Musculoskeletal (MS) pain is the most common symptom of chronic pain syndromes in ESRD patients [
8]. Few studies have focused on chronic pain in early-stage CKD patients.
Despite the understanding of prevalence and risk factors associated with chronic MS pain in CKD patients undergoing dialysis, the epidemiologic data for factors associated with chronic MS pain in early- and late-stage CKD patients who are not on dialysis, are limited. In addition, information about the prevalence of non-steroidal anti-inflammatory drugs (NSAID) or Chinese herbs used for pain relief in CKD patients is also limited. The aims of this study were to determine the prevalence of chronic MS pain in CKD patients and to identify the factors associated with chronic MS pain.
Discussion
The mechanisms associated with chronic MS pain in CKD patients are multi-factorial. The present study enrolled mostly early CKD patients, and for the first time focused on chronic MS pain in this population. The findings demonstrated that chronic MS pain was independently and significantly associated with hyperuricemia and the product of calcium and phosphate levels. In CKD patients with hyperuricemia, chronic MS pain was negatively, independently, and significantly associated with the presence of DM. However, in CKD patients without hyperuricemia, chronic MS pain was positively, independently, and significantly associated with the product of the calcium and phosphate levels. Furthermore, CKD stage 5 patients seemed to suffer from more severe chronic MS pain compared to other stage CKD patients.
These findings suggest that co-morbidity of hyperuricemia may be one of the major co-morbidities that contribute to chronic MS pain in CKD patients after adjustment of other confounders. This finding may account for the high association between hyperuricemia and CKD [
18]. Hyperuricemia could be a consequence of impaired kidney function, diuretic therapy, or oxidative stress [
19]. Therefore, it is not surprising that the co-morbidity of hyperuricemia is associated with chronic MS pain. However, the results demonstrated that there was no significant difference in uric acid levels between CKD patients with and without chronic MS pain. This finding may confirm that normal serum uric acid level at the onset of CKD does not exclude an acute gouty attack [
20]. Adequate uric acid medical control for chronic MS pain patients with hyperuricemia may also explain the similar uric acid levels in the study patients with or without chronic MS pain.
Chronic pain may be caused by various factors. This study only focused on MS pain and excluded other origins of chronic pain, such as neuropathic pain. The possible sources of chronic MS pain are gout, renal bone disease, and ischemic bone pain. The results showed that the calcium × phosphate product levels were significantly associated with chronic MS pain. Renal bone disease is a common complication of CKD. Imbalance of calcium and phosphate, vitamin D deficiency, and hyperparathyroidism are considered to cause renal bone disease [
21]. However, in this study, patients with chronic MS pain had similar serum calcium, phosphate, and iPTH levels as those patients without chronic MS pain. This suggests that renal bone disease may not be the cause of chronic MS pain in the CKD patients under study. The calcium × phosphate product levels had been found to correlate with vascular calcification [
22]. Therefore, vascular calcification-related micro-angiopathy and ischemic bone pain may explain why this product was strongly associated with chronic MS pain, especially in patients without hyperuricemia. Golan et al. [
11] found that higher serum calcium and iPTH levels were independently associated with chronic pain in haemodialysis patients. The differences in the study populations between CKD patients pre- and post-dialysis may explain these different findings. However, these results together suggest that the calcium-phosphate imbalance is a crucial factor for chronic MS pain in CKD patients.
Diabetic nephropathy is a common complication of diabetes mellitus. In the present study, it was found that 30.7% of patients had DM as co-morbidity. This study found that patients with chronic MS pain were less likely to have DM than those with no chronic MS pain (26.7% vs. 35.2%, Table
1). In multivariate analysis, it was found that the co-morbidity of DM was negatively associated with chronic MS pain in CKD patients with hyperuricemia but not in CKD patients without hyperuricemia. One possible explanation is that there is a negative association between co-morbidity of DM and hyperuricemia. However, in the present study it was found that there was no significant association between DM and hyperuricemia. Moreover, several studies have found high prevalence of gout in patients with Type 2 diabetes [
23,
24]. Choi et al. found that hyperuricemia is a risk factor for diabetes mellitus [
25]. Moreover, Lai et al. found that gout and type 2 diabetes mellitus shared the most common genetic factors, which explains why there existed a mutual inter-dependent effect on higher incidences [
26]. This may also be due to diabetic neuropathy. Previous studies have shown that pain-inhibiting neuropathy caused by glucose metabolism dysfunction may hide osteoarthritis pain and delay diagnosis of osteoarthritis [
27]. Moreover, silent ischemia with less chest pain during acute coronary syndrome was significantly higher in diabetic patients, probably due to cardiac autonomic neuropathy [
28]. Consequently, it is possible that diabetic neuropathy in diabetic CKD patients may inhibit or mask chronic MS pain. This may explain the finding of diabetes as a protective factor from chronic MS pain in CKD patients with hyperuricemia.
The study found that patients with chronic MS pain had a similar prevalence of NSAIDs or Chinese herbal medication use as those patients without chronic MS pain. In our study, there was no difference in use of NSAIDs or Chinese herbal medication between patients with hyperuricemia and without hyperuricemia. One possible explanation regarding the lack of association between NSAIDs use in CKD patients with pain may be due to our centre’s policy to reduce the use of NSAIDs in patients with chronic MS pain. Our CKD education provides CKD patients with information on protecting renal function, including better blood pressure control and avoidance of NSAIDs and Chinese herbal medication use. There was a significantly lower rate of NSAIDs use (7.8%) in our CKD study patients with chronic MS pain as compared to the report of Pham et al. (23.2%) [
29]. This may be the reason why our study patients had lower prevalence of NSAIDs use and Chinese herbal medication. Another explanation is that CKD patients in nephrology clinics were usually reminded of avoiding NSAIDs agents in order to protect their kidney function.
The present study revealed that 53.3% patients had chronic MS pain, with a mean eGFR around 65 ml/min. However, Cohen et al. [
10] reported that 69% of CKD patients with eGFR around 33.4 mL/min experience pain. The difference in results may be due to the definition of pain duration. The present study focused on chronic MS pain lasting for more than 3 months. However, Cohen et al. [
10] defined pain duration on the basis of the pain experienced by the patients in the past month. Besides, the present study patients are 100% Asian, whereas 74% of Cohen’s patients were Afro-Americans. Thus, racial differences may also contribute to the difference in prevalence of pain in CKD patients. Nevertheless, these data provide information on the prevalence of chronic MS pain in CKD patients.
The results of the present study indicate a correlation between the co-morbidity of hyperuricemia, the calcium × phosphate product levels, and the co-morbidity of DM with chronic MS pain in CKD patients. This study raises the importance of uric acid control and gout prevention to decrease the possibility of chronic MS pain, thereby improving the quality of life in CKD patients. In addition, the study found that the calcium × phosphate product levels were an important factor for chronic MS pain, especially in CKD patients without hyperuricemia. Results of this study demonstrate that the calcium × phosphate product levels are an important laboratory parameter to consider while treating CKD patients with chronic MS pain and without hyperuricemia. Additionally, it was demonstrated that NSAID or Chinese herb use was not very common in CKD patients. Low prevalence of NSAID and Chinese herb use (7.8% and 9.6%) may indicate either good patient education by healthcare professionals, or an underestimation or inaccurate reporting of NSAID and Chinese herb use by patients.
This study had several limitations. The information regarding pain relief agents was lacking. Furthermore, the colchicine use for gout relief in study patients was not collected. In addition, quality of life was not evaluated in this study. However, we believe that the results provide a solid basis for studies that will further explore these relationships. The ultimate goal should be a better understanding and treatment of chronic MS pain in CKD patients.
Competing interest
The authors declare no financial competing or other competing interest.
Authors’ contributions
H-J H participated in data collection, statistical analysis and manuscript preparation; C-H Y, K-H H, and C-C L participated in statistical analysis; I-W W, M-J H, C-Y S, C-C C, Y-C C helped with data collection; M-F H, C-Y C, C-Y H, and C-J T participated in data interpretation; M-S W participated in study design, coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.