Original ArticlesMineral Metabolism and Bone Disease

Calcium, Parathyroid Hormone, and Vitamin D: Major Determinants of Chronic Pain in Hemodialysis Patients

Eliezer Golan, Isabelle Haggiag, Pnina Os and Jacques Bernheim
CJASN August 2009, 4 (8) 1374-1380; DOI: https://doi.org/10.2215/CJN.00680109

Abstract

Background and objectives: Pain is a frequent complaint of hemodialysis (HD) patients, yet information regarding its causes and frequency is relatively scarce. The aim of this study was to evaluate the frequency and possible causes of chronic pain in patients who are on long-term HD.

Design, setting, participants, & measurements: We prospectively enrolled 100 patients who were undergoing maintenance HD for at least 3 mo. Pain was evaluated using the Brief Pain Inventory. Data collected on each participant included age, gender, ethnic origin, body mass index, smoking habits, time on dialysis, type of blood access, comorbidities, and biochemical and hematologic parameters.

Results: The average age was 64.5 yr; the average time on dialysis 40.4 mo. Forty-five patients were male. Thirty-one participants were of Arabic origin. Fifty-three patients had diabetes, 36 of whom had diabetic retinopathy. Although 51 patients experienced chronic pain, only 19.6% described the pain as severe. Musculoskeletal pain, neuropathic pain, and headache were the most prevalent forms of pain. The presence of diabetic retinopathy and neuropathy (but not diabetes per se) and levels of intact parathyroid hormone, calcium, and calcitriol (but not 25-hydroxyvitamin D3) differed significantly between those who experienced chronic pain and those who did not. On a logistic regression model, higher serum calcium levels and intact parathyroid hormone levels >250 pg/ml were independently associated with chronic pain, as well as the presence of diabetic retinopathy. Calcitriol had a marginal effect.

Conclusions: Disturbed mineral metabolism is strongly associated with chronic pain in long-term HD patients, along with microangiopathy.

Pain is a frequent complaint of hemodialysis (HD) patients (1–3), yet information regarding its origins, frequency, and management is relatively scarce. Most published data come indirectly from studies focusing on health-related quality of life (1,3). The reported frequency of pain varies widely in these patients. Murtagh et al. (4), in a review of symptoms in ESRD, reported a weighted mean pain prevalence of 47%, with a range of 8 to 82%.

Although well-accepted guidelines are available for the management of cancer-related pain (5), no such recommendations exist for pain associated with HD. One review (6) suggested using the same step-wise approach promulgated by the World Health Organization to treat cancer pain; however, the treatment of HD patients is complicated by the need to adjust frequently the dosage of analgesic drugs and by increased risk for adverse effects (7,8). It is of no surprise, therefore, that an article from the Dialysis Outcomes and Practice Patterns Study (DOPPS) by Bailie et al. (9) reported an undertreatment of pain in HD patients. In fact, pain was not treated adequately in the majority of patients. The purpose of this study was to evaluate the frequency and possible associations of chronic pain in patients who are on long-term HD.

Materials and Methods

We prospectively enrolled 100 patients who had been undergoing maintenance HD for at least 3 mo at the Meir Medical Center. The institutional clinical research ethics review board approved the protocol. All patients provided written informed consent.

The majority of patients were treated thrice weekly for 4 h. Cellulose-triacetate hollow fiber dialyzers (Sureflux150E or Sureflux 190E; Nipro Corp., Osaka, Japan) were used on AK200 or AK200S dialysis machines (Gambro Ltd., Lund, Sweden) with blood flow of 280 to 350 ml/min and dialysate flow of 500 ml/min.

At the time the study was performed, 67 patients had native arteriovenous fistula as their blood access, 24 had a polytetrafluoroethylene graft (GoreTex; W.L. Gore and Associates, Flagstaff, AZ), and nine had a tunneled central vein double-lumen catheter (PermCath; Quinton Instrument Co., Seattle, WA). Eighty-eight patients received intravenous recombinant human erythropoietin, either Epoetin Alfa (Eprex; Cilag Ltd., Schaffhausen, Switzerland) or Epoetin Beta (Recormon; Hoffmann-La Roche Ltd., Basel, Switzerland), and intravenous iron therapy (Venofer; Vifor Int., St. Gallen, Switzerland).

The data collected on each participant included age, gender, origin, body mass index, smoking habits, time on dialysis, type of blood access, comorbidities, and biochemical and hematologic parameters. Comorbidities included malignancy, hypertension, ischemic heart disease (IHD), stroke, peripheral arterial disease (PAD), diabetes, diabetic retinopathy, and neuropathy. The laboratory profile included serum calcium, phosphorus, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D3 [25(OH)D3] 1,25-dihydroxyvitamin D3 (calcitriol), albumin, hemoglobin, iron, vitamin B12, folic acid, ferritin, glucose, and C-reactive protein. For patients with diabetes, we also measured glycated hemoglobin (HbA1c). The calcium-phosphorus product was calculated for each patient, as well as Kt/Vurea, using the second-generation Daugirdas formula (10). Calcium levels were corrected for albumin. Levels of vitamin D [25(OH)D3 and calcitriol] were determined by radioimmunoassay (DiaSorin, Stillwater, MN) and iPTH levels by immunoradiometric assay (N-TACT PTH SP IRMA; DiaSorin). A Hitachi 747 Clinical Analyzer was used to determine the serum levels of albumin, glucose, iron, calcium, and phosphorus. A Hitachi 917 was used for C-reactive protein, and Immulite 2000 (DCP, Los Angeles, CA) was used for ferritin. Access (Beckman, Fullerton, CA) was used for B12 and folic acid. Advia 120 (Bayer, Leverkusen, Germany) was used to determine hemoglobin levels.

All patients were interviewed by the same investigator (I.H.) during an HD session. Pain was evaluated using the Brief Pain Inventory (BPI). This is an instrument for evaluating pain that assesses the intensity and characteristics of pain and determines the impact of pain on important aspects of a patient's life. The BPI uses a 10-point scale whereby 0 = “no pain” and 10 = “pain as bad as you can imagine” to evaluate intensity of pain (11). The BPI has shown its validity across cultural and linguistic backgrounds (12–15) as well as diverse clinical situations (16–19), including dialysis patients (1,20). On the basis of the BPI scale, pain was classified as mild (1 to 4 points), moderate (5 to 6 points), or severe (7 to 10 points) (20).

Chronic pain was defined as pain of >3 mo duration (20). Pain related to repeated dialysis access cannulation was assessed separately, including questions regarding the regular use of local anesthetic spray (ethyl chloride, various manufacturers) or cream (eutectic mixture of lidocaine and prilocaine, EMLA 5%; AstraZeneca, London, UK).

Statistical Analysis

Descriptive statistics including frequencies and means ± SD were calculated for demographic variables. Log transformation was used for variables with a skewed distribution. χ2, Fisher test, t tests, and logistic regression using the forward stepwise method were used, as appropriate. Statistical analysis was performed using SPSS 15 (SPSS, Chicago, IL). Statistical significance was set at 5% (P < 0.05).

Results

One hundred consecutive patients participated in the study. Table 1 depicts the basic demographic characteristics and laboratory values of the patients, and Table 2 shows the comorbidities.

View this table:
Table 1.

Demographic characteristics and laboratory valuesa

View this table:
Table 2.

Number of patients with comorbid conditionsa

Forty-five patients were male. There were no statistically significant differences in any of the parameters between male and female patients except for Kt/V (male 1.27 ± 0.18 female 1.45 ± 0.27; P < 0.001), 25(OH)D3 (male 22.0 ± 10.8 female 16.1 ± 8.7; P = 0.004), and smoking habits (current/former: male 4/8 female 4/1; P = 0.018).

Fifty-three patients had diabetes. Because patients with diabetes may have a different form of primary renal disease, diabetic nephropathy was considered to be the primary renal disease only when it was biopsy proven or when diabetic retinopathy was also present and there was no evidence of other renal disease. On the basis of this definition, the primary renal disease was considered to be diabetic nephropathy for 36 patients with diabetes. Twenty-five patients had nephrosclerosis, nine had chronic glomerulonephritis, six had adult dominant polycystic kidney disease, four had chronic interstitial nephritis, three had nephrolithiasis, and 17 had other or unknown type of renal disease.

Time on dialysis was significantly shorter for the 53 patients with diabetes compared with those without diabetes: 29.7 ± 30.0 versus 52.4 ± 49.0 mo (P < 0.05). A higher percentage of patients with than without diabetes had cardiovascular comorbidities: IHD 56.6 versus 34%, hypertension 96 versus 76.6%, stroke 24.5 versus 10.6%, and PAD 22.6 versus 4%, respectively. The difference in IHD and PAD reached statistical significance (P = 0.04 and P = 0.02, respectively). The average HbA1c was 7.05 ± 1.47% (7.20 ± 1.50% for women and 6.80% ± 1.40 for men; the difference between genders was not statistically significant). Compared with those without diabetes, those with diabetes had significantly lower levels of serum calcium, iPTH, calcitriol, and 25(OH)D3. More patients with diabetes complained of chronic pain (56.6 versus 44.7%), but this difference was not statistically significant (Table 1). Thirty-six of the patients with diabetes had diabetic retinopathy. Compared with the 17 with diabetes and without diabetic retinopathy, a significantly higher percentage of them experienced chronic pain (72.2 versus 23.5%; P < 0.01), were younger (62.7 ± 8.6 versus 69.4 ± 11.5 yr; P = 0.04), and were more obese (body mass index 30.1 ± 6.8 versus 25.9 ± 5.1 kg/m2). There were no statistically significant differences in any of the other demographic and laboratory parameters between these two groups of patients with diabetes, although both groups had lower levels of calcium, iPTH, 25(OH)D3, and calcitriol compared with those without diabetes.

Thirty-one patients were of Arabic origin. They had a significantly higher rate of diabetes: 71% (22 of 31) compared with 44.9% (31 of 69) of non-Arabic patients (P = 0.018). The percentage of HbA1c of patients who had diabetes and were of Arabic origin was 7.6 ± 1.6 compared with 6.6 ± 1.3 in non-Arabic patients with diabetes (P = 0.016). Diabetic retinopathy was more prevalent in patients of Arabic origin: 54.8% (17 of 31) versus 27.5% (19 of 69) in non-Arabic patients (P = 0.013). The difference in diabetic neuropathy approached but did not reach statistical significance (13 of 31 versus 15 of 69; P = 0.054).

Eighty-eight patients were receiving erythropoietin. The average dosage was 10,977 ± 7758 U/wk. There was no statistically significant difference between those who received erythropoietin and those who did not in the prevalence or intensity of chronic pain, as well as in any other demographic or laboratory parameter.

A total of 51 patients experienced chronic pain. Table 3 depicts their demographic characteristics and laboratory values compared with the 49 patients who did not report chronic pain. Patients with chronic pain had statistically significant higher levels of calcium and iPTH and lower levels of calcitriol [but not 25(OH)D3] compared with those without chronic pain. More patients with chronic pain experienced diabetic retinopathy and neuropathy compared with patients without chronic pain. None of the other comorbidities differed between the groups, including the incidence of diabetes.

View this table:
Table 3.

Characteristics of patients with and without chronic pain

Of note, although none of the demographic parameters reached statistical significance, patients with chronic pain tended to be on HD for a longer period of time (48.0 ± 50.2 versus 32.5 ± 29.7 mo; P = 0.064). Smoking habits as well as the type of blood access did not differ between the two groups. Diabetes was equally controlled among the patients with diabetes in the two groups, as indicated by the percentage of HbA1c (7.1 ± 1.5% in patients with diabetes and chronic pain versus 7.0 ± 1.5 in patients with diabetes and without chronic pain). Some patients with chronic pain had much higher levels of iPTH that were not found in the group without pain; this is reflected in the higher SD (180 versus 86) noted in Table 3. Ignoring the extreme values, however, had no significant impact on the analysis of our findings. Table 4 depicts the odds ratio for chronic pain, calculated using a stepwise logistic regression model. The independent variables found to be significant were iPTH level >250 pg/ml, the presence of diabetic retinopathy, and a higher serum calcium level. Level of calcitriol >17 pg/ml demonstrated a marginal effect.

View this table:
Table 4.

OR for chronic paina

Twenty-five (49%) patients described their pain as mild, 16 (31.4%) as moderate, and 10 (19.6%) as severe. The blood level of calcium was the only parameter that demonstrated a correlation to the patients' degree of pain (r = 0.305, P = 0.002).

The 51 patients with chronic pain experienced it in diverse organ systems: 28 (54.9%) reported chronic headache, 21 (41.2%) neuropathic pain, 13 (25.5%) back pain, 11 (21.6%) other musculoskeletal pain, six (11.8%) chronic joint pain, and nine (17.6%) abdominal pain. Seven (13.7%) patients had pain from various other sources, such as phantom pain, steal syndrome, and nonspecific diffuse pain.

Each needle insertion in patients with a fistula or graft as their blood access is expected to cause unavoidable pain; however, only 73 (80.2%) of 91 patients considered the procedure to be painful at all, and only 37 (40.6%) believed that it was intense enough to justify the regular use of a local anesthetic before needle insertion. There were no significant differences in demographic or laboratory parameters between patients who considered the needle insertion to be painful and those who did not or between those who regularly used local anesthetics and those who did not.

Discussion

For >40 yr, dialysis has proved to be a successful life-sustaining therapy. As such, its effectiveness has been judged mainly by patient survival; however, as this form of therapy matures and because the majority of patients are older and experience multiple comorbidities, health-related quality of life (HRQoL) becomes increasingly important. Pain is considered to be a highly relevant patient outcome in evaluating HRQoL in HD (1,8,21,22). Moreover, recent studies showed an association between assessment of HRQoL and morbidity and mortality in patients with ESRD (23).

Our study showed that pain is common in patients who are on long-term HD; 51% of our patients experienced chronic pain. This is in agreement with other reports in the literature: Davison (1), in her publication on 205 Canadian HD patients, reported that 50% of patients had chronic pain. In a review, Murtagh et al. (4) reported a weighted mean prevalence of pain of 47% but with a range from 8 to 82%. This wide range is probably due to differences in the definition of chronic pain and the method used to assess it, as well as differences in the perception of pain among the diverse population studied.

Although the prevalence of chronic pain in our study was almost identical to other reports, the severity of pain differed; for example, 55% of Davison's patients rated their pain as severe (1), whereas only 19.6% of our patients did so. Differences in the perception of pain, possibly based on cultural and ethnic factors, may explain these findings. Chiang et al. (24) described similar differences in HD patients in Taiwan as did Kimmel et al. (21) while discussing the impact of spiritual beliefs, psychosocial factors, and ethnicity on HRQoL and HD. Conversely, other than having a higher prevalence of diabetes and retinopathy among patients of Arabic background, ethnic origin by itself had no correlation with pain in our cohort.

Pain of musculoskeletal origin was the most frequent form of chronic pain reported by patients who were on maintenance HD (8). The findings in our study were of no exception, but it should be noted that other forms of pain were frequent as well, emphasizing the complex nature of chronic pain in HD patients. One study that focused on gastrointestinal symptoms in dialysis patients found that abdominal pain was the most frequent gastrointestinal symptom, reported by 72% of HD patients (25).

Headache is very common, usually restricted to the HD session. We also found that a substantial number of patients experience chronic headache, not triggered by the dialysis treatment. This is in accordance with other reports. For example, the 2003 prospective study on headache in HD by Antoniazzi et al. (26) reported that eight (28.6%) of 28 patients who did not experience headache before dialysis developed this form of chronic headache while on HD.

Most published studies have found statistically significant positive correlations between time on dialysis and chronic pain (1). We observed the same trend in our data, but it did not reach statistical significance, probably because of the wide range of time (3 to 204 mo) that our patients were on long-term HD.

Fifty-three of our patients had diabetes, which, by itself, had no impact on the presence of chronic pain; however, we found a strong correlation between chronic pain and diabetic neuropathy and retinopathy. Microangiopathy is an established culprit in the complex pathogenesis of diabetic neuropathy (27). This may point to a significant role of microangiopathy in the creation and perpetuation of chronic pain in these patients.

Our patients with diabetes had significantly lower levels of calcium, PTH, 25(OH)D3, and calcitriol; this is in agreement with other reports (28,29). Low calcium and vitamin D are associated with endothelial dysfunction (30). We speculate that the lower levels of calcium and calcitriol observed in our patients may play a role in the development of chronic ischemic pain in various organs by their impact on endothelial dysfunction. In contrast to others (31), we could not demonstrate a correlation between hemoglobin level and chronic pain. probably because the hemoglobin level of most of our patients was within the recommended range and the cross-sectional nature of our study.

Many of the previously published works on chronic pain in HD patients did not focus on the interrelation between pain and biochemical parameters, especially calcium homeostasis. In our study, calcium was an independent risk factor for chronic pain, whereas calcitriol level had a marginal effect (Table 4). It should be noted that the difference in the average serum calcium levels between the groups with and without pain was relatively small; however, there was strong statistical significance (P = 0.008; Table 3). Moreover, calcium level correlated with the severity of pain, and on a logistic regression model, higher serum calcium levels were independently associated with chronic pain. Taken altogether, it seems that the relatively small difference in the average serum calcium levels is of clinical significance.

Of note, iPTH >250 pg/ml, well within the recommended level for HD patients (150 to 300 pg/ml), is an independent risk factor for chronic pain. Since the publication of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for bone metabolism and disease in CKD (32), there has been an ongoing discussion regarding the optimal treatment of renal bone disease, including the optimal levels of PTH. Although the focus is mainly on bone parameters as well as survival (33), our results add a different aspect that should be taken into account, which is the possible adverse effect on chronic pain if higher levels of PTH will be accepted.

Noordzij et al. (34) analyzed data from the prospective Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) and reported that disturbed mineral metabolism was associated with muscle pain and cramps in dialysis patients. Compared with our results, muscle pain was more prevalent in their study, found in 68% of their patients, and the rate increased to 81% during 4 yr of follow-up. In agreement with our findings, there was a correlation between muscle pain and high calcium and iPTH levels. Noordzij et al. also described a correlation between phosphorus levels and pain; a correlation that we were unable to demonstrate. This difference may result from the tight control of phosphorus in almost all of our patients, both with and without pain, as well as from the different study methods, longitudinal versus cross-sectional, and different estimates of pain.

Because they have a pivotal role in bone metabolism, the correlation of calcium, PTH, and calcitriol with pain may seem obvious, because musculoskeletal pain is regarded as the most prevalent form of chronic pain in HD patients; however, many of our patients frequently experienced other forms of pain, so it seems that calcium, PTH, and calcitriol may be involved in chronic pain in these patients beyond their role in bone metabolism. Our work points out the likelihood that calcium, PTH, and calcitriol play a profound role in the chronic pain experienced by HD patients. Indeed, calcium (35) and vitamin D (36) have been implicated as being directly involved in pain.

The cross-sectional nature of our study as well as the relatively small number of participants, although pointing to a strong association of calcium metabolism with chronic pain in HD patients, precludes drawing firm cause-and-effect conclusions from our data. Nevertheless, we believe that our 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 pain in HD patients.

Disclosures

None.

Acknowledgments

This work was presented as an abstract at the annual meeting of the American Society of Nephrology; October 31 through November 5, 2007, San Francisco, CA; and at the ERA-EDTA Congress; June 21 to 24, 2007; Barcelona, Spain.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Received January 30, 2009.
  • Accepted May 21, 2009.

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Calcium, Parathyroid Hormone, and Vitamin D: Major Determinants of Chronic Pain in Hemodialysis Patients
Eliezer Golan, Isabelle Haggiag, Pnina Os, Jacques Bernheim
CJASN Aug 2009, 4 (8) 1374-1380; DOI: 10.2215/CJN.00680109
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