Musculoskeletal disorders in hemodialysis patients and its impact on physical function (Zagazig University Nephrology Unit, Egypt)

Introduction End-stage renal disease (ESRD) is a major public health problem. In the USA, more than 350 000 patients with ESRD are being treated by dialysis, with about 92% receiving hemodialysis (HD) and about 8% on continuous ambulatory peritoneal dialysis (PD) [1]. The incidence of ESRD in Taiwan has increased in the last decade and reached the highest incidence in the world. The prevalence of ESRD was 1706 per million population in Taiwan, second only to Japan [2]. There is still a paucity of data on the prevalence and risk factors of chronic kidney disease (CKD) in the Middle East. In Egypt, according to the most recent Egyptian renal registry in 2008, the prevalence of ESRD is 483 per million population and the total recorded number of ESRD patients on dialysis is 40 000. Ninety-eight percent of these patients are on HD and 2% on PD [3].


Introduction
End-stage renal disease (ESRD) is a major public health problem. In the USA, more than 350 000 patients with ESRD are being treated by dialysis, with about 92% receiving hemodialysis (HD) and about 8% on continuous ambulatory peritoneal dialysis (PD) [1]. The incidence of ESRD in Taiwan has increased in the last decade and reached the highest incidence in the world. The prevalence of ESRD was 1706 per million population in Taiwan, second only to Japan [2]. There is still a paucity of data on the prevalence and risk factors of chronic kidney disease (CKD) in the Middle East. In Egypt, according to the most recent Egyptian renal registry in 2008, the prevalence of ESRD is 483 per million population and the total recorded number of ESRD patients on dialysis is 40 000. Ninety-eight percent of these patients are on HD and 2% on PD [3].
Long-term regular HD for chronic renal failure for at least 14 years (average 15.7 years) was associated with repeated problems with vascular access surgery and different medical problems mainly involving the musculoskeletal system [4]. Most of the interest in musculoskeletal problems secondary to renal disease has focused on problems occurring in patients with chronic renal failure and specifically in patients on long-term HD [5]. The musculoskeletal involvement in longterm HD may involve the joints, soft tissues, or both. Crystal-induced arthropathy, most commonly caused by basic calcium phosphate crystals, is an important cause of acute joint inflammation in patients with renal

Musculoskeletal disorders in hemodialysis patients and its impact on physical function (Zagazig University Nephrology Unit, Egypt)
Amany R. El-Najjar a , Hanan A. Amar a , Heba A. El wahab Selim a , Enas M. El sherbiny b , Medhat Ibrahem b , Mohamed Fouad b Background A number of musculoskeletal disorders have been reported in hemodialysis (HD) patients and they exert an impact on their functional status.

Objectives
This study was designed to determine the most common musculoskeletal system involvement in chronic HD patients and to show its effect on physical function (disability).

Patients and methods
This study was carried out on HD patients at the Nephrology Unit in Zagazig University Hospitals, Egypt. Pain intensity was measured using a 100-mm pain visual analogue scale. Physical disability was measured using the Health Assessment Questionnaire. A blood sample was obtained to measure calcium, phosphorus, alkaline phosphatase, parathyroid hormone, serum uric acid, serum albumin, serum iron, serum ferritin, and transferrin. Radiography of the symptomatic joints was performed. Dual-energy x-ray absorptiometry was performed at the femoral neck and the lumbar spine.
failure [6]. A triad of shoulder periarthritis, carpal tunnel syndrome (CTS), and flexor tenosynovitis of the hands has been described in patients on long-term HD and PD and has been attributed to β2-microglobulin amyloid deposition [4]. The incidence of septic arthritis has increased in patients undergoing dialysis. Dialysis is also associated with an erosive or a destructive arthropathy of the finger joints, which is not explained by local amyloid deposition [6].
ESRD patients usually have accelerated bone loss because of abnormal bone turnover that leads to a high prevalence of bone health problems, for example, osteopenia and osteoporosis [7]. Furthermore, parathyroid hormone (PTH)-related bone disease influences bone mineral density (BMD) in HD patients, in addition to other important risk factors such as advanced age, age at menarche, female sex, and history of previous fractures. However, protective factors for bone mass loss in this population include body weight, hemoglobin, weekly heparin dose, and a history of parathyroidectomy [8]. ESRD patients with a low bone mass usually have a high incidence of fragility fractures [9]. The overall relative risk for hip fracture was 4.4 for dialysis patients compared with the general population [10]. It is important to periodically evaluate the BMD in these patients with dual-energy x-ray absorptiometry (DEXA). DEXA is reliable for the evaluation of the changes in BMD and bone mineral content at different sites [11].
Musculoskeletal disorders have an impact on the functional status of patients. HD patients have been reported to have elevated pain levels and impaired functional status. The Health Assessment Questionnaire (HAQ) is one of the first self-report functional status (disability) measures, and is used widely worldwide [12,13]. HAQ has been administered and validated in patients with a wide variety of chronic rheumatic diseases and it has also been used for patients with HIV/AIDS and chronic renal failure patients [14].

Objectives
This study was designed to determine the most common musculoskeletal system involvement in chronic HD patients and to show its effect on physical function (disability).

Patients
A total number of 144 HD patients between 19 and 66 years of age, mean ± SD 47.5 ± 11.5 years, and disease duration between 1 and 21 years, mean ± SD 9.8 ± 4.6 years, were recruited during the period from January 2012 to January 2013. Dialysis was performed three times weekly using 3.5 mEq/l dialysate calcium. The duration of each dialysis was 4 h; protocols were not changed during the study.

Inclusion criteria
All chronic renal failure (CRF) patients included in this descriptive cross-sectional study were on HD in the Nephrology Unit in Zagazig University Hospitals for more than 12 months and all were older than 18 years. This study was approved by the institutional ethics committee.
A written consent from all HD patients was obtained before entry into the study.

Exclusion criteria
Patients were excluded on the basis of the following criteria:

Methods
All patients were subjected to a full assessment of medical history and clinical examination.
Demographic data were obtained, along with details of HD (frequency, duration, dialyzer type, and membrane), previous renal transplantation, duration of renal failure, parathyroidectomy, hand dominance, CTS, fistula localization, previous surgical intervention of joints, morning stiffness, and BMI. All the patients underwent a complete musculoskeletal examination by a rheumatologist.

Measurement of pain
Pain intensity was measured by a 100-mm pain visual analogue scale [15].

Measurement of physical disability
Assessment of disability was performed using the HAQ. There were eight groups of questions on activities of daily living included in HAQ (1-dressing and grooming, 2-arising, 3-eating, 4-walking, 5-hygiene, 6-reach, 7-grip, and 8-common daily activities). The scores were determined using standard methods and the total score may range from 0 to 3 [14].

Imaging
Plain radiography of symptomatic joints or parts of the body was performed.

Bone mineral density
DEXA was performed at the femoral neck (FN) and lumbar spine (LS). The T-score is a comparison of an individual's bone density with that of a healthy 30-year-old individual of the same sex. A T-score of −2.5 or lower signifies osteoporosis. A T-score of −1.0 to −2.5 signifies osteopenia, meaning below-normal bone density without full osteoporosis.

Statistical analysis
Quantitative variables were described using means, SDs, medians, interquartile ranges, and 95% confidence intervals for mean. Qualitative variables were described using proportion and percentage. The parametric Student's t-test was used to compare two groups. The Spearman rank correlation coefficient was used to assess the correlation between two quantitative variables. The level of significance in all tests was less than 0.05 (P < 0.05). Statistical analyses were carried out using SPSS version 14 for Windows (SPSS Inc., Chicago, Illinois, USA).
The results showed that osteopenia occurred in three patients (3.4%) and osteoporosis in nine patients (10.4%). T-score results were worse at LS than at FN ( Table 2).
Results also indicated that the duration of HD showed a significant positive correlation with PTH (r = 0.28, P < 0.024) ( Table 3).
The HAQ score showed a highly significant correlation with the PTH level, serum iron, serum ferritin, serum transferrin, (FN) DEXA, and (LS) DEXA.  The results showed that there were highly significant differences in physical function and disability between HD patients with knee pain, hip pain, osteoarthritis (OA), osteoporosis, and those without pain, OA or osteoporosis (Table 4).

Discussion
In HD patients, all parts of the musculoskeletal system (bone, joint, muscle, tendon, and bursa) may be involved and most of the patients show evidence for more than one kind of musculoskeletal involvement [16].
Our results showed that the frequency of OA among HD patients was high (17.2%) ( Table 5). This was in agreement with Duncan et al. [20], who found that the prevalence of grade III or IV OA was three times greater in HD patients younger than 65 years old than in a control population.
The prevalence of CTS among HD patients with musculoskeletal manifestations was 14.9%. The previous result was consistent with that of Badry et al. [21], who reported that CTS is common in patients with end-stage renal failure on dialysis and about 13.3% were diagnosed with CTS depending on the second lumbrical-interosseous latency difference, which is a sensitive test to predict median neuropathy at wrist. Kurer et al. [17] reported that CTS had developed in 26 patients, and was bilateral in 14 of them; at operation, the presence of amyloid was confirmed.
Busch et al. [22] also reported that the prevalence of CTS as a possible manifestation of dialysis-related amyloidosis is still high (31.7%) and the significant predictors of CTS were age, female sex, serum β2-microglobulin, and total protein. This was in  agreement with the study of Kopec et al. [23] who showed that the incidence of CTS among patients treated for a long period of HD (20-30 years) was 10.4% on the basis of signs and physical symptoms, and nerve conduction. They also found that the duration of dialysis treatment was a statistically significant risk factor for the development of CTS (16.05 vs. 4.51 years; P < 0.0001). However, no statistically significant differences were found when comparing CTS incidence by sex or between the development of CTS requiring surgical release intervention and location of the arteriovenous fistula [23].
This study showed that the prevalence of osteoporosis among HD patients with musculoskeletal manifestation was 13.8%. This was not in agreement with Vachtenheim et al. [24], who observed that the prevalence of osteoporosis in HD patients was 12.9%.
In this study, we observed that bone cyst was found in 4.6% of HD patients depending on bone radiographic examination. The characteristic cystic radiolucency (CRL) was observed commonly at pelvis bones, hip bones, and carpal bones. This was in agreement with the study of Maruyama [25], who found that the grade and frequency of characteristic CRL and destructive spondylarthropathy of cervical vertebrae also increased in accordance with age and HD duration and CRL of the carpal bone; shoulder CRL was observed in 39.7%, hip CRL in 25.8%, and destructive spondylarthropathy in 14.3% of cases, respectively; these frequencies increased with an increase in HD duration.
Muscle cramp occurred in 3.4% and bone fracture in 2.3% of HD patients with musculoskeletal manifestations. This was in agreement with Chou et al. [18], who reported that muscle cramps were observed in 24 HD patients, multiple fractures in one patient, symmetrical distal neuropathy in 18 patients, and CTS in nine patients.
It has been shown that the prevalence of crystalline arthropathy including gout and pseudogout was 3.4 and 1.1%, respectively. The incidence of gout in dialysis patients is believed to be rare. A study from Japan showed a 2.8% frequency of gout after the initiation of renal replacement therapy [27]. Vachtenheim et al. [24] reported that crystalline arthropathy with typical attacks of gout was found in only 11 patients (5%). The United States Renal Data System (USRDS) database from 2000 to 2004 reported a prevalence of 5.9% for patients with a history of gout-related nephrolithiasis or obstruction in the ESRD program [28]. The reasons for these disparities are not clear, but may be related to the larger number of patients sampled or differences in lifestyle/diet. It is also likely that a significant number of patients with ESRD had a predialysis episode of gout that could not be identified because of the inherent limitations of an observational study. This would serve to overestimate the actual incidence of gout among patients in the USRDS.
Shoulder pain was recorded in 32.2% of patients, and about 3.4% of these patients had rotator cuff syndrome (Table 5). This was not in agreement with Bernageau et al. [28] who reported spontaneous shoulder pain in 24 HD patients (20 patients had bursitis and 21 patients had glenohumeral synovitis).
Painful shoulder in patients on chronic hemodialyis is most often associated with dialysis arthropathy or accumulation of deposits containing modified fibrils of β2-microglobulin, especially in bones and joints, because of insufficient elimination during the therapy. A study of Barisić et al. [29] showed that the plasmatic level of β2-microglobulin is strongly linked to painful shoulder in dialyzed patients, as well as C-reactive protein as a sign of acute inflammation. They also reported that the previously mentioned morphologic parameters were associated with histologically proved amyloidosis in patients on long-term dialysis of more than 10 years [30]. Bilateral shoulder/upper limb pain could be attributed to subdiaphragmatic irritation with dialysate fluid. The study of Ardalan et al. [30] found that 5% of incident PD patients developed infusionrelated pain. The phrenic nerve (C3, C4, and C5) is the motor nerve of the diaphragm and also contains many sensory and sympathetic fibers. Dialysate fluidinduced irritation of the diaphragmatic peritoneum may result in a referred pain in the distribution of the C5 nerve root along the musculocutaneous, axillary, radial, and median nerves [31].
We recorded one case of septic arthritis (1.1%) ( Table 2). This was not in agreement with a multicenter retrospective review on HD patients from 1999 to 2005. All patients had positive synovial fluid and blood cultures. The organisms isolated were all skin commensals, being staphylococcal in 13 patients and streptococcal in two patients [32]. Diabetes is the number one systemic risk factor identified in general septic arthritis and for sepsis in general, possibly because of sustained hyperglycemia retarding neutrophil chemotaxis [33].
In this study, we reported hypocalcemia in 44 patients (50.5%), hyperphosphatemia in 38 patients (43.6%), increased level of ALP in 66 patients (75.8%), and increased parathormone in 70 patients (80.4%) (Table 1). Similarly, Suwan [36] reported the level of hyperparathyroidism in 29.48% of continuous ambulatory PD patients. He also found significantly lower levels of serum calcium (P = 0.037) and serum phosphate (P = 0.016) and significantly higher serum ALP concentrations (P = 0.029). Billa et al. [37] also reported a high prevalence of hyperparathyroidism in a PD population and the PTH in 47% of patients was more than three times the normal, mean 54.6 ± 35.4 pmol/l. Patients with CKD almost always develop secondary hyperplasia of the parathyroid glands, resulting in elevated blood levels of parathyroid hormone (PTH). This abnormality is due to the hypocalcemia that develops during the course of kidney disease and/ or to a deficiency of 1,25-dihydroxycholecalciferol [l, 25(OH)2D3] that may directly affect the function of the parathyroid glands. With progressive loss of kidney function, a decrease in the number of vitamin D receptors (VDR) and calcium-sensing receptors (CaR) in the parathyroid glands occurs, rendering them more resistant to the action of vitamin D and calcium. In addition, the development of hyperphosphatemia directly affects the function and the growth of the parathyroid glands. These events will allow secondary hyperparathyroidism to worsen [38].
At least 3 hypotheses have been proposed to explain the pathogenesis of the hypocalcemia: (a) Phosphate retention, (b) Skeletal resistance to the calcemic action of PTH, and (c) Altered vitamin D metabolism. Together, these factors form a unified and integrated explanation for the hypocalcemia of CKD, and provide a framework for the management of altered mineral and bone metabolism of CKD [39].
It is evident; that phosphate retention and hyperphosphatemia can provoke secondary hyperparathyroidism in the absence or presence of impaired kidney function. Consequently, because secondary hyperparathyroidism occurs early in the course of CKD, hyperphosphatemia would be expected to develop at an early stage of reduced kidney function [40].
It has been proven that secondary hyperparathyroidism is associated with poor self-reported physical function in HD patients. There were significant correlations between HAQ and PTH (P < 0.02) ( Table 6). Malindretos et al. [41] found that in HD patients, secondary hyperparathyroidism appears to be associated with worse pain component scores (P = 0.036) and physical component scores (P = 0.029).
In this work, upper extremity disability was noted in HD patients, particularly hand dysfunction. The results showed that patients with shoulder pain, wrist pain, and pain of the small hand joints had significantly higher HAQ scores than those without (P < 0.02*, P < 0.03*, P < 0.01*), respectively (Table 4). A study of Hurton et al. [42] showed that the mean Disabilities of the Arm, Shoulder, and Hand score in HD patients was 31 ± 22 points, indicating markedly greater disability than in a normal population. This was in agreement with Limaye et al. [43] who assessed hand function in HD patients using the Sollerman test of hand grip function, and the median Sollerman score was 77, with 19/35 patients (54%) receiving HD having a score below the lower normal value of 78-80. The log Sollerman score correlated significantly with the HAQ score (r s = −0.66, P < 0.00005) and duration of HD (r s = −0.39, P < 0.05). Similar results of impaired hand function in HD patients were observed in the study of Celal Bayar University Medical School Hospital [44]. Impaired hand function in HD patients often has complex pathogenic mechanisms. The accumulation and deposition of β2-microglobulin (polypeptide) in musculoskeletal structures in HD patients leads to amyloidosis and consequently functional impairments or disability [45].
The results of our study showed that there were highly significant differences in physical function and disability using HAQ between HD patients with knee pain, hip pain, OA, osteoporosis, and those without (P < 0.04*, 0.04*, 0.02*, and 0.00*, respectively).

Conclusion
Musculoskeletal system involvement remains a common problem limiting the physical function of renal failure patients, particularly those treated with long-term maintenance dialysis, and requires more attention in its prevention and treatment by the physicians.