Original Papers © 1990 S. K arger AG, Basel 0028 2766/90/0543 0202S2.75/0
Nephron 1990;54:202-207
Technetium-99-Labelled Methylene Diphosphonate Uptake Scans in Patients with Dialysis Arthropathy Dinesh Sethi*. Torn C. Naunton Morganc, Edwina A. Brown*. Reginald F. Jewkesh. Peter E. Gower' Departments of “Medicine and h Nuclear Medicine, Charing Cross Hospital, and cDepartment of Radiology. West Middlesex Hospital, London, UK
Key Words. Beta-2-microglobulin • Arthropathy • Haemodialysis • Technetium-99-labelled methylene diphosphonate • Bone scans • Radioisotope
Abstract. Patients on long-term haemodialysis suffer from dialysis arthropathy due to the deposition of dialysis amyloid. We investigated the use of "Tc-Iabelled methylene diphosphonate bone scans in 17 patients as a possible in vivo diagnostic technique. In most clinically affected joints, with the exception of shoulders and hands, there was increased radioisotope uptake consistent with uptake by periarticular bone. In addition, we describe intense soft-tissue uptake around some clinically affected large joints. In contrast, control groups of patients on haemodialy sis without arthropathy and patients without renal failure did not have increased uptake. A semi-quantitative scale of uptake was devised, and the following correlations were significant: pain perception and isotope uptake score in the ankles and feet, and the number of radiological lesions and isotope uptake scores in the wrists and knees. The following sites where the radioisotope might bind in the affected joints are proposed: amyloid deposits, areas of soft-tissue calcification, or areas of increased bone turnover. It is concluded that whereas the scanning technique cannot make a definite diagnosis of amyloid and, therefore, cannot be expected to supersede histological diagnosis, it is a useful adjuvant investigation, of particular importance in those patients unable or unwilling to undergo biopsy.
Patients on long-term haemodialysis suffer from a disabling complication called dialysis arthropathy which is associated with recurrent carpal tunnel syndrome [1,2], Amyloid deposits that are derived from [T-microglobulin have been implicated in the pathogenesis of the disease [3, 4], These deposits have been found predominantly in the articular tissues of patients with dialysis arthropathy [5,6], but systemic infiltration by this type of amyloid has been described [7, 8], Levels of (L-microglobulin are raised in patients with renal failure, and it is thought that prolonged exposure to these raised levels leads to the formation of amyloid deposits [9, 10]. Methods for diag nosis have to date been dependent on identifying amy loid deposits in histological specimens obtained at bi opsy. However, many of these patients are often unable to undergo the invasive procedures necessary to obtain specimens, and a reliable and sensitive in vivo diagnostic technique is, therefore, required to make the diagnosis. Encouraged by reports in patients with AL amyloid, of
the uptake of "Tc-labelled methylene diphosphonate ("Tc-MDP) and "Tc-Iabelled pyrophosphate [11-13], we investigated the use of bonescans in the diagnosis of joint disease due to pr microglobulin-associated amyloid. Patients and Methods Patients 17 patients with a clinical diagnosis of dialysis arthropathy were studied. Diagnosis was made on the basis of criteria that have been described previously [4] and consisted of (I) limitation of movement of joints in a symmetrical distribution; (2) either arthralgia or joint tenderness; (3) a history of carpal tunnel syndrome: (4) histological evidence of |T-microglobulin amyloid, and (5) absence of other causes of inflammatory or degenerative joint disease. Their mean age was 54 years (range 31-70 years), and their mean duration of haemodialysis had been 12.5 years (range 8-20 years). 3 were female and 14 w'ere male. In 13 of these patients there was histological evidence of |)r microglobulin amyloid, and 8 of these had also had carpal tunnel release surgery. Two patients had a history of previous carpal tunnel release surgery, but no tissue was obtained for histo logical study. The 2 patients without either of these features had clinical criteria considered diagnostic of dialysis arthropathy [4].
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/11/2018 2:10:48 AM
Introduction
Bone Scans in Dialysis Arthropathy
203
Table 1. ‘,gTc-MDP uptake, clinical involvement, and X-ray lesions in joints of patients with dialysis arthropathy
(a) Number with isotope uptake (b) Number clinically affected (c) Number with X-ray lesions (d) Median isotope uptake score (e) Median VAS (f) Median numbers of X-ray lesions
Shoulder
Wrist
Hand
Hip
Knee
Ankle
Feet
All joints
9 16 12 0 35 2
16 13 11 2 17 2
9 17 7 1 30 0
15 17 10 3 8 1
15 14 5 1 13 0
12 9 0 1 0 0
14 7 0 1 0 0
17 17 17 9 131 6
(a-c)= Numbers with isotope uptake, clinical involvement, and radiological lesions in individual sets of joints and collectively in patients with dialysis arthropathy. (d-f) = Median isotope uptake scores, median visual analogue score for pain (VAS 100-mm scale), and median number of radiological lesions in the individual sets of joints and collectively.
Isotope Scantling The technique was conventional bone scanning, and pictures of both large and small joints were obtained. The patients were given an intravenous injection of ““'Tc-MOP and scanned 3 h. later. A semi-quantitative scale was devised to quantify the amount of radio active uptake at each set of joints. For this scale, a reference point, defined arbitrarily as 0, was used for the comparison of uptake by each set of joints. The joints were compared with uptake in adjacent regions as follows (with reference points): shoulders (the upper end of humerus), small joints of the hands and wrists (shafts of radius and ulna), hips (intertrochanteric region of the femur), knees (shaft of femur), ankle, and small joints of the feet (inferior part of the tibia). Scores of uptake of radioactivity were graded from 0 to 3 in the joints. For some joints uptake was considered in more than one region: in the shoulder in the glenoid and humeral head and in the hip in the acetabulum and femoral head. For these joints the maxi mum possible score was 6. The maximum possible total score per patient was, therefore, 27 and was calculated from the sum of the maximum possible scores for each pair of joints as follows: hands 3, wrists 3, shoulders 6, hips 6, knees 3, ankles 3, and feet 3. Since patients with dialysis arthropathy suffer from symmetrical joint disease, only symmetrical joint uptake was considered relevant. Unilateral abnormalities were considered to be due to incidental disease such as osteoarthritis. Radiographs Each patient with dialysis arthropathy also underwent X-ray examination of the above joints. The abnormalities noted were presence of cysts, articular erosions [14,15], soft-tissue calcification, an d /o r hyperparathyroidism. The number of cysts or articular ero sions per set of joints was taken as the total number of radiological lesions per joint.
Clinical Assessment The 17 patients with dialysis arthropathy were examined clin ically using a detailed rheumatological pro forma. A visual ana logue scale was used to assess pain perception in the joints. The joints were examined for tenderness and limitation of range of movements and were considered to be clinically affected if any of these features were present. Statistical Analysis Comparison of the isotope uptake scores between the three groups was made using the Mann-Whitney U test. Correlations between the isotope uptake scores, radiological scores, visual ana logue score of pain, and duration of haemodialysis for the dialysis arthropathy patients were calculated using the Rank Spearman (RS) correlation coefficient. Comparisons between the number of dialysis arthropathy patients, with and without the uptake of isotope in joints, were made for clinical joint involvement and radiological lesions. This was carried out using the chisquared test.
Results Description o f Isotope Uptake Scans in Patients with Dialysis Arthropathy
For most sets of clinically affected joints, with the exception of shoulders and hands, there appeared to be increased uptake of"Tc-MDP in comparison to the point of reference. The highest median isotope uptake score was in the hips followed by that in the wrists. These results are summarized in table 1. The increased uptake appeared to be consistent with the uptake in articular bone as illustrated in figure 1. In addition to the uptake in articular bone, there was also diffuse soft-tissue uptake around some of the large joints. This uptake was sometimes of such intensity as to partially or totally obscure uptake by the articular bone.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/11/2018 2:10:48 AM
Two control groups of patients were also used for comparison. The first group consisted of 8 patients (4 males, 4 females) without arthropathy established on dialysis for a mean duration of 5 years (range I -I I years), mean age 56 years (range 33-67 years), who were referred for bone scanning to investigate metabolic bone disease. The second group comprised 6 patients (2 males, 4 females) without renal failure, mean age 46 years (range 26-68 years), who had bone scans to screen for bone metastases.
Sethi/Naunton M organ/Brown/Jewkes/Gower
204
Fig. 1. Typical scans with increased "Tc-M DP uptake in patients with dialysis arthropathy. Pattern consistent with uptake mainly by periarticular bone. The uptake in shoulders (a), hips (b), hands (c). and feet (d) is shown.
Fig. 2. Extensive uptake of^T c-M D P by soft tissue around shoulders (a, c), hips (b). and knees (d). partly obscuring uptake by periarticular bone.
Table 2. Comparisons of isotope uptake scores for individual joints for patients with dialysis arthropathy, haemodialysis patients without joint symptoms, and patients with normal renal function Isotope uptake all joints
1
1
0-3
0-3
9 2-18
wrists
hands
hips
knees
0
2 0-3
1
0-3
3 0-5
1
0-3
0-3
0 0-1
0 0
0 0
0 0
0
0
0-2
0-1
0-1
1 0-5
0 0
0 0-1
0
0 0-1
0 0-1
1.5 13
These features were seen in the shoulders of 8 patients, in the hips of 6, and in the knees of 4 patients in a symmetri cal distribution. There was no evidence of metastatic calcification on radiography. Figure 2 shows representa tive scans.
0-1
1
1 0-1
■0 0
ankles
Comparison of"Tc-M DP Uptake Scans between Patients with Dialysis Arthropathy and Control Groups
The patients with dialysis arthropathy had the highest median total isotope uptake score of 9 (range 2-18, p < 0.001; table 2). Both control groups had minimal
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/11/2018 2:10:48 AM
Dialysis arthropathy patients Median Range Haemodialysis patients Median Range Normals Median Range
feet
shoulders
articular isotope uptake. The patients on dialysis without arthropathy had a median total score of I (range 0-5), and the patients without renal failure had a median score of 1.5 (range 1-3). When every joint was considered separately, the score was significantly higher in the group with dialysis arthropathy than in the control groups (p < 0.01). Relationship between vvTc-MDP Uptake. Visual Analogue Score for Pain, and Number o f Radiological Lesions in the Patients with Dialysis Arthropathy
There were no correlations between the total "TcMDP uptake score per patient, the total visual analogue scores for pain, and the total number of radiological lesions for the patients with dialysis arthropathy. A sig nificant relationship was found between duration of hae modialysis and the total isotope uptake score (RS = 0.76, p < 0.001). There was no correlation between duration of dialysis and either the visual analogue score or the num ber of radiological lesions. However, when the individual sets of joints were considered, significant correlations were found between the following parameters: (1) isotope uptake and visual analogue score in the ankles (RS = 0.62, p
Nephron 1990;54:202-207
Technetium-99-Labelled Methylene Diphosphonate Uptake Scans in Patients with Dialysis Arthropathy Dinesh Sethi*. Torn C. Naunton Morganc, Edwina A. Brown*. Reginald F. Jewkesh. Peter E. Gower' Departments of “Medicine and h Nuclear Medicine, Charing Cross Hospital, and cDepartment of Radiology. West Middlesex Hospital, London, UK
Key Words. Beta-2-microglobulin • Arthropathy • Haemodialysis • Technetium-99-labelled methylene diphosphonate • Bone scans • Radioisotope
Abstract. Patients on long-term haemodialysis suffer from dialysis arthropathy due to the deposition of dialysis amyloid. We investigated the use of "Tc-Iabelled methylene diphosphonate bone scans in 17 patients as a possible in vivo diagnostic technique. In most clinically affected joints, with the exception of shoulders and hands, there was increased radioisotope uptake consistent with uptake by periarticular bone. In addition, we describe intense soft-tissue uptake around some clinically affected large joints. In contrast, control groups of patients on haemodialy sis without arthropathy and patients without renal failure did not have increased uptake. A semi-quantitative scale of uptake was devised, and the following correlations were significant: pain perception and isotope uptake score in the ankles and feet, and the number of radiological lesions and isotope uptake scores in the wrists and knees. The following sites where the radioisotope might bind in the affected joints are proposed: amyloid deposits, areas of soft-tissue calcification, or areas of increased bone turnover. It is concluded that whereas the scanning technique cannot make a definite diagnosis of amyloid and, therefore, cannot be expected to supersede histological diagnosis, it is a useful adjuvant investigation, of particular importance in those patients unable or unwilling to undergo biopsy.
Patients on long-term haemodialysis suffer from a disabling complication called dialysis arthropathy which is associated with recurrent carpal tunnel syndrome [1,2], Amyloid deposits that are derived from [T-microglobulin have been implicated in the pathogenesis of the disease [3, 4], These deposits have been found predominantly in the articular tissues of patients with dialysis arthropathy [5,6], but systemic infiltration by this type of amyloid has been described [7, 8], Levels of (L-microglobulin are raised in patients with renal failure, and it is thought that prolonged exposure to these raised levels leads to the formation of amyloid deposits [9, 10]. Methods for diag nosis have to date been dependent on identifying amy loid deposits in histological specimens obtained at bi opsy. However, many of these patients are often unable to undergo the invasive procedures necessary to obtain specimens, and a reliable and sensitive in vivo diagnostic technique is, therefore, required to make the diagnosis. Encouraged by reports in patients with AL amyloid, of
the uptake of "Tc-labelled methylene diphosphonate ("Tc-MDP) and "Tc-Iabelled pyrophosphate [11-13], we investigated the use of bonescans in the diagnosis of joint disease due to pr microglobulin-associated amyloid. Patients and Methods Patients 17 patients with a clinical diagnosis of dialysis arthropathy were studied. Diagnosis was made on the basis of criteria that have been described previously [4] and consisted of (I) limitation of movement of joints in a symmetrical distribution; (2) either arthralgia or joint tenderness; (3) a history of carpal tunnel syndrome: (4) histological evidence of |T-microglobulin amyloid, and (5) absence of other causes of inflammatory or degenerative joint disease. Their mean age was 54 years (range 31-70 years), and their mean duration of haemodialysis had been 12.5 years (range 8-20 years). 3 were female and 14 w'ere male. In 13 of these patients there was histological evidence of |)r microglobulin amyloid, and 8 of these had also had carpal tunnel release surgery. Two patients had a history of previous carpal tunnel release surgery, but no tissue was obtained for histo logical study. The 2 patients without either of these features had clinical criteria considered diagnostic of dialysis arthropathy [4].
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/11/2018 2:10:48 AM
Introduction
Bone Scans in Dialysis Arthropathy
203
Table 1. ‘,gTc-MDP uptake, clinical involvement, and X-ray lesions in joints of patients with dialysis arthropathy
(a) Number with isotope uptake (b) Number clinically affected (c) Number with X-ray lesions (d) Median isotope uptake score (e) Median VAS (f) Median numbers of X-ray lesions
Shoulder
Wrist
Hand
Hip
Knee
Ankle
Feet
All joints
9 16 12 0 35 2
16 13 11 2 17 2
9 17 7 1 30 0
15 17 10 3 8 1
15 14 5 1 13 0
12 9 0 1 0 0
14 7 0 1 0 0
17 17 17 9 131 6
(a-c)= Numbers with isotope uptake, clinical involvement, and radiological lesions in individual sets of joints and collectively in patients with dialysis arthropathy. (d-f) = Median isotope uptake scores, median visual analogue score for pain (VAS 100-mm scale), and median number of radiological lesions in the individual sets of joints and collectively.
Isotope Scantling The technique was conventional bone scanning, and pictures of both large and small joints were obtained. The patients were given an intravenous injection of ““'Tc-MOP and scanned 3 h. later. A semi-quantitative scale was devised to quantify the amount of radio active uptake at each set of joints. For this scale, a reference point, defined arbitrarily as 0, was used for the comparison of uptake by each set of joints. The joints were compared with uptake in adjacent regions as follows (with reference points): shoulders (the upper end of humerus), small joints of the hands and wrists (shafts of radius and ulna), hips (intertrochanteric region of the femur), knees (shaft of femur), ankle, and small joints of the feet (inferior part of the tibia). Scores of uptake of radioactivity were graded from 0 to 3 in the joints. For some joints uptake was considered in more than one region: in the shoulder in the glenoid and humeral head and in the hip in the acetabulum and femoral head. For these joints the maxi mum possible score was 6. The maximum possible total score per patient was, therefore, 27 and was calculated from the sum of the maximum possible scores for each pair of joints as follows: hands 3, wrists 3, shoulders 6, hips 6, knees 3, ankles 3, and feet 3. Since patients with dialysis arthropathy suffer from symmetrical joint disease, only symmetrical joint uptake was considered relevant. Unilateral abnormalities were considered to be due to incidental disease such as osteoarthritis. Radiographs Each patient with dialysis arthropathy also underwent X-ray examination of the above joints. The abnormalities noted were presence of cysts, articular erosions [14,15], soft-tissue calcification, an d /o r hyperparathyroidism. The number of cysts or articular ero sions per set of joints was taken as the total number of radiological lesions per joint.
Clinical Assessment The 17 patients with dialysis arthropathy were examined clin ically using a detailed rheumatological pro forma. A visual ana logue scale was used to assess pain perception in the joints. The joints were examined for tenderness and limitation of range of movements and were considered to be clinically affected if any of these features were present. Statistical Analysis Comparison of the isotope uptake scores between the three groups was made using the Mann-Whitney U test. Correlations between the isotope uptake scores, radiological scores, visual ana logue score of pain, and duration of haemodialysis for the dialysis arthropathy patients were calculated using the Rank Spearman (RS) correlation coefficient. Comparisons between the number of dialysis arthropathy patients, with and without the uptake of isotope in joints, were made for clinical joint involvement and radiological lesions. This was carried out using the chisquared test.
Results Description o f Isotope Uptake Scans in Patients with Dialysis Arthropathy
For most sets of clinically affected joints, with the exception of shoulders and hands, there appeared to be increased uptake of"Tc-MDP in comparison to the point of reference. The highest median isotope uptake score was in the hips followed by that in the wrists. These results are summarized in table 1. The increased uptake appeared to be consistent with the uptake in articular bone as illustrated in figure 1. In addition to the uptake in articular bone, there was also diffuse soft-tissue uptake around some of the large joints. This uptake was sometimes of such intensity as to partially or totally obscure uptake by the articular bone.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/11/2018 2:10:48 AM
Two control groups of patients were also used for comparison. The first group consisted of 8 patients (4 males, 4 females) without arthropathy established on dialysis for a mean duration of 5 years (range I -I I years), mean age 56 years (range 33-67 years), who were referred for bone scanning to investigate metabolic bone disease. The second group comprised 6 patients (2 males, 4 females) without renal failure, mean age 46 years (range 26-68 years), who had bone scans to screen for bone metastases.
Sethi/Naunton M organ/Brown/Jewkes/Gower
204
Fig. 1. Typical scans with increased "Tc-M DP uptake in patients with dialysis arthropathy. Pattern consistent with uptake mainly by periarticular bone. The uptake in shoulders (a), hips (b), hands (c). and feet (d) is shown.
Fig. 2. Extensive uptake of^T c-M D P by soft tissue around shoulders (a, c), hips (b). and knees (d). partly obscuring uptake by periarticular bone.
Table 2. Comparisons of isotope uptake scores for individual joints for patients with dialysis arthropathy, haemodialysis patients without joint symptoms, and patients with normal renal function Isotope uptake all joints
1
1
0-3
0-3
9 2-18
wrists
hands
hips
knees
0
2 0-3
1
0-3
3 0-5
1
0-3
0-3
0 0-1
0 0
0 0
0 0
0
0
0-2
0-1
0-1
1 0-5
0 0
0 0-1
0
0 0-1
0 0-1
1.5 13
These features were seen in the shoulders of 8 patients, in the hips of 6, and in the knees of 4 patients in a symmetri cal distribution. There was no evidence of metastatic calcification on radiography. Figure 2 shows representa tive scans.
0-1
1
1 0-1
■0 0
ankles
Comparison of"Tc-M DP Uptake Scans between Patients with Dialysis Arthropathy and Control Groups
The patients with dialysis arthropathy had the highest median total isotope uptake score of 9 (range 2-18, p < 0.001; table 2). Both control groups had minimal
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/11/2018 2:10:48 AM
Dialysis arthropathy patients Median Range Haemodialysis patients Median Range Normals Median Range
feet
shoulders
articular isotope uptake. The patients on dialysis without arthropathy had a median total score of I (range 0-5), and the patients without renal failure had a median score of 1.5 (range 1-3). When every joint was considered separately, the score was significantly higher in the group with dialysis arthropathy than in the control groups (p < 0.01). Relationship between vvTc-MDP Uptake. Visual Analogue Score for Pain, and Number o f Radiological Lesions in the Patients with Dialysis Arthropathy
There were no correlations between the total "TcMDP uptake score per patient, the total visual analogue scores for pain, and the total number of radiological lesions for the patients with dialysis arthropathy. A sig nificant relationship was found between duration of hae modialysis and the total isotope uptake score (RS = 0.76, p < 0.001). There was no correlation between duration of dialysis and either the visual analogue score or the num ber of radiological lesions. However, when the individual sets of joints were considered, significant correlations were found between the following parameters: (1) isotope uptake and visual analogue score in the ankles (RS = 0.62, p
