- Email: [email protected]
Dialysis arthropathy: Outcome after renal transplantation
I
I
Dialysis Arthropathy:
Outcome After Renal Transplantation
Thomas Bardin, MD, Jeanne Louise Lebail-Darn& MD, Johanna Zingraff, MD, Jean Denis Laredo, MD, Paris, France, Marie Catherine Voisin, MD, Crkteil, France, Henri Kreis, MD, Daniel Kuntz, MD, Paris, France PURPOSE:Patients treated by long-term maintenance hemodialysis frequently develop a form of chronic arthropathy that is strongly associated with 6,-microglobulin amyloid deposition and related, at least in part, to 6,-microglobulin retention. Successful renal transplantation is followed by a rapid fall in serum l3,-microglobulin levels and might allow dissolution of amyloid deposits. The purpose of this work was to investigate the effects of renal transplantation on dialysis arthropathy. PATIENTSAno METHODS:Fourteen renal tranplant recipients were selected on the basis of previous hemodialysis treatment for at least 10 years (mean 16) and a history of chronic joint pain prior to transplantation. They all received 10 to 17.5 mg/d of prednisone. Posttransplant rheumatologic manifestations were studied prospectively and compared to pretransplant rheumatologic manifestations recorded in medical charts and reported during patient interviews. Pretransplant and posttransplant articular roentgenograms were separately analyzed by three observers who were blinded to timing of the films. l3,-microglobulin amyloid was identified by Congo red staining and immunohistology. RESULTS:After a mean posttransplant interval of 54 months (range 12 to 121), the atticular condition was improved in 10 patients, unchanged in 1, and worsened in 3, according to patients’ assessments. The number of painful joints decreased significantly (P ~0.05) as compared to the pretransplant period. However, the number and size of subchondral bone erosions remained unchanged, destructive arthropathies generally worsened, and articular 6,-microglobulin amyloid deposits were identified in 2 patients, 2 and 10 years after renal transplantation, respectively. CONCLUSION:Renal transplantation appeared to arrest progression of l3,-microglobulin amyloid in
From the Clrnrque de Rhumatologie, Centre Viggo Petersen (TB, JLLD, DK), Service de Radiologie Osteoarticulaire (JDL), Htrprtal Lariboisiere; Departement de Nephrologie (JZ, HK), Hopital Necker, Paris, France, and, Service d’Anatomre Pathologique (MCV), Hopital Henri Mondor, Creteil, France. Requests for reprrnts should be addressed to Dr T. Bardin, Clinrque de Rhumatologie, Centre Viggo Petersen, 6 rue Guy Pabn, Hopital Lariboisiere, Paris, France. Manuscript submitted June 23, 1994 and accepted in revised form December 7, 1994.
dialysis patients, but it neither led to dissolution of deposits nor prevented progression of destructive arthropathies. Most articular symptoms were improved, probably as a result of cotticosteroid therapy.
T
he importance of rheumatic disorders in patients on long-term hemodialysis has been emphasized during the past years. l-5 These disorders presently appear as the main factor limiting quality of life in longterm survivors. The pathophysiology of joint aherations appears complex and is still incompletely understood. Several factors have been linked with rheumatic disorders, including secondary hyperparathyroidism, aluminum and possibly silicon overload, calcium phosphate and calcium oxalate crystal deposition, and septic complications. 13,Microglobulin amyloid has been demonstrated to be associated with the majority of carpal tunnel syndromes and chronic arthropathies in long-term dialysis patients2” although its responsibility as the initiating cause of arthropathy is still debated, particularly as concerns dialysis-destructive arthropathy,7-g Retention of C$nicroglobulin in dialysis patients is believed to be the central, although not the only, factor in the pathogenesis of amyloid formation.‘O,‘l Renal transplantation is followed by a rapid fall in serum fJ,-microglobulin levels’” and might improve dialysis arthropathy.13-18 We report the results of a prospective study of the effects of successful renal transplantation on dialysis arthropathy and amyloid deposition in a series of 14 patients.
PATIENTS AND METHODS Among patients who underwent successful renal transplantation at the Necker Hospital during the last decade, we selected 14 subjects who were previously treated by hemodialysis for at least 10 years and had a history of chronic joint pain prior to transplantation. There were 7 women and 7 men. Mean age was 47.6 years (range 38 to 57). Mean duration of maintenance hemodialysis before renal transplantation was 195 months (range 120 to 243). Renal failure was secondary to glomerulonephritis in 9 patients, pyelonephritis in 2, and polycystic kidney disease in 1; etiology was unknown in the 2 remaining patients. No patients had amyloid nephropathy or systemic diseases known to cause articular symptoms. Nine patients had a history of deferoxamine treatment for alu-
September 1995 The American Journal of Medicine@Volume 99
243
DIALYSIS ARTHROPATHY/BARDIN
ET AL
TABLE Incidence of Painful Skeletal Sites in 14 Renal Transplant Recipients Before and After Transplantation Pain Before Renal Pain Remaining After New Involvement Site Transplantation Transplantation After Transplantation Shoulder 21 2 1 Knee 12 2 5 Hip 10 4 0 lnterphalangeal joint 8 2 2 Cervical spine 7 1 2 Elbow 7 0 2 Ankle 4 2 0 Trapeziometacarpal joint 2 2 2 Carpal tunnel syndrome 1 0 0
minum overload and 9 had undergone subtotal parathyroidectomy. Three patients had roentgenographic evidence of overt hyperparathyroidism at the time of the transplant procedure. Mean serum calcium (m@) X phosphorus (mg/L) product during the last 3 pretransplantation months ranged from 2,916 to 8,851 mg/L (mean 5,905 f 940). Patients were examined 12 to 121 months after kidney transplantation (mean 53.8). Treatment included prednisone in a daily dose of 10 to 17.5 mg (mean 13.5) in all patients, azathioprine in 5, and/or cyclosporine and azathioprine in 8 patients. Mean plasma creatinine level was 165 + 64.3 mmol/L (range 80 to 510). Mean B,-microglobulinemia, measured using an enzyme-linked immunosorbent assay (Phadezym B2 microtest; Pharmacia, Uppsala, Sweden), was 5.5 * 2.6 mgIL (upper limit of normal 2.4 mg/L). Mean serum calcium (mg/L) X phosphorus (mg/L) product was 4,654 * 367 mg/L. Mean serum uric acid level was 6.8 f 1.1 mg/dL. All 14 patients underwent a rheumatologic evahration and roentgenograms of the hands, wrists, pelvis, shoulders, cervical spine, and knees. Pretransplantation status was retrospectively evaluated on the basis of medical records and patient interviews. The diagnosis of amyloid arthropathy was based on the concomitant presence of chronic arthralgias and multiple, large (ie, diameter >4 mm) subchondral bone cysts. Roentgenograms of the hands and wrists, pelvis, and shoulders had been performed within 3 months before transplantation in all patients. Pretransplant roentgenograms of the knees and cervical spine were available for 7 and 5 patients, respectively. One patient had pretransplantation and posttransplantation roentgenograms of his elbows. Pre- and posttransplant roentgenograms were separately analyzed by three observers, who were blinded to roentgenogram sequence and who assessed the number and size of cysts and periarticular calcium deposits and joint-space width. A consensus was reached concerning the five films for which the three observers initially disagreed. 244
Amyloid deposits in articular samples were identified by Congo red staining, and the nature of the amyloid was determined by immunohistology, using previously reported techniques.6
RESULTS Articular Status Pretransplantation Before the transplantation procedure, the 14 patients suffered from chronic arthralgias involving a total of 71 joints (Table). Eight patients had a history of carpal tunnel syndrome and another had persistent features of this syndrome at the time of renal transplantation. Roentgenograms demonstrated 57 sub chondral cysts in 12 patients. Cervical destructive spondyloarthropathy7 was diagnosed on pretransplant roentgenograms in 5 patients. Destructive arthropathy of the hips and multiple destructive arthropathies of the interphakmgeal joints were found in 1 and 2 patients, respectively. Eight periarticular calcifications were discernible in 7 patients, none of whom experienced acute inflammatory episodes. One of these patients had tumoral cdcinosis involving the elbow. Overall, 12 patients had a pretransplant diagnosis of amyloid arthropathy, confirmed by histologic demonstration of synovial f3,microglobulin amyloid in 7 patients. The 2 other patients did not meet amyloid arthropathy criteria. They experienced chronic arthdgias with destructive arthropathies of the small finger joints (which do not seem to be associated with local amyloid depositiong); 1 of these patients also had carpal tunnel syndrome, which was found to be unrelated to amyloid at surgery.
Articular Status Posttransplantation The only case of carpal tunnel syndrome with symptoms at the time of renal transplantation improved substantially after the procedure. Seven of the 14 patients were totally free of articular pain at the tune of the posttransplant evaluation. Their symptoms resolved over a few days to 6 months after the transplantation procedure. According to the patients’ assessments, articular manifestations improved in 10 patients (meeting cri-
September 1995 The American Journal of Medicine@ Volume 99
DIALYSIS
teria for amyloid arthropathy), remained unchanged in 1 (who did not meet these criteria), and worsened in 3 (1 of whom did not meet the criteria). The number of painful joints decreased after transplantation in 10 patients (9 with amyloid arthropathy and 1 with no criteria for amyloid) and increased in 4 (3 amyloid and 1 nonamyloid arthropathies). The Table shows that most joints considered painful before kidney transplantation were improved at the time of evaluation. Overall, the number of painful joints decreased significantly as compared to the pretransplant status (P ~0.05, Wilcoxon’s rank-sum test for paired observations). However, at the time of our evaluation, 5 patients (of whom 4 met amyloid arthropathy criteria) had a total of 14 joints with restricted mobility, and 3 patients (of whom 2 had amyloid arthropathy) had 7 moderately swollen joints. Two patients experienced tendinous rupture immediately after transplantation and 6 years after transplantation, respectively, but these lesions were asymptomatic at the time of evaluation. Moreover, a number of joints that were not painful before renal transplantation were symptomatic when we examined the patients. One of these patients experienced avascular epiphyseal necrosis of the knee. Two others had interphalangeal arthropathies involving joints that became symptomatic in the posttransplantation period. There were no roentgenographic abnormalities in other new sites of pain. The treatment regimen (ie, corticosteroid dosage and type of immunosuppressive therapy), pretransplantation features, and serum creatinine, uric acid, and I?,,microglobulin levels did not correlate with articular status (data not shown). The number of painful joints at the time of the study was correlated with the time interval since transplantation (r = 0.83, P ~0.01, Spear-man’srank-order correlation test). Analysis of roentgenograms showed that the mnnber of subchondral bone cysts was identical (57) before and after transplantation. There was also no change in cyst size, except for 1 humeral head cyst that appeared slightly enlarged 80 months after renal transplantation (Figure 1). Pretransplant destructive arthropathies generally worsened after the transplantation. In the only patient who had pretransplant destructive arthropathy involving large peripheral joints, joint-space narrowing worsened markedly and total hip replacement was required on both sides because of progressive disability. This patient subsequently had one of her prostheses removed because of infection. Four of the 5 patients with pretransplant cerv&l spondyloarthropathy exhibited further disc space mu-rowing with a concomitant increase in vertebral plate erosion size. One patient developed C4C5 and C5C6 spondylolisthesis responsible for C6 root compression (Figure 2) and required cervical spine surgery. September
ARTHROPATHY/BARDIN
ET AL
Figure 1. Large radiolucent cyst of the humeral head A. before and B. 80 months after renal transplantation. The sclerotic margin of the lesion is more apparent on the post-transplant film. The size of the cyst also appears slightly increased.
Preexisting destructive arthropathies of finger joints in 2 patients appeared unchanged except for one distal interphalangeal joint, which deteriorated markedly (Figure 3); moreover, in these 2 patients, destructive changes developed in four interphalangeal joints that were normal on pretransplantation roentgenograms. One of these 2 patients developed worsening pain and severe joint-space narrowing in his right ankle. He finally required surgical arthrodesis of this joint. The number of periarticular calcifications did not change after transplantation. One calcium deposit near a distal interphalangeal joint disappeared, but another developed in the vicinity of a metacarpophalangeal joint. The tumor-al calcinosis decreased in size, but was still discernible on a roentgenogram taken 10 years after transplantation. Roentgenographic features of hyperparathyroidism present before transplantation in 3 patients were no longer discernible on posttransplantation roentgenograms. 1995
The American
Journal
of Medicinea
Volume
99
245
DIALYSIS ARTHROPATHY/BARDIN
ET AL
Figure 2. A. Lateral views of the cervical spine of the same patient taken before (left) and 10 years after fright) renal transplantation. C5 and C4 slippings and C4C5 destructive spondyloarthropathy are markedly worsened on the posttransplant film. B. Posttransplant magnetic resonance images in the same patient including nonenhanced spin-echo Tl-weighted (left), enhanced spin-echo Tlweighted (middle), and gradient-echo T2-weighted sequences. Destructive changes and spinal cord displacement are discernable at the WC5 and C5C6 levels without significant soft-tissue mass. Also note soft-tissue enlargement behind the odontoid process.
Figure 3. Roentgenograms taken A. before and B. 74 months after
renal transplantation exhibit destructive arthropathies of the distal interphalangeal joints and marked worsening of the forefinger arthropathy.
Joint tissues from 3 patients were available for pathologic examination in the posttransplant period. Ankle synovial and cartilage specimens from 1 of these patients did not exhibit amyloid deposits. Interestingly, this patient was 1 of the 2 who did not exhibit subchondral bone cysts and whose carpal tunnel was found to contain no amyloid upon surgery performed before renal transplantation. In contrast, large B,-microglobulin amyloid deposits were identified in 246
September
1995
The American
Journal
of Medicine@
Volume
articular specimensfrom the 2 other patients who met criteria for amyloid arthropathy before transplantation and who underwent joint surgery 2 and 10 years after renal transplantation, respectively (Figure 4).
DISCUSSION ln this study, the clinical features of dialysis arthropathy, especially those of amyloid arthropathy, appeared to improve overall after renal transplanta99
DIALYSIS
ARTHROPATHY/BARDIN
ET AL
tion. Transplant recipients are exposed to the adverse articular effects of steroids andfor other drugsi including epiphyseal necrosis20 and tendinous ruptures,21 which indeed developed in 1 and 2 of our patients, respectively. Immunosuppression also predisposes to infectious arthriti~,~~ and 1 of our patients developed infection of her hip prosthesis. The patients that we examined prospectively also suffered from arthralgias of uncertain etiology, affecting sites that were not involved in the pretransplant period. Nevertheless, three quarters of our patients reported that their articular condition was improved as compared with the pretransplantation period, and overall, the number of Figure 4. Amyloid deposits in a disk biopsy obtained 10 years after renal transplantation show a strongly positive reaction with antihuman painful joints decreased significantly. l3,-microglobulin antibody (immunoperoxidase preparation; original Such symptomatic improvement of dialysis arthromagnification x 250). pathy has already been reported by several authors,lS these data. Although it has been firmly demonstrated l8 although its mechanism is still unexplained. Atlicular deposition of f+nicroglobulin amyloid in articular and that subchondral cysts in dialysis patients contain periarticular tissues is strongly associated with the ~yloid,WG’6 persistence of the radiolucencies cancarpal tunnel syndrome and chronic arthropathies, not be interpreted as indicative of persistent amyloid, which are frequently observed in patients treated by since dissolution of amyioid may occur without silong-term hemodialysis.lO~ll Overall, 12 of the 14 pa- multaneous bone repair. However, our study demonamyloid can still be tients that we examined had roentgenographic or strated that B,-microglobulin pathologic evidence of amyloid arthropathy according identified in joint structures 10 years after successful renal transplantation, confiig previous findings at to the criteria developed by Jadoul et all5 a shorter posttransplant interval. 14,27Therefore, amyThe pathophysiology of l3,microglobulin amyloidosis is not fully understood and may involve several loid appears to persist in transplant recipients, defactors, including local mediators of amyloid deposi- spite an apparent arrest in disease progression sugtion in addition to hyper-13,microglobulinemia. How- gested by the absence of changes in bone cyst size in ever, IS,-microglobulin retention in uremic patients re- our patients and in other studies.15l16 The negative posttransplantation serum amyloid P mains one of the major pathogenic components of the disease. Restoration of renal function following a scan iodinated 1123 reported by Nelson et al23 may successful kidney transplantation is followed by a re- have indicated the arrest of new cyst formation rather turn of the renal elimination of I&-microglobulin and than the disappearance of amyloid.24 Interestingly, serum µglobulin to nearly normal levels. there is, as yet, little histologic evidence that other One could, therefore, expect that successful renal types of amyloid can be resorbed when the initiating transplantation would lead to the dissolution of l3,- stimulus is eradicated, as in amyloid secondary to inmicroglobulin amyloid, a hypothesis suggested by fection,28 or treated, as in AL amyloidosis.2g Nelson et al23 on the basis of their scintigraphic fmdDestructive arthropathies, characterized by articuings. However, in our opinion, several data suggest lar or disc cartilage destruction resulting in narrowthat the mechanism of joint pain relief in renal trans- ing of joint or disc spaces on roentgenograms, have plant patients is not related to dissolution of amyloid been described in patients treated by long-term hedeposits.24 Whereas carpal tunnel syndrome is usu- modialysis. They involve the spine and large periphally rapidly improved by transplantation, as in our pa- eral joints, usually in association with local amyloid tient, a recent report demonstrated that amyloid de- deposits71s or the small finger joints, where no local posits can be identified at this site 28 months after amyloid deposition has been demontrated.g Renal transplantation. l8 Our study also suggests that suc- transplantation did not appear to protect our patients cessful renal transplantation does not lead to disso- from the progression of destructive-dialysis arthropalution of articular amyloid deposits. thy, and the effect of transplantation on joint sympThe main roentgenographic feature of 13,~mi- toms was substantially less marked in patients with croglobulin amyloid arthropathy is the presence of destructive arthropathies. ’ multiple subchondral bone cysts. Jadoul et al15 and Finally, the contrast between improvements in Campistol et all6 previously reported that these radi- joint symptoms versus worsening cartilage loss and olucent cysts are not modified by renal transpla,nmpersistent amyloid deposits suggests that the effect tion. Our findings in patients seen after a longer post- of transplantation on dialysis arthropathy may be transplantation interval (mean 53.8 months) support mostly symptomatic. Corticosteroid treatment is the September
1995
The American
Journal
of Medicine@
Volume
99
247
most likely explanation for this symptomatic effect. In our experience, treatment of dialysis arthropathy by low-dose prednisone leads to dramatic improvements in symptoms30 Moreover, in patients who resume hemodialysis because of graft rejection, joint pain recurs rapidly after steroid withdrawal, independently from the time of return to dialysis. In conclusion, renal transplantation appears effective in arresting the progression of &,-microglobulin amyloidosis in dialysis patients, but neither allows dissolution of deposits nor prevents progression of destructive arthropathies. This procedure, which is, nevertheless, the sole available means of preventing f3,-microglobulin amyloidosis, should ideally be performed before the development of severe amyloid arthropathy.
ACKNOWLEDGMENT This study was supported in part by a grant from the lnstitut National de la Sante et de la Recherche MBdicale.
REFERENCES 1. Goldstein S. WinstonE. Chung TJ, et al. Chronic arthropathy in long term hemodiaiysis. Am J Med. 1985;78:82-86. 2. Brown EA, Arnold IR, Gower PE. Dialysis arthropathy: complication of long term treatment with hemodialysis. EN. 1986;292:163-166, 3. Bardin T, Kuntz D. The arthropathy of chronic hemodialysis. Clin Exp Rheumatol. 1987;5:379-386. 4. Hardouin P, Flip0 RM, Foissac-Gegoux P, et al. Current aspect of osteo articular pathology in patients undergoing hemodialysis J Rheumatol. 1987;14: 780-783. 5. Kessler M, Netter P, Azoulay E, et al. Dialysis associated arthropathy. A multicentre survey of 171 patients receiving haemodialysis for over 10 years. Br J Rheumatol. 1992;31:157-162. 6. Bardin T, Zingraff J, Shirahama T, et al. Hemodiaiysis-associated amyloidosis and beta-2 microglobulin: a clinical and immunohistochemical study. Am J Med. 1987;83:419-424. 7. Kuntz D, Naveau B, Bardin T, et al. Destructive spondylarthropathy in hemodialysed patients: a new syndrome. Arthritis Rheum. 1984;27:369-375. 8. Kuntz D, Bardin T. Dialysis destructive arthropathies. In: Gejyo F, Brancaccio D, Bardin T, eds. Dialysis Amyloidosis. Milan, Italy: Witchig Editore; 1989: 101-109. 9. Flip0 RM, Le Loet, Siame JL, et al. Destructive arthropathy of the hand in patients treated by long term hemodialysis. Seven cases with pathological examination. Rev Rhum (Engl Ed). 1995;62:241-247. 10. Bardin T, Zingraff J, Kuntz D, Driieke T. Dialysis-related amyloidosis. Nephrol Dial Transplant 1986;1:151-154.
248
September
1995
The American
Journal
of Medicine@
Volume
11. Gaucher A, Kessler ML, Netter PA. Dialysis-associated arthropathy. Can we prevent it? Can it be treated? J Rheumatol. 1992;11:1659-1662. 12. Edwards LC, Helderman JH, Hamm IL, et al. Noninvasive monitoring of renal transplant function by analysis of beta-2 microglobulin. Kidney Int. 1983;23:767-770. 13. Calemard E, Charra B, Uzam M, Laurent G. Improvement of late dialysis periarticular syndrome by changing the mode of renal replacement therapy. Nephrol Dial Transplant 1987;2:433. Abstract. 14. Sethi D, Brown EA, Maini RN, Gower PE. Renal transplantation for dialysis arthropathy. lancet 1988;i:448-449. Letter. 15. Jadoul M, Malghem J, Pirson Y, et al. Effect of renal transplantation on the radiological signs of dialysis amyloid arthropathy. Clin Nephrol. 1989;32: 194-197. 16. Campistol JM, MunozGomez J, Oppenheimer F, et al. Renal transplantatron for dialysis arthropathy. Transplant Proc. 1992;24:118-119. 17. Zingraff J, Drijeke T, Chkoff N. Beta-2 microglobulin amyloidosis after kidney transplantatton. In: Gejyo F, Brancaccio D, Bardin T, eds. Dialysis Amyloidosis. Milan, Italy: Witchig Editore; 1989:145-146. 18. Nelson SR, Sharpstone P, Kingswood JC. Does dialysis-associated amyloidosis resolve after transplantation? Nephrol Dial Transplant. 1993;8: 369-370. 19. Elmstedt E, Svahn T. Skeletal complications following renal transplantation. Acta Orthop Stand. 1981;52:279-286. 20. Rao KW, Andersen RC. Long-term results and complications in renal transplant recipients. Transplantation. 1988;45:45-52. 21. Murison MSC, Eardley I, Stapak M. Tendinitis. A common complication after renal transplantation. Transplantation. 1986;48:587-589. 22. Bomalaski JS, Williamson PK, Goldstein CS. Infectious arthritis in renal transplant patients. Arthritis Rheum. 1986;29:227-232. 23. Nelson SR, Hawkins PN, Richardson S, et al. Imaging of haemodialyslsassociated amyloidosis with 1231.serum amyloid component. lancet. 1991; 338:335-339. 24. Zingraff J, Bardin T, Noel LH, Drtieke T. Lack of haemodialysis-associated amyloidosis. Lancet 1991;338:1089. Letter. 25. Huaux JP, Noel H, Bastien P, et al. Amylose articulaire, fracture du col femoral et hCmodialyse pCriodique chronique. Rev Rhum Mal Ost&Arbculaire. 1985;52:17%182. 26. Fenves AZ, Emmet M, White LG, Greenway G. Carpal tunnel syndrome with cystic bone lesions secondary to amyloidosis in chronic hemodialysis patbents. AmJKidneyDis. 1986;7:13C-134. 27. Kessler M, Netter P, Gaucher A. Outcome of dialysis associated arthro pathy and dialysis-related l3,-microglobulin amyloid after renal transplantation. Rev Rhum (Engl Ed). 1994;61:93S-968. 28. Lowenstein J, Gallo G. Remission of the nephrotic syndrome in renal amyloidosis. NEJM. 1970;282:128-133. 29. Schatter A, Varon D, Green L, et al. Primary amyloldosis with unusual bone involvement: reversibility with melphalan, prednisone and colchicine. Am J Med. 1989;86:347-348, 30. Bardin T. Low dose prednisone in dialysis-related amyloid arthropathy. Rev Rhum (Engl Ed). 1994;61:97S-100s.
99
I
Dialysis Arthropathy:
Outcome After Renal Transplantation
Thomas Bardin, MD, Jeanne Louise Lebail-Darn& MD, Johanna Zingraff, MD, Jean Denis Laredo, MD, Paris, France, Marie Catherine Voisin, MD, Crkteil, France, Henri Kreis, MD, Daniel Kuntz, MD, Paris, France PURPOSE:Patients treated by long-term maintenance hemodialysis frequently develop a form of chronic arthropathy that is strongly associated with 6,-microglobulin amyloid deposition and related, at least in part, to 6,-microglobulin retention. Successful renal transplantation is followed by a rapid fall in serum l3,-microglobulin levels and might allow dissolution of amyloid deposits. The purpose of this work was to investigate the effects of renal transplantation on dialysis arthropathy. PATIENTSAno METHODS:Fourteen renal tranplant recipients were selected on the basis of previous hemodialysis treatment for at least 10 years (mean 16) and a history of chronic joint pain prior to transplantation. They all received 10 to 17.5 mg/d of prednisone. Posttransplant rheumatologic manifestations were studied prospectively and compared to pretransplant rheumatologic manifestations recorded in medical charts and reported during patient interviews. Pretransplant and posttransplant articular roentgenograms were separately analyzed by three observers who were blinded to timing of the films. l3,-microglobulin amyloid was identified by Congo red staining and immunohistology. RESULTS:After a mean posttransplant interval of 54 months (range 12 to 121), the atticular condition was improved in 10 patients, unchanged in 1, and worsened in 3, according to patients’ assessments. The number of painful joints decreased significantly (P ~0.05) as compared to the pretransplant period. However, the number and size of subchondral bone erosions remained unchanged, destructive arthropathies generally worsened, and articular 6,-microglobulin amyloid deposits were identified in 2 patients, 2 and 10 years after renal transplantation, respectively. CONCLUSION:Renal transplantation appeared to arrest progression of l3,-microglobulin amyloid in
From the Clrnrque de Rhumatologie, Centre Viggo Petersen (TB, JLLD, DK), Service de Radiologie Osteoarticulaire (JDL), Htrprtal Lariboisiere; Departement de Nephrologie (JZ, HK), Hopital Necker, Paris, France, and, Service d’Anatomre Pathologique (MCV), Hopital Henri Mondor, Creteil, France. Requests for reprrnts should be addressed to Dr T. Bardin, Clinrque de Rhumatologie, Centre Viggo Petersen, 6 rue Guy Pabn, Hopital Lariboisiere, Paris, France. Manuscript submitted June 23, 1994 and accepted in revised form December 7, 1994.
dialysis patients, but it neither led to dissolution of deposits nor prevented progression of destructive arthropathies. Most articular symptoms were improved, probably as a result of cotticosteroid therapy.
T
he importance of rheumatic disorders in patients on long-term hemodialysis has been emphasized during the past years. l-5 These disorders presently appear as the main factor limiting quality of life in longterm survivors. The pathophysiology of joint aherations appears complex and is still incompletely understood. Several factors have been linked with rheumatic disorders, including secondary hyperparathyroidism, aluminum and possibly silicon overload, calcium phosphate and calcium oxalate crystal deposition, and septic complications. 13,Microglobulin amyloid has been demonstrated to be associated with the majority of carpal tunnel syndromes and chronic arthropathies in long-term dialysis patients2” although its responsibility as the initiating cause of arthropathy is still debated, particularly as concerns dialysis-destructive arthropathy,7-g Retention of C$nicroglobulin in dialysis patients is believed to be the central, although not the only, factor in the pathogenesis of amyloid formation.‘O,‘l Renal transplantation is followed by a rapid fall in serum fJ,-microglobulin levels’” and might improve dialysis arthropathy.13-18 We report the results of a prospective study of the effects of successful renal transplantation on dialysis arthropathy and amyloid deposition in a series of 14 patients.
PATIENTS AND METHODS Among patients who underwent successful renal transplantation at the Necker Hospital during the last decade, we selected 14 subjects who were previously treated by hemodialysis for at least 10 years and had a history of chronic joint pain prior to transplantation. There were 7 women and 7 men. Mean age was 47.6 years (range 38 to 57). Mean duration of maintenance hemodialysis before renal transplantation was 195 months (range 120 to 243). Renal failure was secondary to glomerulonephritis in 9 patients, pyelonephritis in 2, and polycystic kidney disease in 1; etiology was unknown in the 2 remaining patients. No patients had amyloid nephropathy or systemic diseases known to cause articular symptoms. Nine patients had a history of deferoxamine treatment for alu-
September 1995 The American Journal of Medicine@Volume 99
243
DIALYSIS ARTHROPATHY/BARDIN
ET AL
TABLE Incidence of Painful Skeletal Sites in 14 Renal Transplant Recipients Before and After Transplantation Pain Before Renal Pain Remaining After New Involvement Site Transplantation Transplantation After Transplantation Shoulder 21 2 1 Knee 12 2 5 Hip 10 4 0 lnterphalangeal joint 8 2 2 Cervical spine 7 1 2 Elbow 7 0 2 Ankle 4 2 0 Trapeziometacarpal joint 2 2 2 Carpal tunnel syndrome 1 0 0
minum overload and 9 had undergone subtotal parathyroidectomy. Three patients had roentgenographic evidence of overt hyperparathyroidism at the time of the transplant procedure. Mean serum calcium (m@) X phosphorus (mg/L) product during the last 3 pretransplantation months ranged from 2,916 to 8,851 mg/L (mean 5,905 f 940). Patients were examined 12 to 121 months after kidney transplantation (mean 53.8). Treatment included prednisone in a daily dose of 10 to 17.5 mg (mean 13.5) in all patients, azathioprine in 5, and/or cyclosporine and azathioprine in 8 patients. Mean plasma creatinine level was 165 + 64.3 mmol/L (range 80 to 510). Mean B,-microglobulinemia, measured using an enzyme-linked immunosorbent assay (Phadezym B2 microtest; Pharmacia, Uppsala, Sweden), was 5.5 * 2.6 mgIL (upper limit of normal 2.4 mg/L). Mean serum calcium (mg/L) X phosphorus (mg/L) product was 4,654 * 367 mg/L. Mean serum uric acid level was 6.8 f 1.1 mg/dL. All 14 patients underwent a rheumatologic evahration and roentgenograms of the hands, wrists, pelvis, shoulders, cervical spine, and knees. Pretransplantation status was retrospectively evaluated on the basis of medical records and patient interviews. The diagnosis of amyloid arthropathy was based on the concomitant presence of chronic arthralgias and multiple, large (ie, diameter >4 mm) subchondral bone cysts. Roentgenograms of the hands and wrists, pelvis, and shoulders had been performed within 3 months before transplantation in all patients. Pretransplant roentgenograms of the knees and cervical spine were available for 7 and 5 patients, respectively. One patient had pretransplantation and posttransplantation roentgenograms of his elbows. Pre- and posttransplant roentgenograms were separately analyzed by three observers, who were blinded to roentgenogram sequence and who assessed the number and size of cysts and periarticular calcium deposits and joint-space width. A consensus was reached concerning the five films for which the three observers initially disagreed. 244
Amyloid deposits in articular samples were identified by Congo red staining, and the nature of the amyloid was determined by immunohistology, using previously reported techniques.6
RESULTS Articular Status Pretransplantation Before the transplantation procedure, the 14 patients suffered from chronic arthralgias involving a total of 71 joints (Table). Eight patients had a history of carpal tunnel syndrome and another had persistent features of this syndrome at the time of renal transplantation. Roentgenograms demonstrated 57 sub chondral cysts in 12 patients. Cervical destructive spondyloarthropathy7 was diagnosed on pretransplant roentgenograms in 5 patients. Destructive arthropathy of the hips and multiple destructive arthropathies of the interphakmgeal joints were found in 1 and 2 patients, respectively. Eight periarticular calcifications were discernible in 7 patients, none of whom experienced acute inflammatory episodes. One of these patients had tumoral cdcinosis involving the elbow. Overall, 12 patients had a pretransplant diagnosis of amyloid arthropathy, confirmed by histologic demonstration of synovial f3,microglobulin amyloid in 7 patients. The 2 other patients did not meet amyloid arthropathy criteria. They experienced chronic arthdgias with destructive arthropathies of the small finger joints (which do not seem to be associated with local amyloid depositiong); 1 of these patients also had carpal tunnel syndrome, which was found to be unrelated to amyloid at surgery.
Articular Status Posttransplantation The only case of carpal tunnel syndrome with symptoms at the time of renal transplantation improved substantially after the procedure. Seven of the 14 patients were totally free of articular pain at the tune of the posttransplant evaluation. Their symptoms resolved over a few days to 6 months after the transplantation procedure. According to the patients’ assessments, articular manifestations improved in 10 patients (meeting cri-
September 1995 The American Journal of Medicine@ Volume 99
DIALYSIS
teria for amyloid arthropathy), remained unchanged in 1 (who did not meet these criteria), and worsened in 3 (1 of whom did not meet the criteria). The number of painful joints decreased after transplantation in 10 patients (9 with amyloid arthropathy and 1 with no criteria for amyloid) and increased in 4 (3 amyloid and 1 nonamyloid arthropathies). The Table shows that most joints considered painful before kidney transplantation were improved at the time of evaluation. Overall, the number of painful joints decreased significantly as compared to the pretransplant status (P ~0.05, Wilcoxon’s rank-sum test for paired observations). However, at the time of our evaluation, 5 patients (of whom 4 met amyloid arthropathy criteria) had a total of 14 joints with restricted mobility, and 3 patients (of whom 2 had amyloid arthropathy) had 7 moderately swollen joints. Two patients experienced tendinous rupture immediately after transplantation and 6 years after transplantation, respectively, but these lesions were asymptomatic at the time of evaluation. Moreover, a number of joints that were not painful before renal transplantation were symptomatic when we examined the patients. One of these patients experienced avascular epiphyseal necrosis of the knee. Two others had interphalangeal arthropathies involving joints that became symptomatic in the posttransplantation period. There were no roentgenographic abnormalities in other new sites of pain. The treatment regimen (ie, corticosteroid dosage and type of immunosuppressive therapy), pretransplantation features, and serum creatinine, uric acid, and I?,,microglobulin levels did not correlate with articular status (data not shown). The number of painful joints at the time of the study was correlated with the time interval since transplantation (r = 0.83, P ~0.01, Spear-man’srank-order correlation test). Analysis of roentgenograms showed that the mnnber of subchondral bone cysts was identical (57) before and after transplantation. There was also no change in cyst size, except for 1 humeral head cyst that appeared slightly enlarged 80 months after renal transplantation (Figure 1). Pretransplant destructive arthropathies generally worsened after the transplantation. In the only patient who had pretransplant destructive arthropathy involving large peripheral joints, joint-space narrowing worsened markedly and total hip replacement was required on both sides because of progressive disability. This patient subsequently had one of her prostheses removed because of infection. Four of the 5 patients with pretransplant cerv&l spondyloarthropathy exhibited further disc space mu-rowing with a concomitant increase in vertebral plate erosion size. One patient developed C4C5 and C5C6 spondylolisthesis responsible for C6 root compression (Figure 2) and required cervical spine surgery. September
ARTHROPATHY/BARDIN
ET AL
Figure 1. Large radiolucent cyst of the humeral head A. before and B. 80 months after renal transplantation. The sclerotic margin of the lesion is more apparent on the post-transplant film. The size of the cyst also appears slightly increased.
Preexisting destructive arthropathies of finger joints in 2 patients appeared unchanged except for one distal interphalangeal joint, which deteriorated markedly (Figure 3); moreover, in these 2 patients, destructive changes developed in four interphalangeal joints that were normal on pretransplantation roentgenograms. One of these 2 patients developed worsening pain and severe joint-space narrowing in his right ankle. He finally required surgical arthrodesis of this joint. The number of periarticular calcifications did not change after transplantation. One calcium deposit near a distal interphalangeal joint disappeared, but another developed in the vicinity of a metacarpophalangeal joint. The tumor-al calcinosis decreased in size, but was still discernible on a roentgenogram taken 10 years after transplantation. Roentgenographic features of hyperparathyroidism present before transplantation in 3 patients were no longer discernible on posttransplantation roentgenograms. 1995
The American
Journal
of Medicinea
Volume
99
245
DIALYSIS ARTHROPATHY/BARDIN
ET AL
Figure 2. A. Lateral views of the cervical spine of the same patient taken before (left) and 10 years after fright) renal transplantation. C5 and C4 slippings and C4C5 destructive spondyloarthropathy are markedly worsened on the posttransplant film. B. Posttransplant magnetic resonance images in the same patient including nonenhanced spin-echo Tl-weighted (left), enhanced spin-echo Tlweighted (middle), and gradient-echo T2-weighted sequences. Destructive changes and spinal cord displacement are discernable at the WC5 and C5C6 levels without significant soft-tissue mass. Also note soft-tissue enlargement behind the odontoid process.
Figure 3. Roentgenograms taken A. before and B. 74 months after
renal transplantation exhibit destructive arthropathies of the distal interphalangeal joints and marked worsening of the forefinger arthropathy.
Joint tissues from 3 patients were available for pathologic examination in the posttransplant period. Ankle synovial and cartilage specimens from 1 of these patients did not exhibit amyloid deposits. Interestingly, this patient was 1 of the 2 who did not exhibit subchondral bone cysts and whose carpal tunnel was found to contain no amyloid upon surgery performed before renal transplantation. In contrast, large B,-microglobulin amyloid deposits were identified in 246
September
1995
The American
Journal
of Medicine@
Volume
articular specimensfrom the 2 other patients who met criteria for amyloid arthropathy before transplantation and who underwent joint surgery 2 and 10 years after renal transplantation, respectively (Figure 4).
DISCUSSION ln this study, the clinical features of dialysis arthropathy, especially those of amyloid arthropathy, appeared to improve overall after renal transplanta99
DIALYSIS
ARTHROPATHY/BARDIN
ET AL
tion. Transplant recipients are exposed to the adverse articular effects of steroids andfor other drugsi including epiphyseal necrosis20 and tendinous ruptures,21 which indeed developed in 1 and 2 of our patients, respectively. Immunosuppression also predisposes to infectious arthriti~,~~ and 1 of our patients developed infection of her hip prosthesis. The patients that we examined prospectively also suffered from arthralgias of uncertain etiology, affecting sites that were not involved in the pretransplant period. Nevertheless, three quarters of our patients reported that their articular condition was improved as compared with the pretransplantation period, and overall, the number of Figure 4. Amyloid deposits in a disk biopsy obtained 10 years after renal transplantation show a strongly positive reaction with antihuman painful joints decreased significantly. l3,-microglobulin antibody (immunoperoxidase preparation; original Such symptomatic improvement of dialysis arthromagnification x 250). pathy has already been reported by several authors,lS these data. Although it has been firmly demonstrated l8 although its mechanism is still unexplained. Atlicular deposition of f+nicroglobulin amyloid in articular and that subchondral cysts in dialysis patients contain periarticular tissues is strongly associated with the ~yloid,WG’6 persistence of the radiolucencies cancarpal tunnel syndrome and chronic arthropathies, not be interpreted as indicative of persistent amyloid, which are frequently observed in patients treated by since dissolution of amyioid may occur without silong-term hemodialysis.lO~ll Overall, 12 of the 14 pa- multaneous bone repair. However, our study demonamyloid can still be tients that we examined had roentgenographic or strated that B,-microglobulin pathologic evidence of amyloid arthropathy according identified in joint structures 10 years after successful renal transplantation, confiig previous findings at to the criteria developed by Jadoul et all5 a shorter posttransplant interval. 14,27Therefore, amyThe pathophysiology of l3,microglobulin amyloidosis is not fully understood and may involve several loid appears to persist in transplant recipients, defactors, including local mediators of amyloid deposi- spite an apparent arrest in disease progression sugtion in addition to hyper-13,microglobulinemia. How- gested by the absence of changes in bone cyst size in ever, IS,-microglobulin retention in uremic patients re- our patients and in other studies.15l16 The negative posttransplantation serum amyloid P mains one of the major pathogenic components of the disease. Restoration of renal function following a scan iodinated 1123 reported by Nelson et al23 may successful kidney transplantation is followed by a re- have indicated the arrest of new cyst formation rather turn of the renal elimination of I&-microglobulin and than the disappearance of amyloid.24 Interestingly, serum µglobulin to nearly normal levels. there is, as yet, little histologic evidence that other One could, therefore, expect that successful renal types of amyloid can be resorbed when the initiating transplantation would lead to the dissolution of l3,- stimulus is eradicated, as in amyloid secondary to inmicroglobulin amyloid, a hypothesis suggested by fection,28 or treated, as in AL amyloidosis.2g Nelson et al23 on the basis of their scintigraphic fmdDestructive arthropathies, characterized by articuings. However, in our opinion, several data suggest lar or disc cartilage destruction resulting in narrowthat the mechanism of joint pain relief in renal trans- ing of joint or disc spaces on roentgenograms, have plant patients is not related to dissolution of amyloid been described in patients treated by long-term hedeposits.24 Whereas carpal tunnel syndrome is usu- modialysis. They involve the spine and large periphally rapidly improved by transplantation, as in our pa- eral joints, usually in association with local amyloid tient, a recent report demonstrated that amyloid de- deposits71s or the small finger joints, where no local posits can be identified at this site 28 months after amyloid deposition has been demontrated.g Renal transplantation. l8 Our study also suggests that suc- transplantation did not appear to protect our patients cessful renal transplantation does not lead to disso- from the progression of destructive-dialysis arthropalution of articular amyloid deposits. thy, and the effect of transplantation on joint sympThe main roentgenographic feature of 13,~mi- toms was substantially less marked in patients with croglobulin amyloid arthropathy is the presence of destructive arthropathies. ’ multiple subchondral bone cysts. Jadoul et al15 and Finally, the contrast between improvements in Campistol et all6 previously reported that these radi- joint symptoms versus worsening cartilage loss and olucent cysts are not modified by renal transpla,nmpersistent amyloid deposits suggests that the effect tion. Our findings in patients seen after a longer post- of transplantation on dialysis arthropathy may be transplantation interval (mean 53.8 months) support mostly symptomatic. Corticosteroid treatment is the September
1995
The American
Journal
of Medicine@
Volume
99
247
most likely explanation for this symptomatic effect. In our experience, treatment of dialysis arthropathy by low-dose prednisone leads to dramatic improvements in symptoms30 Moreover, in patients who resume hemodialysis because of graft rejection, joint pain recurs rapidly after steroid withdrawal, independently from the time of return to dialysis. In conclusion, renal transplantation appears effective in arresting the progression of &,-microglobulin amyloidosis in dialysis patients, but neither allows dissolution of deposits nor prevents progression of destructive arthropathies. This procedure, which is, nevertheless, the sole available means of preventing f3,-microglobulin amyloidosis, should ideally be performed before the development of severe amyloid arthropathy.
ACKNOWLEDGMENT This study was supported in part by a grant from the lnstitut National de la Sante et de la Recherche MBdicale.
REFERENCES 1. Goldstein S. WinstonE. Chung TJ, et al. Chronic arthropathy in long term hemodiaiysis. Am J Med. 1985;78:82-86. 2. Brown EA, Arnold IR, Gower PE. Dialysis arthropathy: complication of long term treatment with hemodialysis. EN. 1986;292:163-166, 3. Bardin T, Kuntz D. The arthropathy of chronic hemodialysis. Clin Exp Rheumatol. 1987;5:379-386. 4. Hardouin P, Flip0 RM, Foissac-Gegoux P, et al. Current aspect of osteo articular pathology in patients undergoing hemodialysis J Rheumatol. 1987;14: 780-783. 5. Kessler M, Netter P, Azoulay E, et al. Dialysis associated arthropathy. A multicentre survey of 171 patients receiving haemodialysis for over 10 years. Br J Rheumatol. 1992;31:157-162. 6. Bardin T, Zingraff J, Shirahama T, et al. Hemodiaiysis-associated amyloidosis and beta-2 microglobulin: a clinical and immunohistochemical study. Am J Med. 1987;83:419-424. 7. Kuntz D, Naveau B, Bardin T, et al. Destructive spondylarthropathy in hemodialysed patients: a new syndrome. Arthritis Rheum. 1984;27:369-375. 8. Kuntz D, Bardin T. Dialysis destructive arthropathies. In: Gejyo F, Brancaccio D, Bardin T, eds. Dialysis Amyloidosis. Milan, Italy: Witchig Editore; 1989: 101-109. 9. Flip0 RM, Le Loet, Siame JL, et al. Destructive arthropathy of the hand in patients treated by long term hemodialysis. Seven cases with pathological examination. Rev Rhum (Engl Ed). 1995;62:241-247. 10. Bardin T, Zingraff J, Kuntz D, Driieke T. Dialysis-related amyloidosis. Nephrol Dial Transplant 1986;1:151-154.
248
September
1995
The American
Journal
of Medicine@
Volume
11. Gaucher A, Kessler ML, Netter PA. Dialysis-associated arthropathy. Can we prevent it? Can it be treated? J Rheumatol. 1992;11:1659-1662. 12. Edwards LC, Helderman JH, Hamm IL, et al. Noninvasive monitoring of renal transplant function by analysis of beta-2 microglobulin. Kidney Int. 1983;23:767-770. 13. Calemard E, Charra B, Uzam M, Laurent G. Improvement of late dialysis periarticular syndrome by changing the mode of renal replacement therapy. Nephrol Dial Transplant 1987;2:433. Abstract. 14. Sethi D, Brown EA, Maini RN, Gower PE. Renal transplantation for dialysis arthropathy. lancet 1988;i:448-449. Letter. 15. Jadoul M, Malghem J, Pirson Y, et al. Effect of renal transplantation on the radiological signs of dialysis amyloid arthropathy. Clin Nephrol. 1989;32: 194-197. 16. Campistol JM, MunozGomez J, Oppenheimer F, et al. Renal transplantatron for dialysis arthropathy. Transplant Proc. 1992;24:118-119. 17. Zingraff J, Drijeke T, Chkoff N. Beta-2 microglobulin amyloidosis after kidney transplantatton. In: Gejyo F, Brancaccio D, Bardin T, eds. Dialysis Amyloidosis. Milan, Italy: Witchig Editore; 1989:145-146. 18. Nelson SR, Sharpstone P, Kingswood JC. Does dialysis-associated amyloidosis resolve after transplantation? Nephrol Dial Transplant. 1993;8: 369-370. 19. Elmstedt E, Svahn T. Skeletal complications following renal transplantation. Acta Orthop Stand. 1981;52:279-286. 20. Rao KW, Andersen RC. Long-term results and complications in renal transplant recipients. Transplantation. 1988;45:45-52. 21. Murison MSC, Eardley I, Stapak M. Tendinitis. A common complication after renal transplantation. Transplantation. 1986;48:587-589. 22. Bomalaski JS, Williamson PK, Goldstein CS. Infectious arthritis in renal transplant patients. Arthritis Rheum. 1986;29:227-232. 23. Nelson SR, Hawkins PN, Richardson S, et al. Imaging of haemodialyslsassociated amyloidosis with 1231.serum amyloid component. lancet. 1991; 338:335-339. 24. Zingraff J, Bardin T, Noel LH, Drtieke T. Lack of haemodialysis-associated amyloidosis. Lancet 1991;338:1089. Letter. 25. Huaux JP, Noel H, Bastien P, et al. Amylose articulaire, fracture du col femoral et hCmodialyse pCriodique chronique. Rev Rhum Mal Ost&Arbculaire. 1985;52:17%182. 26. Fenves AZ, Emmet M, White LG, Greenway G. Carpal tunnel syndrome with cystic bone lesions secondary to amyloidosis in chronic hemodialysis patbents. AmJKidneyDis. 1986;7:13C-134. 27. Kessler M, Netter P, Gaucher A. Outcome of dialysis associated arthro pathy and dialysis-related l3,-microglobulin amyloid after renal transplantation. Rev Rhum (Engl Ed). 1994;61:93S-968. 28. Lowenstein J, Gallo G. Remission of the nephrotic syndrome in renal amyloidosis. NEJM. 1970;282:128-133. 29. Schatter A, Varon D, Green L, et al. Primary amyloldosis with unusual bone involvement: reversibility with melphalan, prednisone and colchicine. Am J Med. 1989;86:347-348, 30. Bardin T. Low dose prednisone in dialysis-related amyloid arthropathy. Rev Rhum (Engl Ed). 1994;61:97S-100s.
99