We retrospectively reviewed the results of thirty-five joint replacements in nineteen patients who had had both an organ transplantation and at least one joint replacement performed at the University of Michigan Medical Center from January 1968 through January 1994. The patients were identified by a search of the patient database for a cross match of diagnostic codes for joint replacement and organ transplantation. Four hundred and eighty-four liver transplantations and approximately 1650 renal transplantations were performed during this time-period. Nineteen patients who had received a transplant were identified as having had a joint replacement as well.
All of the patients in this study received the standard immunosuppressive induction regimen at the time of the transplantation and were maintained on a combination of prednisone and azathioprine or cyclosporine A, or both.
The arthroplasties included nineteen primary total hip replacements, seven primary hemiarthroplasties of the hip, five revision total hip replacements, and four total knee replacements. The diagnosis leading to the replacement was avascular necrosis for twenty-one joints, degenerative joint disease for seven, a loose primary prosthesis for five, and fracture for two. All of the hip replacements were done through a posterior approach and all of the knee replacements, through a medial parapatellar approach. All but three of the procedures were performed by one of us (L. S. M.) and another senior faculty member in a conventional operating room without isolation-type suits. All patients received a first-generation cephalosporin or a penicillin derivative perioperatively. Bone cement, when used, was not impregnated with antibiotics. Antibiotics were given prophylactically for at least forty-eight hours or until the operative drains were removed. The nutritional status of each patient was adequate at the time of the operation, as determined by the lymphocyte count and the level of albumin21. There was no clinical evidence of any infection at the time of the joint replacements.
Functional Assessment
The Harris hip score16 was used to evaluate the results of the hip replacements, and The Hospital for Special Surgery knee score19 was used to evaluate the results of the knee replacements. Pain, functional capacity, and the range of motion were determined during an office visit for twelve patients. Five patients who had died and two who had been lost to follow-up were evaluated on the basis of the records from the latest clinical examination. Radiographs were reviewed for periprosthetic lucency, subsidence or migration of the implant, pedestal formation, and wear of the polyethylene.
Over-all, twenty-nine joint replacements were performed in sixteen patients who had a renal transplantation and six joint replacements were performed in three patients who had a liver transplantation. The patients were divided into three subsets: those who had a joint replacement before the organ transplantation, those who had a joint replacement after the organ transplantation, and those who had a joint replacement both before and after the organ transplantation (Table I).
Six procedures (four total hip replacements, one revision total hip replacement, and one bipolar hip replacement) were done in three patients before a renal transplantation. The average age was 48.2 years (range, thirty-two to sixty-five years) at the time of the joint replacement. The joint replacements were performed because of degenerative joint disease in two hips, avascular necrosis in two hips, fracture of one hip, and aseptic loosening in one hip.
Fourteen patients had a total of twenty-four joint replacements (eleven total hip and three revision total hip replacements, six hip hemiarthroplasties, and four total knee replacements) after thirteen renal transplantations and one liver transplantation. The average age at the time of the twenty-four joint replacements was 40.9 years (range, twenty-seven to sixty-seven years). Avascular necrosis was the reason for two knee replacements; non-union of a supracondylar femoral fracture, for one; and degenerative joint disease, for one. Seventeen hip replacements were performed for avascular necrosis; two, for aseptic loosening of a prosthesis; and one, for loosening due to infection with Staphylococcus epidermidis.
Two patients had joint replacement both before and after liver transplantation. A total of five joint replacements were done: two total hip replacements were performed before the transplantation, and two total hip replacements and one revision hip replacement were done after the transplantation. The average age at the time of the five replacements was 53.8 years (range, forty-two to sixty-three years). Four of the hip replacements were performed because of degenerative joint disease and one, because of aseptic loosening.
Over-all, the average age of the nineteen patients was forty-four years (range, twenty-seven to sixty-seven years) at the time of the joint replacement and 40.7 years (range, sixteen to sixty-nine years) at the time of the first organ transplantation. The average duration of follow-up was 8.8 years (range, one to twenty-three years) from the time of the first joint replacement. Two patients died one year after the joint replacement.
All nineteen patients were taking prednisone as part of the immunosuppression regimen; in addition, sixteen were taking azathioprine and twelve were taking cyclosporine A.
Functional Assessment
The Harris hip score16, which is derived on the basis of pain and functional capacity, could be determined for only fifteen of the thirty-one hip replacements (Table I). The result was excellent for nine hips (a score of 90 to 100 points), good for four (80 to 89 points), fair for one (70 to 79 points), and poor for one (less than 70 points). A score could not be determined for sixteen hip replacements: five had been revised for aseptic loosening or infection, two had been resected for infection and a revision arthroplasty had not been performed by the time of this study, and six had been in patients who died before a Harris hip score was determined. The Harris hip score for the remaining three replacements (in two patients) could not be determined from the records of the latest clinical examination; one patient, who had had a total hip replacement, had been followed for ten years and one patient, who had had a bilateral revision total hip replacement, had been followed for nine years before being lost to follow-up.
The Hospital for Special Surgery knee score19 was used to evaluate three of the four total knee replacements (Table I); the result was excellent for two knees (a score of 85 points or more) and fair for one (a score of 60 to 69 points). The fourth knee replacement was in a patient who had died of multiple-system organ failure after resection of the prosthesis secondary to infection.
Radiographic Evaluation
Radiographs were available for twenty-seven of the thirty-five joint replacements (Table I). The radiographic appearance of nine replacements in six patients who were unavailable for examination was determined from the records from the latest clinical visit. Of the seventeen joint replacements that had no evidence of loosening, eleven could be graded with the Harris hip score16 or The Hospital for Special Surgery knee score19. Ten of the eleven joint replacements were graded excellent or good. The six joints that could not be graded were in patients who had died or had been lost to follow-up. There was one to two millimeters of clinically inconsequential lucency around six acetabular components. One patient who had a hip replacement and a poor Harris hip score (52 points) had severe periacetabular osteolysis with trochanteric resorption. One patient who had a cemented revision hip replacement with four millimeters of femoral subsidence had a fair Harris hip score (75 points). A patient who had two excellent Hospital for Special Surgery knee scores after bilateral total knee replacement had bilateral polyethylene wear and osteolysis around the tibial tray. Five replacements were revised because of loosening; the area around one of them was found to be infected on intraoperative culture.
Infection
No infection developed after any of the eight joint replacements that had been performed before an organ transplantation. Infection developed around the joint implant in five patients, all of whom had had the joint replacement after an organ transplantation. Four of these five patients were taking cyclosporine A. The average time from implantation of the prosthesis until detection of the infection was 3.4 years (range, one to six years). Over-all, the prevalence of infection was 14 per cent (five of thirty-five joint replacements in nineteen patients were followed by infection). If only the patients who had a joint replacement after an organ transplantation are considered, then the rate of infection was 19 per cent (five of twenty-seven joint replacements in sixteen patients).
CASE 19. A fifty-three-year-old man had a left total hip replacement in 1982 because of degenerative joint disease. Hepatitis C developed following several postoperative transfusions. A liver transplantation was performed six years after the joint replacement. The patient did well for several years, after which pain and radiographic evidence of aseptic loosening of the total hip replacement gradually developed. A revision total hip replacement was performed eighteen months after the liver transplantation. An aspiration arthrogram made before the revision revealed no remarkable findings, and intraoperative cultures were negative. The patient resumed normal activities of daily living until four years later, when insidious pain, which was exacerbated by weight-bearing, developed in the left hip. The patient reported that he had had no fever, chills, or sweating at that time. Radiographs showed mild periprosthetic lucency but no notable interval changes. A bone scan revealed diffuse periprosthetic uptake. A subsequent indium scan revealed diffuse uptake of indium-radiolabeled white blood cells on the left side consistent with periprosthetic infection. An aspiration arthrogram was made. Pseudomonas aeruginosa was grown on culture, and the fluid cell count was 104,500 red blood cells and 90,750 white blood cells with 93 per cent polymorphonuclear leukocytes. A repeat aspiration arthrogram was made, with similar results on culture and with regard to the fluid cell count. The Westergren sedimentation rate was eighteen millimeters per hour, and the C-reactive protein level was 0.8 milligram per liter. A resection arthroplasty was performed, and the patient received antibiotics intravenously for three months and then orally for nine months. The patient was awaiting reimplantation at the time of this review.
A review of the literature suggests that joint replacement is a good procedure for the treatment of osteonecrosis of the hip or the knee in patients who are receiving prednisone and azathioprine for immunosuppression after a renal transplantation. Woods et al., in 1972, reported full rehabilitation twenty-six months after a bilateral Charnley total hip replacement in a patient who had had a renal transplantation31. In 1973, Murray reported on the results of seven hemiarthroplasties and five total hip replacements in nine patients who were receiving prednisone and azathioprine because they had had a renal transplantation26. The patients were doing well two months to four and a half years after the joint procedures. Kenzora and Sledge reported that avascular necrosis developed in thirty-six (17 per cent) of 212 patients who had had a renal transplantation, leading to thirty-two hip replacements in twenty-one patients22. The average age of the patients in that study was thirty-seven years, and the joint replacement was performed an average of approximately twenty-eight months after the transplantation. There were no infections or dislocations at an average of twenty-three months22. In 1976, Gustafsson et al. reported one early dislocation and no other important complications after fourteen hip replacements in eight patients who had had a renal transplantation15. Ibels et al. reported relief of symptoms after twenty-one total hip replacements in patients who had had a renal transplantation18. The association between immunosuppression with steroids and the development of avascular necrosis of the femoral head as well as the benefits of total hip replacement in patients who have had a renal transplantation have been reiterated in several reports4,7,25.
As far as we know, the largest study of joint replacements in patients who had had an organ transplantation was by Bradford et al.2,3. Fifty patients who had had a renal transplantation and one who had had a cardiac transplantation, with prednisone and azathioprine used for immunosuppression, had seventy hip replacements, ten knee replacements, and two shoulder replacements. The average age at the time of the joint replacement was thirty-four years, and each patient had had symptoms related to the joint for an average of approximately twenty-three months before the replacement. There was one staphylococcal infection secondary to a wound infection at less than three months and three cases of late sepsis unrelated to the replaced joint six weeks to nine years postoperatively. However, the rate of dislocation was five to eight times higher than the rate of 2 to 3 per cent in patients who have not had a transplantation24,30.
Radford et al. reported on thirty-one total hip replacements in twenty-one patients after an average of six years29. Although ten patients died, those authors reported no problems with healing of the wound, no infections, and only one dislocation. They stated that total hip replacement was safe and effective in patients who were receiving immunosuppression with prednisone and azathioprine after a transplantation, and they recommended early intervention in view of the limited life expectancy of these patients.
We are aware of two published studies in which implants were inserted without cement in patients who were receiving prednisone and azathioprine after a renal transplantation. Orwin et al. reported fifteen good or excellent results two to four years after sixteen bipolar hemiarthroplasties performed without cement in ten patients who were an average of 34.6 years old28. They reported one infection with Staphylococcus aureus at seventeen months. Alpert et al. performed twenty-seven total hip replacements without cement in seventeen patients who had an average age of thirty-nine years1. After an average of forty-eight months, all of the patients had a good or excellent result1. The results of these studies are in contrast to those reported by Chandler et al., who found a high rate of loosening of hip replacement prostheses in patients who were less than thirty years old and who had not had an organ transplantation6.
The present study is unique in several respects. First, many of our patients were taking cyclosporine A. Second, three of our patients had had a liver transplantation. Third, we found a dramatically high prevalence of infection in patients who received cyclosporine A as part of their immunosuppression regimen.
Twelve of nineteen patients in our series were taking cyclosporine A as a part of the immunosuppression regimen. Cyclosporine A specifically blocks the transmission of the antigen-mediated signal to the synthetic machinery of T-cells through inhibition of the production of interleukin-2, a proliferative factor necessary for the induction of cytotoxic T-lymphocytes. To our knowledge, the only other report in the literature that involves joint replacement in patients receiving immunosuppression with cyclosporine A after an organ transplantation was by Isono et al.20, who reported the results of nine bilateral total hip replacements and one bilateral total knee replacement for steroid-induced avascular necrosis in ten patients who had had a cardiac transplantation. Three of the ten patients were taking cyclosporine A. Sixteen joints had excellent function at an average of thirty-four months. Late hematogenous seeding of a hip with an atypical Mycobacterium occurred in one patient seven years after the joint replacement and three months after a renal transplantation that was done eleven years after a cardiac transplantation performed for cyclosporine-induced nephrotoxicity20. In the present study, infection ultimately developed around the joint implant in four of the twelve patients who were taking cyclosporine A.
Three patients in our series had had an orthotopic liver transplantation and were taking cyclosporine A as part of the immunosuppression protocol. We did not find any report in the literature on patients who had a joint replacement after a liver transplantation. Typically, these patients are taking higher doses of immunosuppressants than those who have a renal transplant, and this may have contributed to the high prevalence of devastating infection (two of three) in the patients who had had a liver transplantation in our series.
Finally, we found an extremely high prevalence of infection in our series of patients who had a hip or knee joint replacement after an organ transplantation. An infection developed around the joint implant in two of the three patients who had had a liver transplantation and in one of the sixteen patients who had had a renal transplantation. The over-all prevalence of infection was 14 per cent—an infection developed after five of thirty-five joint replacements. If only the patients who had a joint replacement after an organ transplantation are considered, then the rate of infection was 19 per cent (five of twenty-seven joint replacements). During the same period at our institution, the rate of infection after all hip and knee replacements in patients who had not had an organ transplantation was slightly more than 1.2 per cent. This is in agreement with the published rates of infection of 0.8 to 3 per cent seen at other institutions at which a large number of total joint replacements are performed5,12,17,27. We found that increasing pain, both at rest and with walking, was the primary symptom of infection. Fever, the Westergren sedimentation rate, and the peripheral white blood-cell count were less indicative of infection. This is consistent with some of the findings in larger series of infections around hip implants12,13.
In summary, we reported our experience with a unique group of patients who had a joint replacement, whose numbers will undoubtedly increase with the success of organ transplantation. While we agree that joint replacement in this group of patients can provide an excellent functional outcome, we found an alarmingly high prevalence of infection. With the advent of more intensive immunosuppression regimens that include cyclosporine A, and with the proliferation of liver, lung, and cardiac transplantation, orthopaedic surgeons will undoubtedly see more patients with a transplant who are candidates for joint replacement. In order to avoid the devastating morbidity and mortality of periprosthetic infection, it is important to develop better preventative measures as well as to encourage a higher level of clinical suspicion and early action on the part of the surgeon. New pain at the site of a hip or knee total joint replacement in a previously asymptomatic patient who has an organ transplant should immediately raise the suspicion of infection. While this study did not directly address possible methods to prevent infection, several measures that might be of benefit include broader perioperative antibiotic coverage, including vancomycin and aminoglycosides; the use of antibiotic-impregnated cement; the use of operating rooms with laminar airflow; the use of isolation-type suits by operative personnel; and prophylaxis for dental and urological procedures. If infection is suspected, indium scanning, aspiration arthrography, and antibiotic suppression should be considered without delay14. With respect to joint replacement after organ transplantation, our goal as orthopaedic surgeons is to maximize the function of patients who have an increased risk of morbidity and mortality.