Frank P. Stuart

Increased Risk of Fracture in Patients Receiving Solid Organ Transplants

The success of organ transplantation is related to advances in immunosuppressive therapy. These medications are associated with medical complications including bone damage. The objective of this study was to estimate and compare age, gender‐specific fracture incidence between transplant recipients, and a large sample representative of the civilian noninstitutionalized United States population using the 1994 National Health Interview Survey (NHIS). This was a cohort study set in tertiary care centers. Five hundred and thirty‐nine individuals who received abdominal organ and 61 heart transplants surviving at least 30 days at our institution from 1986 to 1996 were included in the study. Incident fractures were ascertained by mail, in‐person interview, telephone survey, or medical record review. All fractures were verified. Organ‐, age‐, and gender‐specific fracture numbers and rates and person‐years of observation, were calculated for the transplant patients. Weighted age‐ and gender‐specific fracture rates from the 1994 NHIS were applied to the number of person‐years of observation for each organ‐specific age and gender category of transplant patients to generate an expected number of fractures. The ratio of observed to expected number of fractures was used to compare fracture experience of transplant patients to that of the national sample from the 1994 NHIS. Fifty‐six of 600 (9.3%) patients had at least one fracture following 1221 person‐years of observation. The sites of initial symptomatic fracture were as follows: foot (n = 22), arm (n = 8), leg (n = 7), ribs (n = 6), hip (n = 4), spine (n = 3), fingers (n = 3), pelvis (n = 2), and wrist (n = 1). Fracture incidence was 13 times higher than expected in male heart recipients age 45–64 years; nearly 5 times higher in male kidney recipients age 25–44 and age 45–64 years; and 18 times and 34 times higher in female kidney recipients age 25–44 years and 45–64 years compared with NHIS data. We have shown an increased incidence of fractures and estimated the magnitude of this problem in patients undergoing solid organ transplantation. Our work defines the need for a long‐term prospective study of fracture risk in these patients.

Alemtuzumab Induction and Prednisone‐Free Maintenance Immunotherapy in Kidney Transplantation: Comparison with Basiliximab Induction—Long‐Term Results

This study examined alemtuzumab (anti‐CD 52, Campath‐1H) and basiliximab (anti‐CD 25, Simulect) as induction immunosuppression in kidney transplantation.

Complications and monitoring of OKT3 therapy

Complications of OKT3 therapy were studied in 122 treatment episodes in renal allograft recipients (83 for rejection treatment, 39 for immunosuppression induction). A febrile first-dose reaction to OKT3 was common; no severe pulmonary complications were encountered. Other toxicities of OKT3 therapy were observed later in the treatment course. Most severe were the occurrence of aseptic meningitis in four patients (3%), and seizures in eight (6%). Seizures occurred only when OKT3 was given to patients with nonfunctioning grafts due to acute tubular necrosis. Infections were the only significant late adverse sequelae of OKT3 therapy and occurred more frequently after multiple exposures to the drug (53%) than after a single exposure (22%). IgG antibodies to OKT3 developed after 45% of exposures to the drug in the 74 patients in whom appearance of anti-OKT3 antibodies was monitored. In two patients (3%), anti-OKT3 antibodies were detected before the end of the OKT3 treatment course, neutralizing the immunosuppressive property of the drug. In five patients (7%), strong anti-OKT3 antibody responses were present at the time of subsequent rejection, which precluded reuse of the drug. In 17 other cases, no or only a weak anti-OKT3 response was detectable at the time of rejection following initial OKT3 exposure. Retreatment with OKT3 was successful in reversing rejection in 15 cases (88%). No untoward sequelae were noted after reexposure to OKT3, except the high incidence of subsequent infections.

A prospective study of rapid corticosteroid elimination in simultaneous pancreas-kidney transplantation: comparison of two maintenance immunosuppression protocols: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus.

Background. We examined the feasibility of rapid corticosteroid elimination in simultaneous pancreas kidney transplantation. Methods. Forty consecutive simultaneous pancreas-kidney (SPK) transplant recipients were enrolled in a prospective study in which antithymocyte globulin induction and 6 days of corticosteroids were administered along with tacrolimus and MMF (n=20) or tacrolimus and sirolimus (n=20). Mean±SD follow-up for recipients receiving tacrolimus/MMF and tacrolimus/sirolimus were 12.7±3.9 and 13.4±2.9 months, respectively. Patient and graft survival, and rejection rates were compared to an historical control group (n=86; mean follow-up 41.5±15.4 months) of SPK recipients that received induction and tacrolimus, MMF, and corticosteroids. Results. Demographic characteristics of recipient and donor variables were similar among all groups. The 1-year actuarial patient, kidney, and pancreas survival rates in the 40 SPK transplant recipients with rapid corticosteroid elimination were 100, 100, and 100%, respectively. In the historical control group the 1-year actual patient, kidney, and pancreas survival rates were 96.5, 93.0, and 91.9%, respectively. The 1-year rejection-free survival rate recipients in the rapid steroid elimination group collectively was 97.5 vs 80.2% in the historical control group (P =0.034). At 6 and 12 months posttransplant the serum creatinine values remained stable in all groups. Conclusions. We conclude that chronic corticosteroid exposure is not required in SPK transplant recipients receiving antithymocyte globulin induction and maintenance immuno-suppression consisting of either tacrolimus and mycophenolate mofetil or tacrolimus and sirolimus.

A Randomized Clinical Trial Of Induction Therapy With Okt3 In Kidney Transplantation

A randomized, prospective multicenter trial was conducted to compare the safety and efficacy of OKT3 as an induction therapy with that of conventional immunosuppressive therapy administered to cadaveric renal allograft recipients. Two hundred fifteen patients were treated either with OKT3 plus azathioprine and steroids for 14 days with the delayed addition of cyclosporine on day 11, or with conventional immunosuppression (steroids, azathioprine, and cyclosporine). OKT3 patients had significantly fewer rejection episodes (51% vs. 66%, P=0.032), a longer time to initial rejection (46 days vs. 8 days, P=0.001), and fewer rejection episodes per patient (0.82 vs. 1.14, P=0.014) than conventionally treated patients. Kaplan-Meier estimates of two-year graft and patient survival rates were 84% and 95%, respectively, for the OKT3-treated group, and 75% and 94%, respectively, for the conventionally treated group. Following a subsequent first rejection episode, OKT3 reversed 93% of the rejections in patients receiving OKT3 induction therapy and 94% in patients receiving conventional therapy. Adverse experiences reported during OKT3 induction therapy were similar to those seen when the drug was used for rejection. Following initial exposure, 40.3% of the patients tested were positive for anti-OKT3 antibody, only 6.7% of which were of high titer (1:1000). In the presence of low titer (1:100 or less) antibody, OKT3 was successful in reversing rejection in five of six retreated patients tested. In conclusion, treatment with OKT3 (in combination with azathioprine, steroids, and the delayed addition of cyclosporine) is an effective approach for renal allograft maintenance.

Laparoscopic live donor nephrectomy: Is it safe? Analysis of 80 consecutive cases and comparison with open nephrectomy

Background. Laparoscopic live donor nephrectomy (LDN) is a less invasive alternative to open nephrectomy (ODN) for living kidney donation. Concerns have been raised regarding the safety of LDN, the short and long term function of kidneys removed by LDN, and a potential higher incidence of urologic complications in LDN transplant recipients. Methods. Between October 1997 and May 1999, 80 LDNs were performed at our center. All patients were followed longitudinally with office visits and telephone interviews. These LDNs were compared with 50 ODN performed from January 1996 to October 1997. Results. LDN procedures took significantly longer than ODN (4.6 vs. 3.1 hr). However, LDN was associated with significant reduction in i.v. narcotic use, a rapid return to diet, and shorter hospital stay. Of the 80 LDN procedures, a total of 75 (94%) were completed laparoscopically. Five patients were converted to laparotomy: three for hemorrhage and two for complex vascular anatomy. ODN conversion was associated with large donor body habitus and/or obesity. Seven LDN patients had minor complications and 4 had major complications. All major complications consisted of vascular injuries (2 lumbar vein injuries, 1 renal artery, and 1 aortic injury). All patients made complete recoveries. All LDN kidneys functioned immediately posttransplant. We have observed 100% patient and 97% 1-year actuarial graft survival in LDN transplant recipients. There have been no short-or long-term urologic complications in this series. Conclusion. With increasing experience and standardization of technique, LDN is a safe and effective procedure. Patients undergoing LDN demonstrate clinically significant, more rapid postoperative recoveries and shorter hospital stays than ODN patients. Excellent initial graft function and long-term graft survival have been observed with LDN kidneys. Urologic complications can be avoided. LDN has become the preferred surgical approach for living kidney donation at our center.

Rejection of Renal Allografts: Specific Immunologic Suppression

Kidneys were transplanted across a major genetic barrier (Ag-B locus), from LewisxBN F1 hybrid rats into bilaterally nephrectomized Lewis rats. Survival of grafts is prolonged (indefinite?) in rats treated with a combination of (i) intravenous injection of donor spleen cells 1 day before the graft, and (ii) passive immunization with antiserum prepared in rats of the recipient strain against donor spleen and lymph-node cells. The recipients immune response to other antigens is not impaired.

Specific Suppression of Immune Responses

The models we have discussed in detail demonstrate specific suppression of immune reactivity produced in normal adult animals by antibody and antigen. The mechanism of homeostasis of suppression in these models depends on continued exposure to antigen and on an active response by the host. The active response may include production of antibody directed against specific receptors as well as antibody directed against antigen. Thus, specific regulation of both antibody and cell mediated immunity to an antigen might be achieved by the use of only the biological agents of the response: antigen, antibody, and possibly antibody to receptors. The general implication is that these same biological agents are responsible for autoregulation of immune reactions occurring in nature. Presumably, these agents may be used to suppress or reverse immune responses for appropriate clinical objectives.

OKT3 treatment of steroid-resistant renal allograft rejection.

The monoclonal antibody, Orthoclone OKT3 (OKT3), has been used with great efficacy in a prospective multicenter trial as therapy for first rejection episodes in cadaveric donor (CD) renal allograft recipients treated with azathioprine (AZA) and prednisone (P). However, although almost all rejection episodes were reversed, recurrent rejection occurred in approximately two-thirds of OKT3-treated patients in this earlier trial; infections also occurred in about two-thirds of patients, often related to the additional immunosuppression necessary to reverse the rerejection episodes. In the current series of patients, OKT3 was used to treat rejection in CD renal graft recipients in a protocol differing from the multicenter trial in two respects: (1) baseline immunosuppression was cyclosporine (CsA) and P or CsA, AZA, and P (probably more potent immunosuppressive combinations than the AZA and P in the multicenter trial); and (2) OKT3 treatment was reserved for rejection episodes resistant to 3 bolus infusions of methyl-prednisolone (MP), 5–10 mg/kg, rather than as primary therapy for first rejection episodes. Using this protocol, 46 of 74 rejection episodes (62%) diagnosed between 3/85 and 3/86 in CD renal allograft recipients were treated successfully with MP. Of the remaining 28 steroid-resistant rejection episodes, 27 (96%) were reversed with a 7–14-day course of OKT3, 5 mg/day. Only 5 recurrent rejection episodes (19%) have been observed in the 2–14-month follow-up period after OKT3 treatment; infections have occurred in 10 patients (36%), and three grafts (11%) have been lost in OKT3 treated patients. These results suggest that recurrent rejection and subsequent infection after OKT3 is used to treat rejection may be reduced in a protocol where CD renal allograft recipients are treated with baseline immunosuppression regimens including CsA and where OKT3 is reserved for steroid-resistant rejection. This approach appears to be both more cost-effective than, and as effective therapeutically as, treating all first rejection episodes with the monoclonal antibody.

Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases.

BACKGROUND The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described. METHODS Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described. RESULTS Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposis sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant. CONCLUSIONS We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.