David Shaffer

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

Designing a computer‐based simulator for interventional cardiology training

Interventional cardiology training traditionally involves one‐on‐one experience following a master‐apprentice model, much as other procedural disciplines. Development of a realistic computer‐based training system that includes hand‐eye coordination, catheter and guide wire choices, three‐dimensional anatomic representations, and an integrated learning system is desirable, in order to permit learning to occur safely, without putting patients at risk. Here we present the first report of a PC‐based simulator that incorporates synthetic fluoroscopy, real‐time three‐dimensional interactive anatomic display, and selective right‐ and left‐sided coronary catheterization and angiography using actual catheters. Significant learning components also are integrated into the simulator. Cathet. Cardiovasc. Intervent. 51:522–527, 2000.

Mathematics and Virtual Culture: an Evolutionary Perspective on Technology and Mathematics Education

This paper suggests that from a cognitive-evolutionary perspective, computational media are qualitatively different from many of the technologies that have promised educational change in the past and failed to deliver. Recent theories of human cognitive evolution suggest that human cognition has evolved through four distinct stages: episodic, mimetic, mythic, and theoretical. This progression was driven by three cognitive advances: the ability to ‘represent’ events, the development of symbolic reference, and the creation of external symbolic representations. In this paper, we suggest that we are developing a new cognitive culture: a ‘virtual’ culture dependent on the externalization of symbolic processing. We suggest here that the ability to externalize the manipulation of formal systems changes the very nature of cognitive activity. These changes will have important consequences for mathematics education in coming decades. In particular, we argue that mathematics education in a virtual culture should strive to give students generative fluency to learn varieties of representational systems, provide opportunities to create and modify representational forms, develop skill in making and exploring virtual environments, and emphasize mathematics as a fundamental way of making sense of the world, reserving most exact computation and formal proof for those who will need those specialized skills.

Screening asymptomatic diabetic patients for coronary artery disease prior to renal transplantation.

Background. Coronary artery disease (CAD) is a significant contributor to excess mortality in renal transplant candidates with diabetes mellitus (DM). Prior studies relating to risk stratification for significant CAD in diabetics are confined to Caucasian type 1 DM patients. Methods. To assess the prevalence of clinically silent CAD and to identify variables that are associated with CAD, we retrospectively analyzed the cardiac catheterization data of 97 asymptomatic type 1 and 2 DM kidney and kidney-pancreas transplant candidates. Results. Thirty-three percent of type 1 and 48% of type 2 DM patients had significant stenosis (≥70%) in 1 or more coronary arteries. On multivariate logistic regression analysis, body mass index (BMI) >25 was significantly associated with CAD (relative risk = 4.8, P = 0.002). The age of the patient (7% increase in risk/year, P = 0.01; or relative risk = 3.0 if age >47 years, P = 0.032) and smoking history (2% increase in risk/pack-year of smoking, P = 0.10) were also associated with CAD. African American patients, who comprised 30% of the sample, had a 71% lower risk compared with Caucasian patients (P = 0.03). Factors that were not significantly associated with CAD included gender, type of diabetes, and whether dialyzed for >6 months prior to catheterization. Conclusions. We conclude that a notable proportion (approximately one-third to one-half) of asymptomatic type 1 and type 2 diabetic renal transplant candidates have significant CAD. Additionally, young African American DM patients with no smoking history and a BMI ≤25 are at reduced risk, and invasive tests may not be necessary in this group.

A pilot protocol of a calcineurin-inhibitor free regimen for kidney transplant recipients of marginal donor kidneys or with delayed graft function

Abstract: Background: The worsening shortage of cadaver donor kidneys has prompted use of expanded or marginal donor kidneys (MDK), i.e. older age or donor history of hypertension or diabetes. MDK may be especially susceptible to calcineurin‐inhibitor (CI) mediated vasoconstriction and nephrotoxicity. Similarly, early use of CI in patients with delayed graft function may prolong ischaemic injury. We developed a CI‐free protocol of antibody induction, sirolimus, mycophenolate mofetil, and prednisone in recipients with MDK or DGF.

STUDIES IN SMALL BOWEL TRANSPLANTATION: Prevention of Graft-Versus-Host Disease With Preservation of Allograft Function by Donor Pretreatment With Antilymphocyte Serum

Donor pretreatment with antilymphocyte serum (ALS) effectively prevents graft-versus-host disease (GVHD) in a unidirectional (parent—to—F1 hybrid) rat small bowel transplantation model. ALS must be administered prior to or at the time of transplantation, and the intraperitoneal route is more effective than subcutaneous administration. Donor pretreatment with ALS uniformly prevents GVHD without impairing subsequent allograft function as measured by absorption of dietary energy and nitrogen, weight gain, and bowel morphology. These rodent studies suggest that ALS treatment of donors as well as recipients in small bowel transplantation may be a highly effective, simple, and easily applicable method to prevent or ameliorate GVHD in human small bowel transplantation.

Use of Dacron cuffed silicone catheters as long-term hemodialysis access.

Sixty-five Dacron™ cuffed, dual lumen, silicone central venous dialysis catheters (Quinton PermCath, Seattle, WA) were inserted in 51 patients as the sole form of permanent access for chronic hemodialysis. Six and 12 month actuarial survival rates of patients for all catheters were 53% and 35%, respectively. When calculations included revisions, 6 and 12 month actuarial catheter survival rates were 61% and 43%, respectively. The major limiting factors in survival using long-term catheters remain infection and thrombosis. Dacron cuffed, dual lumen, central venous, dialysis catheters can provide long-term vascular access for hemodialysis in high risk patients.

Polyclonal antibody-induced serum sickness in renal transplant recipients: treatment with therapeutic plasma exchange.

Serum sickness is an immune-complex mediated illness that frequently occurs in patients after polyclonal antibody therapy (ATGAM or thymoglobulin). Serum sickness presents with significant morbidity but is self-limited and resolves with prolonged steroid therapy. We present five renal transplant patients who developed serum sickness after polyclonal antibody treatment with severe symptoms that persisted after being started on systemic steroids. These patients underwent one or two courses of therapeutic plasma exchange (TPE) with subsequent complete resolution of their symptoms. Renal transplant recipients with serum sickness after polyclonal antibody therapy may benefit from TPE by accelerating their time to recovery and thereby reducing overall morbidity.

Correlation of clinical outcomes after tacrolimus conversion for resistant kidney rejection or cyclosporine toxicity with pathologic staging by the Banff criteria.

BACKGROUND Refractory rejection and cyclosporine (CsA)-induced nephropathy remain important causes of renal allograft loss. Previous studies demonstrated that 70-85% of the episodes of refractory acute rejection (AR) occurring in renal allograft recipients on a CsA-based immunosuppressive regimen could be salvaged by conversion to tacrolimus. No data are available regarding the correlation between allograft histology at the time of conversion and the response to tacrolimus. We examined the response to tacrolimus conversion in relation to preconversion biopsies stratified by the Banff criteria. METHODS Since May 1992, we have converted 22 patients from CsA to tacrolimus as part of a rescue protocol. We report on 18 patients in whom 6-month follow-up was available after conversion for biopsy-proven AR (n=13) or CsA toxicity (n=5). Sixteen patients were recipients of renal allografts, including three second transplants, and two were recipients of kidney-pancreas transplants. All patients with AR were treated with one or more courses of methylprednisolone and OKT3 before conversion. Renal allograft biopsies were interpreted by a transplant pathologist blinded to the clinical history, and graded according to the Banff criteria. Responses to tacrolimus were scored as improved (creatinine returned to within 150% of baseline), stabilized (creatinine rise arrested), or failed (returned to dialysis). RESULTS; Mean follow-up was 17.3+/-8 months. Fourteen of 18 patients (78%) showed improvement or stabilization in renal function as assessed by creatinine at 6 months or 1 year (when available). Of the 13 patients with histological AR, nine (69%) improved, including five of six with borderline AR, two of three with grade I AR, and two of four with grade II AR. Of the four other patients with AR, two stabilized and two failed. Three of five patients with severe clinical rejection requiring dialysis (range 2-16 weeks) recovered renal function after conversion. Of five patients with CsA toxicity, two (40%) improved. Seven of eight patients who were converted to tacrolimus less than 90 days after transplantation improved, compared with only 4 of 10 who were converted more than 90 days after transplantation. No grafts were lost in patients with a creatinine <3.0 mg/dl at the time of conversion versus two of seven grafts lost when the creatinine was 3.1-5.0 mg/dl and two of eight grafts lost when the creatinine was >5.0 mg/dl. CONCLUSION The majority of steroid and antilymphocyte antibody (OKT3 or ATGAM) unresponsive rejections in patients on CsA-based immunosuppression will improve or stabilize after conversion to tacrolimus. There was no correlation with allograft histology stratified by the Banff criteria and the response to tacrolimus. Although there was a trend toward a poorer response with more severe histological rejection, higher serum creatinine at the time of conversion, and longer time from transplantation to conversion, favorable responses were noted in all groups. This indicates that a trial of conversion is warranted, irrespective of the histological severity of injury.

Virtual rounds: simulation-based education in procedural medicine

Computer-based simulation is a goal for training physicians in specialties where traditional training puts patients at risk. Intuitively, interactive simulation of anatomy, pathology, and therapeutic actions should lead to shortening of the learning curve for novice or inexperienced physicians. Effective transfer of knowledge acquired in simulators must be shown for such devices to be widely accepted in the medical community. We have developed an Interventional Cardiology Training Simulator which incorporates real-time graphic interactivity coupled with haptic response, and an embedded curriculum permitting rehearsal, hypertext links, personal archiving and instructor review and testing capabilities. This linking of purely technical simulation with educational content creates a more robust educational purpose for procedural simulators.