David Ludwin

A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

Early function as the principal correlate of graft survival. A multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine.

Abstract We examined the factors determining graft survival in 200 consecutive cadaveric renal transplants managed on a quadruple-therapy protocol: Minnesota antilymphoblast globulin, cyclosporine, azathioprine, and low-dose prednisone. Perioperative central venous pressure monitoring and volume expansion were emphasized. To avoid CsA nephrotoxicity in the early posttransplant period, patients were treated with ALG until renal function was established (a mean of 7 days). Therapeutic CsA levels were achieved before ALG was discontinued. Azathioprine was used to supplement CsA in patients with nephrotoxicity or rejection. Twelve-month graft survival was 85% (first transplants 86%, retransplants 79%), with patient survival of 95%. ALG was not associated with excessive clinical cytomegalovirus infections, which occurred in 5% of patients, or with malignancy. When 3 technical failures were excluded, an analysis of numerous factors in the pretransplant and peritransplant period revealed that the strongest correlate of one-year graft survival was early renal function. Grafts with delayed function (DF) had 75% survival, compared with 91% for grafts with good early function (EF). A multivariate analysis confirmed this association: the relative risk of graft loss was increased 2.86 times for DF compared with EF. The mechanism of the deleterious effect of DF was apparently multifactorial: the DF group, by definition, contained all the kidneys that never functioned, but some risk also persisted in kidneys that achieved function. One reason for this may be that DF kidneys that achieved function had higher mean serum creatinine values at 1 month: elevated serum creatinine values at 1 month were strongly associated with increased risk of graft loss regardless of initial function. There was also a higher number of rejection episodes diagnosed in the DF group. These observations suggest that early renal function is a major determinant of graft outcome and should be a target for efforts to further improve renal graft survival.

The quality of life in renal transplantation : a prospective study

Methodologically sound measures of quality of life are required to judge accurately the impact of successful renal transplantation on patient well-being. The time trade-off (TTO) method is a reproducible and valid measure which we used to prospectively assess changes in the quality of life of 27 patients on maintenance dialysis who subsequently underwent renal transplantation. TTO scores approaching 0 signify a very poor quality of life, while scores approaching 1 represent perfect health. Of 98 dialysis patients who completed baseline TTO interviews, 31 consecutive patients subsequently received 28 cadaveric and 3 living related kidney transplants. Four of 31 patients did not complete a second TTO assessment, because of death in 2 patients and graft loss in 2 others. The remaining 27 patients completed a second TTO interview an average of 30.9 months following transplantation (range 1.5-52, 95% confidence interval [CI] 24.4-37.5) and formed the study cohort. At the time of study the mean serum creatinine for the cohort was 173 mumol/L (range 90-290, 95% CI 152-195 mumol/L). The employment rate rose 27% following transplantation (P = 0.10); but when males alone were analyzed, a significant increase of 38% (P = 0.048) was noted. During the dialysis period, the mean baseline TTO score was 0.41 (95% CI 0.33-0.49), confirming the observations of others. Following transplantation, the mean TTO score rose to 0.74 (95% CI 0.67-0.81), a difference that is statistically significant (P < 0.001). The mean increase in TTO score observed as a result of successful transplantation was 0.33 (95% CI 0.26-0.40). This magnitude of improvement was found in 20 of 27 patients (74%), whose TTO scores lay within or above the 95% CI (0.26-0.40) for the mean change in score of 0.33. One patients score fell, while the remaining 6 patients had improvements in their TTO score which fell below the lower 95% CI value (0.26) for the mean change in score. We conclude that the 95% CI of 0.26-0.40 identifies a range in which clinically important improvements in quality of life will be found for the majority of patients receiving successful kidney transplants.

Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (NeoralTM) therapy, and that CsA exposure early post‐transplant may correlate significantly with reduced risk of acute graft rejection.

A comparison of evaluative indices of quality of life and cognitive function in hemodialysis patients

In the setting of end-stage renal disease, the reproducibility and responsiveness of three health-related quality-of-life instruments were evaluated. The Time Trade Off instrument (TTO) is a generic instrument used to evaluate the utility of a health state. The Hemodialysis Quality-of-Life questionnaire (HQL) is a disease-specific instrument. A series of function-specific tests evaluated neurocognitive function. The TTO and HQL instruments are patient centric in that patient values define the health status while the neurocognitive function tests reflect the values of healthcare professionals. Forty-seven chronic hemodialysis patients participated. Those with adequate dialysis, defined as a Kt/V (a measure of small solute removal during hemodialysis) above 1.0 were maintained at the level for two administrations of the three instruments separated by six to eight weeks. The test-retest intraclass correlation coefficient exceeded 0.90 for all five domains of the HQL questionnaire and exceeded 0.70 for nine neurocognitive function tests. Patients with inadequate dialysis (Kt/V less than 0.8) had Kt/V increased to above 1.0. The TTO was not responsive. For the HQL questionnaire, an item was considered responsive if a 1-point improvement, on a 7-point Likert type scale, occurred significantly more often among those with an improvement in hemodialysis treatment compared to those without improvement. Only one item had such a change and therefore the HQL cannot be considered responsive.(ABSTRACT TRUNCATED AT 250 WORDS)

The development and evaluation of a fuzzy logic expert system for renal transplantation assignment: Is this a useful tool?

Abstract Allocating donor kidneys to patients is a complex, multicriteria decision-making problem which involves not only medical, but also ethical and political issues. In this paper, a fuzzy logic expert system approach was proposed as an innovative way to deal with the vagueness and complexity faced by medical doctors in kidney allocation decision making. A pilot fuzzy logic expert system for kidney allocation was developed and evaluated in comparison with two existing allocation algorithms: a priority sorting system used by multiple organ retrieval and exchange (MORE) in Canada and a point scoring systems used by united network for organ sharing (UNOS) in US. Our simulated experiment based on real data indicated that the fuzzy logic system can represent the experts thinking well in handling complex tradeoffs, and overall, the fuzzy logic derived recommendations were more acceptable to the expert than those from the MORE and UNOS algorithms.

Development of a Central Matching System for the Allocation of Cadaveric Kidneys A simulation of Clinical Effectiveness versus Equity

Objectives: 1) To develop a computer-based simulation to prospectively study the impacts of explicitly incorporating different equity criteria into the process of allocating kidneys to recipients, given the scarcity of this resource. 2) To assess the tradeoffs between systems that allocate kidneys based only on medical criteria, systems that allocate kidneys based only on equity criteria, and systems that consider both medical and equity criteria. Methods: A computer-based simulation was developed that describes the flows of patients and kidneys. This model provides information at various time points about the number of patients in the system who are awaiting transplants, the number of kidneys available for transplantation, the number of transplantations performed for each matching algorithm, and the number of kidneys discarded (when applicable), as well as the means and standard deviations of the HLA-match scores, number of days from registration to transplantation, and number of days (from registration) of those who are still waiting for transplants. Five different matching algorithms were compared, ranging from determination of the allocation by a single medical criterion (i.e., HLA match) to determination by a single equity criterion (i.e., relative position in the waiting queue). The remaining algorithms represent different strategies of weighting these two considerations. Estimates regarding the main parameters of the model were derived utilizing data collected through the Multiple Organ Retrieval and Exchange Pro gramme of Ontario, Canada. Results : The simulation was set to run for a period of ten years. A tradeoff between graft survival (or improved HLA matching) and equal treatment of patients regardless of their likelihood to benefit was found. It is clear that an algorithm that allocates kidneys based only on temporal location of patient on the waiting list is likely to be unac ceptable because of the very poor average HLA-match scores that it yields. Pool size was found to be a major determinant in the attainment of optimal matching from a medical perspective. Conclusions: 1) The final choice about any allocation algorithm to be used requires that a value judgment be made, i.e., how great a reduction in HLA-match score should be traded in order to improve equity score (or vice versa). 2) A computer-based simulation model is a feasible way to prospectively test the impact of any given allocation algorithm on any given system. Key words: simulation; kidney transplant; equity; efficiency. (Med Decis Making 1994;14:124-136)

An internet-based fuzzy logic expert system for organ transplantation assignment

Organ transplantation is lifesaving. However, the demand for organs far exceeds supply. Due to the resource scarcity (i.e. organs), the special medical requirements for organ transplanting and the urgency in getting the organ to the recipient, it is critical to use information technology to coordinate the organ procurement and transplanting process and to allocate donated organs to recipients quickly, fairly and effectively. In this paper we analyse how information technology can be used to improve organ transplantation services and propose the use of an internet-based fuzzy logic expert system to assist physicians in solving the multi-criteria kidney allocation problem. A pilot fuzzy logic expert system for kidney allocation was developed and evaluated in comparison with two existing allocation algorithms a priority sorting system used by the Multiple Organ Retrieval and Exchange (MORE) program in Ontario, Canada and a point scoring systems used by the United Network for Organ Sharing (UNOS) in the USA. Our simulated experiment based on real patient data confirms that the fuzzy logic system can represent the experts thinking in a satisfactory manner in handling complex trade-offs and overall, the fuzzy logic derived recommendations were more acceptable to the expert than those from the MORE and UNOS algorithms.

Early Function as the Principal Correlate of Graft Survival. A Multivariate Analysis of 200 Cadaveric Renal Transplants Treated with a Protocol Incorporating Antilymphocyte Globulin and Cyclosporine

We examined the factors determining graft survival in 200 consecutive cadaveric renal transplants managed on a quadruple-therapy protocol: Minnesota antilymphoblast globulin, cyclosporine, azathioprine, and low-dose prednisone. Perioperative central venous pressure monitoring and volume expansion were emphasized. To avoid CsA nephrotoxicity in the early posttransplant period, patients were treated with ALG until renal function was established (a mean of 7 days). Therapeutic CsA levels were achieved before ALG was discontinued. Azathioprine was used to supplement CsA in patients with nephrotoxicity or rejection. Twelve-month graft survival was 85% (first transplants 86%, retransplants 79%), with patient survival of 95%. ALG was not associated with excessive clinical cytomegalovirus infections, which occurred in 5% of patients, or with malignancy. When 3 technical failures were excluded, an analysis of numerous factors in the pretransplant and peritransplant period revealed that the strongest correlate of one-year graft survival was early renal function. Grafts with delayed function (DF) had 75% survival, compared with 91% for grafts with good early function (EF). A multivariate analysis confirmed this association: the relative risk of graft loss was increased 2.86 times for DF compared with EF. The mechanism of the deleterious effect of DF was apparently multifactorial: the DF group, by definition, contained all the kidneys that never functioned, but some risk also persisted in kidneys that achieved function. One reason for this may be that DF kidneys that achieved function had higher mean serum creatinine values at 1 month: elevated serum creatinine values at 1 month were strongly associated with increased risk of graft loss regardless of initial function. There was also a higher number of rejection episodes diagnosed in the DF group. These observations suggest that early renal function is a major determinant of graft outcome and should be a target for efforts to further improve renal graft survival.

An intelligent agent approach to improving the coordination efficiency in the donor kidney distribution process.

Kidney transplantation is an effective treatment for an end-stage renal disease. Donor kidneys need to be matched with appropriate patients, distributed and transplanted very quickly (less than 40 hr) in order to achieve optimal medical results. In this paper we analyse the bottlenecks in the current donor kidney distribution process and investigate how agent technology can be applied to improve this process. We propose a distributed multi-agent system operating in a mobile communication environment to assist transplant coordinators in coordinating with multiparties in this time-critical distribution process. A prototype system has been developed to demonstrate the feasibility of such a system.