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The Canadian Journal of Urology; 6(5); October 1999

Accepted for publication May 2000Address correspondence to Dr. Philip Belitsky, MD,Professor of Urology, Dept. of Urology, Faculty of Medicine,Dalhousie University, Rm.294 5 South, Victoria Building,1278 Tower Road, Halifax, Nova Scotia B3H 2Y9Tel: (902) 473-5469 Fax: (902) 473-5850

Introduction

Renal transplantation is the preferred treatment forvirtually all causes of end-stage renal disease (ESRD).Since the description of the first renal transplants in non-immunosuppressed patients by Hume, 50 years ago, wehave been witness to remarkable improvements inclinical outcomes.

Graft survival has increased andepisodes of acute rejection have decreased. We have abetter understanding of the complex immunologicalprocesses involved in transplantations that have aidedthe development of immunosuppression regimesmeant to target specific T-cell interactions and to interruptdistinct biochemical pathways. There has been a paradigmshift from broad nonspecific immunosuppression to newcombinations aimed at lowering overall doses andmaximizing outcomes, while minimizing toxicities.

Modern immunosuppression has catapulted

the

Progress in renal transplantation

Christopher G. French, MD, Philip Belitsky, MD, Joseph G. Lawen

Department of Urology, QEII Health Science Center, Dalhousie University, Halifax, Nova Scotia

FRENCH CG, BELITSKY P, LAWEN JG. Progress inRenal Transplantation. The Canadian Journal of Urology. 2000;7(3):000-000.

Purpose:

The improvements in renal transplantationover the last 10 years have been one of the great successstories in medicine. We have reviewed these successeswith a focus on the following: changes in demographicsof donors and recipients in Canada, the benefits of newimmunosuppressive regimes and the efforts to minimizetheir toxicity and finally, our understanding of measuresto circumvent chronic rejection.

Materials and methods:

A review of current transplantation literature was performed and pertinent data presented. As well, information from the CanadianOrgan Replacement Register was selected to provide anoverview of changes in renal transplantation in Canada.

Results:

Despite the stable rate of transplantation inCanada, the number of new patients starting dialysis each year roughly equals the entire national renal transplant waiting list. These patients are older and have morecomplex co-morbidities, mandating prudent use of immunosuppression so as to minimize toxicity. Standard triple therapy consists of a calcineurin inhibitor, anantimetabolite and corticosteroids. Antibody therapy isindicated in sensitized recipients and newer monoclonalhumanized antibodies offer less toxicity. Nonspecifictherapies are less favorable, due to unwanted side effects.We can now identify subsets of patients who are most likely to benefit from specific therapy. Newer non-nephrotoxic agents hold promise for future regimens. However, a paucity of large, multicenter, randomized trials, tested against standard protocols, limits their current indications. Many immunologic and non-immunologic factors influence the outcome of renaltransplantation and play a role in the development of acuteand chronic rejection.

Conclusions:

The challenges of renal transplantationover the next 10 years are: 1) in the development of specifictherapies that can be altered according to patient co-morbidities and other factors influencing outcome;2) minimizing toxicity; 3) preventing chronic rejection;and 4) improving our national organ donation network.

Key

Words:

transplantation, kidney,

immunosuppression

The Canadian Journal of Urology; 6(5); October 1999

success of renal transplantation. This has provided thenecessary foundation for foreshortening thedevelopment of transplantation of other organs. Wenow live in era where the majority of deaths inpatients with a functioning graft are caused bycardiovascular and infectious complications. Diabetesis the number one cause of ESRD. As our populationages, a greater number of older patients with morecomplex co-morbidities will develop ESRD.

2,3

These factors emphasize the importance of limitingthe complications that shorten the lifespan of transplant recipients.The

success of renal transplantation produces anew set of problems. That is, we have far more patientsentering transplant annual waiting lists than there areavailable kidneys. Many ethical questions arise whenwe consider allocating organs to those with the mostfavorable probable outcome. Most centers in Canadaprimarily allocate cadaveric organs to those longeston the waiting list, as opposed to those with favorablecharacteristics. The boundaries of living donortransplantation have broadened to include non-relateddonors, which have undermined the importance of histocompatibility. Similarly, there is acceptance of marginal cadaveric renal donors at ages less than5 and greater than 60 years of age. Organ donationrates for industrialized countries, including Canada,unfortunately remain low. The critical nature of increasing the public awareness and understandingof issues surrounding brain death and the benefits of a life-saving transplant has been recognized by bothgovernments and transplant scientists.In this article we will discuss the advances in renaltransplantation that have occurred within the lastdecade. We will focus on the following issues: changesin demographics of donors and recipients; the benefitsof new immunosuppressive regimes; and the effortsto minimize side effects and circumvent the insidiousgraft deterioration seen in chronic rejection.

Demographics and outcomes

The total number of renal transplants per year hasremained relatively stable in Canada. In 1993 there were890 renal transplants performed in Canadian patients.Five years later, in 1997, that number rose to only 969.The renal transplant rates per-million population (rpmp)were 29.6 and 32.3 respectively. In 1997, the number of new patients starting dialysis in Canada (hemodialysisand peritoneal dialysis) was 3649, which is slightlyhigher than the total number of patients on the waitinglist for transplantation, 3434.

New dialysis rates areclimbing and with it are the average age of startingdialysis (Figure 1). Elderly patients are more likely to

New Patients by Age Group (65-74 & 75+) and Dialysis Typeat Registration, Canada 1988

1998(Age-specific Rate Per Million Population)

50045040035030025020015010050019881989199019911992199319941995199619971998

Haemo Age 65-74Peri Age 65-74Haemo Age 75 plusPeri Age 75 plus

RPMP

Figure 1

TABLE 1.

International organ donation rate (1997 data)

CountryPopulation x 106No. of donorsPMP

ET*113.4163414.4France58.899316.9Spain39.99125031.5Switzerland710815.4UK and Ireland62.7184613.5Australia18.7519610.5Canada30.2943614.4Organ donation rate is expressed in pmp (per million population).*ET – Eurotransplant: Germany, Austria, Belgium, Luxemburg,NetherlandsThe source of data for these international organ donationrates for 1997 (excluding Canada) is the ONT (NationalOrganization of Transplants, Spain) International Data onOrgan Donation and Transplantation. The source of data forthe Canadian organ donation rate is the 1999 CORR Report.

TABLE 2.

Factors influencing the outcome of renaltransplantation

Immunologic

immunosuppressionrejectionsensitizationmatching for HLA

In part immunologic

delayed graft functionischemic timesrecipient ageoriginal diseasedonor ageracebilateral nephrectomy

Nonimmunologic

compliancecardiovascular diseasecenter effectclinical care

start hemodialysis, thus increasing the overall cost of renal replacement therapy. Transplantation has beenclearly shown to decrease overall mortality, improvequality of life, and lessen the financial burden to thehealth care provider.One of our greatest challenges is in increasing thenumber of kidneys available for transplantation. Thesources of kidney transplants remains varied accordingto center but, as living related donation increases, thesource of donors approaches an equal distribution of living related and cadaveric donors. Success in livingrelated transplantation is important but this is dwarfedby our failure to procure many organs at the time of brain death. Canadian donation is on par with mostindustrialized countries (Table 1) but falls behind themost successful by more than 50%. The Spanishtransplant organization boasts a per million populationcadaver donation rate of 31.5 compared to 14.4 inCanada. Thus we need to educate our population andimplement strategies to increase these numbers.The results of living related transplantation areconsistently better than cadaver transplants. The one-year graft survival in each group approaches 100%.However, cadaveric transplants are at a much greaterrisk of delayed graft function, acute rejection, andprogressive deterioration. These all highlight theimportance of avoiding ischemic injury andundermine the importance of histocompatibility. Theimplications are that we now commonly performspouse to spouse, six antigen, mismatched, livingrelated transplants without fear of increased acuterejection. The factors influencing the outcomes of renal transplantation are listed in Table 2.The most important predictor of acute rejection incadaveric transplantation is delayed graft function.Once there is an early immunological injury, chronicrejection becomes more likely. Each adverse eventincreases the risk of functional compromise andplaces the graft at risk for a different adverse event.The maintenance of early graft function and thedevelopment of early pharmacological tolerance arekey factors for long-term graft survival.

Immunosuppression

Advances in immunosuppression have led thetransplantation community to important crossroads(Table 3). The introduction of Cyclosporin (Csa) by Calneas the mainstay of transplant immunosuppressionsingle handedly initiated the era of multiorgantransplantation.

The development of a new Csaformulation, Neoral

, has improved bioavailability anddemonstrated to be superior to the previous oil-based