immunosuppressive medications for renal transplantation: a multiple choice question

Kidney International, Vol. 59 (2001), pp. 388–402

NEPHROLOGY FORUM

Immunosuppressive medications for renal transplantation:A multiple choice question

Principal Discussant: Gabriel M. Danovitch

UCLA School of Medicine, Los Angeles, California, USA

loci. Donor-specific T-cell cytotoxic crossmatch was stronglypositive, and the kidney was declined. The following month,she was admitted to the hospital with an episode of staphylococ-cal line sepsis, treated with a course of vancomycin.

Four months later, a zero-HLA-mismatched kidney was of-fered to her via the United Network for Organ Sharing (UNOS)six-antigen-match program. The donor, a resident of Maryland,was a 61-year-old victim of a cerebrovascular accident and hada five-year history of treated hypertension. The donor’s serumcreatinine at the time of harvesting was 1.4 mg/dL after reachinga post-admission peak of 2.2 mg/dL. A renal biopsy performedat the time of harvesting showed 8 of 50 totally sclerosed glome-ruli and “minimal” interstitial atrophy. Both standard T-cellcytotoxic and flow cytometry crossmatching were negative. Boththe donor and recipient were positive for cytomegalovirus anti-body. After a discussion with the patient and her nephrologistCASE PRESENTATIONregarding the implications of accepting a kidney from a physio-A 48-year-old black woman started hemodialysis six yearslogically marginal donor, the transplant was carried out. Theago after a 15-year history of systemic lupus erythematosus,elapsed time from kidney harvesting to completion of the vas-for which she had received high doses of oral steroids andcular anastomosis was 32 hours. Evaluation of the donor biopsyazathioprine. Six months after starting dialysis, she was referredspecimen after transplantation showed extensive nephroscl-to the UCLA renal transplant program. She was obese (BMI,erosis with moderate chronic parenchymal injury (Fig. 1).33 kg/m2) and had a long personal and family history of hyper-

Transplantation was technically uneventful. Urine output intension. Her family history also was notable for type-II diabe-the first 12 hours varied from 30 to 60 mL/hr despite a low-dosetes; she had no potential living donors. An adenosine cardiolytedopamine infusion, saline infusion, and high-dose intravenouscardiac perfusion study was normal. Her name was placed onfurosemide. Immunosuppression was commenced with OKT3the cadaveric transplant list.in a dose of 5 mg in the operating room and daily for the followingIn the four years that elapsed before she eventually received10 days. Prednisone, 1000 mg, was given in the operating rooma cadaveric transplant, she was evaluated on an annual basisand followed by 150 mg on the first day and tapered by 10 mgby the transplant program staff. Additionally, her blood wasdaily. A daily infusion of intravenous ganciclovir was given.tested monthly to measure the level of panel-reactive antibod-On the first postoperative day, a transplant ultrasound withies against T-cells, which varied from 50% to 80% before ab-power Doppler showed no obstruction and good parenchymalsorption with dithiothreitol (DTT) and 20% to 40% after ab-flow; diastolic flow was reversed, and the resistive index was 1.1.sorption. She was admitted to the hospital on 11 occasions forDialysis was required on the second day. The patient remainedcomplications related to recurrent thrombosis of her vascularoliguric and was dialyzed every other day. On the seventh post-access. At the time of her transplant, she was being dialyzedoperative day, cyclosporine (Neoral), 4 mg/kg twice daily, andvia a graft in her left thigh, and she was receiving therapy withmycophenolate mofetil, 1500 mg twice daily, were started. Trans-low-dose warfarin. Anticardiolipin antibodies were negative.plant biopsy, scheduled for postoperative day 10, was cancelledA cadaveric kidney became available for her two years ago.when her urine output began to increase steadily. The lastThe kidney was from a 22-year-old victim of a gunshot wounddialysis was on the 10th postoperative day, and the patient wasand was mismatched at four human leukocyte antigen (HLA)discharged from the hospital two days later. Her medicationsat the time of discharge are shown in Table 1, column 1.

The patient was followed in the renal transplant outpatientKey words: acute rejection, tacrolimus, mycophenolate mofetil, basilix-clinic every two to three days. Her renal function began toimab, daclizumab, sirolimus, CD25 receptor, cyclosporine.improve, and no further dialysis was required. By postoperative

The Nephrology Forum is funded in part by grants from Amgen, day 24, her serum creatinine had fallen to 3.8 mg/dL but thenIncorporated; Merck & Co., Incorporated; AstraZeneca LP; Dialysis rose to 4.2 mg/dL. Renal ultrasound was unremarkable. AClinic, Incorporated; and R & D Laboratories. transplant biopsy showed findings consistent with healing acute

tubular necrosis, tubulitis consistent with a Banff grade-II acute 2001 by the International Society of Nephrology

388

Nephrology Forum: Immunosuppression for transplantation 389

Table 1. Post-transplant medication regimen

Postoperative day

Drug 12 42 360

Cyclosporine 200 mg bid 150 mg bid 125 mg bidMMF 1500 mg bid 1500 mg bid 1000 mg bidPrednisone 40 mg bid 15 mg qd 7.5 mg qdGanciclovir 1000 mg bid 1000 mg tid —TMP-SMX Ss qd Ss qd —Nystatin tid — —Atorvastatin 20 mg qd 20 mg qd 20 mg qdDiltiazem CD 180 mg qd 180 mg qd 180 mg qdClonidine 0.2 mg tid — —Enalapril — 5 mg qd 10 mg qd

Abbreviations are: MMF, mycophenolate mofetil; TMP-SMX, trimethoprim-sulfamethoxazole; qd, once daily; bid, twice daily; tid, thrice daily; Ss, singlestrength.

fibrosis and tubular atrophy. The patient’s medications at thattime are shown in Table 1, column 3.

DISCUSSION

Dr. Gabriel M. Danovitch (Medical Director, KidneyTransplant Program, Division of Nephrology; and Pro-fessor of Medicine, UCLA School of Medicine, Los Angeles,California, USA): This patient illustrates many of the“multiple choice questions” faced by transplant programsas they attempt to take advantage of the expanding arma-mentarium of immunosuppressive medications at theirdisposal. Moreover, difficult choices commonly have tobe made, as in this case, about whether to accept anorgan, the functional quality of which was less than ideal.

Fig. 1. Donor kidney biopsy obtained at the time of harvesting, stained Should this particular kidney have been offered to her?with Masson’s trichrome. (A) Foci of tubular atrophy and interstitial On what basis was the decision made to choose herfibrosis (arrows) involve 20% of the renal parenchyma (350). (B)

immunosuppressive protocol? How can we best protectMarked arteriolar hyalinization (arrowhead) with an adjacent glomeru-lus showing mild ischemia and atrophic tubules with associated intersti- her from the life–threatening complications that are atial fibrosis (3200). potential consequence of intensive immunosuppression?

What can be done to maximize the functional life of hertransplant after she had spent half a lifetime with end-stage renal disease? This Forum will attempt to answerrejection, and vascular changes thought to be of donor origin.these questions or, at the very least, provide a rationalShe received daily infusions of 5 mg/kg methylprednisolone

for three days; her oral prednisone dose was rapidly tapered basis for addressing them.to 20 mg daily. Her serum creatinine fell to 2.2 mg/dL at six To understand the design of the immunosuppressiveweeks post transplant. Her medications at that time are shown protocol, one must not only be familiar with the medica-in Table 1, column 2. tions per se, but also with the evolution of their introduc-

Over the ensuing year, the patient was seen regularly at thetion into clinical transplantation. In the 1960s and 1970s,transplant clinic. She felt good and returned to work. Her courseutilization of corticosteroids, azathioprine, and the earlywas complicated by an episode of graft dysfunction ascribed topolyclonal antilymphocytic agents was based largely oncyclosporine toxicity, a urinary tract infection with E. coli treated

with ciprofloxacin, and a three-day hospital admission for an individual center experience without rigorous multicen-episode of bacterial pneumonia treated empirically with azithro- ter trials or predetermined end-points [1]. In the last twomycin. She gained an additional 8 kg in weight. Blood pressure decades, all the new immunosuppressive agents have beenwas 130/90 mm Hg. Total serum cholesterol was 190 mg/dL introduced after clinical trials. The design of these trialswith a low-density fraction of 120 mg/dL. At the end of the

and the end-points used to assess efficacy have had a majorfirst post-transplant year, the serum creatinine fluctuated be-influence on the way in which the new agents are used.tween 2.2 and 2.5 mg/dL, and a 24-hour urine collection con-When the first clinical trials for cyclosporine were de-tained 2.5 g of protein. A transplant biopsy showed evidence

of chronic transplant glomerulopathy with patchy interstitial signed in the late 1970s and early 1980s, the primary end-

Nephrology Forum: Immunosuppression for transplantation390

point used was “improvement of patient and graft sur- safely reduce the incidence of episodes of acute rejectionthus has become the major yardstick by which new agentsvival,” which cyclosporine indeed achieved [2]. The re-

sults of renal transplantation were relatively poor at that are assessed. It therefore behooves us to understand theimplications and rationale for choosing this particulartime, so it was not hard to recognize the dramatic benefit

of cyclosporine, which produced statistically significant end-point.improvement in patient survival and permitted graft sur-

Incidence of acute rejection episodes as an end-pointvival rates of greater than 80% at one year. In Europefor studies of new immunosuppressive drugscyclosporine was often used alone, while in the United

States it was usually combined with prednisone and aza- The incidence of acute rejection episodes, typically“biopsy-proven,” has become the most frequently usedthioprine. Azathioprine was regarded as an adjunctive

agent to cyclosporine and the combination was often marker of the effectiveness of new immunosuppressivedrugs for the following reasons:called “triple therapy.” Although the benefits of cyclo-

sporine were clear cut, its capacity to produce both acute (1) The excellent results of renal transplantation usingcurrently available immunosuppressive agents, which yieldand chronic nephrotoxicity was soon recognized to be a

major “thorn in its side” [3]. In 1985, OKT3, the first a one-year graft survival of close to 90% and minimalmortality in most centers, make it extremely difficult tomonoclonal antibody used in clinical medicine, was intro-

duced into routine clinical care based on its capacity to use patient or graft survival as markers to prove statisti-cally significant benefit from the use of a new agent.successfully treat first acute rejection episodes [4]. But

the toxicity of the drug tended to restrict its use to epi- (2) Acute rejection is a potent risk factor for the devel-opment of chronic allograft failure. In retrospective anal-sodes of rejection that were resistant to high-dose ste-

roids and, in some programs, to its use for the induction yses, patients who have suffered episodes of acute rejec-tion have a long-term graft survival of 20% to 45% lessof immunosuppression as an alternative to polyclonal

antibody preparations. With these medications—cyclo- than patients who have not [13].(3) Acute rejection episodes are morbid events insporine, azathioprine, corticosteroids, and the antibody

preparations—the transplant community entered the 1990s themselves, requiring intensification of immunosuppres-sion and sometimes hospital admission.achieving, with justifiable pride, success rates of up to

90% and minimal mortality in many centers. The number (4) Most acute rejection episodes take place withinthe first few months of transplantation, and their pres-of available immunosuppressive medications was small,

so relatively little variation existed among the protocols ence can be proven by biopsy [14]. This pathophysiologicsequel permits rapid evaluation of the effectiveness ofused in different programs.

Major developments occurred in the 1990s. Tacroli- a new agent or protocol (a luxury not available whenimmunosuppressive drug trials are performed in othermus (FK506) was introduced into liver transplantation

and eventually into renal transplantation as an alterna- clinical circumstances, such as in systemic lupus erythe-matosus, rheumatoid arthritis, etc.).tive to cyclosporine because of its ability, proven in ran-

domized clinical trials, to produce equivalent patient and As an example of this approach for evaluating theeffectiveness of new immunosuppressive agents, Figure 2graft survival [5]. Mycophenolate mofetil (MMF) was

found to be a more effective adjunctive agent than aza- contains data from one of the pivotal trials leading to theintroduction of MMF [6]. This trial was a randomized,thioprine by virtue of its capacity to reduce the incidence

of acute rejection episodes when used with cyclosporine double-blind, placebo-controlled, multicenter, phase-IIIstudy to evaluate the efficacy of MMF in the prevention[6], and later with tacrolimus [7], and corticosteroids.

Two new humanized monoclonal antibodies, basiliximab of acute rejection episodes during the first six monthsfollowing renal transplantation. In this trial, standardand daclizumab, both targeted against the interleukin-2

(CD25) receptor, were approved for use in renal trans- therapy consisted of cyclosporine, prednisone, and aza-thioprine. The study compared two doses of MMF (1.0 gplantation in 1998, again because of their ability to re-

duce the incidence of acute rejection episodes [8, 9]. twice daily and 1.5 g twice daily) or azathioprine in com-bination with cyclosporine and prednisone. In the UnitedThymoglobulin, a polyclonal antibody available in Eu-

rope for several years, was approved for use in the US States, the study involved 500 recipients of a first cadav-eric transplant (very similar studies involving anotherfor the treatment of acute rejection [10]. In late 1999,

sirolimus (rapamicin) was added to the immunosuppres- 1000 patients were performed in Europe, Canada, andAustralia). Figure 2A illustrates the clear-cut benefit ofsive menu, again because when combined with cyclospor-

ine and corticosteroids, it reduced the incidence of acute MMF with respect to the primary end-point: a statisti-cally significant reduction in the incidence of acute rejec-rejection episodes [11, 12]. Several new agents also are

being evaluated in a similar fashion, that is, by their tion episodes, from nearly 50% in the azathioprine groupto approximately 25% in both the MMF groups. Theability to reduce the incidence of acute rejection epi-

sodes. The ability of a new immunosuppressive agent to use of high-dose steroids and OKT3 also was markedly


Fig. 2. Impact of mycophenolate mofetil(MMF) on incidence of acute rejection andgraft survival. (A) Cumulative incidence ofacute rejection episodes within the first sixpost-transplant months. (Reprinted with per-mission from Transplantation [6]). Symbolsare: (m) azathioprine group; (s) MMF 2.0 gdaily; (d) MMF 3.0 g daily. (B) Three-yearfollow-up of graft survival from the samestudy. (Reprinted with permission from theAmerican Journal of Kidney Disease [15]).

reduced in the MMF groups. However, this study, which “standard therapy” with cyclosporine and prednisone(typically combined with azathioprine in the US andhad a major impact on the way immunosuppression is

practiced, did not demonstrate a statistically significant placebo in Europe). The success of MMF in reducingthe incidence of acute rejection led to it becoming partbenefit of MMF with respect to patient or graft survival

when estimated at either one or three years [15] (Fig. 2B). of an updated standard therapy protocol in many centers.In future trials of newer agents, MMF, or possibly siroli-Pivotal clinical trials led to the introduction of MMF,

sirolimus, and the anti-CD25 monoclonal antibodies in mus, will represent standard therapy, and statistical proofof further reduction in the incidence of acute rejectionclinical transplantation (Table 2). A statistically signifi-

cant reduction in the incidence of acute rejection epi- will likely be more difficult to achieve. Similarly, it isbecoming more difficult to introduce new drugs basedsodes within the first six post-transplant months was

achieved for each of these drugs. However, on prospec- on their capacity to reverse episodes of acute rejection,as these episodes have become less frequent.tive analysis, neither patient nor graft survival was statis-

tically significantly improved in any of these studies, ei- Although researchers have been unable to demon-strate statistically significant improvement in long-termther on short- or long-term follow-up.

As new immunosuppressive drugs and protocols are graft survival in prospective analyses of the new genera-tion of immunosuppressive agents, evidence emergingintroduced and the incidence of acute rejection falls, it

has become increasingly difficult to prove the statistically from large transplant registries indicates that the half-lifeof cadaveric kidneys is improving [16]. This discrepancysignificant benefit of even newer agents. In the pivotal

trials leading to the introduction of MMF, sirolimus, and could reflect the lack of statistical power of the smallerprospective studies in proving the significance of smallthe anti-CD25 monoclonal antibodies [6, 8, 9, 11], the

incidence of acute rejection in the patients receiving the differences in graft survival. For example, if a new drugor protocol reduces the incidence of acute rejection epi-experimental drug protocol was compared to the inci-

dence of acute rejection in patients receiving so-called sodes by 20%, and patients who suffer an episode of


Table 3. Components of the immunosuppressive protocolTable 2. Incidence of biopsy-proven acute rejection episodes fromselected randomized clinical trials using standard dose of

Class of agent Optionsexperimental agent

Calcineurin inhibitor Cyclosporine, tacrolimusAgents compared % Acute rejectionCorticosteroids Dose and regimenAdjunctive agent Azathioprine, MMF, sirolimusControl Experimental Control Experimental ReferenceAntibody induction OKT3, ATGAM, thymoglobin

CsA, Aza FK, Aza 6 31 5 Anti-CD25 monoclonal antibody Basiliximab, daclizumabCsA, Aza CsA, MMF (2 g) 41 20 6 Supplementary agents CCB, HCRIFK, Aza FK, MMF (2 g) 44 27 7 Infection prophylaxis TMP-SMX, antiviralsCsA CsA, basiliximab 48 33 8

Abbreviations are: MMF, mycophenolate mofetil; CCB, calcium channelCsA, Aza CsA, daclizumab 43 27 9blocker; HCRI, HMG CoA reductase inhibitor; TMP-SMX, trimethoprim-sulfa-CsA, Aza CsA, rapa (2 mg) 24 15 12methoxazole.

Abbreviations are: CsA, cyclosporine; Aza, azathioprine; FK, tacrolimus;MMF, mycophenolate mofetil; rapa, sirolimus. All trials included standard dos-age of corticosteroids. From Ref. 12.

which often have been developed in response to localexperience. The components of a standard immunosup-

acute rejection have a 25% increased chance of graft pressive protocol (Table 3) are relevant to all recipients,loss at three years post transplantation, then the potential with the possible exception of two-haplotype-matchedimpact of the drug or protocol on three-year graft sur- living related donors [21]. Since the risk of acute rejectionvival would be only 5%. Several thousand patients would is highest in the first weeks and months after transplanta-need to be followed for three years for the study to have tion (induction phase) and diminishes thereafter (main-the statistical power to prove this difference, and such tenance phase), immunosuppression is at its highest levelprospective studies are logistically impractical. Hun- in this early period and is reduced for long-term therapy.sicker and Bennett have estimated that to detect with The most feared side effects of immunosuppression—80% power a 30% reduction in late graft loss, a five- opportunistic infection and malignancy—tend to reflectyear follow-up of 1500 patients would be required; they the total amount of immunosuppression given rather thandescribed this phenomenon as the “price of success” [17]. the dosage of a single drug. The availability of multipleRegistry data permit retrospective evaluation of many potent immunosuppressive agents might tempt practi-thousands of patients and are not constrained by the tioners into a potentially dangerous polypharmacy. Thenecessity for prospective follow-up of individual patients. benefit of the new agents in terms of their capacity toIn a retrospective analysis of approximately 8,500 renal reduce the incidence of acute rejection episodes shouldtransplant recipients who received MMF with cyclospor- be weighed against their cost, both economic and clinical.ine and corticosteroids between 1992 and 1997, Ojo et The total quantity of immunosuppression should be mon-al reported that the risk of chronic allograft failure was itored and considered in all stages of the post-transplant

course.reduced by 27% compared with those patients who re-Cyclosporine or tacrolimus? One or the other of theseceived azathioprine with cyclosporine and corticoste-

two drugs currently comprises the backbone of transplantroids. This effect appeared to be independent of theimmunosuppression. Although much has been made ofimpact of MMF on the incidence of acute rejection [18].some distinct differences between cyclosporine and ta-It is also possible that the improvement in long-termcrolimus, the fact is that they are remarkably similar,graft survival is not related to the introduction of newand both are highly effective [22]. Both drugs exert theirimmunosuppressive agents but is due to other factorsaction by inhibiting the cytosolic phosphatase enzymesuch as better clinical care, better treatment of hyperten-calcineurin, thereby preventing the passage through thesion, more effective infection prophylaxis, and increasednuclear membrane of activating factors for critical cyto-use of HLA-matched cadaveric donors [19]. The factkine genes, particularly interleukin-2 [23]. The nephro-that registry data show improvement is all the moretoxicity of both drugs has been well documented and can-remarkable at a time when the overall quality of thenot be differentiated pathologically. Transforming growthcadaveric donor pool is steadily deteriorating (as re-factor (TGF-b1) might play a major role in their acuteflected by increased donorage, incidence of hyperten-and chronic nephrotoxic effects and on their impact onsion, and non-traumatic cause of death) [15, 20].the natural history of malignant tumors [24, 25]. Trans-

General principles of immunosuppressive plant registry data show no significant difference in long-protocol design term graft survival for patients taking cyclosporine or

tacrolimus [26], so the choice between them is basedThe variety of immunosuppressive drugs now avail-able for use in clinical transplantation permit consider- largely on the profile of their side effects (Table 4). For

example, tacrolimus is more toxic to pancreatic isletsable permutations in immunosuppressive protocols. Trans-plant centers tend to be loyal to their own protocols, than is cyclosporine, and this effect is manifest clinically,


Table 5. Antibody preparations for renal transplantTable 4. Comparative side effect profile of cyclosporineand tacrolimusa immunosuppression

IndicationCyclosporine Tacrolimus

Induction RejectionDrug interactions Similar SimilarNephrotoxicity 1 1

MonoclonalHypertension andOKT3 (1) 1sodium retention 1 1 1Basiliximab 1* 2Pancreatic islet toxic 1 1 1Daclizumab 1* 2Neurotoxicity 1 1 1

PolyclonalCosmetic side effects 1 1 1ATGAM 1 1GI side effects 2 1Thymoglobulin (1) 1Hyperkalemia 1 1

Hypomagnesemia 1 1 Symbols are: 1, approved indication; (1), unapproved but commonly usedindication; 1*, concomitant administration of calcineurin inhibitor recommended;Hypercholesterolemia 1 2(2), not indicated.Cost Similar Similar

Signs are: (1) known effect; (1 1) effect more pronounced; (2) no or littleeffect.

a Summarized from [21, 22, 27, 35, 48]

a protein, target-of-rapamicin (TOR), which plays a piv-otal role in cell cycling, and does not inhibit calcineurin[29]. It is unclear at this time to what extent transplant

particularly in African American patients [5]. Cyclospor- programs will prescribe sirolimus as a replacement forine therefore might be the better choice in some centers MMF. Both sirolimus and MMF were licensed based onwhere the population of African American patients is their use in combination with cyclosporine and predni-large because of the increased incidence of post-trans- sone. Post-licensing studies have shown that MMF, ta-plant glucose intolerance in patients who receive tacroli- crolimus, and prednisone comprise an effective combina-mus. Tacrolimus might be preferred in adolescent and tion [7]. It was originally believed that sirolimus andother “cosmetically concerned” patients because of the tacrolimus should not be used together, as they occupymore marked cosmetic changes associated with cyclo- the same receptor (FK-binding protein); preliminarysporine [21]. Cyclosporine might be more suitable in studies suggest that this combination is acceptable andsome patients because of the generally milder neurologic effective because the receptor is not fully occupied evenside effects [22]. Tacrolimus might be the preferred when both are used [30]. Although sirolimus and MMFchoice in recipients of simultaneous kidney and pancreas have not been compared directly, sirolimus is probablytransplants because of its somewhat greater immunosup- a more potent immunosuppressant and its side effectpressive potency despite its greater islet toxicity [27]. In profile differs from that of MMF. In particular, sirolimusthe United States, approximately 70% of renal trans- might have an unfavorable impact on the lipid profile,plantation programs base their immunosuppression pro- and MMF might produce troubling gastrointestinal sidetocols on cyclosporine and the remainder on tacrolimus. effects [6, 11]. Both drugs can suppress the production

Which adjunctive agent? In this discussion I use the of formed blood elements to a degree comparable toterm “adjunctive agent” to describe the immunosuppres- azathioprine [21].sive drugs that are used, or were developed for use, in Antibody induction. A variety of antibody prepara-combination with a calcineurin inhibitor to enhance the tions are available for use in clinical transplantation,potency of the immunosuppressive protocol, as measured either for the treatment of acute rejection episodes or,by a decreased incidence of acute rejection episodes. in the early post-transplant phase, for the induction ofMost programs in the United States use an adjunctive immunosuppression (Table 5). Antibody induction ther-agent for prophylactic purposes starting from the imme- apy generally refers to the use of OKT3 or a polyclonaldiate post-transplant period; some programs choose to antibody (ATGAM or thymoglobulin) in the first 7 tointroduce adjunctive therapy only in the event of an 14 days after transplantation. The calcineurin inhibitoracute rejection episode. Azathioprine has been replaced is withheld, or its dose is kept to a minimum until 2 to 3by MMF in most centers because of its superior ability days before the antibody course is completed. Inductionto reduce the incidence of acute rejection (Fig. 1A and protocols using OKT3 or a polyclonal antibody representTable 2) [6]. Azathioprine and MMF are both antimetab- an alternative to the use of a calcineurin inhibitor inolites and inhibit purine metabolism, but MMF does so the early post-transplant period. When the anti-CD25in a more selective fashion through inhibition of the monoclonal antibody preparations are used, concomi-enzyme inosine monophosphate dehydrogenase [28]. tant use of a calcineurin inhibitor is recommended [8, 9].

Sirolimus became available for clinical use in late 1999. In so-called “sequential therapy,” OKT3 or the poly-It is biochemically similar to tacrolimus and occupies the clonal antibody is administered and the calcineurin in-

hibitor is introduced only when renal function has fallensame receptor, but its mode of action is unique. It targets


to a specified level (for example, a plasma creatinine with the calcineurin inhibitors for clearance by the P450enzyme system, resulting in higher drug levels and per-of 3 mg/dL). The antibody is discontinued as soon as

adequate calcineurin inhibitor levels are achieved. A mitting administration of a lower dose [40]. Calcium-channel blockers also might have some intrinsic immuno-patient with a graft that functions well thus might receive

only a few days of antibody treatment. modulatory activity of their own that is related to therole of cytosolic calcium levels on gene activation [35].Evaluation of data from the large transplant registries

has shown no long-term graft survival benefit of antibody The routine inclusion of calcium-channel blockers in thepost-transplantation protocol has been reported to im-induction in the majority of patients [31]. Patients at high

immunologic risk, African American patients, children, prove one-year graft survival by 5% to 10% [41].The HMGCoA reductase inhibitors (HCRIs) haveand patients with delayed graft function might benefit

from their use [32–34]. Antibody induction also might been shown to safely lower cholesterol levels and reducethe incidence of clinically severe rejection in cardiacbe indicated for patients requiring anticonvulsant drugs,

which can make achieving therapeutic levels of calci- transplant recipients [42]. A similar beneficial effect hasbeen observed in a preliminary study in renal transplantneurin inhibitors difficult in the early post-transplant pe-

riod [35]. Use of the polyclonal preparations obviates recipients [43]. The mechanism of this effect might berelated to the ability of HCRIs to suppress the cytotoxicthe first-dose side effects of OKT3; however, OKT3 is

easier to administer [35] and is somewhat cheaper (,$600 activity of natural killer cells [43]. Also, HCRIs mightbe important in the long-term post-transplantation regi-per dose compared to $800 per dose for the polyclonals).

In the doses typically administered, thymogobulin is prob- men by virtue of their capacity to reduce the cardiovascu-lar risk, the major source of morbidity and mortalityably a more effective polyclonal agent than ATGAM [10]

and evidence suggests that its administration immedi- after transplantation [44].The prevention of infection remains a critically impor-ately prior to transplantation reduces the incidence of

delayed graft function, possibly by reducing the expres- tant part of modern immunosuppressive protocols [37].A full review of this topic is beyond the scope of thission of adhesion molecules [36]. The use of OKT3 or

the polyclonal antibodies is associated with a small but discussion. The benefit of the new agents and protocolsin terms of patient mortality and long-term graft survivalfinite increase in the incidence of post-transplant malig-

nancy and opportunistic infection; this risk increases if is small, so any measurable increase in opportunisticinfections and malignancy must be treated with greatuse of these drugs is prolonged or repeated [35–38].

The availability of MMF and the anti-CD25 monoclonal concern. The danger can be illustrated by two examples:the high incidence of Epstein-Barr virus–related lympho-antibodies has reduced the use of OKT3 and the poly-

clonal antibodies at most centers. The two available anti- proliferative disorders in pediatric recipients of livertransplants immunosuppressed with tacrolimus [45], andCD25 monoclonal antibodies, daclizumab and basiliximab,

are very similar. From the therapeutic standpoint, they an outbreak of fatal Pneumocystis carinii infection in thephase-II trials of sirolimus at centers that were not usingboth have the capacity to reduce the incidence of acute

rejection episodes by approximately 15% compared to pla- routine prophylaxis [46]. Ganciclovir and trimethoprim-sulfamethoxasole remain the “unsung heroes” of trans-cebo (Table 2), and they are both remarkably free of side

effects [8, 9]. The approved dosage regimen for basi- plant immunosuppression.liximab (two doses of 20 mg at postoperative day 0 and

Immunosuppressive drug avoidance and withdrawal4) is more convenient than that for daclizumab (1 mg/kgon postoperative day 0 and at two-week intervals for The availability of multiple effective immunosuppres-

sive agents has stimulated attempts at minimizing ora total of five doses); however, a shortened course ofdaclizumab appears also to be effective. In the absence avoiding the most toxic components of the standard pro-

tocol. The most obvious targets for such efforts are corti-of side effects, the decision to use these agents is basedon each center’s assessment of their benefit, that is, the costeroids and the calcineurin inhibitors.

Steroid withdrawal, the discontinuation of steroid ad-effectiveness in reducing the incidence of acute rejection,compared to their cost, approximately $1000 per dose. ministration post-transplantation, needs to be differenti-

ated from steroid avoidance, in which steroids are admin-The anti-CD25 monoclonal antibodies are not indicatedfor the treatment of established acute rejection. istered only in the event of rejection. Steroid avoidance

has never been popular in the United States, although itSupplementary agents. The inclusion of calcium-chan-nel blockers, usually either diltiazem or verapamil, in has been applied in Europe [47]. Steroid withdrawal is

currently being re-evaluated in a multicenter trial in thethe standard immunosuppressive regimen has severalpotential advantages. In addition to their antihyperten- US using a cyclosporine- and sirolimus-based protocol.

Steroid withdrawal is a tempting approach in selectedsive properties, both drugs reduce calcineurin inhibitor-induced vasoconstriction and protect against ischemic patients, although the anxiety associated with withdrawal

(both for the patients and their physicians!) has limitedgraft injury and nephrotoxicity [39]. Both drugs compete


its popularity. A randomized, blinded trial of steroid with- Individualization of immunosuppressive protocolsdrawal at four months post-transplantation was per- All patients are not equal with respect to the chancesformed in a group of patients with good graft function, of rejection, graft loss, and development of drug-inducedwho had not suffered rejection episodes, and who were side effects, and protocols should take this into account.receiving cyclosporine and MMF in standard doses (ab- Patients who have received more than one transplantstract; Matas et al, Transplantation 6:269, 1999). The trial and patients with high levels of preformed antibodieswas discontinued because of a 20% incidence of acute can require more intense therapy [21, 35]. Young pa-rejection in the group in whom the steroid was with- tients tend to be immunologically aggressive and mightdrawn, compared to a 5% incidence in the control group. benefit from routine antibody induction [34]. Older pa-Most of the rejection episodes occurred in African Ameri- tients have decreased tolerance for potent immunosup-can patients. Steroid withdrawal thus should be consid- pression [53].ered only in patients who are at least several months The role of race in the success of renal transplantationpost-transplant, have not suffered recent or recurrent has been the subject of considerable debate and investi-rejections, and have excellent graft function [48, 49]. gation. In the clinical trials leading to the introductionAfrican American patients might not be suitable candi- of tacrolimus, MMF, and sirolimus, African Americandates for withdrawal and all patients should be warned patients have required higher doses of immunosuppres-of a small but finite increased incidence of rejection. A sive drugs to achieve the same immunosuppressive bene-clear-cut benefit of withdrawal, in terms of certain ste- fit as did whites [5, 46, 54], and some programs routinelyroid-related side effects (for example, bone disease, hy- take this into account in protocol design [21, 33, 35]. Asperlipidemia) has not been demonstrated, presumably I said, African American patients are more likely tobecause most of the familiar steroid-related problems suffer acute rejection when steroids are withdrawn. Inare produced by the high doses used in the early post- the US, allograft survival in African American recipientstransplant period [48]. Several studies have suggested tends to be approximately 10% to 20% less than thatthat steroid-withdrawn patients might be subject to long- for white recipients whether the transplant was from aterm deterioration in graft function, so enthusiastic re- living or cadaveric donor [19, 55]. Several factors haveports of successful withdrawal should be evaluated with been proposed to explain the lower survival, includingcare [47–49]. noncompliance and socioeconomic factors [55], the preva-

In the pivotal trials leading to the introduction of lence of hypertension in blacks [56], evidence of strongercyclosporine, tacrolimus, MMF, and sirolimus, the drugs immune responsiveness [57], and faster metabolism ofwere continued over the long term, and the safety of their immunosuppressive medications [58].discontinuation was not studied in a rigorous fashion. It All donor kidneys are not equal with respect to theirmight be possible to withdraw these drugs in some stable susceptibility to the immune or non-immune injury. Re-patients [50] or to reduce their dose. Randomized trials cipients of living related transplants, particularly fromare in progress to provide a definitive answer to the two-haplotype-matched donors, might require less im-safety of this approach. Trials also are in progress using munosuppression [21, 35] and these kidneys are morelow doses that target lower blood levels of the calcineurin likely to function well over the long term. On the con-inhibitors in various combinations with MMF, sirolimus, trary, kidneys that suffer delayed graft function are moreand the anti-CD25 monoclonal antibodies. The potential susceptible to acute rejection and to chronic allograftadvantage of these protocols is that they could maintain failure [35, 59], particularly when mismatched for HLAimmunologic effectiveness while minimizing short- and [60]; the same is true for kidneys if early function im-long-term nephrotoxicity. Large multicenter European proves only slowly [61]. Delayed graft function also hastrials have evaluated protocols that do not use calci- been shown to be a risk factor for long-term patient mor-neurin inhibitors, replacing them with sirolimus or a com- tality [62]. A variety of factors related to the donor, thebination of sirolimus and MMF [51, 52]. When sirolimus cause of the donor’s death, and the circumstances ofwas used alone, graft survival (,90%) and the incidence organ retrieval and transplantation predispose to ische-of acute rejection (,50%) did not differ significantly mic injury, delayed graft function, and poorer long-termbetween the patients who received a calcineurin inhibitor prognosis [35, 59].and those who did not [51]. Renal function was better

Should the kidney have been offered to this patient?in the calcineurin inhibitor-free group. Until the long-term results of these trials can be evaluated critically, The decision to transplant a kidney into this womanone should carefully evaluate and review, together with should be considered in the overall context of her end-the patient, the known risks and benefits of avoidance, stage renal disease and the difficult clinical dilemma re-withdrawal, or radical dose reduction of steroids and sulting from her prolonged wait for a cadaveric kidney

and her access failure. She had no potential living donorscalcineurin inhibitors.


because of the strong family history of renal disease because her African American race, her preformed cyto-toxic antibodies, the donor’s age and cause of death,and hypertension. Two years ago, she had a positive

crossmatch to a poorly histocompatibility matched, but and the prolonged cold ischemia time resulting from theorgan’s transfer from the East Coast of the US to theotherwise excellent, cadaveric kidney and was in dire

need because of her access failure and preformed cyto- West put her at increased risk of delayed graft functionand early acute rejection [21, 32, 34, 59]. We chose OKT3toxic antibodies. The transplant team was then faced

with a difficult and irrevocable decision—should they rather than ATGAM because of its greater ease of ad-ministration. Thymoglobulin was not available. The anti-offer her the kidney that became available four months

later? The kidney was a full histocompatibility match to CD25 monoclonal antibodies were not used since theirdocumented clinical benefit has been in a low-risk popu-her and the crossmatch was negative, but the organ had

several features that predisposed it to delayed graft func- lation [8, 9]. Cyclosporine was chosen as her calcineurininhibitor rather than tacrolimus, as she was deemed totion. There were several donor-related problems, includ-

ing advanced age, death by cerebrovascular accident, a be at particular risk of post-transplant diabetes mellitusbecause of her African American race, obesity, and fam-history of hypertension, pre-harvesting acute renal dys-

function and a prolonged cold-ischemia time [16, 19, 20, ily history of diabetes [5, 70]. We chose MMF as theadjunctive agent because it is more effective than azathio-35, 59]. These features appear to outweigh the benefits

of favorable histocompatibility matching [63, 64]. A his- prine [15]; sirolimus was not available. The dose of MMFwas 1500 mg twice daily rather than the standard 1000 mgtory of hypertension is now obtained in approximately

25% of all donors in the US; both hypertension and death twice daily because of evidence that African Americanpatients require the higher dose to achieve the sameby cerebrovascular accident in the donor predispose to

hypertension in the recipient [20, 65]. Hypertension is degree of reduction of risk of rejection as do non-AfricanAmerican patients [15, 54]. She received a standard ta-an important factor in determining racial differences in

renal allograft survival [56]. pering dose of prednisone. We gave her ganciclovir intra-venously and then orally as a form of “pre-emptive”The unfavorable histologic changes might have been

underestimated in the original pathology report; 16% of therapy to prevent cytomegalovirus (CMV) infection. Shewas at high risk for CMV infection because we had ad-the glomeruli were sclerosed, and interstitial and vascu-

lar changes were present. The increased use of physiolog- ministered OKT3 and because of evidence of prior donorand recipient CMV infection [36]. Bactrim (TMP-SMX)ically marginal donor kidneys has led to an increased

reliance on donor biopsies, taken at the time of organ and nystatin were used as prophylaxis against oral candi-diasis, urinary tract infection, and P. carinii pneumonia.retrieval, as a guide to the advisability of transplanting

them, or even of transplanting both kidneys to a single Diltiazem was used as part of her antihypertensive regi-men and to permit a lower dose of cyclosporine [39, 40].recipient [66–69]. These biopsies are often performed

outside of normal working hours, under intense time Its dose was fixed to avoid fluctuations in the cyclosporinelevel. Atorvastatin was used both for its effect on lipidconstraints, with less than ideal tissue fixation and stain-

ing. Under these circumstances, the percentage of scle- levels and its potential immunologic benefit [42, 43].Four weeks after receiving the transplant, the patientrosed glomeruli has become a convenient marker of organ

quality. Two groups have suggested that the determining was treated with high-dose corticosteroids for what wasprobably a mild acute rejection episode in a backgroundfeature should be the presence of 15% or 20% glomeru-

losclerosis [66, 67], and Remuzzi et al favor a scoring system of resolving acute tubular necrosis and chronic histologicchanges. High-dose “pulse” corticosteroids remain thethat also includes interstitial and vascular changes [68]. A

multivariate analysis, however, has shown that donor first-line therapy for most episodes of mild rejection, andantibody preparations usually are held in reserve forbiopsy information adds little to what is already known

from the donor’s age and circumstances of death [69]. recurrent episodes or first episodes that are severe, par-ticularly if there is a component of vascular rejection [35].Despite the unfavorable features of the kidney that

became available, the significance of which were ex- The patient had received OKT3 for induction therapy; asecond course of an antibody preparation within the firstplained to her, the transplant team decided to offer her

the kidney because she desperately needed it and be- eight weeks after transplantation greatly increases therisk of lymphoproliferative disease and should be avoidedcause it was difficult to predict whether a more favorable,

crossmatch-negative kidney would become available for if possible [38]. By three months after transplantation,her infection prophylaxis had been discontinued, andher in the near future.enalapril had been substituted for clonidine for blood

Choice of immunosuppression and management of pressure control. Angiotensin-converting-enzyme inhib-today’s patient itors and angiotensin II antagonists are safe and well

tolerated in renal transplant patients [71]. Angiotensin IIImmunosuppression was commenced with antibodyinduction using OKT3. Antibody induction was used receptor blockade can decrease the levels of TGF-b that


have been implicated in the fibrogenesis that is a feature gans inexorably lengthens, great care will be required touse the organs and drugs at our disposal wisely.of chronic allograft nephropathy [72].

By one year after transplantation, she had evidenceof chronic allograft failure. This term is now preferred

QUESTIONS AND ANSWERSto the previous, loosely used “chronic rejection” because

Dr. Nicolaos E. Madias (Executive Academic Dean,of the contribution of both immune and non-immuneTufts University School of Medicine, Boston, Massachu-factors to its pathogenesis [73]. Retrospective analysessetts): Thank you, Dr. Danovitch, for a fine presentation.have convincingly shown that the acute rejection episodeYou reviewed the issue of individualization of patientthat she suffered increased her risk of chronic allograftprotocols. Yet, as you indicated, most patients tend to befailure [13, 16]. The episode was made more likely by herimmunosuppressed in a very similar fashion. The result isdelayed graft function, and it occurred despite an immuno-that we likely are over-immunosuppressing many pa-suppressive regimen of proven effectiveness. The unfa-tients and are under-immunosuppressing others. Whyvorable donor factors that I mentioned conspired to fur-have we not been more successful in this regard?ther impair the long-term graft function through a process

Dr. Danovitch: Indeed, the transplant field has beenthat has been likened to accelerated senescence [74].more successful in developing new immunosuppressiveThe optimal management of chronic allograft failureagents than in determining who should receive them.remains unclear, and it has proven exceptionally difficultWith the exception of fully HLA-matched sibling pairs,to design clinical trials that would define effective strate-the available immunologic and histocompatibility mark-gies [17]. Intensification of immunosuppression is gener-ers have not proved to be adequately predictive for indi-ally not effective and is potentially dangerous; increasingvidual patients. So, for the moment, we are left with thethe dose of the calcineurin inhibitor is likely to exacer-rather broad demographic parameters that I outlinedbate its nephrotoxicity [35, 75]. Single-center studies have[21]. Hutchinson and colleagues reported that certainevaluated the strategy of adding MMF to the immunosup-cytokine gene polymorphisms in transplant patients arepressive regimen while reducing the dose of cyclosporine.associated with increased cytokine production and rejec-The results have been mixed [75–77]. Replacement oftion risk [78]. Recognition of these polymorphisms even-the nephrotoxic calcineurin inhibitor with sirolimus is atually might permit more individualized therapy. An-tempting strategy that is yet to be tested systematically.other way to approach immunosuppression is to startApplication of principles similar to those used for thewith a less aggressive protocol, such as by excludingmanagement of chronic renal failure in native kidneyscorticosteroids or the adjunctive agent, and only intensi-might be effective, and blood pressure control with ACEfying immunosuppression in the event of an acute rejec-inhibitors or angiotensin II receptor blockers might slowtion. This approach is more popular in Europe than inthe progression of allograft failure [71, 72]. Death of thethe United States. Concern about the impact of acutepatient accounts for more than 40% of all graft loss [44].rejection on long-term function has led to the trend ofThe most common cause of late post-transplant deathusing intensive immunosuppression in the early post-is cardiovascular disease [20, 44]. Today’s patient hastransplant period. We are then left, as I said, with decid-multiple risk factors for coronary artery disease and, ining which agents can be safely withdrawn and when. Wethe absence of studies directly addressing these factorsobviously need more data.in the transplant population, it would seem appropriate

Dr. Madias: Can available medications used in differ-to extrapolate from recommendations made to the gen-ent combinations further improve the outcome of trans-eral population. Therefore, we aggressively try to controlplantation? Do you anticipate that a further reductionher lipid levels and blood pressure while encouragingin the incidence of acute rejection will have a favorableweight loss and regular exercise [20]. Attention to ath-impact on graft longevity?erosclerotic risk factors could be the most important

Dr. Danovitch: Many transplant programs are achiev-contribution to the improvement of the longevity of pa-ing greater than 90% success, as measured by graft func-tients with successful renal transplants [44].tion at one year. There will inevitably be occasional graftThe management dilemmas that have faced this pa-loss due to technical or other complications. Therefore,tient and her caregivers are by no means unique. Al-we are approaching the maximization of short-term re-though the immunosuppressive choices that were madesults. The current challenge lies in improving long-termwere successful in permitting her to navigate the firstsuccess. A further reduction in the incidence of acutepost-transplant year, the quality of the kidney that wasrejection might well be reflected in an improvement intransplanted might well come back to haunt her in thelong-term function, although I suspect that this improve-months and years ahead. No immunosuppressive regi-ment will be relatively small and difficult to measure. Inmen, no matter how effective, is likely to permit a physio-our enthusiasm to reduce the incidence of early acutelogically marginal kidney to function as well as one from

an “ideal” donor. As the waiting time for cadaveric or- rejection episodes by using potent immunosuppressive


protocols, we must ensure that we do not engender mor- might have some degree of ischemia in the immediatesubcapsular zone.bid complications that will negate their benefit. Many of

the so-called “antigen-independent” causes of long-term Dr. Danovitch: At the behest of our nephropathologycolleagues, several of the immunosuppressive trials I re-graft loss are related to the quality of donor organs and

pre- and post-transplant recipient cardiovascular disease ferred to have included baseline and protocol biopsies;in patients in clinical trials, this is certainly appropriate.[20, 74].

Dr. Alan Wilkinson (Division of Nephrology, UCLA It is not yet clear to what extent the information obtainedwill affect routine clinical care. I am reluctant to recom-Medical Center): I suspect that some of the discrepancy

that you describe between the measurable impact of mend routine inclusion of additional procedures untilwe know more. I should add that in clinical trials it hasacute rejection on long-term function in retrospective

analyses compared to the lack of measurable impact on sometimes proved difficult to persuade stable patientsto undergo a protocol biopsy, and the degree of enthusi-prospective analyses also might be due to the fact that

not all rejections are equal. In clinical trials, most rejec- asm of the treating physicians for the procedure also hasbeen variable. As a result, the statistical analysis of thetions are recognized early and treated quickly and there-

fore could have a lesser impact on long-term graft loss. biopsy data often has been incomplete [15].Dr. Cohen: Could you comment on the finding ofDo you think that clinical trials accurately reflect routine

clinical experience? polyoma viral infection in transplant patients? One re-cent report suggests that patients who receive tacrolimusDr. Danovitch: That is a good point. Indeed, it is

common for patients enrolled in clinical trials to do bet- are at much greater risk for developing this infection[80]. Does this risk enter into your consideration forter than their non-trial counterparts even if they are in

the control group, presumably because of the intensity of selecting that drug versus cyclosporine? Why is polyomaviral infection of the transplant so rarely encountered?clinical monitoring and the early histologic confirmation

and treatment of acute rejection. Fortunately, the clinical Dr. Danovitch: Human polyoma BK virus indeed hasbecome a more frequently recognized infectious agenttrials have had an impact on clinical management and

the tendency now in most transplant programs is to in immunosuppressed patients, but I suspect that it’sbeen there all along, but missed. It presents clinically inbiopsy the transplant to confirm a clinical impression

of rejection rather than to treat a suspected rejection heavily immunosuppressed patients as a severe acuterejection that appears unresponsive to further intensifi-empirically [59].

Dr. Michael Bunnapradist (Division of Nephrology, cation of immunosuppression, and the kidneys are usu-ally lost [80]. It takes an astute pathologist like yourself toCedars Sinai/UCLA Medical Center): What is your opin-

ion of the role of the “protocol biopsy” in post-transplant suspect its presence. The biopsy specimens show severetubulointerstitial nephritis with large basophilic intra-immunosuppression management?

Dr. Danovitch: Dr. David Rush and colleagues have nuclear inclusions. Special staining with polyoma virusmonoclonal antibody confirms the diagnosis, and thepioneered the evaluation of the protocol biopsy in post-

transplant management [79]. In doing so, they proposed viral DNA can be identified in plasma. Most of the caseshave occurred in patients who have received tacrolimus,the concept of “sub-clinical” acute rejection, which is

defined by a usually mild lymphocytic infiltrate in the but the drug has typically been given for “rescue” afterthe use of antibody preparations and other agents. Iabsence of an elevation in the serum creatinine level [55].

There is some question as to the pathologic significance doubt that the infection is specific for tacrolimus, andconsideration of this risk does not influence the choiceof these infiltrates, but treating them as rejections might

improve long-term graft function [79]. If this important of agent. Rather, this virus is a reminder to us that weshould always consider what our infectious disease col-observation can be confirmed, then the introduction of

a protocol biopsy into routine care certainly would be a leagues call “the net state of immunosuppression” [37]and avoid excessive intensification of our regimens withrational way to guide immunosuppressive management.

Dr. Arthur Cohen (Department of Pathology, Cedars the potent agents now available.Dr. Harry Ward (Division of Nephrology, King Drew/Sinai/UCLA Medical Center): A discussion of protocol

biopsies should include consideration of a baseline biopsy UCLA Medical Center): Irrespective of how well we aredoing with improved immunosuppressive protocols, weat the time of transplantation. This approach permits

identification of pre-transplant immunologic and non- are still faced with a serious shortage of cadaveric organs.Considering the ratio of people awaiting organs to theimmunologic damage and the more accurate interpreta-

tion of biopsies performed after transplantation. The availability of donors, do you think that we will haveto ration cadaveric kidneys using some kind of broadlybaseline biopsy has to be performed by the surgeon cor-

rectly. It is not adequate to shave the immediate subcap- accepted criteria such as age, prior transplantation, orexpected longevity? Should we direct the marginal kid-sular zone of the kidney, which can be a very unrepresen-

tative part of the kidney, especially in older donors who neys to older patients or other high-risk groups?


Dr. Danovitch: The question you raised is an inescap- Dr. Danovitch: In principle, all patients on chronicdialysis or with irreversible end-stage renal diseaseable one, and the nephrology and transplant communi-

ties as well as the general public will need to come to should be regarded as potential transplant recipients.When making decisions as to the appropriateness ofgrips with it in the years ahead. It will not be resolved

until xenotransplants become a clinical reality. Person- transplant candidacy for individual patients, we shouldemploy an evidence-based approach whenever possibleally, I am very reluctant to exclude, disadvantage, or

promote certain patient groups with respect to access and avoid making value judgments. Transplant programsand nephrologists need to educate patients about theto transplantation, because all potential recipients can

benefit from it either in terms of improved mortality rates relative risks and benefits of transplantation to help themmake informed decisions. The American Society ofor quality of life [44]. I don’t have any easy solutions. I

do know that nobody wants to return to the kind of Transplantation has published guidelines for the evalua-tion of transplant recipients. These guidelines will be“thumbs-up, thumbs-down” decision-making that was a

feature of the early days of hemodialysis. updated on a regular basis and address in a detailedfashion the difficult issues to which you refer [81].Dr. Madias: Could you please comment on the avail-

able experience with dual grafting? Dr. Robert Ettenger (Department of Pediatrics,UCLA Medical Center): Would you comment on theDr. Danovitch: I will ask my surgical colleague to

respond. contribution that noncompliance with medications mightmake to the evolution of chronic graft dysfunction?Dr. H. Albin Gritsch (Department of Urology, UCLA

Medical Center): By dual grafting I presume you are Dr. Danovitch: You are certainly in order to bringup the issue of noncompliance in a discussion of thereferring to the simultaneous use of both kidneys from

older “marginal donors.” The use of both kidneys from intricacies of transplant immunosuppression. In renaltransplantation, clinically important noncompliance haspediatric donors transplanted “en bloc” is also a form

of dual grafting. Both these maneuvers are a reflection of been reported in 15% to 20% of recipients, and it sub-stantially increases the risk of adverse immunologicour attempts to maximally exploit the available cadaveric

donor pool. Marginal kidneys are sometimes discarded events and even death [82]. Several social and demo-graphic variables appear to affect the likelihood of non-for fear they will not provide adequate renal function

for their recipients if they are used individually. Some compliance [83]. These include young age, psychiatricillness, low socioeconomic status, financial hardship, andcenters now advocate the use of two kidneys from donors

over the age of 60 if the renal function is impaired or if a history of substance abuse. Noncompliance increasesthe risk of graft loss by three- to fivefold and is a commonthe biopsy taken at the time of organ retrieval reveals

significant histologic damage [67]. One kidney can be cause of late graft loss [82].The approach to noncompliance by the transplantplaced in each iliac fossa using a preperitoneal midline

incision or separate lower abdominal incisions. Alterna- community needs to proceed both on a national andindividual level. The financial strain on patients has beentively, both kidneys can be placed on one side, with

anastomosis of the vessels of one kidney to the common alleviated somewhat by the extension of Medicare cover-age to 44 months, and the Institute of Medicine hasiliac artery and the vena cava. Early experience with

transplantation of double marginal kidneys suggests that recommended eliminating all time limits on Medicarecoverage of immunosuppressant medications. As always,results of graft survival and renal function are compara-

ble to that achieved with single kidneys from older do- the development and maintenance of a trusting relation-ship between the patient and the caregiver is key tonors [67, 68]. Older recipients might benefit more with

kidneys from older donors, as their metabolic demands optimal outcome [82, 83].Dr. David Lee (Division of Nephrology, Sepulvedacan be fewer. As yet, no nationally accepted guidelines

exist for determining whether one or both kidneys should Veterans Administration Hospital): You spoke of an in-crease in live kidney donation in the United States. Werebe transplanted; the decision has been made by individ-

ual transplant centers. the donors related or non-related? Please comment onthe future, at least in the United States, of living non-Dr. Gerald Friedman (Nephrologist, Upland, Cali-

fornia): You discussed the problem of the shortage of related donation.Dr. Danovitch: Most of the increase in living donationcadaveric organs and the deteriorating quality of the

cadaveric donor pool. What about the marginal recipi- in the United States has come as a result of donation frompeople who are not biologically related. Non-related, orent? I have patients in my practice who have been illicit

drug users, patients who are noncompliant with therapy, the term I prefer “emotionally related” donors, nowaccount for approximately one-third of all living dona-and patients in their late sixties or older who end up

on the transplant list and who receive kidneys before tions. A major stimulus for this expansion came as aresult of the landmark report in 1995 by Terasaki andpotentially better-suited recipients. Should we be more

selective about the patients to whom we give organs? colleagues that the results of such donation approxi-


cost information for immunosuppressive drugs was provided by themated the results of donation from the more traditionalUCLA Department of Pharmaceutical Services.biologically related sources [84]. Most of the biologically

unrelated donors are spouses, close or distant relatives, Reprint requests to Dr. G. Danovitch, Kidney and Pancreas Trans-plant Programs, UCLA School of Medicine, 10833 Le Conte Avenue,close friends, or adopted family. Some programs acceptBox 95176, Los Angeles, California 90095-1796, USA.donors who have no personal relationship with the recip-E-mail: [email protected]

ient, so-called “good Samaritan” or altruistic donors. Ifeel strongly that our obligation to the health of donors REFERENCESrelates not just to their physical health but also to their

1. Hamilton D: Kidney transplantation: A history, in Kidney Trans-emotional well-being, and when the motive for the dona-plantation: Principles and Practice (4th ed), edited by Morris PJ,tion is not evident, it is very important that a careful London, Saunders, 1994, pp 1–15

psychiatric evaluation be included in the workup. In our 2. Calne RY, Rolles K, White DJG, et al: Cyclosporin A initiallyas the only immunosuppressant in 36 recipients of cadaveric organs.transplant program, we have quite lively discussions onLancet 2:1033–1036, 1979this issue. I tend to be conservative and feel more com- 3. Myers BD, Ross J, Newton L, et al: Cyclosporin-associated

fortable when I can identify a clear-cut emotional tie chronic nephropathy. N Engl J Med 311:699–704, 19844. Cosimi AB, Colvin RB, Burton RC, et al: Use of monoclonalbetween the prospective donor and recipient. A recent

antibodies to T-cell subsets for immunologic monitoring and treat-Nephrology Forum by Dr. Susan Hou dealt with thisment of recipients of renal allografts. N Engl J Med 305:308–313,

issue in detail [85]. 1981Dr. Alice Peng (Division of Nephrology, UCLA Med- 5. Pirsch JD, Miller J, Dierhoi MH, et al: A comparison of tacroli-

mus (FK506) and cyclosporine for immunosuppression after cadav-ical Center): Rapamicin appears to be a potent but noteric renal transplantation. Transplantation 63:977–992, 1997nephrotoxic immunosuppressive agent. What do you 6. Sollinger HW, the US Renal Transplant Mycophenolate Mo-

think its role should be in future transplantation proto- fetil Study Group: Mycophenolate mofetil for the preventionof acute rejection in primary cadaveric renal allograft recipients.cols?Transplantation 60:225–231, 1995Dr. Danovitch: Rapamicin was introduced into clini-

7. Shapiro R, Jordan ML, Scatlebury VP, et al: A prospective,cal transplantation after clinical trials in which it was randomized trial of tacrolimus/prednisone versus tacrolimus/pred-

nisone/mycophenolate mofetil in renal transplant recipients. Trans-used as an adjunctive agent to full-dose cyclosporineplantation 67:411–414, 1999[11]. This combination might not be the most favorable

8. Kahan BD, Rajaagopalan PR, Hall M, et al: Reduction of theone for exploiting the features of the drug, and I do not occurrence of acute cellular rejection among renal allograft recipi-think that this is the way the drug will be generally ents treated with Basiliximab, a chimeric anti-interleukin-2-recep-

tor monoclonal antibody. Transplantation 67:276–284, 1999used. In Europe, rapamicin has been used without a9. Nashan B, Light S, Hardie IR, et al: Reduction of acute renalcalcineurin inhibitor, and it appeared to be similar in its allograft rejection by daclizumab. Transplantation 67:110–115, 1999

effectiveness to cyclosporine [51]. I am concerned that 10. Gaber AO, First MR, Tesi RJ, et al: Results of the double-blind,randomized, multicenter, phase III clinical trial of thymoglobulinusing both drugs in full doses will prove too toxic. Someversus ATGAM in the treatment of acute graft rejection episodespreliminary results suggest that using rapamicin with lowafter renal transplantation. Transplantation 66:29–37, 1998

doses of tacrolimus or with mycophenolate mofetil is 11. Kahan BD, Podbiel J, Napoli KL, et al: Immunosuppressive ef-fects and safety of a sirolimus/cyclosporine combination regimensafe and effective [30, 52]. Rapamicin, together with ta-for renal transplantation. Transplantation 66:1040–1046, 1998crolimus and daclizumab, but in the absence of cortico-

12. Kahan BD, the Rapammune US Study Group: Efficacy of siroli-steroids, has been used in the first consistently successful mus compared with azathioprine for reduction of acute allograftimmunosuppression protocol for pancreatic islet trans- rejection: A randomized multicentre study. Lancet 356:194–202,

2000plantation [86]. Clinical trials are in progress to critically13. Humar A, Hassoun A, Kandaswamy R: Immunologic factors:evaluate these combinations. The major risk for decreased long-term renal allograft survival.

In some tantalizing studies in small animal models, Transplantation 68:1842–1846, 199914. Amend WC, Vincenti F, Tomlanovich SJ: The first two post-the tolerogenic effect of blockade of co-stimulatory mol-

transplant months, in Handbook of Kidney Transplantation (3rdecules is increased by the induction of apoptosis in theed), edited by Danovitch GM, Boston, Lippincott Williams &

responding T-cells. The calcineurin inhibitors impair this Wilkins, 2001, pp 163–182effect by blocking the induction of apoptotic signals, 15. U.S. Renal Transplant Mycophenolate Mofetil Study Group:

Mycophenolate mofetil in cadaveric renal transplantation. Am Jwhereas rapamicin promotes apoptosis and improvesKidney Dis 34:296–303, 1999graft tolerance [86]. These observations have important 16. Hariharan S, Johnson CP, Bresnahan BA, et al: Improved graft

clinical implications because they eventually might per- survival after renal transplantation in the United States, 1988 to1996. N Engl J Med 342:605–612, 2000mit an advance from the global immunosuppression pro-

17. Hunsicker LG, Bennett LE: Design of trials of methods to reduceduced by combinations of the agents currently at ourlate allograft loss: The price of success. Kidney Int 48(Suppl

disposal to a more selective immunosuppression pro- 52):S120–S123, 1995duced by the apoptotic cell death of activated T-cells. 18. Ojo AO, Meier-Kriesche H, Hanson J, et al: Mycophenolate

mofetil reduces late renal allograft loss independent of acute rejec-tion. Transplantation 69:2405–2409, 2000ACKNOWLEDGMENTS

19. Carpenter CB: Improving the success of organ transplantation.N Engl J Med 342:647–648, 2000The pathologic evaluations of biopsy specimens for the presented

patient were performed by C. Nast, M.D., and A. Cohen, M.D. All 20. Danovitch GM: The epidemic of cardiovascular disease in chronic


renal disease: A challenge to the transplant physician. Graft 2:S108– receiving tacrolimus-based immunosuppression. TransplantationS112, 1999 68:1851–1854, 1999

21. Danovitch GM: Choice of immunosuppressive drugs and individu- 46. Kahan BD, Julian BA, Pescovitz MD, et al: Sirolimus reducesalization of immunosuppressive therapy for kidney transplant pa- the incidence of acute rejection episodes despite low cyclosporinetients. Transplant Proc 31(Suppl 8A):2S–6S, 1999 doses in Caucasian recipients of mismatched primary renal allo-

22. Danovitch GM: Cyclosporin or tacrolimus: Which agent to grafts: A phase II trial. Transplantation 68:1526–1532, 1999choose? Nephrol Dial Transplant 12:1566–1568, 1997 47. Stegall MD, Wachs M, Everson GT, et al: Corticosteroid with-

23. Liu J, Farmer JD, Lane WS, et al: Calcineurin is a common target drawal in solid organ transplantation. Transplant Rev 12:140–145,of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 199866:807–901, 1991 48. Danovitch GM: Immunosuppressant induced metabolic toxicities.

24. Sharma VK, Bologa RM, Xu GP, et al: Intragraft TGFb mRNA. A Transplant Rev 14:1–18, 2000correlate of interstitial fibrosis and chronic allograft nephropathy. 49. Hollander AA, Hene RJ, Hermans J, et al: Late prednisoneKidney Int 49:1297–2002, 1996 withdrawal in cyclosporine-treated kidney transplant patients: A

25. Hojo M, Morimoto T, Maluccio M, et al: Cyclosporine induces randomized study. J Am Soc Nephrol 27:293–297, 1996cancer progression by a cell-autonomous mechanism. Nature 397: 50. Kasiske BL, Heim-Duthoy K, Ma JZ: Elective cyclosporine with-530–534, 1999 drawal after renal transplantation: A meta-analysis. JAMA 269:395–

26. Opelz G, The Collaborative Transplant Study Group: Effect 400, 1993of immunosuppressive therapy on graft half-life projections. Trans- 51. Groth CG, Backman L, Morales JM, et al: Sirolimus (rapamicin)-plant Proc 31(Suppl 7A):315–336, 1999 based therapy in human renal transplantation. Transplantation

27. Stratta RJ: Review of immunosuppressive usage in pancreas 67:1036–1042, 1999transplantation. Clin Transplant 13:1–9, 1999 52. Kreis H, Cisterne JM, Land W, et al: Sirolimus in association

28. Natsumeda Y, Ohno S, Kawasaki H, et al: Two distinct cDNAs with mycophenolate mofetil induction for the prevention of acutefor human IMP dehydrogenase. J Biol Chem 265:5292–5295, 1990 allograft rejection in renal allograft recipients. Transplantation

29. Sehgal SN: Rapamune (RAPA, rapamycin, sirolimus): Mecha- 69:1252–1260, 2000nism of action immunosuppressive effect results from blockade of 53. Meier-Kriesche I, Friedman G, Jacobs M, et al: Infectious compli-signal transduction and inhibition of cell cycle progression. Clin cations in geriatric renal transplant patients: Comparison of twoBiochem 31:335–340, 1998 immunosuppressive protocols. Transplantation 68:1496–1502, 1999

30. McAlister VC, Gao Z, Peltekian K, et al: Sirolimus-tacrolimus 54. Halloran P, Matthew T, Tomlanovich S, et al: Mycophenolatecombination immunosuppression. Lancet 355:376–377, 2000 mofetil in renal allograft recipients. Transplantation 63:39–44, 1997

31. Szczech LA, Berlin JA, Feldman HI, et al: The effect of antilym- 55. Butkus DE, Meydrech EF, Raju SS: Racial differences in thephocyte induction therapy on renal allograft survival. Ann Intern survival of cadaveric renal allografts: Overriding effects of HLAMed 128:817–826, 1998 matching and socioeconomic factors. N Engl J Med 327:840–845,

32. Gaston RS, Hudson SL, Deierhoi MH, et al: Improved survival 1992of primary cadaveric renal allografts in blacks with quadruple im- 56. Cosio FG, Dillon JJ, Falkenheim ME, Tesi RJ, et al: Racialmunosuppression. Transplantation 53:103–108, 1992 differences in renal allograft survival: The role of systemic hyper-33. Ettenger RB, Rosenthal JT, Marik JL, et al: Improved cadaveric

tension. Kidney Int 47:1136–1141, 1995renal transplant outcome in children. Pediatr Nephrol 5:137–141,57. Van Buren DH: Renal transplantation outcomes in African-1991

American patients. Transplant Immunol Lett 15:6–11, 199934. Shoskes DA, Halloran F: Delayed graft function in renal trans-58. Schroeder TJ, Hariharan S, First MR: Relationship betweenplantation: Etiology, management and long-term significance. J Urol

cyclosporine bioavailability and clinical outcome in renal trans-155:1831–1842, 1996plant recipients. Transplant Proc 26:2787–2790, 199435. Danovitch GM: Immunosuppressive medications and protocols

59. Danovitch GM, Nast C: Diagnosis and therapy of graft dysfunc-for kidney transplantation, in Handbook of Kidney Transplantationtion, in Dialysis and Transplantation, edited by Owen WF, Pereira(3rd ed), edited by Danovitch GM, Boston, Lippincott Williams &BTG, Sayegh MH, Philadelphia, Saunders, 2000, pp 568–583Wilkins, 2001, pp 62–111

60. Shoskes DA, Hodge EE, Goormastic M, et al: HLA matching36. Brennan DC, Flavin K, Lowell JA, et al: A randomized, double-determines susceptibility to harmful effects of delayed graft func-blinded comparison of thymoglobulin versus ATGAM for induc-tion in renal transplant recipients. Transplant Proc 27:1068–1071,tion immunosuppressive therapy in adult renal transplant recipi-1995ents. Transplantation 67:1011–1018, 1999

61. Humar A, Johnson EM, Payne WD, et al: Effect of initial slow37. Fishmann JA, Rubin RH: Infection in organ-transplant recipients.graft function on renal allograft rejection and survival. Clin Trans-N Engl J Med 338:1741–1751, 1998plant 11:623–627, 199938. Paya CV, Fung JJ, Nalesnik MA, et al: Epstein-Barr virus-induced

62. Troppman C, Gillingham KJ, Benedett E, et al: Delayed graftpost transplant lymphoproliferative disorders. Transplantation 68:function, acute rejection and outcome after cadaver renal trans-1517–1525, 1999plantation. Transplantation 59:962–968, 199539. Fassi A, Sangalli F, Colombi F, et al: Beneficial effects of calcium

63. Terasaki P, Gjertson D, Cecka M, et al: Significance of donorchannel blockade on acute glomerular hemodynamic changes in-age effect in kidney transplantation. Clin Transplant 11:366–369,duced by cyclosporine. Am J Kidney Dis 33:267–275, 1999199740. Campana C, Regazzi MB, Buggia I, et al: Clinically significant

64. Matas AJ, Gillingham K, Payne WD, et al: Should I accept thisdrug interactions with cyclosporine. Clin Pharmacokinet 30:141–kidney? Clin Transplant 14:90–95, 2000156, 1996

65. Strangaard S, Hansen U: Hypertension in renal allograft recipi-41. Dawidson I, Rooth P: Improvement of cadaver renal transplantents may be conveyed by cadaveric kidneys from older donorsoutcomes with verapamil: A review. Am J Med 90:375–395, 1991with subarachnoid hemorrhage. Br Med J 292:1041–1044, 198642. Kobashigawa JA, Katznelson S, Laks H, et al: Effect of pravas-

66. Gaber LW, Moore LW, Alloway RR, et al: Glomerulosclerosistatin on outcomes after cardiac transplantation. N Engl J Medas a determinant of post transplant function in older donor renal333:621–627, 1995allografts. Transplantation 60:334–338, 199543. Katznelson S, Wilkinson A, Kobashigawa JA, et al: The effect

67. Jerius JT, Taylor RJ, Murillo D, et al: Double renal transplantsof pravastatin on acute rejection after kidney transplantation: Afrom marginal donors: 2-year donor results. J Urol 163:423–425,pilot study. Transplantation 61:1469–1474, 1996200044. Ojo A, Hanson JA, Wolfe RA, et al: Long-term survival in renal

68. Remuzzi G, Grinyo J, Ruggenenti P, et al: Early experience withtransplant recipients with graft function. Kidney Int 57:307–313,dual kidney transplantation. J Am Soc Nephrol 10:2591–2595, 19992000

69. Pokorna E, Vitko S, Chadimova M, et al: Proportions of glomeru-45. Shapiro R, Nalesnik M, McCauley S: Post-transplant lympho-proliferative disease in adult and pediatric renal transplant patients losclerosis in procurement wedge renal biopsy cannot alone dis-


criminate for acceptance of marginal donors. Transplantation 69: 79. Nickerson P, Jeffery J, Gough JJ, et al: Beneficial effects of36–43, 2000 treatment of early subclinical rejection: A randomized study. J Am

70. Miles AM, Sumrani N, Horowitz R, et al: Diabetes mellitus after Soc Nephrol 10:1801–1806, 1999renal transplantation. Transplantation 65:380–384, 1998 80. Nickeliet V, Klimkait T, Binet IF, et al: Testing for polyoma

71. Stigant CE, Cohen J, Vivera M, et al: ACE inhibitors and angio- virus type BK DNA in plasma to identify renal allograft recipientstensin II antagonists in renal transplantation: An analysis of safety with viral nephropathy. N Engl J Med 342:1309–1315, 2000and efficacy. Am J Kidney Dis 35:58–63, 2000 81. Kasiske BL, Ramos EL, Gaston ES, et al: The evaluation of

72. Campistol JP, Inigo P, Jiminez W, et al: Losartan decreases plasma renal transplant candidates: Clinical practice guidelines. J Am Soclevels of TGFb1 in transplant patients with chronic allograft ne- Nephrol 6:1–44, 1995phropathy. Kidney Int 56:714–719, 1999 82. Gaston RS, Hudson SL, Ward M, Jones P, Macon R: Late renal

73. Massy ZA, Guijarro C, Wiederkehr MR, et al: Chronic renal allograft loss: Noncompliance masquerading as chronic rejection.allograft rejection: Immunologic and nonimmunologic risk factors. Transplant Proc 31(Suppl 4A):21–25, 1999Kidney Int 49:518–524, 1996 83. Rudman L, Gonzales MH, Borgida E: Mishandling the gift of

74. Halloran PF, Melk A, Barth C: Rethinking chronic allograft life: Noncompliance in renal transplant patients. J Appl Soc Psy-nephropathy: The concept of accelerated senescence. J Am Soc chol 29:4–9, 1999Nephrol 10:167–181, 1999 84. Terasaki PI, Cecka JM, Gjertson DW, et al: High survival rates75. De Mattos AM, Olyaei A, Bennett WM: Nephrotoxicity of im-

of kidney transplants from spousal and living unrelated donors.munosuppressive drugs: Long term consequences and challengesN Engl J Med 333:333–337, 1995for the future. Am J Kidney Dis 35:333–346, 2000

85. Hou S: Expanding the kidney donor pool. Kidney Int 58:1820–1836,76. Glicklich D, Gupta B, Schurter-Frey SM, et al: Chronic renal2000allograft rejection: No response to mycophenolate mofetil. Trans-

86. Shapiro AMJ, Lakey J, Ryan E, et al: Islet transplantation in sevenplantation 66:398–399, 1999patients with type I diabetes mellitus using a glucocorticoid-free77. Weir MR, Anderson L, Fink JC, et al: A novel approach toimmunosuppressive regimen. N Engl J Med 343:230–238, 2000the treatment of chronic allograft nephropathy. Transplantation

87. Li Y, Li XC, Zheng XX, et al: Blocking both signal 1 and signal34:1706–1709, 19972 of T-cell activation prevents apoptosis of alloreactive T-cells and78. Hutchinson I, Pravicia V, Sinnot P: Genetic regulation of cyto-induction of peripheral allograft tolerance. Nat Med 5:1298–1300,kine synthesis: Consequences for acute and chronic rejection. Graft

1:186–192, 1998 1999

immunosuppressive medications for renal transplantation: a multiple choice question

Documents