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2000年美国肾脏学会肾脏周热点 （2000-10）

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摘要：2000年美国肾脏学会肾脏周热点2000年10月13-16日加拿大多伦多HighlightsFrom2000AmericanSocietyofNephrologyRenal......

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2000年美国肾脏学会肾脏周热点

2000年10月13-16日

加拿大多伦多

Highlights From 2000 American Society of Nephrology Renal Week
October 13-16, 2000
Toronto, Canada

Flavio Vincenti, MD

 

Introduction

Renal transplantation accounts for an ever-increasing component of the practice of clinical nephrologists worldwide as they care for and make critical decisions regarding the outcomes of patients both before and after transplantation.

The American Society of Nephrology 33rd Annual Meeting and Scientific Exposition, attended by more than 10,000 physicians and scientists, provided a forum for dissemination of new information and ideas related to improvement of the care of people with kidney disease. A number of symposia and other presentations at this meeting addressed various aspects of renal transplantation, including the donor organ shortage, biopsy of the renal allograft, viral infection in renal transplant recipients, immunosuppressive agents, novel methods for diagnosing acute and chronic rejection, and predictors of immune events and outcomes posttransplantation. Selected presentations on these aspects of renal transplantation are summarized in this report.

Organ Shortage: A Global Problem

Currently, there is an organ donor shortage crisis in the United States. The number of patients on the cadaver waiting list has increased dramatically from 13,948 in 1988 to more than 46,000 at present. As of October 28, 2000 there were more than 72,000 people on the United Network for Organ Sharing (UNOS) national patient waiting list[1] (see Table), a number that is projected to increase by 20% annually. In 1999, 8026 patients -- only a fraction of those waiting, received transplants from cadaver kidney donors.

The average waiting time on the cadaver kidney waiting list at the present time is more than 3 years and is expected to increase to over 10 years by the year 2010.[2] Thus, according to William Harmon, MD,[3] of Children's Hospital, Harvard Medical School, Boston, Massachusetts, it is imperative to maximize organ donation.

The estimated potential cadaver donor pool is 55 donors per million population in the United States. However, the actual number of donors is less than half that, 25 per million. Limiting factors have been identified:

Thus, efforts must be made to bring the actual closer to the potential.

The number of cadaver donors varies widely among countries. Cadaver donation rates in North America are contrasted with those in Spain, the world leader, below.

  Spain United States Canada Cadaver donors 31.5 22.7 13.7 Living donors .5 15.8 12.0

Spain has the highest rate of donation in the world. The Organizaciòn Nacional de Transplantes coordinates and monitors activities at all transplantation centers in Spain. The presumed consent legislation that has been enacted in Spain and the financial incentive payments that are being distributed to donor families and productive transplantation centers are important factors in that country's success.

Strategies for Meeting the Demand for Donor Organs

In the United States, where individual liberties supersede the needs of the society, it is unlikely that presumed consent laws will be enacted. Roy First, MD,[3] of the University of Cincinnati, Ohio, suggested that the following alternative strategies may need to be employed[4]: implementing a model similar to the Spanish model in which organ procurement is more centrally coordinated; changing organ allocation policies, with the possibility of rationing organs; increasing live donation rates (which already comprise 31% of all kidney transplants in the United States); using non-heart beating donors (NHBDs); age matching for elderly recipients; using dual kidneys when the donor is considered marginal[5]; and expanding kidney donor selection criteria[6] to include donors who have a history of malignancy or who are:

More controversial solutions -- such as the state financial incentive program for living donors that has been implemented in Iran, China's use of organs from executed criminals, and treating donation as an industry -- were briefly mentioned.

Organs From Executed Chinese Prisoners

The transplantation of organs from executed prisoners is routinely practiced in Mainland China. Arguments against the use of executed prisoners' organs include the possibility that the death sentence or the execution might be manipulated for the express purpose of obtaining organs.[7] Although the reason for this concern is obvious, there is no hard evidence in this regard. Others support the use of executed prisoners' organs for transplantation, arguing in favor of its potential benefit of providing organs for the greater good of society and the opportunity for prisoners to "repay" their debts to society.

Expanded Donor Criteria: Is There a Price to Pay?

Persons with end-stage kidney disease comprise the largest group in need of an organ transplant. However, no significant growth in kidney donation has occurred over the past decade.[8] The impact of expanding the donor pool on renal transplant function was addressed by was Emilio Ramos, MD,[3] of the University of Maryland Hospital, Baltimore. The outcomes of renal transplantation from NHBDs, donors with a history of hypertension, and donors with vascular abnormalities such as aneurysms, fibromuscular disease, and multiple arteries were discussed. As the shortage grows and evidence accumulates in support of selective use of marginal and expanded criteria donors, transplant physicians may need to reevaluate current standards for donor acceptance.

In donors with impaired renal function, transplantation of dual kidneys has resulted in acceptable long-term renal function. Delayed graft function is rare in kidneys procured via the open surgical approach; the incidence is higher in laparoscopically procured kidneys. At the University of Maryland, the current incidence of delayed graft function is 6% in laparoscopically retrieved kidneys. Living donors who undergo laparoscopic nephrectomies typically report less pain, an earlier return to normal activity, less extensive scarring postoperatively when compared with donors who undergo conventional surgery, and shorter hospital stays.[8] At the University of Maryland, most living donors spend no more than 60 hours in the hospital.

Long-Term Outcome and Organ Senescence

Donor age is a major determinant of graft outcome and events surrounding brain death, and procurement of organs from cadaver donors may lead to accelerated nephron senescence, according to Philip Halloran, MD,[3] of the University of Edmonton, Canada. Understanding the pathophysiology of organ senescence could lead to future interventions to minimize injury, accelerated glomerular senescence, and the irreversible progression of chronic transplant nephropathy.

The impact of donor age on outcome is more striking in recipients of cadaver kidneys than in live donor recipients.[9] Kidneys from older donors show poorer immediate function, lower glomerular filtration rates, are associated with more acute rejection, and have lower graft survival. In the review of causes of liver transplantation graft loss, Dr. Halloran noted that death with a functional graft accounts for 50% of losses, while chronic allograft dysfunction accounts for about 40% of late graft losses.

New Insights and Controversies in Renal Allograft Pathology

New research has questioned whether findings from renal biopsies are predictive of allograft clinical outcomes. According to Lorraine Racusen, MD,[10] of John Hopkins Hospital, Baltimore, Maryland, kidney biopsies are performed for 3 reasons: (1) after transplantation for cause, when rejection is clinically suspected; (2) after transplantation as part of a clinical or research protocol; and (3) to establish baseline information on the donor kidney.

Kidney Biopsy for Cause

In patients who undergo kidney biopsy for cause and are found to have rejection, reversal of the rejection is clearly dependent on the histologic severity. Grade 1 rejection (no evidence of vasculitis) is reversible in 93% of patients, while grade 3 rejection is reversible in only 50%. To categorize a kidney biopsy as grade 1, the specimen should have at least 4 arteries in the core to minimize the likelihood that vasculitis is not missed due to sampling error. When grade 1 rejection is diagnosed from such a specimen, the response to corticosteroids is good. Biopsy features associated with poorer outcome include the presence of eosinophils and/or macrophages, signifying possible progression from acute to chronic rejection, and the presence of plasma cells.

The Protocol Kidney Biopsy

Protocol biopsies of stable, well-functioning renal allografts reveal a high prevalence (30% in the first 3 months by the Banff criteria[11]) of clinically unsuspected acute and chronic pathology. According to Dr. Racusen, if these histopathologic findings are both pathogenic and predictive of long-term allograft outcome, they can uncover and allow for the early treatment of subclinical rejection. Therefore, although invasive, protocol biopsies may be indicated for optimal posttransplant surveillance until noninvasive methods are available.

A study by Rush and The Winnipeg Transplant Group[12] was performed to determine whether the treatment of subclinical rejection with corticosteroids improved outcomes in renal transplant recipients. Patients were randomized either to no protocol biopsy or to protocol biopsy at 1, 3, 6, and 12 months; patients were treated if they were found to have subclinical rejection based on histologic findings. At 24 months, patients in the treatment group had better outcomes than patients in the control group. Treatment of subclinical rejection with corticosteroids decreased late clinical rejections and improved graft function at 2 years.

Implantation Kidney Biopsy

Although biopsy of the procurement or implantation kidney biopsy is considered valuable, there is no consensus on the relationship of the presence of various histologic abnormalities (ie, hyaline arterial changes, glomerulosclerosis, and fibrosis) with delayed graft function and final outcome.

Abdi and colleagues[13] assessed the impact of glomerular maximal planar area (MPA) in baseline biopsy specimens of 96 human renal allografts on later graft function. They found that larger glomeruli at baseline provided an early predictor of risk for late allograft dysfunction. Pokorna and colleagues[14] prospectively evaluated the potential of the implantation renal biopsy as an instrument for expanding the criteria for acceptance of marginal donors. Two hundred consecutive donors (387 renal grafts) were evaluated for proportion of glomerulosclerosis, vascular and tubular changes, and interstitial fibrosis. The percentage of glomerulosclerosis correlated with posttransplantation renal function. However, when age was taken into account, the correlation was not statistically significant. Furthermore, glomerulosclerosis up to 25% or more was associated with an acceptable 3-year graft survival rate of 74.7%. Thus, the implantation biopsy provides only limited information regarding donor acceptability and selection. However, Dr. Racusen reported from her studies of implantation donor biopsies that the presence of increased glomerular size (just suggesting hypertrophy because of reduced renal mass) may correlate with poor outcome after transplantation.

Viral Infections in Renal Allograft Recipients

Updates on 2 viral infections associated with the renal allograft, cytomegalovirus (CMV) and polyomavirus infection, were presented by Volker Nickeleit, MD,[10] of the University of Basel, Basel, Switzerland. The prevalence of CMV infection in the renal allograft is quite rare, less than 0.3%.

Polyomavirus

More important is the recent emergence of the polyomavirus type BK infection in the renal allograft. The polyomavirus manifests as a latent infection in uroepithelial cells and appears to be reactivated in the setting of intense maintenance immunosuppressive therapy, particularly with tacrolimus (TAC). The diagnosis of polyomavirus infection in the renal allograft was initially described in 1995; the prevalence is about 4.5% and the infection typically occurs at about 10 months after transplantation.

Polyomavirus infection in the renal allograft is limited to the collecting system. Thus, patients may present with either increasing serum creatinine levels or ureteral obstruction. Patients at risk are identified by the presence of cells containing viral inclusion bodies (decoy cells) in the urine or by biopsy of allograft tissue. However, only 27% of patients with decoy cells in the urine have renal polyomavirus infection. The use of polymerase chain reaction for detecting polyomavirus DNA in plasma is a sensitive and specific method for identifying polyomavirus nephropathy in renal transplant recipients.[15] As with other viral reactivation infections, there is no treatment for polyomavirus infection except reducing the immunosuppression therapy.

Hepatitis C Virus (HCV) Infection

The high prevalence of HCV infection presents a challenge in organ donor selection. It has been recommended that the use of HCV-positive kidneys be restricted to HCV RNA-positive recipients, but long-term follow-up of outcomes with this policy is lacking. Dominguez-Gill and associates[16] analyzed the long-term outcome of a group of HCV RNA-positive patients who received a kidney from an HCV-positive donor (group 1, n = 61) to that of a group of HCV-positive patients who received a kidney from an HCV-negative donor (group 2, n = 97). The mean follow-up was approximately 3.5 years. There were no significant differences between group 1 and group 2 with regard to the percentage of recipients who were HCV RNA positive, or with regard to evolution to severe chronic liver disease. No death occurred from liver disease in either group. Graft survival was 82% and 85% and patient survival was 89% and 93% in groups 1 and 2, respectively. These results strongly support transplanting kidneys from HCV-positive donors into HCV RNA-positive recipients.

Immunosuppression in Transplantation: Lessons Learned From Recent Clinical Trials

A number of current biologic agents are currently used for induction therapy for renal transplantation: the polyclonal agents antithymocyte globulin and thymoglobulin; the murine anti-CD3 monoclonal antibody, OKT3; and the new anti-interleukin-2 (IL-2) monoclonal antibodies -- basiliximab, a chimeric antibody, and daclizumab, a fully humanized antibody. Daniel Abramowicz, MD,[17] of the Hospital Erasme, Brussels, Belgium, reviewed a report of 2 meta-analyses by Szczech and colleagues,[18] which showed that patients treated with antilymphocyte antibody induction biologic agents had significantly better graft outcomes at 2 years compared with patients who received induction therapy with cyclosporine (CsA), azathioprine, and prednisone. Induction therapy was particularly beneficial among patients with pretransplantation panel-reactive antibodies (PRA) greater than 20%.

He also reviewed the study by Kirkman and colleagues[19] utilizing daclizumab, mycophenolate mofetil (MMF), CsA, and prednisone as well as the recent trial by Lawen[20] utilizing basiliximab, CsA, MMF, and prednisone. In this prospective randomized trial, patients treated with quadruple therapy had a biopsy-proven rejection rate to 26.6% vs 15.3% for patients treated with CsA, MMF, and prednisone.

Dr. Abramowicz concluded that for patients who are at high immunologic risk (ie, patients with high PRA or retransplants who rejected the first kidney early after transplantation), the optimal induction therapy agents are the polyclonal antibodies or OKT3. Patients with moderate risk factors such as African American race, young age, and transplantation with kidneys with prolonged cold ischemia time or HLA-mismatched recipient-donor pairs respond well to the anti-IL-2 monoclonal antibodies and experience minimal toxicities. Patients with low immunologic risk may not require any therapy with these biologic agents unless they are treated with corticosteroid or calcineurin inhibitor-sparing regimens.

Strategies for Sparing of Calcineurin Inhibitors and for Steroid Withdrawal

The introduction of calcineurin inhibitors (first and most notably CsA, then TAC) greatly reduced the incidence of acute rejection and dramatically improved 1-year allograft survival rates. However, these therapies have had little effect on the rate of late allograft failure, and are associated with a variety of serious immune and nonimmune drug toxicities.

Corticosteroids or glucocorticosteroids have been used in clinical transplantation since the 1960s. These drugs exhibit a wide range of effects on almost every phase of the immune and inflammatory response; they have a profound effect on the concentration of peripheral leukocytes. Long-term use of corticosteroids has been associated with significant side effects leading to considerable morbidity: hypertension, hyperlipidemia, diabetes mellitus, opportunistic infection, osteoporosis, Cushing's syndrome, acne, striae, hirsutism, cataract formation, and growth retardation in prepubertal children. In response to long-term effects, various attempts have been made at immunosuppressive regimens that minimize or eliminate calcineurin inhibitors or corticosteroids altogether.

Flavio Vincenti, MD,[17] of the University of California at San Francisco, summarized studies of steroid withdrawal late after transplantation. In summary, the advantages of complete avoidance or very early withdrawal of corticosteroids after transplantation are as follows:

The most recently published study of steroid withdrawal in renal transplantation included patients treated with CsA, MMF, and prednisone who had no rejection at 3 months.[21] Patients were randomized in a double-blind fashion to continue prednisone therapy or to discontinue prednisone over the next 2 months. The study was stopped by the trial's Data Safety and Monitoring Board when enrollment had reached 266 patients because of a statistically increased incidence of rejection (Kaplan-Meier projections were 30% vs 10% in the maintenance group) early in the trial period in the group randomized to steroid withdrawal. However, after a closer analysis of the data, it was determined that African Americans were the group at most risk for rejection following steroid withdrawal. The risk of rejection was significantly higher (P < .001) in blacks (39.6%) than in nonblacks (16.0%). At 1 year posttransplantation, however, there were no differences between the groups with regard to graft and patient survival. The most important conclusion from this study was that steroid withdrawal late after transplantation in non-African American patients with no history of rejection who receive triple immunosuppressive therapy was safe and was associated with benefits such as reduced serum lipid levels and less need for antihypertensive medications.

Newer anti-IL-2 antibodies have long half-lives and prolonged biologic effects, making them ideal agents to be used in steroid elimination or early withdrawal regimens after transplantation. In a multicenter, open-label, Canadian trial, 57 recipients of cadaveric or living-donor kidneys were treated with daclizumab 1 mg/kg preoperatively and at 4 weekly intervals thereafter, CsA 8-10 mg/kg/day, and MMF 2 g; they received no corticosteroids.[22] Twenty-six percent of patients had delayed graft function. At 1 year, the rejection rate was 25%; the majority of rejection episodes occurred in the first 3 months, and all except 1 rejection episode was reversed with corticosteroids. There were no graft losses from rejection.

In another randomized, prospective, multicenter trial using CsA, MMF, and basiliximab 20 mg preoperatively and 20 mg on day 4 posttransplantation,[23] patients were randomized to treatment with either conventional maintenance doses of corticosteroids or corticosteroid therapy for only 1 day preoperatively and at 4 days posttransplantation, after which corticosteroids were completely discontinued. Forty patients were randomized to the steroid withdrawal group, and 43 patients were randomized to the conventional steroid group. At 1 year, the biopsy-proven rejection rate was not significantly different between the 2 groups -- 20% in the steroid withdrawal group vs 18% in the steroid maintenance group. All rejection episodes in the steroid withdrawal group were mild and were reversed with corticosteroids.

The conclusion from these studies is that in low-risk patients, induction with an anti-IL-2 antibody allows avoidance or very rapid elimination of corticosteroids soon after transplantation with an excellent outcome. However, longer-term follow-up of these studies is still required.

Sparing Calcineurin Inhibitors

Calcineurin inhibitors, although effective immunosuppressive agents, are associated with appreciable graft dysfunction and a high incidence of chronic transplant nephropathy. Two recent studies utilizing regimens that eliminated calcineurin inhibitors were reviewed. In a randomized, multicenter, European trial by Kreis and colleagues,[24] 80 patients were randomized to receive either CsA, MMF, and corticosteroids; or sirolimus, MMF, and corticosteroids. At 1 year, the rejection rate was 18% in the CsA-treated group vs 27% in the sirolimus-treated group. The rejection episodes in the sirolimus-treated group were moderate to severe (10 of 11 were grade 2). Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between the sirolimus and CsA groups, whereas safety profiles were different; more than 40% of sirolimus-treated patients had to discontinue the regimen at 1 year due to thrombocytopenia and diarrhea.

A multicenter, open-label trial evaluating a regimen of daclizumab, MMF, and corticosteroids in patients receiving primary renal transplants from cadaver or living donors was reported.[25] Ninety-eight patients were enrolled; 75% received kidneys from cadaveric donors. At 6 months, the biopsy-proven rejection rate was 48%; rejection occurred at a median of 39 days posttransplantation. The majority of rejection episodes were reversed with corticosteroids. One-year patient and graft survival were 97% and 96%, respectively. The mechanism of rejection was unclear, since lymphocytes obtained from the circulation as well as the graft at the time of rejection showed complete saturation of the IL-2 receptor. Dr. Vincenti speculated that rejection may have occurred through activation of T cells by other cytokines such as IL-7 or IL-15.

A new immunosuppression protocol currently being used at the University of California at San Francisco combines daclizumab, sirolimus, MMF, and corticosteroids. This regimen may be especially beneficial in patients with delayed graft function. Two of the 14 patients treated with this regimen had acute rejection, and both had subtherapeutic levels of sirolimus.

Generic Formulations of Immunosuppressive Agents

Substitution of generic immunosuppressive agents in organ transplant recipients has raised serious concerns among transplant physicians. Hal Heldermann, MD,[17] of Vanderbilt University, Nashville, Tennessee, reviewed the various formulations of CsA, including the 2 generic formulations currently on the market, and the problems associated with random CsA substitution. Since CsA has a narrow therapeutic index, small changes in bioavailability can result in important clinical adverse events. CsA is characterized by a narrow therapeutic range, high intra-individual variability, formulation-dependent bioavailability, and serious consequences for under- or overdosing. U.S. Food and Drug Administration (FDA) bioequivalent guidelines are available and include important information on drug and disease interactions, patient characteristics, and inactive ingredients.[26] Furthermore, pharmacokinetic studies in healthy individuals may not be reflective of effects in transplant recipients. Dr. Heldermann made the following recommendations: (1) patients should be maintained on a consistent drug formulation rather than being switched from one formulation to another; (2) pharmacists should notify physicians and patients if they switch immunosuppressant formulations; and (3) physicians should report adverse events from drug switching to the FDA. Most importantly, multiple switches among the different formulations of CsA should be avoided.

Therapeutic Bioequivalence

The FDA uses established criteria to determine whether 2 drugs are therapeutically equivalent and thus interchangeable in all patients: (1) pharmaceutical equivalence (ie, the 2 drugs contain the same dose of the same drug in the same form); (2) proven to be bioequivalent in 18-36 healthy young subjects, usually male. The current statistical standard for bioequivalence is that the confidence interval of the difference between the log-transformed means of the biopharmaceutical parameters area-under-the-time concentration curve (AUC) and peak concentration (Cmax) for the 2 products must be between - 20% and + 25%. M. Roy First, MD,[17] of the University of Cincinnati, Cincinnati, Ohio, reviewed his work on Gengraf, an oral capsule formulation of CsA.

His first study was a pharmacokinetic conversion study in stable renal transplant recipients who were 6 months posttransplantation. The study design was as follows: an initial screening period followed by 2 weeks of twice-daily dosing with Neoral, followed by 2 weeks of twice-daily dosing with Gengraf, and finally, 1 week of twice-daily dosing with Neoral. Twelve-hour pharmacokinetic studies were obtained on treatment days 1, 14, 15, 28, and 29. Results from 21 patients were that the pharmacokinetics (Cmax, time to reach Cmax [Tmax], trough level [Ctrough], and AUC) of Gengraf were identical to the pharmacokinetics of Neoral when patients were switched from Neoral to Gengraf and back to Neoral on a 1:1 basis. Thus, these drugs appear to be fully interchangeable.[27]

The second study is a 6-month, open-label study conducted at 22 transplant centers in the United States.[28] The study included 101 de novo, unsensitized renal transplant recipients receiving primary grafts from cadaver or living donors. Patients were randomized 1:1 to receive twice-daily dosing of either Gengraf or Neoral as part of their triple immunosuppressive regimen, including MMF and prednisone. A total of 75 subjects completed the study (39 Gengraf-treated and 36 Neoral-treated patients), with no differences between groups regarding reasons for discontinuation of the study. There was no difference in the mean CsA trough levels, adverse-event profiles, number of episodes of acute rejection, or graft survival for that period between subjects treated with Gengraf and those treated with Neoral.

Recently, a new CsA soft-gel capsule was approved in the United States as a generic equivalent of Neoral. To date, however, no data on this drug have been published. Approval was based on a 3-way, single-dose, bioequivalence fed study in 18 healthy volunteers. The new drug showed equal bioequivalence and complete interchangeability with Neoral. However Dr. First reiterated the need for pharmacists to inform patients and physicians prior to any switch in CsA formulation and the need for patients to be monitored carefully after such switching.

Serial Monitoring of Urine as a Noninvasive Approach to Diagnosing Allograft Rejection

Macrophage migration inhibitory factor (MIF) is an important mediator of the cellular immune response and is upregulated locally in human and experimental renal allograft rejection. Urine MIF levels measured by enzyme-linked immunosorbent assay (ELISA) were monitored in 9 patients after renal transplantation.[29] Immediately posttransplantation, the urine MIF level was elevated compared with that of normal volunteers. Five patients had an uncomplicated course; in these patients, a fall in urine MIF level paralleled a fall in serum creatinine level. By contrast, 4 patients with biopsy-proven acute rejection had an increase in the urine MIF level that occurred prior to the increase in the serum creatinine level. In a separate study, the urine and serum MIF levels were assessed in 23 renal transplant patients.[29] An increase in the urine MIF level was seen in patients with acute rejection (440 +/- 32 pg/micromol creatinine, mean +/- SD) when compared with normal volunteers (96 +/- 1960, P < .001) and patients with CsA nephrotoxicity (145 +/- 12, P < .01). The authors concluded that increased urine MIF levels in acute rejection suggest that monitoring of individual patients could be useful to differentiate between acute rejection from nephrotoxicity and acute rejection from calcineurin inhibitors.

Hartono and colleagues[30] tested the hypothesis that increased expression of mRNA, including perforin and granzyme B in urine cells, would distinguish acute rejection from other allograft diagnoses. Urine samples from 151 patients with different histologic diagnoses were analyzed. Urinary mRNA levels were reported as log fg/ug RNA. Patients with acute rejection had significantly higher levels of perforin and granzyme B. The authors suggested that noninvasive diagnosis of acute rejection in renal allografts is feasible by quantification of cytotoxic genes in urinary cells. Whether serial monitoring of these genes precedes the onset of rejection and can be used to predict patients at risk of rejection remains to be determined.

A study by Wang and colleagues[31] measured the level of TGF-beta1 expression in urinary cells to establish a noninvasive method for the diagnosis of renal allograft rejection. Urine samples were collected from renal transplant patients at the time of kidney biopsy. Patients were divided into 3 groups according to clinical as well as histologic diagnosis: (1) chronic rejection, n = 13; (2) acute rejection, n = 8; and (3) no rejection, n = 10. TGF-beta1 expression was highest in patients with chronic rejection and lowest in patients without rejection. The authors concluded that levels of TGF-beta1 expression in the urine can be used to diagnose chronic renal allograft rejection. This test could also be used as a surrogate marker for chronic transplant nephropathy.

Cytokine or Receptor Gene Polymorphism

One of the most challenging and promising areas of genetics and transplantation is the potential role of cytokine or receptor gene polymorphisms as predictors of immune events. Cytokine single nucleotide polymorphisms were determined by sequence-specific primers on genomic DNA of renal allograft recipients (n = 118).[32] The frequencies (%) of low, intermediate, or high phenotype expression were as follows: TNF-alpha (75, 25, 3), IL-10 (51, 57, 12), IFN-gamma (44, 41, 15), and TGF-beta (1, 12, 87). Multivariate logistic regression modeling was used to determine the adjusted odds ratio (OR) at 95% confidence interval for the risk of recurrent early rejection, recurrent late rejection, and vascular rejection. The risk of early recurrent rejection was greatest when phenotype expression was high and lowest when phenotype expression was low for IFN-gamma and TNF-alpha. The risk of late recurrent rejection was greatest when phenotype expression was high and lowest when phenotype expression was low for TNF-alpha and TGF-beta; in addition, the risk was lowest when phenotype expression was high and greatest when phenotype expression was low for TGF-beta. The risk of vascular rejection was greatest when phenotype expression was high and lowest when phenotype expression was low for TNF-alpha.

In conclusion, the authors found that high TGF-beta phenotype is protective, while high IFN-gamma, TNF-alpha, and IL-10 phenotypes are predictors of adverse outcomes. Cytokine genotypic analyses identified individuals who may benefit from more intense surveillance and treatment early posttransplantation. In the future, immune therapy could be individualized based on the cytokine genetic profile of the patient.

Chemokines regulate movement of inflammatory cells, including T cells, into allografts. A 32 bp deletion of the chemokine receptor CCR5 (CCR5 32) renders it nonfunctional, while a nucleotide substitution variant of CCR5 (a g 59029) is associated with slower progression of HIV disease. Furthermore, the T-cell receptor alpha chain genotype (a g) is associated with a high rate of renal failure in patients with IgA nephropathy. The impact of these variants was assessed in 166 patients transplanted over a 5-year period.[33] The results from the analysis showed that acute rejection rates were twice as high in individuals who were heterozygous or homozygous for CCR5-59029. There was also a significant trend toward a higher incidence of acute rejection with higher gene doses of TCR-alpha (G) variant. There was no increased risk of rejection as a function of the presence of the CCR5 32 variant.

The chemokine receptor CCR5 mediates effect of chemokines RANTS, mip-1 alpha, mip-1 beta, and mcp-2. At 5 centers, 1218 patients were screened for the 32 mutation with PCR DNA isolated from peripheral blood.[34] Graft survival was calculated for patients with and without 32/ 32 mutation. Of 20 patients with the 32// 32 mutation, only 1 lost graft function during follow-up. The calculated graft half-life was approximately 48-57 years, vs 17 years for patients with normal CCR5. The authors concluded that patients homozygous for the 32 mutation for CCR5 show an improved outcome after renal transplantation.

Pharmacokinetics of Immunosuppressive Agents

MMF is routinely administered in a fixed daily dose regimen (usually 2 g/day), although there has not been a correlation between this fixed dose and clinical outcome. Cattaneo and associates[35] examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring of mycophenolic acid (MPA), the active metabolite of MMF, in 25 stable kidney transplant patients. Despite a comparable MMF dose, large interindividual variability in both MPA area AUC and in Ctrough were found. Both MPA AUC and Ctrough positively correlated with patients' creatinine clearance, but not with a given dose. Patients with AUC greater than 40 mcg/mL showed better renal function than patients with lower AUC (serum creatinine 1.2 +/- 0.2 vs 1.48 +/- 0.3 mg/dL, P < .05), despite no difference in CsA dose or levels. Free plasma MPA, but not total MPA, correlated with the risk of toxicity. The authors concluded that these findings suggest the need for therapeutic drug monitoring to optimize MMF dosing.

The requirement of monitoring of MPA plasma concentration to improve efficacy in patients taking MMF has not been well established. The purpose of the study by Wong and colleagues[36] was to assess the pharmacokinetic profiles of MPA in 124 kidney transplant recipients receiving a standard dose (1-2 g) or a low dose (< 1 g) of MMF, and to correlate the profiles with toxicity and efficacy. In addition to MMF, patients were receiving tapering doses of prednisone in conjunction with either CsA or TAC. Blood samples were obtained at Ctrough or 1-2 hours after an oral dose of MMF. Blood samples were also obtained early after transplantation and at every clinical event such as rejection or occurrence of side effects. There was great variability of MPA trough levels among the renal transplant patients. The standard-dose group had a higher Ctrough than the low-dose group (2.95 +/- 1.8 mcg/mL vs 1.212 +/- 0.9 mcg/mL, P < .05). Although no differences were observed in the MPA trough levels, peak and MPA concentrations during the first 2 hours after the oral dose were associated with an increased risk of side effects. Six patients experienced acute rejection after reduction of the MMF oral dose. The Ctrough in these patients was lower than in patients receiving standard doses of MMF (0.85 +/- 0.5 mcg/mL vs 2.95 +/- 1.8 mcg/mL, P < .05). The authors concluded that these data illustrate the importance of therapeutic drug monitoring in order to optimize clinical efficacy of MMF therapy.

SDZ-RAD

SDZ-RAD 40-O-(2-hydroxyethyl)-rapamycin is a novel macrolide immunosuppressant currently under investigation. A multicenter, double-blind, randomized trial assessed the safety and efficacy of a 3-dose regimen of RAD (1 mg, 2 mg, or 4 mg per day) in 103 de novo renal transplant patients receiving Neoral and corticosteroids.[37] One-year patient and graft survival were excellent: 95% and 92%, respectively. Efficacy failure as defined by the composite end point of biopsy-proven acute rejection, graft loss, and patient death or loss to follow-up was 43%, 29%, and 29% in the 1 mg per day, 2 mg per day, and 4 mg per day groups, respectively. The incidence of acute rejection at 1 year was lower in the 2 mg per day and 4 mg per day groups (21% and 29%, respectively) compared with the 1 mg per day group (38%). The immunosuppressive activity of RAD was further confirmed by a significant reduction in the severity of acute rejection in the 4 mg per day group compared with the 1 mg per day group (P = .05). The authors concluded that RAD was safe and well tolerated with excellent patient and graft survival at 1 year. The safety and efficacy of RAD is being further evaluated in phase 3 clinical trials.

Table. UNOS National Patient Waiting List 10/28/00[1]

Type of Transplant Patients Waiting for Transplant Kidney 46,803 Liver 16,423 Pancreas 971 Pancreas islet cell 147 Kidney-pancreas 2,426 Intestine 133 Heart 4,114 Heart-lung 217 Lung 3,638 Total 72,585* NOTE: UNOS policies allow patients to be listed with more than 1 transplant center (multiple-listing); thus, the number of registrations is greater than the actual number of patients.
*Some patients are waiting for more than 1 organ; therefore, the total numberof patients is less than the sum of patients waiting for each organ.

Dr. Vincenti is a Professor of Clinical Medicine at the University of California, San Francisco.

References

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