Deceased donor kidney transplantation in elderly patients: is there a difference in outcomes?

INTRODUCTION: There is a paucity of data on long-term outcomes of older kidney recipients. Our aim was to compare the early and long-term outcomes of deceased donor kidney transplantation in patients aged >or=60 years with outcomes in younger recipients. MATERIALS AND METHODS: From 1998 to 2005, we performed 271 deceased donor kidney transplants. There were 76 recipients (28.1%) >60 years old. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. Demographic data, including clinical characteristics, early complications, mortality, and patient and graft survival rates, were collected and analyzed. RESULTS: Older patients had comparable perioperative mortality and morbidity, incidence of delayed graft function (DGF), length of stay, and readmissions compared with younger patients. The rates of acute rejection and major infections were also comparable between the 2 study groups. Among older recipients, 25/76 (32.1%) patients received extended criteria donor kidneys compared with only 35/195 (17.9%) of younger patients (P < .001). Nevertheless, equivalent 1-, 3-, and 5-year allograft survival rates were observed in elderly and young patients; 91.5% versus, 92.5%, 78.5% versus 81.9%, and 75.6% versus 78.5%, respectively. Overall patient survival was also comparable in both groups. CONCLUSION: Kidney transplantation in appropriately selected elderly recipients provides equivalent outcomes compared with those observed in younger patients. These observations support the notion that older recipients should not lose access to deceased donor kidney transplantation in the effort to achieve a perceived gain in social utility.

Outcome of kidney transplantation using expanded criteria donors and donation after cardiac death kidneys: realities and costs.

Expanded criteria donors (ECDs) and donation after cardiac death (DCD) provide more kidneys in the donor pool. However, the financial impact and the long-term benefits of these kidneys have been questioned. From 1998 to 2005, we performed 271 deceased donor kidney transplants into adult recipients. There were 163 (60.1%) SCDs, 44 (16.2%) ECDs, 53 (19.6%) DCDs and 11 (4.1%) ECD/DCDs. The mean follow-up was 50 months. ECD and DCD kidneys had a significantly higher incidence of delayed graft function, longer time to reach serum creatinine below 3 (mg/dL), longer length of stay and more readmissions compared to SCDs. The hospital charge was also higher for ECD, ECD/DCD and DCD kidneys compared to SCDs, primarily due to the longer length of stay and increased requirement for dialysis (70,030 dollars, 72,438 dollars, 72,789 dollars and 47,462 dollars, respectively, p < 0.001). Early graft survival rates were comparable among all groups. However, after a mean follow-up of 50 months, graft survival was significantly less in the ECD group compared to other groups. Although our observations support the utilization of ECD and DCD kidneys, these transplants are associated with increased costs and resource utilization. Revised reimbursement guidelines will be required for centers that utilize these organs.

Putative antibody-mediated rejection with C4d deposition in HLA-identical, ABO-compatible renal allografts.

We sought evidence for non-MHC antibody-mediated rejection in renal allografts by a systematic study of rejected HLA-identical sibling renal allografts. Among 162 recipients of HLA-identical, ABO-compatible sibling donor kidneys transplanted at the Massachusetts General Hospital from 1964 to 2005, we identified 15 grafts that were lost from rejection and two additional grafts with reversible acute rejection, which provided 30 samples for study. All samples were stained for C4d by immunofluorescence in frozen tissue (n = 7) or by immunohistochemistry in paraffin embedded tissues (n = 10). We found that two of 17 grafts had positive C4d staining of peritubular capillaries. Histology revealed acute antibody-mediated rejection in one and acute cellular rejection type 1 in the other. Both grafts were matched at HLA-A, B, and C loci and had a nonreactive mixed lymphocyte response. Genotyping and serological analysis were not available. Compared with a published series, C4d+ irreversible rejection was more common in HLA nonidentical than HLA-identical grafts (75% vs 6.7%, respectively, P < .002). We conclude that antibody-mediated rejection, presumably due to non-MHC antigens other than ABO-blood groups does occur, but infrequently. This may account for some of the HLA antibody negative cases that develop antibody-mediated rejection.

BK virus in solid organ transplant recipients: an emerging syndrome.

BK virus is a human polyomavirus associated with a range of clinical presentations from asymptomatic viruria with pyuria to ureteral ulceration with ureteral stenosis in renal transplant patients or hemorrhagic cystitis in bone marrow transplant recipients. Infection of renal allografts has been associated with diminished graft function in some individuals. Fortunately, however, the majority of patients with BK virus infections are asymptomatic. The type, duration, and intensity of immunosuppression are major contributors to susceptibility to the activation of BK virus infection. Histopathology is required for the demonstration of renal parenchymal involvement; urine cytology and viral polymerase chain reaction methods are useful adjunctive diagnostic tools. Current, treatment of immunosuppressed patients with polyomavirus viruria is largely supportive and directed toward minimizing immunosuppression. Improved diagnostic tools and antiviral therapies are needed for polyomavirus infections.

Human leukocyte antigen matching in renal transplantation: an update.

Cadaveric kidney allocation, in most countries, is based on human leukocyte antigen matching of the donor kidney with the recipient. Traditional human leukocyte antigen matching is based on defining human leukocyte antigen specificities by antibodies. Newer techniques have emerged from the tissue typing laboratory, which challenge the accuracy of serological typing and crossmatching. Improvements in renal allograft survival, predominantly as a result of newer immunosuppressive drugs, have led to longer survival times even in poorly matched human leukocyte antigen renal allografts. The scarcity of donor organs has focused attention on organ allocation policies, and the exact role of human leukocyte antigen matching in renal transplantation is under scrutiny. In this review, we examine developments in human leukocyte antigen matching as well as attempts to utilize this information to allocate cadaveric kidneys optimally.

IFN regulatory factor-1 plays a central role in the regulation of the expression of class I and II MHC genes in vivo.

Transcription factor interferon regulatory factor-1 (IRF-1) is implicated in regulating class I MHC expression in vitro. We investigated the in vivo relationship between IRF-1 and MHC expression in kidney and other nonlymphoid organs, assessing MHC expression in mice with disrupted IRF-1 genes (IRF-1 KO) compared with mice with intact IRF-1 genes (WT). In kidneys of IRF-1 KO mice, basal class I expression was decreased, particularly on arterial endothelium, but basal class II expression was unchanged. The induction of both class I and class II expression by injected rIFN-gamma was reduced in IRF-1 KOs, compared with WT mice. Similarly, stimuli that induce endogenous IFN-gamma production (LPS or oxazolone) massively increased MHC expression in kidneys of WT mice, with little increase in IRF-1 KO mice. Impaired class II induction by rIFN-gamma in IRF-1 KO mice probably reflects the role of IRF-1 in regulating class II transactivator (CIITA) expression: rIFN-gamma induced CIITA mRNA less in kidneys of IRF-1 KO mice than in WT mice. In organs of WT mice, IRF-1 mRNA was expressed in the basal state, and rIFN-gamma treatment increased IRF-1 mRNA before the induction of class I or CIITA mRNA. Treatment of WT mice with cycloheximide plus rIFN-gamma superinduced IRF-1 mRNA expression, but partially inhibited CIITA mRNA expression, indicating that IRF-1 mRNA induction is not dependent on new protein synthesis, unlike CIITA. Thus, in vivo, IRF-1 plays a major role in basal and induced class I expression and in induction of class II by IFN-gamma, probably via CIITA induction.

In vivo class II transactivator expression in mice is induced by a non-interferon-gamma mechanism in response to local injury.

BACKGROUND: Tissue injury induces MHC class II expression, which could be important in the recognition of that tissue as an allograft. The class II transcriptional activator (CIITA) is the major regulator of basal and induced MHC class II expression and is essential for antigen presentation. The role of CIITA in the induction of class II by tissue injury is unknown. In this study, we examined CIITA induction in the course of acute ischemic or toxic renal injury in mice, including the role of interferon (IFN)-gamma and of the transcription factor, interferon regulatory factor (IRF)-1. METHODS: Kidneys were injured by ischemia or by gentamicin toxicity and were then studied for changes in gene expression using Northern blot, reverse transcriptase-polymerase chain reaction, radioimmunoassay, and tissue staining. We compared wild-type (WT) mice to IFN-gamma knockout (GKO) or IRF-1 knockout mice. RESULTS: Ischemic injury induced CIITA and class II expression in the kidney, in WT and GKO mice. Gentamicin injury also induced both CIITA and class II expression, independent of IFN-gamma, in WT and GKO mice. After ischemic injury, the induction of class II protein levels and CIITA and class II mRNA levels were induced, to a lesser degree, in IRF-1 knockout mice. CONCLUSIONS: These data indicate that CIITA is induced by tissue injury, and probably accounts for class II induction during tissue injury. CIITA induction by injury is largely IFN-gamma independent but requires IRF-1. The similarities of the pattern of CIITA and class II induction in ischemic and toxic injury suggest that this is a stereotyped response of injured tissue and not a consequence of a particular mechanism of injury.

The unique role of interferon-gamma in the regulation of MHC expression on arterial endothelium.

We examined the expression of MHC class I and II in the arterial endothelium of interferon-gamma (IFN-gamma, GKO) and IFN-gamma-R (IFN-gamma-R, GRKO) gene knockout mice in comparison with mice with intact IFN-gamma and IFN-gamma-R genes, BALB/c and 129Sv/J wild-type, respectively. The GKO and GRKO were produced by gene targeting. MHC class I and II expression was assessed by mAb binding to frozen tissue (kidney, spleen, heart, liver) sections by immunoperoxidase staining in the basal state and after various stimuli: allogeneic cells, oxazolone skin sensitization, LPS, and rIFN-gamma. As controls, we also examined the expression of two other IFN-gamma inducible genes present in the endothelium, Ly-6 and ICAM-1. We found that basal class I expression was present in the small arteries and arterioles of BALB/c and 129Sv/J wild-type mice but absent from arterial endothelium of GKO and GRKO mice. Class I was induced in the endothelium of BALB/c and 129Sv/J wild-type mice by three in vivo stimuli: allogeneic, LPS, and oxazolone, whereas class II was only induced after allogeneic stimulus. Administration of rIFN-gamma induced class I in the endothelium of GKO and BALB/c wild-type mice. The basal expression of Ly-6 and ICAM-1 was similar in the arteries of GKO and BALB/c wild-type mice, indicating that, the basal expression of these proteins in endothelium is IFN-gamma independent, unlike class I. In summary, basal class I expression in arterial endothelium is not constitutive as previously believed, but is dependent on basal IFN-gamma production. IFN-gamma has an essential role in the induction of class I and II expression in arterial endothelium. The fact that MHC class I is induced in endothelium may be useful therapeutically for reduction of immune recognition in transplantation.

The induction of class I and II major histocompatibility complex by allogeneic stimulation is dependent on the transcription factor interferon regulatory factor 1 (IRF-1): observations in IRF-1 knockout mice.

Hosts undergoing allograft rejection show increased MHC expression locally in the graft and systemically in the normal host organs, mediated principally by IFN-gamma. The transcription factor IRF-1 has been implicated in the regulation of MHC expression by IFNs in vitro as well as in the regulation of production of some cytokines. We investigated the role of IRF-1 in vivo in the systemic regulation of MHC expression in hosts undergoing rejection of allogeneic tumors by comparing MHC induction in mice with normal IRF-1 genes (wild type or WT mice) with mice with disrupted IRF-1 genes (IRF-1 knockout or IRF-1 KO mice). We assessed MHC product expression by immunohistology and by radiolabeled antibody binding to tissue homogenates, and MHC mRNA levels by Northern blotting. By immunohistology in mice undergoing allogeneic stimulation by the ascites tumor cells, kidneys of WT mice showed massive class I and II induction, but kidneys from IRF-1 KO mice showed almost no class I and II induction. Allograft rejection also increased class I and II product levels by radiolabeled antibody binding and steady state mRNA levels, but again IRF-1 KO mice showed severe impairment of MHC induction. Similar impaired MHC class I and II induction was seen in heart and spleen, but in liver the IRF-1 mice showed impaired class I induction but unimpaired class II induction. The results indicate that IRF-1 has an essential role in both class I and class II MHC induction in allogeneic responses, but that a component of IRF-1 independent MHC induction is also demonstrable in some tissues. The reduction in MHC induction by allogeneic stimulation probably reflects decreased response to IFN-gamma and other cytokines as well as some reduction in the amount of cytokines produced.

Evidence for the in vivo role of class II transactivator in basal and IFN-gamma induced class II expression in mouse tissue.

The class II transactivator (CIITA) is a protein that induces the transcription of MHC class II genes. We studied the expression of CIITA in vivo, comparing steady state levels of CIITA and class II mRNA in various mouse tissues. Many tissues in normal mice contained mRNA for CIITA, correlating with class II mRNA. The basal expression of CIITA and class II mRNA in mice with disrupted IFN-gamma genes (GKO mice) was similar to that in wild-type mice. Injection of rIFN-gamma strongly induced CIITA and class II mRNA: CIITA mRNA increased at 2 hr and declined to baseline by 48 hr, whereas class II mRNA increased at 24 hr and returned to baseline at 7 days. Proinflammatory stimuli that induce IFN-gamma production (allogeneic cells and LPS) induce CIITA and class II expression in wild-type mice, but not in GKO mice. CIITA induction by IFN-gamma was partially sensitive to cycloheximide, suggesting that another protein is required for CIITA induction. The data suggest that CIITA is a major regulator of basal and induced class II expression in vivo.

Effect of recombinant human insulin-like growth factor-1 on the inflammatory response to acute renal injury.

Renal ischemic injury evokes an inflammatory response with increased cytokine and major histocompatibility complex (MHC) expression and a mild interstitial infiltrate. This "injury response" could contribute to the tendency of ischemically injured renal transplants to reject. The studies presented here evaluated the ability of recombinant human insulin-like growth factor-1 (rhlGF-1) given after renal injury to prevent renal inflammation. The left renal pedicle of CBA and BALB/c mice was clamped for 60 min, and rhlGF-1 (25, 50, 100 micrograms) was administered sc at 2, 24, 48, 72, and 96 h after reflow. Cytokine and MHC expression was monitored in the injured kidney, compared with the contralateral kidney. In untreated mice, a single episode of injury induced the expression of MHC mRNA and products and tumor necrosis factor-alpha (TNF-alpha) mRNA, and depressed preproepidermal growth factor (ppEGF) mRNA, for up to 5 wk. With immunohistology, epithelial Class I and II MHC expression was shown to be increased for 2 wk, and Class II positive interstitial cells were shown to be increased for up to 5 wk. The ischemically injured kidneys from mice treated with rhlGF-1 and examined at 5 days showed a dose-dependent normalization of all of the changes of the injury response. This included prevention of the increased expression of MHC and cytokines and the Class II positive interstitial cells, and restoration of ppEGF mRNA. Thus the complex and long-lasting increase in proinflammatory cytokines and MHC expression that follow renal ischemia can be interrupted by treatment with rhlGF-1 beginning 2 h after the injury. This therapy may have applications to the injury response in renal transplants.

Acute renal injury in the interferon-gamma gene knockout mouse: effect on cytokine gene expression.

We studied major histocompatibility complex (MHC) and cytokine mRNA induction after renal injury in the absence of interferon-gamma (IFN-gamma) using IFN-gamma gene knockout (GKO) mice. The left renal pedicle of normal (wild-type) and GKO BALB/c mice was clamped for 60 minutes; cytokine and MHC mRNA expression were monitored in the injured kidney and compared to the contralateral control kidney. After a single episode of ischemic injury, the expression of mRNA for MHC class I and II, interleukin-2, interleukin-10, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and transforming growth factor-beta 1 was increased in wild-type and GKO mice, whereas preproepidermal growth factor (ppEGF) was reduced. IFN-gamma expression was induced in wild-type mice but absent in the GKO mice. Therefore, local injury was equally effective in both wild-type and GKO mice with equivalent cytokine and MHC mRNA induction, proving that local tissue injury can induce MHC expression by non-IFN-gamma factors.

Disturbed MHC regulation in the IFN-gamma knockout mouse. Evidence for three states of MHC expression with distinct roles for IFN-gamma.

We compared the expression of MHC class I and II products in tissues of IFN-gamma knockout (GKO) vs normal (wild-type) BALB/c mice. We studied expression in the basal state, after local tissue injury, after stimuli that induce systemic MHC expression (allogeneic cells, oxazolone skin painting, or LPS), and after rIFN-gamma. Basal class II expression in interstitial cells was not reduced in GKO mice. However, GKO mice had less basal class I expression in kidney, liver, heart, and arterial endothelium than wild-type mice. Local renal ischemic injury increased class I and II expression in kidney tubules of both GKO and wild-type mice, but induction in GKO was less than in wild-type. Potent inflammatory stimuli increased systemic MHC class I and II markedly in kidney, liver, and heart of wild-type mice, but induced no increase in GKO mice. rIFN-gamma induced class I and II equally in GKO and wild-type mice. Thus, three states of MHC expression can be defined that differ in their dependencies on IFN-gamma: basal, locally induced, and systemically induced. Basal class II expression in interstitial cells is IFN-gamma independent, but basal class I expression, particularly in arterial endothelium, is partially dependent on IFN-gamma. The local increase in MHC class I and II in parenchymal cells in response to injury reflects both IFN-gamma and a non-IFN-gamma factor. Systemic MHC class I and II induction is almost exclusively due to IFN-gamma.

Strategies to improve the immunologic management of organ transplants.

After a decade of little change, many changes in the immunologic management of organ transplant recipients are now imminent. Basic science is revealing mechanisms and developing new reagents, and clinicians are identifying opportunities for application of this new knowledge. The interaction between the laboratory and the clinic, and the renewed interest in clinical trials, guarantee that transplantation practice will evolve rapidly in the new few years. The examples mentioned here high-light the scope of the possibilities for progress.

Ischemic acute tubular necrosis induces an extensive local cytokine response. Evidence for induction of interferon-gamma, transforming growth factor-beta 1, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-10.

We noted previously that ischemic acute tubular necrosis (ATN) induces local expression of MHC products in renal epithelium. The present investigations were conducted to establish the role of IFN-gamma in the regulation of MHC antigen expression in ATN and to explore the changes in cytokine and growth factor expression induced by ischemic renal injury. We produced unilateral ischemic ATN in mice by clamping the left renal pedicle. MHC class I and II steady state mRNA induction was assessed by northern blot analysis, and MHC product was quantified by the extent of binding of radiolabeled monoclonals to tissue homogenates. The steady state mRNA levels for IFN-gamma, IL-2, IL-10, and granulocyte-macrophage CSF were assessed by reverse transcriptase polymerase chain reaction and the levels for transforming growth factor-beta 1 and prepro-epidermal growth factor (ppEGF) were assessed by Northern blot analysis. In the injured kidneys, steady state mRNA levels for IFN-gamma, IL-2, IL-10, granulocyte-macrophage CSF, and transforming growth factor beta-1 were increased, whereas ppEGF mRNA was markedly decreased. The MHC expression was inhibited by treatment of mice with an anti-IFN-gamma mAb (R4-6A2). Murine EGF, administered in an attempt to accelerate recovery, did not reduce the cytokine and MHC changes. These data indicate that ischemic injury, and possibly other forms of injury, triggers a complex circuit of proinflammatory cytokines. This "injury response" could be relevant to clinical renal transplants, where ATN is associated with poor graft outcome.