Risk Factor For Allograft Rejection Research Articles

Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis

Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

Delayed Graft Function Among Kidney Transplant Recipients Is Associated With an Increased Risk of Urinary Tract Infection and BK Viremia.

Delayed graft function (DGF) among deceased donor kidney transplant recipients (DDKTRs) is a well-known risk factor for allograft rejection, decreased graft survival, and increased cost. Although DGF is associated with an increased risk of rejection, it is unclear whether it also increases the risk of infection. We reviewed all adult DDKTRs at our center between 2010 and 2018. The primary outcomes of interest were BK viremia, cytomegalovirus viremia, pneumonia, and urinary tract infection (UTI) within the first year of transplant. Additional analysis was made with censoring follow-up at the time of allograft rejection. A total of 1512 DDKTRs were included, of whom 468 (31%) had DGF. As expected, several recipient, donor, and baseline immunological characteristics differed by DGF status. After adjustment, DGF was significantly associated with an increased risk of BK viremia (hazard ratio: 1.34; 95% confidence interval, 1.0-1.81; P = 0.049) and UTI (hazard ratio: 1.70; 95% confidence interval, 1.31-2.19; P < 0.001) but not cytomegalovirus viremia or pneumonia. Associations were similar in models censored at the time of rejection. DGF is associated with an increased risk of early infectious complications, mainly UTI and BK viremia. Close monitoring and appropriate management are warranted for better outcomes in this unique population.

Pretransplant BMI Should Be

The aim of this study was to determine the appropriate body mass index (BMI) in Japanese kidney transplant (KTx) recipients. We analyzed the effects of pre- and post-transplant (Tx) obesity on graft and patient survival, perioperative complications, post-transplant diabetes mellitus (PTDM), and cardiovascular disease (CVD) in Japanese KTx recipients. This retrospective study included 269 recipients who underwent KTx from 2008 through 2020 at Niigata University Hospital. Obesity was defined as a body mass index (BMI) ≥25 kg/m2. We examined the association between pre- and post-Tx obesity and graft survival, patient survival, the incidence of PTDM and CVD, and perioperative surgical complications. The graft survival rate was lower in the pre-Tx BMI ≥25 kg/m2 group, although there was no significant difference in patient survival. There was no difference in graft and patient survival between the post-Tx BMI ≥25 kg/m2 group and the <25 kg/m2 group. A pre-Tx BMI ≥25 kg/m2 was an independent risk factor for biopsy-proven allograft rejection. New-onset DM after transplantation was significantly more common in the BMI ≥25 kg/m2 group than in the BMI <25 kg/m2 group (36% vs 13%; P=.002). The incidence of CVD was significantly higher in the post-Tx BMI ≥30 kg/m2 group than in the BMI <30 kg/m2 group (50% vs 11%; P=.023). There were no differences in surgical operating time, intraoperative blood loss, or perioperative complications between the obese and non-obese groups. Pre-Tx BMI ≥25 kg/m2 may be a risk factor for allograft rejection and graft loss. Post-Tx BMI should be <25 kg/m2 to reduce the risk for PTDM.

Lymphatic Trafficking in the Eye: Modulation of Lymphatic Trafficking to Promote Corneal Transplant Survival.

(Lymph)angiogenesis into the cornea prior to and after corneal transplantation is a critical risk factor for allograft rejection. Lymphatic vessels even more than blood vessels seem important in mediating immune responses, as they facilitate allograft sensitization in the draining lymph nodes. Thus, the concept of modulating lymphatic trafficking to promote corneal graft survival seems promising. A variety of approaches has been developed to inhibit progressive lymphangiogenesis in experimental settings. Recently, additionally to pharmacological approaches, clinically available techniques such as UVA-based corneal collagen crosslinking and fine needle diathermy were reported to be effective in regressing lymphatic vessels and to experimentally promote graft survival. Clinical pilot studies also suggest the efficacy of blocking antigen presenting cell trafficking to regional lymph nodes by regressing corneal lymphatic vessels to enhance allograft survival in high-risk eyes. In this article, we will give an overview of current strategies to modulate lymphatic trafficking with a special focus on recently reported strategies, which may be easy to translate into clinical practice. This novel concept of temporary, pretransplant regression of lymphatic vessels at the site of transplantation to promote subsequent corneal transplant survival (“lymphangioregressive preconditioning”) may also be applicable to other transplantation sites later.

Medication nonadherence after kidney transplantation: an internet-based survey in Japan

ABSTRACTNonadherence to immunosuppressive medications after kidney transplantation is a major risk factor for allograft rejection and graft loss. Transplant recipients tend to conceal nonadherence in clinical settings. We conducted an internet-based cross-sectional survey aimed to clarify the prevalence and risk factors of patient nonadherence after kidney transplantation in Japan. The Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS©) was used to detect nonadherence. In this survey, patients were asked about their relationship with medical staff and their self-efficacy for taking medication, along with other questions. A total of 219 kidney transplant recipients were included in the analysis. Ninety-four demonstrated nonadherence (42.7%). The following factors were associated with nonadherence: short dialysis period prior to transplantation; undergoing transplantation at least twice; male sex; lack of satisfaction with the explanation of immunosuppressive medication; and absence of medical staff to consult upon forgetting to take drugs. The nonadherence group reported low self-efficacy for medication in many settings. This anonymous survey provides valuable insight into the actual nonadherence rate, factors associated with nonadherence, and life situations that may complicate medication-taking.

Risk of Corneal Graft Rejection After High-risk Keratoplasty Following Fine-needle Vessel Coagulation of Corneal Neovascularization Combined With Bevacizumab: A Pilot Study

Background.Corneal neovascularization is considered an important risk factor for allograft rejection after corneal transplantation (keratoplasty). Therefore, the aim of this study was to determine whether preoperative reduction of corneal neovascularization by fine-needle thermal cauterization combined with bevacizumab reduces the incidence of allograft rejection after subsequent high-risk keratoplasty.Methods.In this interventional uncontrolled clinical pilot study, 31 eyes of 31 patients with corneal neovascularization in at least one corneal quadrant were included. All eyes were treated by fine-needle thermal cauterization of corneal vessels and subconjunctival injection of bevacizumab. Both treatments were repeated in the cases of visible reperfusion of occluded vessels. Afterward, penetrating keratoplasty was performed. When corneal neovascularization was present on the day of keratoplasty, additional vessel cauterization and injection of bevacizumab was performed. Patients were then followed to determine the incidence of allograft rejection.Results.In 18 eyes, vessel cauterization with bevacizumab injection was performed once before keratoplasty, whereas 13 eyes required retreatment before keratoplasty. No complications were observed. In 23 eyes, corneal neovascularization was present on the day of keratoplasty due to reperfusion of previously occluded vessels and simultaneous vessel cauterization with bevacizumab injection was performed. During follow-up (mean: 560 days; range: 59–1095 days), 4 graft rejection episodes in 4 eyes were observed. Estimated probabilities of corneal graft survival were 92.9% after 1 year (number at risk: 23), 78.4% after 2 years (number at risk: 9), and 78.4% after 3 years (number at risk: 3).Conclusions.Our initial results indicate that angioregressive treatment of pathological corneal vessels by fine-needle thermal cauterization combined with subconjunctival injection of bevacizumab before high-risk keratoplasty seems to result in graft survival rates comparable to survival rates seen in normal-risk keratoplasty. The findings of our pilot study warrant further controlled clinical trials with longer follow-up in a larger patient cohort.

Low Radiation Dose and Low Cell Dose Increase the Risk of Graft Rejection in a Canine Hematopoietic Stem Cell Transplantation Model

The canine hematopoietic stem cell transplantation (HSCT) model has become accepted in recent decades as a good preclinical model for the development of new transplantation strategies. Information on factors associated with outcome after allogeneic HSCT are a prerequisite for designing new risk-adapted transplantation protocols. Here we report a retrospective analysis aimed at identifying risk factors for allograft rejection in the canine HSCT model. A total of 75 dog leukocyte antigen–identical sibling HSCTs were performed since 2003 on 10 different protocols. Conditioning consisted of total body irradiation at 1.0 Gy (n = 20), 2.0 Gy (n = 40), or 4.5 Gy (n = 15). Bone marrow was infused either intravenously (n = 54) or intraosseously (n = 21). Cyclosporin A alone or different combinations of cyclosporine A, mycophenolate mofetil, and everolimus were used for immunosuppression. A median cell dose of 3.5 (range, 1.0 to 11.8) total nucleated cells (TNCs)/kg was infused. Cox analyses were used to assess the influence of age, weight, radiation dose, donor/recipient sex, type of immunosuppression, and cell dose (TNCs, CD34+ cells) on allograft rejection. Initial engraftment occurred in all dogs. Forty-two dogs (56%) experienced graft rejection at median of 11 weeks (range, 6 to 56 weeks) after HSCT. Univariate analyses revealed radiation dose, type of immunosuppression, TNC dose, recipient weight, and recipient age as factors influencing long-term engraftment. In multivariate analysis, low radiation dose (P < .001) and low TNC cell count (P = .044) were identified as significant independent risk factors for graft rejection. Peripheral blood mononuclear cell chimerism ≥30% (P = .008) and granulocyte chimerism ≥70% (P = .023) at 4 weeks after HSCT were independent predictors of stable engraftment. In summary, these data indicate that even in low-dose total body irradiation–based regimens, the irradiation dose is important for engraftment. The level of blood chimerism at 4 weeks post-HSCT was predictive of long-term engraftment in the canine HSCT model.

LBP22: STRONG DONOR SPECIFIC ANTI-HLA DR53 ANTIBODY DETECTED BY SINGLE-ANTIGEN BEADS SHOULD NOT ALWAYS PREVENT TRANSPLANTATION

Background Donor-specific antibodies towards HLA-DR51/52/53 were reported both as risk factors for allograft rejection, and as specificities with poor response to desensitization therapy. Here we present a case with strong antibody towards HLA-DR53 who was successfully transplanted. Case study. 47-year-old male renal transplant candidate with cPRA of 68%, was repeatedly detected with anti-HLA DR53 antibodies by Luminex single-antigen beads. HLA-DR53 was a mismatched antigen for his potential living donor (Table 1). Antibody IgG strength for a-HLA DR53 ranged between 7500 and 10000 MFI over one-year period. At these MFI values, our lab usually expects a positive cytotoxic B-cell crossmatch, or at least a positive B-cell flow crossmatch. However, both cytotoxic and flow crossmatches with his living donor were negative. To address this issue, we tested the living donor with other two sera known for a-HLA DR 53 activity, both in neat, and 1:4 and 1:8 dilutions, by flow crossmatch. All these combinations provided positive results of > 180 MCS above cutoff (1024 scale). Alternatively, candidate recent and peak sera was flow crossmatched with other two HLA-DR 53 cells, giving again negative results. Under the hypothesis of cryptic epitope DR53 reactivity, we also tested candidate sera with Luminex beads of different antigenic source (mixed and PRA), which have shown no DR53 reactivity. Under these circumstances, we concluded that the virtual crossmatch between the transplant candidate and his living donor was negative. Post transplant monitoring shows no signs of rejection at one year of follow-up. Conclusion Although solid-phase methods for antibody detection became mandatory in renal transplantation, a combination of technologies, rather than a single one, would be more adequate for antibody detection and identification. Table 1 ABO A B C DR DRw DQ DP Patient B 1 80 71 72 2 7 11 8 52 7 0301 0101 Donor 1 B 2 23 27 51 1 2 11 4 52 53 7 8 0401

Thrombospondin-1 Polymorphisms Influence Risk of Corneal Allograft Rejection

We investigated single nucleotide polymorphisms (SNPs) of thrombospondin-1 (TSP-1) on the risk of corneal allograft rejection. The TSP-1 is known to be involved in the immune response of the anterior chamber of the eye, activating TGF-β2, promoting peripheral and systemic tolerance, and counteracting the proangiogenic activity of VEGF. Three tagging SNPs spanning the TSP-1 region (rs1478604, A>G; rs2228261, C>T; and rs2228262, A>G) were genotyped. Association with risk of rejection was investigated in a group of 378 corneal transplant recipients with risk factors for allograft rejection. Transplant recipients had completed 3-year follow-up. The TSP-1 rs1478604 A SNP was associated significantly with an increased risk of corneal allograft rejection (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.02-2.45; P = 0.04) and there was a trend toward the rs1478604, rs2228261, rs2228262 ACA haplotype increasing risk of rejection. The results suggest that TSP-1 rs1478604 AA homozygotes may be at increased risk of corneal transplant rejection, especially if they carry the ACA haplotype.

Early Urinary Complications in Renal Transplantation: A Potential Risk Factor for Allograft Rejection

Objective: A recently debated and poorly understood mechanism involving immunologic activation by bacterial infection among recipients of abdominal allografts has been proposed. Specific to the topic of renal transplantation are the contributions of urinary tract infections (UTIs) and acute graft pyelonephritis (AGPN) to this hypothesis. We sought to further investigate the contribution of early urinary complications on renal transplant allograft failure. Methods: A single institution retrospective analysis of primary renal transplants was conducted to identify the incidence of early urinary complications (within one year post-transplant) and determine their effects on allograft survival. All identified urinary strictures/stenoses as well as leaks not requiring surgical or endourologic intervention were excluded from our study. Immunologic risk factors (CMV/BK polyoma viremia,induction/maintenance immunosuppression, HLA data, peak PRA) were reviewed and analyzed. A time-varying covariate was constructed using the presence of a urologic complication(s) post-transplantation to investigate its effect on renal allograft survival. Results: 3902 primary renal transplants were performed from January 1995 to December 2010. Of those organs transplanted, 59.4% were from cadaveric donors. 125 (3.2%) patients had a urinary stricture while 62 (1.6%) had a urinary leak. 1253 patients had > 2 UTIs during the overall cohort study period of which 32.1% occured within the first year. Presence of Cytomegalovirus (CMV) Viremia (HR 1.66, P < 0.0001), BK polyoma Viremia (HR 1.62, P < 0.0001) and > 2 UTIs (HR 1.85, P < 0.0001) within the first year post-transplant were identified as significant risk factors associated with decreased allograft survival. Urinary strictures (HR 1.26, p 0.085) trended toward but were not found to be statistically significant.Table: [Postoperative Urinary Complication Data]Table: [Urologic Disease/Risk Factors]

Early Urinary Complications in Renal Transplantation: A Potential Risk Factor for Allograft Rejection

Objective: A recently debated and poorly understood mechanism involving immunologic activation by bacterial infection among recipients of abdominal allografts has been proposed. Specific to the topic of renal transplantation are the contributions of urinary tract infections (UTIs) and acute graft pyelonephritis (AGPN) to this hypothesis. We sought to further investigate the contribution of early urinary complications on renal transplant allograft failure. Methods: A single institution retrospective analysis of primary renal transplants was conducted to identify the incidence of early urinary complications (within one year post-transplant) and determine their effects on allograft survival. All identified urinary strictures/stenoses as well as leaks not requiring surgical or endourologic intervention were excluded from our study. Immunologic risk factors (CMV/BK polyoma viremia,induction/maintenance immunosuppression, HLA data, peak PRA) were reviewed and analyzed. A time-varying covariate was constructed using the presence of a urologic complication(s) post-transplantation to investigate its effect on renal allograft survival. Results: 3902 primary renal transplants were performed from January 1995 to December 2010. Of those organs transplanted, 59.4% were from cadaveric donors. 125 (3.2%) patients had a urinary stricture while 62 (1.6%) had a urinary leak. 1253 patients had > 2 UTIs during the overall cohort study period of which 32.1% occured within the first year. Presence of Cytomegalovirus (CMV) Viremia (HR 1.66, P < 0.0001), BK polyoma Viremia (HR 1.62, P < 0.0001) and > 2 UTIs (HR 1.85, P < 0.0001) within the first year post-transplant were identified as significant risk factors associated with decreased allograft survival. Urinary strictures (HR 1.26, p 0.085) trended toward but were not found to be statistically significant.Table: [Postoperative Urinary Complication Data]Figure: [Urologic Disease/Risk Factors]Conclusion: Urinary complications, specifically those influenced by the presence of viremia or recurrent urinary tract infections, contribute to the multi-factorial phenomenon of post-transplant renal allograft failure.

Impact of HLA-G 14-bp polymorphism on acute rejection and cytomegalovirus infection in kidney transplant recipients from northwestern China

Human leukocyte antigen (HLA)-G plays an important role in promoting transplant tolerance and helping human cytomegalovirus (CMV) to subvert host defenses. Strong evidence suggests that HLA-G 14-bp insertion/deletion polymorphism influences the stability of HLA-G mRNAs and levels of protein expression. We hypothesized that HLA-G 14-bp polymorphism of recipients has an influence on the risk of acute rejection (AR) and CMV infection. We investigated the impact of HLA-G 14-bp polymorphism on a total of 363 unrelated Chinese Han individuals who included 42 kidney transplant recipients with AR, 43 recipients with CMV infection, 102 recipients with stable allograft function (STA), and 176 healthy controls (HC). No statistically significant difference was found between all kidney transplant patients and HC (P=0.149). But, our data showed an increased frequency of homozygous genotype +14/+14bp (Pc=0.004) and allele +14bp (Pc=0.002) in patients with AR when compared with STA, with the odds ratio of 3.17 and 2.28, respectively. Moreover, we found that the frequency of the −14/−14bp genotype (Pc=0.008) and the −14bp allele (Pc=0.016) was increased in patients with CMV infection when compared with STA, with the OR of 2.66 and 1.96, respectively. Multivariate analysis further demonstrated that HLA-G homozygous +14bp and −14bp genotypes were an independent risk factor for allograft rejection and CMV infection, respectively. In conclusion, this study identified an important genetic risk factor for acute allograft rejection, and it was the first to show a significant correlation between HLA-G 14-bp polymorphism and CMV infection after kidney transplantation from northwestern China.

Herpes Simplex Virus Keratitis: Histopathologic Inflammation and Corneal Allograft Rejection

To identify whether histopathologic and immunoassay biomarkers of inflammation are predictive for allograft rejection after penetrating keratoplasty (PKP) for herpes simplex virus (HSV) keratitis.Retrospective, interventional case series with prospective component of pathologic evaluation of frozen tissue.Sixty-two consecutive patients with HSV keratitis who underwent PKP.A chart review and histopathologic examination of the excised host corneal button was performed to identify associations between clinical data and histopathologic presence of inflammation. Enzyme-linked immunosorbent assay for interleukin (IL)-8 and monocyte chemotactic protein-1 (MCP-1) chemokines and immunohistochemical staining for human leukocyte antigen (HLA)-DR and intercellular adhesion molecule-1 (ICAM-1) antigens was also performed in inflamed and noninflamed specimens.To determine whether the presence of subclinical inflammation at the time of PKP predicts allograft rejection.Although 81% of patients had clinically quiescent disease, histopathology revealed that 74% had active corneal inflammation, a finding that was associated with the presence of clinical neovascularization (P = 0.01). Allograft rejections were experienced by 34% of the patients in this cohort. The histopathologic presence of inflammation was a risk factor for allograft rejection (P = 0.02). Corneal specimens demonstrating inflammation had significantly increased IL-8 (P = 0.0005) and MCP-1 (P = 0.003) levels, and greater immunoreactivity for HLA-DR and ICAM-1 when compared with specimens without inflammation. Treatment with IL-10 ex vivo significantly inhibited IL-8 (P = 0.006), and MCP-1 (P = 0.01) chemokines, and qualitatively substantially reduced HLA-DR, but not ICAM-1, expression.Histopathologic inflammation is a risk factor for corneal allograft rejection.

Intragraft TNF Receptor Signaling Contributes to Activation of Innate and Adaptive Immunity in a Renal Allograft Model

Increased levels of tumor necrosis factor (TNF) are a risk factor for allograft rejection. In vitro studies have shown that binding of TNF to its receptor activates signaling cascades that induce expression of many genes involved in inflammation. The role of intragraft TNF receptor (TNFR) signaling in activation of gene expression in allografts has not been studied. Gene expression profiling and quantitative real-time polymerase chain reaction analysis were used to investigate the role of TNFR signaling in the early intragraft activation of cellular gene expression in renal allografts at 2 days posttransplant. The TNFRs play a critical role in activating intragraft expression of transcription factors controlling innate and adaptive immunity and stress responses (interferon regulatory factor [IRF]1, IRF 8, Isgf3g, and ATF3) of cytokines and receptors mediating inflammation (TNF, interleukin [IL]-6, interferon-gamma, oncostatin M receptor [OMCR], toll-like receptor [TLR]2, and IL-2Rgamma), of chemokines and adhesion molecules that recruit inflammatory cells (Cxcl9, Cxcl11, E-selectin, and intracellular adhesion molecule [ICAM]-1), of genes involved in costimulation of T cells and processing and presentation of antigens (H2-DMb, Psmb8, and CD40), and genes that mediate the response to interferons. In addition to its proinflammatory role, TNFR signaling induces expression of SOCS3, a negative regulator of IL-6 and OSMR signaling and Nfkbie, and a negative regulator of TNFR signal transduction. These studies illustrate the pleiotropic effect of TNF in both activation and down-modulation of the immune response and the complex interactions between the TNFRs and other cytokine signaling pathways in the early allograft response.

200: Clinical Experience with the Use of Virtual Crossmatch in Adult Lung Transplantation

Anti-human leukocyte antigen (HLA) antibodies in the recipient are considered a risk factor for allograft rejection and poor graft survival.Techniques including flow cytometry and solid-phase assays allow predetermination of HLA antibody specificity. The Virtual Crossmatch (VXM) strategy utilizes the results of this antibody screening to predict acceptable HLA mismatches.We reviewed our clinical experience with the use of the VXM and its influence on lung transplant (LTx) outcomes.

The Natural Course of Cytomegalovirus Infection and Disease in Renal Transplant Recipients

A series of prospective studies of a large cohort population of renal transplant recipients who did not receive cytomegalovirus (CMV) prophylaxis or preemptive therapy examined the effects of CMV infection and disease on renal allograft rejection, long-term recipient and graft survival, and new-onset diabetes mellitus. CMV infection and disease were found to be independent risk factors for allograft rejection and new-onset diabetes mellitus within 100 days posttransplantation, and for recipient mortality and uncensored graft loss beyond 100 days posttransplantation. Additional studies are needed to determine whether CMV prophylaxis or preemptive therapy may be of benefit in preventing these complications.

The impact of cytomegalovirus disease and asymptomatic infection on acute renal allograft rejection

Background Cytomegalovirus (CMV) disease is a risk factor for allograft rejection in renal transplant (RTx) recipients. However, the role of asymptomatic CMV infection remains controversial. Objectives To determine the impact of CMV disease and asymptomatic infection on biopsy-proven acute rejection (BPAR) during 12 months post-RTx. Study design A total of 106 consecutive RTx recipients at risk for CMV (donor and/or recipient CMV seropositive) were followed prospectively for 12 months post-RTx. CMV activity was monitored using nested PCR from whole blood. Three-month prophylaxis with valacyclovir or ganciclovir was given to 94 patients. BPAR episodes were classified according to the Banff 97 criteria. Multivariate Cox proportional hazards model was used to estimate the effect of CMV disease, asymptomatic infection, and other covariates on BPAR. Results Asymptomatic CMV infection occurred in 23% of the patients and 10% developed CMV disease. The incidence of BPAR was 29%. CMV disease was an independent risk factor for BPAR (HR = 3.0, P = 0.014), while asymptomatic CMV infection was not ( P = 0.987). In addition to CMV disease, expanded criteria donor and donor age were independent predictors for BPAR. In univariate analysis, valacyclovir (HR = 0.26, P = 0.008) decreased the risk of BPAR. A similar trend was observed with ganciclovir (HR = 0.42, P = 0.058). Only valacyclovir remained significant in multivariate analysis (HR = 0.18, P = 0.044). Conclusions CMV disease, but not asymptomatic infection, is an independent risk factor for BPAR during the first 12 months post-RTx.

A 10-Year Review of Penetrating Keratoplasty

Purpose: To survey the changes in indications for penetrating keratoplasty (PKP) and re-evaluate the risk factors for allograft rejection and graft failure. Methods: We evaluated the records of 396 eyes of 335 patients who had undergone PKP at the Tokyo University Hospital between 1987 and 1997. Clinical results were analyzed by the Kaplan-Meier life table method and the log-rank test. Results: The overall rates of graft survival and rejection-free graft survival at 10 years were 72.2% and 76.8%, respectively. The rates of graft survival and rejection-free graft survival were 98.8% and 86.6% in keratoconus, 87.0% and 56.5% in herpetic keratitis, 76.9% and 73.1% in corneal dystrophy and degeneration, 69.4% and 80.6% in nonherpetic keratitis, 62.5% and 75.0% in chemical burns, 61.8% and 72.1% in regrafting, and 51.1% and 79.8% in bullous keratopathy, respectively. The graft survival rates were statistically higher in the PKP alone group than in the combined operation group. The graft survival and rejection-free graft survival rates were statistically higher in the first operation group than in the regrafted group, and in the avascular cornea group than in the vascular cornea group. Conclusions: We recognized changes in indications for PKP. Combined operation, reoperation, and vascularization of recipient cornea were risk factors for graft failure.