Cellular immunology markers postransplantation predictive of long-term graft outcome.
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Biomarkers↗
Biomedical subjects
A J Matas
Publications and source records attributed to A J Matas.
5,000 kidney transplants--a single-center experience.
Between 6/1963 and 12/1998, 5,069 kidney transplants were done at the University of Minnesota. Of these, about half have been living donor, half cadaver. The majority (83%) have been primary transplants. Recipients were grouped in 6 eras based on changes in our immunosuppressive protocols--6/63-12/67 (n = 98); 1/68-7/79 (n = 1,188); 8/79-6/84 (n = 789); 7/84-9/90 (n = 1,006); 10/90-12/95 (n = 1,050; 1/96-12/98 (n = 718)--and their outcomes were compared. Recent eras contained a higher proportion of recipients aged > 50. Since the inception of the program, there has been a steady improvement in actuarial patient survival, graft survival, and death-censored graft survival. Short-term outcome for primary and retransplant recipients has been similar; however, long-term outcome seems worse for retransplant recipients. Importantly, acute rejection and infectious death have become rare causes of graft loss. Chronic rejection and death with function (most often due to a cardiovascular event) have become the predominant causes of graft loss. Recent changes in immunosuppressive protocols (Era VI) have included more aggressive attempts to maintain CsA levels > 150 ng/ml (by HPLC) in the first 3 months and the substitution of mycophenolate mofetil for azathioprine. As a result, the incidence of acute and chronic rejection has decreased and graft survival has improved.
Adolescent↗
Immunologic factors: the major risk for decreased long-term renal allograft survival.
BACKGROUND: Both antigen-dependent (immunologic) and non-antigen-dependent (nonimmunologic) factors have been implicated in long-term renal allograft loss. Differentiating between these two factors is important because prevention strategies differ. METHODS: To isolate the importance of these 2 factors, we studied long-term actuarial graft survival in a cohort of adult kidney recipients who underwent transplants at a single institution between January 1, 1984 and October 31, 1998. Excluded were recipients with graft loss as a result of death with function, technical failure, primary nonfunction, and recurrent disease, leaving 1587 recipients (757 cadaver [CAD], 830 living donor [LD]) who would be at risk for graft loss secondary to both immunologic and nonimmunologic factors. These recipients were analyzed in the following 2 groups: those treated for a previous episode of acute rejection (AR) (Group1; n = 588; 328 CAD, 260 LD) and those with no AR (Group 2: n = 999; 429 CAD, 570 LD). Actuarial graft survival and causes of graft loss were determined for each group. Presumably, graft loss in Group 1 would be caused by immunologic and nonimmunologic factors; graft loss in Group 2 would be caused primarily by nonimmunologic factors. RESULTS: The 10-year graft survival rate (censored for death with function, technical failure, primary nonfunction, and recurrent disease) in Group 2 was 91%. In contrast, the 10-year graft survival rate in Group 1 was 45% (P<0.001 vs. Group 2). Causes of graft loss in Group 2 were chronic rejection in 1.8% (3.0% CAD, 0.9% LD), de novo disease, 0.4%; sepsis, 0.2%; discontinuation of immunosuppressive therapy, 0.3%; and unknown, 0.6%. In contrast, 23.8% (29.9% CAD, 16.2% LD) of recipients in Group 1 had graft loss caused by chronic rejection (P = 0.001 vs. Group 2). CONCLUSIONS: This very low incidence of chronic rejection in recipients without previous AR suggests that immunologic factors are the main determinants of long-term kidney transplant outcome; nonimmunologic factors in isolation may have only a minimal impact on long-term graft survival.
Adult↗
Association between cytomegalovirus disease and chronic rejection in kidney transplant recipients.
BACKGROUND: It has long been suggested that cytomegalovirus (CMV) disease plays a role in the pathogenesis of chronic rejection (CR). However, its role has been difficult to prove, given the strong association between acute rejection and CMV, and the even stronger association between acute rejection and CR. To try to isolate the relative contribution of CMV infection in the pathogenesis of CR, we used multivariate techniques to examine risk factors for CR, including CMV disease. METHODS: Our study population consisted of adult recipients of a first kidney graft who underwent transplantation at a single center between 1/1/85 and 6/30/97 (n = 1339). RESULTS: Multivariate analysis using time to CR as the dependent variable demonstrated acute rejection to be the strongest risk factor (relative risk [RR] = 17.8, P = 0.0001), followed by older donor age (RR = 1.46, P = 0.01). The presence of CMV disease showed a trend toward increased risk for CR (RR = 1.30, P = 0.10), although the association was not as strong as with the other two variables. Comparing only those recipients with acute rejection and CMV disease versus those with acute rejection but no CMV disease, the relative risk of developing CR was 1.37 times higher in the former group. Recipients with acute rejection and CMV developed CR sooner and with a higher incidence versus those with acute rejection but no CMV (P = 0.002). It is interesting, however, that CMV disease was only a risk factor for CR in the presence of acute rejection. Recipients with no acute rejection and CMV disease did not have a higher incidence of CR versus those with no acute rejection and no CMV (P = NS). CONCLUSION: CMV disease seems to play some role in the pathogenesis of CR but only in the presence of acute rejection. Reasons may include (i) the inability to adequately treat acute rejection due to the presence of CMV disease or (ii) the increased virulence of latent CMV virus in recipients being treated for acute rejection. Our data may suggest a role for more aggressive prophylaxis against CMV disease, especially at the time of treatment for acute rejection.
Acute Disease↗
Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.
BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.
Blood Preservation↗
Features of acute rejection that increase risk for chronic rejection.
BACKGROUND: Acute rejection (AR) has been shown to be a significant risk factor for chronic rejection (CR) in kidney transplant recipients, yet many recipients with AR do not progress to CR. The purpose of this study was to determine if certain AR episodes are associated with a worse prognosis. METHODS: The study group consisted of 279 kidney transplant recipients, all treated for a single episode of biopsy-proven AR. All AR episodes were initially treated with steroids; steroid-resistant rejection was managed with an antibody preparation. RESULTS: First, by univariate techniques, we determined the clinical impact of severity of AR (as estimated by delta creatinine [dCr], defined as the change in baseline serum creatinine level 6 weeks after AR treatment) on two different endpoints--biopsy-proven CR and graft survival. Irrespective of 6-week dCr, all recipients with AR had a significantly increased risk of CR vs. those with no AR (P<0.01). Recipients with dCr between 0.5 and 1.0 mg/dl had a significantly higher incidence of CR vs. those with dCr <0.5 mg/dl (P<0.05), but a significantly lower incidence vs. those with dCr >1.0 mg/dl (P<0.05). We then performed multivariate analysis. We used severity of AR in addition to other variables (e.g., timing of AR, donor age) to determine which factors were most associated with risk for CR and graft loss. Risk for CR increased with AR episodes occurring >6 months after transplant (relative risk [RR] = 3.8, P = 0.005); with moderate or severe (vs. mild) AR episodes (RR = 2.7, P = 0.05); and with dCr >0.5 mg(dl (vs. <0.5 mg/dl) at 6 weeks after AR treatment (RR = 2.3, P = 0.1). Findings were similar when graft survival (death-censored) was the endpoint instead of CR. CONCLUSIONS: All AR episodes are associated with some increase in the risk for CR. But AR episodes occurring >6 months after transplant and those of increased severity (as assessed qualitatively by histologic grading and quantitatively by dCr) confer the greatest risk. Recipients with these risk factors could be targeted with measures to decrease their risk for CR, including trials of novel immunosuppressive regimens.
Acute Disease↗
Administration of OKT3 as a two-hour infusion does not attenuate first-dose side effects.
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Adult↗
Living donors >55 years: to use or not to use?
BACKGROUND: Kidney transplants using older donors are becoming increasingly accepted as a strategy for alleviating the growing donor organ shortage. Most studies to date have shown decreased graft survival associated with the use of older cadaver donors; however, studies on the effect of living donor age on graft survival are less clear-cut. METHODS: We studied the effect of donor age on patient and graft survival after 1126 consecutive cyclosporine-treated primary kidney transplants performed between January 1, 1985 and December 31, 1995. Of these grafts, 598 were from living donors (74 from donors >55 years old) and 528 from cadaver donors (54 from donors >55 years). We calculated actuarial patient survival, graft survival, and death-censored graft survival for recipients of both living donor and cadaver kidneys. Living donors were then further divided by HLA mismatch (0 vs. 1 - 6) and the presence or absence of an acute rejection episode. Multivariate analysis of factors associated with decreased graft survival was performed for recipients of both living and cadaver donor kidneys. Factors included for analysis were donor age >55 years, recipient age >50 years, the presence of diabetes mellitus, HLA mismatch (0 vs. 1 - 6), and the presence of an acute rejection episode. RESULTS: For cadaver kidneys, univariate analysis indicates that both overall (P=0.004) and death-censored (P=0.001) graft survival was significantly better with younger cadaver kidneys. This is supported by our multivariate analysis, which shows that cadaver donor age >55 years is an independent predictor of poor actuarial graft survival (P=0.0003). For living donor kidneys, univariate analysis also indicates that both overall (P=0.045) and death-censored (P=0.005) graft survival was significantly better with younger living donor kidneys. However, in the absence of acute rejection, 10-year death-censored graft survival for patients with older vs. younger living donor kidneys was 93% vs. 94%, whereas in the presence of one or more acute rejection episodes, 10-year death-censored graft survival dropped markedly to 39% with older and 54% with younger living donors. Kidneys from living donors >55 years had significantly better long-term graft survival than cadaver donors >55 years (P=0.012) and had comparable graft survival to younger cadaver donors. In contrast to our univariate analysis, multivariate analysis of our living donor data shows that decreased actuarial living donor death-censored graft survival was significantly associated only with the presence of one or more acute rejection episodes (P<0.0001). Living donor age >55 years was not independently associated with decreased graft survival. CONCLUSIONS: Ours is the largest single-center study of outcome for recipients of kidneys from living donors >55 years. Using univariate analysis, we have shown that graft survival of kidneys from older living donors is significantly better than that of kidneys from older cadaver donors and is comparable to that of kidneys from younger cadaver donors. Using multivariate analysis, we have shown that the presence of one or more acute rejection episodes significantly shortens both cadaver and living donor long-term graft survival. Most significantly, we have shown that, although the use of kidneys from cadaver donors >55 years is associated with significantly decreased long-term graft survival, no such association exists for recipients of kidneys from living donors >55 years. We feel that our data support the continued use of kidneys from older living donors.
Adolescent↗
Impact of transfusions and acute rejection on posttransplantation donor antigen-specific responses in two study populations. Cooperative Clinical Trial in Transplantation Research Group.
BACKGROUND: We participated in a protocol supported by the National Institutes of Allergy and Infectious Disease, Cooperative Clinical Trial in Transplantation (CCTT), which was designed to investigate the effect of peritransplant donor-specific transfusion in non-HLA-identical living donor kidney recipients. METHODS: We determined the donor antigen-specific responses at 1 year after transplantation for the 79 CCTT donor-recipient combinations in this study. A lower rate of donor antigen-specific hyporeactivity was seen in the CCTT recipients (6 of 79=8%) versus our recipients at the University of Minnesota who underwent transplantation in the same period (9 of 55=16%, P=0.16) and versus our combined historical data (33 of 131=25%, P=0.002). Therefore, we studied the differences in the two recipient populations to determine why hyporeactivity was lower in the CCTT group than at our center. RESULTS: Significant differences were seen in the acute rejection rates and the frequency of pretransplantation random transfusion. Overall and early (<3 month) acute rejection rates were higher in CCTT versus Minnesota recipients (overall: 51% vs. 20%, P=0.001) (early: 43% vs. 16%, P=0.001). The frequency of pretransplantation random transfusion was 40% for CCTT recipients (34%) versus 80% for Minnesota recipients (75%) (P=0.0004). CONCLUSIONS: These results provide provocative, although not conclusive, evidence for the importance of pretransplantation transfusion and acute rejection episodes in the development of donor antigen-specific hyporeactivity. Pre-, peri-, and posttransplantation clinical events undoubtedly have an impact on posttransplantation immune parameters.
Azathioprine↗
Long-term follow-up of living kidney donors: quality of life after donation.
The University of Minnesota has been a strong advocate of living donor kidney transplants. The benefits for living donor recipients have been well documented. The relative low risk of physical complications during donation has also been well documented. Less well understood is the psychosocial risk to donors. Most published reports have indicated an improved sense of well-being and a boost in self-esteem for living kidney donors. However, there have been some reports of depression and disrupted family relationships after donation, even suicide after a recipient's death. To determine the quality of life of our donors, we sent a questionnaire to 979 who had donated a kidney between August 1, 1984, and December 31, 1996. Of the 60% who responded, the vast majority had an excellent quality of life. As a group, they scored higher than the national norm on the SF-36, a standardized quality of life health questionnaire. However, 4% were dissatisfied and regretted the decision to donate. Further, 4% found the experience extremely stressful and 8% very stressful. We used multivariate analysis to identify risk factors for this poor psychosocial outcome and found that relatives other than first degree (odds ratio=3.5, P=0.06) and donors whose recipient died within 1 year of transplant (odds ratio=3.3, P=0.014) were more likely to say they would not donate again if it were possible. Further, donors who had perioperative complications (odds ratio=3.5, P=0.007) and female donors (odds ratio=1.8, P=0.1) were more likely to find the overall experience more stressful. Overall, the results of this study are overwhelmingly positive and have encouraged us to continue living donor kidney transplants.
Adolescent↗
Mouse-to-rabbit xenotransplantation: a new small animal model of hyperacute rejection mediated by the classical complement pathway.
BACKGROUND: Hyperacute rejection of porcine organs transplanted into primate recipients is initiated by the binding of preformed xenoreactive natural antibodies to the vascular endothelium of the graft and activation of the classical complement pathway. Several small animal models are currently employed to study various aspects of xenograft rejection; however, none has been shown to manifest hyperacute rejection mediated by the classical pathway of complement activation. METHODS: We performed heterotopic mouse heart transplants into weanling rabbits, adult rabbits, and C6-deficient rabbits. The recipients received no immunosuppression. Rejected grafts were subjected to histologic analysis and immunofluorescence staining for rabbit IgG, IgM, and C3. Levels of preexisting cytotoxic antibodies as well as classical and alternative complement pathway activities were determined in rabbit serum using mouse red cells as targets. RESULTS: Mean graft survival was 37+/-9.6 min for mouse-to-weanling rabbit transplants (n=10), and 40+/-11.1 min for mouse-to-adult rabbit transplants (n=5). Rejected grafts showed diffuse interstitial hemorrhage, endothelial cell damage, myocyte necrosis, moderate diffuse deposition of rabbit IgG, and dense deposition of rabbit IgM and C3 on the vascular endothelium of the graft, consistent with hyperacute rejection. One mouse-to-C6-deficient rabbit transplant was rejected at 21 hr with severe interstitial hemorrhage, cellular necrosis and a moderate cellular infiltrate consisting primarily of neutrophils and some mononuclear cells. A second transplant in a C6-deficient rabbit was functioning when the recipient died at 6.5 hr as a result of complications of surgery; the graft had normal myocytes and vasculature with minimal spotty interstitial hemorrhage. Both weanling and adult rabbit serum were found to have high titers of cytotoxic IgM anti-mouse antibodies and strong classical complement pathway activity with minimal alternative pathway activity towards mouse red cells. CONCLUSIONS: The mouse-to-rabbit species combination manifests hyperacute xenograft rejection. In vitro studies suggest that this process is mediated by IgM anti-mouse natural antibodies and activation of the classical pathway of complement.
Aging↗
Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion.
Chronic rejection accounts for most renal allograft losses after the first year posttransplantation. On March 24 and 25, 1997, a roundtable of five transplant surgeons, two nephrologists, and one pathologist assembled in Dallas, Texas, to review critical issues surrounding chronic renal allograft rejection. This article summarizes the presentations and relevant discussions of this meeting regarding the cause of chronic rejection, clinical diagnoses, risk factors, future prospects for intervention strategies, and general recommendations for the transplant community. Growing evidence indicates that chronic rejection is the aggregate sum of irreversible immunologic and nonimmunologic injuries to the renal graft over time. A history of acute rejection episodes and inadequate immunosuppression, likely attributable to inconsistent cyclosporine exposure or poor patient compliance, are among the most recognizable immunologic risk factors for chronic rejection. Donor organ quality, delayed graft function, and other donor and recipient variables leading to reduced nephron mass are nonimmunologic factors that contribute to the progressive deterioration of renal graft function. Clinical management of renal transplant recipients should incorporate both immunologic- and nonimmunologic-based intervention strategies aimed at minimizing risk factors to thwart the progression of chronic rejection and improve long-term allograft and patient survival.
Biopsy↗
Clostridium difficile colitis after kidney and kidney-pancreas transplantation.
OBJECTIVE: To determine the timing and risk factors involved in the development of Clostridium difficile (CD) colitis in kidney and kidney-pancreas transplant recipients. BACKGROUND DATA: The incidence of CD colitis after kidney and kidney-pancreas transplantation has not been studied in detail. The question of whether the immunosuppressed transplant recipient is more prone to CD colitis and its complications (i.e., megacolon, perforations) and the risk factors involved have not been determined. METHODS: We retrospectively reviewed our experience in kidney and kidney-pancreas recipients who received transplants between January 1, 1985 and December 31, 1994. We divided these recipients into three groups: pediatric kidney recipients, adult kidney recipients, and kidney-pancreas recipients. For each group, we assessed the timing of infection, primary disease, colitis treatment, and any concurrent complications or risk factors. RESULTS: Of 1932 transplants, 159 recipients developed post-transplant CD colitis. 132 charts were available for review. Forty-three pediatric kidney recipients developed CD colitis. Their mean age was 3.2 yr; 74% (n = 37) of them developed their colitis during their initial hospital stay, with the mean timing of infection being 33 d. Forty-one (95%) had undergone intra-abdominal placement of the graft, with renal artery anastomoses to the aorta. Fifty adult kidney recipients developed CD colitis. Thirteen (26%) developed colitis during their initial hospital stay, with the mean timing of infection (for all adult kidney recipients) being 15 months. Thirty-nine kidney-pancreas recipients developed CD colitis. Mean timing of infection was 6 months. The overall incidence of CD colitis was 8%, with 16% in the pediatric kidney group, 15.5% in the kidney-pancreas group, and 3.5% in the adult kidney group. The difference in mean timing of infection was significant between the three groups (p < 0.001 for pediatric versus adult kidney recipients, p = 0.002 for pediatric kidney versus kidney-pancreas recipients, and p = 0.2846 for adult kidney versus kidney-pancreas recipients). CONCLUSION: The incidence of CD colitis is increased in pediatric kidney and kidney-pancreas recipients. Young recipient age ( < 5 yr), female gender, treatment of rejection with monoclonal antibodies, antibiotic use, and intra-abdominal graft placement have been shown to increase the incidence of this disease. Further studies concerning prevention in the high-risk groups are needed.
Adolescent↗
Decreased acute rejection in kidney transplant recipients is associated with decreased chronic rejection.
OBJECTIVE: To determine whether a recent decrease in the rate of acute rejection after kidney transplantation was associated with a decrease in the rate of chronic rejection. SUMMARY BACKGROUND DATA: Single-institution and multicenter retrospective analyses have identified acute rejection episodes as the major risk factor for chronic rejection after kidney transplantation. However, to date, no study has shown that a decrease in the rate of acute rejection leads to a decrease in the rate of chronic rejection. METHODS: The authors studied patient populations who underwent transplants at a single center during two eras (1984-1987 and 1991-1994) to determine the rate of biopsy-proven acute rejection, the rate of biopsy-proven chronic rejection, and the graft half-life. RESULTS: Recipients who underwent transplantation in era 2 had a decreased rate of biopsy-proven acute rejection compared with era 1 (p < 0.05). This decrease was associated with a decreased rate of biopsy-proven chronic rejection for both cadaver (p = 0.0001) and living donor (p = 0.08) recipients. A trend was observed toward increased graft half-life in era 2 (p = NS). CONCLUSIONS: Development of immunosuppressive protocols that decrease the rate of acute rejection should lower the rate of chronic rejection and improve long-term graft survival.
Acute Disease↗
Kidney transplantation without a final crossmatch.
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Histocompatibility Testing↗
Venous thromboembolic complications after kidney and kidney-pancreas transplantation: a multivariate analysis.
BACKGROUND: We reviewed the incidence of and risk factors for venous thromboembolic complications in our population of kidney (KTx) and simultaneous kidney-pancreas transplant (SPK) recipients. METHODS: Information was collected retrospectively from a database on 1833 KTx and 276 SPK recipients who underwent transplant surgery between January 1985 and August 1995. RESULTS: The incidence of deep venous thrombosis (DVT) was 6.2% (n= 132), with significantly higher rates after SPK (18.1%) vs. KTx (4.5%) (P < 0.001). The number of DVT episodes was highest in the first month; 17.5% occurred during this time. For KTx recipients, early thrombotic events were more common on the side of the graft (P=0.03); however, after 1 month, no correlation existed between the side of the graft and the side of DVT. For SPK recipients, DVT tended to be more common on the side of the pancreas (57%) vs. the kidney (43%) (P=0.10). By multivariate analysis, risk factors for DVT were: age > 40 years (odds ratio [OR]=2.2, P < 0.001), diabetes mellitus (DM) (OR=2.0, P=0.002), previous DVT (OR=4.4, P=0.001), and SPK transplant (OR=2.8, P < 0.001). Pulmonary embolus (PE) was identified in 44 recipients (incidence, 2.1%) and was fatal in 13 (30%). The incidence was significantly higher in SPK (4.71%) vs. KTx recipients (1.69%) (P < 0.01). The risk of death from PE was 0.5% in KTx recipients and 1.37% in SPK recipients (P=0.08). Risk factors for PE included DM (OR=2.6, P=0.005) and recent DVT (OR=8.9, P=0.0001). CONCLUSIONS: Based on risk and extrapolating from the general surgical literature, our recommendations for prophylaxis against DVT are use of graduated compression stockings for all recipients and, in addition, low-dose heparin for moderate and high-risk recipients (previous DVT, SPK, age > 40 years, DM).
Adult↗
Acute rejection is a major risk factor for chronic rejection.
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Acute Disease↗
Risk factors for chronic rejection--a clinical perspective.
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Child↗