Nonimmunologic Risk Factors Research Articles

Immunologic and nonimmunologic risk factors of chronic rejection

Immunologic and nonimmunologic risk factors of chronic rejection

Heterogeneity of Cardiac Allograft Vasculopathy: Clinical Insights From Coronary Angioscopy

Objectives. With this study, we sought to examine the heterogeneity of cardiac allograft vasculopathy in vivo using coronary angioscopy as an adjunct to intravascular ultrasound, and we evaluated the clinical relations of immunologic and nonimmunologic risk factors with the different forms of cardiac allograft vasculopathy detected angioscopically.Background. Intravascular ultrasound detects vascular intimal proliferation accurately but is limited in its ability to delineate morphologic characteristics. Coronary angioscopy can evaluate intimal surface morphology by direct visualization and can differentiate pathologically distinct forms of plaque topography on the basis of color and contour.Methods. We studied 107 consecutive heart transplant recipients with intravascular ultrasound and angioscopy at the time of their annual angiogram, and we assessed the relation of nonimmunologic and immunologic risk factors to the development of cardiac allograft vasculopathy distinguished angioscopically into a pigmented (yellow) or nonpigmented (white) intimal thickening. We further evaluated the clinical differences in cardiac events among these two forms of angioscopically heterogeneous forms of cardiac allograft vasculopathy.Results. Significant clinical predictors of nonpigmented intimal thickening were advanced donor age and lower mean cyclosporine levels, whereas hyperlipidemia, cumulative prednisone dose and time since transplantation correlated with pigmented intimal hyperplasia. In addition, comparisons between the two angioscopic groups revealed increased intimal thickening, serum cholesterol, low density lipoprotein cholesterol, acute allograft rejection and time since transplantation in the group with pigmented intimal thickening (p < 0.05). With regard to cardiac events, nonpigmented plaque was more frequently found in the sudden death group (53% vs. 20%, p = 0.05), whereas the nonsudden cardiac event group had a significantly higher prevalence of pigmented plaque (80% vs. 47%, p = 0.07).Conclusions. These findings indicate that cardiac allograft vasculopathy is a heterogeneous disease with varied morphologic expressions with different clinical implications. Furthermore, this investigation provides insight into the cohesive, yet diverse influences of various factors, particularly immunosuppression, in these forms of cardiac allograft vasculopathy.(J Am Coll Cardiol 1997;29:1339–44)

Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors

The pathogenesis of chronic renal allograft rejection is unknown. It is also unclear why cyclosporine has failed to prevent chronic rejection. We examined possible risk factors for graft loss to chronic rejection among 706 renal transplants using the Cox proportional hazards model with fixed and time-dependent covariates. Both the number and the severity of acute rejection episodes were independent risk factors for chronic rejection [relative risk (95% confidence interval) 2.31 (2.04 to 2.60) and 1.53 (1.27 to 1.84), respectively]. Cyclosporine and cyclosporine withdrawal had no effect on chronic rejection. Acute rejections occurring within the first three months after transplantation, when cyclosporine most effectively prevented acute rejection, also had no effect on chronic rejection. Risk factors that were independent of acute rejection and not clearly attributable to immune mechanisms included serum albumin [0.20 (0.10 to 0.38) for each g/dl], proteinuria [1.42 (1.29 to 1.57) for each g/24 hr], and serum triglycerides -1.09 (1.03 to 1.16) for each 100 mg/dl-. These results suggest that the reduction in acute rejection episodes from cyclosporine has failed to reduce graft failure from chronic rejection, possibly because the early (within the first 3 months) and mild acute rejection episodes that are most effectively prevented by cyclosporine do not cause chronic rejection. In addition, the results suggest that there may be a number of nonimmunologic risk factors for chronic rejection.

Predictive model to assess risk for cardiac allograft vasculopathy: An intravascular ultrasound study

This study was performed to assess the influence and interdependence of immunologic and nonimmunologic risk factors in the development of cardiac allograft vasculopathy. Another primary objective was to establish a clinically useful model for risk assessment of cardiac allograft vasculopathy that would facilitate identifying those heart transplant recipients likely to have severe intimal proliferation and thereby at greater risk for adverse clinical events. To our knowledge, no comprehensive intravascular ultrasound study has assessed the relative influences of both nonimmunologic and immunologic factors in the development of cardiac allograft vasculopathy, currently the major limitation to long-term cardiac allograft survival. Using a computer-assisted model of stepwise logistic regression, immunologic and nonimmunologic risk factors were evaluated to help identify the development of severe intimal thickening in 101 subjects who underwent intravascular ultrasound. Prospective validation of the findings was performed in a separate consecutive cohort of 37 heart transplant recipients, and the accuracy of this model to predict a relative risk > 1 for the development of severe intimal hyperplasia was assessed. Significant independent predictors of severe intimal hyperplasia in this model included a donor age > 35 years, a first-year mean biopsy score > 1 (a measure not only of severity of rejection, but also of frequency of insidious rejection) and hypertriglyceridemia at two incremental levels of risk (150 to 250 mg/dl [1.70 to 2.83 mmol/liter] and > 250 mg/dl [2.83 mmol/liter]). Based on the absence (0) or presence (1) of these factors, 12 individual categories of risk were ascertained with increasing relative risks and predicted probabilities for severe intimal hyperplasia. Prospective validation of this model revealed a sensitivity and specificity of 70% and 90%, respectively, and the positive and negative predictive values were 85% and 80%, respectively. Additionally, subjects with severe intimal thickening had a four-fold higher cardiac event rate than those without severe intimal proliferation on intravascular ultrasound. This study establishes a clinically useful predictive model that can be applied to individual heart transplant recipients to assess their risk for developing significant cardiac allograft vasculopathy and, thus, aids in the identification of patients at risk for cardiac events in whom closer surveillance and risk factor modification may be warranted.

Cardiac allograft vasculopathy assessed by intravascular ultrasonography and nonimmunologic risk factors

The genesis of cardiac allograft vasculopathy has been linked to nonimmunologc endothellal injury. Studies evaluating the role of nonimmunologic risk factors have thus far been limited to anglographic assessment. Intravascular ultrasound can detect cardiac allograft vasculopathy before it becomes anglographically evident. To assess the influence of nonimmunologc risk factors in the development of cardiac allograft vasculopathy, we studied 101 consecutive cardiac transplant recipients who underwent intracoronary ultrasound imaging during routine, annual coronary angography. Based on the severity of intimal thickening, patients were divided into 2 groups: group 1 = minimal, mild, or moderate intimal thickness; and group 2 = severe intimal thickness. Cardiac transplant recipients with severe intimal thickness had higher levels of total cholesterol (267 ± 70 vs 227 ± 41 mg/dl, p = 0.0008), low-density lipoprotein cholesterol (187 ± 47 vs 139 ± 31 mg/dl, p = 0.0001), and trigycerides (237 ± 75 vs 182 ± 88 mg/dl, p = 0.0004), a higher percentage of weight gain (12 ± 4% vs 8 ± 5%, p = 0.0001), a larger body mass index (30 ± 4 vs 25 ± 3, p = 0.0001), and older donor age (27 ± 5 vs 23 ± 7 years, p = 0.005) than recipients with mild or moderate intimal thickness. Multiple regression analysis established that total cholesterol, low-density lipoprotein cholesterol, triglyceride levels, obesity indexes, donor age, and years following cardiac transplantation (p a0.01) were independent predictors of the severity of intimal thickening, and thus the severity of cardiac allograft vasculopathy. Hyperlipidemia, significant weight gain, and advanced donor age are predictors of the severity of intimal thickness by intravascular ultrasound. These findings may identify a group of cardiac transplant recipients in whom early intervention aimed at modification of hyperlipidemia and weight loss may be beneficial in preventing or delaying the development of cardiac allograft vasculopathy.

Chronic renal allograft loss

The phenomenon of late renal allograft loss accounts for 80% of the patients listed as returning to end-stage renal disease after kidney transplantation. This recidivism problem, which is seen as an inexorable decline in actuarial graft survival following the first year after transplantation, has a number of causes. There is good evidence that both immunologic and nonimmunologic factors are important in late graft loss. Newer DNA-based methods for histocompatibility testing permit more accurate assessment of risk for ultimate graft survival. Nonimmunologic risk factors for chronic graft dysfunction and failure may include donor kidney size that is inadequate for the demands made be the recipient. Distinction should be made between the phenomenon of late acute graft loss due to noncompliance and true chronic renal transplant failure. Patient death is a significant confounding variable, which substantially changes interpretation of chronic graft loss associated with conditions that increase patient morbidity and mortality. Prospective multivariant studies of risk factors and intervention strategies for chronic allograft are in order.

Non-immunological risk factors in paediatric renal transplantation

In paediatric renal transplantation, non-immunological risk factors account for about one-third of graft losses. Recurrence of original disease is observed mainly in primary hyperoxaluria and glomerulopathies such as steroid-resistant nephrotic syndrome and membranoproliferative glomerulonephritis. In both glomerulopathies, 20% of grafts are lost from recurrence. Vascular thrombosis is, in most series, the second cause of graft loss in children, particularly in young recipients or with young donors (under 5 years of age). Non-compliance with treatment is a common non-immunological factor in adolescent recipients, which may trigger a severe rejection process resulting in graft loss. The role of factors related to graft preservation and intra- and post-operative management (ischaemia time, delayed graft function) or to cytomegalovirus infection is less obvious in our series. Prevention of vascular thrombosis and of non-compliance is most important in order to improve the results of paediatric renal transplantation.

Risk factors for development of accelerated coronary artery disease in cardiac transplant recipients

Allograft coronary artery disease (CAD) is the major determinant of long-term survival following heart transplantation (HTx). In a group of 210 heart transplant recipients, we diagnosed CAD in 54 (27.1%) by coronary angiography, postmortem examination or examination of the transplanted heart at the time of retransplantation. Retrospective analysis of potential risk factors for the development of CAD was performed for both immunological (rejection pattern, immunosuppressive therapy, cytomegalovirus [CMV] infection), and nonimmunological (hyperlipidemia, smoking, hypertension, diabetes mellitus, obesity) risk factors. The total number of rejection episodes correlated significantly with the occurrence of CAD (P less than 0.05), showing that patients who experienced two or more rejection episodes had an incidence of CAD of 40%, as opposed to a 23% incidence in patients who experienced no rejection. A composite rejection score derived from multivariate regression analysis of the severity, frequency, and timing of acute cardiac rejection episodes was found to correlate with the development of CAD (P less than 0.05). Postoperative arterial hypertension also correlated significantly with the onset of CAD (P less than 0.01), with a 92.6% incidence of hypertension in the group with CAD versus 76.3% in the group without CAD. Smoking after transplantation correlated significantly with the occurrence of CAD (P less than 0.05). There was no significant correlation with other analyzed factors in this group of patients. In this review, the development of CAD after heart transplantation correlated with treated allograft rejection. Aggressive treatment of hypertension and cessation of smoking may contribute to alleviation of this serious complication.