Donor-recipient gender mismatch affects early graft loss after kidney transplantation

Background

We sought to determine the risk factors influencing the occurrence of early graft loss among kidney transplant recipients.

Study design

One hundred forty-six potential donors and 230 kidney recipients were included in the study. Prior to organ procurement we collected demographic data as well as hemodynamic data of mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, systemic vascular resistance index acquired by means of a thermodilution method. The recipient data included age, gender, prior hemodialysis period, panel-reactive antibodies, cold ischemia time, renal insufficiency cause, and donor-recipient gender mismatch. We assessed the influence of the data on graft loss at 30 days after renal transplantation. To confirm the relationships, we performed statistical analyses using chi-square, Fisher exact, and V. Cramer tests.

Results

There were no significant relationships between the analyzed parameters and early graft loss in the study group except for gender mismatch. The 71 female recipients of male kidneys showed the lowest graft survival: donor/recipient male/female 89%; donor/recipient female/male 97%; no mismatch 97% (P = .01).

Conclusions

Female recipients of male kidneys may experience a greater risk of early graft loss compared with all other gender combinations.     

肺移植闭塞性细支气管炎免疫机制研究进展

闭塞性细支气管炎是影响肺移植患者长期生存的主要因素.适应性免疫一直是肺移植排斥反应的研究重点.但是越来越多的研究表明,体液免疫、自体免疫、固有免疫等亦是闭塞性细支气管炎发生的重要因素.     

Microvascular changes in small airways predispose to obliterative bronchiolitis after lung transplantation.

BACKGROUND: There is strong evidence that obliterative bronchiolitis (OB) in lung transplant recipients is related to acute rejection as graded by parenchymal perivascular infiltrates. OB (chronic rejection) is a small airways, rather than a parenchymal, scarring process. Moreover, there has been no study of the microcirculation in the small airways in lung transplantation. This study assesses the microvasculature around small airways (SA) in post-mortem lung allograft specimens. METHODS: The microvasculature of SA (n = 19) from 5 patients who died within 24 hours of lung transplantation (Group A) and SA in OB lungs (11 patients, median post-transplant survival 1,371 days) was assessed by the use of monoclonal antibodies to the vascular endothelium, namely von Willebrand factor (vWF) and CD31. The second group was further sub-divided into Group B (airways not obliterated, n = 18), Group C (sub-total airways obliteration, n = 21) and Group D (airways with total luminal obstruction, n = 14). RESULTS: The measured median circumference of the SA in the 4 groups was 2.1, 2.1, 2.5 and 2.3 mm, respectively (p = 0.66). Using CD31 as the endothelial marker, the median number of blood vessels per unit length of airway circumference (BVPL) was 3.5 vessels/mm for Group A, 0.8 for Group B, 1.3 for Group C and 2.8 for Group D, (p < 0.001). Large blood vessels (circumference >0.20 mm) were present in 95%, 11%, 14% and 21% of each group, respectively (p < 0.001). Similar trends were confirmed with the vWF endothelial antibodies. CONCLUSIONS: OB after lung transplantation is associated with a decrease in microvascular supply to the small airway. This ischemic event may lead to airway damage or increase the tendency to repair by scarring. The small airways then appear to respond to this insult by angiogenesis, which may either occur too late to prevent permanent airway damage or be inadequate in restoring adequate blood supply to the airway.     

Tests of airway function in detecting and monitoring treatment of obliterative bronchiolitis after lung transplantation.

BACKGROUND: This study evaluated different tests of airway function in detection of obliterative bronchiolitis. It included analysis of spirogram within the time domain in patients with and without obliterative bronchiolitis (OB) after heart lung and lung transplantation. The purpose of this analysis is to evaluate which tests are of greatest value for early recognition of OB. METHODS: The coefficient of variation of different airway function tests was calculated in 13 patients who had no evidence of OB and 12 patients who developed OB post-transplantation. In the patients with OB the effect of treatment with total lymphoid irradiation (TLI) was investigated by comparing the rate of change of lung function before and after TLI. Several lung function tests were used. RESULTS: The measurements that showed the least variation were FEV(1), FVC, PEF, FEV(1)/FVC ratio and the Moment Ratio, while those which became abnormal earlier were FEV(1), FEV(1)/FVC, MEF(50), and the first moment. Additionally, the tests that became abnormal in a higher proportion of patients were MMEF, MEF(50), MEF(75), and the first moment. CONCLUSIONS: The results o thi support the use of simple spirometric indices for the detection of OB. In the patients with OB the rates of decline of lung function were significantly attenuated by treatment with TLI as determined by several different tests. Keywords: obliterative bronchiolitis, lung transplantation, moments analysis, airway function tests, total lymphoid irradiation     

Chronic rejection in single-lung transplantation manifested by obliterative bronchiolitis

Chronic rejection of the lung in patients with heart-lung transplants has most often been associated with the development of obliterative bronchiolitis. Previously only one patient receiving a single-lung transplant suffered from the development of this problem. We describe a patient whose obliterative bronchiolitis developed 9 months after single-lung transplantation. Progressive deterioration occurred until his death from obliterative bronchiolitis at 21 months after transplantation. The functional and histologic changes are described and the possible mechanisms discussed.     

Rabbit antithymocyte globulin versus OKT3 induction therapy after heart-lung and lung transplantation: effect on survival, rejection, infection, and obliterative bronchiolitis

The superiority of different induction therapies after heart-lung and lung transplantation is not clearly established; specifically, whether monoclonal (OKT3) or polyclonal antibody induction therapy provides any advantage. Between 1989 and 1991 we used induction therapy with either rabbit antithymocyte globulin (RATG) or OKT3, given at random based on the availability of RATG. RATG was used in 25 patients (RATG group 1) and OKT3 in 38 patients (OKT3 group 1). Early results suggested a survival advantage with RATG. From 1992 until 1997 we used RATG induction therapy in 108 patients (RATG group 2). This study analyzed longer-term survival, infection, rejection, and obliterative bronchiolitis (OB) rates for RATG group 1 and OKT3 group 1 and assessed outcomes for RATG group 2. The 1-, 3-, and 5-year survival for RATG group 1 was 72 %, 72 %, and 52 % and for OKT3 group 1 was 63 %, 49 %, and 34 % (P < 0.05). The 1- and 3-year survival for RATG group 2 was 84 % and 74 %. The 1-, 3-, and 5-year actuarial freedom rates from lung rejection for RATG group 1 were 38 %, 38 %, and 31 % and for OKT3 group 1 were 21 %, 0 %, and 0 % (P < 0.01). The linearized rate (events/100 patient days) of all infections at 3 months was 1.55 ± 0.28 for RATG group 1 and 2.19 ± 0.27 for OKT3 group 1 (P = NS). The infection rate for RATG group 2 was 1.60 ± 0.13. The actuarial rates of freedom from OB at 1, 3, and 5 years for RATG group 1 were 84 %, 51 %, and 45 % and for OKT3 group 1 were 77 %, 61 %, and 36 % (P = NS), while for RATG group 2 the rates were 97 % and 92 % at 1 and 3 years (P < 0.01 vs RATG group 1 and OKT3 group 1). The use of RATG induction therapy from 1989 through 1991 resulted in improved actuarial survival and less rejection, without increased infection rates. The use of RATG since 1992 has continued to result in similar outcomes for survival, infection, and rejection. The time to onset of OB has improved further in recent years. This may be a result of recent improvements in cytomegalovirus (CMV) prophylaxis. Received: 10 February 2000 Accepted: 30 March 2001     

Cryptogenic obliterative bronchiolitis in adults.

Patients referred for assessment of severe chronic airflow obstruction over a three-year period were reviewed, and when all smokers and ex-smokers, those with asthma, chronic bronchitis, emphysema, and other specific pulmonary diagnoses were excluded 10 patients remained. Their clinical, lung function, and bronchographic features were consistent with obliterative bronchiolitis. Nine were women, five had rheumatoid arthritis, and five had survived for more than 10 years after first symptoms. Obliterative bronchiolitis has not previously been considered as a cause of chronic airflow obstruction but the distinctive features suggest that it is a true disease entity.     

Size mismatch in deceased donor liver transplantation and its impact on graft survival

The impact of size mismatch in deceased donor liver transplantation is unknown. BSA has been demonstrated to be an accurate indicator of liver volume. We developed a model to match livers by BSA and estimate the impact of size mismatch on graft survival. Using the Standard Transplant Analysis and Research (STAR) database we selected solitary primary liver transplants recipients of any age, transplanted between 3/6/2002 and 12/31/2016. Using the Cox proportional hazard model, and controlling for donor and recipient factors, we determined the relative risk for graft survival for four donor/recipient body surface area ratio groups (≤0.68, 0.69‐0.90, 0.91‐1.25, 1.26‐1.5). We studied two groups: recipients with a BSA > 1.6 (adults) and ≤1.6 (children) and a subgroup with a BSA ≤ 0.53 (small infants). In recipients with BSA > 1.6 (adults [n = 71 365]), D/R ratios ≤ 0.68 and > 1.25 had a negative impact on graft survival. In recipients with BSA ≤ 1.6 (children [n = 8339]) D/R ratios <0.75 and >1.25 had a negative impact on graft survival. In the 1725 recipients with BSA ≤ 0.53 (small infants) D/R ratios <1 and >2.3 had a negative impact on graft survival. In deceased donor liver transplantation, the D/R ratio is a significant, yet underestimated predictor of graft survival that should be considered in donor and recipient selection.     

Donor-recipient age difference and graft survival in living donor kidney transplantation

Background

In paired living kidney exchange donation from an old donor to a young recipient, it may be argued that elderly donors provide an inferior quality kidney. However, the impact of donors older than recipients on transplant outcomes remains unclear.

Methods

We retrospectively reviewed the charts of primary living kidney transplantation patients who were divided into two groups based on the age difference between donor and recipient (recipient age subtracted from donor age, donor-recipient < 20 vs ≥ 20). The donor-recipient age difference < 20 group comprised 75 and donor-recipient age difference ≥ 20 group, 25 subjects. Outcome measures included serum creatinine, acute rejection episodes as well as graft and patient survivals at 1 and 5 years after transplantation.

Results

The mean donor age difference cohorts of < 20 and ≥ 20 years showed donor ages of 33 ± 8 and 54 ± 8 years, respectively. The mean recipient age in both groups averaged under 40 years. The acute rejection rate within the first year posttransplantation was greater among age difference ≥ 20 years. The mean serum creatinine values of the donor-recipient age difference < 20 group was lower than the ≥20 years group at 1 and 5 years posttransplant. The 1-year difference was associated with an increased creatinine value at 5 years. However, death-censored graft survival of the age difference of the ≥ 20 years group was not different (hazard ratio [HR] = 0.1, 95% confidence interval [CI] = 0.01-1.37, P = .08). Patient survival of the age difference ≥ 20 years group showed no difference compared with the age difference < 20 years group (HR = 0.25, 95% CI = 0.01-6.35, P = .4).

Conclusion

Although the cohort of a donor-young recipient age difference ≥ 20 years showed a greater risk of an acute rejection episode early posttransplantation, it did not affect graft or patient survivals. When considering paired kidney donation, older age donors should not necessarily be limited.     

Development of obliterative bronchiolitis after allogeneic rat lung transplantation: implication of acute rejection and the time point of treatment.

BACKGROUND: Chronic allograft failure represents the major cause of late morbidity and mortality after solid organ transplantation. Despite the pathological and clinical changes of this disease being well-described, the etiology and the causative factors are still under discussion. Several clinical, as well experimental studies, emphasize the significance of acute rejection. In rat model of left lung allo-transplantation (F344-to-WKY) the influence of acute rejection (AR) on the development of chronic rejection (CR) was studied. METHODS: In Group I (n = 25) no immunosuppression was used, while methylprednisolone (MP) (10 mg/kg) was applied in Group II (n = 20) in the early phase of AR on postoperative Days 9, 10, 11 and in Group III (n = 20) during AR on Day 14, Day 15, Day 16. The rats were sacrificed on Day 5, Day 15/20, Day 30, Day 60, Day 100 and following HE-staining the extend of AR as well CR was graded according to the working formulation of The International Society of Heart and Lung Transplantation. RESULTS: In Group I, AR was found at Day 15 and Day 30 which resolved spontaneously and resulted in CR on Day 60 and Day 100. In Group II, signs of AR were less evident on Day 20, while mild AR persisted on Day 30 and Day 60. On Day 100, normal lung structure was found in all rats. The recipients of Group III showed decreased signs of AR in the early course, however, severe CR was found on Day 60 and Day 100. Extensive airway inflammation with destruction of the subepithelial layer of the smaller airways resulted in severe early obliterative bronchiolitis. CONCLUSIONS: Untreated severe AR in the early course after lung transplantation results in CR in the F344-to-WKY model. Preventive treatment with MP during the early phase of AR clearly diminishes the degree of AR and the graft recovers completely without any evidence of CR. Late application of steroids during the zenith of AR is successful to control the extent of AR, however, it fails to prevent CR.     

Donor-recipient age interaction and the impact on clinical results after heart transplantation

To evaluate the impact of donor-recipient age matching on clinical outcomes after heart transplantation, a total of 509 patients (January 1990-December 2018, mean follow-up 111 ± 80 months) were stratified into 4 groups (young-R/young-D, young-R/old-D, old-R/young-D, old-R/old-D) according to the recipient (young-R < 60, old-R ≥ 60 years) and the donor (young-D < 50, old-D ≥ 50 years) age. No difference was found among 30-day mortality (P = .11) and postoperative complications between groups. Both unadjusted and adjusted survival was significantly higher for group young-R/young-D than that of other groups, in which survival was similar [adjusted HR for mortality of 2.0(1.2-3.4), 2.1(1.4-3.8) and 2.5(1.6-4.1) for groups old-R/young-D, young-R/old-D, old-R/old-D, respectively]. Compared to other groups, the incidence of grade ≥ 2 CAV was significantly lower in old-R/young-D group [adjusted HR 0.4(0.2-0.7)]. Among young recipients, the rate of acute grade ≥ 2 rejection episodes was higher in those receiving an old donor graft (P = .04). Old recipient groups were more affected by neoplasms and severe renal failure than young recipient groups (P < .01). Employment of hearts from donors ≥50 years of age adversely affects survival in recipients <60 years of age but does not influence outcomes in older recipients. Also, donor and recipient ages seem to have opposite effects on incidence of rejections and CAV of high grade.     

Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation.

BACKGROUND: Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-beta has been implicated in the pathogenesis of fibrosis. METHODS: We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-beta polyclonal antibodies. OB and interstitial fibrosis were diagnosed and graded in all biopsies. Other potential histologic and clinical risk factors for OB were analysed. RESULTS: Procedures were heart and lung (n = 32), bilateral sequential lung (n = 18), and single lung transplantation (n = 41). The incidence of OB in this group was 28.5%. In all patients with OB, TGF-beta was immunolocalized in the airways and lung parenchyma. TGF-beta expression was greater in OB patients (median score 8, range 5-12) in comparison to patients without OB (median score 4, range 1-13), p < .0001. Positive TGF-beta staining preceded the histologic confirmation of OB by 6 to 18 months. The development of OB was associated with two HLA mismatches at the A locus (p = .02); recurrent acute rejection episodes (p < .0005); lymphocytic bronchiolitis (p = .0001); and tissue eosinophilia, regardless of the rejection grade (p < .0001). CONCLUSIONS: Increased expression of TGF-beta is a risk factor for the development of OB. Other risk factors are recurrent acute rejection, lymphocytic bronchiolitis, tissue eosinophilia, and two mismatches at the HLA-A locus. This suggests that the pathogenesis of progressive small airway fibrosis characteristic of OB may be inflammatory damage, followed by an aberrant repair process due to excessive TGF-beta production following allograft injury. Hence, modulation of TGF-beta levels or function by antagonists may represent an important approach to control OB.     

Influence of gender donor-recipient combinations on survival after human lung transplantation

BackgroundIn the current practice of lung transplantation, donor and recipient genders are neither directly considered nor matched. However, some data have suggested a possible effect of gender combinations on survival following lung transplantation.MethodsA total of 249 adult lung transplant recipients at a single center between February 1988 and December 2008, were analyzed retrospectively for donor-recipient gender matching. We compared the mortality by calculating one-term survival rates after transplantation using the Kaplan-Meier method with comparisons using the log-rank (Mantel-Cox) test. Statistical significance of the mean effects of size matching was assessed by paired Student t tests and Wilcoxon signed rank tests.ResultsKaplan-Meier survival analysis shown that male compared to female recipients did not have an effect on outcomes after lung transplantation at 5 years (P = .5379), 10 years (P = .107), 15 years (P = .0841), 20 years (P = .0711). No effect of gender on lung transplantation outcomes was observed with donor-recipient gender mismatches at 5 years (P = .1804), 10 years (P = .1457), 15 years (P = .0731), or 20 years (P = .0629). Similarly, no differences were observed for each gender combination. The degree of size matching was defined as the ratio of donor-to-recipient predicted total lung capacity. The ratios were similar for the donor-recipient gender match and significantly different for the donor-recipient gender mismatch.ConclusionsThese analyses suggested that gender was not a significant independent risk factor affecting survival after lung transplantation. Size mismatch caused by gender mismatch did not increase mortality.     

Donor-recipient lung volume matching in double lung transplantation. Value of left lower lobe graft]

For double lung transplantation, lung volume matching is easier comparing the predicted total lung capacities of the donor and recipient and the recipient's true TLC. The major concern in the inability to close the chest when the donor lungs are too large. The technique reported of left lower lobe implantation during bilateral single lung transplantation might be of great value in patients with small lung volume.     

Matrix metalloproteinase induction in post-transplant obliterative bronchiolitis.

BACKGROUND: Epithelial cell injury, inflammation, fibrosis, and airway obliteration are associated in post-transplant obliterative bronchiolitis. Fibrosis is a consequence of fibroblastic activity and of collagen deposition after disturbances in the balance of protein formation and degradation. Proteolytic enzymes such as the matrix metalloproteinases mediate degradation. To assess matrix metalloproteinases during obliterative bronchiolitis development, we studied porcine, heterotopic bronchial allografts. METHODS: A total of 119 allografts or autografts were harvested serially at 3 to 60 days after transplantation and processed for histology and in situ hybridization for matrix metalloproteinases 2 and 9. Immunocytochemistry for vimentin and alpha-smooth-muscle-cell actin was performed with specific antibodies. RESULTS: Implants had initial ischemic injury to airway epithelium and to the bronchial wall. Recovery was rapid in autografts and in immunosuppressed allografts. In matrix metalloproteinase-2 mRNA activity in fibroblasts, correlation with endothelial expression and expression in macrophages occurred during intense fibroproliferation. We observed intense matrix metalloproteinase-9 positivity during onset of inflammation and fibroproliferation in endothelial cells (p < 0.01), fibroblasts (p < 0.05), macrophages (p < 0.05), and lymphocytes (p < 0.05). Matrix metalloproteinase-9 mRNA activity in fibroblasts correlated with that in endothelial and inflammatory cells and also proved predictive of early obliteration. CONCLUSIONS: Matrix metalloproteinase-2, and especially matrix metalloproteinase-9, gene activity was associated with onset of inflammation and fibroblastic proliferation in allografts, predicting early obliteration. Although this may be the case in the model described, its role in human-allograft post-transplant obliterative bronchiolitis requires further supportive data.