Organ donor management in Canada: recommendations of the forum on Medical Management to Optimize Donor Organ Potential.
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Brain Death↗
Biomedical subjects
Peter Nickerson
Publications and source records attributed to Peter Nickerson.
The relative importance of cytokine gene polymorphisms in the development of early and late acute rejection and six-month renal allograft pathology.
BACKGROUND: Acute rejection episodes and 6-month protocol biopsy acute pathology are highly correlated with long-term outcomes in renal transplant recipients. Recurrent, vascular, and late rejections are particularly deleterious. METHODS: We determined the relative contribution of human leukocyte antigen matching, cytokine genotypes, delayed graft function (DGF), and baseline immunosuppression to the development of acute rejection and allograft pathology in 118 renal transplant recipients. RESULTS: Multivariate logistic regression modeling demonstrated that the adjusted odds ratio and 95% confidence interval for recurrent (> or =2) early rejections (0-3 months) increased linearly for high (H) > intermediate (I) > low (L) interferon-gamma (1.8; 1.1-3.2) and tumor necrosis factor (TNF)alpha (3.0; 1.3-6.9) genotype, whereas every 1 microg/L increase in the cyclosporine A level was protective (0.991; 0.984-0.999). The odds ratio for recurrent late rejections (4-6 months) increased for H > I > L TNFalpha (5.1; 1.8-14.7) genotype and DGF (7.1; 1.6-30.2), whereas H > I/L transforming growth factor-beta1 genotype decreased the relative risk (0.09: 0.02-0.49). Vascular rejection was only predicted by H > I > L TNFalpha phenotype (3.0; 1.2-7.9). The odds ratio for the 6-month Banff Acute Score (6A > or= 4) increased for H > I > L TNFalpha (2.7; 1.1-6.7) and interleukin-10 (3.4; 1.2-6.2) genotype, and DGF (3.4; 1.1-11.5). Treatment of early subclinical rejection decreased the relative risk (0.20; 0.07-0.62). CONCLUSIONS: High transforming growth factor-beta1 producer phenotype seems to be protective against acute inflammation, whereas H and I interferon-gamma, TNFalpha, and interleukin-10 producer genotypes correlate with adverse outcomes. Cytokine genotyping identifies individuals who may benefit from more intensive surveillance and treatment posttransplant.
Adult↗
Detection of a single nucleotide polymorphism in the IL-6 promoter region of ancient nuclear DNA.
In the current study a method was developed to examine the G/C single nucleotide polymorphism (SNP) at position -174 in the IL-6 promoter from nuclear DNA samples isolated from human skeletal remains from Manitoba, Canada, dating to as early as 3500 years ago. The IL-6 (-174) SNP was detected in three ancient samples and determined, as expected, in three out of three to be homozygous G/G. The analysis of cytokine SNPs of ancient nuclear DNA may provide novel insights into the genetic basis of autoimmune diseases and the susceptibility/resistance to infectious agents.
Anthropology↗
The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease.
BACKGROUND AND AIMS: Emerging data indicate that alterations in cytokine synthesis may play a role in inflammatory bowel disease (IBD) pathogenesis. The differential production of cytokines has been linked to single nucleotide polymorphisms in gene promoter regions, signal sequences, and gene introns. The aim of this study was to assess the relationship between polymorphisms involving five cytokine genes (TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma), and IBD susceptibility and disease phenotype. METHODS: Cytokine genotyping was performed utilizing polymerase chain reaction. The specific gene polymorphisms that were probed for included: -1082(G/A), -819(T/C), and -592(A/C) in the IL-10 promoter, -308(G/A) in the TNF-alpha promoter, codon 10 (T/C), and codon 25 (G/C) of the TGF-beta signal sequence, +874(T/A) of intron 1 of IFN-gamma, and -174(C/G) in the IL-6 promoter. RESULTS: A total of 193 IBD patients (138 Crohn's disease (CD) and 55 ulcerative colitis (UC)) and 92 controls were evaluated. No association between IBD, UC, or CD susceptibility and the cytokine gene polymorphisms were found. Patients with ileocolonic CD were more likely to possess the IL-6 -174 GG genotype compared to those with nonileocolonic disease (p= 0.006). Patients with ileal CD were more likely to possess the IL-6 -174 GC genotype compared to those with nonileal disease (p= 0.0004). An increased number of CD patients with isolated colonic disease possessed the IL-6 -174 CC genotype compared to those with nonisolated colonic disease (p= 0.032). CONCLUSION: The cytokine gene polymorphisms studied here do not appear to influence IBD susceptibility. There does, however, appear to be an influence on disease phenotype, particularly on CD site.
Adult↗
Proteomic-based identification of cleaved urinary beta2-microglobulin as a potential marker for acute tubular injury in renal allografts.
Our aim is to develop noninvasive tests to monitor the renal allograft posttransplant. Previously, we have reported that an unbiased proteomic-based approach can detect urine protein peaks associated with acute tubulointerstitial renal allograft rejection. Identification of these proteins peaks by mass spectrometry demonstrated that they all derive from nontryptic cleaved forms of beta2-microglobulin. In vitro experiments showed that cleavage of intact beta2-microglobulin requires a urine pH < 6 and the presence of aspartic proteases. Patients with acute tubulointerstitial rejection had lower urine pH than stable transplants and healthy individuals. In addition, they had higher amounts of aspartic proteases and intact beta2-microglobulin in urine. These factors ultimately lead to increased amounts of cleaved urinary beta2-microglobulin. Cleaved beta2-microglobulin as an indicator of acute tubular injury may become a useful tool for noninvasive monitoring of renal allografts.
Amino Acid Sequence↗
Familial seropositive rheumatoid arthritis in North American Native families: effects of shared epitope and cytokine genotypes.
OBJECTIVE: A number of North American native (NAN) populations have high prevalence rates of both rheumatoid arthritis (RA) and the shared epitope (SE). We examined the phenotype and familial incidence of RA in a NAN population, and investigated how the SE and cytokine genes may affect disease risk within affected families. METHODS: NAN patients with seropositive RA or polyarthritis rheumatoid factor (RF) positive juvenile idiopathic arthritis (JIA) were identified from clinical databases. Patients were recruited consecutively as they presented for clinic visits. Family pedigrees were constructed and consenting relatives were interviewed and examined. The risk of RA within families was calculated by multiple logistic regression. Input variables were the SE and cytokine genotypes. Probands and affected relatives were entered as the affected group, and unaffected relatives within families as the unaffected group. Results were confirmed among unrelated subjects, i.e., unrelated patients and unaffected relatives of other probands. RESULTS: The familial prevalence of RA was 0.50 (95% confidence intervals 0.30, 0.70) among 28 families studied. The interleukin 10 (IL-10) promoter -1082 G/A genotype decreased the odds of RA relative to the A/A genotype in affected families (OR 0.247, 95% CI 0.081, 0.751; p = 0.014) and among unrelated subjects (OR 0.203, 95% CI 0.064, 0.640; p = 0.006). The G/G genotype yielded an OR of 0.093 (95% 0.013, 0.676; p = 0.019) among unrelated subjects. The SE had no effect in these calculations. CONCLUSION: There was a high familial prevalence of RA in this NAN cohort. In susceptible NAN families, the risk of RA was reduced by IL-10 genotypes, whereas the SE did not affect risk. Study of healthy NAN controls is required to determine if these conclusions apply to this NAN population as a whole.
Adolescent↗
Proteomic-based detection of urine proteins associated with acute renal allograft rejection.
At present, the diagnosis of renal allograft rejection requires a renal biopsy. Clinical management of renal transplant patients would be improved by the development of non-invasive markers of rejection that can be measured frequently. This study sought to determine whether such candidate proteins can be detected in urine using mass spectrometry. Four patient groups were rigidly defined on the basis of allograft function, clinical course, and allograft biopsy result: acute clinical rejection group (n = 18), stable transplant group (n = 22), acute tubular necrosis group (n = 5), and recurrent (or de novo) glomerulopathy group (n = 5). Urines collected the day of the allograft biopsy were analyzed by mass spectrometry. As a normal control group, 28 urines from healthy individuals were analyzed the identical manner, as well as 5 urines from non-transplanted patients with lower urinary tract infection. Furthermore, sequential urine analysis was performed in patients in the acute clinical rejection and the stable transplant group. Three prominent peak clusters were found in 17 of 18 patients (94%) with acute rejection episodes, but only in 4 of 22 patients (18%) without clinical and histologic evidence for rejection and in 0 of 28 normal controls (P < 0.001). In addition, the presence or absence of these peak clusters correlated with the clinicopathologic course in most patients. Acute tubular necrosis, glomerulopathies, lower urinary tract infection, and cytomegalovirus viremia were not confounding variables. In conclusion, proteomic technology together with stringent definition of patient groups can detect urine proteins associated with acute renal allograft rejection. Identification of these proteins may prove useful as non-invasive diagnostic markers for rejection and the development of novel therapeutic agents.
Acute Disease↗
Leukocyte reduction of red blood cell transfusions does not decrease allosensitization rates in potential kidney transplant candidates.
A significant proportion of potential kidney transplant candidates continue to periodically require blood transfusions that carry a risk of allosensitization. Leukocyte reduction (leukoreduction) of blood products has been proved to reduce transfusion-associated allosensitization in patients with hematologic malignancies; however, the effect in potential kidney transplant candidates is unknown. A total of 112 kidney transplant candidates who received red blood cell transfusions while on the transplant waiting list were identified retrospectively. Sixty received a transfusion before leukoreduction (non-LR), and 52 received a transfusion after the local implementation of universal leukoreduction of blood products (LR). There was no difference in transfusion-associated allosensitization rates in patients who received a transfusion during the two eras (non-LR 27% [16 of 60] versus LR 33% [17/52]; NS). Likewise, no difference was observed in subgroups identified as being at high risk of allosensitization (previous pregnancy, transplant, or five or more previous transfusions) or at low risk (no previous allogeneic exposures) (high risk: non-LR 52% versus LR 55%; low risk: non-LR 10% versus LR 8%). Multivariate analysis revealed previous pregnancy to be the only significant risk factor associated with transfusion-associated allosensitization (relative risk, 8.2; 95% confidence interval, 2.4 to 24.0; P = 0.0001). Leukoreduction, in particular, was not associated with any protective effect. In summary, leukoreduction of red blood cell transfusions does not confer any protection against transfusion-associated allosensitization for potential kidney transplant candidates. Physicians who care for patients with ESRD must continue to practice careful transfusion avoidance while alternative strategies to minimize transfusion associated allosensitization are sought.
Adult↗
Urine protein profiling with surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry.
BACKGROUND: In the last few years there has been an increasing interest in exploring the human proteome. In particular, efforts have focused on developing strategies to generate reproducible protein maps of normal cells, tissues, and biologic fluids, from which studies can then compare protein expression between different groups (e.g., healthy individuals vs. those with a specific pathologic state). METHODS: Various extrinsic factors (instrument settings, matrix composition, urine storage post void, freeze-thaw cycles) and intrinsic factors (blood in urine, urine dilution, first-void vs. midstream urine) were analyzed with respect to their impact on urine protein profiling using surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS: Extrinsic factors that critically influenced reproducibility and peak detection of urine protein profiling were matrix composition and instrument settings, while freeze-thaw cycles had minimal impact. Midstream urines samples did not undergo changes in their protein profile when stored for three days at 4 degrees C. Intrinsic factors that influenced normal urine protein profiling were blood in the urine and urine dilution. Female first-void urine had a significantly different ratio of proteins present compared to a midstream urine sample. Limitations of the SELDI-TOF-MS technique included ion suppression and quantification of individual proteins when protein composition was complex. CONCLUSION: SELDI-TOF-MS offers a unique platform for high throughput urine protein profiling; however, standardization of analysis conditions is critical, and both extrinsic and intrinsic factors must be taken into account for accurate data interpretation.
Female↗
National conference to assess antibody-mediated rejection in solid organ transplantation.
The process of humoral rejection is multifaceted and has different manifestations in the various types of organ transplants. Because this process is emerging as a leading cause of graft loss, a conference was held in April 2003 to comprehensively address issues regarding humoral rejection. Though humoral rejection may result from different factors, discussion focused on a paradigm caused by antibodies, typically against donor HLA antigens, leading to the term 'antibody-mediated rejection' (AMR). Conference deliberations were separated into four workgroups: The Profiling Workgroup evaluated strengths and limitations of different methods for detecting HLA reactive antibody, and created risk assessment guidelines for AMR; The Diagnosis Workgroup reviewed clinical, pathologic, and serologic criteria for assessing AMR in renal, heart and lung transplant recipients; The Treatment Workgroup discussed advantages, limitations and possible mechanisms of action for desensitization protocols that may reverse AMR; and The Basic Science Workgroup presented animal and human immunologic models for humoral rejection and proposed potential targets for future intervention. This work represents a comprehensive review with contributions from experts in the fields of Transplantation Surgery, Medicine, Pathology, Histocompatibility, Immunology, and clinical trial design. Immunologic barriers once considered insurmountable are now consistently overcome to enable more patients to undergo organ transplantation.
Antibodies↗
Pre-transplant assessment of donor-reactive, HLA-specific antibodies in renal transplantation: contraindication vs. risk.
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Antibodies↗
Heightened peripheral blood lymphocyte CD69 expression is neither sensitive nor specific as a noninvasive diagnostic test for renal allograft rejection.
It has been reported that acute allograft rejection is associated with heightened expression of the peripheral blood lymphocyte (PBL) early activation marker CD69 and that this may serve as a potential biomarker of rejection. This study sought to determine whether PBL CD69 expression correlates with both acute clinical and subclinical renal allograft rejection as well as clinically inapparent cytomegalovirus (CMV) infection. Flow cytometric determination of PBL CD69 expression was performed at the time of clinical and protocol biopsies (n = 131) in 45 renal transplant recipients. Nineteen patients also underwent weekly monitoring of PBL CD69 expression for the initial 15 wk after transplantation. Simultaneous screening for CMV viremia was performed with a semiquantitative PCR assay. No differences were seen in either CD4+ or CD8+ lymphocyte CD69 expression between the biopsy diagnoses. CMV viremia however, independent of rejection, was associated with greater CD69 expression on CD8+ lymphocytes (17.8 +/- 10.4% versus 9.6 +/- 4.8%; P < 0.0001) but not CD4+ lymphocytes. No individuals experienced clinical CMV disease. Weekly monitoring of PBL CD69 expression did not change coincident with the diagnosis of rejection; however, CMV viremia coincided with a substantial rise in the proportion of CD8+69+ lymphocytes in a number of individuals. Thus, PBL CD69 expression is neither sensitive nor specific for the noninvasive diagnosis of renal allograft rejection. Furthermore, clinically inapparent CMV viremia is associated with heightened expression of this activation marker on CD8+ lymphocytes. This latter finding suggests that clinically inapparent CMV viremia may be a potential confounder for biomarkers of rejection that examine peripheral blood lymphocytes.
Antigens, CD↗
Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function.
Chronic allograft nephropathy (CAN) is a major problem in posttransplant management. The lack of a reliable and early surrogate marker of CAN has hampered patient care and research. In this study, the Cortical Fractional Interstitial Fibrosis Volume (V(IntFib)), quantitated with computerized image analysis of Sirius Red-stained protocol biopsies, was examined as a potential surrogate for time to graft failure (TTGF) in 68 renal allograft recipients. At 6 mo posttransplant, V(IntFib) was highly correlated with TTGF (r = 0.64, P < 0.001). Both the Banff Chronic Sum and the Acute Sum Scores were also correlated with TTGF, but less strongly (r = 0.28, P < 0.02; r = 0.35, P < 0.003, respectively). As V(IntFib) was not correlated with the Banff Chronic Score, a multivariate model was created that incorporated V(IntFib) and both Acute and Chronic Banff pathology. This model was highly correlated with TTGF (r = 0.7, P < 0.0001). These findings suggest that V(IntFib) determined by computerized image analysis of Sirius Red-stained protocol biopsies at 6 mo posttransplant, with or without incorporation of Banff acute and chronic scoring, may provide an early surrogate for time to graft failure in renal allograft recipients.
Adult↗
Reproducibility of the Banff schema in reporting protocol biopsies of stable renal allografts.
BACKGROUND: There is evidence that biopsy of stable renal allografts may be of value in predicting chronic allograft nephropathy, the main cause of graft loss. However, the reproducibility of such histological evaluation has not been tested in this setting. We tested the reproducibility of the Banff schema for this purpose. METHODS: We rated acute and chronic changes in 184 protocol biopsies. Individual pathologists at two different Canadian transplant centres reported independently. RESULTS: There was agreement in 73.53, 42.86, and 77.08% of cases in assigning a diagnosis of acute rejection, borderline changes (as defined in the schema), and no acute rejection, respectively. Applying kappa statistics, there was very good agreement in making the diagnosis of acute rejection vs no acute rejection (kappa 0.77). There was good inter-observer agreement in scoring glomerulitis, intimal arteritis, interstitial infiltrates, tubulitis, and arteriolar hyalinosis. Rating chronic changes also gave good inter-observer agreement (kappa=0.53, 0.65, and 0.62, respectively, for mild, moderate, and severe chronic allograft nephropathy). Agreement on transplant glomerulopathy was, however, poor. CONCLUSIONS: We conclude that the Banff classification provides a reproducible method for the histological assessment of protocol renal allograft biopsies in stable grafts. Such biopsies may be valuable in detecting subclinical rejection and early chronic allograft nephropathy and may also be used as surrogate end-points in the evaluation of therapy to prevent the latter.
Biopsy↗
Flow cytometric crossmatching in primary renal transplant recipients with a negative anti-human globulin enhanced cytotoxicity crossmatch.
Flow cytometric crossmatching (FCXM) and panel reactive antibody (PRA) screening techniques are more sensitive than anti-human globulin enhanced cytotoxicity (AHG-CDC) techniques at detecting anti-HLA antibodies. The clinical significance of a positive FCXM in primary renal transplant recipients with a negative AHG-CDC crossmatch is unclear. We performed retrospective FCXM and flow cytometric panel reactive antibody (FlowPRA) determinations in primary renal transplant recipients with a negative T cell AHG-CDC crossmatch and a negative B cell CDC crossmatch pretransplant. Eighteen (13%) of 143 patients exhibited a positive retrospective T cell FCXM. Of these patients, six (33%) experienced early graft loss with explant histology, demonstrating antibody-mediated rejection in five of six cases. The 12 patients with positive T cell FCXM who maintained their grafts experienced more adverse events posttransplant, including more early, steroid-resistant, and recurrent rejection. Furthermore, in a subgroup of patients undergoing protocol biopsies, those with a positive T cell FCXM exhibited more subclinical rejection. Anti-HLA antibodies were detected by FlowPRA in all 18 patients with a positive T cell FCXM, whereas AHG-CDC PRA detected antibodies in only 8 of 18 patients. Therefore, flow cytometric techniques identify sensitized primary renal transplant recipients undetected by AHG-CDC techniques. In those patients, a positive T cell FCXM is associated with an increased risk of early graft loss due to antibody-mediated rejection and may represent a relative contraindication to transplantation. Moreover, those patients are also at increased risk of severe and recurrent rejection, which may carry implications for long-term graft outcomes.
Adult↗