Anti-HLA alloantibody is a risk factor for graft loss, but does not indicate which kidneys are experiencing antibody-mediated rejection (ABMR). C4d staining in biopsies is specific for ABMR but insensitive. We hypothesized that altered expression of endothelial genes due to alloantibody acting on the microcirculation would be sensitive indicator of ABMR. We identified 119 endothelial-associated transcripts (ENDATs) from literature, and studied their expression by microarrays in 173 renal allograft biopsies for cause. Mean ENDAT expression was increased in all rejection but was higher in ABMR than in T-cell-mediated rejection and correlated with histopathologic lesions of ABMR, and alloantibody. Many individual ENDATs were increased in ABMR and predicted graft loss. Kidneys with high ENDATs and antibody showed increased lesions of ABMR and worse prognosis in comparison to controls. Only 40% of kidneys with high ENDAT expression and chronic ABMR or graft loss were diagnosed by C4d positivity. High ENDAT expression with antibody predicts graft loss with higher sensitivity (77% vs. 31%) and slightly lower specificity (71% vs. 94%) than C4d. The results were validated in independent set of 82 kidneys. High renal endothelial transcript expression in patients with alloantibody is indicator of active antibody-mediated allograft damage and poor graft outcome.

Background: Gene-set analysis evaluates the expression of biological pathways, or a priori defined gene sets, rather than that of individual genes, in association with a binary phenotype, and is of great biologic interest in many DNA microarray studies. Gene Set Enrichment Analysis (GSEA) has been applied widely as a tool for gene-set analyses. We describe here some critical problems with GSEA and propose an alternative method by extending the individual-gene analysis method, Significance Analysis of Microarray (SAM), to gene-set analyses (SAM-GS).

Microarrays offerpotential for objective diagnosis and insights into pathogenesis of allograft rejection. We used mouse transplants to annotate pathogenesisbased transcript sets (PBTs) that reflect major biologic events in allograft rejection-cytotoxic T-cell infiltration, interferon-c effects and parenchymal deterioration. We examined the relationship between PBT expression, histopathologic lesions and clinical diagnoses in 143 consecutive human kidney transplant biopsies for cause. PBTs correlated strongly with one another, indicating that transcriptome disturbances in renal transplants have a stereotyped internal structure. This disturbance was continuous, not dichotomous, across rejection and nonrejection. PBTs correlated with histopathologic lesions and were the highest in biopsies with clinically apparent rejection episodes. Surprisingly, antibody-mediated rejection had changes similar to T-cell mediated rejection. Biopsies lacking PBT disturbances did not have rejection. PBTs suggested that some current Banff histopathology criteria are unreliable, particularly at the cut-off between borderline and rejection. Results were validated in 51 additional biopsies. Thus many transcriptome changes previously described in rejection are features of a large-scale disturbance characteristic of rejection but occurring at lower levels in many forms of injury. PBTs represent a quantitative measure of the inflammatory disturbances in organ transplants, and a new window on the mechanisms of these changes.

Herpes zoster (HZ) infection is a frequent and serious complication of organ transplantation that has not been examined in the current era of immunosuppression.All solid organ transplants performed between 1994 and 1999 (n = = 869) at our center were analyzed to determine the incidence, complications and risk factors for developing HZ.The overall incidence of HZ was 8.6% (liver 5.7%, renal 7.4%, lung 15.1% and heart 16.8%). The median time of onset was 9.0 months. We observed high rates of cutaneous scarring (18.7%) and post-herpetic neuralgia (42.7%). Independent organ-specific risk factors included: female gender and mycophenolate mofetil therapy (liver), and antiviral treatment other than prolonged cytomegalovirus (CMV) prophylaxis (renal and heart). For all organs combined, induction therapy and antiviral treatment other than prolonged CMV prophylaxis were independent predictors for the development of HZ.Herpes zoster is common and results in significant morbidity for solid organ transplant recipients. Risk factors include induction therapy and antiviral drug therapy other than CMV prophylaxis. The latter variable identifies a subpopulation that is likely at increased risk of latent herpesvirus reactivation. The high first-year post-transplant incidence rate suggests immunization pretransplant, even in varicella zoster virus immunoglobulin seropositive individuals, may be preventative. Key words: Herpes zoster, infection, transplantationReceived 12 March, revised 22 July, re-revised 18 August and accepted for publication 19 August 2003Varicella zoster virus (VZV) is the most infectious of the human herpesviruses and infection is almost universal (95%) by adulthood in North American and European populations. Reactivation of latent VZV [herpes zoster (HZ) or shingles] is a painful, cutaneous eruption, dermatomal in distribution, associated with a risk of dissemination. Previously described risk factors for HZ include age, malignancy, HIV infection, organ transplantation, immunodeficiency and treatment with immunosuppressive medications (1).Herpes zoster leads to significant morbidity and its most frequent complication (2) is post-herpetic neuralgia (PHN), which is associated with persistent pain for 30 or more days after acute infection, lasting years in some cases (3). Unfortunately, immunocompromized patients tend to have the most severe complications of reactivation with a greater tendency for a prolonged course of disease (4). Severely immunocompromized patients with HZ have a risk of dissemination of up to 40%, which can result in mortality rates, despite antiviral therapy, of between 4 and 34% (5-7).Previously reported incidences vary widely (8-17) and, to our knowledge, no population-based studies have been performed that define the incidence of HZ in adult multiorgan transplant cohorts. However the following incidences have been suggested in this population: renal 3-10%, liver 5-10%, lung 8-12% and hearts 20-25% (7). Possible reasons for this variation include center effect, the immunosuppressive drug ...

Subjective symptom assessment should be a fundamental component of health-related quality of life (HRQL) assessment in end-stage renal disease (ESRD). Unfortunately, no symptom checklist has established reliability or validity in ESRD. We report the validation of a modified Edmonton Symptom Assessment System (ESAS) in 507 dialysis patients who concurrently completed the Kidney Dialysis Quality of Life-Short Form (KDQOL-SF) questionnaire. The ESAS demonstrated a mean of 7.5+/-2.5 symptoms. The symptoms reported as most severe were tiredness, well-being, appetite, and pain. The overall symptom distress score was strongly correlated with the KDQOL-SF subscales symptom/problem list (r=-0.69, P<0.01), effects of kidney disease (r=-0.52, P<0.01), and burden of kidney disease (r=-0.50, P<0.01), as well as lower RAND-12 physical health composite (PHC) (r=-0.54, P<0.01) and lower RAND-12 mental health composite (MHC) (r=-0.62, P<0.001). In the multivariate regression analysis, after controlling for potential confounding variables including comorbidity using the modified Charlson Comorbidity Index, the ESAS symptom distress score remained strongly associated with the MHC (slope=-0.82+/-0.07, P<0.01) and PHC (slope=-0.48+/-0.07, P<0.01). The ESAS symptom distress score accounted for 29% of the impairment in PHC and 39% of the impairment in MHC. The intraclass correlation coefficient for the total symptom distress score in a 1-week test-retest was 0.70, P<0.01. Symptom burden is high and adversely affects HRQL in dialysis patients. The modified ESAS is a reliable, valid, simple, and useful method for regular symptom assessment in this patient population.

Symptom burden in end-stage renal disease was substantial and had a tremendous negative impact on all aspects of hemodialysis patients' HRQL. These patients, therefore, would likely benefit from the institution of programs to reduce symptom burden.

Higher CRP and sTNFrii are independently associated with faster rates of kidney function loss in chronic kidney disease. Pravastatin appears to prevent loss of kidney function to a greater extent in individuals with greater evidence of inflammation, although this was of borderline significance. These data suggest that inflammation may mediate the loss of kidney function among subjects with chronic kidney disease and concomitant coronary disease.

Simple clinical and laboratory assessments are useful aids in the prediction of survival in patients with solid malignant neoplasms at the onset of terminal stages. Methodological improvements in the design and implementation of survival studies may reduce prognostic uncertainty and ultimately provide better care for the terminally ill patients and their families.