Anti-vimentin Antibodies Present at the Time of Transplantation May Predict Early Development of Interstitial Fibrosis/Tubular Atrophy.

BACKGROUND: Anti-vimentin (a cytoskeletal protein) autoantibodies in renal transplant recipients have been correlated with interstitial fibrosis/tubular atrophy (IFTA). In this study, we examine the association between pretransplantation anti-vimentin antibodies and the subsequent development of IFTA. METHODS: Sera obtained before renal transplantation from 97 transplant recipients were analyzed for the presence of anti-vimentin antibodies via Luminex assays to determine the concentration of anti-vimentin antibodies. Results were correlated with findings of IFTA on biopsy as well as graft function and patient and graft survival. RESULTS: In our patient population, 56 of 97 patients were diagnosed by biopsy with IFTA 2.9 (±2.1) years after renal transplantation. Patients with IFTA on biopsy had higher mean concentration of anti-vimentin antibodies when compared to patients without IFTA (32.2 µg/mL [3.97-269.12 µg/mL] vs 14.57 µg/mL [4.71-87.81 µg/mL]). The risk of developing IFTA with a concentration of anti-vimentin antibody >15 µg/mL before transplantation was 1.96 (95% CI = 1.38-2.79, P = .011). Patients with elevated anti-vimentin antibody concentrations (>15 µg/mL) at the time of transplantation also had a higher risk of developing IFTA (81.4% vs 41.2%; P < .05). In addition, graft function was worse at 1, 3, and 5 years posttransplantation in patients with elevated concentrations of pretransplantation anti-vimentin antibody. Although there were more graft losses in the IFTA groups (49.12% vs 25.64%, P = .021) and the IFTA patients loss their grafts earlier (4.3 years vs 3.6 years), there was no statistical difference in graft loss rates. CONCLUSIONS: Pretransplantation anti-vimentin antibody concentrations >15 µg/mL may be a risk factor for IFTA.

HLA-A2 reactive antibodies in a patient who types as HLA-A2: The importance of high resolution typing and epitope-based antibody analysis.

This report describes a case of a highly sensitized patient who had serum antibodies reacting with HLA-A2 but whose phenotype included HLA-A2. The determination of HLA mismatch acceptability at the antigen level was problematic, but high-resolution HLA typing information and epitope-based antibody specificity analysis based on the nonself-self paradigm of HLA epitope immunogenicity have provided a solution. This case supports the concept that HLA typing at the allele level offers a better approach to identifying suitable donors for sensitized patients.

Graft-versus-Host Disease after Living-Unrelated Kidney Transplantation.

Graft-versus-host disease (GVHD) is a rare complication after solid organ transplantation and consists of a reaction of donor derived immune cells directed against host tissues. The vast majority of cases reported in the literature involve liver, small intestine and pancreas transplantation. We report a case of GVHD in a 48-year-old man after living-unrelated kidney transplantation at another center. Six months postoperatively he developed a skin rash, anorexia, and diarrhea that resulted in malnutrition and a 90 pound weight loss. At this point he was transferred to our center with a BMI of 16 and severe cachexia. Intravenous hyperalimentation was initiated and an extensive work-up for an infectious etiology was performed and was negative. An esophagogastroduodenoscopy was performed and revealed nodularity of the gastric mucosa, atrophy, and edema in the first and second portion of his duodenum. Biopsy findings were consistent with GVHD. Aggressive immunosuppressive therapy was instituted with a good response. The anorexia and diarrhea resolved, and he was discharged on hospital day 20. Three months later, there had been no recurrence of the diarrhea, the patient had gained an additional 40 pounds, BMI of 25, and a repeat upper endoscopy revealed complete resolution of the initial endoscopic abnormalities.

Long-term quality of life after living kidney donation.

BACKGROUND: The supply of deceased donor kidneys available for transplantation is not sufficient to meet the demand. Despite a low rate of complications for donors and superior outcomes for recipients, living kidney donation (LKD) is on the decline for reasons that remain unclear. METHODS: We performed a retrospective review and analysis of living kidney donors (LDs) who underwent donor nephrectomy between January 1, 2000 and December 31, 2010. Candidates who were excluded from LKD were identified as control subjects (CSs). LDs and CSs were invited to voluntarily undergo a quality of life assessment using Short Form 12 v1.0 Questionnaire (SF-12) and an addendum questionnaire (AQ). The SF-12 and AQ were administered by telephone. Statistical analysis of the results was performed to obtain the SF-12 physical component score (PCS), SF-12 mental component score (MCS), and the AQ score. PCS and MCS for the general population were obtained from the 1998 National Survey of Functional Health Status. RESULTS: During the study period, 83 LDs and 116 CSs were interviewed. LDs were noted to have higher PCS (54.1 vs 49.6) and MCS (55.7 vs 49.4) compared with the general population. Ninety-nine percent of LDs believed that their quality of life did not decrease after LKD; 21.7% reported experiencing complications. Half of the LDs (48%) reported missing 1 day of work for evaluation; 71% of LDs reported missing at least 4 weeks of work after LKD. Nearly all LDs (99%) would undergo donation again. Fifty-two percent of LDs reported adhering to the recommended 2-year follow-up schedule with the transplantation team; 87% of LDs reported seeing their primary care physician. CONCLUSION: LDs are physically and mentally healthier after LKD compared to the general population. Most donors miss at least 1 month of work for LKD and undergo some form of post-donation monitoring. Despite this commitment, LKD is a very satisfying experience.

Antithymocyte antibody-induced coagulopathy in renal transplant recipients.

BACKGROUND: Antithymocyte antibody (ATA) remains the most commonly used induction immunosuppressive agent in renal transplantation (RT). To date, few case reports of ATA-induced coagulopathy exist. METHODS: We performed a single-center, retrospective analysis of renal transplant recipients (RTRs) who underwent RT followed by ATA therapy between 2007 and 2011. The protocol used for deceased donor and unrelated living donor recipient immunosuppression was Thymoglobulin (TMG), methylprednisolone, Cellcept, Prograf, and Rapamune. In related living donor recipients, Simulect (SIM) was substituted for TMG. The international normalized ratio (INR) was routinely checked on days 0 and 2, and thereafter at the discretion of the surgeon. RTRs were transfused packed red blood cells (PRBCs) or fresh frozen plasma (FFP) at the discretion of the surgeon. RESULTS: During the study period, 257 RTs were performed at our institution. The following 18 RTR were excluded: simultaneous kidney and pancreas transplant recipients (4), RTRs on warfarin at the time of admission (2), RTRs who received OKT3 (2), and RTRs with INR ≥ 1.2 at the time of admission (10). Of the remaining 239 RTR, 208 (87%) underwent TMG induction therapy; 31 RTR (13%) underwent SIM induction therapy. The mean INR peaked in both groups on day 4 but was higher in TMG recipients (TMG 1.35, SIM 1.20). FFP was transfused in 65 TMG (31%) and 3 SIM (10%) recipients (P = .01); PRBCs were transfused in 88 TMG (44%) and 6 SIM (19%) recipients (P = .02). No patients returned to the operating room for bleeding complications within 7 days of RT. Patient age, gender, ethnicity, and diabetes status were not statistically significant factors in the development of coagulopathy. CONCLUSION: TMG administration is associated with coagulopathy. Using an INR screening protocol and an aggressive transfusion protocol, bleeding complications associated with coagulopathy can be avoided in this higher-risk group.

Comparison of three real-time PCR for the quantification of polyomavirus BK.

BACKGROUND: Reactivation of latent polyomavirus BK is associated with nephropathy (PVAN) after renal transplantation. BK viral load determinations are a highly sensitive and specific method for predicting risk for PVAN. OBJECTIVES AND STUDY DESIGN: The performance of three real-time PCR for BKV DNA quantification (MultiCode(®)-RTx BK virus ASR [MC-RTx], MGB-Alert BKV ASR [MGB] and a laboratory developed assay [LDA]) were evaluated against a conventional PCR (test of record, TOR) in terms of linearity, dynamic range, and accuracy. RESULTS: The LOD (log(10) copies/ml) were 2.0, 2.0 and 3.0 for MC-RTx, MGB and LDA, respectively with a commercial plasma panel and 2.0, 2.6 and 3.5 with a urine panel. These assays demonstrated excellent linearity (r(2) = 1.0) and reproducibility (CV range = 0.7-20.4%, 0.9-13.2%, and 0.5-13%, respectively). In an analysis of 100 clinical specimens, all 76 samples defined as true positive for BKV DNA (positive by two or more methods or a recent history of positivity) were detected with MC-RTx, while only 64 were detected with MGB and 55 were detected with LDA. BKV DNA was not detected by any method in the true negative specimens. Based on these results, the sensitivities were 100% for MC-RTx, 84% for MGB and 72% for LDA. The greatest linear correlation with the mean concentration was observed with MC-RTx (r(2) = 0.96) with two samples (3%) with greater than 0.5 log(10) variance in quantification versus seven (11%) with MGB and ten (18%) with LDA. CONCLUSIONS: These real-time assays for BKV load demonstrated excellent performance characteristics, with the MC-RTx demonstrating the greatest sensitivity.

Ureteral stents: a risk factor for polyomavirus BK viremia in kidney transplant recipients undergoing protocol screening.

BACKGROUND: Polyomavirus BK nephropathy (BKN) remains a common cause of early renal transplant dysfunction and graft loss. To date, little has been reported on the role, if any, of transplant ureteral stents in the development of polyomavirus BK viremia (BVK) and BKN. METHODS: We performed a single-center, retrospective analysis of renal transplant recipients who underwent renal transplantation followed by monthly BKV screening at Albany Medical Center between January 1, 2006, and December 31, 2009. A transplant ureteral stent was placed at the discretion of the surgeon. The immunosuppression protocol employed for deceased donor and unrelated living -donor recipients was antithymocyte antibody induction with methylprednisolone, mycophenolate mofetil, tacrolimus, and sirolimus. RESULTS: During the study period, 186 recipients were identified; 124 (67%) underwent intraoperative transplant ureteral stent placement, while 62 patients (33%) did not undergo stent placement. With our monthly screening protocol, we detected BKV in 32 of the 186 recipients (17%) following transplantation; 27 of the 32 (84%) viremic patients were stent recipients. In all patients who developed BKV, an immunosuppression dose reduction protocol was employed. Ureteral stent placement conferred a statistically significant elevated risk of developing BKV (odds ratio = 3.17, 95% confidence interval 1.16-8.70). Patient gender, age, ethnicity, diabetes status, and retransplant status were not statistically significant factors in the development of BKV. CONCLUSION: Our study demonstrated the elevated risk of BKV in recipients who undergo transplant ureteral stenting. Monthly BK polymerase chain reaction screening appears to be a useful tool for the early detection of BKV in this higher-risk group.

Initiation of a screening protocol for polyoma virus results in a decreased rate of opportunistic non-BK viral disease after renal transplantation.

BACKGROUND: Polyoma BK virus nephropathy (PVN) is a leading cause of renal allograft injury and loss. The mainstay of treatment, as there are no target therapies approved by the US Food & Drug Administration, is reduction in immunosuppression. However, current approaches are shifting to screening for viremia as an indicator of oncoming nephropathy, with subsequent reduction in immunotherapy. We attempted not only to replicate these data but also to evaluate the utility of polyoma viremia as a surrogate marker for overimmunosuppression in general, thus allowing prevention not only of PVN but also of other viral opportunistic infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) disease. PATIENTS AND METHODS: We conducted a retrospective cohort analysis of renal transplant recipients at our center. The historical controls (2003-2005, n = 134) had received their allograft before the institution of a monthly serum polymerase chain reaction (PCR) polyoma screening protocol. The screened cohort received their allograft afterwards (2006-2008, n=134). Screening was performed using PCR techniques with prompt reduction in immunosuppression for viremic patients. The patients were followed for the development of PVN, acute rejection, renal allograft function, and survival. RESULTS: Polyoma viremia was noted in 16% of the screened population, with none developing PVN after prompt reduction of immunosuppression. Clearance of the viremia occurred by 6 months in 95% of the patients after reduction of immunotherapy. No patient in the screened group developed CMV or EBV disease. Of the controls, 7 (5%) developed PVN and 12 (9%) developed CMV or EBV disease, compared with none of the screened patients (P<0.05). The incidence of acute rejection was comparable between the groups (4% controls, 5% screened). No deleterious effects were noted on patient or allograft survival, allograft function (measured by serum creatinine), rates of fungal infection, or the rate of post-transplant lymphoproliferative disorder in the screened patients. CONCLUSIONS: Monthly PCR monitoring for BK viremia, together with a modest decrease in immunotherapy, is not only safe but also effectively prevents PVN and is associated with a significantly decreased rate of CMV and EBV disease in renal transplant patients. BK viremia may also serve as a surrogate marker for overimmunosuppression.

Sirolimus immunotherapy: the Albany Medical Center experience.

At the Albany Medical Center, we have a long-term experience, mean follow-up of 61 months, in 31 renal transplant recipients treated with sirolimus, cyclosporine microemulsion formulation, and prednisone. In these patients the rate of acute rejection was 13%, actual patient and graft survival at 1 year was 100%, and the mean serum creatinine at 1 year was 1.3 mg/dL. Furthermore, long-term graft survival was 90%. The success of this regimen stimulated us to evaluate a subsequent sirolimus-based protocol, initiated in April, 2001, which decreased exposure to calcincurin inhibitors at 3 months posttransplant (n = 50). At a mean follow-up of 10 months, graft survival was 96%. The rate of acute rejection was only 10% and the mean serum creatinine was 1.5 mg/dL. Furthermore, no acute rejection episodes have developed subsequent to the reduction in calcineurin inhibitor dosing at 3 months. Sirolimus is an effective immunosuppressive agent that safely allows for a reduction in calcineurin-inhibitor dosing.

TNF-alpha, IL-6, IFN-gamma, and IL-10 gene expression polymorphisms and the IL-4 receptor alpha-chain variant Q576R: effects on renal allograft outcome.

BACKGROUND: There has been much interest recently in the effects of various cytokine gene expression polymorphisms on graft outcome. However, the results of these investigations reveal the outcomes to be organ-specific and center-specific. We sought to confirm and add to some of the earlier findings by studying the impact of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) polymorphisms and the interleukin-4 (IL-4) receptor alpha-chain variant on posttransplant renal allograft outcome. METHOD: TNF-alpha, IL-6, IFN-gamma, and IL-10 gene promoter region polymorphisms were assayed genotypically by PCR-SSP on 120 patients transplanted at the Albany Medical Center. These patients were also typed for the IL-4 receptor alpha-chain variant Q576R. RESULTS: Producers of high levels of the proinflammatory cytokine TNF-alpha were found to be at increased risk for acute rejection episodes if the allograft was mismatched for the molecular products of the class II region of the human major histocompatibility complex (HLA-DR). Expression level polymorphisms of the IL-6, IFN-gamma, and IL-10 genes were not associated with acute rejection episodes, nor was the IL-4 receptor alpha-chain variant Q576R. CONCLUSIONS: These data would suggest that the production of high levels of the cytokine TNF-alpha is especially detrimental to graft survival when the recipient's T-helper lymphocytes are being activated by mismatched donor HLA-class II antigens. Typing all potential kidney recipients for TNF-alpha, and providing well-matched organs for high producers of this cytokines, may be expected to increase rejection-free graft survival in these patients.

Promoter-region alleles of the TNF-alpha and IL-10 genes have no effect on pretransplant alloantibody production.

BACKGROUND: The presence of high levels of alloantibodies are known to be a risk factor in renal graft outcome. Expression level polymorphisms in cytokine genes are also thought to have an effect on allograft outcome, but the studies examining this have been inconsistent. This may be due to center-specific differences in immunosuppressive protocols. Therefore, we studied the effects of these polymorphisms on pretransplant class I alloantibody production in nonexogenously immunosuppressed candidates. METHODS: Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) gene polymorphisms were assayed genotypically by PCR-SSP on 177 renal transplant candidates. Candidates with a peak goat antihuman immunoglobulin-enhanced T-cell panel reactive antibody (PRA) of >or=10% were considered to be positive for alloantibody (32% of 177 total). RESULTS: Previous transplants, transfusions, or pregnancies were all associated with alloantibody production, but TNF-alpha and IL-10 phenotypes were not. High levels of alloantibody production (peak PRA >50%) were also not effected by cytokine phenotype. CONCLUSIONS: These data suggest that differences in TNF-alpha and IL-10 phenotype do not effect a patient's likelihood of becoming sensitized by transfusions, pregnancies, and prior transplants.

Prevalence of donor-specific anti-HLA antibodies during episodes of renal allograft rejection.

BACKGROUND: Recent studies suggest that the appearance of anti-HLA antibodies in the early posttransplant period is associated with an increased incidence of acute and chronic rejection months later. However, very little is known about the prevalence of anti-HLA antibodies at the time that the rejection episodes are diagnosed. The purpose of this study was to analyze retrospectively 420 sera from 263 renal allograft recipients who were readmitted to the hospital for any reason between 1989 and 1998 in order to determine if a correlation existed between the presence of donor-specific anti-HLA antibodies and graft rejection. METHODS: Sera were assayed for IgG HLA class I and II antibodies by ELISA. The ELISA results were analyzed using contingency tables with Fisher's exact test and compared with mismatched antigens in the donor. RESULTS: Antibodies to donor HLA class I molecules in the posttransplant sera were extremely rare, occurring in only 6 of the 420 sera (1.4%) analyzed. Antibodies to donor class II antigens were slightly more common, occurring in 25 of the 420 sera (6%). In 21 of these 25 cases (84%), the presence of donor-specific HLA class II antibodies was associated with episodes of either acute (n=14) or chronic rejection (n=7). Five patients had antibodies to both class I and class II donor antigens, and all five of them lost their grafts to rejection. CONCLUSION: Although the presence of donor-specific HLA antibodies presented a significant risk for acute or chronic rejection, 77% of all acute and chronic rejections occurred in patients without detectable HLA antibodies.

The impact of allergies and allergy treatment on worker productivity.

Allergic disorders are a chronic and highly prevalent condition in the general population and the workforce. Their effect on workers and corporate costs go beyond the direct cost of treatment, as the condition can lower a worker's productivity. Previous research includes estimates of the decrease in productivity associated with allergic disorders. None of these studies, however, offered an objective measure of how worker productivity is affected by allergic disorders. In the present study, the productivity of telephone customer service representatives suffering from allergic disorders is examined before, during, and after the ragweed pollen season. In addition, these workers were surveyed as to the type of medication they used in response to their condition. A significant correlation was observed between an increase in pollen counts and a decrease in productivity for workers with allergies. Compared with workers without allergies, employees with allergies who reported using no medication showed a 10% decrease in productivity. No differences were observed among workers with allergies using different types of medications, although the medication groups had significantly higher productivity than the no-medication group. The expected lowered productivity of those workers with allergies who used sedating antihistamines may have been offset by their relatively lower level of symptom severity and by the nature of the job and the productivity measures used.

Disability management: corporate medical department management of employee health and productivity.

This study describes a proactive in-house program for managing short-term disability (STD) in the workforce of a very large banking system. The goals of this program were to (1) minimize the personal and economic impacts of STD by early intervention, (2) validate the extent and duration of STD, and (3) coordinate medical services and provide guidance to managers that would facilitate an early return to work. This program was made possible by the installation of a comprehensive database, called Occupational Medicine and Nursing Information System. This database mainly includes employees' claims for inpatient and outpatient health services, disability and workers' compensation benefits, wellness program participation, medical examinations and laboratory tests, use of prescription drugs, and results of Health Risk Appraisals. As a result of these efforts, STD event duration declined after this STD management program was implemented in locations heretofore outside the system, and by providing full pay for part-time work after STD, within the system as well. Of note, the average number of STD days per employee showed substantial variation by health plan, including the fact that it was higher (3.9 STD days/employee) for health maintenance organization participants than for indemnity plan members (2.7 STD days/employee).

Failure of ganciclovir prophylaxis to completely eradicate CMV disease in renal transplant recipients treated with intense anti-rejection immunotherapy.

Ganciclovir prophylactic regimens have been shown to be effective in renal transplant recipients at risk for primary (donor seropositive/recipient seronegative) and secondary (recipient seropositive) cytomegalovirus (CMV) disease. However, in addition to serologic factors, the type and intensity of the administered immunosuppression is a strong risk factor for CMV disease. Since January 1995, we have utilized a potent immunosuppressive protocol selectively in recipients at high risk for immunologic graft loss, defined as retransplant recipients, recipients with delayed graft function, non-Caucasian recipients, and recipients suffering from acute rejection. Between January 1995 and December 1996, 110 consecutive renal transplants were performed in recipients who were either CMV seropositive or received an allograft from a CMV-seropositive donor. All recipients received ganciclovir prophylactic therapy for 3 months post-transplant. Group I (N = 43) consisted of recipients at high-immunologic risk for graft loss as defined above. These recipients were treated with an intense anti-rejection immunotherapeutic regimen consisting of Cellcept, Neoral, and prednisone, with the frequent addition of antilymphocyte antibody therapies and intravenous methylprednisolone. The remaining 67 recipients (group II) were treated with a less intense immunotherapeutic regimen consisting of azathioprine, Neoral, and prednisone. The incidence and severity of CMV disease and the patient and allograft survival were compared. The incidence of CMV syndrome was greater in group I (28%) compared with group II (7%), and was statistically significant (p < 0.05). The 1-yr patient and graft survival were similar, 95 and 91%, respectively, for group I compared with 97 and 97%, respectively, for group II. These data suggest that 3 months of ganciclovir prophylactic therapy is significantly less effective for the prevention of CMV disease in renal transplant recipients at high risk for acute rejection treated with an intense immunotherapeutic regimen. These data suggest that more effective prevention of CMV disease in these high-risk recipients will require the addition of other anti-viral agents, such as immunoglobulin preparation to the prophylactic regimen.

Diverticulitis and polycystic kidney disease.

Patients with adult polycystic kidney disease (PKD) have previously been shown to have an increased incidence of complicated diverticulitis after renal transplantation. The purpose of this study was to assess the risk of diverticulitis in the PKD population. We retrospectively reviewed patients with advanced PKD, defined as end-stage renal failure requiring dialysis. Patients were obtained from a single nephrology group practice between January 1985 and January 1997, or from all patients being evaluated or actively considered for renal transplantation at our institution as of May 1997. The incidence and severity of diverticulitis in these patients was compared with that observed in a similar cohort of patients with end-stage renal disease due to other etiologies. The study population consisted of 184 renal failure patients, 59 with PKD and 125 with other causes of end-stage renal disease. Twelve (20%) patients with PKD had a history of active diverticulitis, whereas only 4 (3%) of the non-PKD controls had diverticulitis (P = 0.0003, Fisher's exact test). Six of the 12 PKD patients required surgical intervention. Patients with renal failure due to PKD experience a significantly higher rate of diverticulitis than do other patients with end-stage renal disease. Furthermore, diverticulitis is frequently severe in PKD patients, with 50 per cent requiring surgical intervention. These data suggest that diverticular disease may be an extrarenal manifestation of polycystic kidney disease.

The role of health risk factors and disease on worker productivity.

The costs attributed to employee health problems are usually measured by employers in terms of direct health care costs, such as medical plan claims. Although it has been understood that employee health problems also produce indirect costs for employers, their measurement has been far less frequent. At best, studies have recorded one component of indirect health costs: the time lost to employee absenteeism and disability. The study presented here includes a measure of the actual decrease in the productivity of employees while they are on the job, in addition to measures of absenteeism and disability. These three measurements were combined to produce a Worker Productivity Index (WPI). The WPIs of 564 telephone customer-service agents were correlated with the employees' number and type of health risks, as measured by a Health Risk Appraisal. Additionally, the WPI was also examined across different disease states in the same population of employees. As the number of health risks increased, an employee's productivity decreased. The nature of the health risk may also differentially affect the pattern of the decrease. Finally, disease states were also associated with different patterns of productivity reduction.