Transplantation of en bloc pediatric kidneys when the proximal vascular cuff is too short.
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Child↗
Biomedical subjects
Ron Shapiro
Publications and source records attributed to Ron Shapiro.
Pancreas transplantation under alemtuzumab (Campath-1H) and tacrolimus: Correlation between low T-cell responses and infection.
BACKGROUND: Alemtuzumab induction and tacrolimus-based immunosuppression has been effective in pancreas transplantation. Despite the encouraging results of this minimalistic approach to immunosuppression, infection still remains a significant cause of morbidity. The Cylex ImmuKnow [corrected] assay was used in this study to compare pancreas recipient clinical states (stable, rejection, infection) with T cell responses. METHODS: Blood samples were taken from pancreas recipients pretransplant and at approximately three-month intervals posttransplant for analysis of T cell responses. When possible, T cell responses were also quantified during changes in clinical status (infection or rejection). RESULTS: A range between 100-300 ng/ml adenosine triphosphate (ATP) was found in stable patients (mean 194+/-123, n = 51) with good graft function and no infection or rejection. A low T cell response was highly correlated with infectious states. The fourteen patients with infections/posttransplant lymphoproliferative disease had a mean ATP of 48 ng/ml. Risk hazard analysis showed that patients with ATP levels <100 ng/ml were four to seven times more susceptible to infection compared to stable patients. Four patients with rejection showed a T cell response of 550 ng/ml ATP, which was statistically significant compared to stable patients, although the sampling numbers (9) were too small to be conclusive. CONCLUSION: The Cylex ImmuKnow [corrected] assay is a valuable tool to more precisely modulate immunosuppression in pancreas transplant patients. In particular, the assay is extremely useful in detecting overly immunosuppressed patients vulnerable to infections.
Adenosine Triphosphate↗
Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: One- and two-year outcomes.
BACKGROUND: Alemtuzumab (Campath-1H) induction with tacrolimus monotherapy has been shown to provide effective immunosuppression for kidney, liver, lung, and small bowel transplantation. This drug combination was evaluated in pancreas transplant recipients. METHODS: Sixty consecutive pancreas transplants (30 simultaneous pancreas-kidney, 20 pancreas after kidney, and 10 pancreas alone) were carried out under this protocol between July 2003 to January 2005. The mean follow-up was 22 months (range 17-33). RESULTS: One-year patient, pancreas, and kidney allograft survival were 95%, 93%, and 90%, respectively. With 22 months follow-up, patient, pancreas, and kidney survival were 94%, 89%, and 87%, respectively. The rejection rate was 30% (18/60), with four patients (7%) experiencing steroid-resistant rejection. Major infection occurred in three (5%) patients resulting in two (3.3%) deaths from disseminated histoplasmosis and a herpes virus infection. One patient with cryptococcal meningitis was successfully treated. Seven (11.7%) patients experienced cytomegalovirus infection, all of whom responded to treatment with ganciclovir. One (1.7%) case of polymorphic posttransplant lymphoproliferative disease was seen, which regressed with a temporary discontinuation of tacrolimus and high-dose ganciclovir. The mean serum creatinine of the 30 simultaneous pancreas-kidney transplants at one year posttransplant was 1.37+/-0.33 mg/ml. The preexisting creatinine in pancreas after kidney transplants was not adversely affected by this immunosuppressive protocol. CONCLUSION: A single dose of perioperative alemtuzumab followed by daily tacrolimus monotherapy provides effective immunosuppression for pancreas transplantation, but the optimal use of this drug combination is not yet clear.
Alemtuzumab↗
Opportunistic infections in 547 organ transplant recipients receiving alemtuzumab, a humanized monoclonal CD-52 antibody.
BACKGROUND: Alemtuzumab is being increasingly used for the prevention and/or treatment of acute allograft rejection in organ transplant recipients. We assessed the risks of infection in, to our knowledge, the largest cohort and broadest range of organ transplant recipients yet reported to have received alemtuzumab. METHODS: All patients who received alemtuzumab from September 2002 through March 2004, either as induction therapy at the time of transplantation or for the treatment of rejection, were evaluated for the development of an opportunistic infection (OI) until death or for 12 months after receipt of the last dose of alemtuzumab. RESULTS: A total of 547 recipients were included, 65% of whom received alemtuzumab for induction therapy only. Overall, 56 recipients (10%) developed 62 OIs, including cytomegalovirus disease (n = 16), BK virus infection (n=12), posttransplantation lymphoproliferative disease (n=5), human herpesvirus 6 infection (n=1), parvovirus infection (n=1), esophageal candidiasis (n=12), cryptococcosis (n=2), invasive mold infection (n=4), Nocardia infection (n=4), mycobacterial infection (n=3), Balamuthia mandrillaris infection (n=1), and toxoplasmosis (n=1). Patients who received alemtuzumab for induction therapy were significantly less likely to develop an OI, compared with patients who received alemtuzumab for rejection therapy (4.5% vs. 21%; P<.001). Independent predictors of the development of an OI were administration of alemtuzumab for rejection therapy (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8-6.8; P<.001), allograft failure (OR, 2.1; 95% CI, 1.1-4.4; P=.04), and receipt of a lung transplant (OR, 3.7; 95% CI, 1.7-8.0; P=.001) or an intestinal transplant (OR, 8.3; 95% CI, 3.5-19.5; P<.001). CONCLUSIONS: Patients who received alemtuzumab for the treatment of allograft rejection were significantly more likely to develop an OI, compared with patients who received alemtuzumab for induction therapy only. Such data have implications for new antimicrobial prophylactic strategies.
Adolescent↗
Proteomic analysis of urine in kidney transplant patients with BK virus nephropathy.
The differentiation of BK virus-associated renal allograft nephropathy (BKVAN) from acute allograft rejection (AR) in renal transplant recipients is an important clinical problem because the treatment can be diametrically opposite for the two conditions. The aim of this discovery-phase biomarker development study was to examine feasibility of developing a noninvasive method to differentiate BKVAN from AR. Surface-enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry analysis was used to compare proteomic profiles of urine samples of 21 patients with BKVAN, 28 patients with AR (Banff Ia to IIb), and 29 patients with stable graft function. SELDI analysis showed proteomic profiles that were significantly different in the BKVAN group versus the AR and stable transplant groups. Peaks that corresponded to m/z values of 5.872, 11.311, 11.929, 12.727, and 13.349 kD were significantly higher in patients with BKVAN. Bioinformatics analyses allowed distinction of profiles of patients with BKVAN from patients with AR and stable patients. SELDI profiles also showed a high degree of reproducibility. Proteomic analysis of urine may offer a noninvasive way to differentiate BKVAN from AR in clinical practice. The identification of individual proteomic peaks can improve further the clinical utility of this screening method.
Adult↗
Low incidence of BK virus nephropathy after simultaneous kidney pancreas transplantation.
BACKGROUND: BK virus renal allograft nephropathy (BKVAN) in the setting of simultaneous kidney-pancreas transplantation (SKPT) has been inadequately studied and reported. We analyzed our data on the incidence of BKVAN and its outcome in SKPT recipients at University of Pittsburgh Medical Center (UPMC) and affiliated centers and report significant differences compared to previous studies. METHODS: This study used retrospective review and case studies. RESULTS: A review of 243 consecutive SKPT recipients from January 1, 1996 to December 31, 2004 identified seven cases (three females; ages = 23-54 yrs) of BKVAN following SKPT (incidence = 2.9%). The immunosuppressive protocols during this period were divided into: Period I (pre-August 2001) with no antibody induction and Period II (post-August 2001) with alemtuzumab or antithymocyte globulin induction with steroid avoidance. One BKVAN case was diagnosed in Period II (incidence = 1.4%). Six of seven patients were treated with intravenous cidofovir (0.20-0.50 mg/kg) every two to four weeks over one to six months. Three patients lost the renal allograft 8-22 months following diagnosis of BKVAN, whereas four patients had prolonged allograft survival. Pancreatic function was well preserved in five; one patient lost the pancreatic function due to surgical complications and one has had partial preservation. CONCLUSIONS: There was a relatively lower incidence of BKVAN among SKPT patients at our center. Although overall graft loss rate was comparable to other series, BKVAN patients had a slightly prolonged graft life. The BKVAN incidence was further reduced in patients receiving modified immunosuppression with antibody preconditioning. The underlying reasons may include less toxic immunosuppressive protocols, earlier diagnosis and the use of antiviral therapy.
Adult↗
Proposed live donor nephrectomy complication classification scheme.
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Humans↗
Detection of CD8+ T cells sensitized to BK virus large T antigen in healthy volunteers and kidney transplant recipients.
BK virus (BKV) infections after renal transplantation are increasingly recognized. Development of immune monitoring strategies against BKV requires definition of antigenic epitopes. Hence, T cells from HLA-A02-positive healthy subjects and kidney transplant recipients were stimulated by BKV lysate pulsed on mature autologous dendritic cells and screened against four different T antigen peptides or against BKV lysate. IFN-gamma production was measured by ELISPOT assays. The peptide BKV362-371 (MLTERFNHIL) was naturally processed and recognized by five of six healthy subjects (39 +/- 11 IFN-gamma spots/100,000 cells) and five of seven kidney transplant recipients (21 +/- 12 IFN-gamma spots). Less frequent and weaker CD8+ T-cell responses were detected against three other peptides. Thus, BKV large T antigen is a target for CD8+ T-cell immunity. T-antigen-specific T-cytotoxic cells circulate in healthy blood donors, implying that transient expression of T antigen presumably occurs at sites of viral latency and helps maintain a constant pool of circulating CD8+ T memory cells.
Adult↗
Bloodstream infections in organ transplant recipients receiving alemtuzumab: no evidence of occurrence of organisms typically associated with profound T cell depletion.
BACKGROUND: Alemtuzumab is a humanized monoclonal antibody directed against CD52, a cell surface antigen expressed on B and T lymphocytes, monocytes and NK cells. Its use results in a profound decrease in CD4 positive T lymphocytes. Alemtuzumab is used as induction immunosuppression and therapy for rejection in organ transplant recipients in some centers. We followed a cohort of 449 consecutive transplant recipients who received alemtuzumab to determine the occurrence of bloodstream infections, particularly those previously associated with decrease in CD4 positive T lymphocytes. PATIENTS AND METHODS: Fifteen percent (69/449) patients had at least one episode of bloodstream infection. However, no patient had bacteremia with Streptococcus pneumoniae, Listeria monocytogenes, non-typhoidal Salmonella or Mycobacterium avium complex. Fungaemia was rare, occurring in 1.5% of patients. The most common organisms isolated from the blood were Staphylococcus aureus (21 episodes), coagulase negative Staphylococcus (14 episodes), Klebsiella pneumoniae (12 episodes), Enterococcus faecium (11 episodes), Pseudomonas aeruginosa (10 episodes), Enterococcus faecalis (9 episodes) and Escherichia coli (7 episodes). DISCUSSION: We conclude that although alemtuzumab use is associated with profound CD4 positive T lymphocyte depletion, alemtuzumab does not seem to be associated with an increased risk of bloodstream infection with pathogens typically seen in other disorders of CD4 cell depletion, such as acquired immunodeficiency syndrome.
Adolescent↗
The pathobiology of polyomavirus infection in man.
This article traces the discovery of polyomaviruses and outlines investigations, which shed light on potential modes of transmission of this increasingly important group of human pathogens. The pathobiology of the virus is summarized with particular reference to interactions with host cell receptors, cell entry, cytoplasmic trafficking, and targeting of the viral genome to the nucleus. This is followed by a discussion of sites of viral latency and factors leading to viral reactivation. Finally, we present biochemical mechanisms that could potentially explain several key elements of tissue pathology characteristic of BKV mediated damage to human kidney.
Humans↗
Diagnosis and treatment of BK virus-associated transplant nephropathy.
The incidence of polyoma virus infection, particularly that of BK virus (BKV) in kidney transplant recipients has been increasing steadily since early 1990s. The diagnosis is generally made by a renal allograft biopsy. However the diagnosis can sometimes be difficult because of the pathological similarities between BKV associated nephropathy (BKVAN) and acute cellular rejection. In addition to the difficulties in making a diagnosis, the treatment of BKVAN can also be very complex. Reduction in immunosuppression is generally advocated as the initial therapeutic option for the management of BKVAN. Despite reduced immunosuppression, BKV can persist in the renal allograft and lead to gradual loss of kidney function. Hence, new therapeutic options are being evaluated for treatment of BKVAN. Cidofovir, an anti-viral agent with known nephrotoxic effects, has been successfully used in very low doses to treat patients with BKVAN, with serial measurement of the blood and urine BKV load with PCR assays. More recently several other agents have also been utilized to treat BKVAN, with variable success. This chapter summarizes the current diagnostic modalities and therapeutic options for BKVAN.
BK Virus↗
Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation.
OBJECTIVE: Heavy post-transplant immunosuppression may contribute to long-term immunosuppression dependence by subverting tolerogenic mechanisms; thus, we sought to determine if this undesirable consequence could be mitigated by pretransplant lymphoid depletion and minimalistic post-transplant monotherapy. STUDY DESIGN: Lymphoid depletion in 17 unselected pediatric recipients of live (n = 14) or deceased donor kidneys (n = 3) was accomplished with antithymocyte globulin (ATG) (n = 8) or alemtuzumab (n = 9). Tacrolimus was begun post-transplantation with subsequent lengthening of intervals between doses (spaced weaning). Maintenance immunosuppression, morbidity, graft function, and patient/graft survival were collated. RESULTS: Steroids were added temporarily to treat rejection in two patients (both ATG subgroup) or to treat hemolytic anemia in two others. After 16 to 31 months (mean 22), patient and graft survival was 100% and 94%, respectively. The only graft loss was in a nonweaned noncompliant recipient. In the other 16, serum creatinine was 0.85 +/- 0.35 mg/dL and creatinine clearance was 90.8 +/- 22.1 mL/1.73 m2. All 16 patients are on monotherapy (15 tacrolimus, one sirolimus), and 14 receive every other day or 3 times per week doses. There were no wound or other infections. Two patients developed insulin-dependent diabetes. CONCLUSION: The strategy of lymphoid depletion and minimum post-transplant immunosuppression appears safe and effective for pediatric kidney recipients.
Adolescent↗
Oxidative stress: a potentially important new marker in renal transplantation.
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Adrenergic beta-Antagonists↗
Sirolimus rescue for tacrolimus-associated post-transplant autoimmune hemolytic anemia.
Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post-transplant. We report on a 3-yr-old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.
Anemia, Hemolytic, Autoimmune↗
Living donor kidney transplantation in pediatric recipients.
Living donor kidney transplantation has increased in frequency in pediatric patients, accounting for 43% of cases performed between 1987 and 1991, and 52% of cases performed between 1987 and 2004 in North America. Patient survival has remained excellent over the years, and is currently over 96% at five years. Graft survival has improved over the years, and is currently over 95% at one year. Rejection rates have fallen over the years, and are currently <25% overall, with selected centers having very low rejection rates. The reasons for these improved outcomes are likely related to improvements in maintenance immunosuppression, which include a transition from cyclosporine to tacrolimus-based regimens, and from azathioprine to mycophenolate mofetil or sirolimus as adjunctive agents. Steroid withdrawal and steroid avoidance are beginning to be utilized by several centers, with excellent early outcomes. Finally, while there may be center effect/learning curve issues involved, the type of donor nephrectomy has recently been shown to influence early outcomes, particularly in very young recipients.
Child↗
Protocol biopsies should not (yet) be the standard of care in pediatric renal transplant recipients.
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Biopsy↗
Ether lipid ester derivatives of cidofovir inhibit polyomavirus BK replication in vitro.
Polyomavirus BK is a significant pathogen in transplant recipients, but no effective antiviral therapy is available. We show that cidofovir can inhibit BK virus replication in vitro. Esterification of cidofovir with hexadecyloxypropyl, octadecyloxyethyl, and oleyloxyethyl groups results in up to a 3-log lowering of the 50% effective concentration and an increased selectivity index.
Antiviral Agents↗
Immunoglobulin G, A, and M responses to BK virus in renal transplantation.
Immunoglobulin G (IgG), IgA, and IgM antibodies were measured in serum samples from 71 organ donors, 81 kidney transplant recipients at transplantation, and 67 patients during the posttransplant period by using a virus-like particle-based enzyme-linked immunosorbent assay (ELISA). BK virus (BKV) and JC virus DNA were detected in urine and plasma by real-time PCR. IgG antibodies to BKV were demonstrated in the majority (80.3 to 100%) of patients irrespective of clinical category, but titers were highest in patients with active viral replication. IgA antibodies were present with greater frequency (72.7 to 81.3% versus 0 to 23.6%; P < 0.001) and higher titer (mean optical density, 0.11 to 0.15 versus 0.05 to 0.08; P < 0.001) in patients who were BKV DNA positive than those who were BKV DNA negative. IgM antibodies showed a similar pattern of reactivity but lower frequency in the setting of active viral replication (9.1 to 43.7% versus 0 to 1.4%; P < 0.001). A rise in IgG level of >0.577 optical density (OD) units or a rise in IgA or IgM level of >0.041 OD units was strongly associated with active viral replication. Urine viral load showed a positive correlation with IgM titer (r = 0.22) but a negative correlation with IgG titer (r = -0.28) and IgA titer (r = -0.1). Chronic dialysis patients typically did not have serologic or virologic evidence of active BKV infection. Anti-BKV titers did not rise in patients with JC viruria. In conclusion, measurement of anti-BKV antibody titer and class response can be used to detect the onset of viral replication. ELISAs can be quite specific despite considerable sequence homology between BK virus and JC virus.
Adolescent↗