Amy L. Friedman

Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy.

BACKGROUND Posttransplant lymphoproliferative disorder (PTLD) has been observed with increasing frequency consequent to the availability of more effective and potent immunosuppression. Prior work suggested that a peripheral blood monitoring strategy detecting peripheral B lymphoproliferation was effective in the early diagnosis of PTLD among 7 of 179 (3.9%) consecutive transplant recipients. Each of those seven patients received at least one course of antithymocyte globulin, Minnesota antilymphocyte globulin, or OKT3 before developing PTLD. METHODS To determine whether antiviral prophylaxis might reduce the incidence of PTLD, a subsequent group of 198 consecutive recipients received either ganciclovir or acyclovir during antilymphocyte antibody administration. When the donor or recipient were cytomegalovirus-seropositive, ganciclovir was given; acyclovir was used when both were cytomegalovirus-seronegative. Baseline and protocol posttransplant cell surface profiles were obtained using immunofluorescence and flow cytometry to detect T cells, lymphocyte activation markers, and the CD19 B cell antigen. RESULTS Demographic factors, including the incidence of recipients more than 50 years of age, non-Caucasians, previous transplantation, and diabetes mellitus, were similar in both groups. Additionally, the number of patients receiving antilymphocyte preparations was similar. However, only one patient (0.5%) from the latter group who received preemptive antiviral therapy developed PTLD. Although elevations in CD19+ B cells preceded clinical PTLD among each of the seven earlier patients, evidence of peripheral B cell proliferation was not demonstrated for the sole patient from the latter group, which suggests a possible effect of antiviral therapy. CONCLUSIONS Prophylactic antiviral therapy may reduce the sensitivity of peripheral monitoring for B lymphoproliferation, but the dramatic reduction in PTLD incidence strongly supports its use among transplant recipients at risk.

Fatal and nonfatal hemorrhagic complications of living kidney donation

Objective:After anecdotal reports of severe hemorrhage from failure of surgical clips to sustain closure of renal artery stumps in live donor nephrectomies were received, this study was designed to identify specific surgical techniques that are associated with an increased risk of failure to control bleeding and might represent opportunities to improve patient safety. Background:Preventing complications for living kidney donors must be paramount in addressing end-stage renal failure through living kidney donation. Major hemorrhage from technical failure, albeit an infrequent occurrence, can cause significant, yet preventable, morbidity or death. Open and laparoscopic approaches to living kidney donation use several vascular control methods, some of which may be more prone to failure and life-endangering hemorrhage than others. Methods:To define hemorrhagic complications of living kidney donation, a survey was sent to all 893 surgeon-members of the American Society of Transplant Surgeons. Descriptive and bivariate analyses were used to ascertain study participant characteristics, most frequently used vascular control techniques, and incidence of events (death, transfusion, reexploration or conversion to open nephrectomy, or contralateral [remaining kidney] renal failure). Outcomes of hemorrhage and comments by respondents were sought as were data from other sources. Results:In 213 surveys returned (24%), 66 and 39 episodes of arterial and venous hemorrhage were reported, respectively. Among arterial control problems, 2 resulted in donor death and 2 resulted in renal failure; 19 episodes required transfusion. Open conversions in laparoscopic nephrectomy or late reoperations for hemorrhage were reported for 29 cases. Locking and standard clips applied to the renal artery were associated with the greatest risks. Conclusions:Significant hemorrhagic complications occur with living kidney donation in both open and laparoscopic approaches. Loss of arterial control jeopardizes donor life and health, especially when it occurs in the postoperative period. Vascular transfixion provides the best vascular control of major vessels.

Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil

Mycophenolate mofetil, an immunosuppressive agent, is frequently used following bone marrow and solid organ transplantation. Diarrhea is a commonly seen side effect of mycophenolate mofetil, which may necessitate colonic biopsy in some patients. The histologic changes found in this setting have been reported to mimic self-limited colitis, graft-vs-host disease or inflammatory bowel disease in isolated case reports, and could pose diagnostic and management difficulties. The goal of this study is to define the spectrum of histologic changes in colonic biopsies associated with mycophenolate mofetil usage. All solid organ transplant patients who received mycophenolate mofetil and underwent colonic biopsy for gastrointestinal symptoms from 1999 to 2007 were included in the study. Patients who did not receive mycophenolate mofetil were used as controls. Various histologic features including architectural distortion, apoptosis, inflammatory infiltrate, Paneth cell metaplasia and mucin depletion were subjectively evaluated and scored (scale: 0–3) by two independent reviewers in a blinded fashion. Forty solid organ transplant patients underwent colonic biopsy for gastrointestinal symptoms during the study period. Biopsies from 69% of patients on mycophenolate mofetil showed histologic changes. Apoptosis (41%) and architectural distortion (66%) were seen more frequently in patients receiving mycophenolate mofetil as compared to the control group (13%). The histologic changes in patients receiving mycophenolate mofetil were categorized as normal/near normal (31%), inflammatory bowel disease-like (28%), graft-vs-host disease-like (19%), ischemia-like (3%) and self-limited colitis-like (16%) changes. Of the controls, only one patient showed a graft-vs-host disease-like histologic pattern. In conclusion, histologic changes are frequently associated with mycophenolate mofetil use and can resemble self-limited colitis, graft-vs-host disease and inflammatory bowel disease leading to diagnostic difficulties. Increased awareness of the histologic spectrum of mycophenolate mofetil-induced changes is required by the pathologist to avoid diagnostic errors.

A recent decrease in the time to development of monomorphous and polymorphous posttransplant lymphoproliferative disorder.

&NA; We have noted a decrease in the time to development of posttransplant lymphoproliferative disorder (PTLD) over the last two and one-half years in our multiorgan transplant program. From February 1965 until December 1990, 1622 transplants were performed including 1489 kidneys (KTxp), 87 livers (LTxp), and 46 pancreata. Between February 1965 and July 1988 (group 1), there were 1260 transplants performed and nine cases of either monomorphous PTLD (M-PTLD, n=8) or polymorphous PTLD (P-PTLD, n=1) were diagnosed. The mean time to development of PTLD was 163±128 weeks, all after KTxp. Five of these nine patients received haploidentical living-related grafts. All patients had presented with advanced disease, none had transplant nephrectomy, and all died of their disease. Between July 1988 and December 1990 (group 2), 362 transplants were performed, and four cases of M-PTLD and three cases of P-PTLD were recognized. Of the seven cases of PTLD in group 2, six developed within 90 days posttransplant (early PTLD). The mean time to development of PTLD was 11±16 weeks. This was significantly earlier than group 1 (P<.01). Four of the five cases after KTxp had a 1 or 2 DR-matched donor. Five of these seven patients had serological evidence of recent Epstein-Barr Virus infection, and four of these five had received OKT3 and then developed early PTLD. In group 2, three patients are alive 7–15 months after KTxp nephrectomy, the remaining four have died. We hypothesize that risk factors for the development of PTLD may include heavy immunosuppression, including the use of OKT3, good DR matching, and active EBV infection. Treatment should include graft removal, if applicable, and reduction or cessation of immunosuppression.

Live and Deceased Donor Kidney Transplantation in Patients Aged 75 years and Older in the United States

Objective: To examine the outcomes of geriatric ESRD patients selected for kidney transplantation. Design: Data were extracted from the USRDS Standard Analysis Files (SAF). All persons ages 75 and over who received a kidney transplant from 1994 to 2000 were compared with those remaining on dialysis or on a transplant waiting list. Data on mortality or removal from the waiting list were obtained from the United Network for Organ Sharing (UNOS). The main outcome measure was patient and kidney transplant survival. Results: Superior five year survival after kidney transplantation was attained by the geriatric cohort given a live donor transplant (59.9%), compared with recipients of deceased donor kidneys (40.3%), dialysis patients waiting for transplant (29.7%), and those who were not selected for kidney transplantation and remained on dialysis (12.5%). The likelihood of being removed from the waiting list for any reason was higher in this group (over 75) (30.3%) than in the 66–75 age group (26.8%). Their average annual mortality rate on the waiting list was 7.9, compared to 6.6% for those 66–75. Conclusion: Even after the age of 75 years, kidney transplantation provides substantial life prolongation and excellent graft survival.

Parameters of high bone-turnover predict bone loss in renal transplant patients: a longitudinal study.

BACKGROUND Osteoporosis is a serious complication of kidney transplantation. Various factors have been postulated to contribute to posttransplant bone loss, among them treatment with corticosteroids, the use of cyclosporine and cyclosporine-like agents, and persistent hyperparathyroidism. In a previous cross-sectional study of long-term renal transplant recipients, we observed that osteoporosis or osteopenia was present in 88% of patients. Because biochemical markers of bone formation (serum osteocalcin) and bone resorption (urine pyridinoline, PYD, and deoxypyridinoline, DPD) were elevated in the majority of study subjects, we hypothesized that elevated rates of bone-turnover contribute to posttransplant bone loss in long-term renal transplant patients. This study was performed to examine this hypothesis. METHODS The study population was composed of 62 patients who were more than 1-year postrenal transplantation and who had preserved renal function. They were followed prospectively for 1 year. Biochemical markers of bone-turnover were measured at study entry, and patients were classified as having high bone-turnover based on elevated urinary levels of at least one marker of bone resorption (i.e., PYD or DPD) and/or serum osteocalcin (group 1). If none of these were present, they were classified as having normal bone-turnover (group 2). Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at time of entry into the study and again after 1 year of follow-up. The changes in BMD at the lumbar spine, hip, and wrist over the period of the study were compared between the high and normal bone-turnover groups. RESULTS Forty-three patients (69%) were classified as having high bone-turnover (Group 1), and 19 patients (31%) were classified as having normal bone-turnover (Group 2). There was a statistically significant difference in change in BMD between the two groups at the lumbar spine (-1.11+/-0.42%, high bone-turnover, vs. 0.64+/-0.54%, normal bone-turnover; P=0.02) and the hip (-0.69+/-0.38%, high bone-turnover, vs. 1.36+/-0.66%, normal bone-turnover; P=0.006). Whereas group 2 had stable bone mass, group 1 exhibited bone loss at these skeletal sites. CONCLUSIONS Our results indicate that bone loss is greater in renal transplant recipients with elevated biochemical markers of bone-turnover, suggesting that these markers may be useful in identifying patients at risk for continued bone loss. These data support the hypothesis that continued bone loss in long-term renal transplant recipients is associated with high bone-turnover. If accelerated bone resorption does play a role in posttransplant bone loss, this would provide a strong rationale for use of antiresorptive therapy for the prevention and treatment of this complication.

Treatment of Osteoporosis and Osteopenia in Long-term Renal Transplant Patients with Alendronate

Bone mineral density (BMD) and biochemical markers of bone‐turnover were evaluated in a 2‐year study in 58 long‐term renal transplant recipients with good renal function. In the first year of study, data were collected and patients with osteoporosis and parameters of high bone turnover were classified as being at high risk for on‐going bone loss (Group A; n = 29). Patients with lesser degrees of bone loss or without biochemical parameters of high bone turnover were followed longitudinally (Group B; n = 29). Group A patients were then placed on alendronate 10 mg/day and both groups were followed for an additional year. Changes in regional BMD and bone‐turnover markers between the first and second year within each group were analyzed using paired tests. BMD in Group A, which had declined at the lumbar spine (− 1.6 ± 0.5%) and total femur (− 1.5 ± 0.4%) during the first year of the study, increased on alendronate therapy at both the lumbar spine (+ 3.4 ± 0.6%, p = 0.001) and total femur (+ 1.6 ± 0.6%, p < 0.001). These patients also experienced a significant decline in levels of serum alkaline phosphatase, osteocalcin, urinary levels of deoxypyridinoline and pyridinoline. In contrast, neither BMD nor biochemical markers changed significantly over 2 years in Group B. The current results demonstrate that renal transplant patients with osteoporosis and biochemical parameters of high bone turnover are at continued risk for bone loss. Therapy with a bisphosphonate can reverse this bone loss and even increase bone mass in these patients. Whether patients with lesser degrees of bone loss and/or patients without parameters of high bone turnover can also benefit from bisphosphonate therapy deserves further study.

HCV response in patients with end stage renal disease treated with combination pegylated interferon α-2a and ribavirin

Goals To determine the efficacy and safety of combination therapy in patients with hepatitis C virus (HCV) and end-stage renal disease (ESRD). Background There is little data on the treatment of ESRD patients with pegylated interferon and ribavirin. We designed a pilot study to determine the initial and 12-week posttreatment viral response. Study A nonrandomized, prospective observational study of adjusted-dose combination therapy. Twenty patients were enrolled and began pegylated interferon at 135 μg/wk SC, and 4 weeks later ribavirin was started at 200 mg PO weekly, increasing gradually to 3 times a week for a total of 48 weeks. Results Twenty patients: M:F 18:2; mean age 52.4 years; genotype 1: 18, non-genotype 1: 2. Of the 20 patients, 5 withdrew before starting treatment. Of the 11 patients who reached 3 months, 6 had early virologic response, defined as at least a 2-log drop in their HCV count (54.5%). Of the 5 patients who were treated for 1-year, only 1 patient had a response 12 weeks after treatment. Side effects included 4 cases of anemia and 1 patient with headache. Conclusions The initial response rate in individuals taking 3 months of treatment in our study is comparable with studies in non-ESRD patients with no serious adverse side effects. However, the sustained posttreatment rate was low. This demonstrates that combination therapy is a safe therapeutic option in the ESRD population with HCV infection which needs further testing to determine if increasing the length of treatment and/or the dose of ribavirin will affect posttreatment rates.

Carcinoid tumor of the common bile duct producing gastrin and serotonin.

Carcinoid tumors of the biliary tract are rare. We report a 47 year-old man who was unexpectedly found to have a nonobstructing carcinoid tumor of the common bile duct during orthotopic liver transplantation for decompensated cirrhosis. No metastases were noted. Five months after resection of the common bile duct and liver transplantation, the patient had no evidence of residual tumor. The carcinoid was a sclerotic tumor of insular type and was immunoreactive for gastrin and serotonin, but nonfunctional. We review the literature on carcinoids of the extrahepatic bile duct.

Renal transplant recipients over aged 60 have diminished immune activity and a low risk of rejection

Strict consideration of the renal transplant candidate’s chronologic age is generally supplanted by more subjective reflection on his (her) physiologic state. In the US, patients over 64 years old represented 9.0% of renal transplant recipients in the year 2000, yet little prior experience is available with which to guide the management of geriatric patients. Two hundred and forty six consecutive recipients of primary kidney transplants at the Yale–New Haven Organ Transplant Center between 1990 and 1995 were included in an outcome analysis. Age at transplantation ranged from 2 to 68 years; the study group consisted of the 16 (6.5%) over age 60. The immunosuppressive protocol was uniform for all patients. There was a disproportionately high use of cadaveric organs by older patients; only 1/16 (6.3%) received a living donor kidney. The overall rate of rejection within the first 90 days was 6.7% of cadaveric recipients over 60 versus 37.6% of younger recipients, P=0.001. Actual patient survival rates at 6 years were 100% of patients younger than 11 years versus 69% (11/16) of those older than 60 years. Death censored 5 year graft survival was 100% in older patients versus 85% among the younger patients. The older and younger patients received quantitatively equivalent immunosuppression, but acute rejection was uncommon in the former (6%) versus the younger cohort (34%). It seems logical to consider whether older renal transplant recipients may benefit from a less aggressive immunosuppression strategy.