Hemorrhagic Herpes Simplex Virus Type 1 Nephritis: An Unusual Cause of Acute Allograft Dysfunction.

Interstitial nephritis due to viruses is well-described after solid organ transplantation. Viruses implicated include cytomegalovirus; BK polyomavirus; Epstein-Barr virus; and, less commonly, adenovirus. We describe a rare case of hemorrhagic allograft nephritis due to herpes simplex virus type 1 at 10 days after living donor kidney transplantation. The patient had a favorable outcome with intravenous acyclovir and reduction of immunosuppression.

A novel mouse model of podocyte depletion.

AIM: The goal of this study was to examine the capacity for glomerular repair after a podocyte-depleting injury. METHODS: We created transgenic (TG) mice expressing the yeast enzyme cytosine deaminase specifically in glomerular podocytes. In these TG animals, the prodrug 5-flucytosine (5-FC) is converted to 5-fluorouracil and promotes cell death. RESULTS: Treatment with increasing dosages of 5-FC caused graded increases in proteinuria 1-2 weeks after treatment, which returned to control levels by the 10-week time point. Light microscopic examination revealed minimal pathology at the 2-week time point, but electron microscopy revealed found foot process effacement as well as focal areas of glomerular basement membrane duplication, and immunohistochemical studies detected podocyte apoptosis and a decrease in the number of Wilms' tumor protein 1 (WT1)-positive cells. By the 10-week time point, however, the number of WT1-positive cells was similar to controls and a few mice had developed focal areas of glomerulosclerosis. Consistent with the effects of 5-FC on podocyte number, expression of the podocyte mRNAs for nephrin, podocin, synaptopodin and podocalyxin were altered in a similar temporal fashion. CONCLUSION: The glomerulus has a significant capacity for repair after a podocyte-depleting injury.

Fatal Apophysomyces elegans infection transmitted by deceased donor renal allografts.

Two patients developed renal mucormycosis following transplantation of kidneys from the same donor, a near-drowning victim in a motor vehicle crash. Genotypically, indistinguishable strains of Apophysomyces elegans were recovered from both recipients. We investigated the source of the infection including review of medical records, environmental sampling at possible locations of contamination and query for additional cases at other centers. Histopathology of the explanted kidneys revealed extensive vascular invasion by aseptate, fungal hyphae with relative sparing of the renal capsules suggesting a vascular route of contamination. Disseminated infection in the donor could not be definitively established. A. elegans was not recovered from the same lots of reagents used for organ recovery or environmental samples and no other organ transplant-related cases were identified. This investigation suggests either isolated contamination of the organs during recovery or undiagnosed disseminated donor infection following a near-drowning event. Although no changes to current organ recovery or transplant procedures are recommended, public health officials and transplant physicians should consider the possibility of mucormycosis transmitted via organs in the future, particularly for near-drowning events. Attention to aseptic technique during organ recovery and processing is re-emphasized.

Symptomatic pulmonary allograft Kaposi's sarcoma in two lung transplant recipients.

Kaposi's sarcoma (KS) is associated with solid-organ transplantation, but is extremely rare after lung transplantation. In this report, we describe two unique cases of lung transplant recipients who developed KS in the lung allograft and were treated with sirolimus and liposomal doxorubicin. One patient survived 12 months after the diagnosis of KS; the other survived 3 months after diagnosis and was found to have concomitant EBV-negative, HHV-8-positive B-cell lymphoma. We demonstrate a partial response of pulmonary KS to reduced immunosuppression and the initiation of sirolimus in one patient, as well as an association between increasing HHV-8 viremia and progression of pulmonary KS. Our report highlights the importance of secondary malignancies in patients with transplant-related KS and supports the association between HHV-8 infection and EBV-negative PTLD.

Successful bilateral lung transplantation for lymphangiomatosis.

Lymphangiomatosis is a rare disease of lymphatic proliferation for which no adequate treatment is known. We report the first successful case of bilateral lung transplantation for the treatment of end-stage pulmonary lymphangiomatosis. A successful outcome was achieved with continued survival beyond 4 years posttransplant and stable lung function. The primary obstacles to significant gains in pulmonary function were thoracic, skeletal and abdominal lymphangiomatosis, which led to pulmonary restriction. Our report demonstrates that pulmonary lymphangiomatosis should be included among those diseases for which lung transplantation is considered potentially beneficial treatment but also emphasizes the importance of screening patients carefully for chest wall and abdominal lymphangiomas that may impede recovery.

Chronic aspiration of gastric fluid induces the development of obliterative bronchiolitis in rat lung transplants.

Long-term survival of a pulmonary allograft is currently hampered by obliterative bronchiolitis (OB), a form of chronic rejection that is unique to lung transplantation. While tracheobronchial aspiration from gastroesophageal reflux disease (GERD) has clinically been associated with OB, no experimental model exists to investigate this problem. Using a WKY-to-F344 rat orthotopic left lung transplant model, the effects of chronic aspiration on pulmonary allograft were evaluated. Recipients received cyclosporine with or without 8 weekly aspirations of gastric fluid into the allograft. Six (66.7%) of 9 allografts with aspiration demonstrated bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy, consistent with the development of OB. In contrast, none of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002). Of the grafts examined grossly, 83% of the allografts with chronic aspiration but only 20% without aspiration appeared consolidated (p = 0.013). Aspiration was associated with increased levels of IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha and TGF-beta in BAL and of IL-1 alpha, IL-4 and GM-CSF in serum. This study provides experimental evidence linking chronic aspiration to the development of OB and suggests that strategies aimed at preventing aspiration-related injuries might improve outcomes in clinical lung transplantation.

Lambda light chain deposition disease in a renal allograft.

Light chain deposition disease (LCDD) of the kidney is characterized by deposition of monoclonal light chains predominantly in glomeruli and in tubular basement membranes. The disease is frequently associated with a lymphoproliferative disorder, and the majority of cases are caused by deposition of kappa light chains. Although the occurrence of de novo multiple myeloma after renal transplantation is uncommon, there are several reports of LCDD involving renal allografts, either de novo or in patients with a diagnosis of LCDD prior to transplantation. To the best of our knowledge, all previously described cases in allografts have been in patients with kappa chain deposition. The relative importance of intrinsic properties of the kidney in predisposing to either kappa or lambda light chain deposition is not known. We present a case of LCDD caused by deposition of lambda light chains in a patient who received a cadaveric renal transplant.

Clinical significance of eosinophils in suspicious or borderline renal allograft biopsies.

AIMS: Renal allograft biopsies play a critical role in renal transplantation. Acute rejection characterized by tubulitis and intimitis is of primary concern. There is an association between eosinophilic infiltrates and irreversible acute rejection; however, the significance of eosinophils in biopsies that fall short of the diagnostic threshold for acute rejection has not been well studied. This report describes clinical course, treatment and long-term outcome of 5 transplant recipients with biopsy histology that showed borderline changes associated with eosinophilic infiltrates. METHODS: Clinical records were selected for review on the basis of biopsy histology satisfying the following criteria: presence of interstitial infiltrates with eosinophils, absence of definitive criteria for acute rejection and absence of findings suggestive of infection or cyclosporine toxicity. RESULTS: All identified biopsies occurred within the first month of transplantation, and histology showed varying degrees of patchy mononuclear cell infiltrates composed of lymphocytes, with eosinophilic infiltrates, but no evidence of acute rejection based on Banff criteria. These patients were taking trimethoprim-sulfamethoxazole and ranitidine at the time of biopsy. Serum creatinine returned to baseline levels in each case after stopping both drugs, and remained stable during the duration of follow-up without any documented episode of acute rejection. No patient received specific therapy for acute rejection. CONCLUSION: This report suggests that independent of decisions on treatment with high-dose steroids or anti-lymphocyte antibody preparations, the management algorithm should include stopping drugs associated with acute interstitial nephritis when non-diagnostic biopsies show eosinophilic infiltrates.

Laparoscopic antireflux surgery in the lung transplant population.

BACKGROUND: Lung transplantation has emerged as a viable therapeutic option for patients with a variety of end-stage pulmonary diseases. As immediate posttransplant surgical outcomes have improved, the greatest limitation of lung transplantation remains chronic allograft dysfunction. Gastroesophageal reflux disease (GERD) with resultant aspiration has been implicated as a potential contributing factor in allograft dysfunction. GERD is prevalent in end-stage lung disease patients, and it is even more common in patients after transplantation. We report here on the safety of laparoscopic fundoplication surgery for the treatment of GERD in lung transplant patients. METHODS: Eighteen of the 298 lung transplants performed at Duke University Medical Center underwent antireflux surgery for documented severe GERD. The safety and benefit of laparoscopic fundoplications in this population was evaluated. RESULTS: The antireflux surgeries included 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen (converted secondary to extensive adhesions). Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating). There were no deaths from the antireflux surgery. After fundoplication surgery, 12 of the 18 patients showed measured improvement in pulmonary function (67%). CONCLUSIONS: GERD occurs commonly in the posttransplant lung population. Laparoscopic fundoplication surgery, when indicated, can be done safely with minimal morbidity and mortality. In addition to the resolution of reflux symptoms, improvement in pulmonary function may be seen in this population after fundoplication. Lung transplant patients with severe GERD should be strongly considered for antireflux surgery.

Influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome.

Influenza infection is increasingly recognized to cause significant morbidity and mortality in the community, especially in pediatric patients and elderly persons. Influenza infection, however, has not been well described among thoracic organ transplant recipients. We provide the first detailed clinical, radiographic, and histologic description of influenza pneumonia among three lung transplant recipients. The presentation varied considerably among the three patients and, in some cases, was atypical for influenza. Despite treatment, a persistent decline in pulmonary function occurred in all three patients after the acute illness. Interestingly, on follow-up biopsy specimens, each patient had histologic evidence of acute rejection and/or obliterative bronchiolitis. Additional research, therefore, is needed to clarify the relationship between influenza infection, acute rejection, and obliterative bronchiolitis.

Biliary stricture secondary to donor B-cell lymphoma after orthotopic liver transplantation.

Biliary complications after orthotopic liver transplantation (OLT) lead to considerable morbidity and occasional mortality after surgery. Bile duct strictures secondary to localized lymphoproliferative disorder of the porta hepatis is rare, with only 12 cases reported in the English literature. Posttransplant lymphoproliferative disorder develops in up to 9% of liver allograft recipients. We describe 2 adult patients who developed Epstein-Barr virus-associated localized B-cell lymphoma of donor-tissue origin confined to the porta hepatis 3 and 5 months after OLT. Both patients were administered cyclosporine (CyA) and prednisone as primary immunosuppression. One patient was administered basiliximab as induction therapy. Neither patient had CyA trough levels greater than 250 ng/mL. Both patients were treated with a hepatojejunostomy, 75% reduction in immunosuppression therapy, and acyclovir. One patient had complete involution of the tumor, and the second patient had an 80% reduction of the tumor at the 2-year follow-up visit. This report illustrates the need to consider localized lymphoma post-OLT as a cause of obstructive jaundice even within the first 6 months after surgery. Aggressive reduction of immunosuppression in conjunction with acyclovir remains a highly effective therapy.

A role for fractalkine and its receptor (CX3CR1) in cardiac allograft rejection.

The hallmark of acute allograft rejection is infiltration of the inflamed graft by circulating leukocytes. We studied the role of fractalkine (FKN) and its receptor, CX(3)CR1, in allograft rejection. FKN expression was negligible in nonrejecting cardiac isografts but was significantly enhanced in rejecting allografts. At early time points, FKN expression was particularly prominent on vascular tissues and endothelium. As rejection progressed, FKN expression was further increased, with prominent anti-FKN staining seen around vessels and on cardiac myocytes. To determine the capacity of FKN on endothelial cells to promote leukocyte adhesion, we performed adhesion assays with PBMC and monolayers of TNF-alpha-activated murine endothelial cells under low-shear conditions. Treatment with either anti-FKN or anti-CX(3)CR1-blocking Ab significantly inhibited PBMC binding, indicating that a large proportion of leukocyte binding to murine endothelium occurs via the FKN and CX(3)CR1 adhesion receptors. To determine the functional significance of FKN in rejection, we treated cardiac allograft recipients with daily injections of anti-CX(3)CR1 Ab. Treatment with the anti-CX(3)CR1 Ab significantly prolonged allograft survival from 7 +/- 1 to 49 +/- 30 days (p < 0.0008). These studies identify a critical role for FKN in the pathogenesis of acute rejection and suggest that FKN may be a useful therapeutic target in rejection.

Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation.

Gastroesophageal reflux (GER) is increasingly recognized as contributing to a number of pulmonary disorders. The relationship of GER to pulmonary allograft dysfunction after lung transplantation is unknown. In this report, we describe a lung transplant recipient who developed an acute decline in pulmonary function several months after a retransplantation for chronic rejection. A pulmonary workup at that time, including bronchoscopy with biopsy, revealed bronchial inflammation with no allograft rejection or infection. Because of increasing GI symptoms after retransplantation, the patient also underwent additional testing, which revealed severe acid reflux. The treatment of this patient's acid reflux with Nissen fundoplication surgery resulted in a prompt and sustained improvement in his pulmonary function. We suggest that GER should be considered among the potential causes of allograft dysfunction after lung transplantation.

Enhanced green fluorescent protein as a marker for localizing murine cytomegalovirus in acute and latent infection.

A recombinant murine cytomegalovirus (mCMV) that expresses enhanced green fluorescent protein (EGFP) under control of the native immediate-early 1/3 promoter was constructed to detect directly sites of viral activity in latent and reactivated infections. The recombinant virus had acute and latent infection characteristics similar to those of wild-type mCMV. Rare green-fluorescing foci were observed in paraffin sections from lungs and spleens infected latently. Positive immunoperoxidase staining for EGFP in sections of the same lung tissues suggests that these cells may be sites of restricted viral gene expression. EGFP was detected easily in tissue explants reactivating from latent infection in vitro. Morphology and adhesion characteristics of fluorescing cells suggest that viral reactivation occurs in tissue macrophages in explant cultures. The observations presented in this study demonstrate the usefulness of EGFP-expressing recombinants as tools for direct tracking of mCMV activity in vivo and in vitro.

Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients.

BACKGROUND: Panel-reactive antibody (PRA) is used to estimate the degree of humoral sensitization in the recipient before transplantation. Although pretransplant sensitization is associated with increased complications in other solid organ transplant recipients, less is known about the outcome of sensitized lung transplant recipients. Therefore, we sought to determine the impact of elevated pretransplant PRA on clinical outcomes after lung transplantation. METHODS: The records of the first 200 lung transplant operations performed at Duke University Medical Center were reviewed. The outcomes of sensitized patients, PRA greater than 10% before transplantation (n = 18), were compared with the outcomes of nonsensitized patients. RESULTS: Sensitized patients experienced a significantly greater number of median ventilator days posttransplant (9 +/- 8) as compared with nonsensitized recipients (1 +/- 11; p = 0.0008). There were no significant differences between the number of episodes of acute rejection; however, there was a significantly increased incidence of bronchiolitis obliterans syndrome occurring in untreated sensitized recipients (56%) versus nonsensitized (23%; p = 0.044). In addition, there was a trend towards decreased survival in the sensitized recipients, with a 2-year survival of 58% in sensitized recipients as compared with 73% in the nonsensitized patients (p = 0.31). CONCLUSIONS: Sensitized lung transplant recipients experience more acute and chronic complications after transplantation. These patients probably warrant alternative management strategies.

Prolonged rewarming time during allograft implantation predisposes to recurrent hepatitis C infection after liver transplantation.

The majority of patients undergoing orthotopic liver transplantation (OLT) have end-stage liver disease secondary to hepatitis C virus (HCV) infection. Although OLT does not cure the disease and recurrent virus is present in all patients, relatively few patients with recurrent viremia develop clinical disease. When the disease recurs, however, the results can be devastating. Factors associated with increased risk for recurrent HCV disease remain controversial. We hypothesized that preservation injury may predispose to the severity of HCV disease after OLT. We reviewed our series of OLTs performed for HCV cirrhosis between January 1994 and December 1998 (n = 56; 62 transplants). Patients were grouped according to the severity of recurrent hepatitis C. Group 1 had no or mild HCV disease (n = 36), and group 2 had moderate to severe HCV disease (n = 20). The duration of ischemic rewarming during graft implantation was significantly associated with the severity of recurrent hepatitis C (P <.04). The estimated chances of severe disease within the first year post-OLT after 30, 60, or 90 minutes of ischemic rewarming time were 19%, 40%, and 65%, respectively. Cold ischemia time, transaminase levels, and prothrombin time did not correlate with the severity of hepatitis C. In conclusion, our data suggest that the duration of ischemic rewarming predisposes to severe recurrent hepatitis C. This finding warrants the investigation of the pathogenesis of recurrent HCV disease after ischemic injury. Reduction of rewarming time should be stressed in OLT, particularly in patients with HCV cirrhosis.

The pathology of liver-localized post-transplant lymphoproliferative disease: a report of three cases and a review of the literature.

Post-transplantation lymphoproliferative disease (PTLD) is a complication of solid organ transplantation that is typically of B-cell origin and associated with Epstein-Barr virus (EBV). In patients receiving orthotopic liver transplantation (OLT) and treated with cyclosporin A. PTLD typically presents between 6 and 17 months post-transplantation as a systemic illness with involvement of the hepatic graft in a minority of cases. A small number of cases of biopsy-proven PTLD arising in the hepatic graft and limited to the liver and periportal structures have been previously reported. This report describes three additional cases of liver-localized PTLD and reviews similar cases in the literature. The donor/host origin of PTLD may have prognostic significance because the two cases in this report that are of donor origin had different clinical and pathologic features compared with the case of host origin. A rapid PCR-based technique for determining the origin of PTLD is described.

Glomerulopathies with fibrillary deposits.

Renal diseases involving glomerular deposits of fibrillary material are an important diagnostic challenge for the ultrastructural pathologist. Two primary disorders of this type, termed "fibrillary glomerulonephritis" (characterized by fibrils measuring approximately 20 nm in diameter) and "immunotactoid glomerulopathy" (characterized by larger, microtubular deposits), have been described. The possible relatedness of these two disorders and their potential association with other systemic illnesses are subjects of current debate. Other multisystemic diseases, including amyloidosis and various forms of cryoglobulinemia, can also present with fibrillary or microtubular deposits in the kidney. Five cases are presented in which fibrillar or microtubular structures were identified in renal biopsies by ultrastructural examination. The distinction between fibrillary glomerulonephritis, immunotactoid glomerulopathy, and other processes that have similar ultrastructural features are discussed.