John L. Smith

Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisone

We have documented seven B cell lymphomas over a six-month period in 132 (5.3%) kidney and heart allograft recipients immunosuppressed with cyclosporine, azathioprine, and prednisone (triple therapy). This is a significant increase (P less than 0.0001) over the number of such tumors seen by us previously. Only 2 lymphomas had occurred in 669 cadaver and 29 living-related kidney allografts treated with azathioprine and prednisone alone (0.3%). In 160 cadaver kidney recipients treated with cyclosporine and prednisone there have been no lymphomas. Similarly in 14 living-related kidney recipients who were transplanted since the introduction of triple therapy for cadaver grafts, but continued to receive only azathioprine and prednisone, no lymphomas occurred. There seemed to be a clear relationship between this increase and the use of triple therapy. This led us to examine other possible contributing factors. A case control study has not shown any other factor that differs in patients in whom lymphomas developed. We have only been able to demonstrate Epstein Barr virus nuclear antigen in the cells of one tumor. Four of these 7 tumors were monoclonal, one polyclonal, and two indeterminate. All patients had their immunosuppression withdrawn and six received intravenous acyclovir. Three patients have shown some response but four patients died. Triple therapy is being used by many centers to reduce the level of cyclosporine toxicity. We wish to sound a note of caution that this may result in an increased incidence of posttransplant lymphomas.

Use of gadolinium-enhanced, ultrafast, three-dimensional, spoiled gradient-echo magnetic resonance angiography in the preoperative evaluation of living renal allograft donors.

BACKGROUND Renal allograft retrieval from live donors requires an accurate determination of kidney anatomy including the renal arterial supply. Traditionally, conventional angiography has served as the gold standard for obtaining this information. More recently, magnetic resonance angiography (MRA) has been compared with conventional angiography. Although MRA has been shown to be more cost effective and to have none of the co-morbidity associated with the angiographic process, it still has been perceived to be less accurate than angiography. METHODS We compared images obtained using a relatively new technique of gadolinium-enhanced, ultrafast, three-dimensional, spoiled gradient-echo MRA with surgical findings in 15 living renal donors. In addition, average patient charge for MRA was compared with that of conventional angiogram. RESULTS Fourteen patients were evaluated with the gadolinium-enhanced, ultrafast, three-dimensional, spoiled gradient-echo modality and the findings confirmed at surgery. On one occasion, a discrepancy occurred in which an accessory renal artery was suggested on the MRA but was not detected by conventional angiography. The accessory renal artery was later encountered at surgery. MRA was also used to evaluate patient 15 but was unsuccessful due to technical error. This patient was later found to have a positive cross-match with the recipient and therefore did not undergo surgery. CONCLUSIONS We have found the gadolinium-enhanced MRA technique to be 100% accurate and as reliable as conventional angiography in determining renal vascular anatomy in living kidney donors. Additionally, it shares none of the associated potential angiographic complications and allows a 31% cost savings over angiography.

APPEARANCE OF TYPE II DIABETES MELLITUS IN TYPE I DIABETIC RECIPIENTS OF PANCREAS ALLOGRAFTS

To determine the cause of hyperglycemia appearing after pancreas transplantation in type I diabetic recipients, we performed 65 oral glucose tolerance tests with serum insulin and C-peptide determinations in 32 patients with pancreas grafts functioning two or more months following transplantation. We correlated these results with estimates of graft size obtained by magnetic resonance imaging (MRI) and values of urinary amylase as a measure of pancreatic exocrine function. A total of 33 studies were obtained in 20 patients at times of normal glucose tolerance, and normal ranges for serum insulin and C-peptide levels were established; 32 studies in 17 patients during periods of glucose intolerance revealed values of serum insulin and C-peptide that were within the normal range, though the time to peak values was delayed to 2 hr, characteristic of type II diabetes. Only 3 of 17 patients examined by MRI had significant pancreatic allograft atrophy. These patients also had low urinary amylase excretion, and the only values for serum C-peptide that were below the normal range. The other 14 hyperglycemic patients had normalized pancreas grafts, normal urinary amylase excretion, and normal values for serum insulin and C-peptide. In our experience, then, in 76% of patients with hyperglycemia more than 2 months following pancreas transplantation, the cause was appearance of type II diabetes rather than destruction of the allograft with recurrence of type I diabetes. This observation has important implications for the definition of pancreas allograft failure and for the management of pancreas allograft recipients with hyperglycemia.

Urinary levels of activated trypsin in whole organ pancreas transplant patients with duodenocystostomies

Urinary levels of trypsinogen and active trypsin were measured in 34 urine samples from 14 patients an average of 23 months following whole organ pancreas transplantation and duodenocystostomy. Timed urine specimens obtained 30 min and 90 min following a time zero void were collected from 5 patients in an effort to define the kinetics of trypsinogen secretion and activation. Total urinary protein and urinary pH were correlated with urinary levels of trypsin and trypsinogen. Twenty-one specimens from 8 normal volunteers and a single specimen from a pancreas transplant patient with a duodenoenterostomy served as controls. Activated trypsin was present in 33 of 34 specimens from 13 of the 14 transplant patients. The average total trypsin activity in all samples was 84.4 μg/ml urine (±SE 9.6). Trypsinogen was present in 13 of 34 samples, from 7 of 14 patients. The average trypsinogen concentration of all 34 samples was 9.6±6.2 μg/ml. No trypsin or trypsinogen activity was identified in any control sample. In the 5 patients undergoing timed urine collections total trypsin increased an average of 1.3-fold at 30 min and 1.1-fold at 90 min relative to time zero. Urinary trypsinogen increased an average of 7.1-fold at 30 min and 3.1-fold at 90 min following the initial void. Urinary pH and total urinary protein failed to show a significant correlation with urinary levels of total trypsin or trypsinogen. These data suggest that trypsinogen is rapidly converted to active trypsin following secretion into the bladder, resulting in the high urinary trypsin levels that were detected in the majority of patients.

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report

The presence of preexisting (memory) or de novo donor‐specific HLA antibodies (DSAs) is a known barrier to successful long‐term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state‐of‐the‐art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.

Application of Magnetic Resonance Imaging in Pancreas Transplant

Various imaging methods have been used in the differential diagnosis of pancreas-transplant dysfunction. As early as 1977, angiography and radionuclide studies ([75Se]seleno-DL-methionine) were used to evaluate pancreas allografts. More recently, the use of 99mTc-labeled DTPA, computed tomography, and ultrasonography has been described, and abnormal findings associated with rejection have been reported with these imaging methods. However, no attempt has been made to determine the ability of each method to detect rejection and to differentiate graft dysfunction caused by rejection from dysfunction by other causes. We summarize our experience with the application of magnetic resonance imaging (MRI) in pancreas transplantation and a comparative study of radionuclide 99mTc-DTPA scans, ultrasonography, and MRI in the detection and differentiation of pancreas-graft dysfunction.

Techniques and experience of pancreatic transplantation with bladder drainage

Our group at lowa was the first to show that combined liver-pancreas retrievals could be accomplished with successful implantation of both organs into different individuals (1). We and others have subsequently performed this procedure routinely, and it has been shown that results of liver transplantation are not compromised (2).