J. M. Grierson

Percutaneous biopsy of bladder-drained pancreas transplants

Percutaneous biopsy is a valuable investigation in the management of allograft rejection for all solid organs. Pancreas transplants have not been biopsed percutaneously, though open and percystoscopic biopsies have proved useful. We have compared percutaneous needle core biopsy with fine-needle aspiration cytology for the diagnosis of rejection in 18 patients receiving combined kidney and pancreas transplants and in one who was transplanted with the pancreas alone. Percutaneous needle core biopsy was successful in 37 of 40 attempts (93%), while fine-needle aspiration yielded diagnostic material on 33 of 47 attempts (70%). Transient hyperamylasemia occurred in 29%, returning to baseline in three days. One patient twice developed transient macroscopic hematuria. There was agreement between needle core biopsy and fine-needle aspiration on the diagnosis of rejection on six occasions and for the absence of rejection on 16. There was an 8% false-positive rate for fine-needle aspiration. In 13 instances of histologically proved renal rejection, concurrent pancreas biopsy revealed rejection in 69%. Pancreas rejection was not, however, seen in the absence of renal rejection. In this pilot study, percutaneous biopsy of the bladderdrained pancreas allograft was shown to be a practicable and valuable investigation without major complications.

Simultaneous pancreas and kidney transplant rejection: separate or synchronous events?

The results of simultaneous pancreas and kidney transplantation (SPK) cannot be matched by pancreas transplantation alone (PTA), in part because an independent diagnosis of pancreas graft rejection remains difficult. The relationship between rejection of the pancreas and rejection of the kidney is poorly understood, and it is not known whether simultaneous transplantation of both organs confers true protection to either graft. To study these questions, reliable canine allotransplant models of kidney transplantation alone (KTA), PTA, and SPK were established. Sixty-seven mongrel dogs received KTA (n=21), PTA (n=23), or SPK (n=23) with either no immunosuppression, low-dose cyclosporine (CsA)-based immunosuppression, or high-dose CsA-based immunosuppression. Needle core biopsy (NCB) and fine needle aspiration biopsy (FNAB) were performed at 0, 2, 4, 7, 9, 11, 14, 21, and 30 days or at the time of graft failure. Pancreas and kidney graft survival after SPK was significantly shorter in dogs given low-dose CsA than in dogs given high-dose CsA (pancreas, P<0.04; kidney, P<0.03). Concurrent NCBs and FNABs were performed on 227 occasions in pancreas grafts and 229 occasions in kidney grafts. The time to initial evidence of rejection by NCB was not different in any immunosuppressed group. Synchronous rejection occurred in 73% of immunosuppressed SPK biopsies. Kidney-only rejection occurred in 23% of biopsies and pancreas-only rejection occurred in only 3% after SPK. All markers of pancreas graft rejection were poor, with the most sensitive being NCB of the simultaneously transplanted kidney. In summary, recipients of SPK required more immunosuppression than recipients of PTA, and improved PTA survival should be achievable with more sensitive markers of rejection. Markers of kidney rejection were the most sensitive indicators of pancreas rejection, and independent pancreas rejection was uncommon after SPK.

Early diagnosis of rejection of canine pancreas allografts by fine-needle aspiration biopsy.

In pancreatic allograft transplantation with bladder exocrine drainage, falls in urinary amylase (UA) levels have been shown to be an earlier marker of rejection than rises in fasting blood glucose levels. Nevertheless, this is often too late for reversal of the rejection process. In an attempt to diagnose rejection earlier, fine-needle aspiration biopsy was correlated with UA and graft histology. Sixteen dogs were given total pancreatic allografts, 10 without immunosuppression and 6 with triple therapy. FNAB and needle-core biopsies were performed on days 0, 2, 4, 7, 9, 24, and 30 and/or at functional rejection, defined as a fasting UA level of less than 5000 IU/L. Cytocentrifuge preparations of the FNABs were evaluated by total corrected increment (TCI) scores. These increased significantly from 1.0 (+/- 0.4; mean +/- SEM) 6 days, to 3.0 (+/- 1.2) 4 days before functional rejection. The increase was due to the presence of blast cells and macrophages. The TCI of healthy immunosuppressed grafts remained below 1.6 for 30 days after transplantation and was greater than 5.0 when pancreatitis or acute rejection was seen on conventional histology. Minimal histologic change had significantly lower TCI scores than both acute rejection (P less than 0.01) and pancreatitis (P less than 0.001). Acute rejection and pancreatitis were distinguished by a significant difference in increments of monocytes/lymphocytes and macrophages. In contrast to FNAB, UA levels did not differentiate minimal change from acute rejection but were a reliable marker of end-stage rejection.

A Case of Cholangitis Glandularis Proliferans and Cholangiocarcinoma of the Common Bile Duct

A case of Cholangitis Glandularis Proliferans (CAGP) in association with a cholangiocarcinoma of the common bile duct as described. This is the eighth case of CAGP described and the second association with cholangiocarcinoma.

Canine pancreas and kidney transplantation following total-lymphoid irradiation.

The effect of total-lymphoid irradiation on survival of canine pancreas and kidney allografts was studied. TLI had a marked immunosuppressive effect as measured by in vitro immune responses and reduced circulating leukocytes. Despite the changes, median graft survival times for animals treated with 800 cGy (9 days) or 1800 cGy (9.5 days) were not significantly different from untreated control animals (7 days). The addition of low-dose antithymocyte globulin (10 mg/kg/day) on post-transplant days 0, 2, 4, 6, 8, and 10 had no measurable synergistic effect. Similarly, median segmental pancreas allograft survival times after 1700-2200 cGy of TLI treatment (16.5 days) were only marginally longer than those of untreated controls (9 days). The only animal to maintain a graft for greater than 200 days was matched to the donor in mixed lymphocyte culture (MLC). This animal was able to reject a third-party skin graft after 8 days while a graft from the original donor was still surviving after 21 days when the pancreas graft failed from a chronic-type rejection. These results indicate that TLI alone or in combination with ATG will not be predictably effective as a method of prolonging allograft survival. The role of matching major histocompatibility complex antigens in TLI treatment requires clarification.

Long-term duct-occluded segmental pancreatic autografts: Does fibrosis lead to graft loss?

In clinical pancreas transplantation, duct-occluded segmental allografts are often used. There is concern that fibrosis following duct-occlusion may lead to progressive graft failure. In this study, sequential histology and endocrine function in long-term (up to 5 years) canine autografts were assessed. Segmental pancreatic autografts with residual pancreatectomy were performed, and the pancreatic duct was occluded with cyanoacrylate glue. Serial i.v. glucose tolerance tests (IVGTT) and percutaneous needle-core biopsies of the grafts were performed as long as grafts functioned. Ten dogs were long-term (>18 months) survivors: 8 dogs had functioning grafts for a median of 48 months (range 1860) after transplantation, and 3 dogs had graft failure at 21, 27, and 60 months. The mean 40-min blood glucose concentration (BGL-40′) after i.v. glucose injection did not increase with time up to 5 years after grafting. Graft biopsies showed a universal picture of aggregated islet cells and fibrous replacement of acinar tissue. The total amount of fibrosis did not change with time, but the existing fibrosis became less cellular and more dense. This long-term study showed that in autografted animals, adequate endocrine function was maintained in the majority of cases, and progressive replacement of islet tissue by fibrosis could not be demonstrated in serial biopsies taken between 18 months and 5 years after autotransplantation. We therefore conclude, that while duct-occlusion results in extensive fibrosis, the process is not progressive, and although fibrosis may contribute to late graft failure this is not inevitable.

Percutaneous fine needle aspiration biopsy in clinical pancreas transplantation

Lack of reliable and specific independent monitoring of pancreas allograft function prompted evaluation of fine needle aspiration biopsy (FNAB) as a safe and reliable method for determining cellular rejection. Ultrasound localised 22G FNAB and 20G needle core biopsy (NCB) were performed between 6 and 90 days. Twenty patients received combined kidney and pancreas transplants and one patient, a pancreas alone. There were no significant biopsy complications. Cytocentrifuged aspirates were considered adequate if 10 or more clusters of pancreas acinar cells were present. Thirty four of 52 (65%) attempted FNAB were satisfactory for assessment. Based on a previous canine pancreas allograft model, a diagnosis of rejection was made when the total corrected increment (TCI) was > 2.6, provided that more than 50% of this value comprised blasts, or blasts and macrophages. Concurrent FNAB and NCB were assessable on 22 of 35 occasions. Compared to NCB, the sensitivity and specificity of FNAB for a diagnosis of rejection were 83.3% and 87.5% respectively. Graft survival, followed from 3 to 46 months for pancreas and kidney was 85% and 95% respectively. In conclusion, FNAB was shown to be a safe and specific method of following intragraft cellular events in the pancreas.