Desmopressin Impairs Microcirculation in Donor Pancreas and ... : Transplantation (original) (raw)

Analyses And Commentaries

WHY DO PANCREAS TRANSPLANTS THROMBOSE?

Thrombosis of the pancreas early after transplantation has been a consistent cause of pancreas allograft failure. The surgical procedure has inherent difficulties with vascular supply, especially from multiorgan donors, when priority is given to retrieval of the liver transplant, invariably leading to the need to reconstruct the arterial and venous supply of the pancreas using donor iliac vessels. The resulting complexity of back table revascularisation of the pancreas has been presumed to be the usual initiating event in thrombosis of the allograft.

Technical failure was the cause of graft loss for between 6.9 and 19.2% of pancreas allografts between 1996 and 1999 in the USA (1). Enteric drainage of exocrine secretion was associated with higher levels of technical failure than bladder drainage although simultaneous pancreas/kidney transplants had the lowest rates compared with pancreases transplanted after kidneys or alone. Graft thrombosis is the commonest cause of technical failure accounting for more than 70% of all technical failures, thus leading to loss of 5.4% of SPK pancreases compared to only 1.5% lost to rejection in the first year. The risk of technical failure is significantly associated with older donors an d cerebrovascular causes of donor death.

The report from Keck et al. suggests that a new factor should be examined in a clinical pancreas transplant setting. This report provides experimental evidence for the hypothesis that use of desmopressin before organ retrieval may impact adversely on the state of the pancreas and increase the risk of thrombosis. Desmopressin is an analogue of the hormone vasopressin, which is normally secreted from the pituitary tract but is usually lost after brain death. Absence of vasopressin leads to diabetes insipidus with high levels of diuresis, loss of free water, dehydration, and hypovolemia. It is thus standard practice to maintain brain dead patients with desmopressin. In Australia and New Zealand, desmopressin was used between 61 and 75% of all donors between 1995 and 1999 with a trend to increase the proportion in 1998 and 1999 (75 and 72%, respectively) (2).

There has been conflicting evidence on the effect that desmopressin may have on renal function after transplantation. There has been one controlled study of 155 brain dead patients who were randomised to desmopressin use or not (3). Of these 97 became organ donors, but there was no impact of desmopressin on any measures of recipient renal outcome in this trial. There were only three pancreas transplants in this series and they were excluded from analysis. However, it has generally been thought safe to use in organ donors and makes management easier in the time between brain death and donation.

Desmopressin has high antidiuretic potency and relatively weak vasopressor activity compared with the natural hormone arginine vasopressin, but it also induces P-selectin expression and release of von Willebrand factor. It has thus been used in high risk patients to induce hemostasis during surgery and after renal biopsy in uremic patients. P-selectin is expressed on endothelial cell surfaces and is involved in leukocyte-endothelial rolling and adhesion, as well as in platelet interactions with both leukocytes and the endothelium. Thrombosis is one of the pancreas transplant surgeons’ biggest concerns and it is thus timely that Keck et al have provided ex-perimental data addressing this issue.

Intra-vital microscopy has been used to view the microvasculature of the transplanted rat pancreas and to measure the effect of desmopressin on platelets and leukocytes after transplantation. Prolonged pretreatment of donors with desmopressin led to increased platelet and leukocyte interaction with the endothelium of the transplanted pancreas. Immunohistochemistry allowed the investigators to confirm the expected up-regulation of P-selectin. Finally, the study demonstrated significant histological damage to the endothelium with acinar vacuolization and necrosis in the desmopressin treated pancreases. There is thus unequivocal evidence of a potentially serious impact of the use of desmopressin in experimental pancreas allograft donors and thus excellent reason to believe that it may be relevant to the outcome of clinical pancreas transplants.

This study has already prompted us to undertake a retrospective analysis of the use of desmopressin in 122 consecutive clinical pancreas transplant donors in our unit. Desmopressin was used in 86 of the 122 donors at a variety of doses (range 1 to 40 μg). Pancreas thrombosis was seen within 15 days of simultaneous pancreas/kidney transplantation in 8.3% of 36 donors given no desmopressin, 13.6% of 66 given doses of <6 μg and 30% of 20 given ≥6 mcg. These figures do not quite reach statistical significance but the fact that pancreases from 6 of 20 donors given high doses of desmopressin had early graft thrombosis is certainly enough for us to agree with Keck and colleagues’ conclusion: “The effects of desmopressin under clinical conditions should therefore be carefully investigated.” Perhaps this “Achilles heel” of pancreas transplantation may have a solution.

The implications of the work should probably be taken further and thought given again to the effects desmopressin and the impact of increased thrombogenesis and endothelial damage in all forms of transplantation. If the data from clinical practice support the experimental results then there will need to be a new approach to the management of diabetes inspidus in the brain dead patient, with use of desmopressin replaced by aggressive fluid and electrolyte replacement.

Jeremy R. Chapman

Paul Robertson

Richard D. M. Allen

National Pancreas Transplant Unit

Westmead Hospital,Westmead

Sydney, NSW 2145, Australia

REFERENCES

1. Bland BJ. International pancreas transplant registry. Minneapolis: University of Minnesota. 2000; 12: 1.

Cited Here

2. Herbertt KJ, Russ G. Australia and New Zealand organ donor registry. Queen Elizabeth Hospital, Adelaide Australia, 2000.

Cited Here

3. Guesde R, Barrou B, Leblanc I, Ourahma S et al. Administration of desmopressin in brain-dead donors and renal function in kidney recipients. Lancet 1998; 1: 1178.