After pancreas transplantation with bladder drainage, increased urinary amylase has been shown to be associated with pancreatic injury, however, this is at the expense of bladder and urethral injury from the enzymes. As I recall, urine amylase levels require correction for pH (pH5, 2.5X; 6, 1.5X; 7, 1X; and 9, 1.2X).

In our center, we found that the use of bladder drainage and urinary amylase monitoring was problematic and did not meet its perceived benefit. One reason was that the measurement was tricky, prone to fluctuation due to hydration status of the patient, and establishing a clear baseline was difficult. More importantly, the technique made patients miserable, with a high rate of cystitis and other complications. Considering that solitary pancreas transplantation is performed for quality of life, this technique seemed to undercut the benefits to the patients. About 10 years ago, our centre, which regularly performs solitary pancreas transplantation, switched to universal use of portal-enteric drainage. The technique is easy and involves less dissection. The patients have few side effects and we use serum lipase/amylase elevation to trigger a biopsy, with a low threshold to investigate. The biopsy itself is easy to do and problem free, as the pancreas is positioned just below the anterior abdominal wall.

An integral component of our protocol is the use of induction agents such as ATG or alemtuzumab, and this too is borne out by registry data. Our results are very satisfying. Despite high levels of BPAR compared to kidney transplants, the graft survivals are excellent, with >60% insulin independence at 5 years. For more information, please see N. Smail et al, Curr Opin Organ Transplant, 2012; 17: 73-9.

Historically, bladder drainage of transplant pancreas was the best option to monitor pancreas function. In recent years this technique has been used in increased frequency to transplant marginal pancreas graft (e.g. DCD donors) or in Pancreas Transplant Alone, when graft monitoring is difficult.

Generally, this technique gives us excellent access to monitor pancreas function (urine amylase) mainly to detect rejection. In addition cystoscopy combined with pancreatic biopsy is excellent tool for diagnosis pancreas dysfunction (rejection).

However, on the other side, quite large proportion of patient suffer from dehydration, recurrence of UTI, haematuria, metabolic acidosis, leading to sever comorbidities, hospital re-admissions and frequently it requires enteric conversion.

In our practice, preliminary we implant pancreas head down with enteric drainage. Bladder drainage is reserved only for marginal pancreas or in a case of re-operation for major complication.

Dodeno-duodenostomy is novel described technique, for good post-transplan monitoring of pancreas graft. It allows endoscopic access to pancreas graft (biopsy to diagnose rejection).

Following publications:

Clin Transplant. 2012 Jul-Aug;26(4):550-7. doi: 10.1111/j.1399-0012.2011.01563.x. Epub 2011 Nov 29.

Duodenoduodenostomy in pancreas transplantation.

Gunasekaran G, Wee A, Rabets J, Winans C, Krishnamurthi V.

Hummel R, Langer M, Wolters HH, Senninger N, Brockmann JG. Exocrine drainage into the duodenum: A novel technique for pancreas transplantation. Transpl Int. 2008 Feb;21(2):178-81.

Bladder drainage is an historical procedure. The rate of complications and poor quality of life is so high so this should be abbandoned. More than 50% of the cases require enteric conversion which has also associated morbidity. In front of a well trained surgeon with a basic knowledge of bowel anstomosis enteric diversion is a safe and symple procedure. In front of (early) elevated amylase, lipase or blood glucose the gold standard for rejection diagnosis remains the US or CT guided pancreas graft biopsy.

Bladder drainage is well known for the increased morbidity in terms of UTIs and metabolic acidosis. In Oxford we offer bladder drainage for all Pancreas Alone transplants unless there are issues i.e. dysfunctional bladder. The idea is to achieve better/easier monitoring by measuring urinary amylase. On top of that we also perform regular glucose tolerance tests- 3monthly for the first year and 6monthly thereafter, for better monitoring of the endocrine function as well. Patients are offered enteric conversion after the first year if dictated by symptoms.

We have observed a 20% increase in survival since we started offering the bladder drained procedure- studies will be soon published.

Food for thought: we are now offering a forearm sentinel skin flap for early, patient delivered monitoring.

My interest in this topic is because I have experience of managing a small number of patients (51) post solitary pancreas transplantation. I am familiar with the history and find it intriguing that bladder drainage continued to be used for a significantly larger proportion of solitary transplants (as compared to SPK) in the early part of the last decade, as documented in Fig 9 of Angelika Gruessner’s 2011 review of IPTR data. Although there has been a bit of a catch up, PTA in particular still seems to lag behind SPK. Even more intriguing is that this seems to be true for PTA but less so for PAK, where the challenges of graft monitoring are the same. So I am particularly interested in exploring the reasons for this, hoping people who make these decisions will contribute further.

The downside of bladder drainage is of course the morbidity, which for the patients I managed was significant. In fact I would go as far as saying intolerable for a significant number. I guess I am in the same place as Steven Paraskevas. And this is why I am interested in why bladder drainage hangs on in there. What am I missing? I am particularly interested in the fact that the idea that bladder drainage facilitates monitoring will not go away. I am not convinced by urinary amylase and continued to use serum lipase and amylase. But these are of course imperfect also. The one advantage of bladder drainage that I can see is the possibility of endoscopic biopsy. I also still hear/read comments about bladder drainage facilitating monitoring for rejection. Surely it does not? It MAY allow monitoring for graft injury/dysfunction (I agree with Steven’s comment re baseline definition) but does not address the aetiology of graft dysfunction. All that goes wrong in transplantation is not rejection. I am wary also of data comparing outcomes as for instance in my own practice 5 patients treated by solitary pancreas transplantation with enteric drainage lost grafts due to reasons definitively not attributable to the technique used for management of exocrine secretions. The same could be said for only one patient in the bladder drainage group. With large numbers this would not matter. With small denominators (even in the 100s) this sort of ‘noise’ matters and power calculations for these studies would be interesting.

Finally, I must challenge the use of the OGTT to inform us about graft function. Here I have definitive data, presented in abstract form at BTS 2011 (see abstract on RG page) and now being written up. Unfortunately the OGTT is a very blunt instrument. It is perhaps better than fasting plasma glucose and HbA1c, which tell us very little, but still it is not much use. Paul Robertson has of course written extensively on this as have a number of other authors. We have just completed a study finding, as reported by Robertson, the arginine enhanced IVGTT to be the only simple technique to give useful information about graft function, with loss of glucose stimulated insulin release and perhaps more importantly alteration of the glucose/arginine stimulated release ratio to be useful.

I am not sure the answers are out there so nothing I write is critical of any particular practice. I just think we need to nail this one. Let the debate continue!

Bladder drainage for solitary pancreas transplantation is a double-edged sword. There is a trade off between complications from the procedure and the quest for a marker (however crude) to understand the processes and timing of rejection or any other non-immunological process that would impair pancreatic graft function. I agree that rejection is not the only process involved in graft loss but am also cognisant of the fact that it may be one of the major players. Ischemia reperfusion (IR) injury related to donor or recipient risk factors possibly plays an equally important role in the long-term survival of the graft. The level of IR and its effect on outcome is not quantifiable at this moment in time. I suspect the ability to derive a marker that combines the processes of rejection and IR injury (that may not be mutually exclusive) may be the future for solitary pancreas transplantation.

There have been significant improvement anc changes in the management and outcome of pancreas transplants, the major ones being improved immunosupression therby reducing the incidence of rejection and having a robust description of pathology of rejection and the increase in direct allograft biopsy by an ultrasound guided needle. This in my view makes the downside of complications from bladder drainage far outweigh the percieved advantage of graft monitoring. This remains the smallest subgroup of pancreas transplants, and changes are slow perhaps due to this.

PTA is still the troublemaker in pancreas transplantation with 1 year graft loss of 20% according to the IPTR data. Every attempt made to decrease this number is welcome. I agree with Anil that BD is a double-edged sword; however, the program started in Oxford shows very good results with this technique. Regarding the monitoring, it may be not crucial what to monitor in the early period post transplantation but just to do the close monitoring. Rejection or vascular complications, both lead to a decrease in urinary amylase, and both eventually lead to graft loss. If you have the chance to monitor the graft function closely and non invasively it is worth doing it. Given that you can achieve with PTAs similar long-term results as with SPK if the PTA survives the first year (Gruessner A 2012), these 12 months seem to be of vital importance and could be “bridged” with the BD technique. A conversion to ED is then necessary if the patient should suffer from frequent QoL-decreasing BD associated complication.

I agree that with new techniques in enteric drainage the endoscopic biopsy might be easier to perform, however, it is still more invasive compared to a cystoscopy. In contrast to routinely performed urinary tests which are more sensitive compared to serum amylase/lipase plus-minus cystoscopy, frequent endoscopies are probably less well accepted by patients even though as an effort to prolong the grafts life.

BD might be not the "holy grail" in PTA recipients, however, the results of BD-PTAs presented by Oxford at the recent meeting have to be taken seriously since in PTAs we have stil not reached satisfactory results.

With regard to the 'ease' of biopsy alluded to by some respondents above, I'm not at all sure I agree with the concept that monitoring the bladder drained graft is so simple. I'm not a urologist, but a cystoscopic biopsy of a pancreas graft on the bladder would seem to involve intravenous sedation at minimum, and a general anaesthesia more likely. I'm not sure how this compares favourably to ultrasound-guided percutaneous biopsy of the mesenteric-drained pancreas allograft under local anaesthesia.

Cystoscopic 'biopsy of pancreases' at Oxford infact entails only sampling the duodenal mucosa with a biopsy forceps introduced down a cystoscoe. This is then interpreted by applying the criteria established for small bowel transplant rejection. The backgraound for this approach is from data published by the Minnasotta group in the mid 90's where transcystoscopic needle biopsies of the pancreas 'captured' the duodenal mucosa and there was good correlation between immunologic activity in the pancreas and the duodenal mucosa. Furthermore, our understanding of the characteristics of rejection in bowel mucosa has improved over the years.

Routine surveillance of this duodenal mucosa may also help to pick up chronic changes in the graft may it be of an immunologic, ischemic or any other mechanistic pathway that may or may not cause a drop in the urinary amylase. This provides data that could lead to two avenues: firstly providing a platform to introduce various modalities of 'rescue' therapy to improve graft survival in a clearly dysfunctional pancreas and secondly a method of predicting the trajectory of the graft in the long term.

While I certainly appreciate that some centres will develop facility with a certain way of performing transplants and following them, and the Oxford program have an admirable track record in many such facets, I would add a word of caution as regards the interpretation of mucosal biopsies compared to pancreatic parenchymal evaluation. Certainly, when adapting novel findings to clinical care, we should strive to establish evidence-based consensus as much as possible, and the field of transplantation is one where evidence and consensus have accrued with difficulty. With respect to the diagnosis of pathologic changes in the duodenal mucosa of a pancreas allograft, there are currently no recommendations to do so. "The Banff schema for grading pancreas allograft rejection: A working proposal by a multi-disciplinary international consensus panel" by Drachenberg et al, Am J Transplant, 2008, as well as the follow-up paper, "Guidelines for the diagnosis of antibody-mediated rejection in the pancreas allograft- Updated Banff grading schema", also by C Drachenberg et al, Am J Transplant, 2011, are two examples of the type of evidence-based consensus we should strive to develop, implement, and improve. Neither of these guidelines makes any reference whatsoever to the duodenal mucosa in their grading schemes. In fact, there are structures observed in the Banff schemes, such as small and large artery endothelium, which would be completely unavailable in a mucosal biopsy, to say nothing of the pancreatic parenchyma itself. How we would grade the duodenal mucosa in cases of antibody mediated rejection, for example, remains somewhat obscure to this reader. Furthermore, the application of small bowel grading schemes in cases of pancreas transplantation seems a bit odd, although I do get the connection, and prone as well to some important differences. In our historical experience with bladder drained grafts, there appeared to be an atrophy of the duodenal mucosa on chronic exposure to urine. Would this not confuse the diagnosis of chronic changes, if one were using small bowel criteria in which atrophy may have a completely different prognosis? Just a thought. While it is admirable that the Oxford group have adapted some interesting findings and made correlations with other types of allografts, I think when trying to make decisions and compare cases, the transplant team and the transplant pathologists need to speak the same language. This is the purpose of grading schemes such as Banff, imperfect though they may be.

Completely agree with all the points put forward in the last dialogue and we have had those discussions in-house too. However, we believe the proof of the pudding may be in the success of the approach measured by outcomes, keeping in mind that this approach does not have a deleterious effect on potential recipients. Thus if success is to be measured by graft outcomes, this would need time to collate data over a period of 3 and 5 years and if favourable, may have to re-think the Banff criteria on rejection in pancreas transplantation.

In the meanwhile, we have not experienced any untoward effects using this strategy as well as have not lost any grafts due to lack of monitoring.

Richard,

Thank you for getting this debate started. All authors have valid view points and the last has not yet been said or written in the setting of Pancreas Transplant done independently either as a PAK or PTA.

The UK data reflects international experience, of an initial loss of allografts in the first year, but also a steady attrition over the ensuing 3-5 years.

In the face of this the Oxford group changed its practice in April 2011 ( you were not very keen on this, as you had a better experience with your cohort of patients using serum amylase & lipase and Arginine GTT.)

Anil Vaidya & Manuel Maglione are right in saying that they will only be able to discuss their experience with any measure of confidence , once their patients have had a sufficient length of follow-up.

It is clearly too early to cast a vote , the jury is still out!

Could this forum become a platform for Collaborators to discuss the possibility of an International Multicentre Trial with 3 arms - ED vs BD vs BD (+the sentnel forearm flap)

a 10% reduction in graft loss in the first year (to match SPK's) would need how many patients to be enrolled in any possible study

Sanjay: you are quite right in guessing that my main aim was to prompt debate and of course be a little controversial along the way! As you are well aware I was never completely convinced by the advantages of bladder drainage but the fantastic results delivered by the Oxford team always won the day. The problems associated with BD made me think long and hard about what the real reasons were for poorer outcomes with PTA. I remain unconvinced about the lack of the kidney as a sentinel organ simply because in the SPK patients I looked after it was not uncommon to see elevations of lipase and amylase responsive to corticosteroids with no increase in creatinine and on some occasions normal kidney biopsy. This is no more than 'uneasiness'. I bow to the opinions of those with infinitely more experience than me. But I remain uneasy. I recognise that the literature on concordance between kidney and pancreas rejection does not give a clear answer and we of course did not biopsy the pancreas in Bristol (although did do some cystoscopic duodenal loop biopsies which I found helpful) so this is just anecdote, but all good science/medicine starts with these observations, then to be tested properly. I also often wondered whether PTA and SPK recipients differed in other ways. The PTA recipient is typically obsessional about glycaemic control hence the severe hypoglycaemia and lack of microvascular complications often seen. The SPK recipient (and interestingly probably PAK recipient also) is perhaps at the other end of the spectrum. This may result in a very different response to the challenges of the post-transplant course. I am going to push this a little further. I'm sure we all agree that it is the first year that is particularly difficult. It is interesting that this first year is when graft losses for PTA and SPK differ most (the ongoing attrition being recognised). Is it that the PTA recipient is less well equipped to deal with the rigours of the first year than the SPK recipient and perhaps this contributes to the increased graft loss? I am of course continuing to be mischievous but I am concerned that if we do not have the right diagnosis the wrong treatment will be given. I will leave my thoughts on antibody mediated rejection (Banff notwithstanding) to another day or perhaps another question!

A large multi-center randomized trial of the two techniques (with standard immunosuppression regimens and protocol biopsy schedules) would put a lot of this discussion to rest - but that would take the fun out of RG!

Two people now suggesting a RCT? Could it happen? But time for a bit more fun first!

Recently one of our paper entitled "Life and Consciousness - The Vedāntic View" has been published in the Journal Communicative & Integrative Biology. An interesting discussion on this paper can be found at: https://groups.google.com/forum/#!topic/online_sadhu_sanga/Mcv2O-yhqLE

From paper:

"The scientific confirmation of the existence of consciousness in unicellular organisms and plants certainly establishes that the brain is not the source of consciousness. Several decades back, research in medical science has also proven that the brain is not the source of consciousness. In 1970, Robert White and his team successfully transferred the head of a rhesus monkey to the headless body of another monkey. The monkey survived for 8 days.68 Researchers are also attempting to perform the same scenario with human beings.69 It is reported that if a human head has been detached under controlled conditions, it must be reconnected to the circulatory flow of other person's body (which is conscious or living) within one hour.70 Therefore, brain-based analysis for understanding consciousness (neuronal analysis) does not have very bright prospects."

Paper: Life and Consciousness - The Vedāntic View

DOI: http://dx.doi.org/10.1080/19420889.2015.1085138

Journal: Communicative & Integrative Biology

Publication date - 09 Oct 2015

Author: Bhakti Niskama Shanta - http://orcid.org/0000-0002-2039-3249