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Therapy of diabetes mellitus. Pancreas
transplantation, islet transplantation, stem cell and gene
therapy.Internist
(Berl). 2006 May;47(5):489-96,
498-501.
The
long-term normalization of glucose metabolism - a prerequisite
for the prevention of secondary complications in patients with
diabetes mellitus - is only possible by transplantation of a
whole pancreas or a reasonable number of islets. An absolute
indication for pancreas grafting is given in type 1 diabetic
patients with end-stage renal disease. The 1-year survival after
simultaneous kidney/pancreas transplantation is, according to
the international registry, 94-100% for patients, 89-92% for
kidneys and 85-87% for the pancreas. The high success rate with
long lasting normalization of glucose metabolism leads to a
stabilization and/or amelioration of secondary complications, to
an increase in quality of life and, most importantly, to a
significant reduction in mortality when compared to diabetic
kidney recipients. The indications for islet transplantation are
similar to those for pancreatic grafting. Islet grafting is only
a minor surgical procedure, but islet isolation is difficult.
The 1-year survival for the recipients is 98%, for the islets
82% and for insulin-independency 42%. There is a significant
decline of islet function to 10% 5 years after transplantation.
Stem cell therapy would provide a definitive treatment solution
not only for patients with type 1 diabetes. So far, this
therapeutic option is still at an early stage of development.
Current
indications for pancreas or islet transplant.Diabetes
Obes Metab. 2006 Jan;8(1):1-7.
Pancreas or
islet transplantation can provide good glycaemic control and
insulin independence. Pancreas transplantation has been
associated with improvement in diabetic retinopathy,
nephropathy, neuropathy and vasculopathy, but has the associated
morbidity of major surgery. Both forms of therapy require
long-term immunosuppression and its attendant risks and both
achieve insulin independence rates of about 80% at 1 year.
Pancreas transplantation at the same time as a renal transplant
is a worthwhile option to employ, especially if the diabetes has
been difficult to control. Diabetes associated with frequent
severe hypoglycaemia or extreme lability, despite optimization
of diabetes management, may benefit from either pancreas or
islet transplant alone with the latter being the lower-risk
procedure. More quantitative measures of hypoglycaemia and
lability are now available to facilitate the assessment of the
severity of these problems with glucose control. Diabetic
patients with renal involvement (macroproteinuria, but no major
elevation of creatinine) and unstable diabetes may be helped
with an islet or pancreas transplant, but this approach should
still be considered experimental and such a transplant may
hasten the need for renal replacement therapy. In the setting of
well-controlled diabetes and intact renal function, it is
difficult to justify pancreas or islet transplant alone given
the risks of immunosuppression.
Pancreas
transplantation: indications and consequences.Endocr
Rev. 2004 Dec;25(6):919-46.
Pancreas
transplantation continues to evolve as a strategy in the
management of diabetes mellitus. The first combined
pancreas-kidney transplant was reported in 1967, but pancreas
transplant now represents a number of procedures, each with
different indications, risks, benefits, and outcomes. This
review will summarize these procedures, including their risks
and outcomes in comparison to kidney transplantation alone, and
how or if they affect the consequences of diabetes:
hyperglycemia, hypoglycemia, and microvascular and macrovascular
complications. In addition, the new risks introduced by
immunosuppression will be reviewed, including infections,
cancer, osteoporosis, reproductive function, and the impact of
immunosuppression medications on blood pressure, lipids, and
glucose tolerance. It is imperative that an endocrinologist
remain involved in the care of the pancreas transplant
recipient, even when glucose is normal, because of the myriad of
issues encountered post transplant, including ongoing management
of diabetic complications, prevention of bone loss, and
screening for failure of the pancreas graft with reinstitution
of treatment when indicated. Although long-term patient and
graft survival have improved greatly after pancreas transplant,
a multidisciplinary team is needed to maximize long-term
quality, as well as quantity, of life for the pancreas
transplant recipient.
Transplant options for patients undergoing total
pancreatectomy for chronic pancreatitis.J
Am Coll Surg. 2004 Apr;198(4):559-67.
BACKGROUND:
Total pancreatectomy to treat chronic pancreatitis is associated
with severe diabetic control problems in 15% to 75% of patients,
causing up to 50% of deaths late postoperatively. We report our
experience with islet autotransplants at the time of, or with
pancreas allotransplants after, total pancreatectomy. STUDY
DESIGN: Between February 1, 1977, and June 30, 2003, we
performed 112 islet autotransplants at the time of total
pancreatectomy; we also performed 20 pancreas allotransplants in
13 patients who had already undergone total pancreatectomy
months to years earlier. RESULTS: Islet autotransplants at the
time of total pancreatectomy in patients who had not had
previous operations on the body and tail of the pancreas were
associated with a high islet yield (>2,500 islet equivalents/kg
body weight), and >70% of the recipients achieved complete
insulin independence. In contrast, a previous distal
pancreatectomy or a Puestow drainage procedure was associated
with a low islet yield in 75% of them and with complete insulin
independence in <20%. A pancreas allotransplant after total
pancreatectomy was not associated with any transplant-related
mortality at 1 and 3 years posttransplant. The pancreas graft
survival rate at 1 year posttransplant was 77% with tacrolimus-based
immunosuppression (versus 67% with cyclosporine). Enteric (over
bladder) drainage was preferred to manage exocrine graft
secretions, to cure pancreatectomy-induced endocrine and
exocrine insufficiency. CONCLUSIONS: Our series shows that
pancreas allotransplants can be performed without
transplant-related mortality and, when tacrolimus-based
immunosuppression is used, with 1-year pancreas graft survival
rates >75%. In contrast to a simultaneous islet autotransplant,
a pancreas allotransplant has the disadvantage of requiring
lifelong immunosuppression, but the advantage of not only curing
endocrine but also exocrine insufficiency. Both transplant
options, if successful, improve the recipient's quality of life.
A new
indication for pancreas transplantation: high grade pancreatic
dysplasia.Clin
Transplant. 2004 Feb;18(1):105-7.
A
42-yr-old male presented with a family history of pancreatic
carcinoma inherited an autosomal dominant pattern. The
development of endocrine and exocrine pancreatic insufficiency
served as early markers for neoplastic transformation. Screening
endoscopic ultrasound and ERCP showed abnormalities suggestive
of pancreatic dysplasia. Total pancreatectomy was performed and
pathology confirmed carcinoma in situ, also known as high-grade
pancreatic ductal dysplasia or Pan IN-3. The patient's
post-operative course was complicated by life threatening,
brittle diabetes. Pancreas transplantation was successfully
performed. One year following transplantation, the patient has
excellent pancreas graft function. He remains insulin free and
has no signs of malignancy. Total pancreatectomy followed by
pancreas transplantation is a viable therapeutic option for
patients in the dysplastic but still pre-malignant phase of
familial pancreatic adenocarcinoma who develop hypoglycemic
unawareness following total pancreatectomy.
Organ transplantation in
endocrinology. Islet cells and pancreas.Internist
(Berl). 2004 Nov;45(11):1268-80.
Pancreas
transplantation is a successful and effective procedure
resulting in tight glucose control. Due to the postoperative
morbidity and the need for immunosuppression pancreas
transplantation should be considered at the time of kidney
transplantation. Besides this, pancreas transplantation alone
should be considered for patients with unacceptably poor
metabolic control and quality of life despite optimal medical
treatment. Recently, islet transplantation became a less
invasive alternative to pancreas transplantation. Due to the
lack of long-term follow-up and due to the need of multiple
donor grafts for one recipient, islet transplantation should be
performed under experimental settings in experienced centers.
New developments in protecting transplanted islets and in the
induction of donor-specific tolerance could increase the
indication to perform the procedure. Therefore alternative
sources of beta-cells have to be identified.
Pancreatic autotransplantation in chronic pancreatitis.World
J Surg. 2003;27(11):1235-40.
The
apancreatic state secondary to resective surgery for chronic
pancreatitis is associated with a high rate of late morbidity
and mortality that is due, in part, to endocrine insufficiency.
Resective procedures should, therefore, be used very
selectively. Over the last 2 decades we have seen a shift from
extensive distal resections to limited proximal resections. This
is because of the lowering of the operative mortality of
pancreatic head resection and its better results in pain relief,
while preserving in situ the body and tail of the gland with its
metabolic functions. Islet autotransplantation and segmental
pancreatic autotransplantation were introduced in 1977 and 1978,
respectively. Over 150 and 25 cases of these operations have
been reported, respectively. Both techniques are evolving with a
goal to improve results. Procedures placing the graft in the
iliac fossa and anastomosing the pancreatic duct to the jejunum
are now favored over groin placement and duct occlusion. Islet
autotransplants achieve a higher yield of islet cells and
decrease the exocrine impurity of the preparation. Both methods
can prevent or delay the onset of diabetes mellitus, and when
diabetes mellitus does occur, it is frequently easier to manage.
The long-term function of the grafts appears to be dependent on
the beta-cell mass available in the diseased pancreas, the loss
of cells related to the transplant procedure, and the
characteristics of gradual loss of function from the type of
transplant used. Although extensive pancreatic resections are
occasionally required, the possibility of autotransplantation
should be considered in those patients.
Pancreas
transplantation: the histologic morphology of graft loss and
clinical correlations.Transplantation.
2001 Jun 27;71(12):1784-91.
BACKGROUND:
Graft losses due to leaks, bleeding, thrombosis, infections, and
early pancreatitis are grouped together under the category of
technical failure. Among these complications, massive vascular
thrombosis continues to be the most important cause of early
graft loss due to technical failure. Pathological evaluation of
most allografts lost early in the posttransplantation period
shows vascular thrombosis with associated proportional
parenchymal necrosis. The morphological findings in allografts
that are considered to be lost due to technical failure has not
been systematically addressed. In particular, the role of acute
rejection in early graft loss has not been well studied.
METHODS: Seventy-four consecutive pancreas graft
pancreatectomies were studied histologically to evaluate for
thrombosis (recent versus organized), type of vessel involved by
thrombosis (arteries, veins, or both), acute rejection grade,
chronic rejection grade, endotheliitis, transplant arteritis,
coagulation necrosis, acute pancreatitis, presence of infectious
organisms, transplant (obliterative) arteriopathy, neoplasia,
relative proportions of alpha and beta islet cells, and
immunoglobulin and complement deposition. The histological
findings were correlated with donor and recipient data as well
as clinical presentation. RESULTS: In 23 out of 39 grafts lost
in the first 4 weeks posttransplantation, the only pathological
changes found were vascular thrombosis and bland ischemic
parenchymal necrosis. In these cases, no underlying vascular
pathology or any other specific histological change was
identified. Most of these grafts (78%) were lost in less than 48
hr and all in the first 2 weeks posttransplantation. Massive
vascular thrombosis occurring in an otherwise histologically
normal pancreas was the most common cause of graft loss in the
first 4 weeks posttransplantation (59%). In most of the
remaining cases (33%), although the clinical presentation
suggested technical failure, there was clear histological
evidence that the massive thrombosis resulted from vascular
injury due to immune damage (acute and hyperacute rejection).
Increased incidence of early graft thrombosis was seen in grafts
from older donors and longer cold ischemia times. After the
first month posttransplantation, graft pancreatectomies revealed
a wider variety of pathological processes that included severe
acute rejection, combined acute and chronic rejection, chronic
rejection, and infections. Acute and chronic vascular thrombosis
in large and small vessels was commonly seen at all times
posttransplantation; chronic, organized thrombosis was strongly
associated with chronic rejection. CONCLUSIONS: (a) Early acute
thrombosis occurring in a histologically normal pancreas defines
a true technical failure. This study showed that acute rejection
leading to massive thrombosis, which clinically simulates
technical failure, results in a significant proportion of early
graft losses. (b) Systematic histological evaluation of failed
grafts is absolutely necessary for the accurate classification
of the cause of graft loss. (c) There is morphological evidence
that chronically ongoing thrombosis is an important, common,
contributing factor for late graft loss.
Pancreas
rejection. Significance of histopathologic findings with
implications for classification of rejection.
Am J Surg Pathol. 1992 Nov; 16 (11):1098-107.
To
determine the significance of various histopathologic features
of pancreatic rejection, we reviewed the pathology of 53
biopsies taken to rule out rejection [32 bladder drained, (BD);
18 non-BD]. Twenty-six biopsies from 23 patients with allografts
which ultimately failed (FLD) (7 BD, 16 non-BD) were compared
with 27 biopsies from 27 patients with allografts which continue
to function (FXN) (25 BD, 2 non-BD). The groups are similar in
regard to age, sex, and time after transplant to biopsy. The
mean follow-up is 13 months for FLD grafts versus 35 months for
FXN grafts (p < 0.0001). In BD grafts, decreases in urine
amylase usually led to biopsy, while in non-BD grafts,
hyperglycemia usually prompted biopsy. More patients with
ultimately FLD organs (17 of 26) presented with elevated blood
glucose (BG) than patients with FXN grafts (2 of 27) (p <
0.0001). Multiple histologic features were examined related to
the acinar tissue, pancreatic ducts, islets, vessels, and
nerves. Features which strongly correlated with a negative
outcome included moderate to severe inflammation of acinar
tissue (p < 0.0001), acinar tissue loss and fibrosis (p <
0.0087) and vascular luminal narrowing due to chronic rejection
(p < 0.003). Twenty-one pancreases showed chronic rejection and
were treated with OKT3 or anti-lymphocytic globulin (ALG), six
of these continue to function 1.6-9 years after biopsy,
including two who presented with elevated BG levels. A normal
biopsy was found in nine pancreases, all of which continue to
function. Vasculitis was only seen in biopsies with moderate to
severe inflammation, whereas endothelialitis was also seen in
association with mild inflammation, suggesting that vasculitis
is a more aggressive lesion. A rejection classification is
proposed with endothelialitis partly defining mild rejection and
vasculitis defining severe rejection. We conclude that several
biopsy features and elevation of BG are strongly correlated with
a high probability of failure; however, antirejection therapy is
justified because recovery of function occurs in some cases. A
normal biopsy obviates the need for therapy and predicts a good
outcome, as do mild histological findings of rejection.
Pancreas
transplant pathology. A morphologic, immunohistochemical, and
electron microscopic comparison of allogeneic grafts with
rejection, syngeneic grafts, and chronic pancreatitis.Am
J Surg Pathol. 1991 Mar; 15 (3):246-56.
In an
effort to establish diagnostic criteria for rejection and
recurrent disease in transplanted pancreas, a comparative study
was performed based on clinical diagnosis. Clinical rejection
was diagnosed in patients who had decreased urinary amylase or
increased blood glucose; they were treated for rejection and
improved. A clinical diagnosis of recurrent diabetes was made in
syngeneic transplant recipients with islet dysfunction. In
addition, two control groups were used--nontransplant,
nondiabetic pancreatitis patients and pretransplant normal
biopsies from patients in the study. Morphologically, tissues
were assessed for acinar inflammation, ductal changes, islet and
nerve inflammation, and vascular changes. Immunohistochemical
staining for insulin and glucagon was also performed to
quantitate differences between the groups. Vascular changes (endothelialitis,
vasculitis, obliterative endarteritis) were specific for
rejection. Also, rejection was characterized by a lymphocytic or
mixed infiltrate that involved the ducts. Recurrent diabetes was
characterized by selective loss of beta cells with isletitis.
Leukocyte common antigen and UCHL1 staining was helpful in
identifying islet inflammation. An insulin/glucagon ratio of
less than 1.0 appears to be specific for recurrent disease and
in the absence of isletitis is a reasonable method for detecting
recurrent disease at an early stage.
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