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Transplantation Surgery

Team of doctors:
Assoz.-Prof. Priv.-Doz. Dr. Rupert Oberhuber, PhD, FEBS
Dr.ⁱⁿ Cäcilia Augustin
Dr.ⁱⁿ Eva Braunwarth
Dr. Benno Cardini, FEBS
Priv.-Doz.ⁱⁿ Dr.ⁱⁿ Katrin Kienzl-Wagner
Assoz.-Prof. Priv.-Doz. Dr. Manuel Maglione, MBA MCI, HSG
Priv.-Doz. Dr. Herbert Maier
Priv.-Doz. Dr. Christian Margreiter, FEBS (currently on leave)
Priv.-Doz.ⁱⁿ Dr.ⁱⁿ Franka Messner, PhD
Dr. Stefan Scheidl, FEBS , Priv.-Doz. Dr. Thomas Resch, PhD,
Univ.-Prof. Dr. Stefan Schneeberger, Executive MBA, HSG,
Ass.-Prof.ⁱⁿ Priv.-Doz.ⁱⁿ Dr.ⁱⁿ Annemarie Weißenbacher, DPhil, FEBS

Transplant Coordination:
Tuesday 08.00 - 16.00 Uhr
Tel.: +43 512 504 22603
Fax: +43 512 504 22605
lki.ch.transplant-office@tirol-kliniken.at

At the Clinical Department of Visceral, Transplant and Thoracic Surgery the following organ transplants are performed:

Kidney Transplantation
Liver Transplantation
Pancreas Transplantation
Small intestine and multivisceral transplantation
Hand Transplantation

Kidney Transplantation

According to international statistics, the most common underlying diseases are Chronic glomerulonephritis, diabetic nephropathy, polycystic kidney disease, chronic, pyelonephritis/interstitial nephritis, severe malformations of the renal/urinary tract, severe hypertension

Rarer basic diseases are among others: Good Pasture syndrome, lupus erythematosus, Wegener's granulomatosis, Alport syndrome, gestational gestosis, hemolytic-uremic syndrome, severe kidney damage caused by painkillers (= analgesic anephropathy), drug-induced chronic kidney disease

In individual cases, any existing progressive kidney disease must be examined for its curability before the indication for kidney transplantation is established. This is done together with the transplant surgeon after detailed preliminary examinations and preliminary discussions with the patient. The waiting period for a kidney transplantation at our center is currently about two to six years, whereby it should be emphasized that the allocation of suitable donor kidneys to recipients is strictly carried out by the organization "Eurotransplant" (based in Leiden, Netherlands) according to tissue group similarity (=HLA histocompatibility) by means of computer calculation after the respective blood tissue group findings of donor and recipient are available. The regrettably long waiting time is explained by the increasing number of patients who wish to have a kidney transplant and the unfortunately internationally known general shortage of donor organs.

A favorable option in this problem situation is living kidney donation.

There is no definitive age limit for kidney transplantation. Subject to physical conditions (checked by preliminary examinations), kidneys can be transplanted from infancy to old age. The successful Eurotransplant senior program, which provides for the transfer of kidneys from donors over 65 years of age to recipients who are also over 65 years of age, should be emphasized. The goal of our kidney transplant program is to ensure stable long-term kidney function with a good quality of life, resuming professional activity as early as possible, and implementing private/family interests.

Living kidney donation

Is there after careful consideration, extensive investigations and consultation in the family surrounding field or the emotionally close circle of acquaintances a person ready for the freiwillige kidney donation this likewise an intensive medical check UP submitted. This includes a thorough evaluation of the donor's general health, his medical suitability as a kidney donor, and the anatomy and quality of the potential donor kidney. Donor and recipient must also undergo a detailed psychological consultation. If all medical and psychological requirements are met, the donor's kidney is removed and transferred to the recipient in a procedure that is usually minimally invasive (i.e. using the "keyhole technique").

One of the great advantages of living kidney donation is the ability to plan the timing of the operation. While the recipient is on dialysis to the donor organ of a deceased person, his or her state of health can often slowly deteriorate. The early performance of a living donation (possibly even as a preventive transplantation before the recipient is required to undergo dialysis) can prevent this. The recipient is therefore "healthier" at the time of transplantation and thus recovers more quickly from the procedure. Another advantage is the better quality of the organ, as the donor organ can be carefully selected. In addition, the time between organ removal and transplantation, during which the donor organs must be cooled and stored (so-called "cold ischemia time"), can be reduced to a minimum due to the plannability of the procedure. As a result, the results are significantly better than those of the deceased donation, i.e. longer patient survival and longer functional duration of the transplanted kidneys. On average, 5-year transplant survival (= the percentage of kidneys that are still functioning well five years after transplantation) is approximately 90%.

The procedure of kidney removal as well as the subsequent life with only one kidney are not completely risk-free for the donor. The operation itself has the usual risks of surgical complications (e.g. post-operative bleeding or infections), which are rather low compared to other major abdominal operations. In addition, the donor has a slightly increased risk of developing high blood pressure (arterial hypertension) or other cardiovascular diseases in the next 10 to 20 years compared to the general population. This seems to affect all donors, but especially older donors. About 30% of all donors over 60 years of age develop high blood pressure requiring treatment within 5-10 years. The risk of becoming a dialysis patient within 10 years after the donation of a kidney is estimated at about 1%. Although the overall risk for the donor is manageable, the absolute voluntariness of a kidney donation should be emphasized again in view of these figures. In addition, all donors should undergo regular check-ups by an internist after the removal of the kidney. The inpatient stay of the donor of usually 5-10 days is followed by a recovery phase of usually 4-6 weeks.

Here, after a precise medical examination of a person from a family or emotionally close circle of acquaintances who is willing to make a voluntary donation, a donor kidney is transferred to the recipient after a precise medical examination of the kidney quality, clinical suitability and anatomy (see below for the surgical technique). The advantage of living kidney donation is the ability to plan the time of surgery, a short waiting period and especially a very short "cold ischemia time" (= time of the kidney outside the bloodstream), which is longer in the case of kidneys from deceased donors due to possible longer transport distances.

Surgical technique

The donor kidney is transplanted to the recipient through an arch-shaped incision in the left or right lower abdomen, but below the actual abdominal cavity. In order for the kidney in the recipient to resume its normal function, its vessels must be connected to the blood supply of the recipient. The renal artery and vein are connected to the pelvic vessels, i.e. the pelvic artery or vein of the recipient. The ureter located on the donor kidney is sewn into the bladder. To protect the suture, a splint is inserted during the operation. The splint is removed at a later time by means of a bladder examination. Furthermore, a small drainage tube (=redon drainage) is inserted into the operating area at the end of the operation in order to drain any remaining tissue fluid or blood to the outside. This drainage is also removed after a few days. After the operation, regular ultrasound checks are carried out, as well as daily laboratory checks of the patient's blood values, especially the renal function values. In addition, for the exact adjustment of immunosuppression (see below), the blood concentrations of the corresponding medication must be determined daily. This serves as an ongoing prevention against possible rejection reactions. In some cases, if the kidney needs some "warm-up time" after the operation, some dialysis is necessary until the transplant achieves optimal blood washer function and urine production. An acute rejection reaction corresponds to a defence reaction of the body's own immune system against the transplanted, foreign tissue. By means of careful, close-meshed examinations (laboratory chemistry, ultrasound, taking samples of kidney tissue = biopsy), an acute rejection reaction can be quickly recognized and almost always treated successfully: the so-called cellular (= caused by T-lymphocytes) rejection reaction responds very well to a high-dose cortisone therapy. The rarer, "antibody-mediated" rejection reaction is improved by plasma exchange (elimination of antibodies), supplemented by drug infusion therapy to suppress lymphocytes. If the course of the treatment is unproblematic, the patient with stable graft function can be discharged in good general condition after 1 to 3 weeks with the agreement of regular outpatient follow-ups at our center or in good cooperation with the home centers of patients who live geographically further away.

Immunosuppression

The acceptance of the foreign kidney transplant in the recipient organism is not a matter of course. Rather, the recipient organism would be biologically prepared to recognize the new tissue as foreign and to fend it off by means of an inflammatory reaction (rejection). In order to prevent this step, a drug therapy against the body's own defense system is administered from the time of transplantation. This therapy initially also contains cortisone, which in the longer term can be reduced or ideally discontinued. A combination of drugs is administered which suppresses the readiness of the defence cells (=lymphocytes) to multiply without, however, destroying them completely, as they are needed for other protective functions (against infections and tumours). A number of drugs are suitable for the prevention of rejection: a combination of i) calcineurin inhibitors (Tacrolimus or Cyclosporin-A), ii) an inhibitor of cell division (mycophenolic acid, mTOR inhibitor, azathioprine) and iii) cortisone have proven to be effective. These drugs are a long-term continuous therapy, but their dose can be significantly reduced in the longer term, so that a good quality of life and physical performance is possible under this medication. In addition, to induce immunosuppression in many patients, an antibody is administered during and shortly after transplantation, which reduces the number of immune cells in the recipient. An important task of the above-mentioned regular outpatient follow-ups is to control the dosage and determine the level of effectiveness of these drugs in order to avoid over- or underdosage and potential side effects. Since patients, physicians and the pharmaceutical industry are very interested in the optimization of this therapy and its further development, the approval of new immunosuppressive drugs can be expected in the next years.

Side effects of immunosuppression

Due to the artificially suppressed immune system, an increased risk of infection can be expected, especially in the first phase after transplantation. Patients are informed and advised in detail in preliminary talks before transplantation and during their stay in hospital. Discharge after transplantation is planned as soon as the patient can feel infectiologically safe. In the first two months after transplantation, careful handling of potential sources of infection is recommended: In this phase, larger crowds of people, direct contact with infectious persons or heavy exposure to dust and dirt are not recommended. In the course of the following months, this risk becomes smaller as the dose of the drugs mentioned above is reduced. Our special concern is a good personal contact with our patients: Therefore, we attach great importance to telephone enquiries for any interested questions or problems.

Results

Between 1974 and 2016, over 4,000 kidney transplants were performed at our center. The "durability" of kidney transplants is very good nowadays. Somewhat better than international statistics, our 10-year kidney transplant survival rate is 75%. Those transplants that cease to function in the long term suffer in most cases from a so-called "chronic rejection reaction", which is less an immunological defense reaction than a sum of chronic renal tissue/vascular changes, which ultimately lead to poor renal blood supply and scarring of renal tissue, thus impairing filtering performance. However, one can live with such a disorder for several years without returning to dialysis. In the event of transplant loss, a second or third kidney transplantation is sought, which is technically feasible if the clinical conditions correspond to the above-mentioned preliminary examinations for a new transplant, whereby an increased resistance of the recipient against the new kidney is to be expected.

Liver Transplantation

The need for liver transplantation arises in many cases of advanced liver disease after exhaustion of the non-surgical treatment options. In principle, liver transplantation is considered for patients with liver tissue diseases, diseases of the bile ducts, certain metabolic diseases, selected liver tumors, acute liver failure and other, rarer causes.

The decision on the listing for a liver transplantation is made together with the referring hepatologist and our colleagues at the Univ. Clinic for Internal Medicine I (Head: Univ. Prof. Dr. Herbert Tilg) (please link to their homepage). In each case the individual situation of a patient is discussed together and the decision on transplantation is made in a joint committee. The timing of the listing depends on the liver function but also on the progression of the underlying disease and the general condition of the patient. Criteria that are taken into account in the decision making process are, in addition to liver function, the presence of ascites ("abdominal fluid"), peritonitis, loss of consciousness, physical weakness, poor performance or increasing fatigue, bleeding in the stomach or esophagus, the type, size and recurrence of a tumor, and kidney dysfunction caused by liver disease.

It is important not to list a patient too late for transplantation, because the results after transplantation also depend on the general condition of the patient before transplantation.

The so-called MELD-Score (Model for End stage Liver Disease) is used to assess the degree of liver transplantation. The MELD Score indicates the degree of liver disease.

List of liver diseases for which a liver transplantation is possible:

• Liver parenchyma diseases
ZCirrhosis due to hepatitis B or C, cirrhosis due to autoimmune hepatitis, fatty liver cirrhosis, cirrhosis of unknown cause

• Cholestatic liver diseases
Primary biliary cirrhosis (PBC), secondary biliary cirrhosis, primary sclerosing cholangitis (PSC), secondary sclerosing cholangitis (SSC), extrahepatic bile duct atresia, progressive familial intrahepatic cholestasis (Byler's disease), Aalagille syndrome, congenital fibrosis, graft-versus-host disease (GvHD), chronic rejection, cholestatic sarcoidosis, drug-toxic cholestasis, caroli syndrome

• Primary metabolic diseases
a1-antitrypsin deficiency, Wilson's disease, hemochromatosis, tyrosinemia, galactosemia, glycogen storage diseases, lysosomal storage diseases, Crigler-Najjar type I, primary hyperoxaluria type I, erythropoietic protoporphyria, primary bleeding disorders (possibly with Budd-Chiari syndrome), disorders of the urea cycle (e.g. citrullinemia), familial amyloidosis

• Secondary metabolic diseases
for short bowel syndrome

• Acute liver failure
Fulminant viral hepatitis (Hepatitis A,B,C,D,E), intoxications, Amanita phalloides, paracetamol (acetaminophen), halothane, carbon tetrachloride, ecstasy and others, acute fatty liver during pregnancy, HELLP syndrome, Budd Chiari syndrome, primary non-function of a transplanted liver

• Tumors
Hepatocellular carcinoma, neuroendocrine tumors (strict indication), hepatoblastoma, cholangiocellular carcinoma (strict indication), liver metastases of colorectal carcinoma (strict indication)

• Other causes
multiple liver cysts, consequences of severe liver trauma

History
The first human liver transplantation was performed in 1963 by T.E. Starzl in Denver/USA. Since then, there have been a number of improvements in diagnostics, surgical technique, organ preservation, suppression of immune response as well as treatment of post-transplant complications. At the Medical University of Innsbruck the liver transplantation of em. Prof. Dr. h.c. Raimund Margreiter. Under his direction more than 100 liver transplantations were performed and complex forms of transplantation such as transplantation of liver parts, transplantation using living donors and children's liver transplantation were established. Today, liver transplantation is the treatment of choice for a variety of advanced liver diseases. The majority of liver transplantations are performed after removal of the diseased liver using cadaveric organs. Alternatively, liver transplantation can be performed as part of a "living donation". In this case, part of the liver of a healthy donor is transferred to the sick recipient. This procedure has proven to be particularly effective for small children (see also Children's liver transplantation).

Organ Allocation
The allocation of organs for transplantation is basically based on two pillars: Equity and utility. All patients listed for liver transplantation have the same right to a transplant, and the urgency and match between donor and recipient must be considered in the selection process.

In order to meet these two basic values, the distribution of organs in many countries including the USA, Germany, France, Italy and Switzerland is based on the Model For End-Stage Liver Disease (MELD) point system. Creatinine and total bilirubin levels in the blood, as well as the INR (International Normalized Ratio) are taken into account to estimate the severity of liver disease. For hepatocellular carcinoma (hepatocellular carcinoma), the MELD value only reflects the risk of the disease to a limited extent. For this reason, an "exceptional MELD" of 22 points can be applied to the listing if the tumor is within a defined size (Milan criteria).

Organ allocation at the Medical University of Innsbruck is primarily based on the MELD value and the degree of severity of the disease expressed in this value. However, other factors not represented in the MELD system are also taken into account for the decision, which also play a major role in the result:

The waiting time is stressful for the patient and indicates how long the patient has been suffering from such a serious illness. Especially for patients with very similar MELD, the waiting time is taken into account in the decision.

Other factors are also taken into account in the decision-making process:

The correspondence of height and age and weight
Suitability of the organ for a "complex" transplantation, e.g. in cases of vascular occlusion (e.g. thrombosis of the portal vein), or a retransplantation
Suitability of the organ for a child recipient
Distance to center for short time window
Speed of disease progression
Liver transplantation as part of a simultaneous transplantation of several organs

The allocation of organs is documented and reviewed annually by a delegation of the Ministry of Health together with representatives of the Austrian transplant centers.

Surgical technique
Today, liver transplantation is an established procedure following a well-standardized procedure. After opening the abdominal cavity, the liver is exposed. The vessels and bile ducts are then visualized, the hepatic artery and bile duct are severed, and the portal vein is left in place for the time being. Now the inferior vena cava is looped above and below the liver and the liver is completely exposed. The liver is removed after the vena cava and the portal vein are clamped and cut. Now the new liver is placed in the abdominal cavity and the vessels of the recipient are connected to those of the donor organ (vena cava, portal vein, hepatic artery). Once the vascular connections are completed, blood flow is restored and the liver begins to function. Finally, the bile duct is restored by connecting it to the recipient's bile duct or with a loop of small intestine. Finally, drains are inserted to drain off the resulting secretion and the abdomen is closed. The average duration of a liver transplantation operation is 4-6 hours. After the operation, patients are transferred to the intensive care unit for monitoring, and usually after a few days to the transplantation surgery normal ward, where they are cared for by specially trained nursing staff. The inpatient stay after liver transplantation is 2-3 weeks.

Liver transplantation in children

Immunsuppression
The immune system recognizes a transplanted organ as foreign. In order to prevent rejection of the transplanted organ, the immune system must be suppressed by medication. A number of drugs are available for this purpose. It is crucial to use the right choice and the right amount of medication. If the immune system of the organ recipient is not suppressed enough, a rejection reaction will occur. If the dosage of immunosuppressive drugs is too high, however, there is a high risk of infections and tumor diseases. Immunosuppression is usually carried out with three substances. A combination of 1) calcineurin inhibitors (Tacrolimus or Cyclosporin-A), 2) an inhibitor of cell division (mycophenolic acid, mTOR inhibitor, azathioprine) and 3) cortisone have proven to be effective. These drugs are a long-term continuous therapy, but their dose can be significantly reduced in the long term, so that a good quality of life and physical performance is possible under this medication. In some cases, an antibody is administered at or shortly after transplantation to initiate immunosuppression, which is intended to reduce the number of immune cells in the recipient. In the months and years following transplantation, an adjustment of immunosuppression is necessary again and again. The long-term care and thus the adjustment of the drug treatment is carried out by your hepatologist. It is crucial that essential changes in treatment are discussed with us or our colleagues at the Univ. Clinic for Internal Medicine I (head: Univ. Prof. Dr. Herbert Tilg).

Side effects of immunosuppression
Unfortunately, the use of the drugs to prevent rejection is often associated with the occurrence of side effects. Typical side effects are: kidney function impairment, headache, tremors, diarrhea, increased blood lipids, stomach ulcers and osteoporosis. However, by reducing the dose or switching to another medication, undesirable side effects can usually be eliminated or at least reduced. Due to the artificially suppressed defence reaction of the body, an increased risk of infection must be expected, especially in the first phase after transplantation. In the first two months after transplantation, additional risks of infection should be avoided: in this phase, larger crowds of people, direct contact with infectious persons or heavy exposure to dust and dirt are not recommended. In the course of the following months, this risk becomes smaller as the dosage of the drugs mentioned above is reduced.

Results
Since 1977, more than 1500 liver transplants have been performed at the Transplantation Center Innsbruck. The 1-year patient survival after liver transplantation at our center is 90-95%, the 5-year survival is 70-80%. More than 50 transplantations were performed as living donor liver transplantation in adults or children. More than 120 transplantations in children were performed at our center. In cases of severe forms of transplant rejection that cannot be treated with medication or in cases of severe vascular or biliary complications that cannot be controlled otherwise, a new liver transplantation may become necessary.

Pancreas Transplantation

In 1966, the first pancreas transplantation was performed in the USA. Since then, this operation has evolved from an experimental approach to a standardized and recognized therapeutic option for patients suffering from insulin-dependent diabetes mellitus (blood sugar disease). Ongoing advances and improvements in surgical technique, organ preservation, immunosuppression and also the prevention and treatment of infectious complications have made combined renal-pancreas transplantation the treatment of choice for patients with insulin-dependent diabetes requiring dialysis. The aim of pancreas transplantation is to replace the missing insulin production by the newly implanted organ and thus to achieve a blood sugar level within the normal range by means of a continuous, almost physiological insulin release. In addition to the significant increase in quality of life that accompanies a successful transplantation, long-term results also show an extension of average life expectancy through a reduced progression or even a decrease in concomitant diseases.

At the University Clinic for Visceral, Transplant and Thoracic Surgery more than 590 pancreas transplantations were performed between 1979 and 2016, making the Innsbruck Transplant Center one of the most experienced in Europe in this field.

Indication

According to the current state of knowledge, combined renal-pancreatic transplantation is the therapy of choice for insulin-dependent patients with end-stage renal failure. In addition to the significant improvement in quality of life associated with a successful transplantation, a stabilization or decrease in diabetes-related complications (vascular disease, neuropathies) has been observed. Furthermore, the combined transplantation of both organs prevents a recurrence of diabetic kidney disease. The advantage of combined kidney-pancreas transplantation is confirmed by the long-term results. The mean life expectancy of a patient requiring insulin and dialysis without transplantation is 8 years. Kidney transplantation extends this to 13 years, while a successful combined renal-pancreas transplantation increases the mean life expectancy even to 23 years. Regardless of the type of diabetes mellitus, only patients who have to inject insulin daily and are on dialysis or have such limited kidney function that dialysis is imminent are listed. The upper age limit is set at 55 - 60 years. Since being overweight represents a risk for transplantation, a body mass index (BMI, relation of body weight and height) of less than 35 is required. Pancreas transplants alone are also performed. This is indicated for insulin-dependent patients who are unable to detect low blood sugar levels (hypoglycemia unawareness) or who have highly fluctuating blood sugar levels despite regular insulin administration (Brittle diabetes). Both diseases are life-threatening situations. Other indications for pancreatic transplantation alone are patients who have already received a kidney transplant alone or patients with a loss of pancreatic transplant function.

Surgical technique

After the removal, the organ should be implanted in the recipient as early as possible in order to minimize the damage to the organ. Usually, the entire organ is implanted with part of the duodenum. The implantation is performed through an incision in the middle of the abdomen. The pancreatic graft is connected to an artery in the right lower abdomen and to the inferior vena cava or a mesenteric vein. The duodenum is connected to the recipient small intestine approximately 60 cm below the stomach exit. This technique allows later graft evaluation and sampling by means of a gastrointestinal endoscopy. In combined renal-pancreatic transplantation, the kidney is connected to the left pelvic vessels (artery and vein). The ureter is sewn into the bladder. If the pancreas transplant loses function, a new pancreas transplant is also possible. Early pancreatic graft losses are observed in 5% - 10%, the most common causes being occlusion of the graft vessels, infections in the abdominal cavity and graft pancreatitis.

Die Immunosuppression (suppression of the immune response) in pancreatic transplantation usually consists of a triple maintenance therapy (cortisone, calcineurin inhibitors, mycophenolate mofetilic acid) combined with an initial "induction therapy" using an antibody directed against T lymphocytes. In the further course of the treatment, the dose of cortisone is reduced with the aim of being able to discontinue it after 6 to 12 months. Also the remaining immunosuppressive drugs are reduced by the treating physician to such an extent and thus "tailor-made" that over the years on the one hand rejection is prevented and on the other hand undesirable side effects are minimized. Reduction of kidney function, headaches, tremors, diarrhea, increased blood lipids, stomach ulcers and osteoporosis are among the most common side effects. However, thanks to an increasingly broad range of immunosuppressive drugs, it is usually possible to eliminate or reduce undesirable side effects by reducing the dose or switching to another drug. Due to the strong immunogenicity of pancreatic transplants, dosages are higher than e.g. in liver recipients. Furthermore, fluctuations in the uptake of medication by the intestine and the varying "rejection readiness" of the recipients force individual therapies to be optimized in the course of regular follow-up treatment in consultation with the treating physician. The longstanding close and good cooperation with the referring internists enables the patients to carry out the aftercare checks in their home hospital. After receipt of the laboratory findings and the examination results, possible changes in therapy are carried out after consultation with our transplant center. Of course it is also possible to carry out the aftercare at our center. If rejection is suspected, its extent can be assessed by means of a gastrointestinal endoscopy, in which a tissue sample of the co-transplanted duodenum is taken and examined. The further therapy is determined on the basis of the present result. Alternatively, a biopsy of the transplanted kidney can be taken, since in case of rejection both organs are usually affected.

Results

The International Pancreas Transplantation Registry (IPTR) collects the results of pancreatic transplant recipients worldwide. The current status indicates a 3-year patient survival of over 90%. Depending on the type of transplantation, 3-year pancreas transplant survival varies between 60% (pancreas transplant alone) and 80% (combined renal-pancreas transplantation). With over 95% 3-year patient survival and almost 90% 3-year pancreas transplant survival in combined renal-pancreas transplantation, the results at our clinic are above the international average. The 3-year transplant and 3-year patient survival rates are 60% and 85% respectively.

Small intestine and multivisceral transplantation

Small bowel transplantation, i.e. the replacement of the body's own small bowel by a donor small bowel from a deceased donor or a living donor, is the only causal therapy for short bowel syndrome. It represents an alternative method to artificial feeding and is the therapy of choice when complications of artificial feeding (serious liver dysfunction, venous catheter-related infections, loss of venous access) have occurred. If the artificial nutrition has already caused irreversible damage to the liver, a combined small intestine and liver transplantation is performed. Multivisceral transplantation is the replacement of several abdominal organs (liver, stomach, duodenum, small intestine, colon, pancreas, kidneys). The first transplantation of the small intestine in humans was performed in 1967 (University of Minneapolis). In 1989, Prof. Raimund Margreiter performed the world's first successful multivisceral transplantation in an adult at our clinic.

Indication

Small bowel transplantation is the only curative therapy for patients with short bowel syndrome and the need for a lifelong artificial intravenous diet. Various diseases can lead to short bowel syndrome. Further indications are functional disorders of the small intestine. Here, a disturbed function of the small intestine makes artificial nutrition necessary. A combined small intestine and liver transplantation is performed in patients who already have cirrhosis of the liver. Multivisceral transplantation is a separate indication for patients with Gardner syndrome and patients with severe scarring of the abdominal cavity as a result of several operations.

Occlusion of the vessels supplying the bowel, volvulus, injury/accident, Crohn's disease, necrotizing enterocolitis, atresia of the small bowel, gastroschisis, pseudoobstruction, malabsorption syndrome, myogenic or neurogenic dysfunction

Surgical technique

After opening the abdominal cavity, all adhesions are first released. In case of functional disorders of the intestine, it is removed. Suitable blood vessels are then sought out to establish the vascular connections and exposed for transplantation. The arterial vascular connection is usually made with the abdominal aorta, the venous connection is made either via the inferior vena cava or the portal vein/V. mesenterica superior. After opening the blood flow into the new organ, a connection is now made between the beginning of the graft small intestine and the patient's own remaining small intestine and a connection to the patient's own colon, if it is still present. The end of the small intestine is drained through the abdominal wall via an artificial intestinal outlet (stoma). Finally, the abdominal wall is closed, in some cases this requires a temporary abdominal wall plastic surgery. If the small intestine is accepted, the stoma can be relocated several weeks after the transplantation.

Multivisceral Transplantation After opening the abdominal cavity, all organs that are to be replaced are first removed. Now a suitable site on the abdominal aorta is found and prepared for the arterial connection. Both large arterial vessels (Truncus coeliacus, A. mesenterica superior) are anastomosed together with a piece of donor aorta. The venous outflow of the organ package is produced by replacing the inferior vena cava. After the blood supply to the organ package is restored, the connection between the stomach of the recipient and the donor is established. Finally, the end of the intestine is connected to the colon and temporarily or permanently drained (stoma). The abdominal wall is usually closed in several stages. The stoma can be relocated several weeks after the transplantation.

Immunosuppression

In order to prevent rejection of the transplanted intestinal/organ package, the immune system must be suppressed by medication. Especially for the small intestine there is a high risk of rejection, therefore a higher immunosuppression is performed compared to other organs. In addition to the combination of calcineurin inhibitor (tacrolimus), ii) an inhibitor of cell division (mycophenolic acid) and cortisone i.v.) an antibody directed against immunoreactive T cells is routinely administered in the first days after transplantation. It is often necessary to intensify immunosuppression in the first weeks after transplantation with high doses of cortisone and sometimes new applications of anti-T cell antibodies. Immunosuppression is a long-term therapy, but the dose of immunosuppressive drugs can be significantly reduced in the long term, so that a good quality of life and physical performance is possible under this medication.

Side effects of immunosuppression

Kidney function impairment, headaches, tremors, diarrhea, increased blood lipids, stomach ulcers and osteoporosis are among the most common side effects. However, thanks to an increasingly broad range of immunosuppressive drugs, it is usually possible to eliminate or reduce undesirable side effects by reducing the dose or switching to another drug. Due to the artificially suppressed immune system, an increased risk of infection is to be expected, especially in the first phase after transplantation. Patients are informed and advised about this in preliminary talks before transplantation and during their stay in hospital. Discharge after transplantation is planned as soon as the patient can feel infectiologically safe. In the first two months after transplantation, careful handling of potential sources of infection is recommended: In this phase, larger crowds of people, direct contact with infectious persons or heavy exposure to dust and dirt are not recommended. In the course of the following months, this risk becomes smaller as the dose of the drugs mentioned above is reduced. In addition to the increased risk of infection, there is a slightly higher risk of developing a tumor under immunosuppression. In the case of intestinal and multivisceral transplants, a so-called graft-versus-host reaction can also occur: here, the immune cells of the donor organ, which are inevitably also transplanted, are directed against the organs of the recipient, which is manifested in particular by the cells of the haematopoietic system, mucous membranes, stomach, intestine, liver and skin.

Results

More than 1200 intestinal/multivisceral transplants have been performed worldwide. Due to improvements in immunosuppression and the prevention/treatment of infections, the long-term survival of intestinal transplanted patients has been significantly improved over the last ten years. One year after transplantation, the majority of patients no longer require additional artificial intravenous nutrition. The 1-year survival is 80-90%, the 5-year survival is 60-80%.

Hand Transplantation

The first successful hand transplantation in September 1998 marked the beginning of a new era in both reconstructive and transplantation surgery: new, potent drugs made the successful transplantation of a hand, larynx or abdominal wall possible for the first time.

Since the first hand transplantation of the "new era" in 1998 in Lyon, France, 33 further transplantations have been performed on 25 patients worldwide. The one-year survival rate of 100% confirmed not only the feasibility of this complex procedure but also an optimal "survival" of the transplanted hands at least in the early phase after transplantation. It also soon became clear that not so much the surgical intervention (a hand transplantation is generally considered technically easier than a replantation), but immunological factors as well as drug side effects and the costly and lengthy rehabilitation are the hurdles for long-term therapeutic success. The establishment of the "International Registry on Hand and Composite Tissue Transplantation" (www.handregistry.com) in May 2002 enables the evaluation of the results of all hand transplantations performed so far. A total of 11 unilateral and 4 bilateral hand transplantations were performed. All recipients were male, the average age at the time of transplantation was 32 years. Under the applied immunosuppressive therapy 26 acute rejection reactions (AR) were observed within the first year after transplantation. Thus, AR is a frequent event after hand transplantation despite the not low immunosuppression. It is characterized by an exanthema, which can occur irregularly distributed at single sites or take up a large part of the hand. In most cases a rejection could be successfully treated by means of cortisone bolus therapy, but in case of repeated rejection reactions the use of mono- or rejection antibodies against lymphocytes became necessary. Transplant survival after 32-87 months (mean: 60.4 months) is 92%, patient survival is 100%. Two hands were removed due to rejection, and 11 patients lost hand function after discontinuing medication.

Surgical complications included two cases of necrosis of small skin areas, arterial thrombosis and in one patient the occurrence of arteriovenous fistula. All these complications could be resolved by minor corrective surgery. It has been shown that the necessary immunosuppression (IS) is approximately comparable to that after pancreas or heart transplantation. Disadvantages of IS are mainly the increased risk of infections and tumors. Besides fungal infections of the skin, infections with the cytomegalovirus have been observed particularly frequently. The analysis of the hand function of the patients transplanted so far showed that a good result could be achieved in almost all patients. The function of the forearm muscles allows a gripping function in all transplanted hands. The gripping force is more than 10 kg in 4 patients, more than 5 kg in 8 patients, more than 2.5 kg in 3 patients and less than 2.5 kg in 2 patients. The finger force is more than 2kg in 4 patients, more than 1kg in 7 patients, more than 0.5kg in 2 patients and less than 0.5kg in 2 patients. All patients developed a protective sensitivity and most patients also developed a good surface sensitivity (Highhet Scale modified according to Dellon). Overall sensitivity was rated excellent in 5 hands, good in 2 and satisfactory in 10. No surface sensitivity was detected in 4 hands. However, it is still unclear whether good function is threatened in the long term by chronic rejection. Evaluations of functional, histological and imaging analyses have so far shown no evidence of chronic rejection, but the risk of such a change occurring cannot be reliably ruled out in the long term.

General requirements

Hand transplantation is a long-term and complex therapy option. In addition to the surgical intervention, intensive physical therapy and regular intake of medication to prevent a rejection reaction are necessary. After a complex clarification, the waiting period until the operation lasts up to two years. The exact time depends on the availability of a suitable donor and can therefore not be predicted. The phase of intensive follow-up treatment lasts for one year, and according to previous experience an improvement of the functional results progresses up to five years after the operation. In addition to general anaesthetic fitness, a stable health condition is therefore also required.

Psychological requirements

A hand transplantation makes enormous demands on the psyche of a patient: From the first day on and especially in the first year after the operation, the patient must consistently follow the chosen path. Even before the operation, regular exercises to train the forearm muscles must be performed. And after the transplantation, the patient can expect to start to feel the mobility and the sensation of touch in the hands only after months of hard work. In addition, even increasing experience in the field of hand transplantation does not allow the exact extent of the function to be achieved to be predicted accurately. As far as can be seen so far, however, an increase compared to the best results of a fitting with mechanical prostheses seems achievable in any case. As in every transplantation, the long-term success is 100% dependent on the patient's cooperation, especially the daily training and the most consequent following of the instructions of the treating physicians, but especially the taking of immunosuppressive drugs.

Surgical requirements

To expect acceptable function after hand transplantation, the amputation residual limb must be in good condition. This essentially includes the length of the forearm stump, which should in principle be as long as possible, but in any case a quarter to third of the original forearm length. The condition of the forearm musculature and the supplying nerves is particularly important here, since these structures must be "connected" in the course of the transplantation. From a neurological point of view, the intactness of the nerves up to the amputation stump is essential.

Logistics and Financing

Although in the past, relevant financial support has always been provided by the Medical University of Innsbruck and TILAK, a commitment from the patient's insurance company is required due to the many years of involvement. This is especially true for a commitment to the costs of a several years' follow-up treatment as well as a lifelong immunosuppressive therapy (according to a scheme to be determined exclusively by the Medical University of Innsbruck). From the point of view of the living situation, an acceptable proximity to the Medical University of Innsbruck should exist, although this will probably have to be clarified in each individual case.

Patient Selection

A hand transplant is a possible therapy for a patient (see Requirements for hand transplantation) with amputation of the hand and parts of the forearm. A further prerequisite is the intactness of the stump of the forearm. At the Medical University of Innsbruck, only bilateral forearm amputation is considered an established indication for transplantation. However, patients with unilateral amputation are also gladly informed about hand transplantation and in individual cases these patients can also be transplanted. In any case, the patient should have attempted the fitting of a myoelectric prosthesis. A hand transplantation is then an option especially for patients who are dissatisfied with such a prosthesis and continue to suffer from the loss of their hands/hand. Specific criteria were defined in Innsbruck for the selection of candidates for hand transplantation: The first and most important criterion is the patient's unconditional desire for therapy. After detailed information not only about the operation, but especially about the necessary physiotherapy and occupational therapy in the course of rehabilitation as well as the necessity of an immunosuppressive long-term therapy and the associated risks, the candidates are given sufficient time for a final decision. The anatomical preconditions were the loss of both hands or forearms, the age limits were 18 and 55 years, respectively. The candidates had to be in good physical and mental condition and free of metabolic diseases, infections and tumors. The amputation residual limbs were examined using x-rays, ultrasound, computer tomography, magnetic resonance imaging, angiography and CT angiography. In order to exclude a malignoma and a focus of infection, the gastrointestinal tract, the urogenital tract, the teeth, the pharynx and the paranasal sinuses were examined in addition to blood analyses.

Physical therapy was designed to support rapid rehabilitation, reduce swelling and pain and prevent stiffening of the joints. "Early Protective Motion - EPM" is a therapy concept that had already been used with good success after hand replantation, that meets the above mentioned criteria and was therefore also applied after hand transplantation. Special attention was also paid to regaining sensitivity and reintegrating the hand into the central nervous system. For this purpose, Perfetti's cognitive exercises became a central component of rehabilitation. The rehabilitation was supplemented by occupational therapy exercises for coping with activities of daily life. Passive exercises were started on the third day after transplantation. From the third week onwards, the muscles within the hand were activated by electrostimulation and one week later active finger exercises were started. From the ninth week on, the therapy was extended by electromyographic feedback training. Variously shaped splints were used to protect the hands and stabilize the wrist. A similar protocol was used after forearm transplantation. However, since this procedure was very different from the first one, the rehabilitation program was adapted to the clinical situation.

Results

The first hand transplantation in Innsbruck was performed in March 2000, five years and six months after amputation of the hands. The reconstruction was performed in the following order: bones, arteries, veins, tendons of the flexors, tendons of the extensors, nerves and finally skin. The surgical procedure on the second patient was performed in February 2003. Since the amputation was performed at the level of the upper forearm, the few remaining forearm muscles could not be used for reconstruction. Therefore the forearm muscles of the donor were fixed to the humerus of the recipient. It was the first transplant of this kind worldwide. The third transplantation was performed in May 2006 and, like the two previous operations, was performed without major complications. Both operations were performed by members of the Department of Plastic and Reconstructive Surgery together with the hand surgery team of the University Hospital for Trauma Surgery. In addition to objective criteria such as motor skills or sensitivity, subjective aspects such as the ability for social interaction or a holistic body perception after hand transplantation also play a significant role in patient satisfaction. The measurability and comparability of such activities, sensations and impressions is limited. Therefore, the patient's opinion about whether and how the hand transplantation has changed his or her life is of crucial importance. Furthermore, each evaluation corresponds to a snapshot, so the time of the survey is important. As mentioned above, the motor function after hand transplantation is clearly superior to that of a myoelectric prosthesis. In particular, composite movements and the fine motor control of movements are easier for the patient. Of particular importance for both patients is the regaining of physical integrity, which was not imparted to them by the prostheses. As a result, the ability for social interaction as well as intimate contacts has improved significantly. Overall, both patients are very satisfied with both the functional and cosmetic results. Although the motor function of the described patients is better after hand transplantation than after forearm transplantation, it is still increasing and the observation period in the second patient is significantly shorter than in the first patient. Overall, the achieved function after hand transplantation is >60% of a normal hand. Together with the very good sensitivity without cold intolerance, the achieved function enables the patient to perform numerous activities that he could not perform with the prostheses. Not only can he perform more complex everyday movements such as buttoning up shirts or picking up small coins from a flat surface, but his self-confidence and thus interaction with his environment has improved significantly. So far, no signs of a functional deterioration or the occurrence of chronic rejection have been observed. Daily life is described by the patient as completely normal, he is fully integrated and committed to his job again. With the transplanted hands he has already undertaken several transcontinental motorcycle trips. The set goal was thus achieved and from the patient's point of view the decision to have a hand transplant was clearly the right one. The result after forearm transplantation is also satisfactory, although several acute rejections and side effects of medication complicated rehabilitation. In the meantime, a stable situation has been established and all side effects have disappeared. The result is impaired by the insufficient sensitivity. It is to be hoped, however, that there will still be an improvement in function in this respect.