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Small bowel transplant - novel indications and recent progress

Expert Review of Gastroenterology & Hepatology

June 2023
17(7)

DOI:10.1080/17474124.2023.2221433

Authors:

Ignazio R Marino

Thomas Jefferson University Hospitals

Salvatore Sorrenti

Sapienza University of Rome

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Introduction: Advances in the management of intestinal failure have led to a reduction in the number of intestinal transplants. The number of bowel transplants has been mainly stable even though a slight increase has been observed in the last five years. Areas covered: Standard indication includes patients with a reasonable life expectancy. Recent progress can be deduced by the increased number of intestine transplants in adults: this is due to the continuous improvement of 1- year graft survival worldwide (without differences in 3- and 5-year) associated with better abdominal wall closure techniques. This review aims to provide an update on new indications and changes in trends of pediatric and adult intestine transplantation. This analysis, which stretches through the past 5 years, is based on a collection of related manuscripts from PubMed. Expert commentary: Intestinal transplants should be solely intended for a group of individuals for whom indications for transplantation are clear and both medical and surgical rehabilitations have failed. Nevertheless, the many protocols developed over the years have not yet solved the key question represented by the over-immunosuppression. Novel indications and recent progress in the bowel transplant field, minimal yet consistent, represent a pathway to be followed.

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Small bowel transplant – novel indications and

recent progress

Noemi Zorzetti, Ignazio Roberto Marino, Salvatore Sorrenti, Giuseppe

Giovanni Navarra, Vito D’Andrea & Augusto Lauro

To cite this article: Noemi Zorzetti, Ignazio Roberto Marino, Salvatore Sorrenti, Giuseppe

Giovanni Navarra, Vito D’Andrea & Augusto Lauro (2023) Small bowel transplant – novel

indications and recent progress, Expert Review of Gastroenterology & Hepatology, 17:7,

677-690, DOI: 10.1080/17474124.2023.2221433

To link to this article: https://doi.org/10.1080/17474124.2023.2221433

Published online: 05 Jun 2023.

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REVIEW

Small bowel transplant – novel indications and recent progress

Noemi Zorzetti

a,b

, Ignazio Roberto Marino

, Salvatore Sorrenti

, Giuseppe Giovanni Navarra

, Vito D’Andrea

and Augusto Lauro

General Surgery, Ospedale Civile “A. Costa”, Alto Reno Terme, Bologna, Italy;

Department of Surgical Sciences, Sapienza University of Rome,

Rome, Italy;

Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

ABSTRACT

Introduction: Advances in the management of intestinal failure have led to a reduction in the number

of intestinal transplants. The number of bowel transplants has been mainly stable even though a slight

increase has been observed in the last 5 years.

Areas covered: Standard indication includes patients with a reasonable life expectancy. Recent pro-

gress can be deduced by the increased number of intestine transplants in adults: this is due to the

continuous improvement of 1-year graft survival worldwide (without differences in 3- and 5-year)

associated with better abdominal wall closure techniques. This review aims to provide an update on

new indications and changes in trends of pediatric and adult intestine transplantation. This analysis,

which stretches through the past 5 years, is based on a collection of related manuscripts from PubMed.

Expert commentary: Intestinal transplants should be solely intended for a group of individuals for

whom indications for transplantation are clear and both medical and surgical rehabilitations have failed.

Nevertheless, many protocols developed over the years have not yet solved the key question repre-

sented by the over-immunosuppression. Novel indications and recent progress in the bowel transplant

field, minimal yet consistent, represent a pathway to be followed.

ARTICLE HISTORY

Received 12 December 2022

Accepted 24 May 2023

KEYWORDS

Intestinal transplantation;

intestinal failure; short

bowel syndrome; home

parenteral nutrition; enteral

autonomy; quality of life

1. Introduction: intestinal failure and short bowel

syndrome

Intestinal failure (IF) is defined as any cause of gastrointestinal

(GI) dysfunction that results in the inability to meet nutritional

demands, necessitating either temporary or indefinite depen-

dence on parenteral nutrition (PN) [1].

IF is mainly due to extensive surgical resection that leads to

short bowel syndrome (SBS) [2] which represents a severe and

rare clinical condition defined by malabsorption with conse-

quent malnutrition, anemia, and weight loss. Different etiolo-

gies, of new onset or chronic ones, are widely described in

literature among adults and the pediatric population [3,4]

Table 1.

Different phases of SBS have been recognized (acute phase,

adaptation phase, and chronic phase). Generally, the reversibil-

ity of this condition could easily appear when there is one of

the following situations:

●more than 35 cm of small bowel along with a jejunoileal

anastomosis and an intact ileocecal valve and colon;

●more than 60 cm of small bowel with a jejuno-colonic

anastomosis;

●more than 115 cm of small bowel with an end

jejunostomy.

The final phase is the maintenance one, characterized by

special diets, supplementation of nutrients, and pharmacolo-

gical treatments [5].

Furthermore, SBS represents nowadays a new frontier in

biomarker research (especially growth factors and citrulline)

for diagnostic, prognostic, or predictive uses. The introduction

of biomarker research into a medical routine is expected to

represent helpful clinical support for patients, their families,

and healthcare systems [6]. However, these tests are still not

widely accepted and not available in all centers, therefore

limiting their clinical utility [7].

Intestinal adaptation (IA) is a response to the loss of the

small intestine and it is essential to restore enteral autonomy

after massive small bowel resection (MSBR): multidisciplinary

management of SBS could allow the patient to achieve nutri-

tional autonomy. In a well-selected population, specific surgical

lengthening procedures plus intestinal medical rehabilitation,

together with novel approaches (such as manipulating micro-

biota or tissue bioengineering), could also be attempted to

wean HPN off [8], while intestinal transplantation (ITx) is

reserved for highly selected patients.

A significant portion of patients are being referred for HPN

as a bridge to reconstructive surgery, and this requires the

close involvement of gastrointestinal surgeons in HPN teams

[9]. Furthermore, the increase in numbers, age, and turnover

of patients dependent on HPN requires more resources and

nutrition teams; the use of technology for remote consulta-

tions can improve the efficiency of clinics and avoid some

patients to travel [9].

If this goal is not achieved, chronic IF appears, with nutrient

deficiencies and other organ-specific complications [Table 2].

CONTACT Augusto Lauro augusto.lauro@uniroma1.it Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY

2023, VOL. 17, NO. 7, 677–690

https://doi.org/10.1080/17474124.2023.2221433

The first-line therapy for IF remains home PN (HPN) and

frequent monitoring. Although this therapy is reliable, it is not

without complications, such as venous thrombosis and IF-

associated liver disease (IFALD), or increased morbidity related

to catheter-associated infections [10–13]. Overall, in both the

adult and pediatric populations, HPN shows a 76% survival

rate at 5 years [14,15].

If we take into consideration the global increase of

patients that undergo HPN (both to support IA in SBS or to

treat IF), their heterogeneity and the relatively few locations

of the specialized centers, we can see how telemedicine

could today become a very helpful tool for these patients.

The possibility of a video call service, alongside with in-

person consultations and visits, could provide not only

a strategy to reduce patients’ need to travel, bettering their

quality of life (QOL) and reducing the economical and geo-

graphical barriers, but also allows equal access to high-

quality care [16,17].

Lastly, as the number of elderly patients that survive the

once fatal illnesses grows, the need for a new at-home or

residential care-supporting model service becomes more and

more crucial [18–20].

2. Timing and extension of small bowel resection:

considerations for general management

The functional consequences of SBS depend on multifactorial

issues such as age, timing, patient’s underlying diagnosis,

overall health and the extension of resection such as the

intestinal tract involved [21]. At birth, the small bowel length

(SBL) of full-term newborns is 250 cm, and it then lengthens

during the first year. One of the main predictive factors for

intestinal rehabilitation after MSBR in the pediatric population

is a residual SBL > 25% of the expected gestational age [22]

while, in the adult population, a residual SBL > 67% of the

normal length (that corresponds to approximately 200 cm) is

the minimum value according to international literature [23].

Furthermore, two other substantial issues have to be consid-

ered for enteral autonomy: the first is the importance of the

colon in continuity with the intestine after MSBR, with its

energy-absorptive function; in fact, half of the colon and 50

cm of small bowel can be considered equal in promoting the

digestive process [3]. The second one is the difference of roles

in digestion in jejunum and ileum: IA is a natural compensa-

tory process but ileum has a better adaptive potential than

jejunum and remnant ileum (above all if in continuity with the

colon) can guarantee a better absorption and a possible faster

weaning from HPN [8,24].

Thus, taking into account all these different aspects, recent

studies [25] have suggested that 75 cm could be the minimum

length of remnant small bowel to obtain nutritional autonomy

after medical rehabilitation in adult patients when the colon

or part of it is present.

Nevertheless, apart from the underlying cause of SBS, the

outcome of enteral autonomy depends on the type of remnant

bowel, the presence of a stoma or an anastomosis, full or partial

presence of the colon, the presence of ileocecal valve (ICV) and

the patient’s age plus his/her general conditions [26,27].

3. Medical approach to short bowel syndrome

At present, one of the main treatment options for SBS is

medical intestinal rehabilitation. In order to improve survival,

Article highlights

●Intestinal transplantation should be strictly reserved to a group of

individuals for whom the indications to transplant are clear and

medical and surgical rehabilitations have failed.

●Medical approaches (such as rehabilitation or in the near future

proteomic therapy) and non-transplant surgical techniques have

a central role in the management of patients with intestinal failure.

●Novel criteria for intestinal transplant are recently emerged imple-

menting new indications to transplant apart from the standard ones.

●Quality of life itself does not represent an option for transplantation

unless other indications are present.

●The intestine is the most immunologically complex solid organ

allograft with the greatest risk of both rejection and graft-versus-

host disease: high levels of immunosuppression are required, increas-

ing morbidity and mortality.

●Tacrolimus-based regimens are the leading induction agents for

immunosuppressive therapies.

Table 2. Intestinal failure organ-specific complications.

Gastrointestinal Hepatobiliary Metabolic Renal

(1) Diarrhea

(2) Steatorrhea

(3) Gastric hypersecretion

(4) Small bowel bacterial overgrowth

(5) Changes in colonic flora

(1) Cholelithiasis

(2) Intestinal failure associated liver disease (IFALD)

(1) Malnutrition

(2) Micronutrient deficiency

(3) Fluid and electrolyte abnormalities

(4) D-Lactic acidosis

(5) Osteoporosis and osteomalacia

(1) Nephrolithiasis

(2) Chronic renal failure

Table 1. Different etiologies of short bowel syndrome.

Adults Children Infants

(1) Postoperative complications

(2) Inflammatory bowel disease (IBD)

(3) Ischemic bowel/mesenteric vascular disease

(4) Trauma

(5) Irradiation

(6) Neoplasia

(7) Other benign causes

(1) Postoperative complications

(2) Trauma

(3) Neoplasia

(4) Neuropathic/myopathic disorders

(5) Pseudo-obstruction syndrome

(1) Necrotizing enterocolitis (NEC)

(2) Bowel atresia

(3) Abdominal wall defects/gastroschisis

(4) Midgut volvolus

(5) Neuropathic/myopathic disorders

678 N. ZORZETTI ET AL.

QOL and intestinal function while weaning off HPN, decreas-

ing both the risk of IF and complications, it is important to

entrust patients to expert teams in Intestinal Rehabilitation

Centers: these expert teams can also list for ITx with the correct

time and appropriate type of transplantation [19].

In recent years, different molecules (hormones, proteins,

and growth factors) have been identified as steps in the IA

after an MSBR. Their research for the diagnosis and treatment

of SBS has raised considerable interest in the so-called ‘pro-

teomic therapy’ [6]: the raising interest for these substances is

justified by the fact that they can promote, after intestinal

resections, crypt and villus enterocytes expansion, increasing

absorptive function in order to obtain enteral independence.

Epidermal growth factor (EGF), glucagon-like peptide-1 (GLP-1),

and glucagon-like peptide-2 (GLP-2) are the molecules that

seem to regulate gene expression, during proteomic analyses

conducted subsequently to MSBR, and could have a role in the

clinical therapeutic field [6].

Among these, glucagon-like peptide-2 analogs (teduglutide

also known as GATTEX®, glepaglutide also known as ZP 1848

developed by Zealand Pharma, and apraglutide also known as

FE 203,799 developed by VectivBio) have been crucial and

allowed for dramatic clinical progress in the treatment of

SBS: many studies have been conducted on the subcutaneous

administration of Human GLP-2 (hGLP-2) and/or its synthetic

analogous, teduglutide, resolving in improvement of intestinal

absorption and creatinine clearance, reduction in fecal weight,

and improved maintenance of fluid and electrolytes, diminish-

ing the need and dependence for HPN [28–31].

In the United States teduglutide was approved by FDA for

adults in 2012 [32] and subsequently for children over the age

of one year in 2019 [33]. The other molecules are still in the

experimental stage as more research will focus on the safety

and long-term side effects. Also defining the correct timing to

initiate these therapies is crucial such as, it is, to underline that

the high cost of these drugs may limit their future clinical

application.

4. Non-transplant surgical techniques and

autologous gastro-intestinal reconstruction

The first surgical treatment of SBS is prevention preserving,

during surgical procedures, as much bowel as possible and,

whenever feasible, the ileocecal region; if intestinal resection is

necessary, the anatomy and the length of the remaining

bowel must be recorded in detail to guide the subsequent

approach [34]. However, even in this case, the evolution in the

management of chronic SBS in the last decade has made

transplantation rarely necessary.

If complications of SBS occur, nontransplant surgical tech-

niques are frequently used for autologous gastrointestinal

reconstruction (AGIR) to improve intestine function and

reduce HPN dependence and its complications, trying to

avoid ITx.

The most recent analysis of the prevalence of HPN noted

that the most common indication in adults was SBS (24%),

above all through a PICC line [35]. Although the catheter is the

lifeline of these patients, that are correctly educated regarding

proper care, complications can occur such as thrombosis,

central line – associated bloodstream infection (CLABSI), or

damage; management of these complications include respec-

tively anticoagulation, IV antibiotics ± removal of CVC and

adequate repairs thanks to specific kits [35]. A recent new

tool is Taurolidine, a derivative of taurine, that prevents micro-

bial adhesion to catheter surfaces and biofilm formation, redu-

cing CLABSI when compared with eparine group but larger

trials are needed [36].

Other common HPN complications include liver failure-

induced liver injury (IFALD) and hyperglycemia. For what

that concern IFALD, prevention is the real goal limiting hepa-

totoxic agents with cycles of HPN and avoiding overfeeding

[37]; for the second one therapy with insulin, added directly to

HPN or provided subcutaneously, is indicated [35].

The same factors concern pediatric population [38].

So, the main goal to reach in SBS patients, both adults and

in children, remains the increased enteral tolerance and wean-

ing from PN support; when the achievement of enteral auton-

omy is not reached, the inability to progress in enteral

tolerance exposes these patients to long-term complications

of PN so, increasing morbidity and mortality: in this context,

with a personalized and multidisciplinary approach, cautiously

selected AGIR can facilitate the fulfillment of enteral auton-

omy, maximizing the absorptive potential of the remaining

gut [39]. When AGIR is not possible or not successful, ITx is

a valid option, alone or in combination with other organ

transplants [21].

These surgical techniques produce excellent results in

terms of enteral autonomy when associated with Intestinal

Rehabilitation Programs (IRPs) and represent, especially in

Western countries, a new frontier for the management of

SBS as they allow specialists to combine their knowledge

and better deal with these complex cases [40].

This approach stemmed from the management of pediatric

patients, combined with the caregivers’ support to patients

and families, increased survival rate in >70% of IRPs centers

[41–43].

Enteral autonomy can be achieved in approximately 25% of

patients subjected to AGIR, reaching 30% of patients when

intestinal segments are dilated [44].

The main targets of autologous intestinal reconstructive

surgery fall into two main surgical settings [39, Box 1]; some

procedures, each with its tailored indications and clinical

applications, are designed to achieve one of these goals

while others can act above multiple aspects.

The most common techniques of autologous intestinal

reconstructive surgery are:

●LILT: designed to double the length of dilated SB loop

(≥4 cm) [45];

●STEP : this lengthening procedure is quite ‘revolutionary’

as it avoids intestinal anastomosis (and its surgical

Box 1. Targets of autologous intestinal reconstructive surgery

1) Slow down intestinal transit increasing contact time between intestinal

mucosa and nutrients;

2) Reduce small bowel dilatation decreasing stasis and bacterial overgrowth

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 679

complications); it can be performed after LILT if re-

dilatation occurs and can also be performed on the

duodenum [45]. Clinical applications are widely

described in literature [46–48]. Also repeated STEP (Re-

STEP) is a possibility to further lengthen the SB when

enteral autonomy is not achieved [48–50];

●SILT: is the newest lengthening technique. It has the

purpose of solving STEP’s main issue: the change of

intestinal muscle fibers’ orientation after stapling.

Limited clinical applications have been reported in litera-

ture so far [51];

●Reconnection surgery without autologous gastrointestinal

reconstruction: it has long been used. The presence of the

colon in continuity with the shorter small bowel could

improve the recovery from SBS after medical rehabilita-

tion [52]. The procedure is required when there is no

small bowel dilatation. Only recently [25] it has been

suggested in an adult population that a residual small

bowel length of a minimum of 75 cm, even if recon-

nected to a part of the colon without autologous gastro-

intestinal reconstruction, seems able to produce an HPN

independence after a minimum period of 1 year-

intestinal rehabilitation.

In conclusion, STEP is the preferred procedure, probably

because it is the easiest technique: there is no need for

bowel suture and there is less chance of damaging the mesen-

tery vascularization [53].

Although AGIR achieves better long-term survival, ITx

shows better reestablishment of nutritional autonomy but,

on the other side, ITx has major disadvantages, complications,

and higher costs when compared to AGIR. In cases where

complications of PN occur, the patient cannot be weaned off

PN and the bowel is too short, the patient should be referred

to a transplant center to be evaluated for transplant treatment

as soon as possible because the prognosis after ITx worsen

when performed in patients with poor conditions and/or liver

failure. Nevertheless, it is still a valid option in patients with

organ failure, and a surgical algorithm has been developed to

select patients for AGIR or transplantation, to be used in

relation to the organ failure of the patient [45].

5. Small bowel transplant: changing indications and

recent progress

5.1. Indications and criteria for transplant

If a patient has permanent IF he has to be managed by

dedicated multidisciplinary intestinal rehabilitation team [21]

in order to evaluate the possibility of an ITx when PN fails [54–

56] Table 3 or if there are no alternative surgical techniques

(unreconstructable GI tract).

According to the American Society of Transplantation,

more indications have been added to the failure of PN

because of the high risk of death attributable to underlying

diseases [Box 2a].

Furthermore, subsequent experts’ indications for ITx [57]

have been annexed, considering both the high risk of death

and the high morbidity or low acceptance of PN [Box 2b].

In the pediatric population, a subset of children with intest-

inal failure remaining dependent on PN will develop life-

threatening complications arising from therapy. Since 2001,

ITx is recommended for this selected group affected by life-

threatening complications, warranting consideration of intest-

inal ITx, similar to the adult population. Children with life-

threatening complications of IF and PN therapy must be

early identified, that is in time to receive suitable donor organs

before they become critically ill [58].

According to the latest analysis confirmed by a recent mul-

ticenter study [58], the pediatric listing criteria for ITx should

be revised to reflect the changes in the natural history of

pediatric IF that have occurred as a result of modern therapies.

In addition, this analysis would suggest that it is possible to

predict who are the children with a high risk of death and the

need of an ITx with a 98% probability, given they meet two

out of three of the proposed criteria [Box 3].

In Europe, the new guidelines agree with the American

ones considering only the actual risk of death on HPN

[54,55]. Different data-reports underline also the fundamental

role of the Intestinal Rehabilitation Center for patients with

chronic intestinal failure (CIF), according to previous docu-

ments and recommendations [59,60], (Table 4).

Particular attention must be paid nowadays to ‘re-

transplantation’ that is a new reality and a current indication

if the failure of the first graft occurs, representing up to 8–9%

of transplant activity worldwide [55]; if listed for retransplant,

most were listed for a liver-containing allograft [61].

In conclusions, a lifesaving ITx is a mandatory therapeutic

strategy for patients that follow the previous indications; for

Box 2a. Extended indications for ITx (part 1)

●Recurrent catheter-associated bloodstream infection (CABSI), especially

fungal

●Unreconstructable GI tract

●Complete porto-mesenteric thrombosis

●Tumors involving the hepatic hilum or root of the mesentery

●Frozen abdomen

Box 2b. Extended indications for ITx (part 2)

1) High risk of death attributable to the underlying disease

●Desmoid tumors associated with familial adenomatous polyposis;

●Congenital mucosal disorders (eg, microvillus atrophy and intestinal

epithelial dysplasia);

●Ultrashort bowel syndrome (gastrostomy, duodenostomy, residual small

bowel 10 cm in infants and 20 cm in adults).

2) IF with high morbidity or low acceptance of PN

●IF with high morbidity (frequent hospitalization, narcotic dependency) or

inability to function (eg, pseudo-obstruction disease, high-output stoma);

●Patient’s unwillingness to accept long-term PN (eg, young patients)

Box 3. Current era listing criteria for pediatric ITx.

●≥ 2 admissions to Intensive Care Unit (ICU)

●Loss of ≥ 3 central venous catheter (CVC)sites

●Persistent elevation of conjugated bilirubin (≥ 75 µmol/L) following 6 weeks

of lipid strategies

680 N. ZORZETTI ET AL.

those who do not have a life-threatening condition,

a preemptive ITx, in the future and in selected cases, might

be considered an indication itself [62].

Taking into account all the recommendations, it is impor-

tant to avoid any delayed referral of these patients to

Intestinal Rehabilitation Centers or directly to a transplant

center in order to choose the correct listing time and graft

type for ITx, bettering the proper allocation of the organs [55].

All unsuccessful prolonged attempts at intestinal rehabilitation

must be avoided because of their consequences, which repre-

sent a risk for early survival, such as the formation of anti-HLA

antibodies or multi-drug-resistance, hazarding ITx if eventually

performed [63–65].

Regarding the waiting list considerations, there has been

a change in trend over time. Initially, most candidates were

on the waiting list for less than 90 days, while over the last

decade more than 50% of the listed patients wait for over 1

year, and 36% over 2 years, making the mortality risk in the

list very high [60]: new indications increase the demand for

suitable donor intestines [62,66,67]. Because of the demand

for so-called ‘excellent donors’ and the related strict criteria,

donations are very rare and the waiting time could be very

long. Lastly, even if the number of new patients on the

2020 waitlist increased over the previous year, with an

increase of adult candidates rather than <18 years, the

trend over the last decade has been marked toward

a reduction of listing.

The overall pretransplant mortality for ITx candidates was

6.5 deaths per 100 waitlist years in 2020 and rates varied by

age, in general, were higher for adults (15.1 deaths per 100

waitlist-years vs 1.9 deaths per 100 waitlist-years in the

pediatric population) and it was inferior for isolated ITx

when comparing the intestine-liver combined trans-

plant [61].

5.2. Surgical techniques

ITx can be isolated or combined with other organs depending

on patient anatomy and comorbidities [55,68], including

a non-vascularized or vascularized abdominal wall [69] when

necessary.

High-volume centers of ITx (>5 patients per year for 5 years)

report for adult patients an overall 5-year survival with

a functioning graft of less than 70%, which is inferior to the

5-year survival obtained on HPN; in the pediatric population,

there is a group of infants and children who have successfully

ended PN and are unlikely to have experienced the morbid-

ities that warrant consideration for transplantation [70,71].

The main graft options are isolated intestine, liver – intes-

tine and multi-visceral transplant; in the adult recipient, the

most common grafts used are isolated intestines, when liver

function is preserved, and multi-visceral grafts [68].

Proper graft selection for each recipient represents the

basis of surgical success. Donors’ criteria that have to be

evaluated are the gastrointestinal history, the absence of any

evidence of intestine trauma, hemodynamic stability, graft

size, and immunologic compatibility. Moreover,

a determinant component of any type of intestinal graft is

the jejunoileum [68].

Table 3. Accepted indications for ITx.

(1) Failed TPN:

●liver failure-induced liver injury (IFALD);

●thrombosis of the major central venous channels (when there is the involvement of two or more major ventral veins, there is a life-threatening complication and

failure of TPN therapy);

●frequent-line infection and sepsis, requiring hospitalization;

●multiple episodes of severe dehydration (diarrhea) despite intravenous fluid supplement

(2) Approved Transplant Facilities:

●ITx is covered by Medicare if performed in an approved facility (10 intestinal transplants per year with a 1-year actuarial survival of 65% using the Kaplan–Meier

technique).

Table 4. Revised criteria related to wait-list for ITx.

●Evidence of advanced or progressive IFALD with:

a. persistent hyperbilirubinemia >75 mmol/l (4.5 mg/dl) > 2 months;

b. any combination of elevated serum bilirubin ± sub-normal albumin or elevated INR ± portal hypertension and hypersplenism > 1 month (without associated

infections).

Notes:

●the stage of liver disease is relevant for both the timing of transplantation and the type of transplant (isolated ITx or combined liver-ITx)

●liver biopsy remains the gold standard

●Thrombosis of three out of four upper body central veins (left subclavian and internal jugular, right subclavian and internal jugular) or occlusion of

a brachiocephalic vein in children (while in adults this criterion should be evaluated on a case-by-case basis).

●Life-threatening morbidity in the setting of indefinite PN dependence of either anatomical or functional cause, as suggested by:

(a) In children after two admissions to an Intensive Care Unit

(b) In adults, on a case-by-case basis taking into account catheter-related bacteremia/sepsis (CRBS) ± of severe dehydration and/or electrolyte disturbances

●Invasive intra-abdominal desmoids in adolescents and adults (mostly as a sequela of familial adenomatous polyposis) above all when greater than 10 cm

with immediate listing

●Acute diffuse intestinal infarction with hepatic failure (sometimes needing a multivisceral transplantation).

●Failure of first intestinal transplant (considering that re-transplant is a possibility when choosing the correct timing).

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 681

It is important to underline that among the pediatric and

adult populations the ‘liver – intestine’ graft differs. In pedia-

trics, it could be used to indicate a composite liver-pancreas-

intestine graft listing the candidate for all three organs; the

surgical technique is easier thanks to the foregut preservation

and en-bloc transplant creating a portocaval shunt [72]. In the

adult population often, there is a combined liver-intestine

graft: the liver is transplanted first, preserving the foregut

anatomy, it is then followed by an isolated ITx: this is called

‘non-composite’ graft [73], requiring an intact and patent

portal vein. A hepatic biopsy is the gold standard, over endo-

scopic ultrasound and transient elastography, to assess the

entity of liver disease severity and the need for simultaneous

intestine – liver transplant [74–76].

In some cases, there is the indication for multi-visceral

transplantation (MvTX), which is a complex procedure that

classically includes stomach, pancreaticoduodenal complex,

small bowel, and spleen with (MVTx) or without (modified

multi-visceral transplantation, MMVTx) the liver; it requires

also the replacement of all abdominal organs with an en-

bloc graft [77]. The main indications are multiple previous

surgeries, porto-mesenteric thrombosis, and abdominal

tumors above all desmoids. Splanchnic thrombosis is

a challenging condition but MvTX manages to reestablish

the venous anatomy and physiology of the abdominal cavity,

resolving completely the effects of portal hypertension and

the baseline disease [78]. Complete foregut resection followed

by MvTX could be a therapeutic option for large intra-

abdominal tumors (desmoid, well-differentiated neuroendo-

crine and gastrointestinal stromal ones) that are slow growing

and tend to locally invade vessels and viscera [79].

Furthermore, the inclusion of a colon component in con-

tinuity with the jejunoileum can be added to all these grafts,

both in pediatric patients and adults [68]: this option leads to

a series of advantages such as 6% superior graft survival at 3

years, higher frequency of formed stool and significant enteral

independence improving QOL [80].

A recent paper [81] has analyzed the outcome following

multi-visceral transplantation without a stoma, routinary cre-

ated during ITx to allow follow-up graft endoscopy and

biopsy. It seems a feasible model without a difference in

clinical outcomes with also better fluid balance, abdominal

wound care, and patient satisfaction. A longer follow-up with

more cases of this potentially attractive procedure will be

needed.

Common surgical complications following ITx are intestinal

obstruction, anastomotic stricture, anastomotic leak, bowel

perforation, enterocutaneous fistula, allograft volvulus, and

bowel internal hernia; they can result in allograft ischemia

and necrosis and may contribute to both early and late graft

loss [82].

5.3. Immunosuppressive therapy

The great amount of lymphoid mucosal tissue, present in the

small intestine and very well represented in ITx recipients with

the subsequent immune response is the primary cause of graft

loss and rejection.

There has been evidence of improvement in graft and

patient survival rates only up to 1-year; beyond that limit

data is unclear [83]. In order to achieve long-term graft survi-

val, it is necessary to obtain a valid immunosuppression (IS),

reduction to the minimum of IS side-effects, early diagnosis of

acute cellular rejection (ACR), accurate ACR treatments, and

improvement of allograft tolerance.

A fundamental part of ITx immunosuppressive therapy is

represented by the induction made via classical and emer-

ging protocols. Antithymocyte globulin (Thymoglobulin), that

induces T-cell depletion, represents the mainstay of IS

induction and is usually used as a primary induction

agent [84]. Basiliximab, a monoclonal antibody that targets

the interleukin-IL2 receptor, is used above all for unsensi-

tized ITx recipients promoting the engraftment of regula-

tory T cells, decreasing steroids and global T cell-depleting

agents [85,86]. Alemtuzumab, a monoclonal antibody that

targets CD52 on mature T cells, leads to excellent 1-year

survival with low rejection rates in combination with tacro-

limus [87]. The emerging protocols include new strategies

such as the Leuven protocol, which is based on broad-based

IS, that promotes a regulatory environment, utilizes donor-

specific blood transfusion, avoids high-dose steroids and

calcineurin inhibitors, and minimizes ischemia-reperfusion

injuries and endotoxin translocation [86]. Moreover,

delayed donor bone marrow infusion combined with ITx

represents a strategic trial of tolerance induction [87,88].

Due to the lack of literature about major induction thera-

pies, the current consensus is based on a comparison of large

single-center series. The safest and most established agent is

Thymoglobulin, even if there is a risk of infective complica-

tions. For unsensitized patients, Basiliximab is a good option

to prevent rejection and lastly Alemtuzumab may reduce both

rejection and GVHD: the first monoclonal antibody is reported

to avoid adverse effects while the use of the second one has

not been clearly evaluated to assess the malignant or infective

risks [89].

Maintenance therapy is more standardized: tacrolimus-

based regimens are the mainstay, used in 73% of recipients,

combined with corticosteroids (37.4%) [61], while mycophe-

nolate mofetil and sirolimus (mammalian the target of rapa-

mycin – mTOR inhibitor) are used in fewer protocols [90,91]. In

addition to standard therapy, tapered off by 6 months post-

transplant, the polyclonal antibody rabbit anti-thymocyte glo-

bulin [92] combined with the chimeric anti-CD20 monoclonal

antibody Rituximab has been used as dual-induction therapy

at Miami Transplant Institute since 2013, based on previously

reported successful results [93]; anti-thymocyte globulin may

also protect against reperfusion injury [94–96]. According to

a recent report [97], a significant reduction of ACR risk can be

obtained when Rituximab is added to the induction therapy,

making it more efficient in removing B cells and therefore

reducing the risk of developing DSAs against the intestinal

graft.

To better understand and avoid rejection, past studies have

investigated the role of antibody-mediated rejection (AMR)

and donor-specific antibodies (DSAs) in ITx: DSAs can be

found prior to transplant or can develop de novo after the

procedure. They can persist after IS doubling the risk of acute

682 N. ZORZETTI ET AL.

humoral rejection and increasing the risk of chronic rejection

[98]. It seems that a combined transplantation with a liver

graft clears the preformed DSAs with a protective role [99].

Moreover, rejection can be induced also by preexisting or de

novo non-HLA antibodies that could act as triggers to a DSA-

mediated allogenic response [100].

Desensitization is a potential option to reduce the number

of preformed antibodies, acting on human leukocyte antigen

(HLA) thus reducing the risk of early graft loss prior to alloca-

tion. Nevertheless, its effective application is limited [101].

Apart from plasma exchange and high-dose intravenous

immunoglobulin (IVIG), emerging strategies to treat it have

been found such as rituximab (a monoclonal antibody against

CD20 found on B-cells) and bortezomib (a selective inhibitor

of the 26S proteasome and nuclear factor-kB that has anti-

plasma cell activity) [102]. However, there is still a lack of an

optimal algorithm able to use immunologic biomarkers or of

the identification of specific patient characteristics to guide its

clinical application.

Because of the immunological complexity of the intestine,

compared with other solid organs, rejection and graft-versus-

host disease (GVHD) frequently occur, requiring high levels of

IS thus increasing morbidity. Standardized and effective ther-

apeutic protocols are still lacking in literature due to the

paucity of centers with experience and the overall low volume

of ITx [89]. Recent insights into specific immunological path-

ways have led to novel and targeted immunomodulatory

strategies that aim to improve outcomes [103].

Classical therapies to treat allo-rejection include high-dose

steroids, increasing calcineurin (Tacrolimus), or mTOR inhibitor

levels [89]. The combination of thymoglobulin with steroids

and rituximab seems to reduce rates of chronic rejection and

PTLD [94] and is reserved for severe or steroid refractory

rejection, but increases the risk of opportunistic infections

[104]. Basiliximab induction therapy reduces the incidence of

ACR after ITx without increasing the incidence of infectious

complications. The use of Alemtuzumab as antirejection ther-

apy seems to be associated with higher rates of PTLD [105]

and infection in some series. Although it is occasionally possi-

ble to treat successfully refractory rejection with strategies

targeting antibodies (IVIG, plasmapheresis) or B cells (rituxi-

mab), it is necessary to find better strategies [106]. Emerging

agents to treat allo-rejection are: 1) vedolizumab, recently

reported off-label and used successfully for the treatment of

ACR after ITx [107]; 2) infliximab, recently described for the

suppression of inflammation [108,109]; 3) bortezomib, which

seems to show effectiveness [110]; and 4) eculizumab,

reported as successful by a single paper [111]. New strategies

under investigation in human intestinal rejection are repre-

sented by the use of probiotics and/or fecal microbiota trans-

plant [112,113].

In terms of immune-monitoring, a recent paper [114] ana-

lyzes peripheral blood samples and intestinal allograft biopsies

from ITx patients with severe rejection. It concludes that it

would be advisable to keep monitoring both parameters in

allograft patients.

Strong IS induction agents such as alemtuzumab and anti-

thymocyte globulin are administered when severe rejection

occurs. When this treatment fails, the re-transplant is a valid

option. Nevertheless, even though the overall short-term sur-

gical outcome has improved in the last decades, the need for

a second round of IS, in patients undergoing re-

transplantation, leads to a state of severe immune deficiency,

together with bone marrow suppression, thrombocytopenia,

and leukopenia thus resulting in infections, malignancies and

an increase in morbidity and mortality [115]. According to this,

to improve long-term results and avoid super-immunization,

prolonged immunosuppression-free periods prior to re-

transplantation should be recommended, in order to reconsti-

tute the host’s immunity. Moreover, it is advisable to use

individualized IS strategies guided by patients’ immunocom-

petency [108].

Recently, there have been reports of operational tolerance

after ITx without evidence of rejection in the absence of

immunosuppression for at least one year [116].

Post-intestine transplant infections (bacterial, viral, and

fungal) are ubiquitous, especially in the pediatric popula-

tion, with rates of 90%, 25%, and 75%, respectively. The

infectious risk was not greatly impacted neither by the

inclusion of the liver or colon component nor by adding

rituximab to the induction protocol [117]. Therefore, in

patients with a lower risk of graft rejection, a lower IS

induction is recommended.

5.4. Outcomes

According to recent data, the five-year survival rate for ITx is

almost 50.5%, unlike that of the liver (72.8%) or kidney

(78.5%). These numbers are due to high rates of rejection,

transplant complications, and related treatment. As

a consequence, ITx is still commonly used as a salvage therapy

for TPN failure or life-threatening complications rather than

a real chance for long-term success [118].

Comparing data of the last decade, a trend of improvement

in 6- and 12-month isolated ITx graft survival: for transplants in

2019, only 4 3.3% of grafts had failed by 6 months and 6.7% by

1 year compared to 23.8% and 31.7% of transplants in 2009

without, on the other side, improvements in 3- and 5-year

(around 40% and 50% respectively) [61].

Among intestine-liver transplant recipients, 42.1% had graft

failure at 6 months and 47.4% at 1 year in 2019, 55.2% at 3

years in 2017, 69.0% at 5 years in 2015, and 75% at 10 years in

2010; there has been no consistent improvement in graft

survival over the last 10 years for liver-inclusive allografts [61].

Comparing ITx with or without a liver in 2013–2015, 1- and

5-year graft survival was 72.8% and 44.8%, respectively, for

recipients 18 years or older and 76.0% and 61.3% for those

younger than 18 years old. One- and 5-year graft survival was

77.7% and 48.9%, respectively, for intestine recipients and

70.6% and 53.2%, respectively, for intestine-liver recipients

[61]. Patient survival at 1 year for transplants in 2013–2015

was higher for recipients of an intestine alone (83.7% vs

75.6% for intestine-liver); however, by 5 years, the patient

survival was identical, at 58.7% for both allograft types [61].

The number of recipients with a functioning ITx reached

a plateau at 1,217, on 30 June 2020, excluding isolated reci-

pients younger than 18 years old. This is probably due to the

fact that ACR and its clinical consequences, that remain the

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 683

leading cause of allograft loss and mortality, not considering

the new strategies of IS [85,104], varies by age and transplant

type in the first year after ITx [61].

Among recipients in 2018–2019, incidence of acute rejec-

tion was highest in adult intestine recipients (41.2%) and low-

est in adult intestine-liver recipients (35.4%) [61].

The most common post-ITx complications are:

●postoperative infection: reported in up to 97% of recipi-

ents, it is the most frequent complication and cause of

graft loss overall due to over-IS and bacterial transloca-

tion [83];

●post-transplant lymphoproliferative disease (PTLD): charac-

terized by uncontrolled B-cell proliferation, often due to

the de-latentisation of Epstein–Barr virus infection fol-

lowing immunosuppression [68]. It can be treated with

a reduction in IS to bolster T-cell responses or, secondly,

with rituximab [119]. Pediatric patients are subject to

a higher risk [120];

●graft-versus-host disease (GVHD): compared to other solid

organ transplantation, GVHD is more common after ITx

and usually appears early but it can be delayed beyond

the first-year post-transplant. It tends to affect the skin,

native bowel, and native liver, manifesting as a rash,

enteritis/colitis, and hepatitis, respectively [120] rather

than the allograft itself. The clinical evaluation is the

basis for the initial diagnosis supported, when necessary,

by skin biopsy. Steroids remain the first line of therapy

for both acute and chronic GVHD [121]. According to

a recent single-center study, accurate donor selection

and adequate IS may reduce GVHD incidence improving

survival. In the pediatric population, younger donors

seem to reduce GVHD risk, whereas including the colon

with the ITx and/or repeat transplantation seems to

increase it. Lastly, in the adult population, the use of

Interleukin-2 plus sirolimus after ITx reduces GVHD risk

[122]. Alemtuzumab shows a significantly favorable

induction effect reducing the development of post-

transplant GVHD, acting both on graft-versus-host and

on host-versus-graft responses [123];

●chronic rejection: it has been recognized as one of the main

causes of late graft loss. It is particularly common in isolated

small bowel transplantation and has a greater risk in teen-

agers and young adults as there is a more frequent non-

adherence to immunosuppressive medications [124].

Clinically, it manifests as a progressive and irreversible loss

of intestinal allograft function over a period of 3 months in

the absence of other causes, it is unresponsive to pharma-

cologic treatment and requires the re-institution of PN sup-

port [125]. In case of sepsis or severe rejection, removal of

the graft and IS can be lifesaving and re-transplantation can

be achieved once the patient recovers [126];

●ischemia-reperfusion injury: it represents a central topic of

recent research that aims to find novel approaches, such

as luminal interventions during cold storage that could

prolong the storage time and alleviate ischemia-

reperfusion injury. It must be taken into consideration

that ischemic susceptibility differs among species

[127,128].

Rejection and infectious complications remain the most com-

mon causes of morbidity and mortality; it is, therefore essen-

tial to monitor closely the intestinal graft to prevent such

occurrences. The absence of a reliable biochemical marker to

help in the graft status follow-up and to promptly diagnose

any dysfunction related to ACR or primary disease recurrence

has led to the need for frequent surveillance via endoscopy

and biopsy (E&B) [129–131]; according to this condition, the

creation of a stoma during ITx can be considered a routinary

act [81], impacting the QOL of the patient.

Likewise, surveillance represents a cornerstone in follow-up

after ITx but the current lack of evidence-based criteria to

create a diagnostic algorithm renders endoscopy and biopsies

necessary [132]. A recent report underlines that the natural

history of disease recurrence after gut failure has yet to be

fully defined but the absence of a universal IS management

protocol is a relevant factor [133].

Long-term patients and graft survival outcomes after ITx

have remained somewhat static in recent years but experi-

enced centers are now reporting improved long- and very

long-term data. Hope for further improvement exists, as stra-

tegies to promote protective T-regulatory cell mechanisms are

developed and the understanding of humoral immunity

increases. Nutritional and QOL outcomes are generally good

and may be better in the future than the ones in patients on

home PN. The psychosocial impact of ITx is high on recipients

and families but most patients reintegrate into society living

fulfilling and productive lives [134].

There is a need for reliable noninvasive diagnostic means in

identifying ITx rejection. A recent paper took into considera-

tion the use of EUS (endoscopic ultrasound) as a tool for

assessing potential CR in long-term follow-ups of intestinal

allograft recipients. Nevertheless, EUS and enteroscopy, while

providing detailed information on the intestinal graft mor-

phology and rheology, are still associated with biopsies mak-

ing partially invasive techniques [135]. A completely

noninvasive method is peripheral blood monitoring using

different potential molecules: plasma citrulline concentration

(CIT), well-known for its role as a noninvasive marker of ACR in

ITx recipients [136], and more recently REG3α, an antimicrobial

peptide secreted by intestinal enterocytes and Paneth cells.

The latter could become a screening biomarker as it can

predict acute allograft rejection a week earlier than the evi-

dence of histopathological changes [137]. Lastly, immunophe-

notyping of peripheral blood T cells has demonstrated its

efficacy in better understanding the immune-mechanisms of

allograft dysfunction, in identifying potential biomarkers in ITx

and in selecting IS therapies [138].

Nevertheless, further studies are needed with larger

cohorts to validate these noninvasive diagnostic tools.

6. OPTN data on rates and trends

According to recent studies, in 2020 ITx donors in the U.S.A

were mainly represented by head trauma or anoxia patients,

usually younger than 18 years [61].

Globally, during the last decades, the trend of ITx is declin-

ing (apart from a small rise in 2019) and adults consistently

exceed the pediatric reports. The pediatric waitlist mortality is

684 N. ZORZETTI ET AL.

decreasing whilst it keeps being relatively stable for adults

[61]; the same occurs for the number of centers performing

this procedure and the annual program volume (median 3.5

ITx in 2020). Although there has not been any apparent

improvement in post-ITx graft survival in the years following

the first, it seems that these data will stabilize while the annual

number of ITx will continue to decline [81].

7. Post-transplant quality of life

Different questionnaires exist in literature for adults and chil-

dren to evaluate the quality of life (QOL) in patients affected

by IF. In both IF groups, QOL is considered generally good.

With regard to ITx, patients assume to have a QOL almost

equal to the general population but the results are completely

different when considering parents/caregivers that report,

both for HPN and ITx, a lower QOL suggesting a negative

perception on family activities. In conclusion, ITx has a good

QOL; however, the possible complications induced by IS or

rejection did not establish the indications for preemptive

transplantation based on QOL [139].

In the future, through controlled studies, specific QOL tools

(such as the combination of HPN-QOL and EuroQol-5) could

provide the guidance needed for ITx [62,140].

8. Cost-effectiveness of intestinal transplant

Cost should never be a prohibitive parameter in considering or

receiving an ITx or other surgical and non-surgical therapies

but, from a socioeconomic perspective, the healthcare burden

of irreversible IF is enormous. Although few studies discuss the

costs of HPN and ITx, no study has definitively established the

cost-effectiveness of ITx: extensive and exact data on costs are

lacking, but according to the literature ITx may become cost-

effective after ∼1–2 years in pediatric recipients who retain

their functional grafts [141].

The non-transplant surgical techniques are useful in

selected patients and have fewer advantages, including

costs, when compared to ITx [45].

Lastly, the high cost of teduglutide prohibits its widespread

use: special attention should be paid to how it is used, and

priority should be given at evaluating strategies to lower its

cost per patient [142].

9. Conclusions

In conclusion, over the last decade, wait-list mortality and

overall ITx rates are decreasing, especially in the pediatric

population [61] while remaining almost similar for adults.

The type of graft that is required is highly individualized

according to the patient’s original diagnosis and status. The

continuous improvement of 1-year graft survival is instead

unaccompanied by the same results in 3- and 5-year. At 5

year, there are no differences between survival rates of iso-

lated and liver-inclusive ITx but still lower than other solid

organ transplants.

It is important to refer to transplant centers selected

patients before they become too ill to be transplanted,

which of course plays a role in a poorer outcome compared

to other solid organ transplantations. One of the issues is that

although it is possible to prolong patient’s lives with IF, this

line of treatment leads to the accumulation of comorbidities

that translates into a more complex surgical procedure and

management.

The use of induction strategies, followed by tacrolimus-

based regimens, still remains the base of IS. The emergence

of both intestinal surgical and medical rehabilitation as speci-

fic subspecialties, due to the success of the larger transplanta-

tion centers, confirms that ITx is a life-sustaining treatment in

the critical case of IF, bettering QOL. Nonetheless, the trend

for the last decades is orientating toward less listing and

transplantation, notably in the pediatric population, consider-

ing, on one hand, the advances in IF care and, on the other

one, the absence of significant improvements beyond 1-year

graft survival. Currently, ITx in adults consistently exceeds the

pediatric population, and the number of listed adult candi-

dates is approaching one of the pediatric candidates [61].

Considering that overall ITx activity represents less than

0.5% of all organ transplants, a limited number of medical

professionals deals with this issue comprehensive of IF man-

agement [143]: it is mandatory, therefore, to assure adequate

education on this topic [144].

As the allocation of liver grafts remains a challenge, the

waitlist mortality persists for chronic IF patients requiring

a liver [145]. For such reason, isolated ITx should be sustained

even if, in these patients, chronic rejection occurs easily.

However, considering that re-transplantation is nowadays

a reality, it must be taken into account that over-IS easily

induces sepsis, which represents the main cause of post-

transplant death.

As there are only a few large centers that perform ITx

worldwide, they should unify efforts to address issues in

order to support those regions/nations without a program

and should cooperate performing multicenter studies to

advance more in this intricate field. Financial support to

a transplant recipient should include easier access to the

referral center for annual follow-up or if complications occur

[123]. The ultimate goal, for both the medical and surgical

transplant community, remains enteral autonomy benefiting

from rehabilitation, AGIR or ITx [123].

10. Expert commentary

Medical rehabilitation in SBS has dramatically improved with

the clinical introduction of Teduglutide while, on the other

hand, AGIR procedures gained success in lengthening and

tapering the remnant small bowel: preserving the ileocecal

valve represents the main predictive factor to achieve enteral

autonomy. Whereas the ileum has shown increased adaptive

function than the jejunum, also colon has great importance in

the digestive process: 1) in the adult population, a residual

small bowel length of a minimum of 75 cm, even if recon-

nected to a part of the colon, seems able to produce a TPN

independence; 2) a colonic graft is nowadays widely used

and 3) the terminal ileum is the selected segment for a living-

related donation.

The Intestinal Rehabilitation and Transplant Association

reached a consensus in 2019 on patients who have failed

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 685

medical and/or surgical rehabilitation. The latter should be

listed for ITx only if they are at actual risk of death on HPN

[Box 2a, 2b, 3].

Post-transplant long-term survival seems to have improved

if we consider the experienced US center (between 60% and

70% at 10 years), whilst it remains stable if we take into

account the International Transplant Registry (41% 10-year

survival). Main shared challenges still remain, such as: over-

IS, rejection, infection, and altered renal function. Chronic

rejection occurs with an incidence of 5–10% after intestinal/

multi-visceral transplant and allograft removal still represents

the main therapy because there is a lack of standardized

pharmacological strategies. Desensitization with

a conventional or novel technique could be adopted as

a protocol before ITx in those candidates who, thanks to

virtual crossmatching, have high levels of preformed donor

anti-HLA antibodies.

Using a de novo DSA monitoring plus treatment protocol

and efforts to establish formal histologic criteria for antibody-

mediated rejection, could further improve post-transplant

results. The adjunct of a liver graft, when re-transplanting,

could be helpful in a sensitized recipient due to its protective

effect against humoral immunity.

Technical surgical challenges for the closure of the abdo-

men at the end of ITx are represented by volume/edema of

donor graft and loss of abdominal domain in the recipient,

due to previous surgeries. Currently, new techniques based on

transplanting a full-thickness abdominal wall from the same

donor, vascularized or not-vascularized, have been adopted in

place of previous techniques such as graft reduction (espe-

cially liver and small intestine) or the volume increase in the

abdomen cavity.

Finally, nutritional outcomes are good with most recipients

achieving enteral autonomy with an unrestricted diet and QOL

improves over time in most psychological-emotional and

social areas. Pregnancy is possible after ITx although two

factors should be taken into consideration: the absorptive

function of the transplanted bowel and the higher need for

IS. Both of them have to be monitored closely with endosco-

pies and biopsies of the graft, to prevent episodes of rejection

and to preserve the fetus from temporary malnutrition.

Novel approaches such as manipulation of microbiota or

tissue bioengineering will be added to medical and surgical

rehabilitation in order to successfully treat short bowel syndrome.

Whenever unavoidable, the intestinal transplant should be

performed, but multiple causes of late graft loss including

chronic rejection, infection, graft-versus-host disease, post-

transplant lymphoproliferative disorder, and post-surgical

complications should be addressed and solved in the next

few years. Disease recurrence represents a drawback of the

procedure and should be faced in addition to neoplastic dis-

orders: disease recurrence could be suspected in patients with

pre-transplant Crohn’s disease, gut dysmotility, hypercoagul-

ability, metabolic syndrome, and some mucosal and neuro-

muscular disorders. Moreover, the role of ischemia-reperfusion

injury among causes of graft loss should be better established.

Graft failure after intestinal transplantation is often treated

by allograft removal due to a lack of effective drugs: multi-

visceral patients can also have the graft removed in refractory

rejection although they can be more challenging to manage.

Re-transplant of such a patient with another multi-visceral

graft is feasible but factors associated with anatomy, vascular

access, size, and sensitization should be evaluated before

making the decision of which organs have to be re-

transplanted.

While the importance of endoscopy and stool studies is

well known as the gold standard for monitoring, calprotectin

and citrulline plus measurements of immunoreactivity and

donor-specific antibodies represent promising tools in graft

follow-ups: for instance, the large amount of blood gran-

zyme-B or perforin before the clinical symptoms and endo-

scopic signs of acute cellular rejection, are produced by

activated recipient ‘circulating’ lymphocytes or by activated

donor-derived ‘resident’ lymphocytes? The question does not

represent a futile topic under the immune-surveillance point

of view. Nowadays, immunosuppression for intestinal trans-

plantation is mainly based on preconditioning protocols that

pre-treat a recipient, but earlier on the elimination by ex vivo

irradiation of mature resident lymphoid elements from the

bowel allografts was used to eliminate the GVHD risk, followed

by infusion of donor bone marrow cells in recipients to

improve tolerogenesis.

Preemptive transplantation in patients affected by irre-

versible intestinal failure is still far to be clinically applied. In

the future, it could be reserved for those patients identified

as the ones at high risk of complications and mortality

while on definitive long-term PN. A preemptive transplant

could be used as a rehabilitative procedure in a well-

selected population, among PN patients at risk of liver fail-

ure, repeated central-line infections, mesenteric infarction,

short bowel syndrome <50 cm or with end stoma, congeni-

tal mucosal disease, desmoid tumors: the development of

simulation models or pre-transplant scoring systems could

help in selecting the candidates to this preemptive

procedure.

Abbreviations

IF Intestinal failure

GI Gastrointestinal

PN Parenteral nutrition

SBS Short bowel syndrome

IA Intestinal adaptation

MSBR Massive small bowel resection

HPN Home parenteral nutrition

IFALD Intestinal failure associated liver disease

ITx Intestinal transplantation

SBL Small bowel length

ICV Ileocecal valve

QOL Quality of life

GF Growth factor

AGIR Autologous gastrointestinal reconstruction

IRPs Intestinal Rehabilitation Programs

LILT Longitudinal intestinal lengthening and tailoring

STEP Serial transverse enteroplasty

SILT Spiral intestinal lengthening and tailoring

IRTA Intestinal Rehabilitation and Transplant Association

ESPEN European Society for Clinical Nutrition and Metabolism

CRBS catheter-related bacteremia/sepsis

OPTN Organ Procurement and Transplantation Network

AMS Antibody-mediated rejection

DSAs Donor-specific antibodies

686 N. ZORZETTI ET AL.

IS Immunosuppression

ACR Acute cellular rejection

HLA Human leukocyte antigen

IVIG Intravenous immunoglobulin

GVHD Graft-versus-host disease

mTOR Mammalian target of rapamycin

E&B Endoscopy and biopsy

PTLD Post-transplant lymphoproliferative disease

MvTX Multi-visceral transplantation

MMvTX Modified multivisceral transplantation

CLABSI Central line – associated bloodstream infection

Acknowledgments

We wish to thank Ms Elena BALDISSONE for her invaluable support in

English editing.

Funding

This paper was not funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any

organization or entity with a financial interest in or financial conflict with

the subject matter or materials discussed in the manuscript. This includes

employment, consultancies, honoraria, stock ownership or options, expert

testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other

relationships to disclose.

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Home Parenteral Nutrition for Children: What Are the Factors Indicating Dependence and Mortality?

Article

Full-text available

Jan 2023

Parenteral nutrition (PN) in children with short bowel syndrome is crucial and lifesaving. Taking care of such patients requires interprofessional practice and multiple team resource management. Home PN (HPN) usage allows patients and families to live regular lives outside hospitals. We share our experiences for the last two decades and identify the risk factors for complications and mortality. A retrospective study of HPN patients was conducted between January 2000 and February 2022. Medical records of age, body weight, diagnosis, length of residual intestines, HPN period, central line attempts, complications, weaning, and survival were collected and analyzed. The patients were classified as HPN free, HPN dependent, and mortality groups. A total of 25 patients received HPN at our outpatient clinic, and one was excluded for the adult age of disease onset. There were 13 patients (54.1%) who were successfully weaned from HPN until the record-enroled date. The overall mortality rate was 20.8% (five patients). All mortality cases had prolonged cholestasis, Child Class B or C, and a positive Pediatric End-Stage Liver Disease (PELD) score. For HPN dependence, extended resection and multiple central line placement were two significant independent factors. Cholestasis, Child Class B or C, and positive PELD score were the most important risk factors for mortality. The central line-related complication rate was not different in all patient groups. The overall central line infection rate was 1.58 per 1000 catheter days. Caution should be addressed to prevent cholestasis and intestinal failure-associated liver disease during the HPN period, to prevent mortality. By understanding the risks of HPN dependence and mortality, preventive procedures could be addressed earlier.

Home Parenteral and Enteral Nutrition

Article

Full-text available

Jun 2022

While the history of nutrition support dates to the ancient world, modern home parenteral and enteral nutrition (HPEN) has been available since the 1960s. Home enteral nutrition is primarily for patients in whom there is a reduction in oral intake below the amount needed to maintain nutrition or hydration (i.e., oral failure), whereas home parenteral nutrition is used for patients when oral-enteral nutrition is temporarily or permanently impossible or absorption insufficient to maintain nutrition or hydration (i.e., intestinal failure). The development of home delivery of these therapies has revolutionized the field of clinical nutrition. The use of HPEN appears to be increasing on a global scale, and because of this, it is important for healthcare providers to understand all that HPEN entails to provide safe, efficacious, and cost-effective support to the HPEN patient. In this article, we provide a comprehensive review of the indications, patient requirements, monitoring, complications, and overall process of managing these therapies at home. Whereas some of the information in this article may be applicable to the pediatric patient, the focus is on the adult population.

Serial transverse enteroplasty (STEP) in case of short bowel syndrome: did we achieve our goal? A systematic review

Article

Full-text available

Jul 2022

Surveys on Serial Transverse Enteroplasty (STEP) published in international literature (1 January 2003– 31 May 2021) were searched. Articles were included from 17 countries: 1/23 comparative and 22/23 cohort studies. STEP was performed on 308 patients: pediatrics, adults, and mixed ages. Pediatric group included 16 studies and the adult 6. Pre-STEP residual small bowell (SB) length for pediatrics and adults ranged from 18 to 26 cm and from 30 to 70 cm, respectively. Post-STEP increased SB length for pediatrics and adults ranged between 42 and 100% and 50% and 176%, respectively. For pediatrics, enteral autonomy was reached in 32.22% of cases, parenteral nutrition (PN) dependence was 36.11%, a repeated STEP procedure (Re-STEP) was needed in 17.22%, and a bowel transplant was performed in 6.11%. In adults, enteral autonomy was achieved in 52.38%, while PN dependence was 37.1%, and no Re-STEP or transplantation were required. For the mixed group, post-STEP bowel length increased from 2 to 50 cm, enteral autonomy was obtained in 43%, PN dependence was 57%, without reported Re-STEP or transplantation. Mortality rates were between 5.55% (pediatric) and 7.14% (adults). Preoperative length with preservation of ileocecal valve represented the main predictive factors to achieve enteral autonomy.

Use of Teduglutide in Children With Intestinal Failure: A Systematic Review

Article

Full-text available

Jun 2022

Background and Objectives Short-bowel syndrome (SBS) results from the loss of a significant portion of the small intestine leading to a state of malabsorption. After an intestinal loss, there is a process of adaptation involving the Glucagon-Like Peptide-2 (GLP-2), an enteroendocrine peptide also involved in nutrient absorption. Teduglutide is a recombinant analog of GLP-2 approved in 2016 to treat selected SBS pediatric patients who are dependent on parenteral support. The present systematic review aims to evaluate the efficacy of Teduglutide in pediatric patients with SBS in reducing the need for parenteral nutrition (PN). Materials and Methods We performed a literature search on MEDLINE and Embase to include articles up to November 2021. We included articles that involved using Teduglutide in the SBS pediatric population to define its efficacy in reducing the need for PN. The key words used were GLP-2, teduglutide, child. Results Fourteen studies completely fulfilled the inclusion criteria. Two hundred 23 patients were treated with Teduglutide, and the median duration of treatment was 45 weeks (IQR: 36–52.5 weeks). One-hundred and fifty-two patients were treated with 0.05 mg/Kg/d of subcutaneous Teduglutide, 38 received 0.025 mg/Kg/d and 8 received either 0.125 mg/Kg/d or 0.20 mg/Kg/d. A total of 36 patients achieved enteral autonomy (EA) after a median of 24 weeks of treatment (IQR: 24–48 weeks) and 149 patients showed a reduction in PN needs in terms of volume, calories, or hours per day. Eleven studies reported complications: gastrointestinal were the most common, with 89 cases reported in treated patients and 11 in non-treated patients. Conclusion Teduglutide appears safe and effective in reducing PN requirements and improving EA in the pediatric population. However, more studies are needed to understand its efficacy in the long term and after discontinuation and possible complications. Systematic Review Registration [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022301593].

HPN Standard of Care and Long-Term Outcomes of CIF Pediatric Patients: Twenty-Eight Years' Experience in a Reference Center

Article

Full-text available

Jun 2022

Background and Aims Chronic intestinal failure (CIF) therapy changed significantly in recent decades, and both survival and complication rates improved over time. International guidelines claim that early referral of long-term home parenteral nutrition (HPN) patients to an expert center with specific standards of care may positively affect long-term outcomes. Herein, we retrospectively analyse the long-term outcomes of a cohort of pediatric patients with CIF followed-up since our Pediatric Intestinal Failure Unit foundation, in 1989. Methods Data of the 120 children followed up at Pediatric Intestinal Failure Unit during the last 28 years were retrospectively collected. Patients' and HPN characteristics, as well as dependence, survival, and complication rates, were described. Results Incidence and prevalence of CIF increased during the study period particularly due to the increase of HPN for non-digestive disease (NDD) CIF (47.5% of the study sample). Catheter-related bloodstream infection (CRBSI) rate decreased over the study period: 0.33 episodes/1,000 catheters days before 2011 and 0.19 episodes/1,000 catheters days afterwards. Only 1 patient out of 12 died because of HPN complications. The survival rate of patients with PDD was 98.4% at 1 year from the beginning of HPN, 96.5% at 2 years, and 93.8% from the fifth year onwards. Concerning the dependence rate, 70.6% of patients were still on HPN 1 year after the start of HPN, 63.7% at 2 years, 52.4% at 5 years, and 40.8% from the 9th year onwards, with no significant difference according to the underlying intestinal pathology. The survival rate of NDD patients was 91.2% at 1 year from the beginning of HPN, 87.4% at 2 years, and 81.9% from the third year onwards. For what concerns the enteral autonomy, it was regained by 56.7% 1 year after the start of HPN, 74.5% at 2 years, and 95.0% in the 5th year. Conclusions Our data confirmed the importance of appropriate standards of care and suggest that applying a specific set of standards and protocols may further improve patients' outcomes and survival. Indeed, both primary and non-digestive diseases HPN showed good outcomes.

Management of long‐term home parenteral nutrition: Historical perspective, common complications, and patient education and training

Article

Dec 2022

Intestinal failure (IF) is a rare disease that requires ongoing intravenous supplementation to sustain growth and health. Advancements in parenteral nutrition (PN) and central venous access in the 1960s and 1970s transformed a life‐limiting disease to a chronic one in which patients are able to administer hydration, electrolytes, micronutrients, and macronutrients in the comfort of their home. However, despite ongoing advancements in the field of home PN (HPN), complications—whether related to central venous catheters or PN itself—remain common and can be associated with significant morbidity and mortality. Central venous access can be associated with thrombosis, central line–associated bloodstream infection, or damage and can result in loss of access over time. PN can be associated with IF‐associated liver disease or hyperglycemia. The key to preserving central venous access and quality of life and maintaining health for patients with chronic IF (CIF) is education focused on prevention and prompt management of CIF complications as they arise. This education typically takes place at the time of initiation of HPN, either in the hospital setting or in the patient's home. The present manuscript describes the historical progression of HPN, prevalence and characteristics of CIF, and an in‐depth discussion of the most common catheter‐related and PN‐related complications and their management, along with a discussion of our education and training process.

Liraglutide attenuates intestinal ischemia/reperfusion injury via NF-κB and PI3K/Akt pathways in mice

Article

Oct 2022
LIFE SCI

Aims Previous studies have reported that glucagon-like peptide-1 (GLP-1) may play a critical role in the development of intestinal ischemia-reperfusion (I/R) injury. The present study aimed to investigate whether liraglutide (GLP-1 analog) protects against intestinal I/R injury and reveals the possible underlying mechanism. Main methods Temporary superior mesenteric artery occlusion was performed to establish an intestinal I/R injury mouse model. Different doses of liraglutide were administered in vivo. Then, the survival rate of mice exposed to different ischemia times, the histopathology, intestinal barrier index, cytokine production, intestinal tissue apoptosis, and the levels of several proteins were detected in each group. Key findings Pretreatment with liraglutide significantly alleviated the pathological changes induced by I/R and increased the overall survival of mice exposed to intestinal I/R injury. Moreover, liraglutide attenuated neutrophil infiltration of intestinal tissues, pro-inflammatory cytokine production (including IL-1β, IL-6, and TNF-α), and apoptosis of intestinal tissues caused by intestinal I/R injury. In addition, liraglutide inhibited the nuclear translocation of nuclear factor-κB (NF-κB) and up-regulated the phosphorylation levels of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) in the I/R group. Significance Liraglutide may attenuate the inflammatory response and the apoptosis of intestinal tissues via the NF-κB and PI3K/Akt pathway, protecting against intestinal I/R.

Article

Aug 2022

Background and aims: Patients with intestinal failure receiving home parenteral nutrition (HPN) are susceptible to central-line associated bloodstream infections (CLABSIs), with crucial roles for adequate (empiric) antimicrobial therapy and effective catheter management strategies. Our aim was to link recent epidemiologic CLABSI data with clinical outcomes and to identify risk factors for therapeutic failure to decide on the safest and most accurate CLABSI management in patients receiving HPN. Methods: A retrospective observational cohort study was conducted. All data on CLABSIs (period 2010-2020) in adult patients receiving HPN were retrieved. The efficacy of attempted catheter salvage and empiric antimicrobial treatment (β-lactam antibiotics) in our center, with a low prevalence of methicillin-resistant staphylococci, was investigated. Multivariate cox-regression analysis was performed to identify risk factors for recurrent CLABSI. Results: 389 CLABSIs occurred in 149 patients. The overall infection rate was 0.64 per 1000 central venous catheter (CVC) days. Most CLABSIs were caused by Coagulase-negative staphylococci (37%). Attempted CVC salvage was successful in 70% of the cases. Empiric antimicrobial therapy was found to be adequate in only 47% of cases, mainly because of insufficient Coagulase-negative staphylococci coverage. According to the Cox model, patients with a replaced CVC had a 50% lower risk of a new CLABSI than patients with a retained (salvaged) CVC during follow-up (HR 0.50; 95% CI 0.35-0.72, P < 0.001). Conclusions: CVC salvage can be achieved in most CLABSI cases but seems associated with a shorter CLABSI-free survival. Importantly, based on our findings, a glycopeptide containing antibiotic treatment regimen will increase the likelihood of adequate empiric coverage.

An international multicenter validation study of the Toronto listing criteria for pediatric intestinal transplantation

Article

Jul 2022

Deciding which patients would benefit from intestinal transplantation (IT) remains an ethical/clinical dilemma. New criteria* were proposed in 2015: ≥2 intensive care unit (ICU) admissions, loss of ≥3 central venous catheter (CVC) sites, and persistently elevated conjugated bilirubin (CB ≥75μmol/L) despite 6 weeks of lipid modification strategies. We performed a retrospective, international, multicentre validation study of 443 children (61% male, median gestational age 34 weeks [IQR 29‐37]), diagnosed with IF between 2010 & 2015. Primary outcome measure was death or IT. Sensitivity, specificity, NPV, PPV, probability of death/transplant (OR, 95% confidence intervals) were calculated for each criterion. Median age at IF diagnosis was 0.1 years (IQR 0.03‐0.14) with median follow up of 3.8 years (IQR 2.3‐5.3). 40/443 (9%) patients died, 53/443 (12%) were transplanted; 11 died post‐ transplant. The validated criteria had a high predictive value of death/IT; ≥2 ICU admissions (p <0.0001, OR 10.2, 95% CI 4.0‐25.6), persistent CB ≥75μmol/L (p<0.0001, OR 8.2, 95% CI 4.8‐13.9) and loss of ≥3 CVC sites (p=0.0003, OR 5.7, 95% CI 2.2‐14.7). This large, multicentre, international study in a contemporary cohort confirms the validity of the Toronto criteria. These validated criteria should guide listing decisions in pediatric IT. *Burghadt KM et al. AJT 2015;15:1674‐81.

Survival In Patients Initiating Home Parenteral Support Due To Nonmalignant Short Bowel Syndrome Compared With Background Population

Article

Jun 2022

Background Survival has frequently been studied and reported in patients with long term intestinal failure (IF). However, studies comparing the survival and mortality rates with the background population are rare. This study compares the survival in an adult IF, non-malignant, short bowel syndrome (SBS) cohort with a control group and with age- and sex-specific background mortality rates. Design Patients with SBS, defined by a small bowel length of 200 cm or less, due to non-malignant disease, were included and followed until death or censoring on 31 December 2017. Causes of deaths occurring during home parenteral support (HPS) were assessed by review of the charts. Each case was matched with ten controls from the background population according to year of HPS initiation, age, and sex, and their survival was compared. Furthermore, age- and sex-specific mortality rates of the background population were used to calculate the standardized mortality ratio (SMR) and excess mortality. Results After five years, patients who initiated HPS had a relative survival of 76%. The SMR was 5.0 and the excess mortality was 50 per 1,000 years. HPS-related deaths were assessed to account for 11% of deaths during HPS and occurred with an incidence of 10 per 1,000 years. The excess mortality was as low as 15 per 1,000 years in cases aged less than 40 years. Patients weaning off HPS had a mortality rate closer to that expected in the background population. Conclusions In adult patients with a non-malignant cause of SBS-IF, the excess mortality was 50 per 1,000 years. However, HPS related deaths were rarely registered with an incidence of 10 HPS related deaths per 1,000 HPS treatment years.

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