TRANSPLANTATION SURGERY AND RESEARCH
Two Decades of Hand Transplantation
A Systematic Review of Outcomes
Michael W. Wells, BEng, MEng,a Antonio Rampazzo, MD, PhD,b
Francis Papay, MD,b and Bahar Bassiri Gharb, MD, PhDb
Abstract: Hand transplantation for upper extremity amputation provides a unique
treatment that restores form and function, which may not be achieved by traditional
reconstruction and prosthetics. However, despite enhancing quality of life, hand
transplantation remains controversial, because of immunological complications,
transplant rejection, and medication effects. This systematic literature review sought
to collect information on current experiences and outcomes of hand transplants to
determine the efficacy and utility of hand transplants. The databases PubMed,
Scopus, and Embase were analyzed with combinations of “hand” or “upper extrem-
ity” or “arm” and “transplant” or “allograft,” with information collected on recipient
characteristics, details of transplant, immunological outcomes, functional out-
comes, and complications. Functional outcomes, as measured by Disabilities of
Arm, Shoulder and Hand score, were compared between patient groups using
Wilcoxon signed-rank test or 1-way analysis of variance test and post hoc Tukey
test. Within the 108 articles that fulfilled inclusion and exclusion criteria, there
were 96 patients with 148 hand transplants. There were 57 patients who experi-
enced acute rejection and 5 patients with chronic rejection. Disabilities of the
Arm, Shoulder and Hand scores significantly decreased after hand transplanta-
tion and were significantly lower for distal transplants compared with proximal
transplants. There were 3 patients with concurrent face transplantation and 2 pa-
tients with simultaneous leg transplants. Sixteen patients experienced amputation
of the hand transplant, and there were 5 deaths. This study found that hand trans-
plantation provides significant restoration of function and form, especially for
proximal transplants. Reduction in complications, such as rejection and amputa-
tion, can be achieved by decreasing medication cost and patient education.
Key Words: hand, transplantation, rejection, upper extremity, immunosuppression
(Ann Plast Surg 2022;88: 335–344)
U pper extremity amputation can have a massive impact on a patient's
physical and psychological welfare and quality of life.1,2 Although
prosthetics and reconstructive surgery have been able to improve qual-
ity of life, patients often still report a deficiency in daily activities and
function.3–6 First successfully performed in 1998, hand transplants are
a form of vascularized tissue allotransplantation that provide a unique
option to restore form and function for upper extremity amputees.6
However, there are a number of complications associated with this com-
plex procedure stemming from immune rejection of the transplant and
adverse effects of immunosuppression.3 This study provides a compre-
hensive overview of the knowledge attained from the hand transplants
performed worldwide and provides insight for future advancements.
Received May 20, 2021, and accepted for publication, after revision September 14, 2021.
From the aCase Western Reserve University, School of Medicine; and bDepartment of
Plastic Surgery, Cleveland Clinic, Cleveland, OH.
B.B.G. formulated the study design and literature search. M.W. and B.B.G. collected
data. A.R. and F.P. assisted with data collection. M.W., A.R., F.P., and B.B.G.
contributed to data analysis and data interpretation. M.W. and B.B.G. wrote the
manuscript. M.W. and B.B.G. prepared the figures and tables. M.W., A.R., F.P.,
and B.B.G. edited the manuscript.
Conflicts of interest and sources of funding: none declared.
Reprints: Bahar Bassiri Gharb, MD, PhD, 9500 Euclid Ave, A6-522, Cleveland, OH.
E-mail: bassirb@ccf.org.
Supplemental digital content is available for this article. Direct URL citations appear in
the printed text and are provided in the HTML and PDF versions of this article on
the journal’s Web site (www.annalsplasticsurgery.com).
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0148-7043/22/8803–0335
DOI: 10.1097/SAP.0000000000003056
Annals of Plastic Surgery • Volume 88, Number 3, March 2022
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
METHODS
Search Strategy and Selection Criteria
A systematic literature review was registered with PROSPERO
(CRD42020214462) and performed in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines for all studies in English from database inception until May 2020.
Combinations of “hand” or “upper extremity” or “arm” and “transplant”
or “allograft” were input into the key word field of 3 online databases:
PubMed, Scopus, and Embase. Results were compared for discrepan-
cies, and duplicate studies were eliminated using Google Sheets. Refer-
ences were surveyed for additional articles. Inclusion criteria were hand
or upper extremity transplants in human patients. Exclusion criteria
consisted of studies with nonhuman subjects, cadaveric studies, nonupper
extremity transplantation, twin-twin transplants, toe-to-hand transfers,
non-English language literature, and review articles. Meeting proceed-
ings, media reports, and personal communications through social media
were screened and information with confirmed sources were included.
Individual patient data were screened and extracted by 2 investigators
(M.W., B.B.G.). In cases of disputes, a third author (A.R.) arbitrated dis-
cussion for final decisions.
Data Collection
Data were collected from each article for unique patient informa-
tion. Patients who appeared in multiple studies were verified through
identifying information, such as patient age, sex, level of injury, and
level and date of transplant, with care taken to discard redundant infor-
mation. Information was collected in the following categories: recipient
characteristics—demographics (age, sex, and comorbidities) and mecha-
nism of injury; details of transplant—date of surgery, number of transplants
(unilateral vs bilateral), level of transplantation (hand, wrist, forearm distal,
midproximal, arm), and repaired structures (arteries, veins, nerves, tendons,
bones); immunological outcomes—human leukocyte antigen mismatch,
induction and maintenance immunosuppressive regimens, and acute and
chronic rejection (number of episodes, grade, time of rejection); func-
tional outcomes—motor and sensory recovery, and preoperative and
postoperative patient-reported outcomes (Disabilities of the Arm, Shoulder
and Hand [DASH] score); and complications/retransplants.
Data Analysis
Data were expressed as mean and standard deviation or median
and interquartile range (IQR). Preoperative and postoperative DASH
scores were compared for unilateral versus bilateral transplants, level
of transplantation, and number of acute rejection episodes using Wilcoxon
signed-rank test or 1-way analysis of variance test and post hoc Tukey test.
Transplants at the level of the hand, wrist, and distal forearm were grouped
as “distal transplants,” whereas transplants at the level of the midforearm,
proximal forearm, and above elbow were categorized as “proximal trans-
plants.” The minimum clinically important difference in DASH score of
15 was used to differentiate between improved and unimproved
patients.7–9 All statistical analysis was performed using SPSS 25.0 for
Mac (IBM Corporation, New York, NY). Because of the heterogeneity
www.annalsplasticsurgery.com 335
Wells et al
of the types of articles, traditional meta-analysis techniques were not
applicable. Articles were assessed individually for risk of bias and fact
checked against meeting disclosures or direct communications with the
surgical teams. The Cochrane tools for assessment of risk of bias among
studies of the same type could not be applied for this study. Two re-
searchers (M.W., B.B.G.) independently reviewed each of the articles to
assess risks of bias and come to agreement on bias for each article. In case
of conflicts, the opinion of a third investigator (A.R.) was sought.
RESULTS
Three hundred four studies were retrieved with an initial data-
base search, and 76 full-length articles were included for final analysis.
An additional 32 external media sources were added, for a total of 108
articles (Fig. 1).10–119
Recipient and Transplant Details
Ninety-six patients received 148 hand transplants (44 unilateral and
52 bilateral) (Supplemental Table 1, http://links.lww.com/SAP/A692).
FIGURE 1. The PRISMA flow diagram. The PRISMA summarizes the results of the screening process and final article selection.
336 www.annalsplasticsurgery.com
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Annals of Plastic Surgery • Volume 88, Number 3, March 2022
Seventy-seven percent of recipients were men, and 23% were women.
The mean age of the patients was 36.8 years (range, 8–68 years). Seven-
teen countries have performed hand transplants (Fig. 2). The first hand
transplant was performed in 1998, and the most recent was performed in
2019 (Fig. 3). The most common etiologies of amputation included explo-
sions (25%), mechanical injury (16%), and septic shock (15%; Table 1).
The most common level of transplant was hand/wrist (32%; Table 2).
In 47% (n = 47) of patients with available information on nerve
repair, the median, ulnar, and radial nerves were repaired. The most
commonly repaired arteries and veins were radial and ulnar arteries
(77%), and 3 unnamed veins (39%), respectively (Table 3).
Immunological Outcomes
In 48 patients, human leukocyte antigen mismatch was reported as
5 (35%), 6 (29%), 3 (19%), 4 (15%), and 2 mismatches (2.1%). Induction
therapy varied considerably and included tacrolimus (FK506, 4–10 ng/mL;
4 mg/d; 57%), antithymocyte globulin (ATG, 75–100 mg/d; 1.25–
1.5 mg/kg; 41%), mycophenolate mofetil (MMF, 100–2000 mg/d; 41%),
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Annals of Plastic Surgery • Volume 88, Number 3, March 2022 Hand Transplantation Literature Review

FIGURE 2. Graphical representation of hand transplants performed per country. The countries that have performed hand transplants
are colored. Most transplants were performed in United States (49), France (16), and China (13).

and prednisone (250–1000 mg/d; 41%; Table 4). Maintenance immuno-
suppression regimen consisted of FK506 (1–3 mg/d; 3–10 ng/mL; 94%),
MMF (1–2 g/d; 84%), and prednisone (5–40 mg/d; 78%; Table 5).
The number of acute rejection episodes was available for 57 pa-
tients and ranged from 0 to 13, with 1 episode being the most common
number of acute rejections (28%). Follow-up for these patients ranged
from 2 months to more than 10 years, with a mean follow-up of
72 months. Banff grades were available for 39 patients and consisted
of grade 1 (10%), grade 2 (58%), and grade 3 (31%) rejection episodes.
The first episode of rejection was recorded between 3 days and
54 months from transplantation, with a median onset after 55 days
(IQR, 80 days). Ninety percent of the initial rejection episodes occurred
within the first 6 months. These were histologically graded as grade 1
(33%), grade 2 (61%), and grade 3 (6%). Evidence of chronic rejection
was reported in 5 patients, with diagnosis occurring after a median of
10 years (IQR, 8.63 years).

FIGURE 3. Plot of hand transplantation by year. The first hand transplant was performed in 1998, with additional transplants performed
yearly. The most transplants were performed in 2016, with 16 hand transplants performed that year.

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Wells et al Annals of Plastic Surgery • Volume 88, Number 3, March 2022

TABLE 1. Etiology of Injury TABLE 3. Repaired Vessels and Nerves

Type of Injury No. Patients (%)* No. Hand

Repaired Nerves Transplants (%*)
Explosion 20 (25.0)
Mechanical injury 13 (16.3) Median, ulnar, radial 22 (46.8)
Septic shock 12 (15.0) Median, ulnar 10 (21.3)
Electrical injury 8 (10.0) Median, ulnar, dorsal/sensory radial 10 (21.3)
Burn 8 (10.0) Median, ulnar, anterior and posterior interosseus 2 (4.3)
Other unspecified trauma 6 (7.5) Median, radial 2 (4.3)
Agricultural trauma 6 (7.5) Radial, axillary, ulnar, and musculocutaneous, lateral/ 1 (2.1)
Automobile accident 4 (5.0) medial roots of medial nerve
Animal attack 1 (1.3) Repaired arteries
Crush injury 1 (1.3) Radial, ulnar 27 (77.1)
Kawasaki disease 1 (1.3) Brachial 5 (14.3)
2 arteries (unspecified) 3 (8.6)
The most common cause of hand amputation in transplant recipients was ex- Repaired veins
plosion (20), followed by mechanical injury (13) and septic shock (12).
3 (unspecified) 7 (38.9)
*Percentage of patients with specific type of injury over total number of pa-
tients with recorded injuries. 4 (unspecified) 4 (22.2)
Basilic, cephalic 4 (22.2)
5 (unspecified) 1 (5.6)
Venae comitantes radial, ulnar arteries, cephalic 1 (5.6)
Functional Outcomes
Basilic 1 (5.6)
The most consistently recorded patient-reported outcome mea- The most commonly repaired nerves were the median, ulnar, and radial (22).
sure was the DASH score. Both preoperative and postoperative scores The most commonly repaired arteries were the radial and ulnar arteries (27) and
were available for 31 transplants in 18 patients (Table 6). These 18 patients brachial artery (5). The most commonly repaired number of veins was 3 veins (7
included: 16 male and 2 female. Thirteen patients underwent a bilateral transplants).
and 5 patients underwent unilateral transplant. The level of transplant *Percentage of patient with specific repaired structure over number of patients
was at wrist (5), midforearm (5), proximal forearm (6), above elbow with recorded repaired structure.
(3), and unspecified (12). The number of episodes of acute rejection
in this cohort was 0 (1 transplant), 1 (4 transplants), 2 (9 transplants),
3 (8 transplants), 4 (5 transplants), and 7 (2 transplants). a median score of 4.06 mm (IQR, 0.7 mm). Grip strength was recorded
Preoperative DASH scores ranged from 25 to 100 (median, 71; in 22 transplants, with a mean of 9.7 ± 5.7 kg (range, 0.3–20 kg).
IQR, 40.5), whereas postoperative scores ranged from 7 to 86 (median,
31; IQR, 49.5). Preoperative DASH scores were not significantly differ-
Medical Complications
ent between patients with different levels of amputation ( P = 0.986).
The DASH scores significantly decreased ( P < 0.001) after hand trans- The most common medical complications included hyperglyce-
plantation. The postoperative disability scores for distal transplants mia (20 patients), diabetes (12 patients), CMV infection (10 patients),
(median, 16; IQR, 31.8) were significantly lower than those of proximal and renal insufficiency (9 patients; Table 7).
transplants (median, 38.5; IQR, 36; P = 0.035). The DASH score was
not significantly different in patients with different numbers of episodes Cotransplants
of acute rejection ( P = 0.056). Cotransplants with hand transplants included face (3 patients)
Sensory recovery was recorded as 2-point discrimination in 16 and legs (2 patients).25–27,88,108,109 One patient was a kidney transplant
transplants, with a median of 11 mm (IQR = 7 mm) and measured recipient before receiving a bilateral hand transplant.24,25 Two bilateral
as the Semmes-Weinstein monofilament test in 30 transplants, with hand transplant recipients experienced deteriorating kidney function
and eventually underwent a kidney transplant.120,121

TABLE 2. Level of Transplantation Graft and Patient Survival

Sixteen hand transplants (10.8%) were amputated during follow-up.
Level of Transplant No. Hand Transplants (%*) The most common cause for amputation was acute rejection following im-
Arm (just below shoulder, arm) 23 (19.0) munosuppression withdrawal (33%). Five amputations were performed in
Proximal forearm 21 (17.4)
China.68,85 In 4 of these cases, a lack of understanding of immuno-
suppression and/or limited access to the medication lead to increased
Midforearm 14 (11.6)
episodes of rejection, whereas in 1 patient, immunosuppression was
Distal forearm (below elbow) 19 (15.7) stopped to treat a pulmonary infection. Additional causes for amputa-
Forearm (unspecified) 5 (4.1) tion outside of China included: chronic rejection (4), distal ischemia
Hand and wrist 39 (32.2) after high-dose vasopressors to address septic shock (2 hands, same
The most common level of transplantation was the hand/wrist (39), with the
patient), intraoperative arterial thrombosis (2), and acute rejection
arm (23) and proximal forearm (21) following. caused by discontinuation of immunosuppressive medications against
*Percentage of patients with specific level of transplant over total number of
medical advice (1).36,55 The allograft amputation rate was at both 5
patients with recorded level of transplant. and 10 years 10.8%. None of the patients who had an allograft ampu-
tated received a second transplant.

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Annals of Plastic Surgery • Volume 88, Number 3, March 2022 Hand Transplantation Literature Review

There were 5 deaths (5.2%). In 2 cases, the transplanted hand

was amputated before death. The first patient, a 37-year-old man, re- TABLE 5. Immunosuppression Maintenance Regimen
ceived a simultaneous face and bilateral distal forearm transplant. The
patient developed venous congestion of the left hand allograft, on post- No. Patients
operative day 3, that worsened despite leech therapy. At the same time, Immune Maintenance (%*)
the patient developed a Pseudomonas aeruginosa infection, requiring FK506 (1–3 mg/d) + MMF (1–2 g/d) + prednisone 28 (56)
debridement of the infected tissues of the face transplant and left upper (5–40 mg/d)
limb. The patient experienced cardiac arrest, on postoperative day 33, FK506 (3–7 ng/mL) 4 (8)
leading to anoxic brain injury and death 65 days after the transplant. FK506 + MMF (2 g/d) 3 (6)
No rejection was noted at autopsy.87,121 FK506 (5–8 ng/mL) + MMF (1 g/d) + prednisone 2 (4)
The second patient was a 27-year-old man who received bilateral (5 mg) + sirolimus (6–80 ng/mL)
arm and bilateral leg transplants. Immediately after transplant, the FK506 (12 mg/d) + MMF (1 g/d) + prednisone (90 mg/d) 2 (4)
FK506 (3 mg/d) + MMF (stopped after 6 mo) 2 (4)
FK506 + methotrexate + prednisone 1 (2)
TABLE 4. Immunosuppression Induction Regimen FK506 (3 mg/d) + prednisone (5 mg/d) + MMF 1 (2)
(stopped after 6 mo)
No. Patients FK506 + MMF (360 mg) 1 (2)
Immune Induction (%*) Sirolimus (rapamycin, 2 mg/d) + MMF (1 g/d) + prednisone 1 (2)
(2.5–5 mg/d)
ATG (1.25 mg/kg) + prednisone (250 mg/d) + FK506 6 (9.4) FK506 (10 ng/mL) + prednisone (7.5 mg/d) 1 (2)
(0.1–9.2 mg/kg/d) + MMF (2 g/d) FK506 (9 ng/mL) + ketaconazole 1 (2)
Prednisone (1000 mg/d) + alemtuzumab (20–30 mg/d) 6 (9.4) Sirolimus (rapamycin) + MMF (2 g/d) 1 (2)
ATG (1.5 mg/kg) 5 (7.8) FK506 (6.8 ug/L) + MMF (1.4 mg/d) + prednisone 1 (2)
FK506 (10–15 ng/mL) + donor BM cells (5–10  108/kg) 5 (7.8) (5 mg/d) + sulfamethoxazole-trimethoprim + metformin
Basiliximab + MMF (2 g/d) + FK506 5 (7.8) Belatacept (350 mg/d) + sirolimus (rapamycin, 3 mg) + 1 (2)
(5 mg/d) + methylprednisolone (1 g/d) prednisone (5 mg)
Basiliximab (20 mg) + MMF (2 g/d) + FK506 5 (7.8)
(15–20 mg/mL) + prednisone (250 mg/d) The maintenance immunosuppression regimen was more homogenous for
hand transplant patients than the induction regimen, with most patients receiving
ATG (80 mg/d) + FK506 (5 mg/d) + methylprednisone 4 (6.3)
FK506, MMF, and prednisone.
(800 mg/d)
*Percentage of patients with specific immune maintenance regimen over total
Campath 1H 4 (6.3)
number of patients with recorded immune maintenance regimens.
ATG (1.25 mg/kg) + prednisone + FK506 (4 mg/d) + 3 (4.7)
MMF (2 g/d)
Donor bone marrow cells 2 (3.1)
ATG (100 mg/d) + methylprednisolone (250–500 mg/d) 2 (3.1) patient went into cardiac arrest, requiring cardiopulmonary support,
ATG (100 mg/d) + FK506 (5 mg/d) + MMF 2 (3.1) hemodialysis, plasmapheresis of more than 200 units of blood products,
(750 mg/d) + methylprednisone (1 g/d) and amputation of all 4 extremities. However, the patient died 4 days af-
Cyclophosphamide (400 mg/d) 2 (3.1) ter the operation because of multiorgan failure.107
5 Doses belatacept (5 mg/kg) + FK506 (8–10 ng/mL) 1 (1.6) The third patient was a 34-year-old man with bilateral arm and
Basiliximab (20 mg) + MMF (100 mg/d) + 1 (1.6)
unilateral leg transplants. The leg was amputated the day after trans-
FK506 + methylprednisone (100 mg/d) + autologous plantation. The patient died 100 days after the transplant.108
mesenchymal stem cells (2  106 cells/kg) The fourth patient was a 57-year-old woman who had a simulta-
ATG (1.5 mg/kg) + FK506 (4 mg/d) + MMF (2 g/d) 1 (1.6) neous face and bilateral hand transplant at wrist and mid forearm level.
Alemtuzumab (30 mg/d) + methylprednisolone (500 mg/d) 1 (1.6)
Mild venous congestion of the hands was identified on the first day. On
the second postoperative day, the patient developed septic shock that ne-
Alemtuzumab + FK506 + MMF + corticosteroid 1 (1.6)
cessitated vasopressors and discontinuation of tacrolimus. Both hand
5 Doses belatacept (5 mg/kg) + FK506 (6–8 ng/mL) + 1 (1.6) transplants were removed on postoperative day 5 because of vascular in-
rapamyin (8–10 ng/mL)
sufficiency manifesting as arterial insufficiency on the right and venous
Methylprednisolone (500 mg/d) 1 (1.6) insufficiency on the left side without evidence of rejection. The patient
ATG (1.25 mg/kg) + prednisone (1000 mg/d) 1 (1.6) died 8 years after the transplant for unknown causes.87,88
5 Doses belatacept (5 mg/kg) + FK506 1 (1.6) The fifth fatality was reported as a patient who underwent an
(4–5 ng/mL) + everlimus (5–6 ng/mL) attempted bilateral hand transplantation and died immediately after in
Basiliximab 1 (1.6) Mexico.122,123
ATG (75 mg/d) + MMF (1000 mg/d) + 1 (1.6)
methylprednisone (500 mg/d)
ATG (75 mg/d) + basiliximab + FK506 + 1 (1.6) DISCUSSION
MMF (2 g/d) + prednisone (250 mg/d) Traumatic limb amputation is expected to affect more than
Belatacept (5 mg/kg) 1 (1.6) 1.3 million people in the United States by 2050.124 Two thirds of these
people are young adults who will face lower life satisfaction due to changes
The induction regimen consisted of a combination of ATG, prednisone,
FK506, MMF, methylprednisone, alemtuzumab, rapamycin, basiliximab, and
in activities of daily living, short- or long-term complications.124,125 Al-
belatacept. though 30% of upper limb amputees abandon prosthetics because of
*Percentage of patients with specific immunosuppressive induction regimen
excessive wear, weight, discomfort, and impediment to sensory feedback,
over total number of patients with recorded immunosuppressive induction. most patients who receive an upper extremity replantation express satis-
faction with replanted arm.126–128 The first of the hand transplants

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Wells et al Annals of Plastic Surgery • Volume 88, Number 3, March 2022

TABLE 6. Preoperative and Postoperative DASH scores

Age Sex Level Uni/Bi HLA Mismatches Acute Rejection Episodes DASH Pre DASH Post Δ DASH * Time to DASH Post, mo
65 M Hand Uni 0 1 59 7 52 NA
68 M Midforearm Bi 5 2 25 40 −15 42
31 M Hand Bi 6 4 92 13 79 12
31 M Hand Bi 6 1 86 9 77 12
33 M Wrist Bi 5 2 86 16 70 NA
52 M Proximal forearm Bi 5 4 50 31 19 24
51 M Above elbow Bi 0 3 76 68 8 18
29 M Above elbow Bi 6 3 71 31 40 24
47 F Wrist Bi 5 2 29 19 10 20
30 M Proximal forearm Bi 0 3 71 37 34 32
58 F Midforearm Uni 0 4 38 23 15 9
22 M Hand Uni 3 2 31 11 20 37
33 M Hand Bi 5 2 86 16 70 NA
47 M Hand Bi 6 3 58 34 24 NA
41 M Proximal forearm Bi NA 7 67 64 3 NA
32 M Midforearm Uni 3 1 100 86 14 NA
30 M Wrist Uni 3 0 96 67 29 NA
50 M Hand Bi NA NA 98 71 27 NA
The change in DASH scores was calculated as preoperative DASH minus postoperative DASH score.
F, female; HLA, human leukocyte antigen; M, male; NA, data not available.

performed in Louisville (1999) demonstrated that upper limb transplanta-
tion is technically and immunologically feasible with satisfactory long-
term functional outcomes. This systematic review questioned if 2 de-
cades later, there was enough evidence to justify hand transplantation
as a life-enhancing procedure.
Standard of care for upper extremity amputations is currently un-
der debate, with treatment options including immediate replantation,
prosthetics, and transplantation from a donor. Salminger et al129 com-
pared the functional outcomes of hand transplants to prosthetics, noting
that below elbow transplantations had the best outcomes due to intact
recipient extrinsic flexor and extensors “moving” the transplanted hand
without the requirement for motor nerve regeneration. In contrast,
above elbow transplants had decreased functional recovery and longer
rehabilitation due to the longer distance required for nerve regeneration.
This systematic review confirmed a significant and clinically relevant
decrease in posttransplant disability scores (minimum clinically impor-
tant difference, 31 ± 27; P < 0.001). Patients who received distal trans-
plants had less disability than proximal transplants postoperatively
( P = 0.035). These data support that hand transplantation is associated
with functional benefits. This review did not find a significant differ-
ence in reduction of disability after transplantation between unilateral
and bilateral transplants ( P = 0.454). McClelland et al130 examined un-
der what conditions a unilateral transplantation would be indicated
using a decision tree with probability of transplant survival of 95%
and complication probability at 20% and found that transplantation
was preferred over alternative treatments if the probability of satisfac-
tory functional outcome (defined as Chen level 1 or 2) was greater than
73%. Therefore, McClelland et al130 argued that unilateral hand trans-
plantation was justified given proper candidate selection.
A recent review on hand replantation concluded that near 100%
of patients recovered protective sensation and 30% to 60% of patients
experienced return of tactile and discriminatory sensation.131 The same
article showed return of protective sensation in 100% of hand transplant
recipients and return of tactile and discriminatory sensation in 80% to
90% of patients. Our systematic review confirmed based on data from
16 patients (16.7%) that transplant recipients recovered protective
sensation (median, 11 mm; range, 7–15 mm). Compared with replanted
hands, transplants seem to display faster and more complete recovery
of sensation, probably because of stimulation of nerve regeneration by
tacrolimus.132
We identified a high allograft survival rate (89.2% at 10 years) com-
pared with kidney (73.6%), liver (63%), and heart (53%) transplants.133–135
This might be related to the exposed nature of the allograft and early detec-
tion and treatment of the rejection episodes. Excluding nonimmunological
causes, there were 12 reported transplant amputations (8.1%), all of
which occurred within the first 5 years, which is comparable with fail-
ure of other organ transplants such as the kidney (10% failure in first
year) and heart (11% in first 3 years).136,137 The incidence of acute rejec-
tion seems to be higher in hand transplants. Although 89% of hand
transplants experienced at least 1 episode of acute rejection, Hamida
et al138 reported an incidence of 40.4% for acute rejection in kidney
transplants. Interestingly, incidence of chronic rejection in hand trans-
plants (5%) is lower than reported for other organs (eg, 17.5% in kidney
transplantation).139–141 One potential cause for this discrepancy is rep-
resented by the relatively short follow-up: as time progresses, there may
be more reported cases of chronic rejection.142 However, early detection
of acute rejection because of the exposed nature of the hand transplants
and resulting timely intervention could play a major role in prevention
of chronic rejection of hand transplants in comparison with solid organ
transplants.
Noncompliance of patients with the immunosuppression regi-
men was the most common cause of amputation after transplantation,
especially in China. This highlights the need to educate patients on both
the cost and physiological toll of immunosuppression. Reduction in
costs of medication, further screening of transplant candidates, and psy-
chological support may improve patients’ compliance. Efforts to increase
adherence to immunosuppressive medications in kidney transplants,
through means such as specialty pharmacies, may also be effective
for hand transplants.143
Medical complications, mainly adverse effects of immunosup-
pressive or antimicrobial therapies, have been reported in hand trans-
plantation, with hyperglycemia (21%) and diabetes (13%) among the

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Annals of Plastic Surgery • Volume 88, Number 3, March 2022 Hand Transplantation Literature Review

of immunosuppression was also sparse (2 patients, 2%, compared with

TABLE 7. Medical Complications liver, 14% and kidney, 6.3%).147–149 Schneeberger et al150 cautioned
against overzealous interpretation of the low incidence, as the relatively
No. Patients short follow-up time provides limited windows for detection of cancer
Metabolic activity. One patient developed basal cell carcinoma 360 days after
Hyperglycemia 20 transplant on the right nasal ala. Since excision, the patient has been free
Diabetes 12 from recurrence.151 The second patient developed marginal zone lym-
phoma, 23 months after transplant, which resolved after discontinuation
Hypoproteinemia 1
of MMF and reduction of tacrolimus.55
Hyperparathyroidism 1 Combination of hand transplantation with face or lower extrem-
Musculoskeletal ity was associated with 80% early and late mortality rate. Extensive
Osteoporosis 2 blood loss, volume shifts and long anesthesia as well as large antigenic
Osteopenia 2 load, reperfusion injury, postoperative ischemia, and infection of the
Osteonecrosis of the hips 2 transplanted tissues have been named as possible contributors to early
Renal/vascular graft and patient loss in this setting.87,152,153 Factors affecting late mor-
Increased creatinine 9 tality were not reported by transplant teams, but adverse effects of im-
Arterial hypertension 6 munosuppressive medications and infections are among the factors that
Kidney failure 4 can contribute to late mortality. The sole patient who survived the si-
multaneous face and hand transplant experienced third-degree burns
Polyuria 1
from a car accident in July 2018. The transplantations were performed
Autoimmune in August 2020, with no currently reported complications.119
Serum sickness 2 Limitations to this systematic literature review include heteroge-
Alopecia 1 neity of the reported data. Specifically, a relatively minimal rate of graft
Rheumatoid arthritis 1 failure (10.8%) in transplanted patients with various confounding fac-
Bullous pemphigoid 1 tors such as concurrent face or lower extremity transplantation, immu-
Pulmonary nosuppressive regiments, and mismatched immune markers limits the
Pulmonary embolism 1 conclusions that can be drawn; an increased sample size for graft failure
Infectious that comes with increased volume of upper extremity transplantation is
CMV 10 necessary to determine the significance of the varying factors. Further-
more, media sources that reported on upper extremity transplantation in
Fungal 3
patients without publications often neglected to rigorously detail data
Herpes virus 3 that could be used in the statistical analysis. Although incorporation
HPV 3 of these patients added to the completion of this review, these sources
Cellulitis 2 also contributed to the heterogeneity of the data available.
Pulmonary infection 2
Acute pancreatitis 1
Conjunctivitis 1 CONCLUSIONS
Clostridium difficile 1 The evidence accumulated in the past 2 decades confirms that
EBV 1 hand transplantation decreases patients' disability especially in bilateral
Herpes zoster virus 1 and distal transplants. Despite higher incidence of acute rejection
Malignancy
compared with other organs, the chronic rejection and reamputation
rates remain low. The transplant recipients experience all the medical
Basal cell carcinoma 1
complications of the immunosuppressive medications reported for
Marginal zone lymphoma 1 solid organs. Mortality is strongly associated with cases of simulta-
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HPV, human papillomavirus. neous transplantation with face and lower extremities.

most common. Gradual decline in kidney function (4.2%) was observed
with the use of calcineurin inhibitors leading to acute and chronic renal
failure. Two cases of renal transplantation after hand transplantation
have occurred, although in 1 case, this was for preexisting renal dis-
ease.24,144 Breidenbach et al145 suspected underreported numbers of re-
nal failure for hand transplantation, as there is a vast disproportion in
comparison with solid organ transplants (16.5%). This finding has
prompted some groups to switch to mTOR inhibitors, such as sirolimus
and everolimus, including 1 case where conversion to belatacept and
sirolimus was successful when the patient faced multiple rejection epi-
sodes with renal failure.43,146,147 However, mTOR inhibitor conversion
or the addition of belatacept has also triggered episodes of rejection, in-
dicating that development of suitable immunosuppression regimens is
an ongoing endeavor.146
Experimental therapies involving donor bone marrow infusions
have been trialed in hand transplantation; however, tolerance has not
been achieved and any other benefits are unclear because of the limited
number of cases and short follow-up.51 Malignancy as a consequence
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