Organ transplantation is still a relatively novel treatment modality; its practice only developed in the latter half of the 20th century, in part due to the advent of immunosuppressive drugs. Key questions driving progress in transplant surgery is how far this science can be pushed, and if any part of the human body can be transplanted.

In urology, transplantation of the kidney was previously inconceivable, but is now well established, following the first successful renal transplant performed in 1950. However, there is minimal evidence in the scientific literature of the successful transplantation of other urologic organs.

There has, in the past, been great interest in exploring this lesser-known area of urologic transplantation, as the morbidity for patients with failure or damage to urologic organs such as the penis, testicle, or bladder is considerable. There is renewed interest in recent years due to the increased prevalence of devastating injuries to the genitalia caused by improvised explosive devices among soldiers stationed in Afghanistan.¹ There is minimal evidence in the literature addressing how these injuries should be best managed or whether transplantation may have a role in helping such patients.

Remarkable progress in transplantation surgery has allowed development of new strategies of treatment for many urologic patients. Greater insight into the practice of transplantation may lead to improved management of other urologic pathologies. We comprehensively reviewed the historical evidence for transplantation of those urologic structures for which the practice is not well established. To our knowledge, no such review exists in the literature.

Methods

A review of the available literature was undertaken using the online databases PubMed and Google Scholar for all scientific articles published in English. No time frame for publication was defined in the searches. The Ovid MEDLINE online database was also used; the domain “In-Process & Other Non-Indexed Citations 1946 to Present” was employed in the search. The searches were supplemented in combination with the Boolean operators “and” and “or.” The literature search was further expanded by applying the “related article” function. A further manual search of the bibliography and reference sections of the generated articles augmented the initial electronic search.

Results

Penile Transplantation

Complete penile amputation is rare, most commonly as a result of trauma, self-inflicted injuries in psychiatric patients, or surgical penectomy for the treatment of advanced carcinoma of the penis. Surgical penectomy is a potentially debilitating procedure. Opjordsmoen and Fosså² studied the long-term psychosocial outcome of patients who had undergone successful surgical treatment for penile cancer, and found that those who had undergone more radical procedures were more likely to have an adverse outcome in sexual function and reinclusion in social activities. Hu and colleagues³ suggested that patients with a penile defect are frequently extremely concerned about the extent to which their problem might affect their social status and the fidelity of their partners.

The current mainstay of surgical management relies on techniques of reconstructive surgery. Penile replantation can be considered in trauma scenarios in which the amputated organ is retrievable; however, this technique is constrained by ischemic time. The most commonly employed alternative is phallic replacement using microsurgical technology and free-flaps from autologous donor sites, combined with a penile prosthetic implant. This approach can potentially preserve sensation and sexual function⁴; however, limitations include the need for multiple procedures and often unsatisfactory final cosmetic results. There is a void between the functional and cosmetic outcome of penile reconstructive surgery and patient expectations.

Experimentation in penile transplantation has only been undertaken in recent years, and its ethical justification has been a topic of debate in the scientific world. Zhang and collagues⁵ argued that the penis is not an “essential” organ for survival, and therefore subjecting a human being to transplantation trials with no previous supporting evidence may be controversial. Similarly, ethical disputes may arise in transgender individuals wishing to convert from the female to male phenotype.

Because penile transplantation is a composite tissue allograft containing skin, immunosuppression is particularly challenging, as with grafts of the hand or face. In the hierarchy of susceptibility of different allografts to autoimmune rejection, skin is associated with one of the most aggressive rejection profiles.⁶

Koga and associates⁷ reported their experience of allogenic penile transplantation using rat models. Twenty-three penises were harvested from one species of rat and transplanted into a pouch created in the omentum of 23 male recipients of a different species of rat. They subdivided organ recipients into two groups: one group received immunosuppression and the other group did not. They found that the treatment group fared well, whereas all grafts were rejected in the control group.

In 2006, the European Association of Urology published the preliminary report from a team of Chinese surgeons of the first case of human leucocyte antigen (HLA)-matched human donor to recipient penile transplantation.⁸ The recipient was a 44-year-old man who had a traumatic amputation of his penis, leaving him with a residual 1-cm stump measured from the pubis. The donor was a 22-year-old brain-dead man, matched for HLA and blood-type. A 10-cm long penis graft was harvested; following vascular control by tourniquet application around the recipient's penile stump, successful anastomoses were created between the urethra, deep dorsal vein, dorsal artery, dorsal nerve, and superficial dorsal vein. Postoperative complications included venous stasis and penile edema on day 3. However, after only 2 weeks the transplanted penis had to be surgically removed due to “a severe psychological problem of the recipient and his wife.” Pathologic examination of the specimen after removal did not show any evidence of graft rejection. To date, this case remains the only reported of human penile transplantation.

Jean-Michel Dubernard, the French transplant surgeon known for having performed the first successful full hand transplant operation in 1998, published an editorial in the same journal in response to the preliminary report of penile transplantation.⁹ He argued that if nonvital transplants had already been performed to replace a hand or a face, then similar favorable ethical reasons can be used in support of transplanting a penis. Dubernard concluded that currently there are many satisfactory ways of performing a penile reconstruction when a sizeable stump of tissue to build upon is present. However, in rare cases in which a stump is not present, penile transplantation could be considered.

A future alternative to penile transplantation may lie within the principles of tissue engineering, which relies on the attainment of a sample of donor cells from a given body tissue. Cells are then expanded in number, either after direct insertion into a recipient or within a culture medium, while retaining the original structure and functionality.

Kwon and associates¹⁰ used rabbit models to apply this concept to grow corpus cavernosal muscle. The corpora cavernosa were removed from all rabbits; one group received harvested autologous donor rabbit cavernosal cells and the second group remained without cavernosal muscle. Rabbits in the treatment group were able to achieve normal-pressure erections, produce sperm, and resume mating within 1 month, whereas rabbits in the control group did not return to normal sexual function.

Testicular Transplantation

There are many causes of a bilateral loss or congenital absence of the testicles, which compromises endocrine, reproductive, and psychological function in men.

The testes can be congenitally absent in conditions such as unresolved cryptorchidism due to bilateral maldescent or atrophy. Acquired causes of anorchia include trauma, torsion, and infections, such as mumps orchitis or bilateral orchiectomy, which may be performed as a treatment for primary testicular cancer. There are many sequelae for patients without testes. Patients are sterile, have increased risk of osteoporosis and pathologic fractures, and are subject to further complications, such as sexual dysfunction, mood changes, severe psychological trauma, altered fat distribution, reduced stamina, and muscle wasting.¹¹

Current strategies of treatment in anorchic patients focus on the medical management of androgenic hormone replacement therapy to avoid the complications associated with hypogonadism. Surgically, the main intervention is the implantation of a prosthetic testis, a procedure which is well accepted by patients and has been shown to subjectively improve body image.¹²

Testicular transplantation had its foundation not as a treatment modality for the recognized complications of anorchism, but for arguably less ethical reasons. The origins emerged from the quest to find the fountain of eternal youth; in this pursuit, the science of endocrinology and experimentation with testicular transplants began in the late 19th century. The French physiologist Charles-Edouard Brown-Sequard (1817-1894) presented the results of an experiment he performed on himself due to his interest in testes and rejuvenation therapy. He believed that aging had robbed him of his mental and physical abilities, and so he proceeded to inject himself with crushed testicular extracts from young dogs and guinea pigs. He reported this technique successfully made him feel 30 years younger, along with increasing his sexual potency and heightening his intellect. This early work reinforced the belief that youth rejuvenation could be achieved through the replacement of endogenous substances, which then led to an increased interest in sex gland transplantation.¹³

The Russian surgeon Serge Voronoff (1866-1951) was a pioneer in this field. He explored the surgical techniques of transplantation as he postulated that he could rejuvenate humans by transplanting testicles from primates. On June 12, 1920, Voronoff performed the first recorded transplantation of chimpanzee testicles to a human recipient, slicing the prepared donor grafts and placing them in the recipient's scrotum for 8 days.¹⁴ The success described in this case quickly resulted in the procedure gathering interest; by the 1930s Voronoff was known as the “famous doctor who inserted monkey glands into millionaires.” The practice even caught on to the professional sports world; in the 1940s, soccer players on the Wolverhampton Wanderers and Portsmouth teams in the United Kingdom underwent the procedure for performance-enhancing therapy.¹⁵ The procedure was so popular that the French government was forced to forbid monkey hunting in its distant colonies.¹⁶ Due to increasing scepticism and criticism among both scientists and ethicists, eventually Voronoff's practice ran out of favor and toward the end of his life his work and professionalism became a subject of ridicule.

Unfortunately, testicular transplantation research led to the notoriety of certain other figures whose medical ethics and integrity were more questionable. G. Frank Lydston (1858-1923), an American urologist, allegedly transplanted entire testicular grafts into humans by fixing them to the recipient's abdominal wall. He reported that his treatment conferred therapeutic benefits for conditions such as dementia, psoriasis, hypertension, and eczema; he even subjected himself to it.¹⁷ However, criticism grew as it became known that he obtained the grafts from dead young men or those who had committed suicide, as Lydston confirmed.¹⁸

Leo Stanley (1886-1976), the staff physician at San Quentin Prison in San Quentin, CA, went further by using the prison inmates as both donors and recipients of testicles in his research into testicular transplantation.¹⁹ However, Stanley soon discovered that the numbers of executions in San Quentin Prison were not keeping up with the numeric demands of his studies, so he decided to use injections of triturated animal testicular tissue instead. By 1922, he was able to publish his experience with 1000 patients who had received such injections, reporting benefits for a wide range of pathologies, including rheumatism, diabetes, and tuberculosis.²⁰

Possibly the most infamous practitioner was John R. Brinkley, who bought his medical diploma in Kansas; as a result of Voronoff's work he developed an entrepreneurial interest in antiaging therapy. Herr²¹ described how Brinkley demonstrated his technique of transplanting goat glands into a man to the engrossed media and a group of attending surgeons. Brinkley's equally unqualified wife acted as attending anesthetist.

The operation he demonstrated involved twin incisions in the patient's scrotum, insertion of donor goat gonads alongside native recipient testicles, and anastomosis of a subsidiary artery and nerve alongside the vas deferens into the epididymis. Herr narrated how he deceived the observers, because he did nothing more than deposit the goat testicles into the recipient's scrotum, a deceit that Brinkley subsequently confessed to many years later, when under oath in court for a defamation lawsuit.²¹ With the advent of synthetic testosterone and other steroid hormones in 1935, the clinical indications of testicular transplantation as a form of androgen therapy gradually became obsolete.

Since the days of Voronoff, Stanley, and Brinkley, testicular transplant research has progressed with arguably more ethical therapeutic intent. Studies using rat models undertaken in the 1960s and 1970s revealed that, if testicles were transplanted with an adequate vascular anastomosis following a bilateral orchiectomy, over time normal levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), as well as sperm count, could be expected in recipients.^22,23

In 1978, Silber²⁴ published a case report claiming the first entire human testis transplant. He described the case of two genetically identical male twins, one born with two normally functioning testicles and the other born with none. Using microvascular techniques, Silber successfully transplanted a testicle from the healthy twin into the anorchic brother, and, within 2 hours of the operation, normal levels of testosterone were measured in both the donor and the recipient. FSH and LH levels also gradually normalized, and, over several months, the sperm count and motility also reached normal levels in the recipient. Silber²⁴ pointed out that, despite his success, the application of his procedure to any scenario that did not involve genetically identical twins awaited the development of more sophisticated methods of immunosuppression.

Zhao and coworkers²⁵ later presented a case series of 11 patients who had undergone a testicle transplant with grafts obtained from deceased donors. The authors reported normal postoperative levels of testosterone and improvement of secondary sexual characteristics. Nugent and coworkers²⁶ disputed these findings, suggesting they were contrary to all other available evidence, made even less plausible because the authors did not report using any form of continuous immunosuppression.

In the 21st century, attention turned to testicular transplantation mainly as a therapeutic intervention for infertility. This scenario arises in oncology patients who face courses of chemotherapy that jeopardize their fertility. Cryopreservation of sperm leaves these patients with a finite resource of fertility and is associated with only modest rates of successful future conception. Cryopreservation is also not a suitable option for prepubertal patients who have not yet started to produce sperm.²⁷

Complex immunologic principles provide a further unique challenge in testicular transplantation. The testes are known to be a site of immunologic privilege, which means they can tolerate the introduction of antigens without the development of an immune response. Fijak and Meinhardt²⁸ suggest that further research into the immune system of the testis may open new avenues for future successful testicular transplantation. It is apparent, however, that despite more than 100 years of effort, evidence of successful entire testis transplantation between humans remains scarce.

Urethral Transplantation

Important etiology of male urethral damage includes trauma, iatrogenic injury following urologic procedures, inflammation and infection, congenital abnormalities, and urethral cancer. Any violation of the urethra's integrity may result in the subsequent formation of strictures.²⁹ Current surgical techniques, including reanastomosis, primary and delayed apposition, or endoscopic realignment, are satisfactory in restoring anatomic integrity but strictures may still develop.³⁰ Complications of urethral strictures include recurrent urinary retention, hydronephrosis, fistulas, and repeated surgical dilatation procedures, which may perpetuate the problem. In his review of the management of complex recurrent urethral strictures, Mundy³¹ explained that current surgical techniques are not always satisfactory.

There is also no agreed consensus on the surgical treatment of urethral cancer despite the poor associated outcome with this malignancy. Urethral transplantation may provide a solution for these voids in current urologic practice.

Muruamendiaraz and colleagues³² published a brief extract describing a man with bulbar stenosis and a history of two previous failed urethrotomies successfully receiving a cryopreserved urethral graft from a cadaveric donor. The patient reportedly experienced no postoperative complications. The authors claim that this is the first reported case of successful human urethra transplantation, yet surprisingly little detail exists in the medical literature about this or three other cases of successful urethral transplantation by the same authors. The authors optimistically suggested that cryopreserved urethral transplant may offer a new treatment for urethral stenosis; however, in over 15 years, their article has only been cited once, and no further similar cases or studies have since been reported.

Transplantation research around the human urethra has concentrated on tissue engineering and biomaterial grafts. A new, similar stem cell-based graft derived from buccal mucosa has since been investigated with reports of success,³³ and was more successful when directly compared for outcomes with bladder-derived counterparts.³⁴ However, it became apparent that, like other small tubularized engineered structures, the urethra tends to form strictures over time, limiting long-term success.

In 2011, Raya-Rivera and coworkers³⁵ harvested bladder-derived autologous cells from five young men with urethral defects, expanded the cells, and seeded them onto a tubularized biodegradable mesh. The mesh was surgically implanted with absorbable sutures into the patients, who were followed for a median of 71 months. The authors found that within 3 months the biopsies from the urethra showed normal histology. The importance of this report was that it was the first of its kind providing long-term follow-up of patients receiving a urethral graft. Clearly, the research focus is currently directed at exploring different forms of tissue engineering and biomaterials, rather than the employment of solid cadaveric human donor grafts.

Vas Deferens Transplantation

Damage to the vas deferens rarely presents in isolation as a result of external trauma. Rather, one of the most common causes of unintended vasal disruption occurs iatrogenically during inguinal hernia repair surgery; the estimated incidence of vas injury associated with this operation is 0.3% in adults and 2% in children.³⁶ Considering that hernia repair is one of the most frequently performed procedures worldwide, it is likely that the burden of this injury is significant. Injuries are likely to be under-reported, as they may only be detected many years later when a patient is independently being investigated for infertility.³⁶ Damage is not only caused by transection; intraoperative compression injuries and subsequent granuloma formation can also lead to malfunction.³⁷

Problems affecting the vas deferens can also arise from congenital pathologies. Unilateral absence of the vas deferens is associated with renal agenesis; Young syndrome can affect the vas deferens and is associated with obstructive azoospermia. Congenital bilateral absence of the vas deferens (CBAVD) is one of the most consistent features of cystic fibrosis.³⁸

The main goal in the surgical management of patients who have damage to their vas deferens or have CBAVD is the restoration of natural fertility. Paternity can be achieved through percutaneous sperm aspiration and intracytoplasmic sperm injection; however, there are no surgical techniques available that permit a patient with CBAVD to inseminate a partner naturally. Vasal patency can be surgically restored using microscopic reanastomotic techniques provided the defect is small (eg, following vasectomy); however, if the injured segment or the interval between segments is long, reanastomosis maybe impossible.³⁹

Gilis and Borovikov⁴⁰ performed vas deferens allografts and autografts (using the contralateral duct) in rats in the 1980s, reporting poor allograft survival but 70% autograft survival with a 40% patency rate. Romero-Maroto and colleagues⁴¹ were simultaneously studying vasal autografting in a rabbit model, evaluating their outcomes with serial seminograms and histologic analyses of the transplanted vas segments. They reported satisfactory outcomes and concluded that their technique is viable in the rabbit model. Despite these promising results in the 1980s, minimal progress has been made and surgical management of patients with long-segment defects or CBAVD remains a dilemma.

In recent years, focus has turned to tissue engineering. The focus is on finding a biodegradable graft that may act as a supporting scaffold to guide the growth of the divided vas deferens or to bridge the vas defect, so that it is more likely later to be amenable to reanastomosis using currently effective microsurgical procedures.

Simons and associates⁴² evaluated whether their biodegradable polymer grafts could be effective in reconstructing obstructed or absent vas deferens in a rat model. They performed a bilateral vasectomy in 47 rats and divided the specimens into three groups according to the length of the defect they had created. They proceeded to reconnect the vas deferens using the biodegradable polymer grafts, and then followed the specimens at 8 and 12 weeks; they found evidence of regrowth at 12 weeks.

The exponential increase in interest and research into reproductive medicine has led to efforts into identifying surgical techniques for treating absent or damaged long segments of vas deferens. In many cases, reproduction can be successfully achieved using assisted reproductive technology, and, for many patients, this may be preferable to a surgical procedure that has minimal supporting evidence in the literature.

Bladder Transplantation

Permanent bladder dysfunction may result from congenital conditions such as spina bifida, bladder exstrophy, and agenesis or acquired neurogenic conditions resulting from spinal cord injuries, herniated intervertebral discs, diabetes, and pelvic surgery. The entire bladder may be surgically removed in the treatment of advanced bladder cancer.

Progress in reconstructive surgery has managed to improve outcomes following radical cystectomy; however, modern procedures using bowel segments are still associated with their own complications, such as recurrent infections, incontinence, incomplete emptying, and sexual dysfunction, all of which have a significant impact on quality of life.⁴³

The search for suitable materials to substitute or augment bladders began almost 100 years ago when Neuhof, in 1917, first attempted to use fascia to augment bladders in dogs. Since then, various endogenous grafts have been investigated, including dura, muscular flaps,⁴⁴and synthetic materials, including polyvinyl composite and Teflon^® (DuPont, Wilmington, DE).⁴⁵ These attempts have failed for a variety of reasons, often due to mechanical, biocompatibility, or functional problems, such that autologous bowel remains the gold standard for neobladder formation and bladder augmentation.

Bladder transplantation has been explored as an alternative option. Takeuchi and associates⁴⁶ studied bladder transplantation using a rat model; 23 rats underwent a cystectomy leaving only the trigone, and then received a harvested rat urinary bladder allograft en-bloc with the abdominal aorta and inferior vena cava. At 4 weeks after surgery recipient survival was 52%; at 6 months, nerve fibers had regenerated in the graft and bladder volume was well preserved.

At the beginning of the 21st century, research using animal models shifted toward partial bladder transplantation. In 2001, Wang and coworkers⁴⁷ used a rat model in which both donor and recipient were live/related and only a partial graft was harvested from the donor, which was then used for bladder augmentation in the recipient. Partial bladder transplants in the form of a “bladder patch” allograft have also been successfully performed in other animals.⁴⁸

In 2008, Kato and associates⁴⁹ performed this technique in a human, and thus claimed to have achieved the world's first human donor-to-recipient partial bladder transplant. The patient was a 6-month-old girl with multiple congenital abnormalities of the urinary tract, including renal hypoplasia and a small nonfunctional bladder. They obtained a complex graft incorporating both kidneys and ureters, and the bladder from a pediatric donor, and transplanted these en-bloc. The donor bladder was opened and bilateral ureteral openings were created—this was then anastomosed to the dome of the recipient's bladder, which had been laid open, similar to the technique of vascular patch grafting. They reported a satisfactory postoperative course with the healthy donor bladder wall observed on cystoscopy 3 weeks later, and proposed that this partial bladder transplant patch technique could benefit patients who require bladder augmentation, as it avoids the use of bowel and its associated morbidity.

More recent research into bladder transplantation has focused on tissue engineering. Atala and colleagues⁵⁰ studied a group of seven patients suffering with bladder dysfunction secondary to myelomeningocele. They harvested urothelial cells via a bladder biopsy, expanded these in culture, and seeded them onto a bladder-shaped collagen scaffold; 7 weeks later the construct was used to surgically augment the patients’ native bladders. The team followed their patients for up to 5 years, and reported promising results with regard to both bladder function and structural integrity. Although there has been intense research directed toward stem cells, to date a stem cell-engineered bladder has not yet been developed and fully transplanted into a human recipient.

Current Techniques in Reconstructive Surgery

The ongoing development of more sophisticated and refined techniques of reconstructive urologic and plastic surgery has, in many instances, supplanted indications for transplantation of urologic organs. Penile reconstruction is particularly challenging, as the patient requirements for a satisfactory outcome include cosmetic appearance, voiding function, and sexual function. The current accepted surgical techniques rely on a variety of different techniques using flaps: radial free forearm, free sensate osteocutaneous fibula, free scapular, vertical rectus abdominis, and suprapubic abdominal wall flaps. None of these techniques have been proven to be significantly superior than others in terms of outcome; however, free radial forearm and sensate osteocutaneous free fibula flaps are the most accepted.⁵¹

Urethral reconstruction relies on two broad management strategies. The anastomotic technique, whereby the narrowest segment of the urethra is resected and proximal and distal ends are rejoined, is an appropriate strategy to manage smaller urethral strictures. The alternative technique relies on tissue transfer, whereby tissue from sites including buccal mucosa, bladder mucosa, or penile skin is grafted and used to enlarge the strictured segment of urethra. This can also be achieved by means of a pedicled local skin flap.⁵²

Bladder reconstruction relies on the use of segments of small and large bowel that can be fashioned according to the patient's requirement. Bowel can be used in various ways: to augment the bladder size and capacity, to form a neobladder to act as urinary reservoir, to create a conduit for urinary diversion, or to fashion a continent cutaneous pouch that requires intermittent self-catheterization.⁵³

Conclusions

In the field of urology, transplantation of the penis, testicle, urethra, vas deferens, and bladder has been described in animal models and human patients, but is far from being routinely performed in current surgical practice. Progress and development of transplantation of these organs has been limited by several factors.

Ethical limitations include the use of animal models for experimentation, and with the testis, recipient fertility with donor sperm. The need for immunosuppression to prevent immunologic rejection of the transplants has inherent risks and challenges; particularly in the case of composite grafts containing skin, further development is needed. In some cases, assisted reproductive technology, exogenous hormone replacement, or acceptable reconstructive alternatives such as vasovasostomy and urethroplasty make transplantation obsolete. In recent years, research and funding have shifted away from transplantation in favor of biotechnology, prosthetic materials, and refined microsurgical techniques. Despite these difficulties and limitations, the field of transplantation remains one of the greatest advances made in modern surgery and one of the most awe-inspiring concepts for patients who rely on it as a treatment for themselves or their loved ones.  

The authors thank Dr. Flavia Donatifor her help and support throughout the production of this manuscript.

The authors report no real or apparent conflicts of interest.

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