Renal transplant surgery – Then and now

Introduction

The concept of replacing diseased tissue or organs has been around since antiquity. Physicians Cosmos and Damian, two brothers who are now celebrated as patron saints of physicians and surgeons, performed the first miraculous transplantation of a leg belonging to a black Ethiopian to a white man, a feat depicted in many paintings dating from the 13th century.

As Singapore General Hospital celebrates 50 years of renal transplantation, we revisit the events, landmarks and people who paved the way for this fantasy to be a reality today.

A Meeting of three pathways

The first successful renal transplant between identical twins was performed 23 December 1954, by Joseph E. Murray. In retrospect, the success of this transplant was not significant in itself because the surgical technique used was nothing new, and that skin grafts between identical twins were not rejected had been known for decades. Dr Murray went on to perform the first successful renal allotransplant in 1959 and in 1962, the first successful deceased donor renal transplant. ¹

In his 1990 Nobel prize lecture, he said, ‘The full story of successful organ transplantation in man weaves together three separate pathways: the study of renal disease, skin grafting in twins, and surgical determination. A leitmotif permeates each of these pathways, ie, a single event or report was critical for medical progress.’ ²

The study of renal disease led to the creation of the Kolff-Brigham ‘artificial kidney’ and later, chronic dialysis by Schribner in Seattle. ³ The successes and failures in skin grafting, reported in the 1930s, contributed to the certainty of permanent survival of skin grafts between monozygotic twins. The dizygotic twin story culminated in the successful skin grafting by Sir Michael Woodruff, a transplant surgeon in Edinburgh, between a pair of twins, one male and the other female. ⁴

Surgical determination can be attributed to many a surgeon who have sealed their names in the history of transplantation. Alexis Carrel is best known for pioneering vascular anastomosis techniques, and later for his work with Charles Lindbergh on the perfusion pump for organ transplantation.^5,6

Soviet surgeon Yu Yu Voronoy of Kiev made the first known attempt at human-to-human renal allotransplantation in 1933. In the 1940s and early 1950s, experimental dog kidney transplantation was actively conducted by surgeons in Paris, Boston, Denmark and London. ⁵

In 1951, David Hume from Boston performed transplants placed in the anterior thigh with the ureter brought out to the skin. ⁷ Concurrently, in Paris, René Küss and Charles Dubost, as well as Marceau Servelle of Strasbourg, performed allotransplantations using donor kidneys from guillotined criminals. The kidneys were placed retroperitoneally in the pelvis revascularised by iliac vessels with the ureter anastomosed to the bladder – Küss’ method that has since been refined by other Parisian surgeons and is still the standard performed today. ⁸

These three pathways merged at Peter Bent Brigham Hospital, culminating in a series of successful renal transplantations and widespread attempts to overcome the immunological barrier that was limiting transplant success to identical twins. Experimental protocols including total body x-ray treatment and marrow infusions finally gave way to the breakthrough of immunosuppressive drugs.^9,10

The Local trailblazers

It is no small feat then, that 5 years after achieving independence as a sovereign nation, Singapore performed its first kidney transplant from a deceased donor in 1970. Dr Chan Kong Thoe, then head of the University of Singapore Department of Surgery, performed the first deceased donor kidney transplant on Doreen Tan, a 30-year-old housewife, on 8 July 1970 at Bowyer Block of Singapore General Hospital (SGH). The donor, Mr Yee Kwok Chong, 20, died of a presumed brain tumour after only 4 days of hospitalization (he was later found to have had an infection). ¹¹

The stage was set in 1961, when the Department of Clinical Medicine at the then–Outram Road General Hospital acquired its first haemodialysis machine. Initially used primarily for the treatment of acute renal failure, pioneering nephrologists gained experience in its use for maintenance treatment of end-stage renal failure. ¹² However, with nearly 200 patients dying annually from end-stage renal failure, the cost was prohibitive, at an estimated $15,000 per patient per year. Renal transplantation thus became a more attractive option and the ideal goal of renal replacement therapy in Singapore.

A proposal was made to the Ministry of Health (MOH) in 1966 to establish an Organ Transplantation Programme. Visits were made to various transplant centres around the world to assess the feasibility of starting a programme in Singapore. Exactly 1 year prior to the first transplant, animal experimental surgery began, allowing Dr Chan and his team of surgeons including Drs Ong Siew Chey, M Sridharan and R Sundarason to gain surgical experience on canine models. A $75,000-donation from an American foundation enabled the setup of an experimental animal laboratory in which one dog renal transplant was performed each week. ¹³ Simultaneously, various protocols were established for the retrieval of cadaveric kidneys, tissue typing and post-operative management of the recipient.

These efforts culminated in Tan’s surgery, which took 3 hours, and within 10 days, the kidney started producing urine. She went on to live another 22 years before succumbing to sepsis, albeit with a functioning graft. ¹⁴

In 1972, the legal framework for retrieval of cadaveric kidneys was passed with the introduction of the Medical Therapy, Education and Research Act (MTERA). This opt-in legislation gave a low yield of deceased donor kidneys (average of three a year), ¹⁵ leading to the development of a living donor kidney transplant programme in SGH. In the early years, this was restricted to parents and siblings of the patient, with a minimum requirement of a single haplotype match on human leucocyte antigen (HLA) testing.

The first recipient received a kidney from his brother on 31 July 1976. With the introduction of cyclosporine A in the 1980s, ¹⁶ living donation was eventually extended to spouses and second-degree relatives. The first spousal kidney transplant was performed in 1991.

Despite this, transplant volumes remained low. A trans-Pacific organ-sharing program between 1983 to 1987 provided 33 additional deceased kidneys from America and Canada to Singaporeans. However, graft survival was extremely poor, likely attributable to the prolonged cold ischaemia times (50-73 hours) and the high degree of HLA mismatches. ¹⁷ This prompted the introduction of the Human Organ Transplant Act (HOTA) in 1987, which was an opt-out, presumed-consent legislation.

In the following decades, with new drugs and improvement in immunosuppression regimens, kidney transplant recipients’ cases at SGH became more complicated, having more comorbidities and/or higher immunological risks. At the same time, advancements in surgical techniques and technology were being explored at transplant centres elsewhere. One area of concern was the morbidity from traditional open donor nephrectomy. The flank incision caused significant trauma to the thoracoabdominal wall with potential complications like pleural injury and long-term wound issues (pseudo-hernia, hypoesthesia and chronic pain). A relatively long convalescence was required for an otherwise healthy donor.

Advances in surgical techniques

The turning point in donor nephrectomy began with the first laparoscopic nephrectomy for a renal tumour performed by Ralph V Clayman at Washington University in St Louis in the United States in 1991. ¹⁸ Subsequent reports on the benefits of this approach, including less wound pain, improved cosmesis and rapid recovery times compared to open nephrectomy, led to the first laparoscopic living donor nephrectomy being performed by Louis Kavoussi and Lloyd Ratner at the Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA, on 8 February 1995. ¹⁹

In 1988, urology became a recognised specialty in Singapore, and Prof Foo Keong Tatt, who is widely recognised locally as the father of urology, was naturally appointed as head of the newly established Department of Urology in SGH. Renal transplant surgery became entrenched as a urological domain, as it was in Europe, and Prof Foo was subsequently appointed as head of the MOH renal transplant team in 1990.

He was succeeded by Prof Li Man Kay in 2001, with Prof Christopher Cheng as deputy head. This was the era when laparoscopy was booming in urology, and thus the duo embarked on efforts to introduce laparoscopic donor nephrectomy. As the norm, when learning new skills, practice began with performing nephrectomies on animal models. As a prelude to donor nephrectomy, the team performed the first hand-assisted laparoscopic (HAL) nephrectomy under the mentorship of Dr David Albala from Loyola University Medical Center in Chicago, Illinois, USA, on September 11, 2001. Unfortunately, the most memorable part of that day to the surgeons was watching horrific events unfold before their eyes on television in the operating theatre after performing the surgery.

Having gained experience performing HAL nephrectomy, the team then proceeded to perform the first HAL donor nephrectomy, again under the mentorship of an expert, Dr Michael Stifelman from NYU Medical Center in the United States in March 2002. From then on, HAL donor nephrectomy became the norm at SGH. Following that, the transition to full laparoscopy was made in 2005 and has remained the standard procedure offered to the majority of living kidney donors today. In 2009, a 75-year-old woman underwent a laparoscopic donor nephrectomy to become our oldest kidney donor to her daughter.

In deceased kidney procurement, minor changes were made over the years; for example, the switch in organ perfusion solutions from Euro-Collins and University of Wisconsin to histidine-tryptophan-ketoglutarate in 2005 following literature reviews and cost considerations to the multiorgan transplant teams. That year, procurement surgeons also ceased having to transport the kidneys in the back of their own vehicles, as new processes were put in place and organs were couriered to their destinations professionally.

In November 2009, HOTA was amended to remove the donor upper age limit of 60 years. This was meant to increase the deceased kidney donor pool by including donors who might have been considered marginal previously. Kidneys from these extended criteria donors were biopsied before being allocated for transplant. Those deemed of intermediate quality (based on the Remuzzi histological scoring system) ²⁰ were allocated together to a single recipient to increase nephron mass.

This presented uncharted territory to our surgeons. Various approaches have been reported, including bilateral extraperitoneal implants using two Gibson incisions and vertical midline transperitoneal implants, in the earlier days. In 1998, Douglas Masson and Thomas Hefty from Virginia Mason Medical Center in Seattle, Washington, USA, described a new technique – essentially extending the usual Gibson incision and placing both kidneys in the same iliac fossa, one superiorly to the other. ²¹ This decreased the operative time and left the other iliac fossa untouched for future transplants. Using this technique, Prof Cheng and Dr Tan Yeh Hong performed the first dual kidney transplantation in Singapore in December 2009.

Maturing into an established programme

Over the years, as the programme matured and workflow became more streamlined, surgical directors were appointed. They ensured oversight over the surgical aspects of the program and worked in tandem with the Medical Director. Dr Sidney Yip succeeded Prof Cheng in 2002, then Dr Ng Lay Guat took over in 2007, followed by Dr Lee Fang Jann in 2013. Dr Lee was the first urologist from SGH to take up a Health Manpower Development Plan fellowship in kidney and pancreas transplantation at Oxford Transplant Centre in the United Kingdom.

My predecessors laid the groundwork and paved the way for transplant to grow as an important subspecialty within urology. Inspired by them, I became the first locally trained female urologist to veer from tradition, pursuing a kidney and pancreas transplant fellowship at Cleveland Clinic and taking over the directorship from my mentor in 2017. Since then, I have started a dedicated urotransplant clinic, striving to provide more holistic surgical care throughout a kidney patient’s transplant journey. This allows me to see waitlist patients and ensure they have no active surgical issues precluding them from transplant when they get called up for a kidney, evaluate potential living kidney transplant donors and recipients, as well as manage kidney donors and transplant recipients post-operatively, some of whom may go on to develop urological malignancies, stones or voiding issues.

In reality, kidney transplant surgery has not changed radically since the early days. The introduction of laparoscopy for donor nephrectomy was the highlight of transplant surgical landmarks. Other techniques described in laparoscopic donor nephrectomy were essentially variations on a theme – retroperitoneal laparoscopy, single-site laparoscopy and natural orifice transluminal endoscopic surgery (NOTES), to name a few.

In this day of minimally invasive surgery, one cannot fail to mention robotic kidney transplant and donor nephrectomy, already touted as the standard of care at some transplant centres. Urologists are very familiar and comfortable with robotic surgery, using it routinely for prostatectomies and partial nephrectomies. In countries where kidney transplants were mainly performed by vascular surgeons, this presented a way for urologists to regain a foothold in transplant. There were doubts in my mind as to the advantage of robotic surgery in this instance, so I embarked on training, performing robotic transplant in pigs, to decide whether the hype was true. The main advantage is decreasing wound infection rates in very obese transplant recipients – a problem we face infrequently, compared to our Caucasian counterparts. There are still issues to overcome, mainly a prolonged ischaemia time and operative time (in most hands), and of course, prohibitive costs, including specialised tools and resources. Till then, I foresee laparoscopic donor nephrectomy and traditional open–kidney transplant techniques remaining at the forefront for some time.

Conclusion

I started this piece by quoting from Murray’s Nobel prize lecture, and will end with more of the same. He describes the moments before performing the first living kidney transplant: ‘The only remaining problem was the ethical decision concerning the removal of a healthy organ from a normal person for the benefit of someone else. For the first time in medical history a normal healthy person was to be subjected to a major surgical operation not for his own benefit.’ ²

His thoughts sum up the most essential part of transplant surgery – not the surgical technique, rather the drive to adhere to transplantation principles and ethics, ensuring that the patient’s safety is at the forefront when he or she is giving or receiving the ‘gift of life’.