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Therapeutic kidney donation; Restored kidney transplantation; Small renal mass; Renal cell carcinoma; Organ shortage; Japan

Introduction

Kidney transplantation is universally recognized as the gold-standard treatment for end-stage kidney disease (ESKD). However, Japan faces a profound and persistent shortage of deceased-donor organs. While approximately 15,000 patients currently remain on the transplant waiting list, annual deceased-donor transplant numbers rarely exceed 250. Consequently, waiting periods frequently surpass ten years, resulting in significant mortality among patients awaiting a graft. This stark disparity underscores the urgent necessity for safe, ethically grounded strategies to expand the donor pool.

Therapeutic Kidney Donation (TKD)—defined as the transplantation of kidneys removed for the donor’s necessary medical treatment—offers a viable solution [1]. The concept is not new; it originated in the United States in 1954 when Hume transplanted a kidney removed for carcinoma of the lower ureter [2]. Japan followed shortly thereafter in 1956 at Niigata University, where a kidney removed for idiopathic renal bleeding was successfully transplanted [3].

Despite this established history, the practice faced regulatory suspension in Japan in 2007 due to ethical controversies regarding donor and recipient selection [4]. However, accumulating international evidence confirming oncologic safety prompted a resurgence of interest [5]. A protocol for living renal transplantation with restored kidneys between family members was established in 2009 [6], followed by a study designated for third-party donors [7]. In 2018, the practice received conditional approval from the Japanese government as an "Advanced Medical Technology." This review synthesizes the history, scientific rationale, and early clinical outcomes of TKD, evaluating its potential role in addressing Japan’s organ shortage.

Historical Evolution and Terminology

Early foundations (1950s–1970s)

The proof of concept for utilizing "therapeutic" kidneys was established in the mid-20th century. Following the initial cases by Hume (Boston, 1954) [2] and Kusunoki (Niigata, 1956) [3], subsequent reports in Japan and Australia demonstrated that kidneys removed for various pathologies—including renal artery aneurysms, benign cysts, ureteral diseases, severe nephrotic syndrome and localized tumors—often retained sufficient function for transplantation. These early experiences proved that ex vivo surgical correction could render a diseased kidney viable for a recipient.

Expansion and controversy (1980s–2000s)

In Japan, the practice expanded significantly through the work of Uwajima Tokushukai Hospital, which performed over 42 Restored Kidney Transplants (RKT) [4]. While graft outcomes were promising, the program faced intense scrutiny regarding donor autonomy, informed consent, and oncologic safety. These ethical concerns, combined with a lack of clear regulatory oversight, led to the effective suspension of the practice in 2007, permitting resumption only within the strict confines of approved clinical trials.

Redefining the practice: From RKT to TKD

In 2016, we introduced the term "Therapeutic Kidney Donation (TKD)" to replace RKT [1]. This terminology explicitly clarifies that the nephrectomy is performed primarily for the donor’s medical benefit, rather than for the purpose of donation. This distinction is crucial for aligning the procedure with international ethical standards and providing a transparent framework for clinical research.

Scientific Rationale: Oncologic Safety and Pathology

International evidence of safety

A robust body of literature supports the safety of transplanting kidneys following the complete excision of small renal tumors. Key findings include:

Penn et al. (1995): Reported no tumor recurrence in a major series of 14 cases following ex vivo resection [8].

Buell et al. (2005): Confirmed that T1a tumors (<4 cm) carry an extremely low recurrence risk when surgical margins are negative [9].

Nicol et al. (2008): Demonstrated excellent graft function with no oncologic events in a 43-case series [5].

Yu et al. (2014): Documented 97 cases of donor kidney transplantation after resection of small renal cancer without pathologically confirmed recurrence [10].

Villani (2024) & Drouin (2025): Recently reviewed over 200 combined cases, finding negligible recurrence rates and survival statistics comparable to standard living-donor transplantation [11-12].

Pathological criteria

Based on global data, the current Japanese clinical trial utilizes strict inclusion criteria to ensure recipient safety [7]. To be eligible for TKD, the donor kidney must present with:

Tumor Size: <4 cm (Small Renal Mass).

Pathology: Clear Cell or Papillary Renal Cell Carcinoma (RCC) of low grade.

Margins: Negative surgical margins.

Metastasis: No vascular invasion or evidence of metastasis.

Clinical Outcomes in Japan

Early clinical research (2009–2017)

Following the regulatory reset, two prospective pathways were initiated in 2009: (1) related-donor RKT and (2) third-party donor RKT using kidneys with small renal tumors [6-7].

By 2017, 13 third-party cases had been performed. Long-term follow-up indicated that 7 grafts remained functioning at 5 years, with no reported tumor recurrences [7]. Regarding living-related kidney transplantation, grafts were utilized after partial nephrectomy and restoration in five cases (three ABO-compatible and two ABO-incompatible). The pathologies were identified as renal cell carcinoma in three cases and angiomyolipoma in two. While one recipient died of sudden cardiac arrest 2.5 months post-surgery (unrelated to the procedure), the remaining four recipients—including two who underwent simultaneous bilateral nephrectomy for polycystic kidneys—reported satisfactory quality of life and functioning grafts beyond 5 years [6]. These outcomes demonstrate that high-risk kidneys can be utilized safely under controlled conditions.

Current advanced medical technology trial

In 2018, the Japanese government approved the program as an "Advanced Medical Technology." While the scientific validity is established, the trial currently faces logistical challenges in recruiting third-party donors. However, the existence of this regulatory framework is pivotal for supporting future expansion and potential public insurance coverage.

Discussion: Positioning TKD in transplant medicine

TKD represents a distinct strategy for expanding the donor pool. To understand its value, it must be compared with established donor expansion pathways: Expanded Criteria Donors (ECD), Donation After Circulatory Death (DCD), and Marginal Donors.

TKD vs. Expanded-Criteria Donors (ECD)

ECD kidneys generally originate from older donors (>60 years) or those with significant comorbidities like hypertension. These kidneys often suffer from reduced nephron mass and vascular sclerosis. In contrast, TKD donors are often younger and biologically healthier, undergoing nephrectomy solely for a localized lesion. Once the tumor is excised, the remaining renal parenchyma is often of superior quality compared to an ECD graft. Thus, TKD expands the pool qualitatively, not just quantitatively.

TKD vs. Donation after Circulatory Death (DCD)

The primary limitation of DCD is warm ischemia time, which correlates with high rates of delayed graft function. TKD procedures are elective and planned, similar to living donations. This results in minimal warm ischemia time and immediate graft function. Furthermore, while DCD is culturally and legally limited in Japan, TKD is logistically feasible given the high volume of nephrectomies performed annually.

The "Marginal Donor" context

"Marginal donors" is a heterogeneous category including those with mild dysfunction or anatomical abnormalities. TKD is unique because the pathology (e.g., a small tumor) is localized and surgically correctable. Outcomes for TKD are highly predictable once the lesion is removed, unlike the variable outcomes seen in other marginal donor categories.

Untapped potential

The incidence of small renal masses is rising, with over 10,000 cases treated annually in Japan. While robotic partial nephrectomy is increasing, thousands of radical nephrectomies still occur. Even utilizing a small fraction of these kidneys could significantly impact the waiting list.

Limitations and Future directions

Despite the potential, challenges remain. First, oncologic vigilance is paramount; expert pathology and long-term recipient imaging are non-negotiable. Second, the historical controversy requires that current programs maintain absolute transparency to build public trust. Finally, urologists play a critical role; establishing a referral system where urologists consider the transplant service before performing a radical nephrectomy is essential for program growth [13]. The consensus among clinicians for the selective use of tumor-bearing kidneys justifies formal trials to increase organ availability [14].

Conclusion

Therapeutic Kidney Donation represents a clinically feasible, safe, and ethically grounded approach to the organ shortage crisis. Historical experience and modern clinical trials consistently demonstrate that kidneys removed for therapeutic reasons—specifically those with small renal tumors—can be safely transplanted when strict criteria are met. These grafts exhibit excellent early function and negligible oncologic risk. As Japan continues to refine its regulatory framework through the Advanced Medical Technology trials, TKD stands to become a vital complement to existing donor strategies, effectively turning a medical by-product into a life-saving resource. Strengthening domestic transplant infrastructure, improving oversight of intermediaries, and aligning national practice with global ethical frameworks are essential to reduce reliance on overseas transplantation and protect both Japanese patients and vulnerable donor populations abroad [15]. Based on sporadic reports like those from Yamauchi et al. and Dale et al., it appears that therapeutic kidney donation is becoming a promising and advancing trend—albeit one that is advancing quite selectively [16-17].

Highlights

Concept: Therapeutic Kidney Donation (TKD) utilizes kidneys removed for the donor’s necessary medical treatment, aligning medical necessity with organ donation.

Safety: International evidence confirms negligible tumor recurrence for small renal masses (< 4 cm) when completely excised with negative margins.

Outcomes: Japanese trials (2009–2017) demonstrated excellent graft function and no oncologic events.

Quality: TKD grafts often have minimal ischemic injury and superior nephron mass compared to Expanded Criteria Donors (ECD).

Potential: With over 10,000 small renal masses treated annually in Japan, TKD offers a substantial, underutilized donor pool.

Declarations

Author contributions: Y.O. conceived and designed the study. Y.K. performed the data collection and analysis. Y.O and Y.K. drafted the manuscript. All authors reviewed and approved the final manuscript.

Funding: This research was conducted under the framework of the "Advanced Medical Technology" program approved by the Japanese Ministry of Health, Labour and Welfare. No specific external grant funding was received for the preparation of this manuscript.

Conflict of interest: The authors declare that they have no conflicts of interest regarding the publication of this paper.

Informed consent: Informed consent was obtained from all subjects involved in the clinical studies referenced within this review.

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