What Disease Conditions could be Considered for Potential Therapeutic Kidney Donations?

The OPTN/UNOS Living Donor Committee, UNOS Policy Department, coined the term “therapeutic organ donor” to describe an individual who has an organ removed as a component of their treatment for a medical problem, and their removed organ is suitable for transplantation into a transplant candidate. The committee suggested that potential therapeutic donors may have conditions, such as renal cell carcinoma (with the tumor removed after recovery and before transplantation), ureteral trauma (a transected ureter), or maple syrup urine disease (which is the most common type of domino liver donor) [1]. Many chronic kidney disease (CKD) patients on a transplant waiting list are eagerly anticipating this new OPTN policy proposal. In this manuscript, we would like to concentrate on the kidney as a therapeutic organ and propose a list of renal conditions associated with “therapeutic donatable kidneys” which include “donatable kidneys that are nephrectomized due to urologic diseases”.

The shortage of donor kidneys is a serious problem in Japan, and this trend has become worse partly because altruistic donations and paired kidney exchange programs are not currently accepted in Japan, while ABO-incompatible living kidney transplantation has increased to 30%. In addition, restored kidney transplantation by “therapeutic kidney donation” was banned by the Japanese government in 2007, with the exception of transplantations conducted as part of clinical trials. This donor shortage crisis prompts dialysis-intolerant patients to seek transplantation and donor kidneys in foreign countries, leading to an increase in transplant tourism. To reverse this situation, the Tokushukai group launched two clinical trials of therapeutic kidney donation (TKD) in 2009, which are still ongoing, to transplant restored kidney allografts in patients without appropriate donors among their family members or who have used all of the possible living donors in their family. Therefore, the Tokushukai group is attempting to save “unrescuable” dialysis patients using restored kidney transplantations conducted as part of clinical trials [2,3]. These restored kidney transplantations include living renal transplantations conducted in clinical studies between family members using restored kidneys with small renal tumors, renal stones, ureteral tumors, ureteral strictures, or renal cysts and a clinical study of living renal transplantations between third parties using restored kidneys (partial resection and renorrhaphy) with a solitary small renal tumor. Therefore, in cases of living related or altruistically donated renal transplantation using therapeutic donatable kidneys, the surgical indication for a therapeutic donor nephrectomy could be elective, while in cases of living unrelated renal transplantations, the surgical indication for a therapeutic donor nephrectomy should be relatively imperative (depending on the decision of an expert urologist regarding whether to perform nephron-sparing surgery or discard the kidney, considering that renal salvage is always a primary goal for the urologist). It is necessary to determine and discuss which conditions could be clinically implicated for potential therapeutic kidney donation (elective or imperative) and transplantation into a transplant candidate. Therefore, in this communication, the relevant literature on “therapeutic kidney donors” was reviewed to identify potential disease conditions and clarify their contextual clues.

The first organ transplant in Japan occurred at Niigata University in 1956 (T. Kusunoki) when a living kidney obtained from a patient with idiopathic renal bleeding was temporarily transplanted to a patient with acute renal failure. In 1964, a living kidney was transplanted into a patient with chronic renal failure at the University of Tokyo, which was the first full-scale transplant intended for permanent grafting [4]. Some empirical experiences with unrelated kidney transplantation have been conducted using therapeutic kidneys that were removed due to kidney diseases, including kidney stones and hydronephrosis; however, most of these sporadic cases were semi-confidentially managed, accepted locally without ethical approval, or not actually reported to the general public. Therefore, only a few people were aware of the data. Mannami et al. reported their clinical experiences using a new source of 42 kidneys, which included eight cases of benign pathologies, eight of small renal cancer, eight cases of ureteral cancer, six cases of aneurysms, four cases of severe nephrotic syndrome, and four cases of ureteral stenosis, that were restored to transplant into “unrescuable” dialysis patient [5]. Kidneys that were removed due to various diseases and used for renal transplantation, according to the Japanese literature, are shown in Table 1. In Australian and Spanish reports, restored kidneys with complex cysts, benign tumors, or complicated ureteric injuries were transplanted after nephrectomy (Table 2) [6,7]. The transplantation of kidneys removed to treat small RCCs has been reported by several investigators and performed in more than 97 patients [8]. Despite differences in the interpretation of the risk categories of tumor transmission by Nalesnik et al. [9] several guidelines for renal transplantation unanimously accept that small renal tumors pose some risk [10,11] and encourage further expansion of the living-donor pool. The renal transplantation procedure is demanding, similar to the living kidney transplantation procedure, and has the advantages of allowing sufficient time for preoperative immunological screening, short ischemic time, and potential immediate renal function; the renal transplantation procedure is also similar to deceased kidney transplantation in terms of providing benefits to unrelated high risk recipients and also expanding the donor pool. The spirit of “Reduce, Reuse, and Recycle” or the “Mottainai campaign” (Prof. Wangari Maathai) should be encouraged to solve the organ shortage crisis by utilizing therapeutic kidneys donated for transplantation. Regarding the discussion about the cancer transmission risk, the perioperative mortality rates for nephrectomy (0.03% of living donor nephrectomies and 0.3-1.7% of RCC nephrectomies) and of transplantation (1.7%) and the transmission risk of small RCCs from the restored kidney (0.015-1%) in clinical settings should be noted [3].

Table 1:Therapeutic donor Kidneystransplanted in Japan

Table 2: Therapeutics donor kidneys retrieved due to urologic disease transplanted in large series

Ex vivo restoration of therapeutic kidney donation is expected to expand the supply of available organs for renal transplantation in the future. However, some problems are still unanswered. Pahernik and colleagues proposed that clinical staging underestimates pathological staging for small RCCs (up to 4 cm) with respect to stage pT3. The rate of multifocality was 2.0%, 5.1%, and 7.05% of cases in the 2, 3, and 4 cm groups, respectively. Advanced tumor stage (pT3) was found in 3.0%, 5.1%, and 12.1%; grade 3 was noted in 7.1%, 9.0% and 14.0%; and metastases at diagnosis were identified in 3.0%, 2.6%, and 6.0% of cases in the 2, 3, and 4 cm groups, respectively [12]. Another study [13] also confirmed similar results and concluded that the aggressive potential of small RCC increases steeply beyond a tumor diameter of 3 cm, suggesting that the threshold for selecting patients for a surveillance strategy should be set well below a tumor size of 3 cm. Smaldone et al. [14] reported a systematic review and pooled analysis of small renal masses under active surveillance (18 retrospective studies comprising 880 patients and 936 SRMs) and revealed that eighteen lesions progressed to metastases with growth rates more than double (0.8 cm/year) those of non-progressors (0.3 cm/year), but these were generally late events (mean time to metastases 40.2 months) [14]. They also discussed one reported case of a 73-year-old male with a 2.4 cm renal mass progressing to bony metastases at 5 months with no increase in tumor size [15]. In consideration of these provocative results, the increased accuracy of diagnosis of frozen section histology performed immediately after tumor removal or biopsy may provide insight into the inherent biology of small renal tumors.

In conclusion, further studies are warranted regarding the following two points: 1) imperative therapeutic kidney donation could include selected cases of small renal cell carcinoma, renal aneurysm, complicated ureter injury, or distal ureteral tumor and 2) elective therapeutic kidney donation may include cases of benign renal tumors (AML), renal stones, renal injury, idiopathic renal bleeding, ureteric stenosis, complex renal cysts. A large-scale national project is necessary to organize transplant surgeons and urologists to work together to recruit therapeutic kidney donations for restored kidney transplantation. This will primarily rescue “dialysis-intolerant” patients who may benefit from renal transplantation. We welcome the therapeutic organ donation policy of the United States and anticipate utilizing living donors with therapeutic kidneys to provide a solution to the worldwide organ shortage problem in the future.