EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Living kidney transplant is still a significant portion of all kidney transplants due to organ shortages and offers the best option for patient survival. Living kidney transplant accounts for 28% of all kidney transplants in the United States,¹ whereas it accounts for 90.8% in Turkey.² Donor candidates are relatively healthy compared with the general population because they undergo a detailed health assessment to determine their suitability as kidney donors. Relevant guidelines focus more on assessment of the risk for chronic kidney disease in the donor or prevention of donor-to-recipient infection or malignant cell transmission.³ In previous studies, the lifetime risk of end-stage kidney disease in living kidney donors (LKD) was lower than in the general population but higher than in healthy individuals with similar characteristics. The lifetime risk of for end-stage kidney disease in LKDs is around 1%.⁴

However, there are few studies on whether the risk of developing cancer in the remnant kidney in LKDs is increased. A recent survey from Engels and colleagues provided valuable data on cancer risk and planning for appropriate follow-up care after kidney transplant in LKDs.⁵ The retrospective cohort analysis used transplant and cancer registry data from the United States to identify incident cancer from the period 1995-2017. In a US data source, approximately 85?000 donors from were compared with 47 451 participants from the Adventist Health Study 2 who had baseline cancer screening and absence of contraindications for any organ donation. The study determined that the risk for kidney cancer (adjusted incidence rate ratio, 2.97; 95% CI, 1.58-5.58) increased at 7 years after donation.⁵ This novel determination will significantly affect the paradigm of living kidney transplant regarding complications and follow-up care.

A 75-year-old male patient donated his left kidney to his wife 11 years ago. In his ultrasonography examination, a heterogeneous internal mass lesion measuring 72 × 70 × 75 mm with exophytic extension was detected in the lower pole of the right kidney (Figure 1). We decided to remove the mass because of contrast enhancement in diffusion magnetic resonance imaging (Figure 2) without involving the renal vessels or lymph nodes. Successful partial nephrectomy was performed through a flank approach, even though the tumor size was over 7 cm. A 10% increase was observed in postoperative serum creatinine levels. The histopathology diagnosis was Fuhrman grade 2, T2aNxM0, papillary variant of renal cell carcinoma (RCC). The surgical margin was intact, and lymphovascular invasion was not detected. Written informed consent was obtained from the patient for publication of this case report.

In our case, a partial nephrectomy performed on an LKD who developed RCC in a remnant kidney is presented. In the literature, cases of RCC that were detected in the donor kidney during transplant or cases of RCC that subsequently developed in the transplanted kidney of a recipient are common. However, there have been only 2 cases of LKDs who developed RCC in the remnant kidney, both of which were reported by Gupta and colleagues.⁶ To our knowledge, ours is the third case reported in the literature (Table 1).

Partial nephrectomy is the preferred approach for kidney masses less than 4 cm without distant metastases; if (1) there is no ipsilateral adrenal gland and lymph node involvement, (2) the mass is not in the central localization, and (3) there is no invasion in the renal vein or inferior vena cava, then partial nephrectomy can be preferred in the larger masses.⁷ Partial nephrectomy provides similar oncological outcomes versus radical nephrectomy and reduces the incidence of CKD.⁸

In such a scenario, it may be necessary to perform radical nephrectomy, after which the need for renal replacement therapy may arise. The polar location of the tumor in our patient may have facilitated partial nephrectomy.

Our purpose to present this case was not to simply describe a successful surgical intervention but, rather, to discuss the development of kidney cancer in LKD when considered together with the data of Engels and colleagues.

Being an LKD is not among the classic risk factors for kidney cancer (eg, smoking, obesity, high blood pressure, family history of kidney cancer, workplace exposure, sex, ethnicity, certain medications such as acetaminophen, advanced kidney disease, and genetic diseases such as von Hippel-Lindau syndrome, Birt-Hogg-Dubé syndrome, Cowden syndrome, and tuberous sclerosis complex). In a retrospective analysis, Lowrance and colleagues evaluated 1?190?538 adults for the association between level of kidney function and subsequent cancer risk.9 Participants who did not have a prior diagnosis of cancer and measurement of kidney functions were included from 2000 through 2008. The primary outcome was incident kidney cancer. The secondary outcome was any incident cancer risk. After regression analysis with adjustment confounders, lower estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) was associated with an increased risk of renal cancer (for eGFR = 45-59, adjusted hazard ratio [HR] was 1.39 and 95% CI was 1.22-1.58; for eGFR = 30-44, HR was 1.81 and 95% CI was 1.51-2.17; and for eGFR <30, HR was 2.28 and 95% CI was 1.78-2.92). The investigators reported that reduced eGFR was independently associated with a higher risk of kidney and urothelial cancer but not another type of cancer.9 Therefore, creatinine clearances of LKDs decreased in the long-term after transplant; it is thought that the risk of kidney cancer development may increase if the LKDs are considered included in the patient pool with CKD.

According to mortality data of LKDs from Davis and colleagues, the most common cause of death after kidney donation was malignancy (10.3%). The investigators reviewed the Organ Procurement and Transplant Network database (51?153 donors), which is the most extensive database in the world on living donors from the United States for the period 1988 through 2008. In the same report, the frequency of death due to cardiovascular disease (cerebral hemorrhage, heart attack, aneurysm) was 6.2%.¹⁰ Cancer subtypes are not specified in this report. In another mortality report from Japan, where kidney transplant primarily depends on living donors, the long-term outcome of LKDs was studied, and malignancy was reported as the leading cause of death.¹¹ Stomach cancer was the most common cancer type in the Japanese analysis.

On the other hand, in a retrospective cohort analysis, Lentine and colleagues evaluated the development of cancer in LKDs (4650 LKDs from 1987-2007, vs United States private health insurers) using the information in the Organ Procurement and Transplant Network database. The investigators reported that the overall frequency of nonskin cancer after living kidney donation was lower (rate ratio, 0.74; 95% CI, 0.55-0.99) than in the nondonor control group except prostate cancer (rate ratio 3.80; 95% CI, 1.42-10.2).¹² The median observation period in that study was 2.1 years, suggesting substantive effect of predonation malignancy screening. The short observation period, uncertainties in cancer diagnosis due to private insurance, and the limited number of cases compared with other analyses create difficulties for the interpretation of these results.

Experimental studies have demonstrated the mechanistic relationship between malignancy and the remnant kidney in LKDs. It is thought that glomerular hyperfiltration, increased production of growth factors13 in the remnant kidney, and immunity deficit due to CKD15 after kidney donation cause the cell growth and carcinoma. One of the most demonstrative experimental studies for this association was from Sui and colleagues.¹⁴

In their longitudinal study, Sui and colleagues studied unilaterally nephrectomized (UNX) rats for 10 months. At month 3, month 7, and month 10, rats were euthanized sequentially, and histomorp-hological changes in the remnant kidney were evaluated. At 3 months after nephrectomy, UNX rats demonstrated glomerular hypertrophy but not malignancy. At 7 months after nephrectomy, UNX rats showed the malignant transformation of tubular epithelial cells parallel to diffuse glomerulosclerosis. At 10 months after nephrectomy, UNX rats revealed nests of RCC parallel to global glomerulosclerosis.¹⁴

In contrast, the control group (sham operation) of rats showed standard renal structure during the study period. The protein expression levels of the insulin-like growth factor signaling pathway were measured by Western blot. The protein expression levels of growth-promoting factors were significantly increased in remnant kidneys in the tenth month. They stated that compensatory renal growth associated with abnormal insulin-like growth factor 1 signaling pathway might be crucial for renal carcinogenesis.¹⁵

In conclusion, through these determinations, after the transplant, a process begins that must be closely monitored for both the recipient and the donor. In the relevant guidelines, follow-up recommendations should be included regarding tumor development in the remnant kidney in LKDs after kidney transplant, especially after 7 years.

Volume: 22 Issue: 10 October 2024

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