Compensation Capacity of The Living-Related Donor’s Remnant Kidney and Recipient’s Transplanted Kidney

Background: Compensatory renal growth following nephrectomy is common. We try to explore the compensatory capacity of the living-related donor’s remnant kidney and recipient’s transplanted kidney in terms of the glomerular ltration rate (GFR) one month after transplantation. Methods: Clinical data of 94 patients who received living-related kidney transplantation in our hospital between June 2007 and December 2017 were reviewed retrospectively. GFR was calculated by 99mTc-DTPA detection. The GFR compensatory capacity of donor’s remnant and donated kidneys in their new milieus after transplantation was compared. The differential value (D-value) of split renal function was dened as postoperative GFR - preoperative ipsilateral GFR. The compensatory percentage (C-percentage) of split renal function was dened as (postoperative GFR - preoperative ipsilateral GFR)/preoperative ipsilateral GFR. Results: The median D-value of the donor’s remnant kidney increased by 20.8 ml/(min·1.73m 2 )[IQR=8.9-29.6 ml/(min·1.73m 2 )] with a C-percentage of 46.6% (IQR=17.0%-73.0%). The median D-value of the donated kidney increased by 30.6 ml/(min·1.73m 2 )[IQR=19.8-42.3 ml/(min·1.73m 2 )] with a C-percentage of 67.8% (IQR=39.6%-94.7%). Multivariable analysis showed that only split preoperative GFR in the donor was the independent predictor for C-percentage of the split kidney. Conclusions: Renal function could be well preserved and compensated after kidney donation in most donors and recipients in Chinese population. Healthy donors with a good GFR before operation possessed a mighty functional compensation capacity. of the donor’s remnant kidneys was 23.5 ml/(min·1.73 m 2 ) (IQR=15.7-29.4 ml/(min·1.73 m 2 )), and the median C-percentage was 49.5% (IQR=32.2-64.9%), showing no signicant difference as compared with that at one month after surgery. These results showed that the donor’s renal function remained at a safe and stable level one month after donation.


Background
Compensatory growth of the contralateral kidney to promote signi cant restoration of the lost renal function is a common phenomenon after unilateral radical nephrectomy [1,2]. The glomerular ltration rate (GFR) is a generally accepted parameter to evaluate the renal function. Living-donor kidney transplantation (LKT) has been recommended as a safe treatment for patients with end-stage renal failure worldwide by virtue of a short duration of organ ischemia, rapid recovery of the graft, and fewer complications [3]. However, the application of LKT in China is still restricted due to the traditional idea and the insu ciency of the evidence in the renal compensation capacity.
LKT is an optimal model to explore the compensatory capacity of split renal function from the donor kidney in real world, because GFR alteration in a recipient who has progressed to uremia before transplantation can clearly show the compensatory capacity of the donated kidney. So we sought to make a retrospective analysis on GFR changes of the recipient's transplant kidney from his/her liverelated donor and the donor's remnant kidney, and explore the GFR compensation capacity of donor's both kidneys in their new milieus.

Study population
We reviewed all cases (136 pairs) of LKT performed in our center between June 2007 and December 2018. A total of 94 pairs of LKT with integrated information (especially preoperative and post-operative GFR) were enrolled in this study. Written informed consent was obtained from all participants and/or their legal guardian/s. Operations were approved by the Ethics Committee of Ruijin Hospital of Shanghai Jiaotong University School of Medicine, China. This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments (as revised in 2013) or comparable ethical standards. We attested that no organs were procured from prisoners. All living kidneys donated were procured under the supervision of the Regulations of Organ Transplantation of the People's Republic of China, without violating the privacy of donors.
In accordance with the Kidney Disease: Improving Global Outcomes guideline [3] living organ recipients are limited to people who are spouses, lineal blood relatives or collateral blood relatives within three generations of living organ donors. Donor evaluation included the performance status, anatomical parameters by spiral computed tomography angiography, serum creatinine (SCr), GFR, and the psychosocial condition. Each pair of the donor and the recipient underwent blood grouping, HLA typing and lymphocytotoxicity cross-matching test.

Renal function assessment
The glomerular ltration rate (GFR), as a main parameter to evaluate the renal function, was calculated by 99mTc-DTPA detection in the donors and recipients perioperatively. The differential value (D-value) of split renal function was de ned as postoperative GFR -preoperative ipsilateral GFR. The compensatory percentage (C-percentage) of split renal function was de ned as (postoperative GFR -preoperative ipsilateral GFR)/preoperative ipsilateral GFR. Knowing that the SCr remains stable one month after surgery in most scenarios [4], we chosen the GFR at one month after LKT as the primary endpoint.

Statistical analysis
Continuous variables were expressed as median and interquartile range (IQR) and compared using Mann-Whitney test. Categorical variables were compared using the chi-square and Fisher's exact tests.
Association between C-percentage of split renal function and the clinical parameters was evaluated using linear regression analysis. All p values were two-tail and p < 0.05 was considered statistically signi cant. Data were analyzed using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA).

Multivariate analysis of factors affecting the GFR C-percentage
Univariate analysis showed that donors aged ≤50 years and the preoperative GFR of the remnant kidney were signi cantly associated with C-percentage of the remnant kidneys after operation (p= 0.006 and p<0.001), while donors' gender and the side of donation were not signi cantly associated with it (p=0.562 and p=0.870 respectively). Multivariable analysis showed that preoperative GFR of the donors' remnant kidneys was an independent predictor of its remnant GFR compensation capacity after operation. Cpercentage of the donated kidneys was independently associated with preoperative GFR of the donated kidneys (p< 0.001), but not donor's age (p=0.675), gender (p=0.051) or the side of donation (p=0.834).

Discussion
The kidney presents a functional reserve capacity after unilateral nephrectomy [1,2]. Many studies reported that the donor's global renal function decreased immediately after kidney donation [5]. Although most of these studies compared the global GFR of the bilateral kidneys before donation with that of the single kidney preserved after nephrectomy [5], they did not compare the functional change of the same donor's remnant and donated kidney in their new milieus after operation. The renal function of split kidneys from living donors can be monitored perioperatively in real world. In this study, we sought to measure the initial GFR of the split kidney and compare it with the kidney preserved and donated respectively, aiming to explore the potential compensation capacity of the split kidney from living donors.

Time and mechanism of the renal compensation phenomenon
Compensatory renal growth of the remnant kidney starts within hours following nephrectomy and reaches a stable compensatory state in varying periods post-operation. For human living kidney donation, GFR of donors and recipients was compensated and remained stable about one month after operation [6,7]. Gong et al.[6] reported that donor's mean GFR remained stable at (85.2±17.6) ml/(min·1.73 m 2 ), (87.2±15.9) ml/(min·1.73m 2 ), (82.1±14.6) ml/(min·1.73m 2 ) and (83.0±13.7) ml/(min·1.73 m 2 ) 5 days, 3 months, 1 year and more than one year after LKT respectively. Knowing that the GFR reached stability about one month after operation in most related studies [4][5][6][7], we used GFR at one month after operation as the main parameter for analysis.
Compensatory renal growth following nephrectomy is predominantly due to renal cell hypertrophy [1,8]. The mechanisms that sense and respond to renal volumetric reduction which generate renal growth remain elusive. Two main mechanisms have been proposed. One ascribes it to the increased activity of the remnant kidney that leads to hypertrophy, and the other attributes it to the release of kidney speci c factors such as insulin-like growth factor 1, epidermal growth factor and hepatocyte growth factor and pathways such as mammalian target of rapamycin in response to unilateral nephrectomy [1,8].

GFR compensation capacity of the remnant kidney
Several studies have reported on the compensatory capacity of remnant kidneys after nephrectomy [2,4,9]. Chien et al. reported that GFR of donor's remnant kidney compensated from 58.2 ml/(min·1.73m 2 ) to 79.6 ml/(min·1.73m 2 ), with a 36.9% increase in C-percentage [4]. Our nding is consistent with the results from other centers in term of the tendency, indicating an acceptable and reasonable compensation in the remnant kidney. In our study, GFR in the remnant kidney averaged a 46.6% increase, which is better than 36.9% reported by Chien.
We also observed a case with the highest C-percentage in a 43-year-old father who donated the left kidney to his 22-year-old son. GFR of the father's right kidney was 51.3 ml/(min·1.73 m 2 ) before operation and increased to 107.0 ml/(min·1.73 m 2 ) after operation, with a C-percentage of 108.6%, indicating that the remnant kidney of a healthy donor possesses a powerful compensation capacity after donation to meet the physiological needs of the donor.

Impact of donor's age on renal function compensation
Serrano et al. [10] reported that donors in the optimal group were signi cantly younger, the optimal/suboptimal ratio being 56.0±10.4 vs. 60.7±8.7 years(p=0.018). Univariate analysis in our study showed a signi cantly higher GFR C-percentage of the remnant kidneys in younger donors ≤50 years than that in older donors (58.2% vs. 26.6% , p=0.005). The above results showed that the remnant kidneys of younger donors have higher compensation capabilities, which is in line with the natural psychological tendency that the renal function decreases with age in ordinary healthy people. However, it is interesting to nd that there was no signi cant difference in the GFR compensation rate of the donated kidneys in the recipients' bodies between the young and old donor age groups [67.9% (IQR=47.6-93.9%) vs. 67.8% (IQR=36.1-95.0%), p=0.675]. The reason may be that transplanted kidneys are affected by multiple factors in the new milieus of the recipients, such as immunological and hemodynamic factors, all of which may attenuate the impact of age on the grafts.
Preoperative assessment of nadir GFR for the kidney to be donated The donated kidney has to adapt to the new milieu before it can gradually recover its function and compensatorily develop its in ltrating capacity in the recipient's body. Further sub-group analysis of our study showed that among 12 donors with donated GFR < 40 ml/(min·1.73m 2 ) before donation, the median GFR D-value was 30.4 ml/(min·1.73m 2 )(IQR=25.7-37.1ml/(min·1.73 m 2 )) and C percentage was 90.2%(IQR=67. 8-127.4%). In the group with GFR of the donated kidneys ≥40 ml/(min·1.73m 2 ) before donation, the median GFR D-value was 18.2ml/(min·1.73 m 2 )(IQR=6. 8-28.1ml/(min·1.73 m 2 )) and Cpercentage was 62.0% (38.4%-92.7%). This indicates that donated kidneys with a relatively low GFR before operation have an even more powerful compensatory capability because the donated kidney is fully compensated in the body of the recipient.
Currently, it is di cult to de ne the acceptable nadir GFR value of the kidney to be donated before operation. Most transplantation centers recommend ≥40 ml/(min·1.73 m 2 ) as the cutoff value [3,11]. But as the compensation capability of the donated kidney is higher than that of the remnant kidney as shown in our study, donated kidneys with an estimated GFR value <40 ml/(min·1.73 m 2 ) before operation can still be considered as potential candidates for donation. We suggest that the GFR criterion for kidney donation could be selectively reduced to 30 ml/(min·1.73 m 2 ) in potential donors. Of course, the baseline GFR of the remnant kidney should be maintained at a ≥40 ml/(min·1.73 m 2 ) level so as to guarantee that the donor's remnant kidney has a good ltering function after nephrectomy [12].
Our study has some limitations. First, it is of retrospective nature with all data retrieved from a single center, which may bring about tertiary selection bias. In addition, sample is relative small due to the gradual application of LKD in our country. Therefore, further studies are required to focus on the compensatory growth after kidney donation.

Conclusion
The human kidney has a powerful compensation capability. Renal function could be well preserved and compensated after kidney donation in most donors and recipients. Healthy donors with a good GFR before operation possess a mighty functional compensation capacity.