Short-term outcome of kidney transplantation from deceased donors with nephrolithiasis

Abstract

Objective

Shortage of kidney allografts is a major barrier to end-stage renal disease patients receiving kidney transplantation, and it is necessary to enlarge the donor pool and find better ways of using available allografts. The global incidence of nephrolithiasis is increasing, nephrolithiasis affects approximately 10% of adults worldwide, and it also affects the kidney donors. However, there is little information about the use of cadaveric kidney allografts with nephrolithiasis. This study aims to evaluate the safety and outcome of kidney transplantation with allografts from the deceased donors with nephrolithiasis.

Methods

A total of 520 deceased donors who was at least 10 years old, and 945 adult recipients with single kidney transplantation at the Department of Kidney Transplantation, the Second Xiangya Hospital from 2016 to 2020 were included in this study. The donors were divided into 2 groups according to nephrolithiasis diagnoses: The donors with nephrolithiasis (D⁺) and the donors without nephrolithiasis (D^-). The recipients were assigned into 3 groups according to their donors and the allografts they received: The allografts from donors without nephrolithiasis (D^-K^-), the allografts without nephrolithiasis from donors with nephrolithiasis (D⁺K^-), and the allografts with nephrolithiasis (D⁺K⁺). The demographic and clinical data of enrolled subjects were retrospectively analyzed. The allograft discard ratio between different donors were analyzed. The one-year survival of allografts and recipients, as well as the allograft function and the complications of kidney transplantation were compared.

Results

Fifty out of 520 donors had nephrolithiasis, and the nephrolithiasis incidence was 9.6%. We recovered 1 040 kidneys, and total discard rate was 4.4% (46/1 040). The D⁺ group had a rate of 7% discard. The donors with kidney discard accounted for 12% in the D⁺ group, and this was higher than that of donors in the D^- group (5.1%, P<0.05). The total incidence of delayed graft function (DGF) was 7.5%, and there were no significant differences in the incidence of DGF in recipients among the D^-K^-, D⁺K^-, and D⁺K⁺ group (7.5% vs 6.5% vs 8.2%, P>0.05). During the one-year follow-up, 8 allografts lost function and 19 recipients died with a functional allograft. Recipients in the D^-K^-, D⁺K^-,and D⁺K⁺ groups also had no significant difference between a one-year allograft and patient survival rate (P>0.05). However, recipients in the D⁺K⁺ group had a higher level of serum creatinine [(139.2±62.46) μmol/L vs (117.19±51.22) μmol/L, P<0.05] and lower estimated glomerular filtration rate [eGFR; (56.67±23.31) mL/(min·1.73 m^-2) vs (66.86±21.90) mL/(min·1.73 m^-2), P<0.05] compared with recipients in the D^-K^- group at 12 months after transplantation. During the first year after transplantation, 4 recipients developed urolithiasis, and recipients who received allografts from the D⁺ group donors had a higher incidence of urolithiasis than those who received allografts from the D^- group donors (2.2% vs 0.2%, P<0.05). There were no significant differences in the incidence of urinary tract infections and ureteral strictures at 1 year between recipients of D⁺ and D^- donors (both P>0.05).

Conclusion

The cadaveric kidney allografts with nephrolithiasis could be safely used for transplantation, and the short-term outcome is acceptable. However, nephrolithiasis in donors may increase the rate of kidney discard, disturb the short-term function of allografts, and increase the risk of urolithiasis in recipients. Further research with a long-term study is needed to verify the long-term outcome of kidney transplantation using cadaveric kidney allografts with nephrolithiasis.

Kidney transplantation is an effective treatment for end-stage renal disease (ESRD). However, an extreme shortage of kidney allografts is a major barrier to ESRD patients receiving kidney transplantation^[1-2]. Therefore, it is necessary to enlarge the donor pool and find better ways of using the available allografts^[3-8]. To date, some donor factors, such as old age and kidney diseases, may limit the use of their kidneys for transplantation. In particular, some diseases, including nephrolithiasis, were originally considered relative contraindication to organ donation^[9]. Unfortunately, the global incidence of nephrolithiasis is increasing, and nephrolithiasis affects approximately 10% of adults worldwide^[10-12], and thus also affects the kidney donors^[13].

Some studies^[13-14] have demonstrated that kidney allografts with nephrolithiasis are satisfactory for living kidney transplantation. However, different centers may have different policies for considering patients with nephrolithiasis as living donors. A recent study^[15] found that 10.2% of transplantation centers declined to consider patients with nephrolithiasis as living donors. There is little information about the use of cadaveric kidney allografts with nephrolithiasis.

The purpose of this study was to evaluate the safety and outcome of kidney transplantation with allografts from deceased donors with nephrolithiasis. We retrospectively analyzed the data from deceased donors and the kidney transplant recipients at the Department of Kidney Transplantation, the Second Xiangya Hospital, Central South University, and we compared the short-term outcomes of kidney transplantation and the complications for recipients.

1. Patients and methods

1.1. Patients and study design

This was a single center, retrospective study of kidney transplantation with cadaveric kidney allografts from donors with nephrolithiasis. The inclusion criteria for this study were as follow: 1) The donors were at least 10 years old, which was determined based on the standard criteria donor guidelines^[16]; 2) the recipients accepted single kidney allografts, not multi-organ or dual kidney transplantation, from these enrolled donors; 3) all of the kidney donations and transplantations were performed at the Department of Kidney Transplantation, the Second Xiangya Hospital, Central South University from 2016 to 2020; and 4) the recipients had complete data during the time period of this study.

The enrolled donors were divided into 2 groups according to nephrolithiasis diagnoses: Donors with nephrolithiasis (D⁺) and donors without nephrolithiasis (D^-). The recipients were assigned into 3 groups according to their donors and the allografts they received: Allografts from donors without nephrolithiasis (D^-K^-), allografts without nephrolithiasis from donors with nephrolithiasis (D⁺K^-), and allografts with nephrolithiasis (D⁺K⁺, Figure 1).

Figure 1. Study design.

The entire process of organ donation and transplantation were adherence to the rules of China Donation after Citizen’s Death and China Organ Transplant Response System, and the Istanbul Declaration, and the study was approved by Ethics Committee of the Second Xiangya Hospital of Central South University (No. LYF2022107).

1.2. Donor nephrolithiasis diagnosis and treatment

The imaging data from donors were reviewed retrospectively, and Doppler ultrasound examination of kidney allografts was performed before organ procurement.

All 62 kidney allografts with nephrolithiasis were treated using ureteroscopic holmium laser lithotripsy ex vivo before transplantation. The ureteroscopic holmium laser lithotripsy ex vivo was carried out as previously described^[17]. Briefly, the kidney allografts were immersed in a sterile, ice-cold saline solution, and the location of nephrolithiasis was determined using Doppler ultrasound. The nephrolithiasis was broken into fragments. The large fragments were removed with a lithotomy forceps, and the small fragments were fall out with ice-cold saline solution. The therapeutic effect of lithotripsy was determined using Doppler ultrasound ex vivo. In all transplantations, a double-J stent was left for 4 weeks. After transplantation, all recipients received prophylactic antibacterial treatment which lasted at least 2 weeks. In addition, the recipients, who received kidney allografts with nephrolithiasis, were treated with potassium sodium hydrogen citrate and sodium bicarbonate for 3 months after transplantation.

1.3. Kidney allograft function evaluation

The allografts were evaluated as previously described^[18]. Briefly, the allograft evaluation methods included clinical data evaluation, perfusion parameter evaluation using hypothermic machine perfusion, and pathological evaluation. For the allografts from donors with serious acute kidney injury, the hypothermic machine perfusion was used, and the allografts were accepted which had a more than 80 mL/min average terminal flow after 2 hours of perfusion^[19-20]. The selective preimplantation biopsy was performed if any of the following conditions was met: The baseline serum creatine was abnormal; the donors were more than 50 years old and died of cardiovascular accident; allografts had an abnormal size (less than 9 cm) or thickness of parenchyma; the conclusion of perfusion parameter evaluation was ambiguous^[18]. The Remuzzi classification score was less than 5 for single-kidney transplantation^[3].

1.4. Induction and maintenance of immuno-suppression

All recipients received methylprednisolone pulses (500 mg per day, 3 doses). Among the included recipients, 447 recipients received T-cell depleting antibodies and 360 recipients received IL-2 receptor antagonist. The maintenance immunosuppression was based on tacrolimus, cyclosporin, or sirolimus and combined with mycophenolate mofetil and steroids^{[4-5, 21]}.

1.5. Follow-up and data collection

All recipients in this study had at least one year follow-up. All recipients were offered a Doppler ultrasound examination once in the first month, once every 2 to 3 months in the first year, and once every 6 months in a long-term follow-up.

Demographic and clinical characteristics of the donors and recipients were collected. Information of allograft and recipient survival, and complications (including ureterostenosis, nephrolithiasis, and ureterostenosis of allografts, and urinary tract infection) were also collected. Delayed graft function (DGF) is defined by the recipient needing dialysis in the first postoperative week^[22]. The estimated glomerular filtration rate (eGFR) was calculated using the modification of diet in renal disease (MDRD) equation^[23].

1.6. Statistical analysis

All data were analyzed using SPSS 22 and GraphPad Prism 7 software. The quantitative data were presented as the mean±standard error of the mean. The quantitative data were analyzed to determine their normal distribution and homogeneity of variance using the Kolmogorov-Smirnov and F tests, respectively. A non-parametric test was used to analyze the quantitative data that did not conform to normal distribution or homogeneity of variance. The Mann-Whitney U test was used to compare data between 2 groups, and Kruskal-Wallis test and Nemenyi test were used to compare data between multiple groups.

The Chi-square test was used to analyze the qualitative data if the following criteria were met: All theoretical frequencies were more than 1; the frequency of theoretical frequencies which were less than 5, was less than 20%. If not, the qualitative data were analyzed using Fisher’s exact test. Because cases of complications after transplantation were rare, and more than 20% of theoretical frequencies were less than 5, we merged the D⁺K^- group and the D⁺K⁺ group, then compared the combined group with D^-K^- group using the Chi-square test or Fisher’s exact test. The survival of allografts and recipients was analyzed using Log-rank test. Statistical significance was set at P<0.05.

2. Results

2.1. Patient characteristics

A total of 520 deceased donors and 945 recipients were included in this study. The demographic and clinical characteristics of donors and recipients in different groups were valued and shown in Table 1 and Table 2. Fifty out of 520 donors had nephrolithiasis, and the nephrolithiasis incidence of donors was about 9.6% (50/520). Among these donors with nephrolithiasis, 36% (18/50) of them were bilateral, and 64% (32/50) of them were unilateral. We recovered 1 040 kidneys, and 6.5% (68/1 040) of the recovered kidneys had nephrolithiasis. It was found that the donors in the D⁺ group were older than those in the D^- group (P<0.05, Table 1).

Table 1.

Characteristics of donors

Groups	n	Age/years	Gender/[No. (%)]			Donor type/[No. (%)]
			Female	Male		DBD‡	DCD§	DBCD¶
P		0.026*	0.715†				0.853†
D-	470	43.11±14.32	85(18.1)	385(81.9)		455(96.8)	13(2.8)	2(0.4)
D+	50	48.90±10.29	8(16.0)	2(84.0)		49(98.0)	1(2.0)	0(0.0)

Groups	Cause of death/[No. (%)]				Terminal serum creatinine/ (μmol·L-1)	Donors with kidney discard/[No. (%)]			Discard kidneys/ [No. (%)]
	Cerebro-vascular disease	Traumatic brain injury	Brain tumor	Others		Bilateral	Unilateral	Nonǁ
D-	231(49.1)	188(40.0)	17(3.6)	34(7.2)	122.57±87.32	15(3.2)	9(1.9)	446(94.9)	39(4.1)
D+	27(54.0)	19(38.0)	2(4.0)	2(4.0)	125.21±103.60	1(2.0)	5(10.0)	44(88.0)	7(7.0)
P	0.811†				0.906*		0.047*		0.187*

*Data were analyzed using the Mann-Whitney U test; †data were analyzed using the Chi-square test; ‡organ donation after brain death; §organ donation after cardiac death; ¶organ donation after brain death plus cardiac death; ǁdonors without kidney discard. D^-: Donors without nephrolithiasis; D⁺: Donors with nephrolithiasis; DBD: Donation after brain death; DCD: Donation after cardiac death; DBCD: Donation after brain death plus cardiac death.

Table 2.

Characteristics of recipients

Groups	n	Age/years	Gender/[No. (%)]			Donor type/[No. (%)]
			Female	Male		DBD§	DCD¶
P		0.602*	0.483†			0.329‡
D-K-	853	39.58±10.01	233(27.3)	620(72.7)		843(98.8)	10(1.2)
D+K-	31	40.77±10.51	9(29.0)	22(71.0)		30(96.8)	1(3.2)
D+K+	61	40.74±8.05	21(34.4)	40(65.6)		60(98.4)	1(1.6)

Groups	Induction therapy/[No. (%)]				Maintenance immunosuppression/[No. (%)]			DGF/[No. (%)]
	T-cell depletion	Non-T cell depletion	Nonǁ		Tacrolimus	Cyclosporin	Sirolimus
P		0.576 †				0.943†		0.955 †
D-K-	408(47.8)	320(37.5)	125(14.7)		801(93.9)	49(5.7)	3(0.4)	64(7.5)
D+K-	12(38.7)	16(51.6)	3(9.7)		30(96.8)	1(3.25)	0(0.0)	2(6.5)
D+K+	27(44.3)	24(39.3)	10(16.4)		57(93.4)	4(6.6)	0(0.0)	5(8.2)

*Data were analyzed using the Kruskal-Wallis test; †Data were analyzed using the Chi-square test; ‡Data were analyzed using Fisher’s exact test; §Organ donation after brain death; ¶Organ donation after cardiac death; ǁTherapy without T-cell or non-T cell depletion antibodies. DGF: Delayed graft function. D^-K^-: Donors without nephrolithiasis. DBD: Donation after brain death; DCD: Donation after cardiac death.

2.2. Allograft discard

In this study, the percentage of donors with unilateral or bilateral recovered kidney discard was 5.8% (30/520). Furthermore, the rate of donors who had unilateral or bilateral kidney discard was higher in the D⁺ group than that in the D^- group (12% vs 5.1%, P<0.05). The total rate of kidney allograft discard was approximately 4.4% (46/1 040). Although there was no statistical difference, it seems that the discard rate of recovered kidneys from the D⁺ group was higher than that from the D^- donor groups (P>0.05, Table 1).

2.3. Outcome and allograft function at one year post-transplantation

All enrolled recipients had at least a one year follow-up after transplantation. Among the recipients, 7.5% (71/945) developed DGF. There were no significant differences in the incidence of DGF in recipients among the D^-K^-, D⁺K^-, and D⁺K⁺ group (all P>0.05, Table 2). In the first year after transplantation, 8 allografts lost function and 19 recipients died with a functional allograft. There were no significant differences in the survival rate of allografts and patients in the recipients among the D^-K^-, D⁺K^-, and D⁺K⁺ groups (both P>0.05, Figure 2).

Figure 2. Pre-transplantation nephrolithiasis in kidney allografts does not affect the one-year survival of allografts and recipients.

A: One-year survival rate of kidney allografts from deceased donors without nephrolithiasis (D^-K^-; n=838), allografts without nephrolithiasis from donors with nephrolithiasis (D⁺K^-; n=29), and allografts with nephrolithiasis from donors with nephrolithiasis (D⁺K^-; n=59) were compared. B: One-year survival rate of recipients transplanted allografts from the D^-K^- (n=846), D⁺K^- (n=30), and D⁺K^- (n=61) donors were compared. Log-rank test for (A) and (B); NS: No statistical difference.

We analyzed allograft function at one year post-transplantation, and it was found that the D⁺K⁺ group had a higher level of serum creatinine [(139.2± 62.46) μmol/L vs (117.19±51.22) μmol/L, P<0.05] and a lower eGFR [(56.67±23.31) mL/(min·1.73 m^-2) vs (66.86±21.90) mL/(min·1.73 m^-2), P<0.05)] than those of the D^-K^- group (Figure 3).

Figure 3. Pre-transplantation nephrolithiasis is a risk for allograft function deterioration 12 months after transplantation.

Level of serum creatinine (A) and estimated glomerular filtration rate (eGFR, B) of recipients’ transplanted allografts from deceased donors without nephrolithiasis (D^-K^-; n=831), allografts without nephrolithiasis from donors with nephrolithiasis (D⁺K^-; n=28), and allografts with nephrolithiasis from donors with nephrolithiasis (D⁺K^-; n=59) were compared. Kruskal-Wallis test and Nemenyi test for (A) and (B); **P<0.01 vs the D^-K^- group.

2.4. Complications

Four recipients developed urolithiasis in allografts during the firstyear after transplantation. Among these recipients, 3 had nephrolith and one developed ureteral calculus. It was found that the recipients who received allografts from the D⁺ group had a higher incidence of urolithiasis than those who received allografts from the D^- group (P=0.041). Forty-two (4.4%) recipients developed a urinary tract infection and 1 recipients developed ureterostenosis without no significant differences among the different recipient groups. (Table 3).

Table 3.

Complications of recipients

Groups	n	Urolithiasis/[No. (%)]	Urinary tract infection/[No. (%)]	Ureterostenosis/[No. (%)]
P		0.041*	0.309†	0.903*
D-	853	2(0.2)	36(4.2)	1(0.1)
D+	92	2(2.2)	6(6.5)	0(0.0)

*Data were analyzed using the Fisher’s exact test. †data were analyzed using the Chi-square test. D^-: Donors without nephrolithiasis; D⁺: Donors with nephrolithiasis.

3. Discussion

This retrospective study demonstrated that the kidney allografts from donors with nephrolithiasis could be safely used for transplantation after pre-transplantation evaluation.

Nephrolithiasis affects about 1 in 10 adults^[10-11]. In line with this data, the nephrolithiasis incidence of donors was 9.6% in this study. Most of the donors with nephrolithiasis were unilateral nephrolithiasis. The percentage of kidney allografts with nephrolithiasis was about 6.5%. In a previous report^[17] from another center in China, this percentage was 3.97%. This may be due to geographical differences. In addition, a systematic review^[13] that analyzed 11 studies about living kidney donors with nephrolithiasis concluded that 8.5% living kidney donors have nephrolithiasis before organ donation.

In this study, the percentage of donors with recovered kidney discard was 7.0% among donors with nephrolithiasis, and it was higher than that of donors without nephrolithiasis. The discard rate of the recovered kidneys from donors with nephrolithiasis was 7.0%, it was higher than that of the recovered kidneys from donors without nephrolithiasis, and no statistical difference exists. In fact, nephrolithiasis is one of the nontraditional risks for chronic kidney disease, and its contribution to chronic kidney disease is increasing^[12].

Many risk factors associate with DGF, for instance, a long cold ischemic time^[24]. Due to the treatment of nephrolithiasis in kidney allografts before transplantation, the cold ischemic time may be prolonged. However, the cadaveric kidney transplantation using allografts with or without nephrolithiasis had comparable cold ischemic time^[17]. In fact, it was reported the lithotripsy could be finished within a short time (e.g. 36 min)^[25]. Compared with other factors, such as organ allocation, this time is insignificant. Then, it seems that the kidney allografts with nephrolithiasis may not be a dominant factor to determine the cold ischemic time of cadaveric kidney transplantation. In line with other research^[17], pre-transplantation nephrolithiasis did not affect the development of DGF in this study.

In the first year post-transplantation, the recipients transplanted with kidney allografts from donors with or without nephrolithiasis had a comparable patient and allograft survival. This observation is in line with the previous study^[17]. It seems that the accepted kidney allografts with nephrolithiasis do not affect the short-term survival of recipients and allografts. However, we found that recipients transplanted with allografts from donors with nephrolithiasis had a higher serum level of creatinine and a lower eGFR than recipients transplanted with allografts from donors without nephrolithiasis. This is contradicting to the previous reports^{[13, 17]}, which concluded the donor’s nephrolithiasis might not disturb allograft function. In fact, nephrolithiasis is one of the risks of kidney deterioration, nephrolithiasis and its urological complications (e.g. urinary infection, obstruction) may impair kidney function^[12]. It was reported that the risk of chronic kidney disease or ESRD may be doubled by nephrolithiasis^[25]. Therefore, it seems that donors with nephrolithiasis may be at risk of allograft function deterioration. However, a long-term study is needed to determine this.

Kidney allografts with pre-transplantation nephrolithiasis may experience some complications, such as urolithiasis recurrence, urinary tract infection, ureterostenosis, and urinary obstruction, after transplantation. The first instance of nephrolithiasis in a transplanted kidney allograft was reported in 1975^[27]. The total incidence of urolithiasis in allografts post-transplantation in this study was 0.4%. This was within the incidence range from 0.17% to 4.4% reported by Henderickx et al^[25]. Furthermore, we found that 2.2% of the recipient who received allograft from donors with nephrolithiasis developed urolithiasis during the first year post-transplantation, which was a significantly greater rate of incidence than for recipients who received allograft from donors without nephrolithiasis. The recurrence of urolithiasis has also been observed by others, who performed kidney transplantations with cadaveric kidney allografts with nephrolithiasis^[17]. This means that using donors with nephrolithiasis is a risk factor for post-transplantation urolithiasis in allografts. There was no difference in the number of urinary tract infections between recipients transplanted with allografts from donors with and without nephrolithiasis. No urinary obstruction was found in recipients during the one-year follow-up. These comparable instances of urinary tract infections and urinary obstruction in different recipients may attribute to the prophylactic antibacterial treatment and the use of double-J stent^[28].

In summary, our results demonstrated that the cadaveric kidney allografts with nephrolithiasis could be safely used for transplantation, and the short-term outcome is acceptable. However, nephrolithiasis in donors may increase the rate of kidney discard, disturb the short-term function of allografts, and increase the risk of urolithiasis in recipients. In addition, the lithotripsy with instruments, which can control the renal pelvic pressure and perfusion flow to an appropriate level, may be useful to prevent allograft injury during lithotripsy ex vivo.Furthermore, further research with a long-term study is needed to verify the long-term outcome of kidney transplantation using cadaveric kidney allografts with nephrolithiasis.

Funding Statement

This work was supported by grants from the Innovative R & D Project of Development and Reform Commission of Hunan Province, China ([2019]875).

Conflict of Interest

All authors declare that they have no conflict of interest to disclose.

AUTHORS’CONTRIBUTIONS

TAN Liang Study design, data analysis, data collection, writing of manuscript; SONG Lei and XIE Yixin Data collection, discussion; PENG Longkai, LAN Gongbin, and ZHANG Hedong Discussion; JIANG Hongyi Discussion, acquisition of funding; XIE Xubiao Study design, reviewing and editing of manuscript drafts, approval of the final draft for submissions. All author have approved the final version of this manuscript.

Note

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2022091217.pdf