Abstract

Objectives: In this study, we analyzed the results of the first 100 kidney transplants from related donors performed at the Republican Research Center of Emergency Medicine in Uzbekistan.
Materials and Methods: This study included 100 patients who underwent kidney transplant from a living donor at the Republican Research Center of Emergency Medicine from March 2018 to January 2021.
Results: Immediate graft function was noted in 84 cases (84%) and delayed graft function in 16 cases (16%). Delayed graft function occurred mainly when multiple vessels were present in a donor kidney (35.5%) compared with the presence of a single renal artery and vein (12.1%). The delayed graft function was influenced by the average duration of warm ischemia (80.26 ± 38.35 min with multiple arteries and 50.44 ± 14.44 min with a single renal artery and vein; P = .001). There were 3 cases (3%) of acute cellular rejection, which was successfully treated with pulse therapy and methylprednisolone; there was also 1 case (1%) of hyperacute rejection, which resulted in graft removal. Complications in the form of ureteral stenosis were noted in 2 cases (2%) and ureteral necrosis with anastomotic insufficiency in 1 case (1%). Two recipients (2%) underwent renal graft nephrectomy. In our short-term study, 1-year survival rate for kidney transplant patients was 93%, with graft survival rate of 91%.
Conclusions: Delayed graft function developed when duration of warm ischemia was increased, which was influenced by the number of vessels in the donor kidney. This is an important prognostic factor for acute rejection development. The risk of vascular complications increases due to postoperative hemodialysis trough, with development of delayed graft function. Recipient deaths during the first year after kidney transplant were mainly from pulmonary embolism, infection, and sepsis as a result of immuno-suppression, hypovolemic shock, and acute ischemic stroke.

Key words : Complications, Delayed graft function, Renal transplant

Introduction

Kidney transplantation (KT) was first successfully performed between twin brothers in 1954 by Joseph Murray.¹ Alternative methods of replacement therapy for chronic renal failure (CRF), when compared with KT, have lower rates with regard to patient quality of life and duration of life.² Progress in the field of transplant has allowed this type of renal therapy to become routine and is now defined as the “gold standard” in the treatment of patients with CRF compared with other methods of substitution therapy.³ Presently, graft survival rate is 95% at 5 years. Graft survival rate at year 1 has also greatly increased to 93.4% with deceased donor KT and to 97.2% with living donor KT.⁴ Improvements in KT are possible due to improvements in immunosuppression protocols.^5-7 However, there are other factors to consider, including surgical complications (urological, vascular, bleeding and hematomas, lymphocele), which have frequencies that range from 15% to 17%,⁸ and nonsurgical complications, such as delayed graft function (DGF).⁹

In this study, we analyzed the results of the first 100 KTs from related donors performed at the Republican Research Center of Emergency Medicine in Uzbekistan.

Materials and Methods

From March 2018 to January 2021, 100 KTs were performed at the Republican Research Center of Emergency Medicine (72 men and 28 women). Complications leading to transplant included chronic glomerulonephritis in 93 patients (93%) with CRF, polycystic kidney disease in 4 patients (4%), pyelonephritis of a single kidney in 1 patient (1%), type 2 diabetes mellitus in 1 patient (1%), and anomaly of the urinary tract in 1 patient (1%). Recipient age varied from 13 to 59 years, with average age of 31.55 ± 9.67 years (95% CI, 29.57-33.53).

All KTs were performed from closely related living donors. There were 45 male donors (45%) and 55 female donors (55%), with age range from 19 to 64 years (mean age of 41.44 ± 10.38; 95% CI, 39.31-43.56). Brothers and sisters made up 48 donors (48%), parents made up 43 donors (43%), uncles and aunts made up 3 donors (3%), and children made up 4 donors (4%); there was 1 husband and 1 niece who comprised the other donors.

Duration of chronic kidney disease ranged from 2 months to 27 years, with an average duration of 42.61 months (95% CI, 32.51-52.71). Hemodialysis duration ranged from 2 weeks to 7 years, with average duration of 1.1 years (95% CI, 0.8-1.4). Sixty-two patients with CRF (82.7%) had arterial hypertension. Chronic anemia requiring correction was noted in 67 cases (67%), and 28 patients (28%) were hepatitis B or C positive.

All donors and recipients showed similar ABO group compatibility. According to tissue typing for HLA-A, HLA-B, and DR, there were 3 mismatches in 51 cases (51%), 4 mismatches in 21 cases (21%), 2 mismatches in 12 cases (12%), 0 mismatches in 10 cases (10%), 1 discrepancy in 3 cases (3%), 5 discrepancies in 2 cases (2%), and 6 discrepancies in 1 case (1%). The average number of discrepancies was 2.78 ± 1.25 (95% CI, 2.52-3.03). Cross-match studies of recipient-donor pairs showed negative results in 53 pairs (53%) and doubtful results in 47 pairs (47%); average was 10.04 ± 4.4% (95% CI, 9.14-10.94).

All recipients underwent heterotopic KT, with extraperitoneal pararectal donor nephrectomy with a semilunar incision¹⁰ on the right in 26 KTs (26%) and on the left in 74 KTs (74%).

The choice of the nephrectomy side was based on the angio-architecture of the donor kidney: a single artery was present in 77 cases (77%), 2 arteries were present in 19 cases (19%), and 3 and 4 arteries were present in 2 cases (2%) each. For donor kidneys with a single artery, arterial anastomosis was mainly applied to the recipient’s internal iliac artery end-to-end in 34 recipients (34%) and to the external iliac artery end-to-side in 43 recipients (43%); in other cases, the above anastomoses were combined. A single vein of the donor kidney was present in 87 cases (87%), with 2 veins in 12 cases (12%) and 3 veins in 1 case (1%). All veins were anastomosed to the recipient’s external iliac vein in an end-to-side manner. Warm ischemia time depended on the number of anastomoses imposed and ranged from 28 to 184 minutes, with average of 59.99 ± 28.55 minutes (95% CI, 54.14-65.84). Cold ischemia duration ranged from 15 to 90 minutes, with average of 32.99 ± 14.94 minutes (95% CI, 29.92-36.04). Ureterovesical anastomosis with stenting was performed in 92 cases (92%) and without stenting in 8 cases (8%). All patients received a standard triple immunosuppressive therapy protocol consisting of calcineurin inhibitors, mycophenolate mofetil, and prednisolone.

Statistical analyses

For statistical analyses of results, we used the SPSS program (version 23) for the Windows XP operating system. Parametric and nonparametric statistical methods were used. Arithmetic mean, standard error, and 95% confidence interval were calculated, as well as the relative risk (RR). The significance of differences between the indicators was calculated using the Mann-Whitney U test, the Kruskal-Wallis test, and the Kolmogorov-Smirnov test. Results with P < .05 were considered significant.

Results

Immediate graft function was noted in 84 cases (84%), and DGF was noted in 16 cases (16%); DGF mainly occurred in the presence of multiple vessels of the donor kidney (35.5%) compared with when there was a single renal artery and vein (12.1%) (RR = 3.99; 95% CI, 1.41-11.32; P = .007); this finding was influenced by warm ischemia duration (average for multiple arteries of 80.26 ± 38.35 minutes [95% CI. 66.19-94.32] vs average for single artery or vein of 50.44 ± 14.44 minutes [95% CI = 46.89-53.99]; P = .001). In 8 cases (8%) with DGF, hemodialysis was required early posttransplant.

We observed significant differences in graft function according to average duration of hemodialysis before KT: immediate function occurred in patients who had duration of 0.97 years (95% CI, 0.7-1.25); however, delayed function occurred in patients who had duration of 1.64 years (95% CI, 0.68-2.6; P = .036). We did not observe significant differences in graft function with regard to cross-match (P = .681) and number of HLA mismatches (P = .603).

For those with acute cellular rejection of the graft, 3 cases were successfully treated with pulse therapy with methylprednisolone. There was 1 case (1%) of hyperacute rejection, which resulted in graft removal. We found development of rejection to be dependent on HLA mismatches and cross-match results, with average number of mismatches in patients with acute rejection of 3.67 ± 0.58 (95% CI, 2.23-5.10) versus average number in patients without rejection of 2.75 ± 1.26 (95% CI, 2.49-3.01; P = .143). The average number of cross-matches in those with rejection was 10.33 ± 3.79 (95% CI, 0.93-19.74) versus 9.92 ± 4.53 (95% CI, 8.99-10.86) in those without rejection (P = .849). Delayed graft function after KT had a significant effect on the development of acute rejection: 1.3% of patients had rejection with immediate graft function versus 10.5% had rejection with delayed graft function (P = .038). The RR for development of acute rejection with DGF was 9.06 (95% CI, 0.78-105.7). Warm ischemia time did not seem to have an effect on acute graft rejection in the early postoperative period, with mean warm ischemia in the absence of rejection of 59.77 ± 28.32 versus 59.67 ± 40.15 minutes in the presence of rejection (P = .614).

Urological complications in the form of ureteral stenosis were observed in 2 patients (2%), and ureteral necrosis with anastomotic insufficiency was observed in 1 patient (1%). Both patients with ureteral stenosis (Figure 1) underwent reimplantation of the ureter into the bladder; for the patient with ureteral necrosis, because reimplantation was not possible due to a short ureter and the development of infectious complications after urinary leakage, an antegrade nephrostomy was installed. Three patients (3%) presented with a diabetic bladder, epididymitis, and ureterohydronephrosis without ureteral stenosis. Urological complications were mainly observed with ureteral-vesical anastomosis without stenting (50%) versus with stenting (4.5%) (RR = 21.5; 95% CI, 3.84-117.57; P < .001).

Graft artery thrombosis was detected in 1 patient (1%); the patient underwent selective angiography with balloon angioplasty and stenting of the common iliac artery and graft artery. Vein thrombosis of the transplanted kidney and external iliac vein was detected in 1 patient (1%) (Figure 2), which was complicated by pulmonary embolism. Bleeding was noted in 8 patients (8%); the source of bleeding was the small vessels of the hilus of the kidney in 2 cases (2%) and the parenchyma of the kidney in 2 cases (2%). Bleeding from the graft artery due to purulent infection of the postoperative wound was shown 2 cases (1%), and anastomotic leakage of the accessory renal artery and of the ureteral arteries was shown in 1 case each (1%). Vascular complications were mainly observed after KT of donor with multiple vessels (19.4%) compared with KT of donors with a single artery and vein (12.1%; P = .332). The RR for the development of vascular complications in multiple vessels of the donor kidney was 1.74 (95% CI, 0.55-5.54). Delayed graft function and postoperative hemodialysis were associated with development of vascular complications, with 31.6% of cases with DGF developing vascular complications and 10.3% with immediate function developing vascular complications (RR = 4.04; 95% CI, 1.2-13.6; P = .018). After postoperative hemodialysis, vascular complications were observed in 62.5% of recipients, whereas only 10.1% without hemodialysis had vascular complications (RR = 14.82; 95% CI, 3.03-72.55; P < .001).

In 13 recipients (13%), purulent-infectious processes were observed, with 9 patients (9.3%) developing wound infections (Figure 3). Among the remaining recipients, 4 (4%) had pneumonia, 1 (1%) had bacterial endocarditis, and 2 (2%) developed sepsis.

Lymphorrhea and lymphocele were noted in 8 patients (8%) (Figure 4); the 2 cases with lymphocele underwent puncture with drainage.

Six patients (6%) had the phenomenon of drug dyspepsia, with exacerbation of chronic hepatitis and nephrotoxicity associated with tacrolimus administration. There was a persistent increase in glucose levels while taking the standard immunosuppression regimen in 12 patients (12%).

Two recipients (2%) underwent renal graft nephrectomy. Indications for nephrectomy were hyperacute graft rejection and bleeding from the renal artery in 1 patient each. In 7 recipients (7%), loss of the transplanted kidney was associated with death of the patient. Causes of death included 2 patients (2%) with pulmonary embolism, 2 patients (2%) with infection and sepsis as a result of immunosuppression, 2 patients (2%) with hypovolemic shock, and 1 patient (1%) with acute ischemic stroke.

In our short-term study, the 1-year survival rate for KT recipients was 93% and the graft survival rate was 91%.

Discussion

According to the Global Observatory on Donation and Transplantation, 95 479 KTs were performed worldwide in 2018, which is 6% more than in 2017; 36% of KT procedures were from living donors.¹¹ The greatest activity among regions is in the United States, where 22 393 KTs were performed in 2018, with an increase of 6.5% compared with 2017; of these, 29.2% were from living donors with an upward trend compared with the previous year.¹² According to the register of the Russian Transplant Society, the KT rate in 2019 was 10.0 per 1 million population, which is more than in previous years, reaching a level of 1473 transplants per year. The average frequency of using living kidney donations was 12.4% of total KTs (versus 14.7% in 2018).¹³

In Uzbekistan, transplant procedures developed in 4 stages.¹⁴ Stage I (1972-1991, USSR period) followed the law on organ and tissue transplantation from 1970. The first KT (from a living donor) in Uzbekistan was conducted in September 1972 by Academician Uktam Aripov. In stage II (1991-1998), there was a break in the field of transplantation due to legal limitations. Stage III (1998-2017) followed an order from the Ministry of Health of the Republic of Uzbekistan on the provision of transplant assistance (with 48 KTs performed from living related donors). During stage IV (2017 to present), a Resolution of the Cabinet of Ministers of the Republic of Uzbekistan No. 859 in October 2017 allowed the “temporary regulation on the procedure for closely related kidney and (or) liver lobe transplantation.”

During this short period from November 2017 to January 2020, 398 KTs from related living donors were performed in Uzbekistan. As of October 2020, with an estimated 3467 patients in the Republic of Uzbekistan on programmed hemodialysis, there are 1148 patients in need of KT. The number of KTs per year remains low at 11.6%.

Our results of the first 100 KTs performed in the Republican Research Center of Emergency Medicine are comparable with the literature. For example, DGF has been shown to occur in 5% to 50% of recipients.¹⁵ Another source showed the rate of DGF after living donor KT to range from 4% to 10%, with occurrence after deceased donor KT of 20% to 50%.¹⁶ We found that the risk of DGF with multiple vessels was significantly (P = .007) increased by 3.99 times than with a donor having a single artery and vein. This is due to longer warm ischemia time, with average duration of warm ischemia with multiple arteries of 80.26 minutes versus 50.44 minutes with a single renal artery and vein (P = .001). Patient stay on hemodialysis also significantly (P = .036) affected development of DGF. Our results suggested the possibility of predicting DGF based on the presence of multiple vessels of the donor kidney, longer warm ischemia time, and prolonged stay of recipient on hemodialysis.

In the early 2000s. the incidence of acute rejection reached about 50%, whereas now it ranges from 12% to 17%.¹⁷ The rate of acute rejection during the first year post-KT is about 7.9% and is lower with living donor KT than with deceased donor KT procedures. This may be because of better selection of a donor kidney and shorter ischemia time.¹⁸ In addition to the duration of ischemia, we found that DGF had a significant effect (P = .038) on development of acute rejection in the early post-KT period (RR = 9.06), which is an important prognostic sign.

The incidence of urological complications after KT in early studies (1970-1990) ranged from 4.2% to 14.1%; in later studies (1990-2000), the incidence ranged from 3.7% to 6.0%. The main urological complications are failure of the newly formed anastomosis (1.5%-6%), obstructive uropathy (0.9%-7.5%), necrosis and stricture of the graft ureter (3%-12.6%), development of vesicoureteral reflux in KT (5%-20%), and recurrent urinary infection (5%-10%).¹⁹ We found urological complications to be dependent on the stenting of the ureteral-vesicular anastomosis. Urological complications during the imposition of a ureteral-vesical anastomosis without stenting were significantly higher, reaching up to 21.5 times versus with stenting (P < .001).

Arterial and venous thrombosis rate can range from 0.5% to 8% and arterial stenosis from 2% to 12% and can even occur in up to 23% of cases.²⁰ We found that the RR of vascular complications in the presence of multiple vessels of the donor kidney was 1.74 (P = .332), whereas DGF and postoperative hemodialysis increased vascular complications by 4.04 (P = .018) and 14.82 (P < .001) times.

Wound infections after KT can occur in 2% to 25% of recipients²¹ and more often develop within the first 3 weeks posttransplant; these are associated with technical complications or with recipient factors such as obesity and diabetes mellitus.²² In our study, wound infections occurred in 9.3% of recipients.

The use of calcineurin inhibitors leads to impaired glucose tolerance and may occur in 30% of patients in the absence of a diagnosis of pre- or posttransplant diabetes (a lower frequency is observed in patients taking cyclosporine compared with tacrolimus). In the absence of diabetes before transplant, about 20% of patients have impaired glucose tolerance after DGF and 5% to 10% require hypoglycemic agents or insulin.^23-25 In our study, 12 patients (12%) had persistently increased glucose levels while taking the standard immunosuppression regimen.

Our observations of the first 100 KTs in the Republican Research Center of Emergency Medicine showed that the cause of nephrectomy in the early postoperative period was hyperacute graft rejection (1%) and bleeding from the graft artery (1%) due to purulent infection of the postoperative wound with spread to the graft. Causes of recipient death included pulmonary embolism (2%), infection and sepsis as a result of immunosuppression (2%), hypovolemic shock (2%), and acute ischemic stroke (1%).

Conclusions

We found that the risk of DGF with multiple vessels was significantly higher by 3.99 times (P = .007) than with a single artery and vein of the donor kidney, which was associated with increased warm ischemia duration of the graft. Duration of a stay on hemodialysis in recipients also affected development of DGF (P = .036). The presence of multiple vessels of the donor kidney, prolonged warm ischemia duration, and prolonged stay on hemodialysis could be used to predict DGF. Delayed graft function was also a reliable (P = .038) prognostic factor for acute rejection in the early postoperative period (RR = 9.06). We also found that ureteral-vesical anastomosis without stenting increased the risk of urological complications by 21.5 times (P < .001). Vascular complications developed 4.04 times (P = .018) more often in the presence of DGF and 14.82 times (P < .001) more often during postoperative hemodialysis. Causes of nephrectomy in the early postoperative period may be hyperacute graft rejection (1%) and bleeding from the graft artery (1%) due to purulent infection. Finally, we observed that causes of recipient death in our cohort in the first year after KT were mainly pulmonary embolism, infection and sepsis as a result of immunosuppression, hypovolemic shock, and acute ischemic stroke.

References:

1. Harrison JH, Merrill JP, Murray JE. Renal homotransplantation in identical twins. Surg Forum. 1956;6:432-436.
   CrossRef - PubMed
   
2. Gautier SV. [Immunosuppression in transplantation of solid organs.] OOO Publishing house Triada, Tver; 2011:382.
   CrossRef - PubMed
   
3. Khadjibaev F, Sharipova V, Sultanov P, Anvarov K, Ergashev D, Ruzibakieva M. The first successful kidney transplant to a child with abnormality of urinary tract in Uzbekistan: case report. Exp Clin Transplant. 2020;18(Suppl 1):44-46. doi:10.6002/ect.TOND-TDTD2019.O22
   CrossRef - PubMed
   
4. Wang JH, Skeans MA, Israni AK. Current status of kidney transplant outcomes: dying to survive. Adv Chronic Kidney Dis. 2016;23(5):281-286. doi:10.1053/j.ackd.2016.07.001
   CrossRef - PubMed
   
5. Gautier SV, Shevchenko AO, Tsirulnikova OM, et al. [COVID-19 in solid organ transplant recipients: initial report from national multicenter observational study «ROKKOR-recipient».] Russian J Transplant Artificial Organs. 2020;22(3):8-17. doi:10.15825/1995-1191-2020-3-8-17
   CrossRef - PubMed
   
6. Bagnenko SF, Reznik ON. [Key issues of the development of transplantation and the objectives of higher medical education.] Transplantologiya. Russian J Transplant. 2017;9(3):192-210. Doi:10.23873/2074-0506-2017-9-3-192-210.
   CrossRef - PubMed
   
7. Ulyankina IV, Reznik ON, Moysyuk YG. [The use of everolimus in kidney transplantation from expanded criteria donors.] Russian J Transplant Artificial Organs. 2014;11(4):103-109.
   CrossRef - PubMed
8. Reyna-Sepulveda F, Ponce-Escobedo A, Guevara-Charles A, et al. Outcomes and surgical complications in kidney transplantation. Int J Organ Transplant Med. 2017;8(2):78-84.
   CrossRef - PubMed
   
9. Khadjibaev FA, Sharipova VK, Sultanov PK. [Analysis of complications after related kidney transplantation: a single center experience.] Transplantology. 2021;13(1):63-73. doi:10.23873/2074-0506-2021-13-1-63-73.
   CrossRef - PubMed
   
10. Haberal M, Kirnap M, Akdur A. The new crescentic incision: a good option for donor nephrectomy. Transplantation. 2018;102:S500. doi:10.1097/01.tp.0000543321.90947.c3
    CrossRef - PubMed
    
11. International Report on Organ Donation and Transplantation Activities. Executive Summary; 2018. http://www.transplant-observatory.org/global-report-2018
    CrossRef - PubMed
    
12. USRDS. 2020 Annual Data Report. November 9, 2020:23. https://adr.usrds.org/2020/end-stage-renal-disease/6-transplantation
    CrossRef - PubMed
    
13. Gautier SV, Khomyakov SM. [Organ donation and transplantation in the Russian Federation in 2019. 12th report from the Registry of the Russian Transplant Society.] Russian J Transplant Artificial Organs. 2020;22(2):8-34. doi:10.15825/1995-1191-2020-2-8-34
    CrossRef - PubMed
    
14. Khadjibaev A, Khadjibaev F, Anvarov K, Sultanov P. Organ donation in Uzbekistan: achievements and prospects for further development. Exp Clin Transplant. 2020;18(Suppl 2):54-57. doi:10.6002/ect.rlgnsymp2020.L8
    CrossRef - PubMed
    
15. Chen R, Wang H, Song L, et al. Predictors and one-year outcomes of patients with delayed graft function after deceased donor kidney transplantation. BMC Nephrol. 2020;21(1):526. doi:10.1186/s12882-020-02181-1
    CrossRef - PubMed
    
16. Wu WK, Famure O, Li Y, Kim SJ. Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation. Kidney Int. 2015;88(4):851-858. doi:10.1038/ki.2015.190
    CrossRef - PubMed
    
17. Shmarina NV, Storozhev RV, Rzhevskaya ON, Zagorodnikova NV, Pinchuk AV. Acute rejection early after kidney transplantation. Transplantology. 2012;(1-2):15-19.
    CrossRef - PubMed
    
18. Naik RH, Shawar SH. Renal transplantation rejection. StatPearls. January 2020. https://www.ncbi.nlm.nih.gov/books/NBK553074/.
    CrossRef - PubMed
    
19. Saydulaev DA, Miloserdov IA, Gautier SV. [Prevention and surgical treatment of urological complications in kidney transplant recipient.] Russian J Transplant Artificial Organs. 2019;21(3):166-173.
    CrossRef - PubMed
    
20. Khubutia MS, Pinchuk AV, Shmarina NV, et al. [Vascular complications after kidney transplantation.] Russian J Transplant Artificial Organs. 2013;15(4):31-39. doi:10.15825/1995-1191-2013-4-31-39
    CrossRef - PubMed
    
21. Barkanova ON, Perlin DV, Shepeleva Borisovna Y, Rebrova EV, Ilchenko OV. [Infectious complications of the early postoperative period in patients after kidney transplantation.] Bulletin of the Volgograd State Medical University. 2016;2(58):32-35.
    CrossRef - PubMed
    
22. Siskind E, Huntoon K, Shah K, et al. Partial closure of skin wounds after kidney transplantation decreases the incidence of postoperative wound infections. Int J Angiol. 2012;21(2):85-88. doi:10.1055/s-0032-1315797
    CrossRef - PubMed
    
23. Danovich GM. In: Moisyuk YG [translator ed.]. Kidney Transplantation. Moscow: GEOTAR-Media; 2014:848.
    CrossRef - PubMed
    
24. Zolota A, Miserlis G, Solonaki F, et al. New-onset diabetes after transplantation: comparison between a cyclosporine-based and a tacrolimus-based immunosuppressive regimen. Transplant Proc. 2018;50(10):3386-3391. doi:10.1016/j.transproceed.2018.08.037
    CrossRef - PubMed
    
25. Ruzibakieva MR, Aripova TU, Khadjibaev FA, Sharipova VK, Sadykov ZB, Sultanov PK. [Predictors of post-transplant hyperglycemia in patients with end-stage chronic renal failure after kidney transplantation.] J Theoretic Clin Med. 2019;6:18-21.
    CrossRef - PubMed