Lymphocele Outcomes After Renal Transplantations Performed by an Experienced Surgeon: Is Meticulously Performed Surgery and Experience Adequate to Prevent Lymphocele?

Background

The most common surgical complications observed after kidney transplantation are lymphocele, urinoma, and hematomas. Lymphocele is a pseudocystic formation filled with lymphatic fluid around the graft in kidney transplant recipients. Its mean incidence rate is 5.2%, but varies from 0.03% to 51%). The diagnosis of lymphocele is usually made by ultrasonography (USG) between the postoperative 2nd week and 6th month. The highest incidence is encountered at the 6th week. However, there is also a case which was reported at 3.7 years after surgery [1–10].

The most important risk factor for postransplant lymphocele (PTL) is the lymphatic injury that occurs during vascular isolation of the iliac vessels. The other known risk factors are advanced age, obesity, urinary tract malformation, autosomal dominant polycystic kidney disease (ADPKD), diabetes mellitus, delayed graft function (DGF), mammalian target of rapamycin (mTOR) inhibitors, diuretic drugs, steroids, acute rejection, renal capsular injury, and donor type [8,10,11].

PTL cases that are asymptomatic are usually diagnosed during routine USG follow-ups. However, symptomatic patients may have pain and tenderness in the right lower quadrant due to compression effect, compression on the urinary bladder and ureter, deep vein thrombosis, ipsilateral extremity edema, infection, and graft loss. In treatment, aspiration and drainage are performed under USG guidance, while laparoscopic or open fenestration is applied in resistant cases [12–14].

Kidney transplantation is a surgical procedure that should be performed by an experienced surgical team. The differences between complications resulting from surgical technique can be minimized by having the same surgeon perform the kidney transplant operations (the primary surgeon who performs the transplantation procedure). The purpose of the present study was to analyze the rate of lymphocele in the kidney transplant operations meticulously performed by the same senior surgeon.

Material and Methods

STUDY DESIGN AND STUDY POPULATION:

The present study included 315 patients who were operated on in our organ transplantation center after July 2013 and followed up in the polyclinic. The approval of local ethics committee was obtained to report the outcomes of our recipients (Gazi Yaşargil Training and Research Hospital, Ethics Commission, Dated 14.07.2023 and numbered 457). USG was performed by a specialist radiologist at least once before discharge in the early postoperative period. Additionally, Doppler USG was performed daily by the transplantation surgeon. After patient discharge, abdominal USG and Doppler USG were performed once weekly in the first month, once biweekly between the 2^nd and 3^rd months, once monthly between the 4^th and 6^th months, and thereafter at least once a year. Patients were retrospectively divided into 2 groups as those with and without lymphocele. Patients who developed lymphocele were classified as those with a size <3 cm, 3–5.9 cm, 6–9.9 cm, and >10 cm. Symptomatic lymphocele (SL) was defined as symptomatic fluid collection around the graft that necessitated an intervention for the graft or patient.

A drainage catheter was applied in patients with symptomatic lymphocele or lymphocele >10 cm by interventional radiology under USG guidance. Patients were re-evaluated by USG after drainage was completed. We removed the drainage catheter if no fluid collection was present. However, the drainage catheter was closed in patients in whom lymphocele continued longer than 2 weeks or when recurrent drainage procedures were needed, and these patients were monitored by USG for 3 days. Laparoscopic fenestration was performed in the cases detected with fluid collection. The cases not detected with fluid collection were monitored with a closed drain for 1 week and the drain was withdrawn if no fluid collection was found by control USG.

The patients who did and did not develope PTL were compared in terms of age at transplantation, sex, the cause of end-stage renal disease (ESRD), the intervention performed for lymphocele, the technique applied for vascular isolation, body mass index (BMI), administered induction and maintenance immunosuppressive treatments, mismatch (MM) count, whether rejection developed, preoperative dialysis method, length of time on dialysis, albumin levels assessed preoperatively and at discharge, albumin/globulin ratio at discharge, donor type, donor operation procedure, side of the transplanted kidney, donor age, length of hospital stay, and levels of de novo donor-specific antigen (de novo DSA; data of only 150 patients were available).

KIDNEY TRANSPLANTATION:

All donor operations were performed by 2 experienced senior surgeons. Laparoscopic and open donor nephrectomy were applied in 165 and 107 cases, respectively. There were 43 cadaveric kidney transplantations. All recipient operations were performed by a senior surgeon who was adequately trained for kidney transplantation. The senior surgeon had 20 years of transplantation experience and performed the transplant procedure during the period between the dates indicated in this study. The retroperitoneal space was entered via a Gibson incision. The abdominal organs were medialized over the psoas muscle without opening the peritoneum. External/common iliac arteries and lymphatic tissue around the vein were dissected and made appropriate for anastomosis. Two separate techniques were applied for this procedure – lymphatic veins crossing the external iliac artery or vein were ligated using 3/0 polyglactin at both ends and cut by Metzenbaum or monopolar electrocautery in the first technique; and lymphatic veins were detached from the vascular structures using the right-angle clamp and dissected after coagulating at a sufficient width using penset and monopolar cautery in the second technique. After completion of donor nephrectomy, cold perfusion was applied using histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin solutions for alive and cadaver kidney donors in the back-table, respectively. In the back-table operation, all lymphatic tissues around the arterial and venous vessels were meticulously dissected and ligated by the senior surgeon who performed the recipient operation. The graft kidney was taken to the recipient operating table and ureteroneocystostomy was performed by making vascular anastomoses using 6/0 polypropylene and the anastomosis between the ureter and urinary bladder using 6/0 polydioxanone suture with Lich-Gregoir technique. Double-J stents were used for ureteroneocystostomy anastomosis. None of the cases required laparotomy. Renal transplantation was performed in the iliac fossa of the contralateral region because of iliac thrombus in 3 cases. A drain was inserted into the posterior of the kidney graft in all cases. In the postoperative period, the drainage catheter was removed when drain output was below 50 mL for 2 consecutive days. In patients without symptomatic lymphocele, the double-j stent was withdrawn on the 21^st postoperative day.

IMMUNOSUPPRESSIVE THERAPY:

A triple immunosuppressive protocol (tacrolimus, mycophenolic acid, and methylprednisolone) was administered in all cases. Anti-thymocyte globulin (ATG) was given as the induction agent at a dose of 2 mg/kg for 3 days in all cases who had a risk factor. No induction agent was used in the cases with mismatch count of 0. In the remaining cases, 20 mg basiliximab was administered as the induction agent on day 0 and day 4. Therapy protocol was changed to everolimus or cyclosporine in patients who developed intolerance to tacrolimus or mycophenolic acid. Methylprednisolone 1000 mg was administered intraoperatively. Methylprednisolone dose was reduced by half every day and 20 mg oral prednisolone was started on the 6^th postoperative day for daily use. The oral prednisolone dosage was gradually reduced to 5 mg a day within the first post-transplant year. Calcineurin inhibitors (tacrolimus or cyclosporine) and mycophenolate sodium (MMF; 1440 mg a day, as 2 divided doses) were used as maintenance immunosuppressants. MMF was used at a dose of 600 mg/m² as 2 divided doses in children.

STATISTICAL ANALYSIS:

All statistical analyses were performed using the IBM SPSS software (IBM SPSS Statistics for Windows, Version 24.0, Armonk, NY: IBM Corp.). Continuous variables are presented as median and interquartile range and categorical variables are presented as counts and percentages. The Kolmogorov-Smirnov test was used to evaluate the distribution normality of the continuous variables. Continuous variables were compared with the t test. ANOVA was used when comparisons were made between more than 1 group or the Mann-Whitney U test, according to the data distribution. Categorical variables were compared with the chi-square or Fisher’s exact tests whenever appropriate. A P value <0.05 was considered as statistically significant.

Results

The study included 315 patients who underwent renal transplantation in our center between August 2013 to January 2023 and were followed up in the polyclinic. Lymphocele was discovered in 82 (26%) patients. An intervention was needed in 16 (5.1%) of these patients. SL was diagnosed at a mean 26.3±16 postoperative days (range, 6–52 days). Only 1 patient was admitted at the 5th postoperative year because of SL causing compression on the ureter and high Cr levels within the first month after an motor vehicle injury that was not encountered in the US images before. Demographic data such as age and sex of both groups were similar (Table 1). Lymphocele cases were mostly asymptomatic, with a size <6 cm (75.6%). However, intervention was needed since 16 (75%) of the patients with a size ≥6 cm who were symptomatic. The reasons for interventions were compression on the ureter and/or high creatine level in all cases. Hypertension was the most common cause of ESRD. No statistically significant difference was found between the groups in terms of all known etiologies, including diabetes mellitus (P=0.153). The comparison of lymphatic vessel control (LVC) with both ligation and coagulation with cautery revealed no superiority between the 2 techniques for prevention of lymphocele. There were 38 (12%) patients with BMI >30. No difference was found between all BMI subgroups regarding formation of lymphocele (Table 2). Everolimus and cyclosporine were not included in the initial therapy protocol for kidney transplantation. However, we also included the patients in whom the tacrolimus drug level was not stable or for whom we had to change the therapy protocol because of early BK virus positivity. No significant difference was found between all induction and maintenance treatments of our study in terms of lymphocele rates. There were 13 (3.9%) patients who received therapy protocols including cyclosporine and everolimus (Table 2).

We detected no impact of receiving dialysis therapy in the preoperative period or dialysis type on lymphocele formation (Table 3). However, the length of time on dialysis in the pre-transplant period was significantly shorter in the lymphocele group (P=0.042). The patients had similar levels of creatine at discharge. The albumin/globulin ratio was not an indicator of preoperative and postoperative albumin levels or probable postoperative inflammation. We detected a lower rate of graft loss in the lymphocele group (P=0.041). De novo DSA monitoring was carried out for 150 patients during the postoperative period in another study [15]. In these patients, the incidence of de novo DSA was not significantly different between groups.

The patients were also evaluated for other complications requiring postoperative surgery. The most common complication was postoperative incisional hernia in 3 cases (0.9%). Subcapsular hematoma, bleeding, renal artery pseudoaneurysm, and ureteroneocystostomy obstruction were observed in 1 patient each.

Discussion

Lymphoceles are the pseudocysts filled with lymphatic fluids that form around the kidneys after kidney transplantation [16]. In the literature, very different rates have been reported related with its incidence resulting from the different definitions. Lymphocele was observed in 82 (26%) patients of our cohort. An intervention was performed in only 16 (5.07%) of those. In the literature, the incidence of SL was reported to be 5.2% [17]. This rate was consistent with our cohort. Although the etiology of lymphocele is unclear, it is considered result from impaired lymphatic flow in the graft or donor. Risk factors other than surgical dissection include use of high-dose corticosteroids, immunosuppressive drugs, cellular rejection, obesity, diabetes mellitus, and PCKD [18–20]. In another recent study, age (50–65 years), PCKD, and need for a drainage catheter were determined to be independent risk factors for kidney transplantations performed by an experienced surgeon or under supervision of this surgeon [21]. In our study, we detected an increased rate of lymphocele due to none of the risk factors mentioned above. However, we could not evaluate the effect of a drainage catheter on the formation of lymphocele since we routinely use drainage catheters in all our patients.

There are studies in the literature that have asserted acute rejection increases the formation of lymphocele through a mechanism similar to inflammation by activating lymphatic angiogenesis [22,23]. Lehner et al found that development of rejection (cellular+humoral) and delayed graft function (DGF) were related with lymphocele formation, but they have detected no relationship between development of de novo DSA and lymphocele formation [24]. We discovered no relationship of DGF and acute rejection with lymphocele formation in our study.

We attempted to develop standardizations to decrease the surgical complications during our experience of transplantation. Therefore, all stages of the transplantation, including meticulous ligation of the lymphatic tissue in the graft after donor nephrectomy and lymphatic dissection of the recipient operation, were performed by the same surgeon. During vascular isolation, the lymphatics were ligated via meticulous coagulation using penset and cautery or polyglactin suture. Dubeaux et al found that meticulous ligation of lymphatics at the back-table stage of donor kidney and implantation significantly (0.6%) reduces the lymphocele rate. Another study found that laparoscopic donor nephrectomy can decrease the frequency of lymphocele. In addition, it has been reported that use of bipolar cautery decreased the formation of lymphocele [25–27]. Serirodoma compared ligation and use of only monopolar cautery for lymphatic dissection and found that lymphocele rates were significantly lower in the ligation group (5.2% vs 11.8, P=0.017) [28]. In our study, we detected a SL rate of 5.07% and this rate reached 26% with addition of the asymptomatic cases. We found no difference between the type of donor operation and performing vascular isolation via coagulation or ligation. This result can be explained by only treating wide coagulation lymphatic vessels using penset and cautery rather than lymphatic dissection using monopolar cautery.

Sayilar et al [29] found a lower serum albumin level in the pretansplant period. However, there was no significant difference between serum albumin levels at time of diagnosis and pre-transplant period in the patients diagnosed with lymphocele. They explained the decreased concentration of serum albumin in the post-transplant period with loss of protein-rich lymphatic fluid. In the same study, preemptive kidney transplantation and dialysis type were not effective in lymphocele formation. Although we found a clinically lower level of serum albumin at time of diagnosis of lymphocele, we found no relationship between pre-transplant and post-transplant levels of serum albumin and formation of lymphocele. We also found no impact of serum albumin/globulin ratio that may be an indicator of inflammation on the formation of lymphocele. No significant difference was present between the types of dialysis in both groups. However, detection of a lower rate of graft loss and shorter length of time on dialysis (it was weakly statistically significant) in the lymphocele group was an unexplainable outcome. Pacovsky found that a serum albumin level that is potentially critical regarding the pathogenesis of post-transplant lymphocele was 44.1 g/L (however, the sensitivity level was only 62%), and they suggested that the essential risk factor for formation of lymphocele was still the skill of the surgeon [30]. We did not observe a significant difference in lymphocele formation when we changed our vascular isolation technique. We also observed that none of the techniques we applied prevented lymphocele formation. This may be due to the lymphatics that we could not control in the retroperitoneal space.

Our study has some limitations. First, there may be unmeasured factors that influenced the association between kidney transplantation and lymphocele formation. Second, our study’s retrospective design, single-center nature, relatively small sample size, and missing de novo DSA data may limit the scope of our results.

Conclusions

Striving to achieve perfection in surgical technique and reducing postoperative complications is the surgeon’s goal. The risk factors reported in the literature related with lymphocele formation were not found to be statistically significant in our study. However, complications, except lymphocele, were observed less frequently, and lymphocele formation were encountered in our cases despite meticulous surgery.