Transcatheter Angiographic Embolization of Percutaneous Nephrolithotomy-Related Bleeding: A Single-Center Experience

Background To evaluate the clinical characteristics and angiographic features of transcatheter angiographic embolization (TAE) in patients with active bleeding after percutaneous nephrolithotomy (PCNL). Methods Between 2009 and 2018, 45 patients who underwent TAE for hemorrhage control after PCNL were reviewed retrospectively. Patient clinical characteristics and angiographic features of TAE were analyzed. Results Of the 3148 patients, 45 (1.4%) patients were treated with TAE after PCNL. The interval from the bleeding episode to TAE was 3 days (1,6). Arterial laceration, arteriovenous fistula, and negative angiographic finding were found in 28 (62.2%), 7 (15.6%), and 10 patients (22.2%). Thirty-five patients (92.1%) achieved primary clinical success. The median-corrected hemoglobin decrease from bleeding episode to TAE was 52 g/L (25.25, 71.00). The median-corrected hemoglobin decrease rate from bleeding episode to TAE was 13.11 g/L·d (5.60, 26.12). The hemoglobin decrease from bleeding episode to TAE was lesser in negative angiographic patients (28.50 (10.75,51.25) g/L VS 53.7 (35.0,73.13) g/L) than in positive angiographic patients (P < 0.05). Conclusions TAE is a safe and effective treatment for post-PCNL bleeding patients. Previous kidney surgery is associated with a higher risk of TAE. Patients with bleeding from multiple negative angiographic findings can be considered for prophylactic embolization.


Introduction
Percutaneous nephrolithotomy (PCNL) is the first line of treatment for large or complex renal stones [1]. Because of the high stone-free rates, it remained the treatment of choice compared to other minimally invasive modalities. Instead, it is used increasingly for the treatment of renal and ureteral stones [2]. However, some potential complications, such as clinically significant bleeding, can occur. A systematic review reported that the transfusion rates after PCNL ranged between 0% and 20%, with an overall rate of 7%, whereas the embolization rates vary from 0.6% to 1.5% [3]. For severe bleeding after PCNL, transcatheter angiographic embolization (TAE) has been recognized as the preferred treatment [4]. Few studies have reported embolization for delayed hemorrhage after PCNL [5][6][7][8]. However, the most suitable timing for performing TAE is still unclear. In addition, few studies have systematically summarized embolization after PCNL.
erefore, this study aimed to evaluate clinical characteristics and angiographic features of TAE in patients with active bleeding after PCNL. Here, we summarize our institutional experience, and provide practitioners a preliminary guidance so that they may best determine which patients could benefit from this treatment approach.

Patients.
Between October 2009 and April 2018, 3148 patients who underwent PCNL at our institution for kidney stones and 45 patients who underwent TAE for hemorrhage control after PCNL were retrospectively analyzed. Ethical approval was obtained for this retrospective analysis, and the requirement for informed consent was waived. PCNL was performed by experienced urologists using the standardized Chinese percutaneous nephrolithotomy technique developed at our institution [9,10]. All surgeons were trained at the same institution. History of kidney surgery includes open kidney surgery and PCNL. Sudden onset bleeding was defined as gross hematuria and/or bloody nephrostomy drainage occurring within 24 h after PCNL, whereas that occurring after 24 hours is considered delayed bleeding. e indications for TAE were renal bleeding not controlled by conservative treatments, such as bed rest, tamponade by clamping the nephrostomy tube, hemostatic drugs, and blood transfusion.
Patient demographics of embolization and total PCNL, interval (days) from the bleeding episode to TAE, bleeding characteristics, angiographic findings, number of embolization, embolic material, hemoglobin levels at TAE, hemoglobin and hematocrit decrease during bleeding episode to TAE, TAE to the first post-TAE day, the first post-TAE day to the third post-TAE day, and the number of units transfused were gathered from the medical records. Hemoglobin levels were corrected for any transfusion between the postoperative bleeding episode and TAE. One unit of concentrated red blood cells or whole blood transfused was defined as the equivalent of 10 g/L hemoglobin lost. Two interventional radiologists reviewed the angiographic findings. Vascular lesions were identified based on the type and location of the segmental artery involved.

Transcatheter Angiographic Embolization.
After routine disinfection in the groin area, local anesthesia was performed with 2% lidocaine. e femoral artery was punctured by Seldinger technique, and a 5-Fr catheter sheath was placed. Abdominal angiography was performed to evaluate for the presence of renal artery bleeding by using a 5-Fr catheter positioned at the renal artery level. Arteriovenous fistulae (AVF) were characterized by early filling of the venous system during angiography. Arterial laceration was defined as the narrowing of the lumen of the renal artery, with contrast medium spillover. Superselective embolization was performed depending on the angiographic findings. e catheter or microcatheter was placed through the renal artery to approach the lesion as closely as possible, and an embolic material was used for occlusion. e embolic materials consisted of gelatin sponge and metallic coils that were selected during the procedure based on the lesion diameter and type of hemorrhage. Angiography was repeated to verify occlusion of the bleeding point. e catheters were subsequently pulled, and the procedure was terminated. Clinical success was defined as clinical and radiographic absence of bleeding and hemodynamic stability. For patients with negative angiography but clinically highly suspected arterial injury, preventive embolization of the artery near the puncture site was performed. Secondary embolization was performed for persistent bleeding after initial embolization.

Statistical Analysis.
All analyses were performed by SPSS software version 24.0. Continuous variables were presented as mean ± standard deviation or median (interquartile range). Statistical analysis was performed with the t-test and Mann-Whitney U test. Categorical variables were presented as frequencies or percentages, and chisquared test was performed. e difference was considered statistically significant if P-value was <0.05 for all analyses.

General Characteristics of TAE.
irty-five patients (92.1%) achieved primary clinical success. A second TAE procedure was required in two patients (4.4%) for uncontrolled persistent bleeding after initial embolization. e first patient underwent a first TAE due to arterial laceration and a second embolization due to bleeding from another renal artery branch. e second patient underwent embolization for arterial laceration and found that there was still bleeding in the same renal artery branch. Prophylactic embolization of the artery near the puncture site was performed in three patients (6.7%) with negative angiography but clinically highly suspected arterial injury; the other seven patients (15.6%) did not undergo embolization due to the negative angiography. e bleeding sites were embolized using gelatin sponge, metallic coils, and combination of metallic coils with gelatin sponge in 7 (15.6%), 3 (6.7%), and 28 patients (62.2%), respectively.

Changes of Hemoglobin and Hematocrit Levels in Patients of TAE.
Changes of hemoglobin and hematocrit levels are summarized in Table 3. e median hematocrit decrease from bleeding episode to TAE, TAE to the first post-TAE day, and the first post-TAE day to the third post-TAE day was 10% (6.55, 16.05), 2.8% (1.45, 4.85), and 1.9% (0.83, 3.45), respectively. e median minimum hemoglobin level before embolization was 89 g/L (72.48, 106). e mean-corrected hemoglobin decrease from bleeding episode to TAE, TAE to the first post-TAE day and the first post-TAE day to the third post-TAE day was 52 g/L (25.25, 71.00), 10 g/ L (−1, 21) and 3.5 g/L (−2.75, 11.00), respectively. e median-corrected hemoglobin decrease rate from bleeding episode to TAE and TAE to the first post-TAE day was 13.11 g/L d (5.60, 26.12) and 6.0 g/L d (−1.5, 10.75), respectively.

Comparison between Negative Angiography and Positive
Angiography. Subgroup analysis was performed to compare patients with negative and positive angiography findings (Table 4). Sex, age, BMI, SSD, history of kidney surgery, and bleeding characteristics were not significantly different between the two groups (P > 0.05). e patients with negative angiography findings had higher minimum hemoglobin level before embolization

Discussion
Compared with the other minimal invasive lithotripsy techniques, PCNL is generally considered as a safe technique offering the highest stone-free rates [11]. However, serious complications still occur following this percutaneous procedure. Severe bleeding requiring transfusion is a relatively rare complication associated with PCNL. Most bleeding complications can be well controlled with conservative treatments [12]. e post-PCNL transfusion rates ranging between 1% and 55% have been documented in recent studies. e use of selective renal artery angiography and embolization has ranged from 0.6% to 1.5% [3,13]. In our study, 45 (1.4%) of 3148 patients underwent TAE following PNL. is rate is in accordance with the literature.
In this study, we found that patients requiring TAE after PCNL had twice hospital stays and hospitalization costs than patients without complications, and it is statistically   caliceal scarring surrounding the kidney may reduce its mobility [15]. erefore, intraoperative manipulation of the nephroscope may produce enough torque to cause lacerations to the kidney with bleeding. Performing PCNL should be more cautious for patients with previous kidney surgery. ere is currently no standard classification for postoperative bleeding from PCNL. Based on the International Study Group of Pancreatic Surgery and Liver Surgery [16,17], early bleeding was defined as post-hemorrhage occurring within the first 24-h postoperatively, whereas >24 h is considered delayed bleeding. Vascular injury during surgical procedures or underlying perioperative coagulopathy may be the main cause of early post-PCNL bleeding. Delay post-PCNL bleeding is typically a surgical complication, with the usual delay from days to weeks [6]. Post-PCNL bleeding is usually caused by pseudoaneurysm, AVF, and arterial laceration in the previously related studies. When renal arterial bleeding does occur, blood from the injured artery can leak freely due to the high pressure, drain into the injured adjacent vein resulting in AVF, or into renal parenchyma or hilar areolar tissue resulting in pseudoaneurysm [5,6,18]. However, in our cases, these life-threatening hemorrhages are usually caused by arterial laceration (28, 62.20%) and AVF (7, 15.60%). e main reason is that our radiologist did not report pseudoaneurysm directly, but attributed it to arterial laceration.
is study evaluated the therapeutic effect of TAE on post-PCNL bleeding. Successful embolization was performed in all 38 patients, including 35 with vascular lesions and three prophylactic embolizations. Primary clinical success was 94.3% (33/35), and only two patients developed second TAE owing to uncontrolled persistent bleeding after initial embolization. With regard to secondary embolization, one patient showed different bleeding sites in the two angiographic results, and another patient showed bleeding at the first embolization site. One patient did not find bleeding site in the two angiographic results, another two patients with clinically highly suspected arterial injury; hence, prophylactic embolization was performed. In most cases, the success rate of embolization is high, but a small number of patients may need secondary embolization because of the poor first embolization effect or undetected bleeding site. For patients with negative first-time  International Journal of Clinical Practice angiography, most of the bleeding was gradually stable, no further embolization was needed, and only one case continued to bleed. No bleeding was found after re-angiography; hence, prophylactic embolization was performed on the artery near the puncture site. We recommend that patients with bleeding from multiple negative angiographic findings can be considered for prophylactic embolization. For urologists, uncontrolled bleeding after PCNL is a stressful complication. e selection of continued conservative treatment or TAE can be difficult. erefore, a clear indication for TAE is very important. Oguz et al. recommended that emergent surgical intervention should be performed if metabolic acidosis and anuria/oliguria accompanied the decrease of hemoglobin [19]. Jinga et al. [20] reported that the variations of hemoglobin, together with the quantity of transfused units, are an indication for TAE. However, these indications lack specific indices and have not been validated. Currently, there are still a lack of strict indications for TAE in post-PCNL bleeding. Hemoglobin decrease is the most common indicator, which is used to assess the severity of bleeding in clinical surgery [21,22]. Li et al. [6] proposed that TAE should be the recommended treatment for delayed post-PCNL hemorrhage in patients with hemodynamic instability and/or corrected hemoglobin decrease of >30 g/L following conservative management. However, relying solely on the hemoglobin decrease to determine the timing of TAE is not adequate. For some patients, hemoglobin decrease may be not obvious, but it occurs in a short time. is situation also requires timely TAE. Hence, we proposed the concept of hemoglobin decrease rate. In our study, we calculated the changes in hemoglobin and hematocrit during bleeding episode to TAE, TAE to the first post-TAE day, and the first post-TAE day to the third post-TAE day, respectively. e decrease of hemoglobin/hematocrit and hemoglobin decrease rate was significantly reduced after TAE therapy, suggesting a good treatment effect. Moreover, we found that some patients still had minimal bleeding after TAE, but most tend to be stable within 1-3 days. Based on these findings, we recommend that hemoglobin decrease of >25 g/L or hemoglobin decrease rate of >5.5 g/L·d following conservative management of bleeding as one of the indications for TAE.
In our study, 10 patients had negative angiographic findings. Choi et al. [8] reported that angiographic findings were not significantly associated with age, sex, and PCNL, and only percutaneous nephrostomy was associated with a higher rate of negative angiographic findings. Our subgroup analysis also shows similar results. However, we found that the decrease of hemoglobin/hematocrit levels in patients with negative angiographic finding was significantly lower than that in patients with positive angiographic finding. Patients with negative angiographic findings also had a lower hemoglobin decrease rate. e minimal bleeding rate required for angiographic detection is 0.5 mL/min. Angiography becomes optimally sensitive when the bleeding rate reaches 1 mL/min, which is equivalent to three units per day [23]. Slow bleeding rate may be one of the reasons of negative angiographic findings. Vasospasm or minor vascular laceration is also an important factor [6]. Vasospasm may occasionally account for a negative result shortly after bleeding [24]. In addition, selective angiography is limited in showing venous bleeding. For the patients with negative angiographic findings, post-PCNL bleeding may be controlled by conservative treatment; hence, embolization may be worth considering. More research is needed to further explore the timing of embolization for these patients. e present study had some limitations. First, it was a single-center retrospective study, which makes obtaining relevant information difficult. Second, our radiologist did not directly report pseudoaneurysm, but attributed it to arterial laceration. Another limitation was this study lacks control and randomization. Multi-center studies with larger samples and longer follow-up periods are needed for further validation. In conclusion, TAE is a safe and effective treatment for patients with post-PCNL bleeding. Previous kidney surgery is associated with a higher risk of TAE. Patients with bleeding from multiple negative angiographic findings can be considered for prophylactic embolization.
Data Availability e data that support the findings of this study are available on request from the corresponding author. e data are not publicly available due to privacy or ethical restrictions.

Disclosure
A preprint has previously been published [25].

Conflicts of Interest
e authors declare no conflicts of interest.

Authors' Contributions
F. Xiao and WJ. Hu contributed to acquisition of data, analysis and interpretation of data, statistical analysis and drafting of the manuscript. QD. Xia and JQ. Zhang performed TAE therapy, analysis, and interpretation of data. F. Xiao and WJ. Hu revised the manuscript for scientific and factual content. Y. Xun and WJ. Hu contributed to study concept and design, analysis and interpretation of data, and drafting of the manuscript. JQ. Zhang supervised the whole study. All authors read and approved the final manuscript.