Anatomical variants of renal veins: A meta-analysis of prevalence

The main aim of this article is to establish the actual prevalence of renal vein variations (circumaortic renal vein, retroaortic renal vein, double renal vein), and to increase awareness about them. To this purpose, we have performed a meta-analysis of prevalence, using the MetaXL package, We included 105 articles in the final analysis of prevalence, of which 88 contained data about retroaortic renal vein, 84 – about circumaortic renal vein, and 51 - about multiple renal veins. The overall prevalence for retroaortic renal vein was 3% (CI:2.4–3.6%), for circumaortic renal vein − 3.5% (CI:2.8–4.4%), and for multiple renal veins - 16.7% (14.3–19.2%), much higher on the right 16.6 (14.2–19.1%) than on the left side 2.1 (1.3–3.2%). The results were relatively homogenous between studies, with only a minor publication bias overall.

Froriep, 1895 (Satyapal, 1999) 48 28 Gerard, 1921 (Satyapal,1999;Yi,2012) 49  Hovelacque, 1914 (Satyapal 1999) 6 20 Izumiyama, 1997 (Satyapal 1999) 6 Japan Autopsy 266 Jambreau, 1910 (Satyapal 1999) 6  www.nature.com/scientificreports www.nature.com/scientificreports/ one article on similar populations, the reviewers being unable to properly assess the clear separation of the study groups in different articles, the use of venography or low-resolution CT, the study was not performed specifically to assess the presence of venous structures, the data was very scarcely presented, the number of cases was low. A low risk of bias was assessed when the inclusion and exclusion criteria were properly defined, the variants were detected through high-resolution CT, anatomy or surgery, during studies aimed specifically for the detection of venous variants, the number of subjects was high. A moderate risk was assessed in studies with intermediate characteristics.

Quality assessment.
We performed the quality assessment using four scales from the Quality in Prognostic Studies Tool 16 (participants, outcome measurement, confounding, statistical analysis and reporting). For each remained subscale (study participation, prognostic factor measurement, outcome measurement, study confounding, statistical analysis and reporting), we graded each study as low quality (0 points), intermediate quality (1 point) or high quality (2 points). This method was previously used by the authors in meta-analyses of prevalence 16 . statistical analysis. We determined the effect size using a random effects model computed in Microsoft Excel 2016 with the MetaXL add-on version 5.3. For each group and subgroup, we performed a forest plot. For the analysis of publication bias, we used the funnel plot and the LFK index. For the prevalence analysis we performed the double arcsin prevalence transformation, we used a continuity correction of 0.5 and 95% confidence intervals. Forest plots were done using Microsoft Excel 2016 with the MetaXL add-on 5.3. The actual prevalence can be obtained by multiplying with 100 the results from the meta-analysis of prevalence.

Results
search synthesis. During the initial database research, we obtained 2586 (Table 1) articles from which, after deleting duplicates and irrelevant studies we selected 132 to be further scrutinized (128 by the first reviewer, 123 by the second, 119 being common). By analyzing their references, we found another 32 potentially relevant articles that were also downloaded (30 and 32 articles, by reviewer 1 and 2, respectively). From the 164 articles, 105 were included in the final analysis of prevalence, of which 88 contained data about RLRV, 84 -about CLRV, and 51 about multiple RVs. Details about the search synthesis are presented in Fig. 1. We detailed the papers contained in the meta-analysis in Table 2.
Quality and risk of bias. Based on the inclusion criteria, we obtained a total number of 105 studies, of which of a high quality (between 6 and 8 points) were considered 28 articles, of a medium quality (between 3 and 5 points) -39 articles, of a low quality (between 0 and 2 points) -21 articles, and for 17 we could not obtain a full electronic text of the manuscript, and therefore the quality score could not be computed. A low bias was assessed  www.nature.com/scientificreports www.nature.com/scientificreports/ in 19 articles, a moderate bias in 53, and a high bias in 17. The number of studies included for each sub-analysis is presented in the respective subheading.
Retroaortic left renal vein. A total number of 88 studies allowed us to estimate the prevalence of RLRV, containing 47461 subjects, of which 1287 were positive. The overall prevalence for RLRV was 0.030 (CI:0.024-0.036) (Fig. 2). The publication bias was minor, with an LFK index of 1.87. See also Fig. 3 (funnel plot). By comparing the prevalence depending on the method, we found very similar results, with a prevalence of 0.031  www.nature.com/scientificreports www.nature.com/scientificreports/ Circumaortic renal vein. A total number of 84 studies allowed us to estimate the prevalence of CLRV, containing 46256 subjects, of which 980 were positive. The overall prevalence for CLRV was 0.035 (CI:0.028-0.044) (Fig. 4). The publication bias was important, with a high number of studies being to the right of the funnel  www.nature.com/scientificreports www.nature.com/scientificreports/ (Fig. 5), and having an LFK index of 4.24, suggesting major asymmetry. By comparing the prevalence depending on the method, we found for the autopsy group, a prevalence twice as high compared to CT and surgery, namely a prevalence of 0.05 (0.035-0.066) for autopsy, 0.026 (0.018-0.035) for CT, and 0.021 (0.005-0.040) for surgery. Fourteen studies separated the cases based on gender. For men, the overall prevalence was 0.036 (0.024-0.049), while for women −0.027 (0.014-0.042).

Multiple renal veins.
A total number of 51 articles allowed us to estimate the prevalence of double renal veins, containing 12773 subjects. Multiple renal veins were identified in 2241 cases, of which 1762 on the right side (RRV) and 221 on the left side (LRV). Double renal veins were encountered in 1450 cases (1317 on the right and 133 on the left side), and triple renal veins in 247 (170 on the right and 77 on the left). The overall prevalence of multiple renal veins was 0.167 (0.143-0.192) (Fig. 6). The publication bias was minor (Fig. 7), and an LFK Index of −1.04, suggesting minor asymmetry. Forty-two studies had data about multiple left renal veins. The overall prevalence was 0.021 (0.013-0.032) (Fig. 8), and publication bias was absent (LFK Index = 0.67, suggesting no asymmetry). Forty-four studies had data about multiple right renal veins. The overall prevalence was 0.166 (0.142-0.191) (Figs 9 and 10), and publication bias was −0.26, suggesting no asymmetry. The prevalence of double and triple renal veins is presented in Table 3.

Discussions
Our study is the first one to properly assess, using a statistical method, the prevalence of three main anatomical variants of the renal veins, namely RLRV, CLRV and MRVs.
These anatomical variants are important for surgeons, as their presence can alter the surgery protocol, and for clinicians, as they might lead to unforeseen clinical manifestations of various disorders (see Table 4 for details). In kidney donation, the morphology and size of the renal vessels is extremely important, as short vessels could increase the difficulty of vascular anastomosis and increase the warm ischemia time during the intervention 17 .
RRV is usually located anterior or inferior from the right renal artery 18 . RRV has less often an extrahilar origin (77.9%), compared to LRV (82.7%) 18 . It has an average length of 3.2cm 19 . Various studies showed RRV to be more often multiple, compared to the LRV; the main reason postulated for the increased prevalence of double RRV compared to LRV is the complex embryogenesis on the left side, discouraging the retention of additional left-sided renal veins 20 . Our study showed an overall prevalence of 16.7% for multiple renal veins, which were about eight times more frequent on the right compared to the left side. In kidney donors, the left one is preferable to be donated, due to a longer vascular pedicle. However, if the left kidney has a more complex vascular anatomy, www.nature.com/scientificreports www.nature.com/scientificreports/ the right one should be harvested. If the donor has one or both kidneys abnormal, the most normal remains to the donor, and the more abnormal one is given to the recipient 21 . Before donation, a complete imaging characterization of the kidneys and the vasculature should be performed, ideally through CT angiography, which yields data about the anatomy and variations of the renal vessels 21 . Some authors consider double right renal veins are a contraindication for donor nephrectomy, due to a higher risk of graft renal vein thrombosis 22 .
LRV can have either an intra or an extrarenal origin, with two or three main tributaries 17,23 , and is located anterior, or inferior of the renal artery, or it may run obliquely towards the IVC 18,24 . It has an average length of 8.4cm 19 , being much larger compared to the RRV, due to the abdominal topography of the IVC. The scientific literature has shown LRV to be less often double, but to present other variants, such as CLRV or RLRV.
According to Gillot, there are three main types of CLRV: (1) CLRV with partial distal bifidity, in which the retroaortic branch receives the root of the hemiazygos; (2) CLRV with partial proximal bifidity, a more common variant, in which the origin is separated, and the two branches join together in front of the aorta; (3) complete CLRV, in which we have two thick venous trunks that are leaving the hilum, and they remain separated until their ending in the IVC. This type has two subtypes: (a) inferior polar, in which the main vein, the superior one   www.nature.com/scientificreports www.nature.com/scientificreports/ is preaortic, and the inferior polar vein is retroaortic; (b) superior polar, in which the main trunk is horizontal, preaortic; it receives the adrenal and sometimes the gonadal gland. The superior polar vein is retroaortic, and usually has an oblique, inferior course toward the IVC 25 . The actual prevalence of the CLRV depends on the attention with which the LRV is analyzed; if we were to consider all small retroaortic vessels draining into the IVC or LRV, the prevalence can be as high as 16% 26,27 . Other authors only included in the CLRV large, persistent collars, importantly decreasing the overall prevalence 27 . Our study confirmed a high variability regarding the reported prevalence of the CLRV and showed its actual prevalence to be around 3.5%.
RLRV can be classified in: RLRV Type 1, caused by the persistence of the left subsupracardinal anastomosis, the intersupracardinal anastomosis and the left dorsal renal vein, associated with the obliteration of the ventral left renal vein, leading to a retroaortic, orthotopic course for the LRV; RLRV Type 2, caused by the persistence of the subsupracardinal anastomosis on the left side, and of the left supracardinal vein, associated with the obliteration of the intersubcardinal and intersupracardinal anastomoses, leading to the appearance of a single retroaortic left renal vein lying at the L4-L5 level, where it joins the gonadal and ascending lumbar veins 10 ; RLRV type III (CLRV); RLRV Type 4, in which the RLRV joins the left common iliac vein 9 , due to an obliteration of the ventral preaortic limb of the left renal vein 28 . The number of studies separating RLRVs into subtypes was small (five); additionally, some authors only scrutinized the first two subtypes, while other analyzed all four subtypes, and therefore we could not do a proper analysis of the prevalence on subtypes of RLRV.
Besides MRVs, RLRV, and CLRV, some authors described other variants, such as the presence of a plexiform left renal vein, with division after emerging from the renal hilum, followed by a redivision and a distal unification in a single terminal renal vein 29 .
The clinical consequences of renal vein abnormalities have been intensely studied; however, for many of them the scientific proofs are not definite. Their presence is however extremely important in the surgery of the abdomen, where they can be associated with significant complications, or the need to change the surgical approach. The main implications of these abnormalities are presented in Table 4.  www.nature.com/scientificreports www.nature.com/scientificreports/ The most important factor causing heterogeneity of the results regarding the prevalence of these variants is, most likely, represented by a variable number of false negative results, the variants being more easily overlooked when not specifically searched for.
Limitations. Some studies did not specified number of cases, but rather a prevalence in percentage 17 ; our reconstruction of primary data was done strictly arithmetical, by multiplying the total number of subjects with the percentage/100, with rounding to the superior value in the obtained number was above 0.5 and to the inferior value if the obtained number was below 0.5. The definition of various anatomical variants, and their classification, differed from study to study, and often there was no detailed description of the variant; therefore, our interpretation might not be exact (e.g. some studies included CLRV in the RLRV category), some studies included all CLRVs in their analysis while other included only those CLRV with both trunks of increased size, etc. Small retroaortic renal veins can be obscured due to volume averaging or limited resolution of the imaging techniques 30 . Many included studies were not designed specifically for the detection of caval abnormalities; many were retrospective, and included patients that were referred for abdominal or pelvic symptoms/disorders.

Variant
Clinical and surgery-related consequences

CLRV
• Risk of injury during surgery 31,110 . Sometimes, the posterior limb is not acknowledged before surgery and the renal vein seems to be normally looking, case in which the surgeon might injure the posterior limb 27 .
• Changes needed of the standard surgery protocol for renal transplantation, aneurysm resection 31 • See also RLRV RLRV • It may have a high number of lumbar retroperitoneal tributaries, forming complex retroaortic systems, which can be easily injured during surgical dissection 27 • Changes needed of the standard surgery protocol for renal transplantation, aneurysm resection 31 • May have a sharp descending trajectory, joining the left common iliac vein, altering the surgical protocol 28 • The presence of a RLRV or CLRV is associated with a decrease of the infrarenal segment of the IVC, which could be an important consideration when placing a IVC filter, some of them being too long for the short infrarenal IVC segment 30 • RLRV has been associated with renal ectopy. For example, Macchi described a case of RLRV that was draining toward the IVS through two vessels which diverged into an acute angle and emptied independently into the IVC, forming a retroaortic juxtacaval aortic ring 5 .
• Can be a correctable cause for varicocele. Arslan found a significant association between varicocele and RLRV 2 • Pelvic congestion syndrome (dysmenorrhea, lower abdominal pain, varices -vulvar, gluteal, thigh) 3 • Left gonadal reflux in men (lower limb varices, varicocele) 3 • Can mimic a cancer 34 • Fistula between the aorta and RLRV has been reported 111,112 • Can cause Nutcracker syndrome/phenomenon. There are two main forms of the Nutracker phenomenon: anterior NP, in which the LRV is caught in the fork between the abdominal aorta and the superior mesenteric artery, and posterior NP, in which there is a decreased space between the aorta and the spine, compressing the RLRV 113 ; this leads to hematuria due to increased pressure in the LRV, causing congestion of the left kidney and the presence of venous communications 9 .
• Can lead to renal vein hypertension 72 with hematuria. For example, Gibo and Onitsuka described the case of a 13 years old girl who accused macrohematuria and low back pain; during the clinical investigation, it was found to have a RLRV, with compression of the vein between the aorta and the spine, causing an increased pressure gradient between the LRV and the IVC (mean of 6.8 mm Hg) 4 (a value above 3 being indicative for renal vein hypertension).
• Can lead to hematuria. For example, Karaman showed that compression of the RLRV is significantly associated with hematuria (out of 16 patients with compression of the RLRV, 15 patients were in the urological group); moreover, the urologic symptomatology was more frequent in RLRV types II and IV 9 .
• Can cause left flank 52 or low-back pain 4 • Can cause ureteropelvic junction obstruction 52 • Renin sampling from the renal vein 3 ; a false lower renin level can be obtained with the catheter tip in the proximal portion of the left renal vein, due to additional supply from the left gonadal, second lumbar and hemiazygous veins 114 • Increase the intrarenal venous impedance index 103 , potentially causing nephrolithiasis or renal cysts 39

MRVs
• Injury during surgery 31 • Changes needed of the standard surgery protocol for renal transplantation, aneurysm resection 31 Table 4. Main clinical consequences of renal vein variants.