Horseshoe kidney: Morphologic features, embryologic and genetic etiologies, and surgical implications

The horseshoe kidney (HSK) is the most common congenital abnormality of the upper urinary tract with an incidence of approximately 1 in 500 in the general population. Although individuals with HSK are often asymptomatic, they are at increased risk for neoplasms, infections, ureteropelvic obstruction secondary to lithiasis or vascular compression. Direct injury from trauma is increased in these individuals as is the risk of intraoperative complications secondary to damage involving the typically complex renal or adrenal vascular supply.


| INTRODUCTION
In the general population, the horseshoe kidney (HSK) is a relatively common congenital renal fusion abnormality with an incidence of 1 in 500 people (Tubbs et al., 2016;Schiappacasse et al., 2015;Kirkpatrick & Leslie, 2021).The incidence of HSK is higher in males with a male to female ratio of 2:1 and is associated with chromosomal disorders such as Edward syndrome and Turner syndrome (Cereda & Carey, 2012;Harris et al., 2000;Ranke & Saenger, 2001).However, a recent study (Sagi-Dain et al., 2018) using chromosomal microarray analyses found that the frequency of abnormal results in fetuses with HSK was no different than that seen in the general population.HSK variants have been found to be higher in children as a concomitant presentation in newborns with multiple congenital variants, some of which are not compatible with long-term survival (Harris et al., 2000;Cereda & Carey, 2012;Ranke & Saenger, 2001;Glodny et al., 2009;Scott, 2002;Basso, 2011) (Table 1).
We describe the gross morphology of the HSK, its atypical vascular anatomy, and its structural relations to the suprarenal glands and other components of the urinary system.We then review the literature regarding the embryological and genetic theories pertaining to the development of HSK malformations and discuss surgical implications in patients with HSK, including those with coexisting abdominal aortic aneurysms.We conclude with a brief description of an illustrative case involving an unusual vascular variation.

| Anatomical organization of the HSK
HSK is characterized by fusion at either the superior pole or more commonly the inferior pole of the kidney, creating an isthmus connecting the two sides forming a well-known U-shaped structure.
Fusion at the inferior pole occurs in over 90% of cases of HSK variants (Kirkpatrick & Leslie, 2021;Tubbs et al., 2016).While the isthmus most often consists of parenchymal tissue with its own blood supply, less commonly it consists solely of fibrous tissue or a mixture of renal parenchyma and fibrous tissue (Eisendrath et al., 1925;Kirkpatrick & Leslie, 2021).HSKs are most frequently positioned anterior to the aorta at spinal segments L3-L4, often the result of developmental impedance by the inferior mesenteric artery (IMA) ascent during weeks 6 to 9 of embryological development (Kirkpatrick & Leslie, 2021;Sadler & Langman, 2018).Some reports suggest that 40% of HSKs have an isthmus residing posterior to the IMA (Kirkpatrick & Leslie, 2021;Taghavi et al., 2016).The correlation between embryological etiologies, renal fusion and associated pathologies remains largely unknown.
While the HSK appears to be a single organ, it in fact represents a fusion of two organs, thus it can be divided at the isthmus with proper attention to the vascular relations.In 15% -20% of cases, the isthmus will be composed of primarily fibrous tissue (Kirkpatrick & Leslie, 2021).In the remainder of cases, the division will be through parenchyma with management being similar to that for renal laceration.The ureters descend from the kidney, anterior to the isthmus, and may follow a circuitous course with the potential of kinking or obstruction by renal arteries.

| Embryological and genetic etiologies
Several embryological theories have been advanced to explain HSK development and the differences in clinical presentations in this unique patient population.Two events related to normal renal development may contribute to the development of HSK.First, the formation of each metanephros requires signaling between the ureteric bud and the metanephric mesenchymal blastema between gestational weeks 5 and 11, and this signaling may be disrupted (Sadler & Langman, 2018).Additionally, each metanephros must relocate during development, ascending from the sacral region of the embryo to a space just below the rib cage between gestational weeks 6 to 9, and this migration might be restricted in these cases (Sadler & Langman, 2018).The wide differences in anatomy, histology and renal vasculature seen with HSK variants suggests that it is possible that multiple mechanisms may be responsible for renal fusion across the midline, and that the effects of disturbances of these mechanisms may occur singly, concurrently or in response to one another.
A common theory of HSK development focuses on aberrant cell migration across the sagittal plane resulting in renal fusion.According to Taghavi et al. (2016), tissue migration may occur between weeks 4 and 6 due to close proximity of the two metanephros (Jain & Chen, 2018;Mandell et al., 1996;Mercader et al., 2019).Fukuoka et al. (2019), in a study examining renal ascent, found no defining fascia or adipose tissue to be present between weeks 5-7 of development, further supporting the possibility that close proximity of the two metanephros may result in fusion.
Aberrant cell migration may explain the varying compositions of the HSK isthmus, whether it is made up of predominantly renal parenchyma or fibrous tissue.The isthmus consists of renal parenchyma in 80% to 85% of reported cases (Kirkpatrick & Leslie, 2021;Hohenfellner et al., 1992).It may also be possible that mutations yielding aberrant renal hyperplasia and/or dysplasia in the medial portion of the metanephros may physically decrease the distance between the two metanephros, thereby influencing renal cell migration.
Altered cell signaling from the abdominal aorta may play a role in the medial cell migration of the metanephros (Majos et al., 2018;Sachsamanis et al., 2019;Wymenga et al., 1995;Armon et al., 1998;Saito et al., 2012).Such studies suggest that the abdominal aorta may act as a morphogenetic signaling center during early development, coordinating cell lineage segregation and migration.Therefore, it may be possible that aberrant signaling from the abdominal aorta during the initial ascent of the left and right metanephros may cause divergent cell migration and renal fusion.
In less common cases where the isthmus is composed of predominantly fibrous tissue over renal parenchyma, mechanical fusion from either rotation of the caudal embryo or lateral flexion of the trunk may be a possible etiology (Hohenfellner et al., 1992;Jain & Chen, 2018;Taghavi et al., 2016).In this regard, patients with HSK variants have been found to be three times more likely to have concomitant congenital vertebral anomalies (Mandell et al., 1996).Considering abnormalities associated with the growth of the axial skeleton, the rate of growth of various organs, including the kidney, may be altered and as a result may be at increased risk for compression resulting from a lack of appropriate skeletal support.
The abnormal renal vasculature coinciding with HSK variants prompts questions about whether the medial fusion facilitates or is the consequence of altered vascular supply.There is little research investigating the embryological relationship between renal development and the associated vasculature.However, one study reported evidence that nephrogenesis occurs after the completion of renal ascent, suggesting that the ascending kidney may not need glomerular blood flow (Fukuoka et al., 2019).If this is the case, it is likely that not only is there significant renal differentiation after the metanephros has reached its final destination, but also any medial fusion of the metanephros may subsequently facilitate the development of an associated anomalous vasculature.
Although there have been few studies reporting direct associations between prenatal environmental toxin exposure and HSK anomalies, the contribution of environmental exposure as a potential etiology cannot be excluded.Thalidomide associated toxicities have been reported to be associated with not only HSK abnormalities, but also renal agenesis, renal hypoplasia, cystic dysplasia and renal ectopia (Majos et al., 2018).
Alternatively, development of the HSK may not necessarily be due to aberrant processes in nephrogenesis, but rather related to disruption of certain signals that function to establish the embryonic midline during the third week of development.The sonic hedgehog (Shh) gene has been well established to play a significant role in this process by repressing left-sided genes from being expressed on the right side of the embryo (Sadler & Langman, 2018).Tripathi et al. (2010) concluded that Shh may help regulate kidney positioning by demonstrating renal fusion in mice with striking resemblance to a HSK.More specifically, these authors found that on the 11th day of embryonic development, a disruption of Shh in the midline did not disrupt nephrogenesis, but rather caused the left and right metanephros to come to lie physically closer together, hypothetically facilitating their fusion (Tripathi et al., 2010).However, Shh signaling has a profound impact on the development of the embryo and is unlikely to be a factor in mildly symptomatic or asymptomatic patients with HSKs.
Mutations to the Wilms' tumor gene 1 (WT1) gene occurring during gestational week 5 has been reported to cause urogenital anomalies such as multicystic kidney.These mutations are present approximately 10%-15% of patients with Wilms tumor (Lipska-Ziętkiewicz, 2021; Schumacher et al., 2006).The metanephric mesenchyme requires WT1 gene expression for proper induction by the ureteric bud within the metanephros and is essential for proper renal cell growth (Sadler & Langman, 2018).Patients with HSK anomalies have a twofold higher risk of Wilms tumor and it is possible that WT1 mutations may be responsible for other HSK variants (Schumacher et al., 2006).

| Clinical implications
Approximately one-third of patients with HSK variants remain asymptomatic, thus the discovery of HSKs in adults is often incidental.The remaining 70% of patients present with associated conditions, the most common of which are hydronephrosis, nephrolithiasis and urinary tract infections (Glenn, 1949;Kang et al., 2021;Kirkpatrick & Leslie, 2021;Lallas et al., 2011;Tubbs et al., 2016).While Wilms tumor has been associated with HSK, the literature remains unclear with regards to the occurrence of renal cell carcinoma (Pinto & Guignard, 1995;Alamer, 2013;Buntley, 1976;Mesrobian et al., 1985;Hoffenfelder et al., 1992;Neville et al., 2002;Smith-Behn, 1988;Kongnyuy et al., 2015;Blackard & Mellinger, 1968;Gay et al.,1983;Benidir et al., 2014).Bhandarkar et al. (2018) found that 45% of patients (9 of 20 patients) with symptoms related to HSK also had associated organ variants.In contrast, patients without associated organ anomalies were reported to be asymptomatic (Bhandarker et al., 2018).It has been suggested that the increased incidence of hydronephrosis and nephrolithiasis in patients with HSKs is due to sharp ureteric angles at the ureteropelvic junction, the abnormal ureter-renal course across a bulky isthmus or abnormal renal vascular supply (Yang et al., 2019).These studies raise the question of whether patients with symptomatic HSK should be screened more extensively for other congenital abnormalities in an effort to help manage or prevent various urinary system related problems from occurring at a later time.
It has been hypothesized that patients with HSK are more prone to renal injury from trauma due to the superficial midline location of the isthmus and absence of partial protection from the rib cage (Dominguez & Ekeh, 2011;Murphy et al., 1996;Shah & Ojili, 2017).
However, the characteristic inferior positioning of the majority of HSK variations may serve to protect the organ from blunt forces.Further study will be necessary to resolve this issue.
Blunt force renal trauma is an uncommon cause of renal problems in patients with HSK, and maybe associated with complications due to the typically complex vasculature organization involving branches from the aorta, mesenteric arteries and/or the common iliac arteries (Cortese et al., 2017;Voelzke & Leddy, 2014).As with kidneys of normal configuration, blunt trauma has been known to cause vascular injury, laceration of the renal parenchyma and retroperitoneal hematomas in HSK (Cortese et al., 2017;Murphey et al., 1996;Dominguez & Ekeh, 2011;Paragi et al., 2011;Krutsri et al., 2020;Daudia et al., 1999;Trottier et al., 2009;Escudero et al., 2012).

| Surgical implications
Surgical management within the upper abdomen in patients HSK presents challenges for urologists and nephrologists as well as general, vascular and trauma surgeons (Bhandarkar et al., 2018;Neville et al., 2002;Strauss et al., 2000).The abnormally low anatomical position of many HSKs and the complexity of the renal vasculature increases the risk of renal infarct, damage to the renal parenchyma and inadequate vascular control in the case where this vasculature is involved.Advances in imaging technology and modeling with 3-D printing have been useful in improving preoperative and intraoperative planning for a variety of procedures, including open and endovascular abdominal aortic aneurysm repairs, partial or complete nephrectomies, renal auto-transplantation, arterial or renal laceration repairs, and pelvic reconstructive surgery (Mercader et al., 2019).
The classification of HSK subtypes has historically been based on the variation of renal vascular supply.Eisendrath et al. (1925) published one of the first HSK subtype classification schemes in 1925.
This simplified system classifies HSK variants into five groups based on their arterial blood supply (Table 2).Other investigators have suggested that the anatomy of the HSK is too complex to be described this simplistically (Glodny et al., 2009).
Most commonly the renal arteries are positioned between the L1 and the L2 vertebrae, just below the SMA and above the gonadal arteries and the IMA (Figure 1).A recent study reported that the renal arteries in patients with HSK were positioned superior to the IMA in approximately 57% of cases, and in between the IMA and aortic bifurcation in approximately 27% of cases (Majos et al., 2018).In patients with HSK, the associated renal arteries are not only more commonly T A B L E 2 Eisendrath classification of the horseshoe kidney Type I 20% One pair of bilateral arteries off the aorta, where each artery supplies one HSK side.
Type II 30% One pair of bilateral renal arteries each supplying a HSK side and one unilateral branch from the aorta supplying the isthmus.
Type III 15% Two pairs of bilateral renal arteries where two renal arteries supply each HSK side and one unilateral branch originating from the aorta supplies the isthmus.
Type IV 15% Two pairs of bilateral renal arteries where two renal arteries supply each HSK side and one or more branches from the iliac arteries supplying the isthmus.
Type V 20% Multiple renal arteries originating from either the aorta or iliac arteries supplying each HSK side and one or two branches from the iliac arteries supplying the isthmus.
F I G U R E 1 Schematic drawing (by author AAH) of variant arterial blood supply in a 100 year old male cadaver donor with a horseshoe kidney and an unremarkable medical history without any associated renal symptoms/conditions (SMA: superior mesenteric artery; IMA: inferior mesenteric artery).
found inferiorly, but may also be formed by more than one pair of arteries, or may be branches of the IMA or the common iliac arteries.
This arterial pattern is unusual since anterior aortic branches are usually associated with unpaired organs.However, some HSKs have at least part of an arterial supply derived from the SMA.
The HSK may be encountered incidentally in emergency situations as well as during preparation for surgery.It is important for the surgeon to understand the implications of HSK complexity.Following identification of a HSK in an asymptomatic patient, it is important to explain the presence of this variant to the patient and explain the risks that may be associated with surgery in this area.
Because not all renal vasculature is located at the hilum, control of the hilum may be insufficient to control bleeding.If unexpected bleeding occurs a search must be made for other vessels derived from different levels of the aorta or from the iliac artery.It is crucial to remember that the isthmus is often supplied by a separate artery or arteries, and that the renal arteries and arteries that supply the isthmus may be derived from the common iliac arteries.Similarly, it is important to consider that aberrant arteries arising from the anterior aorta may supply one or both kidneys (Turyna et al., 2014).
The finding of an abdominal aortic aneurysm (AAA) in individuals with a HSK is not more common than in individuals with normal renal anatomy (Armon et al., 1998;Sachsamanis et al., 2019;Trottier et al., 2009).The presence of a HSK in a patient with an AAA requires particular attention since the HSK may mask or even enclose the aneurysm.The most common challenges of aortic surgery and coexisting HSK include the surgical approach, planning around isthmus and the preservation of blood supply to the kidney (Davidovi c et al., 2011).Endovascular or open approaches to the aorta are possible (Davidovi c et al., 2011;Davidovic et al., 2018;Melmer et al., 2020;Bowden & Roche-Nagle, 2021;Fabiani et al., 2019;Loftus et al., 1998, Kaplan et al., 1999;Ruppert et al., 2004;Frego et al., 2007).
In elective situations, mapping of the HSK and its unique vascular supply is recommended as part of preoperative planning in order to minimize any complications that may arise during or following surgery (Sachsamanis et al., 2019).In addition to preoperative planning with CT angiograms and urograms, aortography, ultrasonography, and pyelograms, modeling of renovascular anatomy with 3-D printing has been reported to be beneficial in surgical planning (Armon et al., 1998;Hohenfellner et al., 1992;Houat et al., 2021;Mercader et al., 2019;Wymenga et al., 1995).Recommended preoperative evaluation for patients with HSK variants have not been standardized in large measure based on the rarity of these variants and the complex differences in their renal vasculature and anatomy (Kotsis & Dellis, 2018).
Of patients with symptomatic HSK, an estimated 45% have associated non-renal variants (Bhandarkar et al., 2018) and appropriate screening should be considered, especially in young patients.Of those with asymptomatic HSK, symptoms are more likely to be related to surgical procedures, either elective or emergent.Illustrations of HSK tend to oversimplify the anatomy and vasculature supply.The surgeon should be aware of the anatomic complexity of the HSK and its implications.

| HSK EXEMPLAR
We provide below a description of a symmetrical HSK in a 100-year- old individual with unusual vascular supply that was discovered during a dissection laboratory in a medical anatomy course.The HSK and suprarenal glands were identified exposing the vascular anatomy and their relationships to surrounding structures.The donor demonstrated a complex vascular supply including one unpaired artery in the midline arising from the anterior surface of the aorta with branches supplying the left and right portions of the HSK.Measurements and photographs were obtained for descriptive and characterization purposes.The HSK specimen was 15.7 cm in the transverse plane.The leftsided component of the HSK was slightly larger than the right-sided component, where the height of the left component was 8.6 cm along the vertical plane, compared to the right component measuring 8.1 cm.Both the left and right components had a similar width or thickness, measuring 3.2 cm anterior to posterior.The HSK was characterized by fusion of the inferior poles.The height of the isthmus in the vertical plane was 3.8 cm and was found to be anterior to the aorta.Both sides of the HSK were estimated to be positioned from the L2 to the L4 vertebrae (Figure2).Each half of the HSK had a single pelvis and single ureter.Both ureters passed anterior to the isthmus and did not cross the sagittal plane as they each ran parallel to each other toward the bladder.Both halves of the HSK were observed with extrarenal calyxes.In the left pelvis, a renal calculus measuring 5 x 2 mm was found.While approximately 75% of the isthmus consisted of renal parenchyma, the remaining portion consisted of fibrous connective tissue.The area of fibrous tissue was located on the posterior aspect of the isthmus and rested directly against a calcified atherosclerotic area on the abdominal aorta.While there was still a thin layer of renal parenchyma anterior to the fibrous portion of the isthmus, it is suspected that the posterior area of fibrous tissue on the isthmus may have been the result of pressure atrophy.The HSK derived its blood supply from four different arteries originating from the abdominal aorta and one originating from the right common iliac artery Three of the four vessels stemming from the aorta were located superior to the IMA, two from the right and one from the left side of the abdominal aorta (Figure2).The right superior component of the HSK received blood supply from the two right renal arteries, with the left superior component being supplied by the single left renal artery.The right inferior component was supplied by one of the right renal arteries and a branch of a unilateral artery, arising from the anterior aspect of the aorta, inferior to the IMA.The left inferior component received blood supply from the single left renal artery and by a branch of the previously described, unpaired artery arising from the anterior aspect of the aorta inferior to the IMA.The right suprarenal gland was identified and was approximately 2.5 x 3.0 cm in size with a clear differentiation visualized between the cortex and medullary tissue layers.It was positioned directly superior to the right side of the HSK.An area of nodular tissue was observed superior to the left side of the HSK that was suspected to have been