Several maternal conditions can affect the in-utero environment and lead to the development of CAKUT (12). These conditions include diabetes, chronic kidney disease, cancer, and obesity (13–15). Excessive intake of folic acid or deficiency in vitamin A during pregnancy is also associated with CAKUT manifestations (1, 3). Furthermore, some medications, such as angiotensin-converting enzyme inhibitors (ACE), can impair kidneys development (8, 16) Maternal malnutrition and a low-protein diet during pregnancy can have a detrimental impact on the developing kidneys system (5).

CAKUT epigenetic factors include DNA methylation, histone modifications, and non-coding RNAs. These epigenetic mechanisms control gene expression via activating or silencing regulatory genes essential for kidney and urinary tract development (3). Alterations to epigenetic marks that regulate developmental genes in the kidney and urinary tract can increase the risk of CAKUT phenotypes (12).

Multiple genetic factors may contribute to CAKUT, including monogenic mutations, copy number, and structural variations, leading to an imbalance in some proteins and dysregulation of essential receptors and signaling pathways. Furthermore, Van der Ven et al. hypothesize that there is a high frequency of CAKUT phenotypes caused by monogenic variations in genes related to kidney development (2). These monogenic mutations account for up to 20% of all CAKUT cases in human populations and include more than 50 genes causing CAKUT, such as PAX2, TBX18, NRIP1, REX, SIX2, and BMP4 (4).

This section explores how variations in single genes increase the risk of CAKUT. Monogenic causes of CAKUT can be detected through various genetic screening techniques, such as single-gene screening, gene panels, and whole-exome sequencing. These techniques offer an in-depth analysis of specific genes or the entire exome, allowing for the identification of single-gene mutations responsible for CAKUT (12). TBX18 and NRIP1 genes are the common monogenic causes of CAKUT. They increase ureteric mesenchymal cell development defects and retinoic acid signaling, contributing to disease pathogenesis (4). PAX2 variants are a known cause of monogenic CAKUT. These mutations are associated with (syndromic CAKUT), which is associated with ocular anomalies. Monogenic variations are caused by a combination of familial genetic, epigenetic, and environmental factors. They account for up to 20% of all CAKUT cases in human populations and include around 68 monogenetic causes (39 dominant, 26 recessive, and 4 X-linked) (Table 1). Mutations in monogenic variants increase the prevalence of CAKUT genes in humans because they create genetic imbalances, alter genetic composition, and modify or delete genes (4).

Copy number variants (CNVs) are a significant genetic risk factor for CAKUT. CNVs can result in kidney and urinary tract defects by altering the expression of genes that are vital for proper kidney formation (3). Specifically, CNVs can lead to deletions or duplications of chromosomal regions that harbor genes necessary for kidney development. These alterations can cause an imbalance in gene expression, ultimately resulting in CAKUT phenotypes (1). Specific CNVs that have been associated with CAKUT include HNFB1/Hepatocyte nuclear factor 1-β (on Chromosome 17) and PAX genes (2). Although CNVs only account for about 5% of CAKUT cases, they provide evidence that other genetic variations can also lead to CAKUT disorders (1).

In CAKUT, severe phenotypes observed in offspring of healthy parents can be attributed to de novo dominant mutations in essential developmental genes or recessive mutations in genes that can tolerate reduced gene dosage. In contrast, familial cases of CAKUT, which represent 10–20% of cases, often exhibit incomplete penetrance as an autosomal dominant trait. This incomplete penetrance may arise from genetic or environmental modifiers that influence disease manifestation, hypomorphic mutations that partially impair kidney development, or disruption of genes and pathways essential for urinary tract development later in life (4). Structural disorders such as vesicoureteral reflux (VUR) and duplex collecting systems (DCS) are more prevalent because they have a lesser impact on overall survival. This is because they can either remain asymptomatic or spontaneously resolve over time. These common disorders may have a polygenic basis, meaning that they are caused by the combined effects of multiple common genetic variants. These variants have modest effects on an individual’s risk of developing the disorder, and they are less likely to be influenced by selective pressures (4).

An early embryonic maldevelopment can result in several kidney parenchymal defects, including:

Kidney agenesis refers to a congenital anomaly characterized by the absence of one or both kidneys (Figure 2A). It can be isolated or part of multi-organ syndromes (5). The exact mechanisms underlying it are not fully understood, but genetic and environmental factors are likely causes. It can be detected early in pregnancy using ultrasonography. The occurrence of kidney agenesis has been linked to pathogenic variants in three specific genes: ITGA8, GREB1L, and FGF20 (17).

Kidney hypoplasia is a congenital kidney malformation characterized by an abnormally small kidney with a decreased number of nephrons (Figure 2B). Kidney hypoplasia has a significant impact on kidneys function, potentially leading to oligohydramnios syndrome during pregnancy and, ultimately, chronic kidney failure in severe cases (5, 18). This disease can be inherited through dominant and recessive inheritance modes (19). Multiple signaling pathways contribute to kidney hypoplasia. These pathways include the Fibroblast Growth Factor (FGF), Hedgehog (HH), Glial Cell Line-Derived Neurotrophic Factor/Ret (GDNF/Ret), and Paired Box 2 (PAX2) pathways (18).

Kidney dysplasia is a kidney malformation that can occur as a result of various dysplastic conditions (Figure 2C), including multicystic dysplastic kidney (MCDK), cystic dysplasia, and obstructive kidney dysplasia (ORD) (18, 20). It can be inherited as an autosomal dominant and is associated with mutations in ITGA8 and FGF20 genes essential for kidney growth and development (21). Furthermore, PAX2 gene mutation or its interaction with p53 pathway can cause kidney dysplasia, leading to impaired nephron induction and abnormal ureteric bud budding from mesonephric duct (20).

Other types of kidney anomalies include ectopic pelvic kidneys, which occur when the kidney fails to ascend to its final position (Figure 2D). Therefore, the kidney will remain in the pelvis, affecting the normal position and function of the kidney (22). A horseshoe kidney occurs when both sides of the vertebral column contain functional kidneys masses fused with uncrossed ureters extending from the kidneys hilum to the urinary bladder (Figure 2E). This malformation affects the kidney’s shape, rotation, position, and vascular supply (23).

Later embryonic maldevelopment causes several ureteral defects, including:

Ureteropelvic junction obstruction is a functional obstruction that causes partial or intermittent complete blockage of urine flow from the kidney, leading to hydronephrosis (Figure 2F) (24). This condition can trigger urinary tract infections or urine retention, resulting in acute kidney injury and even kidneys failure (8). CUPO is a congenital disorder caused by various genes with autosomal dominant inheritance. However, it can also be caused by acquired etiologies resulting in obstruction (25).

Primary non-obstructive non-refluxing megaureters, which occur in males and constitute 5 to 10% of all cases of prenatal hydronephrosis, are caused by congenital dilation of the ureter (Figure 2G) (26, 27). Several causes of megaureters include obstruction, reflex, or neither. As part of the diagnostic process, ultrasounds, cystourethrograms, and isotopic renograms apply to patients with this disease (27).

Duplex kidneys are a rare condition where the kidney pelvis and ureter are duplicated, resulting in a double uretic tip (Figure 2H) (5). This condition is estimated to occur more in females than males. The development of duplex kidneys is caused by a defect in the interactions between the metanephric mesenchymal and the nephric duct, which initiates the ureter. The GDNF/RET signaling axis is a crucial pathway that triggers the RET signaling cascade for the growth of the urinary bladder. The involvement of modifier genes in these cascades could lead to duplex kidney development if disrupted. This condition can lead to several kidneys disorders, including hydronephrosis, pelvic-calyceal dilatation, and cortical scarring (28).

Vesicoureteral reflux (VUR) is a congenital condition where urine flows back from the bladder into the ureters, leading to complications like kidney damage, urinary tract infections, and high blood pressure (Figure 2I) (29). It occurs in 1–2% of the population and can be primary or secondary (30). VUR is caused by ectopic embryonal ureteric budding and is linked to genes like EYA1, ROBO2, RET/GDNF, and PAX2 (31).

As embryonic development continues, a variety of malformations can occur in the lower urinary tract, including:

Bladder exstrophy is a rare congenital malformation that occurs when the bladder develops outside the fetus, causing it to function abnormally (Figure 2J) (32). This condition is caused by a defect in the formation of the cloacal membrane, which eventually ruptures and results in bladder exstrophy (1, 32). Maternal factors like irradiation and smoking in the first trimester can cause severe cases of this malformation. However, folic acid consumption can help reduce the severity of the condition (32).

Bladder agenesis is a rare condition that results from the failure of the mesonephric duct and ureter to interact during embryogenesis (Figure 2K). It leads to the absence of urine distention and ureteric ectopia, causing complications like kidney dysplasia and agenesis (33, 34). Most cases occur in females, who may maintain kidneys function if their ureters drain into the genital tract. However, male neonates cannot survive unless ureters drain into the rectum or urachus. The prognosis and treatment options for this condition are often poor (34).

Posterior urethral valves are abnormal membranes that obstruct urine flow and cause ureter dilation and hydronephrosis (Figure 2L) (8, 35). This condition affects 1 in 5,000 live male births, and 50% of cases progress to chronic kidney failure within 10 years. It can be detected prenatally or after birth, and the severity of the obstruction affects the prognosis (36). Defects in the urinary tract’s development can cause various abnormalities, including duplex kidneys, ectopic tissues, ureteral orifices, and horseshoe kidney (5).

The kidneys system plays a crucial role as an excretory pathway in the human body, and any congenital anomalies in this system can significantly affect an infant’s health. Such anomalies are responsible for approximately 40% of cases of chronic kidney failure in patients who develop the condition within the first three decades of their life. Chronic kidney failure can severely impact the quality of life as it progresses, making early detection and management of such anomalies an essential aspect of patient care (2, 3, 37).

CAKUT encompasses a broad spectrum of kidneys disorders that affect individuals in various ways. While some anomalies can be diagnosed during fetal life through ultrasonography, others may not present until adulthood (3). Genome-wide association studies (GWASs), next-generation DNA sequencing (NGS), and whole exome sequencing (WES) are additional techniques used to diagnose non-syndromic CAKUT. These methods are vital in identifying the underlying genetic causes of the disease (3, 38).