Congenital Anomalies of Kidney and Urinary Tract (CAKUT)-Literature Review

Kidneys as well as urinary tracts are the major excretory organs of the human body and removes waste products of protein metabolism.They also remove surplus water and salts from the blood.Kidneys as well as urinary tracts also important for survival as they are crucial for preserving the fluid-electrolyte balance of the body tissue fluids.The inaccuracies in the embryogenesis of the outflow tractsalong with thekidneys are vulnerable to the environmental endargements and disturb the development throughout gestation.Mutations in the patient with CAKUT are responsible for the chronic renal diseases in the 1 st three decades of life.Fetus dose not survive in severe cases of CAKUT as a result of non formation of kidneys and outflow tract, but in less severe cases there are more chances to survive and may identified in adulthood.Though the critical cases of CAKUT are infrequent, marginal nephron number is considerablyfrequent disorder exerting its effect on renal functions with increasing age. Congenital anomalies of kidney and urinary tract have a wide range ofabnormalities inclusive offatalagenesis of both the kidneys andasymptomatic ectopic kidneys.Hence patient with the solitary kidney should follow-up regularly for better and close monitoring. Review Article Tyagi et al.; JPRI, 34(25B): 1-8, 2022; Article no.JPRI.79375 2 The clinical presentation of CAKUT along with its long term outcomes and epidemiology is covered in this review.With a comphrehensive knowledge of the roots of CAKUT and marginal nephron numbers, identification of preventive treatment and establishment of clinical guidelines for the patients can be begun.Comphrehension of relevant endangerments and changes in the epidemiological trends especially modified maternal factors and delivery services is vital for prompt detection and prediction of prognosis in the course of pregnancy due to subsequent morbidity and mortality as a result of the presence of CAKUT.


INTRODUCTION
Congenital anomalies of the kidneys and urinary tracts (CAKUT), which constitute two in ten of the congenital deformities observed in 0.2% of all live births, are disorders attributable to the flaws in renal embryogenesis along with their efflux tracts [1,2]. Week 3 of the gestation period marks the beginning of the formation of the kidneys and nephrogenesis doesn't stop until 36 th week, hence, the kidneys and efflux tracts are vulnerable to environmental endargementsthat disrupt embryogenesis during the course of pregnancy [1]. Several units of heredity incriminate renal embryogenesis as well as mutations are recognized CAKUT patients, the typical cause in the first three decades of life of chronic kidney disease [1,3]. The fetus does not survive in severe cases of CAKUT as a result of non-formation of kidneys whereas there is a chance of survival ,in cases of less severity, with efflux tract plus kidney defects or may be noted in adulthood [1]. It is noted that morbidity from CAKUTs may not be observed up until adulthood hence patients with a solitary kidney should follow up regularly for better and close monitoring, ideally for the entire duration of their life [4].

Objectives
1. To find out incidence of CAKUT.

To review the available literature on CAKUT
The study is likely to conclude a hypothesis that CAKUT are common and certain CAKUT may predispose patient's urine to get stagnated which may then lead to infection and renal stone formation.

EPIDEMIOLOGY
Congenital anomalies of kidney and urinary tract (CAKUT)have broad spectrum abnormalities inclusive of bilateral renal agenesis as well as asymptomatic ectopic kidneys [5]. Majority of CAKUT are revealed in the antepartum or immediate postpartum period with a notable part, with severity of variable magnitude, ascertained in the adult population [5]. The sonographic detection reported the prevalence of CAKUT to be between 0.1 to 0.7% [6]. In cases of live and still born infants, CAKUT incidence rate is 0.03 to 0.16% and the incidence of non-renal anomalies in infants with CAKUT was noted in 30% of such cases. By coalescence of CAKUT and non renal anomalies, over 200 syndromes are described [7]. The principal root of end-stage renal disease (ESRD) in pediatric age group is CAKUT which furthermore ensues difficulties of the excretory system as adults like nephrolithiasis, inflammation, high blood pressure, and renal failure [5]. It was concluded, after a thorough investigation of chronic renal disease cases worldwide, that roughly 30-50% of all the cases are due to CAKUT and that hardly any of these anomalies can predispose to adult-onset diseases [8].
Chevalier RL 4 (2009) elaborated the various parameters that need to be closely monitored in CAKUT patients of paediatric age group. These parameters include diet and nutrition, growth, blood pressure, serum creatinine and proteinuria(microalbuminuria). This may include renal imaging as per the need [4].
Mnari W et al [9] (2013) stated that CAKUT are a frequent finding in paediatric age group and are a noteworthy root of morbidity in early childhood. Consequently for an accurate diagnosis and appropriate management a better strategy and knowledge of urologic anomalies are crucial [11]. Santos Junior AC [8] (2014) et alput in a nutshell the plausible tools by which genes in charge of renal embryogenesisare probably responsible fordevelopment of CAKUT [8].
Simoes AC et al [10] (2015) summarized that cases of UTIs were observed more in males (3.7%) in comparison to females (2%). Signs and symptoms of UTI are indifferent, particularly in young children, fever being the solitary symptom [10].
Vivante A et al [3] (2015) human CAKUT are a result of the mediating of TBX18 transcriptional repression with dominantnegative TBX18 mutations, thus compromising with the development of unstriated muscle cell in the ureter leading to development of human CAKUT [3].
Ramanathan S et al [5] (2016) highlighted in their study that congenital anomalies of kidney and urinary tract have several types ofabnormalitiesincludingfatal agenesis of both the kidneys as well as asymptomatic ectopic kidneys.
Vieira M et al [12] (2018) ponder that the primary source of chronic renal disease in paediatric population is CAKUT.
Talati AN et al [2] addressed the monogenic origins of CAKUT, affiliated ultrasound features, and reflections for hereditary diagnosis and management,both at antenatal and postnatal levels [2].
Okoronkwo et al [14] (2020) stressed that the incidence of CAKUT is notable. The chief CAKUT were anomalies of the urethra while bladder anomalieswere noted minimally. The paediatricprevelanceofVUR in South African origin is marginalcompared to that offirst world nations. Regular medical follow-up of children with CAKUT should be done to avoid early and late complications [14].
Wu CH et al [5] (2020) stated that extension of FOXC1 phenotype of pathogenic variants may be employed to explain allelism toward involvement of CAKUT [15].

The Excretory System
The development of the excretory system preceeds that of the genital system and includes the kidneys, a pair of ureters, a urinary bladder and a urethra [17].

Kidneys and Ureters
The pronephros, mesonephrosandmetanephros are the three structures that come into view. Out of these three,the metanephros is incharge of the development of the permanent human kidney.Theureteric bud via the mesonephric duct and the metanephrogenic cap via the intermediate cell mass of mesenchyme of the lower lumbar and sacral regions are responsible for the development of the metanephros.

Ureteric Bud
The protuberance of the mesonephric duct is the ureteric bud.The ureter develops from the ureteric bud and then goes on to expand at its apex thus leading to the formation of the renal pelvis.The major calyces are the branches given off by the renal pelvis and the minor calyces,as well as the collecting tubules,are the branches of the major.

Metanephrogenic Cap
The capsule of the glome rulus, the convoluted tubules(both the distal and proximal) as well as the loops of Henleis a result of the condensation of the metanephrogenic cap about the ureteric bud. The in vagination, by a network of capillaries,of the capsule of the glome rulus occurs leading to glomerul us formation. The collecting tubule,derivative of the ureteric bud, is joined by both the distal convoluted tubules, derivative of the metanephrogeniccap. The lobulation of the renal surface which is present at the time of birth starts disappearing shortly after. The middle sacral artery, the perpetuation of the aorta in the pelvic region, provides the arterial supply to the developing kidney which is a pelvic organ at first and later makes its way up the posterior abdominal wall. The maturation of the body in the lumbosacral regions and the upright alignment of the curvature are responsible for the 'ascent of the kidneys'.Side-by-side elongation of the ureters takes place.
Progressively superior lateral splanchnic arteries, branches of the aorta, vascularize the kidneys.

Congenital anomalies of kidney and urinary tract (CAKUT)
Congenital anomalies of kidneys and urinary tract are classified as seen in the mindmap.
Categorization on the basis of embryology can be made into three broad categories:  flaw in the development ofthe parenchyma of the kidney;  deviation from the usual sequence of migration; and  flaw in collecting system development [5].
The disturbance in the embryologically expected migration of the kidneys leads to frequent congenital anomalies of the kidney and urinary tract (CAKUT),renal fusion and ectopy. The usual trend observed in paediatric population with these abnormalities is asymptomatic presentation yet some present with symptomsas a result of complications,for example infection, kidney stones, and obstruction of the urinary tract [18].

Polycystic Kidney
It can be inherited from by either parent.Itpresents as cysts of congenital origin in the hepatic, pancreatic and pulmonary tissues.There is boundless growth of both the kidneys which are also perforated with numerous cysts.Flawinjoiningofcollecting and immature convoluted tubules lead to this condition.Retention cysts are formed due to urine accumulation in the proximal tubules.

Pelvic Kidney
The arrest in the usual ascent, commonly at the pelvic brim results in pelvic kidney. It may have an asymptomatic presentation with normal functionality. Cases of inflamed presentation -due to its abnormal situation-of an ectopic kidney, are normally a mistaken diagnosis.

Horseshoe Kidney
Horseshoe kidney comes into existence due to the fusion of the caudal ends of the two kidneys during development. The ultimate situation of the kidneys in the lower part of the lumbar region is due to the entrapment of the interconnecting bridge at the back of the inferior mesenteric artery during their ascent from the pelvic region.Infection and calculi formation may be a manifestation of the urinary stasis due to kinking of the pair of ureters in the course of their passage inferiorly over the bridge of tissue of the kidney.This condition may be corrected surgically by dividing the bridge.

Unilateral Double Kidney
Presence of two kidneys on one side with separate blood vessels and ureters is what is popularly known as 'unilateral double kidney'.The top extremity unites with the bottom extremity and ureteric bud on one peripherytraverses the centerlineat the time of itsascend,of a kidney of normal situation. Kinking of the ureter results in urinary stasis and thus the need for surgical intervention.

Rosette Kidney
Union of the twokidneys takes place at their hilum and are found situated in the pelvis. They jointly form a rosette which is a result of the perfusion of the pair of ureteric buds.

Supernumerary Renal Arteries
They are comparatively frequent, noted as resolutefetal renal arteries originating in an orderfrom the aorta for the vascularization of the kidney during its ascent from its pelvic situation.They may ultimately result in a condition known as hydronephrosis which is a dilatation of the pelvis as well as the calyces due to urinary stasis as a manifestation of the crossing of the pelvi-ureteral junction by a supernumerary artery.Hence this anomaly draws clinical attention.

Double Pelvis
Generally unilateral,this anomaly is due to partition of the ureteric bud before time close to its termination.The drainage of the upper cluster of calyces is taken up by the upper pelvis and that of the middle and lower clusters by the lower pelvis,lower being larger in comparison to the upper pelvis.

Bifid Ureter
The pair may unite in the lower one-third of their route or may openvia a common opening into the bladderor may open as individual entities into the bladder. In the last-mentioned scenario,one passes over the other paving the way to urinary obstruction. The division of the ureteric bud before time is the reason behind the existence of bifid ureter.On radiological investigations,there exists a mere chance of spotting dual number of ureters and ureters.The likelihood of a bifid ureter becoming infected orbe the site of stone formation is more than that of a normal ureter.

Megaloureter
It may present with laterality, uni or bi, and with total absence of motility with an idiopathic cause. The ureter becomes prone to infection due to accumulation of urine. Surgical intervention of the speciality of plastic surgery, is crucial to revamp drainage rate.

Postcaval Ureter
Obstruction of the right ureter by the inferior vena cava in case of the former's ascent posterior to the latter. The preferred treatment is surgical intervention by rerouting of the ureter along with re-implantation of the distal end into the bladder. The impact of environmental as well as epigenetic variables on natural history of CAKUT together with renal development is held up by several studies,thus drawing the conclusion of multifactorial pathogenesis of this syndrome [13].

Detection of CAKUT
CAKUT are variable thus may show their effects on the kidney(s) alone and/or the lower urinary tract making radiological intervention indispensable.The assessment of children with a urinary tract abnormality query is clarified by the employmentUltrasonography (US),best suited modality for this purpose.The evaluation of the anatomy and abnormalities of the bladder and urethra is done using Voiding cystourethrography (VCUG) which in turn also determines which additional examinations are needed: intravenous urography (IVU), CT scan or MR imaging. One of the most crucial diagnostic tools in the assessment of neonates with hydroureteronephrosis is 99mTc-DTPA dynamic renal scintigraphy [13]. The principalradiological modalities employed in the detection of various CAKUT are ultrasonography,magnetic resonance imaging and computed tomography [5].The majority of CAKUT are spotted by routine antenatal ultrasonography in gestational period [6]. An outstanding predictor of abnormal fetal renal function and CAKUT is oligohydramnios at or after the 20th week of the duration of pregnancy [6]. Illustration of fetalurinary system from early second trimester is permitted by antenatal screening ultrasonography (US) which also ascertains numerousprincipal congenital anomalies of the urinary system [5]. Evaluation of the size, existence and situation of both kidneys and the assessment of their form and echogenicity, scrutiny of fetal bladder, external genitalia and the amount of amniotic fluid is reported in the ultrasound examination of the normal urinary tract. Thickened bladder, hydronephrosis,hydroureter, renal agenesis,small or dysplastic kidney and cystic kidney are some of the abnormalities detected in antenatal US. Antepartum identification of renal abnormalities calls for postpartum renal ultrasound shortly after birth which is to repeated at 4-6 wk of age as well as a physical examination [5]. To keep track of compensatory renal growth of unaffected kidneys in cases of unilateral CAKUT, progressive hydronephrosiswith mild/moderate obstructive uropathy, or changes in the affected kidneys serial ultrasounds are employed [6].Therefore, it is essential to have prompt diagnosis and management, whether medical or surgical, to reduce renal damage and to avert or delay endstage renal damage. Prompt diagnosis, followup,detection of complications ,surgical planning, and associated renal and extra renal malformations is made via radiological imaging [5].

IMPLICATION
The review of literature will help in determining if some patients with certain CAKUT are predisposed in future for renal stone formation. This will ensure appropriate measures to be taken before any pathology develops. This may assist in better management of such cases at an earlier stage with proper medical intervention and consequently may help in prevention of complications like pyelonephritis, hydronephrosis, CRF etc.
Firstly,theepidemiology,its clinical presentation of CAKUT,andthe outcomes that follow in the long run are talked about followed by the endargerments for CAKUT, including participation of hereditary and environmental factors.Marginalnephron number is a by far morefrequentdisorder,despite severe CAKUT being rare,with its ramifications on renal function more and more apparent as a person ages. With the thorough knowledge of the roots of CAKUT and marginal nephron number, identification ofprophylaxis and establishment of clinical guidelines for follow up of these patients can be begun.Understanding of changes in epidemiological trends and relevant endangerments,specifically mutable maternal factors, is emphasized upon for prompt detection and prophecy of prognosis in pregnancy because the presence of CAKUT brings with it implications for ensuing morbidity and mortality. Maria M Rodriguez [19] (2014) reviewed majority of CAKUT and described congenital renal anomalies and analyzed therapeutic interventions. Ishiwa Sho et al [20] (2019) observed HNF1β gene mutation in most of the patients with hypodysplastic kidney with multicystic dysplastic kidney.

CONCLUSION
Prompt diagnosis is the need of the hour in handpicked anomalies to reduce renal damage, avert or slow down the inception of end stage renal disease (ESRD), and delivernurturing care to keep complex ramifications of ESRD at arm's length.However, literature lacks in knowledge about the contribution of congenital urinary tract malformations to chronic kidney disease and consequent renal failure in CAKUT patients as there are gaps in the comprehension of the genomics of the lower urinary tract development.As the inaccuracies in the embryogenesis of the outflow tracts and kidneys are vulnerable to the environmental factors that disturb the development throughout the gestation and mutation with the CAKUT are responsible for chronic,end stage renal diseases and stone formation;the need for better comprehension more environmental parameters should be studied in large number of cases.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.