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-DefinitionA pelvi-ureteric junction (PUJ) anomaly, also known as ureteropelvic junction (UPJ) anomaly,  is defined as impairment to the flow of urine from the renal pelvis into the ureter causing pathological dilatation of the renal pelvis and calyces, and culminating in progressive renal damage. The diagnosis of UPJA can be suspected when an ultrasound scan shows a dilated renal pelvis without ureteric dilatation and a normal bladder6,7.

 -IncidenceUPJA is the most common antenatally-diagnosed urinary tract anomaly29,30, accounting for approximately half of all antenatal hydronephrosis15. The left side is more commonly affected than the right at a ratio of 2:11. UPJA is bilateral in 10% to 20% of cases and is twice to three times as common in males than females7,31. -EtiologyThe majority of UPJA is primary and congenital in origin, although the problem may not become clinically apparent until much later in life. Primary UPJA – Intrinsic:Congenital UPJA is typically characterized histologically by abnormal fibromuscular and neural arrangements at the UPJ32, interfering with the normal peristalsis of urine at this point. Extraluminal: Alternatively or additionally, extrinsic compression of the UPJ, which may be intermittent, can result from, for instance, aberrant vessels crossing to the lower pole of the kidney7.

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Occasionally, the ureter can be compressed by the inferior vena cava or distorted by the isthmus of a horseshoe kidney. Even so, an intrinsic etiology remains more common in a horseshoe kidney with UPJA than distortion by its isthmus.Intraluminal:  Obstruction by stones or fibro-epithelial polyps is uncommon in children.Secondary UPJA:In severe cases of vesico-ureteric reflux, the ureter may become extremely tortuous and kink on itself producing a secondary UPJA. Scarring following previous surgery or impacted stones may result in a stricture at the UPJ.

-molecular controlUp to date the molecular control of a normal ureterogenesis it is still a little bit unknown, and it just begins to be cleared out. We could say that thanks to the models based on animals we have gained out knowledge and experience on their genes, as a result of their high conservancy between the species. So far there have been many works on mice in which shows us the countless genes expressed during the normal development of the urinary tract. There are different techniques used when searching and looking for the function of those genes, and that includes in vitro cell and organ culture experiments, and mouse mutants with specific gene knock-outs.All these are useful when we are trying to identify a particular mutation in a particular human gene in those children that have a urinary tract malformation, in which case, it will give us a wider vision and we can have a better understanding and judgment of it. Up to now, a handful regulatory systems have been proposed and recommended for the ureteric development, and they can be mutually dependent or just work on its own. For instance,  Airik et al indicated an independent role for the transcription factor T-box 18 (Tbx18) on Wnt signaling and on a cascade involving sonic hedgehog (Shh) – Patched1 – bone morphogenetic protein 4 (Bmp4).The highly conserved gene, Teashirt 3 (Tshz3), which encodes a transcription factor, may act downstream or as a permissive co-factor to the Shh pathway and has effects on retinoic acid signaling and on myocardin.

Mouse ureteric smooth muscle precursors express Tshz3. Teashirt 3 null mutant mice have congenital hydronephrosis without anatomical obstruction: increasing hydronephrosis is preceded by failed ureteric smooth muscle differentiation, and ex vivo, their ureters lack peristalsis. Furthermore, a TSHZ3 coding variant appears to be a risk factor for human congenital UPJA, thereby inferring a genetic etiology for this condition.

Null mutants for discs-large homolog 1 (Dlgh1), angiotensin type 1 receptor (Agtr1) or inactivation of its potential downstream effecter gene calcineurinB1 (Cnb1) in urinary tract mesenchyme, also demonstrate defective pelvi-ureteric smooth muscle, with a failure of peristalsis resulting in progressive hydronephrosis.-pathophysAfter a long research on the pathophysiology of the congenital UPJA I can conclude that it is yet something not very precise, neither obvious nor evident. Due to this unclear understanding it has been name as a “functional” obstruction.

It is characterized by an absence of any kind of anatomical obstruction but accompanied with the existence of an abnormal smooth muscle and the ureteral-pyelo junction. In a normal situation the function of the ureter is to expel the urine out of the renal pelvis of the kidney into the bladder. This is achieved by the contractions made by the pacemaker cells in the ureter, which are called peristalsis. These contractions are in a single direction to prevent any kind of reflux of the urine.

When we have a breakdown or collapse of this system the urine will not be able to continue flowing, therefor causing a hydronephrosis. However it exists a kind of mechanism that tried to prevent such rises in pressure. Usually when those cases comes up dilation will be accomplish by the collecting system. When there is a constant and continuos dilation from a defected urinary flow system, this will lead to a hypertrophy which will terminally increase the pressure. All this adjustments will be followed by renal function changes. If we look at the bigger picture we can say that whenever an obstruction happens in the early pregnancy it will lead a defective renal development, generating dysplastic and small kidneys. In the other hand when the obstruction happens later in the pregnancy it usually will cause just a dilation that will eventually start to have functional and histological changes. The fundamental point when talking about congenital UPJA  is to find out which ones will worsen if left untreated and which ones will spontaneously resolve over time.

 Despite the fact that many of the UJPA are diagnosed prenatally with ultrasonography, there are a few clinical features that we should use a red flags on congenital UPJA. Back in the days when ultrasonograhy was not used adequately, an abdominal mass was the most common finding in the childs. Other symptoms that accompanies the latter are those that are gravitated from the dilation of the renal pelvis, such as groin pain, vomit or nausea. When taking into consideration a good clinical history it wont be hard to acknowledge that this pain it is usually aggravated if large doses of liquid are ingested. The less frequent symptoms of UPJA are sepsis, hematuria, hypertension and pyelonephritis.

 There are several other urological anomalies that are related to UPJA,  such as vesico-ureteral reflux (VUR), ureteric hypoplasia, horseshoe kidney, and duplication of the ureter which can be complete or partial. Also we can find a relevant association of congenital heart diseases, anorectal anomalies and VATER syndrome with PUJA. -geneticsWhen talking about congenital UPJA we must know that it appears sporadically and after a search in the literature it is barley found families with a high incidence of hydronephrosis who have been reported. There has been evidence in studies that UPJA can have a genetic cause transmitted as an autosomal dominant disorder with variable expression.

Being more specific it has been was identified a linkage to the HLA region on chromosome 6 arm p. It is found in several families, but not only with PUJ but also with other urological kidney malformations such as renal agenesis and multicystic renal dysplasia (MRD). There are hypothesis going around which mention the possibility of its relationship with the severity of the mutation.Although it is a field we do not have too much information about it, there has been specifically the evidence of three genes related to the development of UPJA. First of all the mutation of ADAMTS-1 gene, desintegrin-like and metallopeptidase with thromnospondin type 1 motif 1. This gene which can cause the UJP obstruction and further urogenital defects by an excessive collagen deposit in the UPJ has been the leading gene in the studies of PUJA. Up to today the mechanism it is still unclear. It is also worth the mention of ID2 (inhibitor of DNA binding 2) and IL-9 (Interleukin 9) mutations due to its mechanism in the UPJ development.

Overall we can say that it is very clear that urinary tract obstruction can result from a wide variety of environmental causes or genetic mutations.  As mentioned before the UPJA is heterogenous and may have drastically different etiologies. Although great progress has been made in the understanding of the genetic and development basis of UPJA, it is still a great challenge to point out the etiology of the patients. We can conclude that further investigation of these is necessary to improve the diagnosis and the treatment. -embryologyDuring the fifth week of gestation the metanephric mesenchyme, which is made of mesenchymal cells situated adjacent to the tips of the branching ureteric bud, will send signals to the ureteric bud to begin its enlargement and bulge out from the posterior aspect of the mesonephric duct into the metanephric blastema. The ureteric bud will give rise to the epithelium of the renal pelvis and the ureter, which is called the urethelium, and will branch out continuously in order to form the so called collecting ducts.

The edges of the newly formed collecting ducts are in charged for the activation of the cell aggregation of the mesenchymal cells, as well as for the indispensable  transformation of the mesenchyme into epithelium for the development of the nephrons. The mesenchymal cells that surrounds the stalk of the ureteric bud will develop into the cells of the lamina propria, smooth muscle and connective tissue of the renal pelvis and ureter. This system of tissue induction between the ureteric bud  (the epithelium) and the metanephric blastema is a reciprocal control, and it is necessary for the right and correct development of its own. By the end of the embryogenesis the formation of the duct inside the ureter will finalize, but the development of the wall of the ureter will continue after delivery. This should give us one of the keys on understanding why diseases observed before birth will spontaneous resolve or improve.diagnosticsAs discovered in previous studies ultrasound and functional imaging are the essential authority in terms on the therapeutic option of the child. Never the less other imaging options are needed for a more accurate assessment.

Both are helpful as well in order to determine the success of a surgery.ULTRASOUNDWhen it comes about the regulation of ultrasonography, it is essential to differentiate the UPJA that will eventually resolve from those that are at a higher risk of renal loss. The management of the patients is usually based on two algorithms, which primary consist in the consecutive control with ultrasound (US). During the first year of life it is performed every 3 to 6 months, followed by every 6 months during the second year of life. There will be annual evaluations and if indicated by any finding in the ultrasound an additional functional imaging (FI).First of all the first thing that it is noticed when performed an ultrasound is the presence of a renal pelvis dilation without any kind of dilation in the ureter and a normal bladder.

The following parameters should me measure to have the best possible assessment: 1.    the location, size and morphology of each kidney,2.    an exact measurement of the renal pelvic diameter in mm in the antero-posterior plane, 3.

    the degree of calyceal dilatation,4.    parenchymal abnormalities, such as renal cortical thinning, lack of cortico-medullary differentiation, cystic changes,5.    indicate unilateral or bilateral pathology, and6.    views of the ureters and bladder including measurement of the bladder volume. In those able to void on volition, a pre- and post-micturition bladder volume should be recordedIf the physician is adequate competent and experienced there will be the choice of employing Doppler Ultrasound, which will give the opportunity to visualize the vessels crossing at the lower pole of the kidney.

Of course the cooperation of the kids must be needed for such thing.RENAL SCINTIGRAPHYIVP used to be the the first choice for checking and classifying the possible patients with UPJA. Now this has been taken over by the usage of diuretic renography. When it comes about a change in any kind of management it is fundamental to see the pros and cons of its usage and declare if its worth the try. In this case when putting it into a balance the positive side will be heavier. The radiation exposure is minimal and without the need of using any iodine-based contrast material, giving overall a better differentiation of the renal function.

Of course there are some disadvantages of it´s own, including that the observation and judgement of the renal anatomy is impossible to obtain.  The most frequent functional imaging used in the possible diagnosis of UPJA is diuretic renopgraphy with mercaptotriglycylglycine (MAG-3). Now the European Association of Nuclear Medicine (***) and the North American Society of Nuclear Medicine (***) have published several protocols for the proper use of  mercaptotriglycylglycine in kids. This specifically renography is advantageous because of it ability to perform the differential renal clearance by measuring the eradication of the tracker in the blood. Another option is to visualize the urinary tract and observe how it disappears.

The best timing to assess the differential renal function is between one and two minutes, and it usually ranges around 45-55%.It is very questionable how the drainage should be assessed. Formerly it was used the classical method, but it has been proven that the slope of the washout curve after furosemide is very susceptible to inaccuracy. If the shape of this curve if changed it can lead to a different reading of the functioning of the kidney.

In other words, the efficacy of the working kidney will be malinterpreted due to the variation of the volumes in the renal pelvis. What make a drainage enough to classify it as normal? If for instance at the end of an study there is just an insignificant amount of tracer within the pelvicaliceal system, it is obvious to conclude that the drainage is satisfactory. There has been a lot of controversy of what it supposed to be defined as a impaired drainage, and it is still on debate. It is essential to obtain images of the curves and be able to compare them with the data obtained. The pelvic excretion efficiency (PEE) or output efficiency (OE) will measure the percentage of the kidney that it is still working during the exposed time of observation. Post-micturition images will also be taken into consideration, it will give the information about the bladder with emptying and on gravity.  This can be measure by the normalised residual activity (NORA), which informs about the residual activity after micturition as a percentage of the renal activity 2 minutes after tracer injection.

****Nevertheless, the following caveats remain: impaired drainage does not necessarily indicate obstruction. Poor hydration and poor overall renal function make accurate estimation of both differential function and drainage impossible. In a grossly hydronephrotic kidney, conclusions on poor drainage is precarious as this may reflect hold-up or simply on-going filling of the capacious system. Sequential renography documenting changes in differential function may therefore be needed to identify those with obstruction, defined by Koff and Campbell16 as a restriction to urine flow which if left untreated will cause progressive renal deterioration.

Another option is the usage of MRI in the diagnosis of urophathies in children (Cáceres Aucatoma et al. 2007). There has been studying that compares its usage to other techniques to observe any kind of physical or socioeconomic impacts. Nevertheless MRI provides the same information than other traditional modalities.

It brings us morphological, functional and even vascular knowledge. On top of its reduction of costs, it can reduce visits, work-days and traveltime. As mentioned in (Cáceres Aucatoma et al.

2007) it is proposed that in a future the option of achieving a cystography and a hydric/diuretic overload test at the same time would be possible, which in fact it will increase the efficacy. Other great precise modality for visualization of the urinary tract is the magnetic resonance urography (MRU) (Wille et al. 2003). MRU is very competent for its availability of achieving both anatomical and functional information.

MRU is exceptional due to its lack of ionizing radiation, also it uses Gadolinium contrast material which is not nephrotoxic and it gives an outstanding image quality that is not intruded by any kind of gas. Because of its highly price it is recommended to have an adequate selection of the patients, giving preference to those with defective renal function especially if there is an allergy to the contrast medium and if previous a surgical reconstruction the anatomy it is not very clear. When performing a MRU general anesthesia is usually needed if the children are under 6 years old. Currently the functional analysis is still under study and there are many protocol developing for its interpretation.


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