STRATEGIES FOR EARLY DIAGNOSIS AND CARE

Eric Girardin, Geneva, Switzerland

Chair: Eric Girardin, Geneva, Switzerland

Adrian Woolf, London, United Kingdom

Prof E. Girardin Unité Néphrologie-Métabolism Pédiatrique Hôpital des Enfants Geneve, Switzerland

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Slide 1

Thank You.

Slide 2

I will first give you some data on epidemiology. You have seen that these malformations, urological malformations are the leading cause of end-stage renal failure in childhood and this in all age groups and it’s also a quite important cause in adulthood.

Slide 3

So how can we screen for these patients? We can screen them with antenatal ultrasonography. Antenatal ultrasonography detects structural abnormalities in 1-3% of all pregnancies and the genitourinary anomalies are identified in 0.5-2.5% of foetuses by the routine obstetric ultrasonography. So in fact, hydronephrosis is the most commonly detected anomaly on foetal urography.

Slide 4

In this slide these authors have pooled several epidemiological data, so there is a huge number of patients and you can see that the leading causes of the antenatal hydronephrosis were in fact non-pathological causes. It’s transient hydronephrosis, physiological hydronephrosis. They account for more than 60% of cases. The first real urological condition is the pieloureteral junction obstruction and it accounts for 11% followed by the VUR, the megaureter, the polycystic kidney disease and you have here the PUV with 1% of cases.

Slide 5

So in fact, the detection of antenatal dilatation of the urinary tract does not always indicate a postnatal urinary tract obstruction or even a significant genitourinary anomaly. So we have a clinical challenge. We have to have strategies to select the patients who would benefit from continuous medical care and for some of them early surgical intervention.

Slide 6

So how to predict the outcome and the renal function?

Slide 7

Can we use biological markers in this field?

Slide 8

To use biological markers we need normal values and these authors have determined values in a cohort of patients of foetuses who had bilateral obstruction but normal renal function after birth at age 1-2 years. So they are really not normal values but it’s the one we need because it’s in these patients that we will have to compare these results.

Slide 9

When they plot data from 70 cases who had a poor outcome either a termination of pregnancy because of renal damage with oligohydramnios or a neonatal death caused by renal failure or some survivals but with renal insufficiency after birth, you can see that for beta2-Microglobulin and for sodium concentration these concentrations are higher in these patients, in these foetuses but you can also see there is some overlaps of the values.

Slide 10

Can we use a magnitude of the antenatally detected hydronephrosis?

Slide 11

Yes, to a certain extent we can and here these authors have divided the patients according to the anterior, posterior dilatation of the prenatal evaluation and they gave us the results of the postnatal findings. The groups are dilatation from 5-9 ml, 10-14 and more than 15 and you can see that the normal findings at birth decrease with the increase of the dilatation and the need for surgery also increased significantly in these three groups of patients. You can also see that there is 15% of the patients with very moderate dilatation who need surgery.

Slide 12

Now we can say that there is currently, in fact, no uniform mechanism that can evaluate the effects of hydronephrosis on the prenatal kidney and definitely predicts the need for postnatal intervention.

Slide 13

But the prenatal evaluation allows us to delineate high risk patients and they are the ones who necessitate an emergency evaluation at birth and so a delivery in a setting where tertiary care services are available. These patients are the ones with severe bilateral hydronephrosis, with distended bladder and oligohydramnios in the male foetus. It’s of course, patients who are supposed to have a posterior urethral valve. It’s the one with severe bilateral hydronephrosis or hydroureteronephrosis and the one with a large cystically dilated kidney suggestive of polycystic kidney disease.

Slide 14

Now, how to predict outcome with a postnatal evaluation?

Slide 15

The renal ultrasound remains one of , in our opinion, very important tools. The classical method of measurement of hydronephrosis is to measure the anteroposterior on the edge of the kidney on a coronal plane and this could overestimate the problem, the clinical problem especially in cases of an extra renal dilatation, which is quite common.

Slide 16

For this reason the Society of Foetal Urology developed a grading system of congenital hydronephrosis. The grade 0 is an intact kidney, 1 is a slight splitting of the pelvis, grade 2 is a more evident splitting of the pelvis but with particpation of the calices. Grade 3, wider splitting and grade 4 there is also a reduced parenchymal thickness.

Slide 17

You can see here the example of a grade 0, a normal kidney and grade 1, 2, 3 and 4 kidney.

Slide 18

If we come back to the anteroposterior diameter, can we predict the follow-up of the uropathy with postnatal evaluation? These authors showed constructing a ROC curve that 10 mm anteroposterior of diameter had a sensitivity of 90% and a specificity of 91% to predict a significant uropathy. Now they also found that 15 mm had a sensitivity of 100% and a specificity of 92.5% to predict for surgical intervention. Of course, this depends also on the indication you use for surgical intervention. In our centre I think that this figure is probably a little too low to have this kind of sensitivity.

 

Slide 19

Now, if you have a significant dilatation, you have to go to scintigraphy. The scintigraphy of choice in these patients is the MAG3 scintigraphy.

Slide 20

I don’t have time to go into detail into this scintigraphy.

Slide 21

I just want to remind you that the first part of the curve, the captation phase is related somehow to renal function, to differential renal function.

Slide 22

And the excretion phase is related to the elimination of the tracer and could give some indication on obstruction.

Slide 23

Now MAG3 scintigraphy has pitfalls and in fact many pitfalls. In cases of impairment of renal function, very important one is hydration state of the patients that could really be a problem in small infants. The bladder capacity, especially in presence of reflux. The dose and the choice of diuretics of course. The presence of complex malformations.

Slide 24

So to second these problems the Society for Foetal Urology developed the concept of well tempered diuretic renogram, now some years ago. But I think it’s a very important concept that we have to follow in the clinical practice. They emphasise especially the role of hydration either orally or IV and the role of bladder catheterisation that we have really to use and to do in every patient.

Slide 25

There are some newer tools. One of them is MR urography. In this paper you can see an example of a 7-week-old girl with a left uteropelvic junction obstruction. On the left, you see a contrast enhanced maximum intensity image that shows, of course, nicely the anatomy and shows also, you can also calculate the differential renal function. On the right, you see the time-intensity curve.

Slide 26

In this paper the authors showed that it was possible not to do only time-intensity curve on the whole kidney but also on different parts of the kidney and here are shown the cortex and the medulla. You can see that there is a delay in the corticomedullary crossover point that suggests an increased tubular pressure and also a decreased amplitude of the medullary peak that indicates impaired concentrating ability of the kidney. So this can give us some clue to the functional aspects of the malformation. You can see here on an older patient the atrophy of the medullary pyramids but you can see also there are no scars on this kidney.

Slide 27

So the MR urography provides excellent anatomic and functional information in children with hydronephrosis. There is a clear visualisation by these authors of 3 phases of the uptake of the contrast material, in the cortex, in the medulla and the collecting system. Both the amplitude of the curve and the washout of the contrast material are predictive of obstruction but, of course, we don’t have too much follow up data and we have certainly less data than with the MAG3 scintigraphy.

Slide 28

Another new tool is the 3D ultrasound. Here you can see an example of how to calculate the whole kidney volume.

Slide 29

How to calculate the volume of the dilatation.

Slide 30

And if you subtract the volume of the dilatation from the old kidney volume, you can have a true kidney renal volume.

Slide 31

This true renal volume correlates very well with the relative function at the scintigraphy and correlates also very well with the volume observed in the MR urography. Then, of course, it is much easier to do 3D ultrasound in infants, so I think it’s a very new tool.

Slide 32

Now, do we have something beyond imagery other than imagery?

Slide 33

Yes we do as you probably are aware of. These authors were able to predict the clinical outcome of congenital not bilateral but unilateral ureteropelvic junction obstruction in a group of newborns by postnatal urinary proteome analysis. In fact, they found a protein that was nearly always decreased in the group of patients who had to be operated and some proteins were increased and they were able to predict with more than 90% accuracy the need for surgery in these patients.

Slide 34

What about renal biopsy? As it was already said, the paediatric nephrologists are really not doing very frequently biopsies in this group of patients. Here you can see that these authors showed glomerular changes quite commonly more than 70% of the cases in patients with urological malformation and obstruction.

Slide 35

They found also evidence of parenchymal maldevelopment especially in the older patients.

Slide 36

So what about postnatal management, how can we put these two things together?

Slide 37

In fact the paediatric urologists and paediatric nephrologists are not only doctors who are taking care of these patients, especially at the beginning, so we have to design some algorithms to help to standardise long-term care of these patients. I’ll show you one that we are using in Western Switzerland. All these algorithms are based on the antenatally detected magnitude of the dilatation. If there is less than 5 mm we do nothing. From 5-10 some other algorithms, say from 7-10 a few more than 10. We will do antibiotic prophylaxis and we will repeat the ultrasound during the first week before the mother goes home. If there is no worsening of the dilatation, we repeat the ultrasound at the end of the first month. In this small dilatation it’s very important to check the ultrasound after one month because we have a lot of false negatives during the first month. We are doing also a VCUJ at day 30. If there is a reflux we take care of the reflux, if there is no reflux we repeat ultrasound without doing scintigraphy in these patients unless there is an increase of the dilatation. If we have more than 10 mm or SFU III and IV, you understand that we are using more and more the SFU grading system we are doing a US at day 1 and if it’s confirmed the dilatation, we are doing the urological workup pretty soon.

Slide 38

So in conclusion, the strategies for early diagnosis. There is a primary prevention diagnosed early and this is the foetal ultrasound. The secondary prevention to select the patients who would benefit from early surgical intervention or also, of course, continuous medical care. There is a tertiary prevention, which is to protect the kidney by the usual method, but I can say also that we don’t have too many data on the effects of this protection in these patients. Thank you very much for your attention.

Slide 39

 

 

Chairman: Thank you very much Eric. So who would like to start the comments or questions? Yes please.

Question: Nice talk. I think although we have flow sheets like you presented and I’m not criticising your flow sheet but we have to be aware that these flow sheets are mainly based on let’s say consensus conferences or anything but not on prospective studies and the difficulty is to decide which, let’s say degree of obstruction or pseudo obstruction we can tolerate without doing something. So I wonder what the last speaker will present but I would like to make the point that most of the data are not coming from prospective studies operation or non-operation. If you have, let’s say if you look to the scintigraphy and you see there’s a washout of about 50% after 20 minutes, you say o.k. I do not have to operate. But it might be that we can also come down a little bit in the future but we have to do other studies.

Prof Girardin: I completely agree. I mean it’s not a few data. The fact is that the main problem is for the patients who are in the grey zone and I mean we have no way to decide really what to do on an evidence based medicine now because no doctor knows this.

Question: Berk, Australia. Do you think it’s really necessary to put all these children on prophylactic amoxycillin or on another antibiotic right from birth say for an isolated hydronephrosis which may just be a PUJ obstruction against somebody who may have gross abnormalities such as valves. My own clinical impression I know there’s no control evidence is that a lot of these children with an isolated hydronephrosis probably don’t develop a urinary tract infection and there’s not a lot of good evidence to show that putting on an antibiotic at birth necessarily makes a big difference. I’m just interested in your comments because I find that some of these parents aren’t keen on their children for going on prophylactic antibiotics.

Prof Girardin: Yes. As you know, there is a lot of question with the antibiotic, the prophylactic antibody and the reflux. We are using it before the VCUJ or in the case of reflux but again we need studies I mean there is no doubt I don’t have data to say it’s the only way to do it. Also for the big obstructive kidney we are using antibiotics but it’s mainly again, you know it’s not really evidence based either.

Question: Because you showed those really beautiful imaging pictures of the congenital PUJ individuals because most of the audience I think are adult nephrologists I just wanted to ask an adult nephrology question because many people in the audience will see adult patients present with intermittent loin pain or acute urinary tract obstruction. They’ll have a kidney scan and they’ll be found to have maybe a unilateral hydronephrosis. Now do you think that those are the same individuals that you’re talking about who are being picked up as foetuses or new born babies or do you think that that’s a different disease? Do you want to comment?

Prof Girardin: It could be of course secondary obstruction but I think that it is well, I don’t know in fact it could be the same disease, of course, do we have complete efficiency with the antenatal ultrasound? The answer is also no. We have some cases even with this quite restrictive algorithm we have some cases that go through we just see them with infection like in the old days so I have no definite answer either.

Chairman: Well, thank you very much. Thanks. Oh we have one more very quick question or comment.

Question: Excuse me Sir. For infants who have prenatal history of hydronephrosis but postnatal ultrasonographies are normal how can you definitely rule out presence of VUR? Do you suggest VCUJ for all infants who have previous history of hydronephrosis?

Prof Girardin: Yes. There’s one group of Belgium who tried to answer this question and they showed that if you have 2 consecutive normal ultrasounds after birth, the chance that you have reflux is extremely low so, in fact, we are using this method and we are not doing VCUJ in these patients, if there are 2 consecutive normal ultrasounds.  Now you know there is also the problem of the reflux that we picked up in this age group because we have data that showed that most of these refluxes are in fact disappearing very quickly after 1 year and I’m wondering if the old concept of some kind of a physiological reflux at birth could be right or not. I am not speaking of the big reflux but the grade 2 reflux for example.

Chairman: Thank you very much. Thanks.