good afternoon and welcome to this earthnet webinar my name is Francesco Emma and I'm speaking from my office in Rome so as usual before starting let me remind you that your microphones are turned off but that during and after the webinar you can send your questions through the go to webinar application that appears on your screen I will ask you a question at the end of the presentation the webinar will last approximately 30 minutes we will then have 15 minutes available for questions our speaker today is Maxine bill uh Dr Lebow is probably known to several of you since he has already given an art Network webinar last year Max is what we call a translational doctor is a pediatric nephrologist and a cell biologist with a specific interest in autosomal recessive polycystic kidney disease and other serial parties in recent years he has also set up a very successful International collaborative registry on polycystic kidney disease that includes bio banking he currently holds the position of head of experimental pediatric Nephrology and head of the interdisciplinary Center for chronically healed children at the University Hospital of cologne the title of his lecture today is autosomal recessive polycystic kidney disease please Max thank you Francesco for the kind words and for the introduction and welcome everyone to this webinar which is on arpkd autosomal recessive polycystic kidney disease um there we go these are my disclosures so arpkd what's arpkd it is a genetic disorder as the name already says it is an autosomal recessive disorder that is mainly caused by variants in one gene which is called pkhd1 for polycystic kidney antibiotic disease one and recently carsten bergman's group described variants in another new Gene called dzip1l as a rare cause of this already rare disease pkhd1 encodes a large protein that is seen on this slide which has a large extracellular part a single transmembrane domain and a short cytoplasmic tail the function of this protein fibrocystein is very poorly understood so clinically um one of the main features of arpkd are these massively enlarged kidneys as shown here on this MRI picture or as you can imagine from this picture of a patient of ours um this extended abdomen and this kidney enlargement is mainly due to the dilatation to the ubiquitous dilatation of the collecting ducts in the kidney so this is different from the main brother of arpkd of adpkd where you see cysts throughout all the parts of the um renal tubule arpkd mainly starts from the collecting duct as seen in this nice drawing by um in the tribute of Ted Wilson so kidneys are usually large kidney function can be very variable so a colleague of mine yesterday suggested that I chose some some pictures of arpkd kidneys so this is what they look like these enlarged round um arpkd kidneys and if you then get closer you can already through the capsule see all these micro cysts small cysts that uh can be seen everywhere if you take off the capsule um of the kidney it's even clearer and if you cut through the kidney you can see these ubiquitous dilatation um of the tubular in histology it looks like this so in addition to um the kidney affection there is obligatory hepatic involvement in arpkd so the liver is always affected and this is due to a defect in liver development that is called ductal plate malformation and this malformation leads to hepatic fibrosis and thus portal hypertension um and another liver phenotype are these dilated bile ducts as seen here on this MRI so important clinical symptoms uh obviously the involvement of the of the kidney with the egfr decline but then in addition severe hypertension and many of these kids need multiple drugs and transient hyponatremia then portal hypertension as a result of the hepatic fibrosis and then there are infectious issues like cholangitis which is rather common in arpkd sepsis and urinary tract infections however overall the clinical courses are very variable and it's very difficult to predict an individual clinical course what are the clinical criteria to diagnose um arpkd these have been established already a while ago by Claus varus it's the combination of the typical findings on renal Imaging and you've seen the MRI um picture so you can imagine that the ultrasound also shows enlarged kidneys um with what is called the typical salt and pepper sign in recent uh in in previous times more recent ultrasound imaging shows um the micro cysts and in addition to these renal Imaging findings you would need one or more of the following which would be Imaging findings consistent with the hepatic involvement or clinical or pathology findings um of liver involvement in addition you're looking for the autosomal recessive pattern of inheritance which is the involvement of a sibling and the absence of renal enlargement or typical findings in parents so the clinical criteria are very good however they were established previous to the so-called genetic Revolution and more recent work has also told us that a number of genes can be affected that result in arpkd like presentations so while the classic PKD genes are still the most common cause for polycystic kidney diseases and there are other genes that may be affected that show overlapping phenotypes so-called phenocopies and as some of these disorders like H and F1 beta Related Disorders have substantial additional features of the disease it is important to identify these diseases early on and that leads us um to the first multiple choice question you know that in these webinars um these MC questions are included and the first question um is um is genetic testing relevant in patients with the clinical diagnosis of arpkd and I guess you will now um see the different options that you can choose from number one would be no genetic testing is not relevant as it does not have clinical consequences number two would be option number two would be no genetic testing is not relevant it's just one gene is important for a PKD num option number three is no genetic testing does not give reliable results in arpkd option 4 genetic testing is mandatory to clearly predict the disease cause or option number five is domestic testing is relevant to differentiate arpkd from phenocopies and I guess it has now been started and the first votes are coming in so we have about um a minute that um we have during and during this minute you can answer the questions so half of the time is over right just a few more seconds to go and obviously the large majority of you um identified the answer that I would chose so genetic testing is relevant to differentiate arpkd um from the pheno copies and 85 percent uh chose this one in general I feel that genetic confirmation of the clinical diagnosis may be helpful for counseling families and when looking for subtle external manifestation in cystic kidney diseases and this includes arpkd all right so let's be a bit more specific a situation that that many of you will know a family comes um because the local um gynecologist has seen something with the kidneys um the woman is in the 25th week of pregnancy and then your colleagues from Ops and guinea come along and show you this picture these enlarged kidneys poor differentiation um and the kidneys are also quite bright this is the classical antenatal finding of arpkd and this is what the pedigree um of the family would look like and again this is compatible with a recessive mode of inheritance so the question that the family will then ask your doctor what can you tell me about survival what can you tell me about renal survival and is there anything that we could do for the kid is are there any treatment options so let's start with survival in general um there are some important and good studies out there there is the work by the Mayo Clinic um and were from the US from Lisa K Woodford um and work from from Europe and what they all show and we've summarized this recently in this um in this work on cystic kidney diseases and perinatal manifestation is um that the survival is maybe even a bit better than many of us would think um with neonatal survival in these four studies um up to even 90 percent and there's five afterwards the survival of the neonatal survivors again is quite good so it is an important disease and the severe disease still and it's still associated with substantial mortality but um kids can survive what are causes of early death in arpkd this is again a picture from a patients of ours it's pulmonary hyperplasia after oligo or anhydramnias it's sepsis and CKD or in patients on kidney replacement therapy can be KRT problems very very early in life or it can obviously be the parent's decision to withdraw care just some some of the examples what about renal survival what can we tell um the families about renal survival um and there are a number of observational studies going on that try to characterize the clinical causes of arpkd that leases work in the U.S there's Larissa karachuk's work um within Reena radar in the UK and we have set up um this a-reg PKD registry that Francesco already mentioned so what are we doing in the registry um we are collecting a basic data set I'm asking for family history the mode of presentation Etc and then we try to follow these patients about once a year asking for sonomorphological changes asking for the development of kidney function Etc currently more than 100 centers from 30 countries um have registered um for this study that is supported by multiple National and international societies including the gpn the ESPN and earthnet um where are we with the patients we have more than 600 patients included by now actually 634 and we have about 3 000 independent visits of these patients and what is important is that we have about 200 patients with five at least five visits and about a hundred patients with 10 visits so that we can now start to follow longitudinal causes of arpkd this is the current cohort it's mainly a pediatric cohort as most of the centers are pediatric Nephrology centers and it covers all age ranges of childhood and Adolescence however there are some adults that are included and they are particularly interesting what about renal survival that was the question that was asked um in our cohort which is a bit special obviously but in this large cohort we see um that about 50 percent um we see about 50 renal Survival by the age of 20 years there are these kids um that are severely affected um and that may require a kidney replacement therapy very very early even when in the first weeks of life um and this is this uh severely affected subcohort that you can see here in this Kaplan Maya curve and then there seems to be some continuous progression of loss of kidney function or of kidney survival are there any particularly risk factors um particular risk factors for early dialysis dependency this is something that we looked at a few years ago and we back then we identified 36 patients that require Dialysis in the first year of life and compared them to about 350 patients that did not require um Dialysis in the first year of Life all of these kids with arpkd and we looked at pre-perry and postnatal information and we're not going to go through all these details what you see is that there are a number of differences between the subgroups as expected and when we take this to the multivariate model um some aspects some parameters remain um Associated that is oligo antidramnios that is prenatally enlarged and kidneys and for example quite interesting also a low apgar score in patients that do require Dialysis in the first year of life based on these data set um we back then established a model to predict probabilities for dialysis or kidney replacement therapy within the first 12 or 36 months after birth and um what this shows you is actually that depending on these markers that you can see easily with ultrasound before birth you have um a stratified risk pattern to develop dialysis dependency in the first year of life so if you just have enlarged kidneys in arpkd the probability to require Dialysis in the first year of life is much lower than if you have oligo and hydramnios and large kidneys and identifiable renal cysts and this can help us to identify a high risk group for example for clinical trials so the antenatal sonographic detection of kidney enlargement renal cysts and oligo or anhydramnios may help to estimate the risk of the risk for early dialysis dependency in arpkd that takes us to the second multiple choice um question so um what is the cause of kidney function in the arpkd First Option all children will require krd within the first weeks of life second option only children with severe liver affection will require KRT third option kidney replacement therapy is generally not needed until 20 years of age fourth option kidney replacement therapy may be required in the first weeks of life of fifth option the kidney phenotype is the only variable in terms of kidney size and now the um you should see the different um options and again we have a minute to vote all right okay and the minute is almost over and most of you have chosen um number four kidney replacement therapy may be required in the first weeks of life which is also like considered best then a number of you and as I read go through the question again I understand why um a number have also chosen um KRT is generally not needed until 20 years of age which um was uh I guess linked to the 50 that I showed so what can we tell um the parents about treatment options is there anything um that we can do and what's the literature on this um there may be um or two um manuscripts that may be important um are the ones that I show here and there's a specific um consensus expert recommendation um for AR PKD um that was published in jpets a while ago after a workshop that Lisa organized um and then from the Germany assist um Consortium um there's this um manuscript on perinatal diagnosis management and follow-up of cystic renal diseases um that was published a couple of years ago in in Jama Pediatrics so to summarize um the key messages um we must say that currently it is still symptomatic treatment that we're doing we should aim for symptomatic treatment under the best possible um conditions for such a child and that may include that you plan delivery in a center where there is a good NICU that is also equipped to treat such a difficult patient where there is multidisciplinary pre and post-natal um care and consultation for these kids and their families as for other renal disorders and peritoneal dialysis um is the preferred method for neonates in arpkd treatment of hypertension may require multiple anti anti-hypertensive agents and it may be helpful to tolerate sodium levels a bit more on the lower side and then a topic that is frequently discussed is the topic of nephrectomies and the rational for unilateral nephrectomy is based on few and small nutritional studies and um in the in the jpets paper we summarize that actually there is no published evidence um that nephrectomy results in respiratory Improvement there's also no published evidence to support nephrectomy for severe hypertension in early arpkd what we looked at in in the Registries uh study now um uh was um the consequences of very early bilateral nephrectomies so what we did um in this area at PKD analysis is we defined four subgroups and these were kids that underwent bilateral nephrectomies within the first three months of life and we called them Feb them for very early bilateral nephrectomies um and we compared them to various control groups one controlled group underwent bilateral nephrectomies in the year afterwards one control group underwent um dialysis but with at least one kidney in place and one control group had total kidney volumes that were comparable to the total kidney volumes of the fapna group and we compared all the pre and perinatal aspects that I've shown you um in the in our first paper for risk factors on um very early dialysis and it did not find um a lot of differences um between all these four groups there were a few differences but not many however what we did see is um that severe neurological complications and we defined this as ischemia in fact and parenchymal defects hypoxic encephalopathy or atrophy of the optical nerve with lots of vision were much more frequently seen in the kids that underwent bilateral nephrectomies in the first three months of life so in 12 out of 19 febner Kids we found some of these severe neurological complications but only in two out of nine um kids with early bilateral nephrectomy in two out of 12 kids with very early dialysis and in none of the kids with um that we called total kidney volume control and these are the the Kaplan Maya curves and comparing these different subgroups for survival without severe neurological complications and you can see that the kids with very early bilateral nephrectomies um showed this rapid decline of survival without complications if we turn it around and look for risk factors that are associated with severe neurological complications in this cohort we could identify two independent risk factors and one was the very early bilateral nephrectomy and the other one was the documentation of severe hypertensive epicents so very early bilateral nephrectomies in children with arpkd may be associated with more neurological complications and this is just um a matter that you know to be considered um when taking that decision for nephrectomy one discussion is about peritoneal dialysis I sometimes see okay it does not work in in arpkd um we compared this in the data set from the ippn registry um organized by by Fran schreffer and we identified 87 arpkd patients and matched them with patients suffering from congenital nephrotic syndrome or cocute one to one or one to two and um in the end could compare 79 AR PKD patients um to CNS and kakud patients and to make a long story a very very short um what we could see that in this um specific cohort of young children not neonates but young children um actually we did not see a difference um concerning the peritoneal dialysis technique survival between the three groups so PD can be used in young children with arpkd as in children with other early onset renal diseases that takes us to the multiple choice question number three what a treatment approaches in a or PKD option one would be gene therapy for arpkd is established and is Curative option two targeted and disease modifying treatment is available treat opt-in 3 treatment remains symptomatic option 4 P peritoneal dialysis is not possible in arpkds kidneys are too large and option 5 arpkd patients must undergo bilateral nephrectomy as soon as possible and I guess you can now vote again okay this is these are the last seconds of the vote and more than 90 or 90 percent um have chosen option three treatment remains symptomatic right um to comment a bit on the limitations of all these data at the end obviously um ahpkd um is an observational um study this is real world clinical data um and not a clinical trial um some limitations include that there are partially missing genotypes they are partially missing data points in some of these data sets for sure this is a registry study and there are various levels of buyers one is a selection bias um in two ways um one selection bias may be that we do not include a lot of the most severely affected children that pass away um quickly as the centers may not dare to approach these families another bias is that mainly tertiary centers are um including data so um we may also have a bias towards um kits that are transferred to tertiary centers and maybe a bit more severely um affected just some of the limitations caveats to keep in mind when looking at this at this data to summarize arpkd and newborns remains a clinical challenge or aopkd in general genetics may be helpful to establish the correct diagnosis treatment for erpkd currently remains largely symptomatic and opinion based first observational evidence is emerging um I've shown you data on the bilateral nephrectomies or the data on the um peritoneal dialysis in young children and then I do very much feel that we need translational International research approaches to progress in this very rare disease as a basis for you know evidence-based and targeted Therapies in pediatric PKD and with that I come to the end I want to thank especially Catherine who does a great job in um you know running the registry and being in touch with all the the centers I want to thank the funding agencies I want to particularly think all the sites that continue to enter data into the registry the collaborators and I want to quickly point to the upcoming webinars in the next week roksana and then Simone and I'd be happy to take questions thank you thank you thank you very much Max for this very interesting webinar and also for showing us some very uh interesting data that that really could only be collected with the registry that you've set up so uh please send in your question I see that some are coming already um the first question is actually one that I also had it comes from Christy um Thomas um and the question is whether you could clearly establish a relationship between the nephrectomy and the hypotensive episodes yeah so that's that's what we all feel um if you look at it from the statistical point of view they come out as an independent uh factors so um we we must say that um that's why I also said it's the documentation of severe hypertensive episodes we must say that um at this point um we can only rely on the data that we have from the centers and um that is just what's being documented in the registry we do not have the full access to all the blood pressure um values all over the time okay and and just quickly as a side question if you have an answer um because uh indeed some of these patients when you nephrectomize them they become really hypertensive um do you have any uh specific uh treatment uh when these patients one with a very low blood pressure what do you do yeah I guess we do we do what everyone else is trying to do um but there is no specific treatment that I'd be aware of that um that would have what we um do um is we we you know um look at um at sodium levels we have added sodium into the PD fluid and some of these patients um we we watch their fluid state is very very carefully um and you know we are fully aware that um there are sometimes situations where you just have no other choice than uh to do the nephrectomy and maybe then in the second step the the second nephrectomy and it's you know we've seen it also in even knowing this data we've seen over here too um we've also had good and bad outcomes um but we just tried to um yeah monitor these these kids very very closely for their fluid status so we basically do we all do the same thing and uh again was actually asking you something that you may already have uh mentioned in your talk but could it be that patients who underwent very early by an effect bilateral defect to me um actually had more severe ARP kidding yeah yeah that's that's the question um that that comes along a few um every now and then I mean we try to um to answer it by having these three control groups and by uh looking at um all these pre-parian postnatal um uh data sets obviously there is not the one way to fully rule out that there may be an additional um independent neurological aspect um of arpkd um that we are not yet aware of okay then we have a question for Dr lokia sifaki from uh Greece uh she uh and starts to thank you for the webinar and um um and and he's asking whether um you would you could comment um renal disease in children and I'm reading her question who is question I apologize um um whether you've comment on the risk of renal disease in children adults with heterozygous mutation for arpqd will present with high renal ecogen City at the ultrasound with no more enough function what is the prognosis in these adults is there any specific recommendation for follow-up apart from evaluating kidney function once a year right um to my knowledge there's mainly one study from the US that looked at obligate um heterozygous carriers of pkhd1 variants um and what they found is exactly what um the colleague describes is um they found some mild um changes on ultrasound without affection of kidney function and so that that's the data we have there are no specific recommendations to my knowledge could there be some modifier change in these patients yes there could be modifier genes that is also um data out there from from cast and bagman and others um that have shown um that a co-occurrence of um variants in different PKD genes um can lead to severe phenotypes and for example the co-occurrence of a PKD two variant with a pkhd1 variants or of H and F1 beta and PK HD1 Etc and this this has been shown and um both in patients and also in multiple Mouse models okay question from Dr Matthew uh what modification do you use in PD in neonates is a mantectomy a must yeah we we usually um perform it just um and um what we've seen in the ippn data is um you know which is not a very big surprise is that we have um had lower uh filling volumes in arpkd patients compared to the other um to the other groups and that they use more Cycles all right so again Dr Christy Thomas is asking um whether in those children with refractory uh hyponatremia and fluid restriction um what should we do next with refractory hyponatremia and fluid restriction um yeah well you've done the first steps so what we would do is then add um sodium what um I tried I um to say is that we would also accept um somewhat lower sodium values in these kids um so in the range of you know low 130 or even to to 130 um we've sometimes seen that um this may directly affect blood pressure foreign frequent problem after renal transplantation children with arpkd no not to my not to my knowledge no and I I don't see a reason why why that would be um why that should be the case now yeah I would agree with you and and and and and you you would you comment on the nephrectomy in patients that undergo transplantation for your PKD yes um so again it is an individual decision um so the colleague um that uh suggested that I um showed the picture just yesterday actually um was doing a transplant um in an arpkd kid in this kit we decided to take out um one of the kidneys um at the time point of the transplantation um and uh I guess from from our experience from the aired PKD data set this is what many many uh centers are doing to take out one kidney at the time Point um of transplant all right so we sometimes see when you when you have to take out one kidney very early in life so independent from from the transplant um is that if you take out one then uh the other kidney sometimes starts to um grow very very rapidly so that you end up in a situation where you have to take out the second one two so that's something to consider when you decide to um to go for unilateral nephrectomy all right so uh Jelena is asking you uh what would you advise in counseling a family for top if they had already um if they had already a sibling with very severe neonatal death right um so it is very it's a very difficult decision um so we know that there may be intra familial variability in a PKD and that is very very poorly understood it is generally believed that about 20 percent of these siblings show some degree of variability um you know top obviously is a matter um that has multiple layers ethical layers religious aspects you know um and obviously the the law aspect um I tend to uh or my my feeling is that we you know should be very open with these families and just you know tell them what we know and what we don't know and right now the apart from the data that I've shown there's hardly any way to really predict um the causes and um so that the family needs to take this decision as well informed as possible but uh let me just follow up on this question but besides what you just mentioned would you comment on on what we know about phenotype genotype correlations there's still some correspondence between severe mutations and milder mutations right so what is known is that um well let me start the other way around it was for a long time thought that by allelic um truncating mutations would not be compatible with Life um now recently um there have been some um first reports emerging um on patients that did survive and had substantial or severe arpkd but but did survived also survived well um and um so so that's an important novel aspect apart from that um in AR PKD we're facing the situation that most of the patients have private variants or private mutations and so there is one mutation that is a bit more common um that accounts for 15 or so but there's not like the one hot spot um as in other other diseases so in general um we can at this point just say that by allele truncating mutations are associated with a more severe phenotype but um also missions mutations can go along with severe phenotypes we're trying to um to identify uh yeah a deeper correlation okay so um uh content bertan is asking you uh when Evolution needs peritoneal dialysis is nephrectomy usually done um is it most frequently uh unilateral nephrectomy to keep diuresis I think you partially already answered this question but I don't know yeah yeah so um yeah my my feeling is if there's a way if the kids are very young if there's a way to keep the kidney in and we would try to keep it in um I know that especially in the first three months of life um and um sometimes it's just impossible and PD will not work then you have to take it out or I have to take one out yeah um we have a question again from mehmed uh trans severe is those patients who underwent um I know I actually um I I guess this was part of the previous question I do apologize because when I asked the question I cancel the question that has been asked that I don't uh make mistakes um so I will I will just go to uh next question guillem pintos Morel is asking you um so we have a pkhd2 type are there phenotypic differences right and so there is this d zip1l a gene that custom identified um however this is this is really very few patients by now um so I wouldn't dare to make um a real uh statement on a specific phenotype um uh yet um so we will we will have to see whether others um whether other centers um also identify additional patients with these 1l variants or um even additional genes foreign also covers the last question by Dr Matthew who wanted you we're asking you to comment on the new Gene phenotype um if I can uh Max before leaving um uh ending the the webinar um can I ask you uh um one last question he said um with the data of your registry do you have any sense that amnio infusion prenatal on your infusion can be helpful in severe cases um I so we're asking for it and the last time I we we looked at it we didn't have um that much data on this specific aspect but um I must say it's been a while since I looked at it so um we will need to check this again um back then we couldn't draw any um any real clear-cut conclusions yet all right and with this Max I really would like to thank you very much for this wonderful update on arkd and to you all I would like to remind you the next webinar especially in these times where we don't get the chance to go to meetings and to uh hear a lot of lectures I think this webinar particularly precious uh the next one will be on access for chronic hemodialysis by Roxanna Shroff and um and then Simone baldovino will give us a lecture on systemic amyloidosis as we probably have mentioned before earthnet is just not pediatric Nephrology that covers all of nephrology and we're very happy to also have some topics there are probably there are more of interest to other nephrologists so thank you again to everybody and um and please join us on May 7th thank you very much and thank you Max foreign