F1000 Reviews are commissioned articles by experts in the field made available on the Open Science publishing platform. In August if this year Mao, Chong and Ong (I am not making this up) published an update on the clinical management of ADPKD.
Here I am noting some of the issues from their paper that seem important.
Prevalence is a measure of how common the disease is – how many individual people are affected by the disease at a particular time – and the stated prevalence of ADPKD in Europe is around 4 in every 10,000 people. This meets the definition of a “rare disease” (less than 1 in 2000). Yet you will also read the phrase “most common inherited renal disease worldwide” and again “the fourth most common cause of end-stage renal disease”. Conflicting messages!
Both statements are of course true. Scientists, maybe too much like politicians, will preface their papers with one or other statement depending on which aspects of the disease they wish to emphasise. So ADPKD is both common and rare – great start! There are funding implications for research and clinical allocations. Philosophy comes into this too as public perception will swing from “rare = unimportant” to “common = uninteresting”, maybe both at the same time. We rely on sufficient medical and scientific people finding it both interesting and worthy of time and money for any progress to be made. So I am really not at all sure what I make of the authors’ description “rare”.
Sadly these just warrant one sentence in this review and although it is sympathetic to the existence of significant psychological burden of the disease, nothing new has been raised or researched in this area.
I began this blog around 2 years ago with a post on genes, concluding that it would be of more than a passing interest to know what my genetic inheritance was exactly. It does look as if that arena has witnessed huge changes and maybe it will become more common in clinical situations (as opposed to research) for ADPKD sufferers to undergo genetic molecular analysis. Most cases of ADPKD are caused by mutations of either PKD1 or PKD2 genes. PKD1 mutations are more commonly seen (85%) and people with these tend to an earlier onset of symptomatic disease with consequent earlier end stage renal disease (ESRD). The proportion who have PKD2 abnormalities vary according to the population under scrutiny – Japan for example, in some studies, has a higher prevalence of PKD2 mutations compared to western populations. But it is roughly 14% and people with these mutations may experience slower progression towards ESRD, some never reaching it. Then there are a very small number of people that appear to have neither of those genetic mutations, so called “genetically unresolved”. One exciting new development has been the identification of another gene that is implicated in ADPKD, GANAB, where patients tend to mild kidney involvement but can have severe liver involvement.
The methods used in genetic testing have changed. This is where it seems very complicated and I don’t have enough knowledge to explain very well, but where past methods have used indirect ways to identify the genes and mutations present the new generation sequencing (NGS) can test for many genes and mutations simultaneously. (Like having four rings on your hob instead of one I suppose). So NGS could bring genetic testing into clinical management. At the moment it has a role for identifying suitable donors, clarifying pathology in young children and in research. However one of the new prognostic scores (see next section) uses genetic information, and for sure we would all like to know more detail about our potential prognosis.
The review mentions a database of genetic information already gathered so of course I surfed over in that direction – Wow! A disclaimer page warns this is just for research and has no clinical application, you can skim over that, then scroll down to the slightly ominous “Enter” button ….. the list pops up with highly detailed naming, and a column on the right stating whether the mutation is pathogenic or not with an alarming shade of red if it is. There are in this repository, 2080 unique pedigrees. I don’t understand it all, but it looks amazing and one paper I read from 2013 referred to just a few hundred genetic mutations having been described so this is an indication that more centres are undertaking genetic analysis.
Two new calculators have been developed: Mayo classification and the PRO-PKD score. The Mayo one is simpler, using height adjusted total kidney volume (htTKV) and age while the other needs the genotype, which isn’t routinely investigated yet. Neither have been tested for validity in clinic use, but both have potential.
Of course this is all about Tolvaptan and a helpful table of eligibility criteria by country is included. An algorithm from NICE for U.K. patients is also given which might help those of us floundering between the GP and nephrology department wondering if it is all just about funding!
The paper mentions a number of other drugs such as somatostatin analogues and tyrosine kinase inhibitors, currently in clinical trials. This comes alongside a note that the previous studies with mTOR inhibitors sound a warning that pre-clinical success does not always lead to positive trial outcomes.
A new patient pathway
This is helpful. I won’t try to replicate it here, but suggest you visit the page
Certainly it could be of use when you attend the next clinic appointment as to what help to ask about. I am not sure the NHS will actually support the steps recommended in visit 2, which includes MRI and psychological support, but one can ask! The authors include a consultant from Sheffield, UK, so it is hopeful that this new patient pathway might be implemented in U.K. There is even mention of benefit from joining local support groups – do you think Facebook counts?!
I like this paper, even though it hasn’t identified anything that we haven’t already discussed, it does talk about a “paradigm shift” in the approach to care and the overall tone is positive.
If you wish to have additional bedtime reading there are 42 references.
Mao Z, Chong J and Ong ACM. Autosomal dominant polycystic kidney disease: recent advances in clinical management. F1000Research 2016,5:2029