In September 2014 the Cleveland Clinic Journal of Medicine carried an article by William Braun a nephrologist with an interest in polycystic kidneys. Entitled “Advances in autosomal dominant polycystic kidney disease – 2014 and beyond” it was written for Medical Grand Rounds, a term used for educational sessions for doctors given by specialists in their field. As one might expect there is considerable medical jargon in the paper, but because it is really interesting for anyone with ADPKD I have attempted a precis (my spellchecker doesn’t like that word and I have no idea how to add an acute accent above the e) and at the end I shall list the key points.
Braun describes the known facts, which, because he is based in America, have a stateside bias to them:
- US prevalence is between 1:400 and 1:1000
- 700,000 patients in US living with PKD
- 6,000 new cases occur each year
- Of the patients with end stage kidney disease, 5% of them will have ADPKD
TWO TYPES—PKD1 IS MORE COMMON AND PROGRESSES MORE RAPIDLY
The detail of this I covered in an earlier post, in summary:
- PKD1 accounts for 85%; is carried on the short arm of chromosome 16; the gene codes for polycystin 1, a large glycoprotein with over 4000 amino acids; this protein sits in the cell membrane with a tail outside the cell that acts as a mechanosensor stimulated by urine flow within the renal tubule; patients with PKD1 tend to have faster disease progression; cyst development occurs early and they tend to have more cysts.
- PKD2 accounts for about 15% cases; the long arm of chromosome 4 carries the gene which codes for polycystin 2; this protein has a role in calcium transport within the cell; typically the disease progresses more slowly in people with PKD2.
Some patients have neither of these genes, but then we get into very complicate genetics.
IMAGING CRITERIA HAVE BROADENED
The old criteria for making a diagnosis from ultrasound were set in 1994 and were based on the natural history of just PKD1 patients, those that tend to present earlier with larger cysts. I was diagnosed in 1980s and before my ultrasound scan was told that to be certain I would have to wait until I was over 30. As it happened there were plenty of cysts so no doubts, but many people with a family history played a waiting game. Now the criteria have been modified – see chart.
So if you are between 15 and 39 and have a positive family history, even if you don’t know which gene type, just 3 cysts will confirm the diagnosis. That is the “positive predictive value” part, while the sensitivity means that some people with the disease will still be missed, but this becomes less likely as they get older. You can see from the chart, however, that for people with relatives carrying the PKD2 gene, where cysts may develop later, an ultrasound scan before 30 will still only pick up around 70% of cases.
DISEASE CAN PRESENT IN MANY WAYS
The presentation of an illness is a term to describe the first symptoms and signs that a patient experiences. Braun lists 8 main ways that a patient with ADPKD might come to medical attention:
1. High blood pressure
3. Urine tract infection
4. Kidney stones
5. Abnormal blood tests showing poor kidney function
6. Cysts in other locations
7. Cardiovascular disease
8. Intracranial aneurysms
Much of this is not new knowledge, but some facts are worth highlighting. For example, the pain can be abdominal, back or flank pain, might be local (can point to it with one finger) or diffuse (all over the place), can be a fullness or a more severe piercing type of pain. The cause of the pain can be enlarged or bleeding cysts, compression of bowels or other organs (reflux or constipation) or diffuse musculoskeletal pain (such as low back pain).
With standard urine infections one expects to find the infecting organisms in the urine test but with PKD the cysts may be isolated from the draining parts of the kidney so a negative urine culture does not rule out infection. Recent work on CT and MRI scans have shown that using both together can increase the chances of diagnosing an infected cyst. Actually this non-communicating issue is relevant with bleeding cysts too since they will not all present with blood in the urine.
Kidney stones are more common in patients with ADPKD – some 20-30% will have them. They are usually composed of uric acid or calcium oxalate.
Cysts can crop up in all sorts of places – liver, pancreas, seminal vesicles and arachnoid. Interestingly liver cysts can be detected by MRI scan in 94% of ADPKD patients over 45.
The cardiovascular disease seen with PKD is usually heart valve abnormalities, mitral and aortic, or aneurysms. I looked at brain aneurysms in another post, the only thing this article adds is a pointer that below 4mm and they have a low risk of rupture while above 7mm and the risk is high.
The CRISP study looked at kidney volume as a marker of progression, studying 241 patients aged 15-46 over a period of 3 years. On average kidney volume increased by 5.3% per year and a larger volume at the beginning of the study indicated more rapid decline in function.
There are several pathways that lead to the formation of the cysts. The 3 major processes involve:
- Calcium transport into the cell
- Vasopressin and cAMP (cyclic adenosine monophosphate)
- mTOR (mammalian target of rapamycin)
This section may be somewhat complex if your starting point is non-scientific but I will try to simplify things.
Calcium transport disruption
Cells have inside them different compartments which are commonly called “organelles” (meaning “small organs” – because each has a specific function as do the organs in the whole body). One of these organelles is the “primary cilium”. The primary cilium is very small, no more than 1 micron (micrometre) and is made of “microtubules”. The protein PC1 (polycystin 1) extends from the primary cilium across the cell and across the cell membrane with its tail sticking out into the urinary space in the renal tubule, where it senses flow of urine inside the kidney. The protein PC2 is right next to the PC1 in the cell membrane and has a role in allowing calcium to enter the cell – a calcium channel. PC1 opens the calcium channel so that calcium can flow into the cell where it controls cell proliferation. In ADPKD kidneys the polycystins, PC1 and PC2, are either sparse or mutated so the calcium transport into the cells is not working properly. This means that the multiplication of tubule cells is not controlled, too many epithelial cells are made and they form cysts.
Activation of cAMP
Vasopressin is a hormone, also known as “antidiuretic hormone” and as its name suggests it acts to keep water inside the body. It works by activating a substance called cAMP, which in turn activates a pathway that plays a part in the tubule cells knowing which way up they are. Normal tubule cells, when they multiply, divide in half horizontally, west to east as it were, so the tubule grows longer. ADPKD cells have lost the instructions to divide this way and so will also divide vertically, or north to south, so increasing the diameter of the tubule and eventually forming a spherical cyst because they have lost all sense of direction. The bottom line is that they do this because there is too much cAMP and too much vasopressin.
This is the underlying physiology for the trials on increasing water intake and those using Tolvaptan, both of which are aimed at blocking the effects of vasopressin. The detail of these trials needs a whole post to itself, but suffice to say that both increasing daily water intake and the use of vasopressin antagonists show promise in the management of ADPKD.
Upregulation of mTOR pathway
The “mammalian target of rapamycin” was named somewhat unimaginatively when it was found to be the pathway that rapamycin (sirolimus) acts upon; mammalian because the study was using mice and not zebra fish – the fish being fascinating, but you will have to wait for a later post!
So the mTOR pathway plays a role in growth and proliferation of the tubule cells. Rapamycin inhibits the pathway therefore it and similar chemicals might have a role in treating ADPKD by inhibiting the cell growth.
The studies on this have so far failed to excite the scientists – while the kidney volume may stabilise using rapamycin or similar drugs the function has continued to deteriorate.
- Specialised cells that promote cyst formation have been discovered
- Visible cysts are the tip of the iceberg – for each cyst detected on MRI there may be a further 60+ smaller cysts. These microcysts may interfere with kidney function. They can compress the normal kidney tissue or block the drainage ducts. Targeting these microcysts before they grow is one approach to be explored.
CURRENT MANAGEMENT OF ADPKD
Blood pressure control – 120-130/70-80mmHg
High fluid intake – suppresses vasopressin; 2-3litres per day
Low sodium diet – lowers BP and may also reduce kidney stones
Limit caffeine – in theory it interferes with the phosphodiesterase that breaks down cAMP and so might lead to increased cAMP; this has not yet been proven to benefit.
Diet – prudent to avoid high protein intake but no evidence on low protein diets
Watch for complications – bleeding, infection, stones, urine tract obstruction
Formal genetic counselling and molecular testing
Renal replacement therapy – transplants have 95% survival at 5 years.
- For patients with a family history criteria for diagnosing by ultrasound now require a minimum total of three renal cysts.
- Screening for intracranial aneurysms is warranted
- CT and MRI scans together should be used to diagnose infected cysts
- Water intake of 2-3 litres per day may slow cyst expansion
- Tolvaptan failed to get FDA approval, trials ongoing.
- Rapamycin has had mixed results in clinical trials
In my summary I have kept to the same headings so for further details it will be easier to find the appropriate section. It is probable that another grand rounds paper will be published from Cleveland in 2015 as I found others from previous years. So this would be a good space to watch!