My Kidneys can’t concentrate
So its not just my brain that has problems concentrating as I get older – a recent study has confirmed that cystic kidneys in ADPKD have major problems when it comes to concentrating urine.
They have an impaired ability to concentrate urine beyond a maximum level and this level falls with the progress of the disease, and more specifically they have an impaired ability to concentrate urea in the urine.
I will work my way through to the implications of this study, but first we need some background physiology.
- The working unit of the kidney is called the nephron.
- Each kidney has about 1.2 million nephrons.
- The nephron starts with a filter, the glomerulus, then has some convoluted tubules (that is their actual name – and describes them perfectly), followed by a long U-shaped loop, the Loop of Henle
(Henle was a 19th century doctor from Bavaria who actually put his name to numerous structures – including a ligament, a membrane and a fissure, but only the Loop of Henle in the kidney has stayed the pace of time.)
- The Loop of Henle has a hair-pin bend as it turns back on itself and runs into some more of those convoluted tubules – these are called ‘distal’ as opposed to the earlier ‘proximal’ tubules, named by their distance from the glomerulus.
- Then finally the tubules run into a collecting duct which goes all the way to the end of the nephron, meeting up with other collecting ducts in the pelvis of the kidney (the funnel part where kidney attaches to ureter)
The structure of the nephron is fundamental to function.
The position of the nephron in the kidney is also vital, with the glomerulus and convoluted tubules sitting in the cortex or outer part of the kidney and the long loop of Henle and collecting duct both dipping into the medulla or middle part of the kidney. The tissue surrounding the nephrons is called interstitium or interstitial tissue.
The process of urine formation begins with filtering the blood. Then in the proximal convoluted tubules about 2/3 of what was filtered is reabsorbed – this includes 65% of the water and sodium, 100% of the glucose and about 90% of the bicarbonate. The fluid flows down through the proximal tubules into the descending arm of the Loop of Henle, also known as the thin arm – because it is thin compared with the ascending loop which is thick.
Nature performed a clever trick when it folded the nephron as this created a counter-current which enables the concentration of urine. As the fluid inside the nephron moves back up the Loop of Henle the salts of potassium, sodium and chloride are pushed out through the cells on the wall of the nephron into the interstitium. But the walls here are impermeable to water so water cannot follow the salts and so the fluid inside the nephron gets more and more dilute as the tissue around the nephron becomes more and more concentrated. This is called the “cortical-medullary osmolarity gradient“. Maintaining this gradient is fundamental to the ability to concentrate the urine.
‘Osmolarity‘ is another word for concentration, measured in amount per litre. It is similar to the other term ‘Osmolality‘ which is a measure of amount per kilogram. I tend to use both terms, biochemists would be horrified at my imprecision!
The process of concentrating the urine depends on what happens to urea in the nephron.
Urea can be thought of as a metabolic waste product, it is a chemical substance that the body uses to dispose of unwanted nitrogen. Urea is freely filtered at the glomerulus but just after the first set of convoluted tubules the nephron becomes impermeable to urea so it has to stay inside the nephron, becoming more concentrated as the fluid progresses through the nephron. Finally, in the last part of the collecting duct which sits in the inner medulla of the kidney, urea finds some special urea-transporters in the cells of the wall of the nephron and it is able to get out of the nephron into the interstitium. Because of the anatomy and the folding of the nephron the collecting duct is lying alongside the descending part of the Loop of Henle and here urea finds itself being secreted into the nephron again, going from the very high concentration of urea in the interstitium to the lower concentrations found inside that part of the nephron. This recycling of urea reinforces the cortical-medullary osmolarity gradient.
Back to the study:
It was a relatively small study undertaken in Netherlands where they performed a water-deprivation test in a group of 15 patients with ADPKD and compared them with a matched group of 15 patients suffering from non-cystic kidney disease (IgA nephropathy).
When you are deprived of water (the paper uses the term “thirsted”) then the pituitary gland releases more vasopressin (AVP) which does its utmost to make you reabsorb more water from the nephron in order to prevent our body from becoming dehydrated. The study hypothesis was that this vasopressin response would be stronger in the ADPKD patients than those with renal impairment due to other causes.
The vasopressin is known to increase the growth of cysts by its effect on cAMP – we will get back to this later.
So, while thirsting the study patients, the team measured urine concentration (osmolality) and compared it with plasma osmolality and they also measured AVP and another marker called copeptin.
Just reading about the methods has made me feel thirsty – it entailed an overnight 14 hour fast and then a further day of fasting and interval blood and urine tests. Then the patients were given a synthetic form of AVP to see if they could concentrate their urine even further.
The results showed that the ADPKD group could not concentrate their urine as well as the control group. Since both groups were matched for degree of renal impairment this difference has to have arisen from something specific to the ADPKD.
Both groups, ADPKD and controls, had an increase in plasma AVP levels and copeptin levels during the study. But the ADPKD group could not keep their plasma osmolality under control as well as the other group despite the high levels of AVP.
Basically the ADPKD group were unable to make the necessary physiological responses in the face of dehydration, they could not concentrate their urine enough.
So what goes wrong in ADPKD?
The study authors have proposed that it is a mechanical disruption to the medullary osmotic gradient perhaps because of all the cysts forming in the renal tissue. The phrase they use is “disruption of renal architecture“. These cysts get in the way of the urea recycling, perhaps stopping it move through the interstitium and back into the Loop of Henle.
It is a vicious circle, as the cysts expand then the urine concentrating capacity falls further, leading to an increase in AVP and then increased cAMP, which in turn leads to more and bigger cysts.
It was previously known that urine concentrating capacity was impaired in ADPKD. This study added in measurements of total kidney volume (height adjusted) and related the concentrating impairment to stage of kidney disease. Their results have confirmed that concentrating capacity falls off even before other evidence of renal impairment – in the very early stages of the disease process. Furthermore the concentrating ability of the kidneys deteriorated in parallel with the progress of the disease.
What are the implications?
In early stages the progress of the disease is not accurately measured by eGFR. However the concentrating capacity is impaired very early on even before GFR falls. This can be measured by the urine to plasma ratio of urea concentration (U:P urea osmolality).
This could be undertaken by most clinical laboratories and the blood and urine tests would be fairly straightforward for the patient. The authors therefore suggest that U:P urea ratio is added to routine clinic tests.
This study also highlights how important it is for ADPKD patients not to become dehydrated.
The physiology relating to dehydration is well described:
A rise in plasma osmolality in dehydration will trigger the release of vasopressin (AVP) from the pituitary gland. This attaches to receptors on the cells of the collecting ducts in the kidneys, makes aquaporin-2 vesicles migrate to the cell surface and fuse with the cell membrane. An aquaporin can be thought of as a pore through which water flows, as its name suggests. Once fixed to the cell membrane the aquaporins enable water reabsorption from the fluid inside the collecting duct back into the interstitial fluid and from there back into the blood stream. All well and good for reversing dehydration but AVP also stimulates the formation of cAMP inside the epithelial cells, which, as we stated earlier, is one of the main triggers to cell proliferation and cyst growth.
ADPKD patients have impaired maximal urine concentrating capacity.
Water deprivation may be deleterious and should be avoided in ADPKD patients.
Urine Concentrating Capacity, Vasopressin and Copeptin in ADPKD and IgA Nephropathy Patients with Renal Impairment
Zittema D, Casteleijn NF, Bakker SJL, Boesten LSM, Duit AAM, et al. (2017)
Urine Concentrating Capacity, Vasopressin and Copeptin in ADPKD and IgA Nephropathy Patients with Renal Impairment.
PLOS ONE 12(1): e0169263.