Slide 1

Good morning. Thank you Peter I’m very glad to be here and I’d like to express my gratitude and thank especially Professor Gross for his kind invitation to this session. After this very nice and pure science lecture about aquaporins I would like to go to the clinical part of this symposium. I think that the first lecture should consider the very important topic of incidence and prevalence of hyponatremia just to be aware how big the problem is.

Slide 2

At the beginning as some of them are probably not familiar with these terms, I would like to give you the definitions of what we are talking about. Hyponatremia is commonly defined as a serum sodium concentration below 136 mmol/l. Of course, as a definition a low concentration which has been taken from text books.
Another, what is incidence? Incidence is a measure of the risk of developing some new condition or disease within a specified period of time and the prevalence of the disease is defined as a total number of cases of the disease in the population at a given time or the total number of cases in the population divided by the number of individuals in the population. Just to be sure what we are talking about.

Slide 3

So the Sodium and it’s accompanying anions are the principle osmotically active solutes in extracellular fluid. The sodium concentration falls and then we talk about hyponatremia when body sodium retains water (without solute) or when there are net external losses of sodium without water. So they are very simple.

Slide 4

How is sodium serum concentration defined? So, the serum sodium concentration is determined by the body’s content of sodium, potassium and Total Body Water (TBW), thus: hyponatremia, we can have different groups of hyponatremia, so the difficulty is to assess the frequency, the incidence and prevalence. Hyponatremia can be with decreased, normal or high total body sodium. Or hyponatremia with extracellular fluid volume depletion, excess of ECF volume, or normal ECF volume.

Slide 5

So traditionally, patients with hyponatremia are divided into categories according to their body sodium content or intravascular volume into these three categories: with low body sodium content and then with volume depletion. Hyponatremia with high body sodium so we have hyponatremia with high body sodium content. Of course, there are some edematous conditions with – volemia. Normal body sodium content and hyponatremia, we call this euvolemic hyponatremia or syndrome of inappropriate antidiuretic hormone secretion. So different types of hyponatremia and different types of volume status.

Slide 6

So therefore, this is a very simple, it looks complicated, but it’s a simple diagram with different forms of hyponatremia and volume status. So we can have hyponatremia with hypovolemia. In these cases we have lower total body water but much lower total body sodium. Then what we do we can assess the urinary sodium excretion and in patients with higher than 20 mmol/l urinary sodium excretion we can predict that we have some renal losses of sodium, diuretic excess, mineralcorticoid salt losing syndrome and so on and so on. When the urinary sodium excretion is lower than 20 mmol/l, we have extrarenal losses like vomiting, diarrhea, third spacing of fluids and so on. On the other side we have hyponatremia with hypervolemia so the total body water is significantly increases and also the total body sodium is increased but much more water is in the body. Again what we do we assess the sodium excretion when we have higher than 20 mmol/l, we can look for acute or chronic kidney disease. When we have lower than 20 mmol/l we look for nephrotic syndrome, liver cirrhosis or cardiac failure. Finally, we have euvolemia, the total body water is increased but we have a normal sodium in the body and then usually we have increased sodium excretion and there are some conditions, the most important is the syndrome of inappropriate antidiuretic hormone secretion.

Slide 7

We should also consider other causes of hyponatremia so-called for pseudohyponatremia which we can find in patients with hyperlipidemia, with multiple myeloma and when the plasma osmolarity is increased also in patients with hyperglycemia or infusion of different solutions.

Slide 8

There is another classification of hyponatremia, patients with so-called hypotonic hyponatremia can be divided into these three categories with impaired, unimpaired, impaired and impaired vasopressin-dependent, this is vasopressin independent and this is vasopressin dependent. You see tat in patients with hyponatremia and unimpaired urine diluting ability we have psychological conditions like psychotic polydypsia and polyuria, beer potomania with people who drink too much beer and very rare infantile water intoxication. With impaired urine diluting ability vasopressin independent is acute renal failure, tubulointerstitial renal disease, is diuretics and very rarely nephrogenic syndrome of antidiuresis.
Finally the urine diluting ability is impaired and is vasopressin dependent there are some conditions like here cirrhosis, congestive heart failure, Addison’s disease and of course, a syndrome of inappropriate antidiuretic hormone secretion.

Slide 9

My co-chairman Professor Gross published some years ago statistics of how often different types of hyponatremia are present and what he did he checked 100 patients with hypotonic hyponatremia and he found that the most frequent causes were volume depletion, advanced heart failure and liver cirrhosis. So already at that time these three conditions were the most frequent causes of hypotonic hyponatremia.
So let’s go through different conditions and look at how frequent they are.

Slide 10

The syndrome of inappropriate antidiuretic hormone secretion you see there is a long list of conditions and the most important are tumours, the small cell lung cancer and some other lung diseases. The other reasons are much, much rarer.

Slide 11

So, SIADH is the most common cause of hyponatremia in hospitalised patients. Patients with this syndrome have serum hypo-osmolality but at the same time they have plasma vasopressin antidiuretic hormone concentration in the so-called normal range. So they should have very low plasma AVP levels but they don’t but they have a normal range. But in this case normal range means they have a too high plasma vasopressin concentration therefore, secretion is an inappropriate term to the current serum osmolality. Also the excretion of AQP2 has been investigated and this should be maybe a marker for the persistent secretion of vasopressin.

Slide 12

As Doctor Soren Nielsen already pointed out we can assess the changes in aquaporin expression in different conditions and there’s a standard control and you see that in many conditions there is depletion of AQP2 expression but in some cases like in heart failure, pregnancy and also in the system of inappropriate vasopressin secretion this AQP2 expression is significantly enhanced.

Slide 13

So as I mentioned the tumours, especially the small cell carcinoma in the lungs, is a very common cause of hyponatremia in the SIADH. Almost 10-15% of patients with this small cell carcinoma are characterised with inappropriate vasopressin secretion. There is even a suggestion in the literature that the estimation of vasopressin can be somehow a marker of this kind of tumour and we can in this selected group of patients try to estimate vasopressin as a marker because sometimes we can diagnose SIADH before the diagnosis of the small cell carcinoma is made.

Slide 14

You should also be aware that there are a lot of different drugs which also cause SIADH. These drugs can enhance vasopressin release, these drugs can potentiate the renal action of vasopressin or there are several drugs of which we still don’t know the pathomechanisms of increased vasopressin secretion.

Slide 15

So coming back to the prevalence and incidence of hyponatremia. We should divide these patients with hyponatremia in hospital care in these two groups; hyponatremia which is present at admission time and the hyponatremia acquired during the stay of the patient in the hospital.

Slide 16

There are some data in the literature, there are not too many papers on this. For example in this series of patients which were consecutively checked during a 3 month prospective study in Rotterdam the incidence of hyponatremia with this level was 30% but when the cut off of plasma sodium was 1,25, the incidence of hyponatremia was 2, 6% of patients.

Slide 17

Another very interesting observation made a very long time ago, more than 40 years ago, serum sodium concentration was 5-6 mmol/l lower in all hospitalised patients in comparison to healthy outpatients. It seems that patients who are admitted to the hospital constitutively have lower sodium concentration than patients in outpatient conditions.
The daily incidence was 10% and prevalence 2.5% in adult patient hospitalised in the medical surgical, obstetric and gynaecologic departments in the USA quite a number.

So, this is a very interesting study you see more than 300.000 sodium samples spanning a two-year period in more than 120,000 patients in Singapore. What they found hyponatremia 136 mmol/l in 42.6%. Below 126 mmol/l in 6.2% and with this severe hyponatremia below 116 mmol/L in 1.2% of patients. This large of patients, large number of samples.

Slide 18

But you see that the frequency of hyponatremia in different types of hyponatremia was quite high. You see these are the results, hyponatremia in different categories are here and estimated at admission time and hyponatremia acquired during the stay in the hospital. You see that even this severe hyponatremia below 116 mEq/L was found quite often the total was 1.2% of all these 120,000 patients.

Slide 19

You see here the age distribution and of course with older subjects, older patients the risk of hyponatremia was significantly greater than in patients of 30 years. So older patents are much more prone to hyponatremia than younger ones.

Slide 20

Also the hyponatremia in the hospital was compared to the frequency of hyponatremia in the ambulatory care and the community care. You see the patients who were admitted to the hospital were characterised with hyponatremia much more frequently than patients in the community care. So hyponatremia is mostly characterised by patients in the hospital than in ambulatory and community care.

Slide 21

When I was asked by Professor Gross to prepare this lecture, I was interested in how often is hyponatremia present in my department. So I asked my colleague to check how often we diagnosed hyponatremia during the last 3 years. So you see the number of subjects, the number of patients who were admitted to my department in Katowice, it’s the department of Nephrology, Endocrinology and Metabolic Diseases at the Medical University of Silesia. We found almost 3% of all of our patients were characterised with hyponatremia as we took this cut off below 131 mmol/l. So it’s a significant number of patients.

Slide 22

We also divided them in hyponatremia at admission and hyponatremia acquired during their stay in the hospital. You see a significant number, the total was 3.1% of all patients which were hospitalised in this 3-year period.

Slide 23

We also looked at the age. We didn’t find this significant increase in all the subjects, however in this group 51-60 was much more frequent than other groups of age.

Slide 24

Finally, what was the mean serum sodium concentration in our patients? As I mentioned, the cut off was below 131 mmol/l and the mean was 131 mmol/l.

Slide 25

And the lowest value, the mean of the lowest value was about 125 mmol/l during these last 3 years.

Slide 26

Also we looked at the causes of hyponatremia in our patients during the last 3 years it was 170 patients altogether and you see that the most frequent cause was the use of diuretics, some problems with the kidney transplants especially after immunosuppressive drugs or interstitial inflammation. Chronic kidney disease, acute renal failure, congestive heart failure, liver cirrhosis and in some cases also Addison’s disease. So a large spectrum of different causes of hyponatremia during the last 3 years.

Slide 27

So, there is also another cause of hyponatremia that is in the postoperative stage and the incidence of hyponatremia in these patients usually it’s euvolemic hyponatremia is about 4%. The causes; administration of hypotonic fluids, high vasopressin status when isotonic fluids are given and some severe underlying diseases. 4% of postoperative stages in our patients.

Slide 28

Another very common cause of hyponatremia is strenuous exercise. For example, in the militarists when boys are doing military training, marathon runners, in triathlon it’s very common. During this quite recent publication in the New England Journal of Medicine you see that in 488 runners in the Boston marathon it was revealed that 13% of the runners had a sodium level below 130 mmol/l. It’s quite often.

Slide 29

Hyponatremia in patient with AIDS. This is a very common disease right now in different countries. 38 patients of all hospitalised patients with AIDS were characterised with hyponatremia and in 2/3 of them SIADH was the underlying cause.

Slide 30

The results as I already mentioned with older age the frequency is much higher than in the younger. 25% of elderly patients that means in rehabilitation centre serum sodium was below 135 quite often. This also interesting observation are the differences between gender, between female and male.

Slide 31

This was a study comparing the frequency of hyponatremia, very low hyponatremia and the average serum sodium was 108. The frequency was similar in females and males however, the brain injury especially during inappropriate therapy of the hyponatremia was much more frequent in females than in males. Also the females with a pre-menopausal type were characterised with a much higher frequency of hyponatremia than the postmenopausal ones.

Slide 32

So I would like to come to my conclusions. The incidence and prevalence of different causes of hyponatremia are very rare. You see the incidence, the prevalence are presented on this table from 87% to 4% and these differences are based on the frequency of estimation of sodium, the cause of hyponatremia and also the health care system.

Slide 33

You see there is a list of different publications made by this interesting paper and different definitions of hyponatremia, different groups of patients and of course, different prevalence of hyponatremia due to different definitions and different patient populations from 29-1.1% of prevalence.

Slide 34

I would like also to stress that hyponatremia is a very severe condition and the mortality is significantly increased in patients with hyponatremia and of course, the mortality depends also upon the sodium cut off point and also on the patient status.

Slide 35

But you see here the mortality was between 50% and 10% but in the control groups from 10-1%. So it was significantly increased in comparison to controls, so the mortality in acute hyponatremic syndromes was between 55-5% and in chronic hyponatremic syndromes between 14-27%. But significantly higher than in comparison with healthy subjects.

Slide 36

Finally, I would like to point out that hyponatremia until now is still grossly underreported. This was a very interesting study where in the international classification of diseases ICD which you probably use very often in your clinical practice this coding system was checked in order to detect the hyponatremia. With this cut off point 135 mmol/l . From the hospital discharge records and it was found only in 2%. With this cut off point with 115 mmol/l it was found in 30% but still the sensitivity is quite low and a lot of patients with hyponatremia are not detected or even the serum sodium concentration is not estimated in all patients in hospital.

Slide 37

So, I would like to conclude that hyponatremia is the most common electrolyte abnormality encountered in clinical practice but frequency of hyponatremia is determined by a number of factors including definition of hyponatremia, frequency of testing, healthcare setting and of course, patient population.

Slide 38

Thank you for your attention.

Slide 39

Chairman: Thank you Doctor Wiecek for your very nice overview of clinical epidemiology of hyponatremia. We have time for questions if this is difficult in your hospital we should ask Doctor Wiecek now. It seems that everybody is in agreement with you surprisingly Doctor Wiecek. Could I ask you, could you say more about this surprising finding that AQP2 in urine is meaningful? This is unusual, if we judge sodium metabolism we don’t look at urinary ENaC. Do you want to make a comment on that?

Prof. Wiecek: On urinary what?

Chairman: Urinary AQP2 measurements, why are they meaningful?

Prof. Wiecek: Yes, of course, it’s a very sophisticated method just to look that there is a condition when the water retention even in spite of hypo osmolality is still present then we can confirm and convince that in spite of hypo-osmolality the level or the action of vasopressin is still present and is inappropriate to the clinical condition.

Chairman: Would you speak up please, we would like to hear you? Could you repeat the question?

Question: Pseudohyponatremia is the question.

Prof. Wiecek: Yes, I mentioned about pseudohyponatremia in different conditions like hyperlipidemia, hyperglycemia, multiple myeloma and scientific cases.

Question: Would you like to say more about this condition of inappropriate nephrogenic antidiuresis what it is?

Prof. Wiecek: It’s a very rare condition caused by an exaggerated vasopressin secretion. Also expression of AQP2 in the kidney so it’s a very rare inherited condition.

Chairman: Well, thank you again Doctor Wiecek.