Concept Map: Thiazide induced hyponatremias(TAH)

We see this form of hyponatremia in several cases, but recently there has been some newer findings on the mechanisms of TAH(*).  In one study published in JCI in 2017, Ware et al showed that there is a subset of patients with a genetic baseline( SLCO2A1 mutation) decrease in prostaglandin(PGE) transport activity which then becomes a risk factor for TAH.  So these patients have increased urinary PGE2 and low AVP levels leading to a pure "nephrogenic" cause of tubular water absorption and dilution hyponatremia. PGE2 is critical in insertion and removal of AQP2 channels in the apical membrane. Increased PGE2 signaling leads to insertion of AQP2 channels into membrane and increase water absorption in an ADH independent manner. This is fascinating. Perhaps then mechanism in NSAIDS as well?
Check out this amazing review in AJKD on this topic. 

Concept map: Hyponatremia in the cancer patient

This concept map was adapted and inspired by Umut Selamet and Ala Abudayyeh, both onconephrologists.

Consult Rounds: Adipsic Hypernatremia

When one encounters really high Na levels- 170-200meq/L range, adipsic hypernatremia should be in the differential; especially if they are asymptomatic. The key question to ask is “ are you thirsty?” Once called essential hypernatremia, this disorder is now called adipsic diabetes insipidus or central diabetes insipidus with deficient thirst or easier to call them adipsic hypernatremia. The most common reasons for these are lesions that affect the thirst center in the brain- craniopharyngiomas, CNS sarcoidosis, germinomas and clipping or rupture aneurysms of the anterior communicating artery of the circle of Willis. 

Tight regulation of water balance is accomplished via the thirst mechanism and ADH. Both are crucial to maintaining a remarkably narrow range of plasma osmolarity of 282–298 mOsm/kg. Osmoregulation of ADH is mediated by osmoreceptors located in the anteromedial hypothalamus near the neurohypophyseal cell bodies in the supraoptic nucleus. These osmoreceptors are extremely sensitive to changes in osmotic pressure. For example, an increase in osmolarity of 1 to 2 percent increases ADH secretion. However, ADH secretion alone is not adequate to prevent dehydration, and an intact thirst mechanism is vital for water homeostasis. Thirst is regulated by hypothalamic osmoreceptors that are sensitive to changes in effective osmotic pressure of body fluids. The osmotic threshold at which the thirst mechanism is activated begins approximately 5–10 mOsm higher than the threshold for ADH release. These two systems work together to maintain plasma osmolality. With both systems intact, hypernatremia is a rare development, but can occur in patients who have lost their ability to maintain or increase free water intake, for example hospitalized patients and particularly the geriatric population. 

There are four variants of adipsic hypernatremia. Type A adipsia is characterized by an upward setting of the osmotic threshold for both thirst and vasopressin release, sometimes called essential hypernatremia. Type B adipsia is characterized by subnormal thirst and vasopressin responses to osmotic stimuli. This is due to partial destruction of the osmoreceptors. Complete destruction of these receptors is classified as type C adipsia, and these patients have complete absence of ADH release and a lack of thirst mechanism. Type D is an extremely rare form that manifests as only a thirst mechanism failure with an intact ADH production.

In all patients with adipsic hypernatremia, a careful neurologic and radiologic evaluation should be performed, looking for a possible treatable disease (such as a benign tumor) that might restore osmoreceptor function. 

Forced drinking to make patients eunatremic is the treatment—that is, scheduled water drinking because there is no thirst mechanism, with some desmopressin if need be—is usually what helps. Surgical correction of the cause will be helpful in cases where it is possible. 

An old case of detective nephron that discusses this in a fun way at ASN Kidney News.

A novel look at hyponatremia in the alcoholics

Tavare and Murray in a recent NEJM image had an interesting case of hyponatremia correction. The case highlights development of central pontine myelinolysis(CPM) despite slow correction of hyponatremia.  CPM is known to occur in alcoholism, liver disease and malnourishment in the absence of hyponatremia, hypokalemia or hypophosphatemia. 

We wanted to suggest an algorithm that can be used in settings where alcoholics present with moderate to severe hyponatremia with similar symptoms as presented in this case and are at risk of CPM.  The figure below is a novel algorithm that uses brain imaging to help us guide the therapy for moderate to severe hyponatremia in alcoholics.  

If the patient is symptomatic with seizures, the correction of hyponatremia should be promptly started.  If the patient is asymptomatic  or with milder symptoms and is encephalopathic ( with several  confounding  etiologies : hyponatremia, alcoholism, liver disease), a MRI of the brain should be performed. If the MRI confirms cerebral edema, hyponatremia should be treated with the usual slow rate of correction of 6-9mmol/L per 24 hours.  If the MRI confirms CPM, the correction of hyponatremia should be put on hold.  

We hypothesize that often the hyponatremia  in alcoholics is  chronic  and correction, regardless of the rate, might cause harm in these patients.

We welcome comments from experts on this concept. 

Kenar D. Jhaveri, MD
Rimda Wanchoo, MD
Alessandro Bellucci, MD

Hyponatremia Guidelines Part 5

What to do for over correction?

1.     Prompt relowering if increased >10mmol/L over 24 hours

2.     Stop ongoing treatment

3.     Nephrology or critical care/ endocrine consultation to see if need for starting electrolyte free water or not and monitoring urine output

4.     Expert opinion re the use of ddavp 2ug

Was interesting to note that the new Stern approach of using 3% and ddavp at the same time was not really entertained. It was mentioned in the rationale discussion but more robust trials are needed in that realm.  

For full review:

http://www.ncbi.nlm.nih.gov/pubmed/24569496

Hyponatremia Guidelines Part 4

Chronic Hyponatremia without severe or moderately severe symptoms              

**Stop non essential offending agents
**Cause specific treatment
**If mild, suggest against treatment with the sole aim to increase the Na( excellent point)
**If moderate to profound, to treat to not more than 10mmol/L over first 24 hours
**Diagnostic workup
**If cause is fluid overload- Fluid restriction is only recommended. They recommend against V2 receptor antagonist and demeclocycline.
**If SIADH, FW restriction as first line treatment.  If profound, suggestion to increase solute intake with 0.25-0.5g/kg/day of urea or a combination of loop diuretics and oral sodium chloride
**If moderate or severe- against demeclocycline.
**If SIADH and moderate, recommend against V2 receptor antagonists( same goes for severe SAIDH)

**If low circulating volume related chronic low Na, use of .9% saline or balanced solutions recommended.

Why V2 receptor antagonists were not recommended in above Volume overload and SAIDH scenerios?

The reviewers of this committee looked at two systematic reviews that compared V2 receptor antagonists to placebo in chronic hyponatremia. The first review had 15 randomized trials and found no significant difference in risk of death and other adverse events although Na did increase by 5mmol/L.  More rapid increases were noted in the V2 arms. The first systematic review did conclude that vasopressin antagonist treatment significantly increased response rate both early (RR, 3.15; 95% CI, 2.27-4.37; 11 trials) and late (RR, 2.27; 95% CI, 1.79-2.89; 4 trials). Response rates were high in trials assessing mostly euvolemic patients and those assessing mostly hypervolemic patients, with greater effect estimate in the former.

The second review was in 2011, eleven trials were identified (1094 patients). Short-term use of VRAs in treating hyponatremia was successful at raising [Na(+)](serum). Additional experience is required to guide their optimal use and minimize safety concerns. There was no change in deaths. 

So if the above two reviews showed positive response- why did they not recommend use of these agents? The authors feel that the quality of evidence was generally reduced by risk of bias due to difficulties with blinding participants, potentially unbalanced use of FW restriction and incomplete outcome reporting in addition to industry sponsorship.  There is also mention in the discussion re the liver toxicities associated with higher doses of these agents when they were studied in ADPKD.  Drug doses administered are lower in hypoantremia management.  Overall, besides all that, the review committee felt that there is a good risk of overly rapid correction of hyponatremia with these agents.  

Interesting thoughts and I commend the reviewers on looking at these agents with an eye of scrutiny. Although the most randomized trials in hyponatremia are with these agents.   

For full review
http://www.ncbi.nlm.nih.gov/pubmed/24569496

Hyponatremia Guidelines Part 3

Hyponatremia with moderately severe symptoms

** Start diagnostic workup
**Stop all meds and contributing factors
** Cause specific treatment(  of course)
**Suggest immediate treatment with bolus of 150ml 3% saline for 20 min( wonder if drip for few hours with equivalent mmol would be good enough as well)- level 2D though
**They suggest aim of 5mmol/l over 24 hours ( not 10, even lesser) level 2D
**The very next suggestion is limiting the increase over 24 hours to 10mmol/L( slightly confusing message)
**Checking serum Na at 1 hours, 6 hours and 12 hours
** This is the category that really needs more research as it’s the gray area. They suggest No suggestions for future research? 

Hyponatremia guidelines Part 2:

First set of guidelines are on which parameters to be used for differentiating hypotonic hypoantremia?

**They recommend urine osmolarity of a spot urine as the first step( - to be honest, takes a day to come back sometimes) although level 1D evidence

**If the urine osm is <100, it is thought the diagnosis is due to water excess intake( tea and toast, beer potamania) – level 1D evidence

**If the urine osm is >100, then a urine Na is ordered.

**If Urine Na <30, low effective arterial volume as the cause of low Na

**If Urine Na>30, ECF should be assessed, and if diuretics are involved

**They suggest against measuring an ADH level

  

First hour treatment of hyponatremia of severe symptoms( acute or chronic)

**Prompt IV infusion of hypertonic 3% saline over 20min( 150cc)

**Checking Na levels after 20 min and repeating a second bolus( bolus vs a drip – and bolus was chosen, level evidence 2D)

**Keep repeating till level over 5 mmol/L corrected.

**Consider ICU setting care

Follow up management after 5 mmol/L increase

**Stop IV infusion of 3% saline

**Diagnostic workup

**Limiting the rise to not more than  10mmol/l in first 24 hours( evidence 1D)

**Checking Na levels after 6 and 12 hours daily till stable

If no improvement of symptoms after 5mmol/L increase

**Continue 3% infusion with additional increase for 1mmol/l per hour

**Stopping 3% when symptoms improve or if Na increase by 10mmol

**Additional diagnostic workup

**Check Na q 4 hours till 3% has been stopped.

Full report at http://www.ncbi.nlm.nih.gov/pubmed/24569496

In the News: Hyponatremia guidelines Part 1

The NDT paper on clinical practice guidelines suggests some interesting changes in diagnosis and treatment in hyponatremia.  In the series of posts , we shall highlight the major findings of their report.

Pathophysiology update:

1.       Once the hyponatremia has been deemed hypotonic – the first test recommended is urine osmolarity and the break down after that is interesting.  If urine osm<100Mosm/kg, primary polydipsia and water intoxication is considered a likely potential.  If urine osm>100, we go into our usual categories and then order a urine Na.  If urine Na <30, low effective arterial volume is deemed and volume exam will determine next cause( from volume loss to CHF).  If urine Na>30, one either has kidney disease or diuretic use and or if ECF is reduced could be renal salt wasting or cerebral salt wasting. But if normal ECF- then SIAD.

2.       A nice table on page 21 discusses the much debated SIADH vs cerebral salt wasting.  While uric acid in the serum is same in both, it’s the BUN that is usually low in SIADH.  Urine volume is much higher in cerebral salt wasting.  And patients are usually orthostatic in the later. CVP is also low in the later.

      

    For full details click here

http://www.ncbi.nlm.nih.gov/pubmed/24569496

CONSULT ROUNDS: IVIG and hyponatremia

What’s the relationship here?

In the 1990s, a paper in NEJM described the first relationship of the two.  Pseudohyponatremia has been classically described with intravenous gamma globulins. Pseudohyponatremia is a laboratory artifact due to hyperlipidemia or hyperproteinemia. Intravenous infusion of immune globulin increases the protein load and as a result the protein phase of serum is higher. Depending on the type of laboratory test used, some centers might note a low Na. Usually, the serum osmolarity then would be normal clinching the diagnosis.

Another mechanism that has been proposed is a form of hypertonic hyponatremia – the one you would see in mannitol or hyperglycemia.  most IVIG preparations contain significant amounts of sucrose or maltose leading to the increased osmolarity and leading to fluid shifts leading to hyponatremia. The magnitude of the Na drop might depend on renal function as well and clearance of sucrose.

Finally, a dilutional variant has been noted as well ( Sosm would be low) and you would have a true hyponatremia due to the volume of IVIG infusion that leads to a form of water intoxication.

Take a look at this case series that combines the latter to mechanisms in their presentations of IVIG induced hyponatremia.  Here is another case report.

Hyponatremia and Edelman equation?

 

Following the simplified Edelman equation: [Na+] = (Nae + Ke)/TBW, hyponatremia can be originated exclusively from a decrease in total exchangeable body sodium (Nae). 

Can you think of clinical scenarios where this might occur and that do not involve patients drinking water or hypotonic fluids ?

What do nephrologists think?

 Please comment with your responses:

Helbert Rondon, MD

Assistant Professor of Medicine

University of Pittsburgh School of Medicine

Hypernatremia and Acute Myeloid Leukemia

Electrolyte abnormalities have been seen with AML. Severe hyponatremia associated with SIADH secretion has occurred at presentation. Hypokalemia is a more frequent finding at presentation and is related to kaliuresis. Hypercalcemia can occur. Severe lactic acidosis prior to treatment has been reported. Hypophosphatemia as a result of phosphate uptake by leukemic cells can occur. But hypernatremia secondary to a diabetes insipidus (DI) is rare but has been described. 
Interestingly, this phenomenon( mostly central) has been seen with certain cytogenetics in AML.  
It appears that when you have monosomy 7 variant of AML, it can also lead to in some cases a central DI. Sometimes CDI might be the primary event presenting the AML. Prior literature is not clear the association of this and doesn't appear its CNS involvement but perhaps a genetic association.  Literature reveals many abstracts when you google and pubmed this entity. 
Typically,one would think that the combination of DI and AML is associated with structural abnormalities of the neurohypophysis. But there are cases presenting without any abnormalities of the neurohypophysis on radiological scanning and with normal cerebrospinal fluid examination. AML may directly result in dysregulation of transcription factors resulting in development of DI in AML patients.
One study even compared monosomy 7 with DI and AML and without DI, the group with DI had a 
poorer outcome. 
This association is hard to understand and why this is the case?


Ref:
http://www.ncbi.nlm.nih.gov/pubmed/19380027
http://www.ncbi.nlm.nih.gov/pubmed/3319680
http://www.ncbi.nlm.nih.gov/pubmed/1398517

CONSULT ROUNDS: Primary Polydipsia

Primary polydipsia is an interesting variant of hyponatremia. Its the exact opposite of adipsic hypernatremia.
Classically one might find urine lytes that are very much like so:
Urine Osm 60, Una<10, UK 10 and U Crt 16. 


This doesn't suggest volume depletion but suggests water intoxication. In the setting of a low Serum osm, the ADH is shut off but thirst is not shut off here and as a result the person keeps drinking water.  This is classically seen in psychogenic variants but cases have been described with CNS trauma as well.  It should be taken very seriously, as the amount of water ingested exceeds the amount that can be excreted by the kidneys,and can on rare occasions be life-threatening as the body's serum sodium level is diluted ( in other words dilutional hyponatremia ) to an extent that seizures and cardiac arrest can occur.
The excessive levels of fluid intake may result in a false diagnosis of diabetes insipidus since the chronic ingestion of excessive water can produce diagnostic results that closely mimic those of mild diabetes insipidus. However, in Diabetes Insipidus patients urinate excessive amounts because of a lack of ADH (central DI) or a lack of sensitivity (Nephrogenic DI). 
One can differentiate between the two patients in an by a water deprivation test. In a patient with primary polydipsia, water deprivation should cause the patient patient to urinate less (because water intake was the cause of the excessive urination). In someone with primary polydipsia, once their water intake were restricted, their normal kidneys would begin to concentrate the urine again. In someone with DI, the urine would remain dilute even in the absence of water intake.


Besides free water restriction and increase solute diet, bio feedback might show some promise.


Another interesting take on treatment was a paper that described using azetazolamide for treatment. The authors reported 5 patients in whom acetazolamide was trialed for this symptom. Acetazolamide improved polydipsia and/or hyponatremia in 4 of the 5 cases. This treatment was well tolerated and allowed 3 of the patients to permanently leave isolation. 

Ref: 
http://journals.lww.com/clinicalneuropharm/pages/articleviewer.aspx?year=2011&issue=01000&article=00002&type=abstract
http://www.ncbi.nlm.nih.gov/pubmed/8188850
http://www.ncbi.nlm.nih.gov/pubmed/21122924

HISTORY LESSON: Story Behind Central Pontine Myelinolysis

Central Pontine Myelinolysis(CPM) is now well established to be associated with over correction of hyponatremia. It is very interesting to note how that came about. Historically, this is a very fascinating story. Here it is in a bulleted summary.

1959: Adams et al described CPM as a potential disorder. They found it in alcoholics and malnourished and chronically ill individuals. They called it "new disease" and no cases reported prior to those years.
1963:  Aleu and Terry noted that perhaps an iatrogenic agents were involved and that it happened predominately in the hospital setting.
1966: More lesions identified and not localized to the Pons.  It became evident by observation that all had chronic conditions such as liver disease, sepsis, burns, and cancer.
1977: Burcar et al identified 15 cases and 12 had hyponatremia. Overall, 61% of cases of CPM were associated with hyponatremia.
1979: Messert et al made the most important observation that CPM was recognized only after the advent of IV fluids therapy in the late 1950s.  ( reminds us of the MRI and gadolinium association )
1979: Kevin Leslie, a pathology resident was doing an autopsy case of CPM in a jaundiced patient.  He noticed a striking green discoloration in the PONS- likely secondary to breakdown of BBB leading to albumin bound bile pigment to get there.  Review of literature confirmed this in many CPM cases.
1979: Scott Venderberg, pathology resident was reviewing a CPM case.  He mentioned; " could this discoloration be due to osmotic stress?".  This bought to light if the correction of the Na was the factor and not the Na itself.
1980-82: 15 cases of CPM with hyponatremia were reviewed and found that all 15 cases had experienced a 20-30meq/L rise in serum sodium in 3-10 days ( mean of 6 days) before CPM developed.
1982: Similar findings were confirmed in rats made hyponatremic and then given hypertonic saline quickly.
1984: patients with hyponatremia for a short period of time( hours to a few days) did not develop CPM but patients with chronic hyponatremia did.

This is a fascinating history and great discovery. This points to a great observation power of these individuals and putting it together and what is now common knowledge in the Nephrology world.

For a complete reference: http://www.ncbi.nlm.nih.gov/pubmed/20182780

Concept Map of Hypernatremia

Concept map of Hypernatremia: By Grace La Torre, MSIV