Topic Discussion: Hyponatremia with Spironolactone

Hyponatremia from MRAs is a rare phenomenon but we have encountered it clinically. There are times, when we check labs after starting spironolactone for HTN, 3-4 weeks later, the Potassium is slightly up and the Na comes back 130 or 131 mmol/L.  What is the data and the mechanism for hyponatremia following spironolactone use? Is this even related.

In an abstract presented at AHA few years ago, small amount of patients were noted in an EHR to have hyponatremia following starting of spironolactone but most were following on after being started on a thiazide.

In another paper, high doses of furosemide and spironolactone, or concomitant use of these diuretics, seem to be an important cause of hyponatremia in HF patients, particularly in combination with advanced age, diabetes, and alcohol consumption. Diuretic dose reduction may help avoid hyponatremia and improve clinical status and prognosis in such patients.

Is it possible that a combination of a thiazide and a K⁺-sparing diuretic such as amiloride and spironolactone can increase the risk of hyponatremia because of the enhanced urinary loss of sodium in the cortical distal tubule? Perhaps not the main mechanism.

What about the concept of vasopressin escape? During hyponatremia, the body limits the degree to which serum sodium concentration falls through a mechanism called "vasopressin escape". Vasopressin escape is a process that prevents the continuous decrease in serum sodium concentration even under conditions of sustained high plasma vasopressin levels. In a recent basic science study, the abilities of aldosterone synthase (Cyp11b2) knockout and wild-type mice to escape from vasopressin were compared. Wild-type mice escaped while the aldosterone synthase knockout mice did not. Both the water channel aquaporin 2 (AQP2) and the urea transporter UT-A1 protein abundances were higher in aldosterone synthase knockout than in wild-type mice at the end of the escape period. Vasopressin escape was also blunted in rats given spironolactone, a mineralocorticoid receptor blocker. The authors results indicate that aldosterone regulates vasopressin escape through calcineurin-mediated protein changes in UT-A1 and AQP2.

    So is it possible that we are blunting the natural vasopressin escape when we combine thiazides with MRAs? Do all MRAs do this?- this is still unclear. Hyponatremia related to MRAs is an understudied area worth exploring.

Topic Discussion: Electrolytes Disorders with COVID19

AKI has been reported with COVID19 ,electrolyte disorders have been less well described. A recent paper in CKJ describe the full spectrum of electrolyte disorders seen with COVID19.

The most common presentation was hyponatremia and hypochloremia together (second vertical bar) in 1289 (12.4%), followed by hyponatremia alone (third vertical bar) in 1150 (11.1%).

What about patients with eGFR<60 but >15? 30.3% had hyponatremia, 11.1% had hyperkalemia, and 19.7% had hypochloremia. Hypocalcemia was seen in 19.2% of patients. Hyperphosphatemia (13.9%) and hypermagnesemia (12.2%) were seen in fewer patients.

What about ESKD patients?

In these patients the most common disorders were hypochloremia (62%), hyponatremia (40.9%), and hyperkalemia (23.4%). Hyperphosphatemia was seen in 45.7% of patients but we had some missing phosphorus data.

What about kidney transplant recipients? The most commonly seen were hyponatremia (42.4%), hyperkalemia (16.7%), and hypochloremia (19%).

Limitations: Purely descriptive.

But highlights for the first time and the largest to date on the various electrolyte disorders in hospitalized COVID-19 patients. Further studies are needed to look at mortality outcomes related specifically to each electrolyte disorder.

Prevalence of Hyponatremia related to COVID19 has been described in the NY region. Looking at the spectrum of both hyponatremia and hypernatremia and it's relation to patient outcomes has not been well studied.

To take this further, Na disorders were evaluated in detail with outcome of mortality. This is published in NDT. Among 9946 patients included in the study ,4808 (48.3%) had normonatremia, 3532 (35.5%) had mild hyponatremia, 904 (9.1%) had moderate/severe hyponatremia, 319 (3.2%) had mild hypernatremia, and 383 (3.8%) had moderate/severe hypernatremia. When examined by decile of age, dysnatremia occurred in 46-54% of patients in each group, with hyponatremia the predominant disorder across all age groups. The proportion of patients who experienced in-hospital death was highest for those with moderate/severe hypernatremia (232/383 [60.6%]), followed by mild hypernatremia (163/319 [51.1%]), moderate/severe hyponatremia (261/904 [28.9%]), mild hyponatremia (818/3532 [23.2%]) and normonatremia (1089/4808 [22.6%]), a trend seen across all age groups. 

U-shaped pattern was seen in the relationship between admission serum sodium level and the odds of in-hospital death, with hyponatremia and hypernatremia both significantly associated with mortality, even after full adjustment for demographics, comorbid conditions and illness severity. Compared to hyponatremia, hypernatremia carried a strong association with in-hospital death, in both mild and moderate/severe categories, and across all ages, a relationship that persisted even following correction for serum glucose. While hypernatremia has  been shown to be  a strong predictor of mortality in prior studies, this finding is novel for COVID-19. 

Both hyponatremia and hypernatremia were also associated with a prolonged hospital length of stay. The magnitude of the odds ratio was substantial, especially for moderate/severe hypo- and hypernatremia, and was not substantively changed after multivariable adjustment. This suggests that at least a portion of the prolonged hospitalization may be directly related to electrolyte disorder management. 

This is the largest study to describe prevalence and outcomes of both hyponatremia and hypernatremia in a diverse population of almost 10,000 patients hospitalized with COVID-19. Other similar studies just published in the endocrine literature as well.

Concept map: Copeptin in Natremias

The above figure summarizes the best data on use of serum copeptin level for diagnosis of diabetes inspidus and primary polydipsia. Copeptin derives from the precursor protein of AVP and has been correlated well with AVP production

What about in cases of increased ADH- such as SIADH? Data on that is poor and only one large study of >200+ patients showed that in hypovolemic hyponatremia ( appropriate ADH), the copeptin levels were >84pmol/L ( spec 90%, sens 23%) and SIADH fell in the 10-30pmol/L categories( not helping much) and hypervolemic and diuretic induced fell in 30-65pmol/L category. Use of this test is currently not recommended in diagnosis of increased AVP production disorders. 

Finally in patients with nephrogenic syndrome of inappropriate anti diuresis, copeptin levels were are low or suppressed. 

This article is an excellent summary of the use of copeptin in Na related disorders
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850413/ 

Topic Discussion: Zytiga (Abiraterone) induced hypernatremia, and HTN

Zytiga (Abiraterone) is a hormonal chemotherapy agent used to treat prostate cancer. It selectively and irreversibly inhibits CYP17 (17 alpha-hydroxylase/C17,20-lyase), an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal, and prostatic tumor tissues. Inhibits the formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione.

Interestingly. it has a high rate of hypernatremia as a known renal complication. In several studies, hypernatremia (33%), hypokalemia (17% to 30%) were reported as known complications. Why? It is postulated that it can increase mineralocorticoids due to CYP17 inhibition may result in hypertension, hypokalemia, and fluid retention (including grade 3 and 4 events) and perhaps some component of hypernatremia as well- almost like a Cushing's state. Per package insert, concomitant administration with corticosteroids reduces the incidence and severity of these adverse events.

In the LATITUDE trial, which used prednisone 5 mg daily in combination with 1000 mg abiraterone acetate daily, grades 3-4 hypokalemia were detected in 10% of patients on the zytiga arm and 1% of patients on the placebo arm, grades 3-4 hypertension were observed in 20% of patients on the zytiga arm and 10% of patients on the placebo arm. Grades 3-4 fluid retention occurred in 1% of patients each arm.

It is recommended that patients get monitored for hypertension, hypokalemia, and fluid retention at least once a month. Treatment of hypertension is recommended, choice of drug is not defined.

This is an interesting toxicity that as nephrologist seeing prostate cancer with CKD and perhaps new onset hypertension, hypokalemia or hypernatremia should consider in the differential diagnosis.

Concept Map: Polyuria

A solute diuresis is defined -- urine osmolality >600 mosmol/kg and a total daily osmolar output >1000 mosmol (calculated as the urine osmolality multiplied by the 24-hour urine output).

A water diuresis is defined with a urine osmolality <600 mosmol/kg and often <300 mosmol/kg and a total daily osmolar output <900 mosmol.

Another way to look at it from pure Uosm perspective is U osm <100mOsm/kg is generally a water diuresis from polydipsia or DI.  

Uosm between 100-300 mosm/kg is usually a mixed polyuria( either a central and nephrogenic partial DI and maybe simultaneous water and solute intake and CKD)

U Osm >300 is generally solute diuresis 

Consult Rounds: Low Urinary Na

Urinary Na concentration is a very useful urinary test that we use in clinical practice to decide the volume status of the patient. It is also very useful in helping decide pre renal vs intrinsic renal disease. 

There are several causes of AKI where urine Na concentration and fractional excretion of Na may be initially low, only to increase later. They are listed below

1.       Radiocontrast agent induced AKI- due to AngII increase and ischemic damage

2.       Sepsis- activation of AngII leads to initial vasoconstriction and low levels of urinary Na

3.       NSAIDs- unopposed vasoconstriction from Ang II

4.       Rhabdomyolysis- mechanism unclear

5.       Acute obstruction( initial phase)- again activation of AngII

6.       Acute GN- cytokines that lead to decrease GFR causing lowering of filtered Na load

7.       Acute rejection- similar to GN

A recent article in CJASN reviews the use of urinary studies in diagnosis of kidney diseases.

Plasma exchange for central pontine myelinolysis?

As we know that a complication of overcorrection of hyponatremia is central pontine myelinolysis(CPM). Once it happens, what can be done to improve the neurological complications?

A recent case report shines light into an older treatment approach from 1990s- plasma exchange. In this case report, a patient received IV bicarbonate therapy for distal RTA from sjorgen’s syndrome and Na corrected from 140s to 170s in 24 hours and then few days later leads to CPM .

Two days of 4+ liters of plasma exchange were done with albumin and FFP replacement. Two days following the treatment, the neurological symptoms improved.  The sodium level also was getting staying stable.

So how does one treat CPM? – besides preventive strategies

There have been some animal  studies investigating the benefits of re-inducing hyponatremia in the case of rapid  overcorrection of hyponatremia in order to avoid osmotic demyelination. So bring the Na back down again to allow for the change to be mitigated.  What about plasma exchange? This was first attempted in 1999 Lancet paper that showed that 3 patients were successfully treated with plasma exchange ( but in those cases were for weeks compared to the above case for only 2 sessions)

Another case report exists in use of this strategy in a liver transplant patient with CPM.
One more in the neurology literature  adds to this potential treatment.

 Myelin toxic compounds may be removed by plasma exchange due to their high molecular weight and preventing the further damage is the suggested mechanism.

Would it be worth doing plasma exchange while correcting for hyponatremia simultaneously in high risk patients? – such as the alcoholic beer potemanias? Some food for thought.

Image source: wikipedia.com

Clinical case and answers 81

What leads to hyponatremia in adrenal crisis?

Pre renal state due to low cortisol	5 (26%)
CRH release leads to hyponatremia	2 (10%)
Cortisol normally suppresses ADH and in adrenal insuff, this doesn't happen	11 (57%)
The mechanism is not known	6 (31%)

The hypersecretion of ADH seen in low cortisol states may be due in part to the reductions in blood pressure and cardiac output. However, a more important mechanism may be that cortisol deficiency lead to increase CRH production leading to increase ADH state.  Cortisol feeds back negatively on CRH and ACTH, an inhibitory effect that is removed with adrenal insufficiency. In addition, cortisol appears to directly suppress ADH secretion. Thus, ADH levels increase when plasma cortisol levels are low.  Alternatively, the hypersecretion of ADH induced by aldosterone deficiency is caused by renal salt wasting with resultant volume depletion. Many studies support the concept that hyponatremia in patients with hypopituitarism is mainly caused by failing inhibition of ADH secretion because of hypocortisolism.

http://jasn.asnjournals.org/content/17/7/1820.long is an amazing reference from JASN that looks at water homeostasis in adrenal disorders. 

Topic Discussion: Genetic Diabetes Insipidus

The arginine vasopressin gene (AVP gene), the arginine vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin 2 [AQP2])—provide the basis for understanding of three different hereditary forms of “pure” diabetes insipidus: Neurohypophyseal diabetes insipidus, X-linked nephrogenic diabetes insipidus (NDI), and non–X-linked NDI(AD and AR), respectively. Four main categories can be considered. 

Neurohypophyseal diabetes insipidus: Autosomal Dominant, they retain some limited capacity to secrete AVP during severe dehydration, and the polyuro-polydipsic symptoms usually appear after the first year of life, when the infant’s demand for water is more likely to be understood by adults. 

Delayed onset of disease and can get worse with age.  The gene mostly involved is AVP gene. 

X-linked NDI: Affected male patients do not concentrate their urine after administration of AVP. Because this form is a rare, recessive X-linked disease, female individuals are unlikely to be affected, but heterozygous female individuals can exhibit variable degrees of polyuria and polydipsia because of skewed X chromosome inactivation.  The gene mostly involved is AVP2 gene. V2 receptors have been tried as chaperone medications as a trial to help overcome the misfolding that happens as a result of the gene mutation and helps in NDI.

Autosomal recessive NDI: Some cases have been identified. They have defect in the AQP2 gene.

AQP2 mutations that are responsible for autosomal recessive NDI are characterized by misrouting of the misfolded mutant proteins and are trapped in the endoplasmic reticulum.
Autosomal Dominant linked NDI: Both males and females affected. A patient who presented shortly after birth and it is a defect in the AQP2 channel gene. 

A nice review can be found at JASN and NDT

Topic Discussion: Rule of 6s

Hyponatremia- Rule of 6 correction.
The Stern Approach

Correction and then over correction is the concern especially in two populations.

Low Solute intake individuals and Alcoholics.

They are the highest risk for CPM following rapid correction.

The cause of hyponatremia and its reversibility must also be considered when deciding a course of action. In hypovolemia-induced hyponatremia, vasopressin levels decline and sodium levels rise as volume status is restored to normal.

The Stern approach from Rochester has come up with a protocol that is worth noting year after year regarding giving hypertonic saline with ddavp. The reason why trouble arises in the treatment with just 3% in the above population is due to emerging quick water diuresis that sometimes gets not well accounted.

Ddavp administered q6-8 hours has been shown by this same Rochester group to be effective and more practical than hypotonic fluids in preventing overcorrection of hyponatremia. They administer desmopressin immediately without waiting for the onset of water diuresis, and concurrently administer 3% saline solution. Based on their data, this prevents significant rises in Na rapidly and provides the “brakes” with the “acceleration”. The formula of the 6s is recommended. Correction with 6mEq in 6 hours on the first day if symptoms are severe with neurological symptoms. 

Sterns approached was studied in a retrospective manner in a CJASN study found free online.  In another article, this approach is discussed using an alcoholic case in AJKD. Concerns using ddavp is that perhaps there is no control  over the effect once you give it. At least with D5W or hypotonic solutions, one can control the rate. Perhaps, more data will be coming out on this approach as years progress. 

In summary, correction of hyponatremia by 4-6 mEq/l within 6 h, with bolus infusions of 3% saline if necessary, is sufficient to manage the most severe manifestations of hyponatremia. Planning therapy to achieve a 6 mEq/l daily increase in the serum sodium concentration can avoid iatrogenic brain damage by staying well clear of correction rates that are harmful. Administration of desmopressin to halt a water diuresis can help prevent overcorrection; if overcorrection occurs, therapeutic relowering of the serum sodium concentration is supported by data in experimental animals and was found to be safe in a small observational clinical trial. 

Concept Map: Hyponatremia( etiology and pathogenesis)

Here is a concept map of hyponatremia created by Dr. Helbert Rondon from 
Division of Nephrology, University of New Mexico School of Medicine. For good size view, download the image and view it.

TOPIC DISCUSSION: SIADH diagnosis

We always struggle to diagnosis this entity in few cases of hyponatremia. Measurement of AVP can prove challenging due to problems of ordering and time it takes to come back. Measurement of copeptin( a 39 amino acid glycopeptide) which is derived from the same precursor peptide as AVP and released in equimolor amounts as AVP might be measurable.  Is that been studied? You bet!

In this one prospective observational study, 106 consecutive hyponatremic patients were classified based on their history, clinical evaluation, and laboratory tests. In patients and 32 healthy control subjects, plasma copeptin concentration and standard biochemical parameters were tested for their utility of diagnosing SIADH.

Plasma copeptin levels were significantly higher in patients with hypo- and hypervolemic hyponatremia compared with SIAD (P < 0.005, respectively) and primary polydipsia (P < 0.001). The copeptin to U-Na ratio differentiated accurately between volume-depleted and normovolemic disorders (area under the receiver-operating characteristic curve 0.88, 95% confidence interval 0.81-0.95; P < 0.001), resulting in a sensitivity and specificity of 85 and 87% if a cutoff value of 30 pmol/mmol was used.  This ratio differentiated between volume-depleted and normovolemic disorders resulting in good specificity and sensitivity in this one study. It did better than copeptin alone as well. Another small swiss study felt that it added very little to the sodium balance information. I guess not much out in the literature. Lets see where this story unfolds and how this becomes real in clinical use.

Ref

http://www.ncbi.nlm.nih.gov/pubmed/18984663

http://www.ncbi.nlm.nih.gov/pubmed/21990032

Hypokalemia quiz answer

Labs on presentation: Na 117, K 1.5, Normal renal function. Exam consistent with volume depletion. EKG changes consistent with hypokalemia. Hyponatremia is asymptomatic

Treatment?

A. Treat hyponatremia first and then hypokalemia

B. Treat hyponatremia and hypokalemia simultaneously

C. Treat hypokalemia first and then hyponatremia  

Any thoughts? What would you do?
Here is what you all said:

" C,  but I believe that, in practice, we'd probably end up doing B."

"I would think treat both. As you improve distal tubular flow with saline , hypokalemia can worsen"

"How about KCl, NaCl and DDAVP with water restriction."

"Treat hypokalemia first.”

”In this case the hyponatremia may be at least partly explained by the huge deficit in total body potassium stores, thus causing intracellular shift of sodium in exchange for potassium. Given that this patient is asymptomatic, option C is probably the safest. Aggressive repletion of K w/150-200 mEq daily for 2-3 days will be necessary to replete his K and the patient's Na may slowly improve as well."


"Treat hypokalemia with IV KCL (ECG abnormalities make it urgent). Repleting volume would probably take care of hyponatremia."

"Patient should only be treated for Hypokalemia first as hypokalemia correction itself will cause improvement in hyponatremia. The theory behind it is with K repletion, there is translocation of K in the cell and Na will move out. Mich. Halperin book has an excellent article on this."

I think all responded practically the right answer. Correction of hypokalemia is very important in setting of hyponatremia and one has to be watchful of not over correcting Na too fast in this setting as correcting the K will correct the Na as one of the commenters pointed out. There have been cases reported of osmotic demyelination from just aggressive correction of K leading to fast Na correction.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/20338465

http://www.ncbi.nlm.nih.gov/pubmed/8192171

"Hyponatremia" not that benign

I urge you all to read the piece from Annals of Internal Medicine by Sagalyn called
" A little hyponatremic". A beautifully written narrative of something we have to all keep in mind.

http://www.ncbi.nlm.nih.gov/pubmed/21969347

TOPIC DISCUSSION: Cirrhosis, Hyponatremia and the role of Vaptans?

CHF and SIADH has clear indications for use of vaptans. What is the data and evidence in cirrhosis associated hyponatremia?


1. No drug has been approved to treat hyponatremia of cirrhotics as of yet
2. Studies from Europe using lixivaptan and satavaptan have shown that short term effects of using them have had increased serum NA levels in cirrhotics and sustained for 1-2 weeks.
3. Unfortunately , only 27-54% had complete normalization of the Na
4. All studies showed increased urinary Na levels
5. Only one study has shown long term effects of captains in cirrhotics and that is using satavaptan. 
The main finding was that the improvement in serum Na obtained in first days of therapy was maintained for one year.
6. Thirst was the biggest side effect.
7. To avoid rapid correction, use of D5W after reaching a certain threshold and matching urine output cc by cc is recommended as risk of ODS is there but not been reported thus far.
8. Patients awaiting liver transplantation should get treatment for Hyponatremia as there have been situations were Na corrects rapidly as the transplant is replaced and subsequently causing neurological sequelae. 


Ref:
http://onlinelibrary.wiley.com/doi/10.1002/hep.22418/pdf
http://www.ncbi.nlm.nih.gov/pubmed/19797900
http://www.ncbi.nlm.nih.gov/pubmed/12671890

http://www.ncbi.nlm.nih.gov/pubmed/18508290

TOPIC DISCUSSION: ADH and Pain?

The relationship of pain and SIADH is well documented. Severe pain can lead to inappropriate ADH production.  Why is that? Why does pain cause ADH release? Looking into the literature, not much has been studied regarding this specific question.
A single paper in 1977 from UCLA describes the effect of pain on plasma ADH concentrations. They studied patients with pain after surgery and compared to controls. Age, smoking and pain came out factors associated with increase in ADH levels. It was a nice and small study but showed that pain led to ADH increase.
Stress might not be the case, might be pain directly. Some studies have shown that stress itself without pain did not led to increase ADH.  Pain has two components:- readily localizable specific sensation that is mediated by the spinothalamic tracts and the second is the arousal of the Reticular formation , ventral thalamus and hypothalamus and perhaps ADH connection might be in this latter portion. Stimulation of the brain stem reticular formation has shown to increase ADH in animals.
When asking few academicians: some responses I got was : Flight and Fight state from an evolutionary standpoint perhaps that wants ADH to be elevated in that state and allow for the beneficial effects.
Also, ADH is produced naturally perhaps in wound healing and in these pain flight and fight situations, leads to such a response.
Interesting , not well defined and studied

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/630725
http://www.ncbi.nlm.nih.gov/pubmed/6399311

TOPIC DISCUSSION: Clinical Pearls for electrolytes!

On a recent reading on Sodium and Water physiology, I realized again and again the following points

1. The best way to identify change in Na balance is to examine the extracellular volume status but there are no good ways to do that clinically( orthostatics, axillary sweat, skin turgor, physical exam??). Perhaps the hemotocrit might be the best marker we have.
2. There are no NORMAL values in electrolyte diseases, there are only what is EXPECTED of the kidney to do or the organ to do for the stimuli.
3. Classic one: " The acute discovery of a chronic condition does not make it an acute disorder"- By ML Halperin
4. Hypernatremia and "no thirst" leads to not a pleasant diagnosis to make requiring a MRI of the brain.

Interesting Urine Lytes

1. Oliguric/anuric individual
Urine lytes obtained after foley inserted:- Una 27, UK 24, UCl 27 and U Crt 9

2. Hyponatremic individual Na 107, conivaptan stated
Urine lytes obtained after 4 hours:- Una <10, UK<10 U Cl <10 and U Osm 150

Any thoughts? on what is going on?

IN THE NEWS- Hyponatremia and Mortality( its the underlying cause that is more important)

Severe hyponatremia (<120 mEq/L) in hospitalized patients has a high mortality rate. This new study in CJASN 2011 issue online reviews this in a retrospective fashion. Medical records of 53 patients who died after developing Na <120 mEq/L before or after admission and of 32 patients who survived after developing Na <110 mEq/L were reviewed. Mortality rates tended to increase as the Na fell from 134 to 120 mEq/L.
Interestingly, Less than Na of 120 mEq/L, the trend reversed, such that the mortality rate progressively decreased as Na fell. More than two thirds of patients who died after Na <120mEq/L had at least two additional acute severe progressive illnesses, most commonly sepsis and multiorgan failure.  Most patients who survived with Na <110 mEq/L had medication-induced hyponatremia. The authors conclude that the nature of underlying illness rather than the severity of hyponatremia best explains mortality associated with hyponatremia. Neurologic complications from hyponatremia are uncommon among patients who die with hyponatremia.
Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21441132

Notes from Dr. RW: Hyponatremia update

Notes from Dr. RW: Hyponatremia update: "This review from CCJM covers the diagnosis and treatment of both acute and chronic forms as well as special considerations in the treatment ..."