The initial data was promising with convincing studies on conivaptan and tolvaptan, but something happened on the way to SIADH nirvana.
First the EVEREST trial went sideways. In heart failure:
- Angiotensin 2 is elevated and blocking it prolongs life
- The sympathetic nervous system is up-regulated and blocking it prolongs life
- Aldosterone is elevated and blocking it prolongs life
- ADH is elevated and blocking it doesn't do a damn thing
With no hope for a heart failure indication the drug was marketed solely as a treatment for hyponatremia where it was shown to be effective. The pitch was that doctors should not discharge people with hyponatremia and tolvaptan was faster and more effective than the previous standard of care. The drug was priced for short-term inpatient use at $300 a pill tolvaptan was a non-starter for chronic outpatient SIADH.
But I held out hope, I felt that as soon as the FDA licensed tolvaptan for ADPKD, the drug would be re-priced for chronic use and the price would come down. In fact during a TEMPO investigator meeting, an Otsuka executive hinted they would lower the price on approval (personal communication). However, despite being the only known treatment that slows the loss of renal function in autosomal dominant polycystic kidney disease, the FDA told Otsuka and the ADPKD community to pound sand.
Somewhere in there, Otsuka changed the labelling and limited tolvaptan to 30 days or less for hyponatremia, so the dream...is officially dead.
But my patients are still alive and they still have sodiums of 125. Demeclocycline, despite being a generic, is very expensive and not a good option. From the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association guidelines on hyponatremia:
The side effects reported for demeclocycline and lithium were such that we recommend not using them for any degree of hyponatraemia.Fluid restriction, the cornerstone of therapy, is difficult to maintain and in severe cases is insufficient to correct hyponatremia (I'm thinking of patients with negative free water clearance). Urea has a good track record but I have not heard of it being used in the United States. Salt tablets can help, but often are inadequate to correct the hyponatremia.
On the list of possible treatments are loop diuretics. I have tried loops in hyponatremia on a number of occasions and though the math works, in my hands I have not found them to be effective. In the past, I have used loops in hospitalized patients with hyponatremia. The results have been underwhelming. But I know have a loop diuretic success story in a patient with significant but stable outpatient hyponatremia.
+1 “@medicalaxioms: Nothing aggravates a nephrologist like a kidney that refuses to obey the math.”
— Joel Topf (@kidney_boy) March 31, 2014
I met the patient when he was admitted to the ICU with mental status changes due to a sodium south of 120. This was not his first episode of hyponatremia. We corrected the sodium and restored normal mentation. We did a thorough work-up, looking for the etiology of the SIADH and despite some promising leads that turned into blind alleys, I am quite confident, now, that this is idiopathic SIADH.
During subsequent outpatient follow-up he had persistent hyponatremia with sodiums running in the high 120's. During this time, treatment consisted of salt tablets and fluid restriction. A couple of visits ago I added torsemide, and boom the two sodiums since have been 138 and 134.
Here is the sodium and urine osmolality over time. It plummets after the torsemide is started. This increases the free water clearance.
I also have data on the urine sodium, to get an idea of the electrolyte free water clearance. The change is not nearly as dramatic or convincing.
I have some of the data to calculate electrolyte free water clearance, but I'm missing urine volumes. We can determine the character of the urine from the following formula:
The following percentages represent the fraction of the urine volume which is electrolyte free water. The first three columns are negative, indicating that the urine the patient is producing has less than no free water. Urinating is more like drinking water as urination actually causes the sodium to fall, rather than rise. For a more in-depth explanation of the electrolyte free water calculation, check out this video.
It will be interesting to see if this improvement continues. I now believe that the reason I was underwhelmed when I used loop diuretics in the hospital is that I was working in the compressed time scale of inpatient medicine and only when you stretch the time horizon to months does the drug become effective. I think the reason it takes so long is that loop diuretics need to wash out the concentrated medullary interstitium, thus preventing the ADH from reabsorbing much water. A drug induced partial nephrogenic diabetes insipidus.