Aquaretics and PCKD

One of the big stories at the ASN this year was the announcement of the results of the TEMPO trial which were simultaneously published in NEJM. It has been known for some time that ADH is implicated in cyst growth in patients with polycystic kidney disease (PCKD) and that suppression of ADH release with high water intake or vasopressin receptor blockade reduces cyst growth in animal models. The TEMPO trial was a 3-year, multicenter controlled trial involving 1445 patients with PCKD who were randomized to receive tolvaptan (a V2-receptor antagonist) or placebo. The primary outcome was the rate of change in total kidney volume while the rate of CKD progression was a secondary outcome.

There was a lower rate of kidney growth in the tolvaptan group (2.8% per year vs. 5.5% per year) and a slower decline in renal function also. These are fantastic results and they should be celebrated, especially considering the disappointment surrounding bardoxolone. However, there are a couple of significant issues which should be considered. All of these patients had normal renal function at the time of entry into the study. The majority of these would progress very slowly to end stage and the cost of treatment with tolvaptan over this period of time would be enormous. Also, about 23% of the participants dropped out due to adverse effects (although, it should be said that 14% of the placebo group also dropped out). The most important side effect was liver toxicity.

So the question arises – who are the patients that will benefit most from vaptan treatment. As the accompanying editorial states – “the development of comprehensive criteria for aquaretic treatment and appropriate patient selection are needed”.

So maybe a recent series of papers from a group in Holland may help provide the answer. Vasopressin is difficult to measure in vivo because of its short half-life and tendency to bind to platelets. However, one of the components of its precursor, copeptin, is stable in plasma and can be used as a surrogate for the serum vasopressin concentration. Last year, this group published a paper which found that, in a group of 102 patients with PCKD, serum copeptin levels were associated with markers of disease severity such as kidney size, GFR and albuminuria. The group published two follow-up longitudinal studies (using historic samples from previous studies) in NDT and AJKD. In a group of 79 patients, higher baseline copeptin levels were associated with more rapid decline in renal function over 11 years follow-up. 8 of the 9 patients that started hemodialysis over the course of the study had copeptin levels above the median. It should be pointed out that baseline copeptin levels were higher in patients with lower GFR at the time of entry to the study and this could have biased the results.

The last paper looked back at 241 patients with normal baseline renal function who were included in a longitudinal study of cyst growth (and measured GFR!) In these patients, higher baseline copeptin levels were associated with a greater change in kidney volume over 8 years follow-up. After full covariate adjustment, there was a trend towards a greater decline in renal function in the higher copeptin group but this was not statistically significant. Again, however, patients with larger kidneys at baseline also had higher copeptin levels. Because of the size of the molecule, there may be some element of reduced clearance in patients with lower GFRs and this could explain some of the differential. Higher copeptin levels have also been noted in patients with other renal diseases so this is not entirely specific. This needs to be further studied.

Still, although not definitive, these studies provide some rationale for a potential means of stratifying patients with PCKD and certainly give a route for further investigation. It would be interesting, perhaps, to go back and measure baseline copeptin levels in the patients in the tolvaptan study to determine if there was a difference in response to therapy based on this promising biomarker.

Why Do Thiazides Decrease Polyuria in Diabetes Insipidus?

I was reviewing the treatment of diabetes insipidus the other day, and was reminded of the paradoxical effect of thiazide diuretics on urine output in diabetes insipidus. How does this work? The traditional thinking is that thiazide-induced blockade of the Na-Cl cotransporter in the distal tubule leads to a decrease in GFR. This decrease is compensated by an increase in proximal tubule sodium and water uptake. Because less water and solute are then delivered to the collecting duct, less water is lost as urine. However, some studies suggest that chronic use of thiazides does not result in a decrease in extracellular fluid volume: cardiac output returns to normal several weeks after initiating therapy, and infusion of salt-free dextran does not increase blood pressure. Studies in rats with central DI have also shown that replacement of renal sodium losses does not prevent the antidiuretic effect of thiazides. Experiments by Kim et al. suggest that thiazides may serve to upregulate aquaporin channels and ENaC subunits. In rates with lithium-induced nephrogenic DI, HCTZ reversed lithium-induced downregulation of AQP2. It also caused an increase in the abundance of ENaC channels. While these results are specific to Li-induced renal effects, they may at least partially explain how a thiazide can serve to decrease polyuria in patients with diabetes insipidus.

Water deprived

Recently in the clinic we were asked to review a patient with suspected diabetes inspidus. She had been taking lithium for more than 20 years for bipolar disorder that was very well controlled. During a routine medical examination, her blood tests revealed a serum creatinine of 1.4 so she proceeded to have a 24-hour urine collection. The result of this showed that her GFR was moderately reduced at 40mls/min but the striking finding was a 24 hour urine volume of 10 liters. The patient herself had no complaints regarding this as she was accustomed to drinking large volumes. She had been advised many years before to take a high salt diet in order to reduce the potential for nephrotoxicity (this sodium would compete for Li uptake in the DCT). Reducing her salt intake cut her urine volume by half which in itself was a great result.

One thing that did not fit entirely with the story was that her serum Na was never >140mEq/L. The impetus for water intake in DI is a high serum Osm but she was often in the 137-138 range suggesting that she was actually keeping her Osm lower than would be expected. The question arose as to whether or not there was a component of polydipsia here unrelated to the possible DI so we admitted her for a water deprivation test.

As mentioned by Nate before, the protocol for this test involves restricting a patient’s access to water and then measuring the plasma and serum osmolarity every 1-2 hours until:

(a) the urine osmolality reaches a normal value (e.g., above 600 mosm/kg, suggesting that both ADH secretion and response to ADH are intact).

(b) the urine osmolality is stable on two successive measurements despite a rising plasma osmolality, or

(c) the plasma osmolality is greater than 295-300 mosm/kg.

At that point DDAVP is administered.

There is one caveat, in the case of this patient, her initial urine Osm was 104 with a serum Osm of 307. According to the protocol above, this would be the time to give her DDAVP. However, her serum Na was only 141. The additional Osmoles were a result of a slightly elevated fasting blood sugar and a high BUN (because of her CKD). Her calculated Osmolarity was 306. As a result, we postponed giving DDAVP at that stage. Her results during the day were as follows:

Serum Na 141 144 149 153 154

Serum Osm 307 315 319 326 329

Urine Osm 104 126 142 154 153

We administered DDAVP when her serum Na was 149 and allowed her to drink again as soon as the next lab was taken. Her final result was after she had been allowed to start drinking again and she was already preventing her Na from increasing any further. The lack of response to DDAVP indicates a diagnosis of nephrogenic DI, almost certainly due to lithium.

The take home points for me here were that a low serum sodium in the steady state does not necessarily mean that the patient does not have DI – in someone like this who has had this problem for years, she has just become accustomed to staying ahead of her thirst. The second point was that a serum sodium always has to be sent with the serum osmolarity as if there are other osmoles around, they can give you a misleading result.