Ask the intern

An interesting case was reported in Nephrology this month that highlights the importance of questioning whether or not a lab result is true. This is a very important skill for all internists but particularly nephrologists who are dependent on lab results for most of our practice. A woman with a history of Still's disease was admitted to hospital with a low grade fever and joint swelling. Her only meds were low dose prednisone and diclofenac (an NSAID). Her labs on admission showed:

Na 170 mmol/L, K 3.2 mmol/L, low-normal urea and creatinine. Her other labs were normal. She denied any thirst and did not look volume depleted. Because of the doubt about the accuracy of the sample, it was repeated. Her repeat sodium was 139mmol/L.

After questioning the intern that took the labs, it became apparent that multiple attempts had been made to take blood. The intern had managed to take a coagulation sample but had failed to get a sample for electrolytes. As a result, she transferred some of the blood from the coag bottle to the lithium heparin bottle. The coag bottle contained trisodium citrate and this had contaminated the serum sample resulting in a spuriously high sodium concentration. This was confirmed by testing the original and repeat sample for calcium. In the original sample it was 1.88 mmol/L and in the repeat it was 2.34 mmol/L. This was due to the chelation of calcium by citrate. Classically, spurious hyperkalemia and hypocalcemia occur in the setting of contamination by EDTA. Pseudohypernatremia is less common but should be considered first in cases of severe asymptomatic hypernatremia. 

A unified view of abnormal sodium regulation in the nephron

Summer has come to the northern hemisphere and it is time to praise our kidneys for all the hard work of preserving the intravascular volume. Although only 30% of Na reabsorption takes place in the distal nephron, this is the place for most common genetic diseases causing abnormal sodium handling:

What are the responsible proteins for these diseases?

1. Bartter syndrome: Na reabsorption decreases via NKCC2 due to defects in NKCC2, ROMK and basolateral Cl channels or from an overactive basolateral CaSR.

2. Gitelman syndrome: Na reabsorption decreases due to a reduced number of NCCs on the luminal membrane.

3. Pseudohypoaldosteronism type 1: Na reabsorption decreases due to the defects in ENaC or mineralocorticoid receptor.

4. Liddle syndrome: Na reabsorption increases due to a higher number of ENaCs on the luminal membrane (they are spared from ubiquitination).

5. Gordon syndrome: Na reabsorption increases due to a higher concentration of NCCs on the luminal membrane (defects in WNK4 or overactive WNK1). More recently, mutations were discovered in the genes encoding KLHL3 and CUL3 proteins.

CUL3 is a component of ubiquitin ligase and KLHL3 is its partner (expressed in the DCT). It is speculated that the defects in these proteins may change the distribution of NCC.

Is this clinically relevant?

In Gordon syndrome, these mutations can occur de novo and are encountered more frequently (47% for KLHL3 and 32% for CUL3) than those involving the WNK kinases (13%). It appears that they are under-diagnosed and some of the cases of RTA type 4 with hypertension could be caused by them!

50 years after Bartter syndrome was described, the work on mechanisms responsible for abnormal Na regulation in the nephron continues…

Posted by Tomoki Tsukahara MD 

 

X-Files

A patient was recently seen on the consult service for evaluation of hyponatremia. She had a history of multiple myeloma and a previous bone marrow transplant and had significant cholestatic liver dysfunction related to GVHD. Her serum sodium at the time of presentation was 120 mmol/L. The initial thought was that she may have SIADH but her serum osmolarity came back at 290 suggesting that we were in fact dealing with a case of pseudohyponatremia.

The commonest causes of pseudohyponatremia are severe hypergammaglobulinemia and hypertriglyceridemia. Neither was present in this case. A previous case report in the NEJM in 2003 described pseudohyponatremia in a patient with cholestatic jaundice that was felt to be the result of accumulation of lipoprotein X. This is formed when there is reflux of cholesterol and phospholipids into the circulation from blocked biliary ducts. Because it is not soluble, it increases the solid portion of plasma and leads to pseudohyponatremia. A plasma sample confirmed to presence of lipoprotein X in this patient.

One point that was raised during the assessment was that the diagnosis of pseudohyponatremia cannot be made by measuring the serum osmolarity alone. It is important to confirm this by measuring the serum sodium with a direct ion sensitive electrode as this will measure the sodium concentration in the plasma water alone and therefore give a true result. This is because there are occasional cases where a patient with true hyponatremia will present after ingestion of a large quantity of alcohol. In this case, the serum sodium will be low, there will be a significant osmolar gap (suggesting that the patient has pseudohyponatremia) but the directly measured serum sodium will also be low – confirming the presence of true hyponatremia.

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.