Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 2014  |  Volume : 25  |  Issue : 3  |  Page : 558--566

Azotemia protects the brain from osmotic demyelination on rapid correction of hyponatremia


Murtaza F Dhrolia, Syed F Akhtar, Ejaz Ahmed, Anwar Naqvi, Adeeb Rizvi 
 Sindh Institute of Urology and Transplantation, Civil Hospital, Karachi, Pakistan

Correspondence Address:
Dr. Murtaza F Dhrolia
Sindh Institute of Urology and Transplantation, Civil Hospital, Karachi, 74200
Pakistan

Abstract

Osmotic demyelination syndrome (ODS) is a dreadful, irreversible and well-recognized clinical entity that classically occurs after rapid correction of hyponatremia. However, it has been observed that when hyponatremia is rapidly corrected in azotemic patients by hemodialysis (HD), patients do not necessarily develop ODS. We studied the effect of inadvertent rapid correction of hyponatremia with HD in patients with azotemia. Fifty-two azotemic patients, who underwent HD at the Sindh Institute of Urology and Transplantation, having pre-HD serum sodium level <125 mEq/L and post-HD serum sodium levels that increased by ≥12 mEq/L from their pre-dialysis level, were studied. Serum sodium was analyzed before and within 24 h after a HD session. HD was performed using bicarbonate solution, with the sodium concentration being 140 meq/L. The duration of the dialysis session was based on the discretion of the treating nephrologist. Patients were examined for any neurological symptoms or signs before and after HD and for up to two weeks. Magnetic resonance imaging was performed in required cases. None of the 52 patients with azotemia, despite inadvertent rapid correction of hyponatremia with HD, developed ODS. This study suggests that patients with azotemia do not develop ODS on rapid correction of hyponatremia by HD, which suggests a possible protective role of azotemia on the brain from osmotic demyelination. However, the mechanism by which azotemia protects the brain from demyelination in humans is largely hypothetical and further studies are needed to answer this question.



How to cite this article:
Dhrolia MF, Akhtar SF, Ahmed E, Naqvi A, Rizvi A. Azotemia protects the brain from osmotic demyelination on rapid correction of hyponatremia.Saudi J Kidney Dis Transpl 2014;25:558-566


How to cite this URL:
Dhrolia MF, Akhtar SF, Ahmed E, Naqvi A, Rizvi A. Azotemia protects the brain from osmotic demyelination on rapid correction of hyponatremia. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Jul 12 ];25:558-566
Available from: http://www.sjkdt.org/text.asp?2014/25/3/558/132183


Full Text

 Introduction



Hyponatremia is the most common electrolyte abnormality seen in clinical practice, and is associated with significant morbidity and mortality in the hospitalized population. [1] Severity of clinical signs is not only related to the absolute measured level of low serum sodium but also to the rate and extent of the drop in extracellular fluid osmolality. [2] While hypo-natremia itself is associated with severe neurological sequelae, its rapid correction (i.e. more than 12 mEq/L in 24 h) can also be hazardous. Central pontine myelinosis (CPM) or osmotic demyelination syndrome (ODS) is a common but serious condition that can develop one to several days after rapid correction of hypo-natremia by any method, including water restriction alone. [3]

The observed central nervous system symptoms of hyponatremia are most likely related to the cellular swelling and cerebral edema that result from acute lowering of extracellular fluid osmolality, which leads to movement of water into cells. In response to this, volume regulatory mechanisms come into play. [4] Studies on rats have demonstrated a prompt loss of both electrolytes and organic osmolytes (such as phosphocreatinine, myoinositol and amino-acids) after the onset of hyponatremia. Some of the osmolyte losses occur within 24 h, but the loss of water becomes more marked in the subsequent days, as this is a time-dependent process. Rapid development of hypo-osmolality results in brain edema before this adaptation can occur. Similarly, the rate at which the brain restores the lost electrolytes and osmolytes, when hyponatremia is corrected, is of great pathophysiological importance in the development of CPM. Sodium and chloride improve quickly; however, the re-accumulation of osmolytes is considerably delayed. This process is likely to account for the more marked cerebral dehydration that accompanies the correction in previously adapted animals (and likewise, patients with chronic hypo-natremia are more at risk from rapid correction). It has been observed that urea may prevent the myelinosis associated with this pathology. This may well be due to the more rapid re-accumulation of organic osmolytes, particularly myoinositol, in the azotemic state. [5] Not much work has been carried out so far on the effect of rapid correction of hyponatremia in patients with azotemia, but it has been observed in clinical settings that when patients with severe hyponatremia are hemodialyzed, they do not develop ODS following accidental rapid correction of sodium with HD. This may be because of the mechanism described above in animal models, [5] or it is hypothesized that with HD, while sodium increases on the one hand urea is removed on the other; therefore, the extracellular fluid osmolality that produces shift of water across the cells is not disturbed. If indeed patients with azotemia do not develop ODS with rapid correction of hyponatremia, they can then be safely dialyzed without taking any specific precautions such as using low sodium concentration dialysate. This study will therefore be very handy to the management of patients with renal failure and hypo-natremia.

 Materials and Methods



Patients of any age and sex who presented to the Sindh Institute of Urology and Transplantation (tertiary renal care center) with renal failure (azotemia) and pre-HD serum sodium level <125 mEq/L and who underwent dialysis and showed within 24 h post-HD an increase in serum sodium by more than or equal to 12 mEq/L were included in the study. Patients with neurological deficit at presentation or those with hyponatremia but serum sodium level more than 125 mEq/L and those without increase of serum sodium level by more than/ equal to 12 mEq/L within 24 h post-HD were excluded.

Fifty-two patients fulfilled the study criteria; all were hemodialyzed using bicarbonate solution with dialysate sodium concentration of 140 mEq/L. The duration of the dialysis session was variable and depended on the treating nephrologist. Patients were examined for any neurological symptoms or signs after HD and serum biochemistry (urea, creatinine and sodium) was analyzed using an automated chemistry analyzer within 24 h of HD. The difference between serum sodium level before and within 24 h after HD was noted. Patients were monitored for any neurological symptoms or signs for at least two weeks. Magnetic resonance imaging (MRI) was performed in selected cases, where required.

 Statistical Analysis



This was a case series study and samples were collected on non-probability convenience technique. Data feeding and analysis were done on SPSS version 10.0. The result was given in text as mean (x) and standard deviation (SD) for continuous variables (age, laboratory investigations such as urea, serum sodium concentration) and frequency and percentage for categorical variables (gender, neurological symptoms and signs, type of renal failure and indication for HD).

 Results



Initially, a total of 83 azotemic patients admitted at the Sindh Institute of Urology and Transplantation with severe hyponatremia over a period of 14 months (from March 2007 to April 2008), and who underwent HD, were studied. Of these, 52 patients met the inclusion criteria. There were equal numbers of males and females (26 each). Their ages ranged between 12 and 80 years, with a mean of 41.3 years. Of the 52 patients, 19.2% presented with acute renal failure, 13.5% with acute on chronic renal failure and 67.3% had stable chronic renal failure. The etiologies of renal failure are summarized in [Table 1].{Table 1}

The mean serum creatinine level of these patients before HD was 13.89 ± 6.29 mg/dL and serum urea was 270.71 ± 105.9 mg/dL. The mean serum sodium was 116.02, with a standard deviation of ±7.19. All patients were dialyzed using standard bicarbonate solution with dialysate sodium concentration of 140 mEq/L. The indications for HD are given in [Table 2]. The duration of HD session was decided by the treating nephrologists. Mean duration of HD was 102 min, with a standard deviation of ±41.38 min [Table 3]. The mean ultrafiltration was 1.4 ± 1.16 L. The mean serum creatinine level within 24 h after HD was 10.42 mg/dL ± 5.55 and serum urea was 190.1 mg/dL ± 84.8. The net difference in serum creatinine and urea levels before and within 24 h of HD was 3.74 ± 5.8 and 82.75 ± 55.29, respectively. The mean serum sodium level within 24 h of HD increased to 131.75 mEq/L ± 6.43; this remained stable at 132.06 mEq/L ± 6.51 and 133.26 mEq/L ± 6.21 after 48 and 72 h, respectively [Figure 1]. The mean net increase in serum sodium level within 24 h of HD was 15.46 ± 3.39 [Table 4]. In 63.5% of the patients, the net increase in sodium was more than or equal to 14 mEq/L within 24 h [Figure 2] and [Figure 3].{Figure 1}{Figure 2}{Figure 3}{Table 2}{Table 3}{Table 4}

Of the 52 patients studied, 47 remained fully awake, alert and oriented while five patients showed mild alteration of mentation. Three of these five patients remained confused for less than 24 h and became fully alert, awake and oriented thereafter. Two patients remained confused for more than 24 h after HD. MRI was performed on these two patients; in one patient, it was unremarkable while in the other, it showed multiple small ischemic infarcts bilaterally in the deep parietal basal ganglia and thalamic region with no demyelinating lesions. Both these patients subsequently became fully alert, awake and oriented with no residual deficit and possibly had dialysis disequilibrium syndrome [Figure 4].{Figure 4}

All patients were found fully alert, awake and oriented with no neurological deficit at the end of two weeks. None of the 52 patients with azotemia developed ODS despite rapid correction of hyponatremia through HD.

 Discussion



ODS is a well-recognized clinical entity and a dreadful complication that classically occurs after aggressive and rapid correction of hypo-natremia. [6],[7] Not much work has been done so far on the effect of rapid correction of hypo-natremia in patients with azotemia, but it has been observed in clinical settings, and there are some individual case reports as well, in which patients with renal failure tolerated rapid correction of hyponatremia with HD without sustaining any neurological damage. [8] The mechanism by which azotemic patients are protected from the effect of rapid correction of hyponatremia remains largely hypothetical. When urea concentration changes rapidly, it acts as an effective osmole as seen in the dialysis disequilibrium syndrome. It has been hypothesized that this effect may help in countering the fluid shift out of the brain cells, which is the main mechanism attributed to cause ODS resulting from rapid correction of hyponatremia.

To support the hypothesis that uremic state protects the brain against myelinolysis, many studies have been conducted on animal models. In one study on a rat model, it was shown that injected urea had specific brain-protective effect against myelinolysis in hyponatremic rats. [9] In another study, it was found that azotemic rats with chronic hyponatremia tolerated a large increase in serum sodium without significant brain damage, concluding that azotemia decreased the risk of myelinolysis in rats after correction of chronic hyponatremia. [10]

To determine how elevated blood urea levels favorably influence brain tolerance to osmotic stress, Soupart studied the changes in brain solute composition that occurred when chronic hyponatremia was rapidly corrected in rats with induced renal failure. [5] In his work, he found that after 48 h of hyponatremia, the brain of azotemic and non-azotemic animals became depleted of sodium, potassium and organic osmolytes. However, after 24 h of rapid correction of hyponatremia in animals without azotemia, the brains remained depleted of organic osmolytes with little increase in myoinositol or taurine contents above those observed in animals with uncorrected hyponatremia. Brain electrolytes rapidly reaccumulate, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myoinositol levels returned to control levels in azotemic rats and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia. No excess increase of brain sodium and water contents was noted after rapid correction in the azotemic animals. This study suggests that rapid accumulation of brain organic osmolytes after correction of hyponatremia could be the mechanism by which azotemia protects the brain against myelinolysis.

What remains as yet unknown is whether the difference in brain osmolyte levels observed in azotemic rats is attributable only to urea or to any other components. Urea might have some protective properties against osmotic stress in azotemic brains. Urea has been demonstrated to have a protective effect on renal medullary cells against the pro-apoptotic effect of hyper-tonic stress induced by sodium chloride. [11] Similarly, the blood urea of dogfish has been shown to have cardioprotective effects against oxidative stress. [12] Additionally, perfusion of isolated hearts with a high concentration of urea has been demonstrated to protect tissues against oxidative injury; [12] this may be of importance in hyponatremia because the hyponatremic brain tissue is depleted of glutathione and other organic osmolytes with antioxidant properties. [13] Also, the Elasmobranches (sharks, skates and rays) that thrive in sea water exhibit high plasma urea concentrations (approximately 400 mMol). Their high plasma urea concentration makes it possible for these organisms to avoid exposure of their cells to the deleterious effects of the high salt concentrations of their marine environment. [14],[15]

The above discussion may point toward a protective role of azotemia against demyelination of brain on rapid correction of hyponatremia, and this hypothesis is also supported by the results of our study.

It is not known whether uremic patients are completely protected against developing ODS on rapid correction of hyponatremia as a case of ODS was reported in a 52-year-old man with uremia and hyponatremia after the first HD session. [16] Brain imaging showed central pontine and extra-pontine myelinosis, and it was emphasized that demyelination syndrome can occur when hyponatremia is corrected too rapidly and that it is recommended, even in uremic patients, to use low sodium dialysate and multiple short sessions of HD with a low blood flow rate.

However, another case study reported findings similar to ODS on MRI in a patient with the disequilibrium syndrome. [17] The study patient had clinical and MRI findings consistent with ODS after the first HD; there was complete neurological improvement without any residual deficit following appropriate treatment, and there was improvement on follow-up MRI as well.

Another study was performed to determine the brain MRI findings during an episode of neurological symptoms and signs, and, at follow-up, to identify the possible factors that may contribute to the development of lesion. It was found that in patients who developed symptoms and signs suggestive of ODS after HD, the lesion may involve the pons or extra-pontine sites, but they resolved rapidly and almost completely on follow-up, favoring transient edema rather than demyelination. Blood chemistries suggested underlying changes in osmolality, particularly as a result of urea shift from the extracellular fluid. [18]

Similarly, five of the 52 patients in our study showed alteration in mentation, which showed complete recovery without MRI findings suggestive of ODS.

The results of our study and the available literature suggest that azotemia protects the brain against demyelination on rapid correction of hyponatremia after HD. The exact mechanism remains hypothetical and further studies on humans are needed to answer this question.

 Limitations of the Study



The rate of development of hyponatremia was not known exactly. Because all patients included in the study were asymptomatic at presentation, it can be presumed that they had chronic hyponatremia.

Sodium levels were not measured immediately after individual HD sessions but were checked within 24 h after a HD session. Because no other method for correction of hyponatremia was used, it can be presumed that the correction of hyponatremia occurred because of HD.

Because MRI was performed only on symptomatic patients, it is possible that MRI findings in asymptomatic patients could have been missed.

 Ethical Issue



No formal written informed consent was taken from the patients. However, they were all informed verbally that their non-identifiable data will be used in a research study.

 Conclusion



This study suggests that patients with azotemia do not develop ODS on rapid correction of hyponatremia through HD. However, the mechanism by which azotemia protects brain from demyelination in humans is yet to be clearly defined. Evaluation of the mechanisms that play a protective role in azotemic patients against osmotic stress may be worthwhile for treating hyponatremia in other conditions.

Conflict of interest: None

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