Toxoplasmic encephalitis (TE) is the most frequent neurologic disorder in patients with advanced human immunodeficiency virus (HIV) infection.1,2 Low CD4+ T-cell count and lack of prophylaxis with trimethropim-sulfamethoxazole are known risk factors for developing TE.3

Although scarcely studied in TE, alterations in serum sodium regulation constitute a common feature in neurologic disorders.4 Neurologic-associated hyponatremia could be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as cerebral salt-wasting syndrome, which is clinically challenging to diagnose with accuracy.5 Hyponatremia per se is associated with a reserved prognosis.6 However, the association with TE is not fully established, with studies suggesting that hyponatremia may be a mere indicator of the severity of illness.7

In the general HIV-infected population, risk factors for developing acute kidney injury (AKI) are well established (hepatitis virus C infection, opportunistic infections, nephrotoxic drugs), as well as their implications on prognosis.8,9 HIV-infected patients with TE are, in theory, at increased risk for developing AKI, mainly because the treatment for TE consists of using a nephrotoxic drug, sulfadiazine.10

Sulfadiazine is a short-acting sulfonamide derivative that undergoes acetylation in the liver to a variable degree (10% to 40%). Sulfadiazine-related nephrotoxicity is through crystalluria due to acidified urine, leading to tubular obstruction.11 Although many published case reports describe sulfadiazine-related crystalluria and its association to AKI, incidence, risk factors, and evolution remain unclear.

Moreover, in some studies, AKI has been independently associated with hyponatremia, with the latter being considered a consequence of the former. This study aimed to analyze hyponatremia in HIV-infected patients with TE, its temporal relationship with AKI, and involved prognostic implications.

The present study found important associations between hyponatremia, AKI and mortality in patients with TE. A significant proportion of patients presented hyponatremia (more than 40% of cases) at hospital admission. AKI-development and mortality were both associated with the severity of hyponatremia. The data also disclosed an independent relationship between hospital-acquired AKI and mortality in this population. This is the first study to evidence these findings in TE and, moreover, to describe a temporal relationship between hyponatremia and posterior AKI development.

There are reports on the literature describing the involvement of kidneys in animals infected with toxoplasmosis.1,12 One of the few articles on this topic reports a case of nephrotic syndrome in an immunocompetent patient with generalized toxoplasmosis, but with normal renal function, who had complete recovery with supportive therapy.13

Infection with T. gondii rarely complicates to AKI, which is described only as a consequence of sulfadiazine crystalluria.14,15 However, in the present study, a significant association between sulfadiazine use and AKI was not observed. Therefore, it is suggested that other mechanisms may be involved in toxoplasmosis-associated AKI, which need to be elucidated. AKI is a frequent complication in patients with infectious diseases,16,17 which could also occur in T. gondii infection.

The majority of patients in the present cohort were on HAART (64%). The mean CD4+ T-cell count was low. All patients were treated with sulfadiazine. In HIV-infected patients, levels of CD4+ T-cell counts inversely correlate with reactivation of T. gondii infection, and can cause severe histopathological changes.18 Low CD4+ T-cell count could explain the severe complications observed in this study.

Hyponatremia on admission was frequently observed in this study sample (46.7%), and was severe in 10.8% of the cases. The most common causes of hyponatremia among hospitalized patients with toxoplasmosis are SIADH and use of diuretics.19 Hyponatremia is the most common electrolyte disorder in clinical practice, known to be associated with increased mortality in patients with different settings.20,21

In the present study, patients with hyponatremia on admission had a history of recent weight loss and fever more frequently than normonatremic patients. Hyponatremia is seldom described in toxoplasmosis, and can be the presenting feature in some cases.22 As reported in the literature, it occurs in approximately 10% of children with acute central nervous system diseases without renal dysfunction or prior use of diuretics, where complications could be due to SIADH or cerebral salt wasting.23 It is suggested that similar mechanisms are involved in patients with TE. In animals with toxoplasmosis, hyponatremia has also been described in one fatal case.24 However, the precise cause of hyponatremia in toxoplasmosis remains unclear. There are descriptions of SIADH and diabetes insipidus in association with this parasitic infection, which could in part justify the occurrence of this electrolyte abnormality.25

In the present study, hyponatremia occurred before the development of AKI, and it proved to be an important risk factor for AKI. A possible mechanism for this finding could be that hyponatremia triggers release of ADH, leading to increased urinary concentration, which in turn predisposes to sulfadiazine crystal deposition. One of the limitations of the present study is that a majority of the patients did not have urinalysis, which would have allowed studying the urine sediment for crystals.

AKI is an important risk factor for death. In their work, Macedo et al.26 showed that oliguria lasting for more than 12h and of more than three episodes had an increased real risk for mortality. In this sample, mortality in patients presenting any degree of AKI was 32%, which was significantly higher than the overall mortality (14%). Similar mortality rates, varying from 15% to 27%, have been reported.27,28 Nonetheless, currently, no report has associated AKI and hyponatremia to increase risk of dying in TE. In the present study, male gender and admission hyponatremia were independently related to AKI development. Survivors had comparable clinical and laboratory findings to non-survivors, except for higher prevalence of hyponatremia at admission, lower serum sodium, and higher incidence of AKI.

In this study serum sodium levels were significantly associated with mortality, evidencing that hyponatremia per se increased mortality, which is different from what has recently been suggested by others,7 who stated that patients died “with” and not “due to” hyponatremia. Another recent study evidenced that outpatients with chronic heart failure who had hyponatremia presented increased mortality, with this electrolyte disturbance being an independent predictor of all-cause mortality.29 Even small increases in sodium levels are associated with higher risk of death.30 Hyponatremia can be a predictor of death in TE because it indirectly reflects a probable, more severe neurological lesion. As a matter of fact, severe or acute hyponatremia can cause life-threatening cerebral edema.6 Thus, hyponatremia can also be a marker of disease severity, since it can be a sign of the presence of important physiologic derangements.6

In summary, AKI and hyponatremia are common events in toxoplasmic encephalitis. Admission hyponatremia is highly associated with AKI and mortality. As patients presented hyponatremia at admisson and developed AKI during hospitalization, hyponatremia might represent an accessible and reliable marker for an increased risk of AKI and perhaps of death. Increased kidney monitoring, and limited use of nephrotoxic drugs or radiographic contrast agent are suggested for these patients. Hyponatremia, a potentially treatable electrolyte abnormality, is a crucial event in this population. It must be identified and correctly treated, considering that it may per se be associated with cerebral edema, coma, and death in these patients.

All the authors declare to have no conflict of interest.