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Hyponatremia Associated with Prophylactic Low-Dose Trimethoprim during Systemic Corticosteroid Therapy for AQP4-Positive Optic Neuritis in a Diabetic Patient.

1. Introduction

Trimethoprim has broad-spectrum antibacterial activity by inhibiting dihydrofolate reductase to prevent microbial growth [1]. As a result of a synergistic effect, it is frequently used in combination with sulfamethoxazole for the treatment of respiratory, intestinal, cutaneous, and urinary tract infectious disease [1]. While trimethoprim-sulfamethoxazole is generally well-tolerated, its use is sometimes associated with diverse adverse effects on the neurologic, hematologic, cutaneous, reproductive, and renal systems [2]. Trimethoprim can elicit hyponatremia and hyperkalemic renal tubular acidosis (RTA) due to its structural similarity with amiloride [3-5]. Hyperkalemia is the most common manifestation of electrolyte/acid-base impairments, and it is potentially life-threatening [4]. Hyponatremia related to high-dose trimethoprim is also common, but low-dose trimethoprim rarely leads to hyponatremia in patients with preserved renal function [3,6]. The main countermeasure for these adverse events is the immediate discontinuation of trimethoprim and associated medications.

While the amiloride-like effect of trimethoprim is to inhibit epithelial sodium channels in the collecting tubule, mineralocorticoids positively regulate and increase renal sodium reabsorption; thus, patients with hyperkalemic RTA are sometimes treated with the mineralocorticoid agonist fludrocortisone [5]. A previous study has reported that concomitant corticosteroid therapy did not influence the incidence of hyponatremia associated with high-dose trimethoprim [3]. However, there is scant information on hyponatremia in patients using low-dose trimethoprim and concomitant corticosteroid. Herein, we describe a patient with no renal dysfunction who nonetheless exhibited hyponatremia related to prophylactic low-dose trimethoprim despite receiving systemic corticosteroid equivalent to a mineralocorticoid effect of 0.06 mg/day fludrocortisone.

2. Case Report

A 57-year-old woman with a history of aquaporin-4 (AQP4) antibody-positive optic neuritis presented with progressive visual impairment of the left eye over two days and was admitted for further evaluation and treatment. The patient had been diagnosed with anti-AQP4 antibody-positive optic neuritis two years earlier due to visual impairment of the right eye. However, no medical treatment had been initiated at that time due to the patient's refusal. On watchful waiting, her visual symptoms had not deteriorated notably until her admission here. Her medical history also included hypertension and diabetes mellitus diagnosed at 47 years of age. The patient had developed diabetic polyneuropathy and proliferative diabetic retinopathy for which pan-retinal photocoagulation was given, but nephropathy had not emerged as a complication. Glycated hemoglobin on admission was 8.0%; at this time, medication consisted of 36 units of insulin glargine U-300 once-daily, anagliptin 200 mg/day, and metformin 500 mg/day. Hypertension was treated with telmisartan monotherapy at 40 mg/day alone and was satisfactorily controlled. The patient drank alcohol only socially and never smoked.

On physical examination, the patient's body mass index was 20.9 kg/[m.sup.2] (height 153 cm, weight 49.0 kg), body temperature was 36.1 [degrees]C, blood pressure was 107/55 mmHg, and pulse was regular at 86 beats/min. While Goldman perimeter testing revealed a newly developed central visual field defect in the left eye, the status of the diabetic retinopathy was not markedly changed. A bilaterally weakened Achilles tendon reflex and impaired vibration sensation over the medial malleolus was observed. Laboratory parameters on admission (Table 1) showed unremarkable electrolytes, preserved estimated glomerular filtration rate, and normo-albuminuria.

The clinical course of hospitalization is shown in Figure 1. From the fourth hospital day, the patient received pulsed intravenous methylprednisolone 1000 mg/day for three consecutive days, followed by oral prednisolone 30 mg/day. Additionally, low-dose trimethoprim- sulfamethoxazole prophylaxis (160 mg and 800 mg daily) was concomitantly administered. Subsequently, the serum sodium level steadily decreased, and the potassium level was slightly elevated despite normal renal function. A second course of pulsed methylprednisolone was given on days 13-15. Telmisartan was stopped on day 16, but electrolyte abnormalities did not improve. Therefore, on day 21, arterial blood gas analysis, urinalysis, and hormonal status tests were carried out in addition to routine examinations and body weight measurements (Table 2). Hypotonic hyponatremia with high urinary sodium excretion and mild hyperkalemia with low urinary potassium excretion were observed. While primary respiratory alkalosis was present, decreased bicarbonate levels greater than compensatory changes and negative base excess indicated the co-existence of primary metabolic acidosis. Based on the above findings and on the normal serum anion gap, the patient was diagnosed as having hyperkalemic RTA. After the discontinuation of trimethoprim-sulfamethoxazole, electrolytes and acid-base imbalances swiftly resolved. Visual impairment also improved and did not recur during prednisolone tapering, and the patient could be discharged on hospitalization day 29.

3. Discussion

Hyponatremia in hospitalized patients is a clinically important issue because it is associated with diverse adverse outcomes, including increased mortality [7]. The development of hyponatremia may be a side effect of many medications including diuretics, antidepressants, antipsychotics, antiepileptics, antidiabetics, nonsteroidal anti-inflammatory drugs, and anticancer agents [8]. Trimethoprim is pharmacologically similar to the potassium-sparing diuretic amiloride, and thus dose-dependently inhibits epithelial sodium channels in the renal-collecting tubule and causes increased sodium excretion and decreased potassium excretion [9,10]. Thus, trimethoprim use can lead to hyperkalemic RTA and hyponatremia.

Hyperkalemia is recognized as a common adverse reaction to trimethoprim, and its use at a high dose, as well as renal impairment, older age, and potassium-retaining medications are reported as contributory risk factors [4]. While hyponatremia frequently develops in patients treated with high-dose trimethoprim, it is less common in those exposed only to low doses of trimethoprim [4,6]. A recent retrospective study reported that the incidence of hyponatremia among hospitalized patients treated with high-dose trimethoprim was as high as 72.3%, with the severity of hyponatremia depending on the duration and cumulative dose of trimethoprim received [3]. On the other hand, another retrospective study reported that electrolyte disorders (hyperkalemia and/or hyponatremia) related to prophylactic low-dose trimethoprim were observed only in 17.5% patients with preserved renal function, and serum sodium levels were not significantly changed [6]. Furthermore, serum sodium concentrations were confirmed to be unchanged after low-dose trimethoprim in a different report, although serum potassium concentrations showed significant elevation in this prospective observational study [11]. In the present case reported here, hyponatremia and hyperkalemic RTA occurred during trimethoprim use at a prophylactic low dose of 160 mg/day and rapidly improved after its cessation. While this clinical course suggests an adverse event due to trimethoprim, several factors influencing the homeostasis of electrolytes and acid-base balance in the kidney may also have had a role in this case (Figure 2).

The first of these factors influencing homeostasis is the systemic corticosteroid that was given at the pharmacologic dose of 30 mg/day of prednisolone. Synthetic corticosteroids have drug-specific glucocorticoid and/or mineralocorticoid properties. The representative corticosteroid serving as a mineralocorticoid is fludrocortisone, which is useful for treating hyperkalemic RTA, primary aldosterone insufficiency, classic congenital adrenal hyperplasia, orthostatic hypotension, and septic shock [5,12-14], Prednisolone is a frequently used corticosteroid for treating diverse inflammatory and autoimmune diseases because of its higher glucocorticoid activity relative to its mineralocorticoid activity. Nonetheless, prednisolone at a dose of 30 mg/day still provides a mineralocorticoid effect equivalent to 0.06 mg/day of fludrocortisone [12]. Thus, concomitant use of prednisolone can activate epithelial sodium channels in the collecting tubules and potentially compensate for the adverse effects of trimethoprim. However, our present case suggests that hyponatremia related to trimethoprim can still occur despite the use of systemic corticosteroid therapy and only a low dose of trimethoprim.

The second factor influencing homeostasis is the use of the angiotensin 2 receptor blocker (ARB) telmisartan in this patient. The co-prescription of trimethoprim and ARB is common in clinical practice due to the wide use of ARBs as anti-hypertensive drugs for patients with diabetes mellitus because of their beneficial renal protective effects [15,16]. However, in previous case- control studies, the use of trimethoprim-sulfamethoxazole together with renin-angiotensin-aldosterone blockade, including ARB, was reported to be associated with an increased risk of hyperkalemia- associated hospitalization and sudden death possibly due to hyperkalemia [17-19]. These results suggest that ARB can amplify adverse impacts of trimethoprim on the renal distal tubule. Although telmisartan was stopped on day 16 in the present case, high plasma renin activities and low aldosterone levels on day 21 and 25 indicated the residual inhibition of angiotensin 2-mediated aldosterone secretion in this patient. Therefore, telmisartan use could have contributed to electrolyte and acid-base imbalances in this case.

A third factor for consideration is the co-existence of diabetes mellitus in this patient. It is clear that patients with diabetes mellitus are susceptible to hyperkalemic RTA for several reasons, including low renin resulting from damage to the juxtaglomerular apparatus, autonomic dysfunction due to neuropathy, volume expansion due to renal salt retention, and weakened prorenin to renin conversion [20]. The patient's baseline renin profile was not known due to the effects of treatment with trimethoprim, prednisolone, and telmisartan on the renin-angiotensin-aldosterone system, but it is possible that her diabetes mellitus was conducive to the development of hyperkalemic RTA.

In addition to an impaired renin-angiotensin system, free water retention can be related to the hyponatremia of this present case. Differential diagnoses of hypotonic hyponatremia with elevated urinary osmolality and high urinary sodium excretion include the syndrome of inappropriate antidiuretic hormone (SIADH), salt wasting, diuretic use, adrenal insufficiency, and vomiting [21]. Antidiuretic hormones mainly determine free water excretion by the kidney and play a crucial role in mechanisms responsible for the development of hyponatremia. While hypertonicity triggers antidiuretic hormone release via osmoreceptors, hypovolemia or a low effective plasma volume also leads to antidiuretic hormone secretion via baroreceptors [21]. Therefore, salt wasting due to trimethoprim results in volume depletion and raises antidiuretic hormone levels, which in turn results in free water retention [22].

Although body weight decrease during the hospitalization period indicated that salt wasting was the main mechanism at play here, SIADH is also pathophysiologically possible. Anti-AQP4 antibody is a disease-specific autoantibody in neuromyelitis optica (NMO) spectrum disorder, which is characterized by immune-mediated demyelination of the central nervous system predominantly affecting the optic nerves and spinal cord [23]. AQP4 is a protein widely expressed in the brain, skeletal muscle, lung, stomach, inner ear, and kidney, contributing to water homeostasis [24]. Although AQP4 is distributed throughout the central nervous system, the basolateral membrane of ependymal cells and glial lamellae of the supraoptic nucleus are particular localizations in the brain [24]. Corresponding to this characteristic localization of AQP4, the brain involvement of NMO is preferentially seen in the periventricular areas, including the hypothalamus [25]. Immune-mediated damage to the hypothalamus may lead to the dysregulation of antidiuretic hormone secretion. Indeed, recent reports indicate that SIADH can be concomitant with NMO, especially in patients with hypothalamic involvement [26,27]. Furthermore, SIADH can occur, albeit rarely, in patients without hypothalamic abnormalities on magnetic resonance imaging [28]. These findings indicate that SIADH can be a potential complication in any patient with NMO. SIADH remains a diagnosis by exclusion, and it is challenging to differentiate SIADH from salt wasting, because these two conditions show similar laboratory profiles [21]. Therefore, SIADH cannot be completely excluded in the case reported here.

4. Conclusions

Hyponatremia concomitant with hyperkalemic RTA associated with trimethoprim can occur despite using only low doses of the drug, and even when combined with systemic corticosteroids with a mineralocorticoid effect. Diabetes mellitus and renin-angiotensin- aldosterone blockade may be exacerbating factors. Therefore, careful monitoring during trimethoprim therapy should be undertaken in patients with these risks.

doi: 10.3390/antibiotics9040201

Received: 18 March 2020; Accepted: 20 April 2020; Published: 23 April 2020

Author Contributions: Conceptualization, S.T. and M.F.; investigation, all authors; writing--original draft preparation, S.T.; writing--review and editing, M.T., M.K., J.I., K.O., Y.S., M.A., H.I. and M.F.; supervision, M.F. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Acknowledgments: Not applicable.

Conflicts of Interest: M.A received consulting fees and/or speaker bureau honoraria from Eli Lilly Japan K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd.; M.A also received scholarship grants from Astellas Pharma, Inc., Baxter Limited, Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Japan, Inc., and Torii Pharmaceutical Co., Ltd.; he also chaired courses endowed by Chugai Pharmaceutical Co., Ltd., Nikkiso Co., Ltd., NIPRO Corporation, Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Terumo Corporation, and Toray Medical Co., Ltd. H.I has served on the scientific advisory board of Astellas Pharma Inc.; received lecture or consulting fees from Astellas Pharma Inc., MSD K.K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., and Novartis Pharma K.K.; and has received grants/research support from Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Co., Eli Lilly and Company, Daiichi-Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., and MSD. K.K. MF has received grant/research support from Life Scan Japan K.K and Ono Pharmaceutical Co., Ltd. MT, ST, MK, JI, KO, and YS have nothing to declare.


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Masahiro Takubo (1,2), Sho Tanaka (2,3) * [ID], Masaru Kushimoto (2), Jin Ikeda (2), Katsuhiko Ogawa (2,4) Yutaka Suzuki (2,4), Masanori Abe (3)[ID], Hisamitsu Ishihara (1) and Midori Fujishiro (1,2), *

(1) Division of Diabetes and Metabolic Diseases, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan

(2) Department of Internal Medicine, Nihon University Hospital, Tokyo 101-8309, Japan

(3) Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan

(4) Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan

* Correspondence: (S.T.); fujishiro.midori@nihon- (M.F.); Tel.: +81-3-3972-8111 (S.T.); +81-3-3972-8111 (M.F.)

Caption: Figure 1. Clinical course. Horizontal axis indicates the time course. Vertical axes indicate electrolyte levels (blue circles and line, sodium level; orange triangles and line, potassium level). The red horizontal bar and arrows indicate steroid treatment. The yellow bar indicates telmisartan 40 mg/day. The green bar indicates trimethoprim 160 mg/day with sulfamethoxazole 800 mg/day.

Caption: Figure 2. Factors influencing the renin-angiotensin-aldosterone system. Red and blue arrows indicate positive and negative regulatory effects, respectively.
Table 1. Laboratory parameters on admission.

Parameters                              Values    Units

White blood cells                       6600      /[micro]L
Red blood cells                         4.31      x[10.sup.6]/gL
Hemoglobin                              13.2      g/dL
Platelets                               133,000   /[micro]L
Total bilirubin                         0.68      mg/dL
Aspartate aminotransferase              18        U/L
Alanine aminotransferase                16        U/L
Gamma-glutamyl transpeptidase           17        U/L
Blood urea nitrogen                     11.2      mg,dL
Creatinine                              0.49      mg,dL
Estimated glomerular filtration rate    9*8       mL.min/1.73[m.sup.2]
Uric acid                               3.8       mg/dL
Sodium                                  143       mEq/L
Potassium                               4.6       mEq/L
Chloride                                108       mEq/L
C-reactive protein                      0.02      mg/dL
Total protein                           7.8       g/dL
Glucose                                 81        mg/dL
Glycated hemoglobia                     8.0       %
Thyroid stimulating hormone             0.84      [micro]lU/mL
Free thyroxine                          1.14      ng/dL
Agti-AQP4 antibody                      >40       U/mL
Urine pH                                5.5
Urine albumin                           20        mg/day

Parameters                              Reference Ranges

White blood cells                       (959500-8600)
Red blood cells                         (3.86-4.92)
Hemoglobin                              (11.6-14.8)
Platelets                               (1595,000-348,000)
Total bilirubin                         (0.4-1.5)
Aspartate aminotransferase              (13-30)
Alanine aminotransferase                (7-23)
Gamma-glutamyl transpeptidase           (9-32)
Blood urea nitrogen                     (8.0-20.0)
Creatinine                              (0.46-0.79)
Estimated glomerular filtration rate    /
Uric acid                               (2.6-7.0)
Sodium                                  (138-145)
Potassium                               (3.6-4.8)
Chloride                                (101-108)
C-reactive protein                      (<1.2)
Total protein                           (6.6-8.1)
Glucose                                 (73-109)
Glycated hemoglobia                     (4.6-6.2)
Thyroid stimulating hormone             (0.34-3.7)
Free thyroxine                          (0.8-1.5)
Agti-AQP4 antibody                      (<3)
Urine pH                                (5-7)
Urine albumin                           /

Reference ranges are shown in parentheses. AQP4, aquaporin 4.

Table 2. Changes of clinical parameters just before and after
trimethoprim cessation.

Parameters                                           Values

                                           Day 21    Day 25    Day 28
Body weight                                 45.4      44.3      43.8
Blood pressure                             128/59    119/66    129/63
Pulse rate                                   81        83        89
Blood examination
  White blood cells                        11,100     8300      4600
  Red blood cells                           4.15      3.62      3.83
  Hemoglobin                                12.7      11.2      11.9
  Platelets                                181,000   156,000   161,000
  Total bilirubin                           0.85      0.65       NM
  Aspartate aminotransferase                 13        23        13
  Alanine aminotransferase                   18        31        20
  Gamma-glutamyl transpeptidase              19        20        13
  Blood urea nitrogen                       11.9       8.0       6.7
  Creatinine                                0.47      0.40      0.41
  Estimated glomerular filtration rate      102.6     122.4     119.2
  Uric acid                                  2.1       2.8       2.2
  C-reactive protein                        0.02      0.01      0.02
  Total protein                              5.9       5.3       5.7
  Glucose                                    149       96        113
  Sodium                                     125       132       134
  Potassium                                  5.2       3.8       3.9
  Chloride                                   96        99        101
  Osmolality                                 264       267       274
  Plasma renin activity                      37        26        24
  Plasma aldosterone                        43.2       38        167
  Brain natriuretic peptide                  7.7       NM        NM
Arterial blood gas analysis
  ph                                        7.438     7.465     7.469
  CO2                                        26       32.3      30.4
  HC[O.sub.3.sup.-]                         17.2      22.7      21.6
  Base excess                               -5.6      -0.4      -1.2
Urine examination
  Sodium                                     92        46        137
  Potassium                                 17.7      24.5       42
  Chloride                                   79        47        151
  Creatinine                                43.8       58       111.3
  Osmolality                                 510       614       785

Parameters                                 Units

Body weight                                kg
Blood pressure                             mmHg
Pulse rate                                 beats/min
Blood examination
  White blood cells                        /[micro]-L
  Red blood cells                          x[10.sup.6]/[micro]L
  Hemoglobin                               g/dL
  Platelets                                /[micro]-L
  Total bilirubin                          mg/dL
  Aspartate aminotransferase               U/L
  Alanine aminotransferase                 U/L
  Gamma-glutamyl transpeptidase            U/L
  Blood urea nitrogen                      mg/dL
  Creatinine                               mg/dL
  Estimated glomerular filtration rate     mL/min/1.73[m.sup.2]
  Uric acid                                mg/dL
  C-reactive protein                       mg/dL
  Total protein                            g/dL
  Glucose                                  mg/dL
  Sodium                                   mEq/L
  Potassium                                mEq/L
  Chloride                                 mEq/L
  Osmolality                               mOsm/kg [H.sub.2]O
  Plasma renin activity                    ng/mL/hr
  Plasma aldosterone                       pg/mL
  Brain natriuretic peptide                pg/mL
Arterial blood gas analysis
  CO2                                      mmHg
  HC[O.sub.3.sup.-]                        mEq/L
  Base excess                              mEq/L
Urine examination
  Sodium                                   mEq/L
  Potassium                                mEq/L
  Chloride                                 mEq/L
  Creatinine                               mg/dL
  Osmolality                               mOsm/kg [] O

Parameters                                 Reference

Body weight
Blood pressure
Pulse rate
Blood examination
  White blood cells                        (3300-8600)
  Red blood cells                          (3.86-4.92)
  Hemoglobin                               (11.6-14.8)
  Platelets                                (158,000-348,000)
  Total bilirubin                          (0.4-1.5)
  Aspartate aminotransferase               (13-30)
  Alanine aminotransferase                 (7-23)
  Gamma-glutamyl transpeptidase            (9-32)
  Blood urea nitrogen                      (8.0-20.0)
  Creatinine                               (0.46-0.79)
  Estimated glomerular filtration rate
  Uric acid                                (2.6-7.0)
  C-reactive protein                       (<0.2)
  Total protein                            (6.6-8.1)
  Glucose                                  (73-109)
  Sodium                                   (138-145)
  Potassium                                (3.6-4.8)
  Chloride                                 (101-108)
  Osmolality                               (276-292)
  Plasma renin activity                    (0.3-2.9)
  Plasma aldosterone                       (29.9-159)
  Brain natriuretic peptide                (<18.4)
Arterial blood gas analysis
  ph                                       (7.35-7.45)
  CO2                                      (35-45)
  HC[O.sub.3.sup.-]                        (22-26)
  Base excess                              (-2-2)
Urine examination
  Sodium                                   (70-250)
  Potassium                                (25-100)
  Chloride                                 (70-250)
  Creatinine                               (100-150)

Reference ranges are shown in parentheses. NM, not measured.
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Author:Takubo, Masahiro; Tanaka, Sho; Kushimoto, Masaru; Ikeda, Jin; Ogawa, Katsuhiko; Suzuki, Yutaka; Abe,
Article Type:Clinical report
Geographic Code:9JAPA
Date:Apr 1, 2020
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