Acid-Base and Electrolyte Teaching Case Trimethoprim-Associated Hyponatremia Revekka Babayev, MD,1 Sofia Terner, MD,1 Subani Chandra, MD,2 Jai Radhakrishnan, MD,3 and Sumit Mohan, MD3 Hyponatremia associated with diuretic use can be clinically difficult to differentiate from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). We report a case of a 28-year-old man with HIV (human immunodeficiency virus) and Pneumocystis pneumonia who developed hyponatremia while receiving trimethoprim-sulfamethoxazole (TMP/SMX). Serum sodium level on admission was 135 mEq/L (with a history of hyponatremia) and decreased to 117 mEq/L by day 7 of TMP/SMX treatment. In the setting of suspected euvolemia and Pneumocystis pneumonia, he was treated initially for SIADH with fluid restriction and tolvaptan without improvement in serum sodium level. A diagnosis of hyponatremia secondary to the diuretic effect of TMP subsequently was confirmed, with clinical hypovolemia and high renin, aldosterone, and urinary sodium levels. Subsequent therapy with sodium chloride stabilized serum sodium levels in the 126- to 129-mEq/L range. After discontinuation of TMP/SMX treatment, serum sodium, renin, and aldosterone levels normalized. TMP/SMX-related hyponatremia likely is underdiagnosed and often mistaken for SIADH. It should be considered for patients on high-dose TMP/SMX treatment and can be differentiated from SIADH by clinical hypovolemia (confirmed by high renin and aldosterone levels). TMP-associated hyponatremia can be treated with sodium supplementation to offset ongoing urinary losses if the TMP/SMX therapy cannot be discontinued. In this Acid-Base and Electrolyte Teaching Case, a less common cause of hyponatremia is presented, and a stepwise approach to the diagnosis is illustrated. Am J Kidney Dis. 62(6):1188-1192. ª 2013 by the National Kidney Foundation, Inc. INDEX WORDS: Hyponatremia; trimethroprim; epithelial Na1 channel (eNaC); syndrome of inappropriate antidiuretic hormone secretion (SIADH); renal salt wasting.
INTRODUCTION Hyponatremia is the most common electrolyte abnormality in patients who are hospitalized.1 Hypotonic hyponatremia represents an excess water state, with the majority of cases related to impaired excretion of free water, and less commonly, inappropriate sodium excretion. The latter condition, either iatrogenic (due to diuretic use) or intrinsic (due to renal salt wasting), is associated with extracellular volume depletion caused by a tubular defect in sodium transport. This results in hyponatremia with urinary sodium excretion .20 mEq/L in the presence of normal renal, adrenal, and thyroid function.2 Apart from differences in volume status, which can be subtle at times, patients with salt wasting have a biochemical profile similar to that of syndrome of inappropriate antidiuretic hormone secretion (SIADH), with hypotonic hyponatremia, hypouricemia, inappropriately high urine sodium excretion (.20 mEq/L), and increased fractional excretion of uric acid (FEuric acid).3 However,
the distinction of the 2 conditions is important because the treatment approach is different. We describe a patient with HIV (human immunodeficiency virus) infection who developed hyponatremia while on therapy with high-dose trimethoprimsulfamethoxazole (TMP/SMX) for Pneumocystis jirovecii pneumonia (PCP). Trimethoprim is a heterocyclic weak base that is related in structure to the potassium-sparing diuretics amiloride and triamterene, acting to block sodium reabsorption at the eNaC (epithelial Na1 channel) in the distal nephron.4,5 The hyponatremia responded to saline administration and corrected with cessation of the TMP therapy. The clinical scenario presented here represents one of the less common causes of hyponatremia, but serves as a branch point for the stepwise approach toward the diagnosis.
CASE REPORT Clinical History and Initial Laboratory Data
From the 1Department of Medicine and Divisions of 2Pulmonary, Allergy and Critical Care and 3Nephrology, Columbia University Medical Center, New York, NY. Received December 11, 2012. Accepted in revised form June 10, 2013. Originally published online July 29, 2013. Address correspondence to Revekka Babayev, MD, 622 W 168th St, Vanderbilt Clinic 2nd Fl, VC 205, New York, NY 10032. E-mail:
[email protected] 2013 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.06.007 1188
A 28-year-old man with a medical history of HIV infection (CD4 count, 106 cells/mL) presented to the emergency department with a 1-month history of dyspnea on exertion and fevers. He was noted to be febrile (temperature, 39 C), hypotensive, tachycardic, and tachypneic. He had dry mucous membranes and bibasilar crackles without jugular venous distention or dependent edema. Laboratory results showed the following values: mildly reduced serum sodium of 135 mEq/L; serum creatinine, 0.78 mg/dL, with estimated glomerular filtration rate of 80.2 mL/min/1.73 m2 (calculated using the CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] creatinine equation); lactate dehydrogenase, 481 (reference Am J Kidney Dis. 2013;62(6):1188-1192
Trimethroprim Hyponatremia
Figure 1. A visual description of the patient’s case. Serum and urinary sodium trends are displayed in this figure, with the top portion of the graph representing various interventions during hospitalization. The shaded portion of the graph corresponds to the saline challenge day when 342.2 mEq of sodium was administered, with improvement noted in serum sodium levels. Corresponding levels of renin/aldosterone and urine osmolality when available also are graphed. Conversion factor for aldosterone in ng/dL to nmol/L, 30.02774. Abbreviations: ICU, intensive care unit; PO, orally.
range, 115-221) U/L; leukocyte count, 14.1 (reference range, 3.5-9.1) 3103/mL; and respiratory alkalosis, with pH 7.46, PCO2, 31 mm Hg; bicarbonate, 24 mEq/L; and wide arterial-alveolar gradient, 17 mm Hg. Imaging with chest computed tomography showed diffuse ground-glass opacities consistent with the clinical diagnosis of PCP, which was confirmed by silver stain of pulmonary secretions obtained by bronchoscopy. The patient was started on treatment with intravenous pentamidine with high-dose steroids due to a reported allergic reaction of hives to TMP/SMX, but subsequently was transferred to the intensive care unit for worsening hypoxia (PO2, 67 mm Hg on room air). There he underwent desensitization to TMP/SMX because of the clinical deterioration and was started on treatment with TMP, 15 mg/kg/d, on day 3 with concomitant discontinuation of pentamidine therapy.
Additional Investigations On day 5 of hospitalization, serum sodium levels started to trend down and decreased to 120 mEq/L on day 9 (Fig 1). Urinary sodium excretion on day 9 was 136 mEq/L, with fractional excretion of sodium (FENa) of 1.5% and normal thyroidstimulating hormone (0.73 mIU/L) and cortisol (29 mg/dL) levels. For a presumed diagnosis of SIADH, the patient was started on fluid restriction. The patient’s volume status was unclear, with mild tachycardia (heart rate, 100-110 beats/min) thought to be secondary to his fevers. With persistent hyponatremia despite free water restriction, tolvaptan treatment was started at a serum sodium level of 121 mEq/L. Increasing doses of tolvaptan (15 mg administered on day 11, and 30 mg, on day 12) did not improve his hyponatremia, with a serum sodium level of 118 mEq/L on day 13 and urine osmolality of 682 mOsm/kg (Table 1). On day 13, the patient was noted to have orthostasis on examination and a collapsing inferior vena cava on a bedside ultrasound, suggesting intravascular volume depletion. This subsequently was confirmed by elevated plasma renin activity of 68.5 (reference range, 0.2-4) ng/mL/h and aldosterone level of 62.4 (reference, #31) ng/dL in the morning. Fractional excretion of phosphate was 76% (reference, ,20%), and FEuric acid was 13.6% (reference, #10%) at the time. As a result, tolvaptan therapy was stopped on day 13 and the patient was given a volume challenge with 2 L of 0.9% sodium chloride solution and 2 salt tabs (34.2 mEq of sodium) for a total of 342.4 mEq. Following administration of that salt load, tachycardia improved and serum sodium level increased to 126 mEq/L, with resolution of orthostasis. Am J Kidney Dis. 2013;62(6):1188-1192
Diagnosis TMP-related hyponatremia.
Clinical Follow-up TMP therapy was continued and the patient was encouraged to maintain a high-salt diet, which allowed his serum sodium level to remain at 127-129 mEq/L, until day 19, when TMP therapy was stopped. Upon discontinuation of TMP/SMX treatment, serum sodium level increased to 134 mEq/L on day 21 and 140 mEq/L on day 27. Renin and aldosterone levels also returned to their normal ranges (18.7 ng/mL/h and 6 ng/dL, respectively) on day 21. At last follow-up 4 months after hospital discharge, serum sodium level remained in the normal range at 138 mEq/L.
DISCUSSION Hypotonic hyponatremia is characterized according to volume status: hypovolemic, euvolemic, and hypervolemic. While hypervolemic hyponatremia is accompanied by signs suggestive of volume overload (elevated jugular venous pressure, edema, and crackles), it can be a challenge to differentiate hypovolemic from euvolemic hyponatremia on clinical examination.6 SIADH is the most frequent cause of hyponatremia in hospitalized patients, but remains a diagnosis of exclusion.7 Although the etiology for this entity is broad, some of the more common causes include pulmonary diseases, heart failure, liver failure, central nervous system processes, malignancies, and medications.7 SIADH should be considered in euvolemic patients with hypotonic hyponatremia who have normal thyroid and adrenal function coupled with laboratory evidence of urinary sodium excretion .40 mEq/L (with normal dietary sodium intake), elevated urinary osmolality (.100 mOSm/kg), and no recent diuretic use.7 HIV-infected patients appear to be particularly susceptible to developing SIADH, with some series reporting SIADH in up to 53% of hospitalized patients with AIDS.8 Additionally, 1189
Babayev et al Table 1. Pertinent Laboratory Data
Weight (kg)
Day 10 Fluid Restriction Started
Day 13 Pre–Saline Challenge
40.3
36.2
Day 13 Post–Saline Challenge
Day 21 Post-TMP/SMX Discontinuation
36.2
40.2
Reference Range
Serum Sodium (mEq/L)
117
118
126
138
136-146
Potassium (mEq/L)
3.9
5.7
4.4
3.5
136-146
Uric acid (mg/dL)
3.4
5
NA
6
3.1-7.0
Osmolality (mOsm/kg)
245
288
NA
285
275-295
Cortisol (mg/dL) TSH (mIU/L)
29 0.73
5-25 0.32-4.05
Renin (ng/mL/h)
NA
68.5
60.0
18.7
0.2-4
Aldosterone (ng/dL)
NA
62.4
56.8
6
#31
Urine Sodium (mEq/L)
136
37
NA
157
43-217
Osmolality (mOsm/kg)
619
682
447
298
500-800
FENa (%)
1.5
0.36
NA
0.4
,1 if YECV
FEuric acid (%) FEPi (%)
NA NA
13.6 76
20.5 50.2
4.6 6.3
#10 ,20
NA
32.3
54.8
NA
1,475
910
1,650
1,100
FEurea (%) Urine volume (mL/d)
Note: Conversion factors for units: aldosterone in ng/dL to nmol/L, 30.02774; uric acid in mg/dL to mmol/L, 359.48. Abbreviations: ECV, extracellular volume; FENa, fractional excretion of sodium; FEPi, fractional excretion of phosphate; NA, data not available; TMP/SMX, trimethoprim-sulfamethoxazole; TSH, thyroid stimulating hormone.
HIV-infected patients tend to develop a high frequency of hyponatremia, in part related to the reset osmostat phenomenon of decreased threshold for ADH secretion, likely secondary to malnutrition.9 Our patient had PCP and low serum sodium level on presentation, but normal sodium level at the conclusion of therapy. This would suggest that the initial low serum sodium level was related to either SIADH secondary to the ongoing pulmonary infection or unrecognized volume depletion rather than the reset osmostat phenomena reported in HIV-infected patients. Given suspected euvolemia together with elevated urinary sodium excretion (136 mEq/L) and osmolality (619 mOsm/kg), the patient initially was treated as a case of SIADH after thyroid and adrenal insufficiency were ruled out. However, the diagnosis was questioned when the patient’s serum sodium level failed to respond to both free water restriction and administration of a vasopressin antagonist, and the patient’s intravascular volume depletion became more clinically evident with the presence of tachycardia, orthostatic hypotension, and inferior vena cava collapse with respiratory variation by bedside ultrasound. Inappropriately high urinary sodium excretion in the setting of hypovolemia is seen in patients with adrenal insufficiency, hypothyroidism, metabolic alkalosis, diuretic use, cerebral salt wasting, and salt-wasting nephropathies (Box 1).10 Diuretics, predominantly thiazide diuretics, are responsible for up to 11% of 1190
hyponatremia in some series.11 Thiazide diuretic use can result in euvolemic hyponatremia related to increased free water intake (due to ADH stimulus) coupled with reduced free-water clearance (due to a defect in urinary diluting capacity), as well as renal sodium and/or potassium loss.12 In light of the normal adrenal and thyroid function and absence of an intracranial pathology or metabolic alkalosis, we reviewed his medication list in search of a drug with a diuretic or salt-wasting effect. A literature search suggested TMP as a likely culprit, with several case reports of TMP/SMX-associated hyponatremia, especially in patients on high-dose therapy and with underlying decreased kidney function.13,14 TMP therapy has been linked to hyponatremia, hyperkalemia, and metabolic acidosis.13-17 While hyperkalemia is the most common electrolyte abnormality associated with high-dose TMP therapy, occurring in as many as 44%-70% of HIV-infected patients with PCP, reports of severe hyponatremia are rare.13,14 Box 1. Differential Diagnosis for Hypovolemic Hyponatremia With Elevated Urinary Sodium
Adrenal insufficiency Hypothyroidism Metabolic alkalosis Diuretic use Cerebral salt wasting Salt-wasting nephropathy
Am J Kidney Dis. 2013;62(6):1188-1192
Trimethroprim Hyponatremia Table 2. SIADH Versus TMP-Associated Hyponatremia
SIADH
TMP-Associated Hyponatremia
Extracellular volume
4 or [
Y
Heart rate
4
[
Serum sodium
Y
Y
Serum potassium
Y
[
Serum urea nitrogen
4 to Y
[
Creatinine clearance Serum uric acid
4 or [ Y
4 or Y 4 to Y
Plasma renin
4 or Y
4 or [
Serum aldosterone
4 to [
[
ADH
[
[
Urinary sodium
[ 4 to [
[ [
Water restriction
Salt supplementation
FEuric acid Correction
Note: In SIADH, urinary sodium excretion is equal to dietary sodium intake. Urinary sodium excretion is elevated (.40 mEq/L) under normal dietary salt intake conditions. Patients on a low-salt diet can have low urinary sodium excretion. Abbreviations: ADH, antidiuretic hormone; FEuric acid, fractional excretion of uric acid; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TMP, trimethoprim.
In our patient, in addition to the development of hyponatremia, a potassium level of 5.9 mEq/L and bicarbonate level of 18 mEq/L were noted on day 9 of TMP/SMX use. Vasopressin escape in SIADH is associated with an increase in the presence of the eNaC in the distal nephron, which, together with an elevated aldosterone level stimulated by hyponatremia, results in hypokalemia.15 Furthermore, bicarbonate levels usually are preserved in SIADH. Thus, the presence of hyperkalemia and reduced bicarbonate level in our patient made SIADH less likely. The pathophysiology of the TMP/SMX effect appears to be linked to the action of TMP on the distal tubule of the nephron. TMP at high doses has been shown to be a reversible direct sodium channel inhibitor at the level of the eNaC in the distal tubule, in effect functioning as a potassiumsparing diuretic.4 TMP also would be expected to create a distal acidification defect, with hyperkalemia contributing to reduced net acid excretion by inhibition of ammoniagenesis and excretion. This results in a decreased serum bicarbonate level consistent with the patient’s clinical findings.17,18 In animal studies, TMP infusions decreased renal potassium excretion by 40% and increased renal sodium excretion by 46%.5 This effect appeared to be dose dependent, with results more pronounced in those receiving treatment doses for PCP compared with the lower doses more commonly used for PCP prophylaxis and urinary tract infections.13,14 The effect on sodium is dose dependent and reportedly Am J Kidney Dis. 2013;62(6):1188-1192
more common in the elderly, particularly those who are also using other diuretics.14,16 The treatment for salt wasting is to offset ongoing sodium losses with either saline solution infusions or salt tabs. Our patient was given 2 salt tabs and a 2-L infusion of 0.9% saline solution, with improvement in 24 hours of his serum sodium level into the mid-upper 120s. Hyponatremia stabilized with a high-salt diet and completely resolved with discontinuation of the drug, confirming the relationship between high-dose TMP and the hyponatremia. Our case highlights the importance of differentiating hypovolemic from euvolemic hyponatremia in patients with elevated urinary sodium concentrations, especially because the management of hyponatremia in these patients is different. Diagnostic features that help distinguish between the 2 include serum potassium, serum urea nitrogen (SUN)/creatinine, and renin/ aldosterone measurements (Table 2).19-21 In general, SIADH is associated with hypouricemia and low SUN level secondary to volume expansion and resultant decrease in proximal tubule reabsorption, resulting in elevated FENa and FEuric acid.19 Renal salt wasting and TMP therapy also have been linked to hypouricemia and persistently high FEuric acid, although SUN levels usually are elevated in this volume-depleted population.20 While patients with SIADH have impaired free water excretion and thus respond to fluid restriction and vasopressin receptor antagonists, patients with inappropriate loss of sodium require sodium supplementation to offset ongoing losses.21 Thus, patients with hyponatremia secondary to high-dose TMP should have liberal sodium intake and not undergo fluid restriction. Teaching points are listed in Box 2. Box 2. Teaching Points Hyponatremia associated with SIADH is characterized by clinical evidence of euvolemia (normal blood pressure and pulse rate, absent edema), but physiologic evidence of volume expansion, as shown by low SUN, low serum creatinine, low uric acid, and low serum renin levels and rapid excretion of administered sodium Hyponatremia associated with thiazides may be difficult to distinguish from that due to SIADH, although the former is likely to have elevated SUN and creatinine levels with activation of the renin angiotensin system Hyponatremia associated with diuretics can be associated with overt clinical or physiologic evidence of hypovolemia. Since evidence of hypovolemia might be subtle, studies to define physiologic evidence of hypovolemia, such as measurement of the renin angiotensin system, can help differentiate the various causes of hyponatremia Trimethoprim is an antibiotic, but because it has structural similarity to potassium-sparing diuretics, it can cause sodium wasting and hyperkalemia. In rare cases, trimethoprim administration also can lead to hyponatremia Abbreviations: SIADH, syndrome of inappropriate antidiuretic hormone secretion; SUN, serum urea nitrogen. 1191
Babayev et al
ACKNOWLEDGEMENTS We thank Dr Simon Tsiouris for help obtaining follow-up data for our patient and Dr Prince Mohan for his contribution to manuscript preparation. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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