Polyuria in a Patient with Aspergillus Infection

Introduction

For most ASN Kidney Week attendees, case-based clinical nephrology talks are one of the most exciting venues. The Nephrology Quiz and Questionnaire (NQQ) is the essence of clinical nephrology and represents what drew all of us into the field of nephrology. This year's NQQ in surprisingly temperate Chicago, with full-house attendance, was no exception. The expert discussants prepared vignettes of puzzling cases, which illustrated some topical, challenging, or controversial aspect of the diagnosis or management of key clinical areas of nephrology. These eight interesting cases were presented and eloquently discussed by our four expert ASN faculty. Subsequently, each discussant prepared a manuscript summarizing his or her case discussions, which serves as the main text of this article. (Mark A. Perazella and Michael Choi, Co-Moderators)

A 69-year-old man is diagnosed with squamous cell carcinoma of the base of the tongue. He undergoes aggressive chemotherapy with a cisplatin-based regimen and develops severe leukopenia approximately 3 weeks into his treatment course. Subsequently, he develops pain and swelling over his right jaw along with low-grade fever. Biopsy of the area reveals infection with Aspergillus fumigatus. He is treated with intravenous amphotericin B (0.3 mg/kg per day). His weight is 70 kg. You are called to see the patient, because his laboratory work shows several abnormalities after 8 days of amphotericin therapy (Table 1). Also of note, his daily urine output has increased to >5 L/d, and a spot urine osmolality on a first morning voided specimen was 99 mosM/kg. At the time that you are seeing the patient, he is complaining of muscle weakness and thirst. He denies nausea, vomiting, or diarrhea. Vital signs and physical examination are essentially normal, with the exception of his jaw swelling and localized tenderness in this area.

Table 1.

Laboratory values

Laboratory Test	Value
Sodium, mEq/L	147
Potassium, mEq/L	2.1
Bicarbonate, mEq/L	7
Chloride, mEq/L	130
BUN, mg/dl	20
Serum creatinine, mg/dl	1.1
Urine pH	7.0

Question 1: What Is the Estimated Water Deficit in This Patient?

1. Not enough information

2. 2 L

3. 4 L

4. 6 L

5. 8 L

The correct answer is B (2 L).

The free water deficit can be calculated by a simple formula that was described over 50 years ago, where total body water losses are estimated as 0.6 (for women, 0.5) × body mass × [1−(140/serum sodium)] (1). Using this formula, one arrives at the answer that the patient would require approximately 2 L water to return his serum sodium to 140 mEq/L. It is critical to understand that this formula is an approximation of water losses and that serial laboratory measures of serum sodium are required to determine the actual water replacement needs of the patient. The formula has significant assumptions that can lead to errors in management if serial laboratory measures are not monitored. For instance, this formula has assumptions both related to body composition (because 60% water may not be true in many individuals) and in setting the normal plasma sodium equal to a population median of 140 mEq/L. The formula also does not account for ongoing water losses that will need continuous replacement.

A recent study investigated the validity of this formula in 36 normal volunteers who underwent controlled thermoregulatory dehydration. In this study, the commonly used formula significantly underestimated total body and free water losses by up to 50% (2). Thus, caution is warranted when using the commonly applied water deficit equation.

Question 2. This Patient is Given a Dose of Vasopressin, and the Urine Osmolality and Urine Output Are Rechecked 1 Hour Later. Which of the Following Would You Expect to See?

1. A rise in urine osmolality and a decrease in urine output

2. A rise in urine osmolality and an increase in urine output

3. No change in urine osmolality and a decrease in urine output

4. No change in urine osmolality and no change in urine output

The correct answer is D (picture consistent with nephrogenic diabetes insipidus [DI]).

This patient is presenting with both polyuria and hypernatremia, and to determine the pathogenesis of these abnormalities, it is important to understand that the body’s primary defenses against hyperosmolality and hypernatremia are an intact thirst mechanism, free access to water, and intact functioning of the arginine vasopressin (AVP)-distal tubule urinary concentrating mechanism with return of water back to the circulation. Alternatively, sometimes renal or extrarenal water losses can be so great that keeping up with them with oral water intake is difficult (3). Thus, the approach to the patient with hypernatremia begins with an assessment of the urine osmolality (4). If the patient is producing a minimal volume of maximally concentrated urine (high urine osmolality), then the etiology is likely insensible water losses, gastrointestinal water loss, or remote renal water losses, and renal mechanisms of water conservation are intact. However, as in this patient, if the patient is producing large amounts of urine, then it is important to determine if the polyuria represents a water or solute diuresis. This can be determined by first excluding causes of osmotic diuresis, such as hyperglycemia, hypercatabolism, or the use of osmotic diuretics, such as mannitol. In patients with solute diuresis, measurement of the daily osmole excretion rate can be diagnostic and is typically >750 mosM/d. In this case, the patient has a low urine osmolality and thus, is experiencing a water diuresis from DI.

Broadly speaking, DI can be due to either central (lack of or decreased production of AVP) or nephrogenic (lack of tubular response to AVP) etiologies. To determine the etiology of DI, vasopressin can be administered, and the urine osmolality can be checked after this provocative maneuver (5). In the case of central DI, urine osmolality will rise and urine output will fall as the tubules retain their ability to respond to exogenous AVP. With nephrogenic DI, AVP administration will not lead to a change in urine osmolality, and urine volume will continue to be high, because the tubules are unable to respond. Between these extremes, patients may have partial defects in central AVP production or tubular responsiveness. In some circumstances, water deprivation is used before the administration of AVP to help test whether polyuria may be due to polydipsia (where water deprivation would result in a normal rise in urine osmolality over time) or partial or central DI (where there would be moderate rises in urine osmolality but not maximal concentration of the urine). In this case, water deprivation would not be required, because the patient was hypernatremic (and thus, already had a physiologic stimulus for AVP production) and had a concomitant low urine osmolality and high urine output. This clinical state would exclude polydipsia as an etiology. The only remaining question is whether this represents central or nephrogenic DI.

It is critical to view this question in the context of the clinical presentation. Here, the notable new event in this patient’s history is the infection with A. fumigatus and the initiation of amphotericin B therapy. There is no reason to suspect a central nervous system lesion (no neurologic findings) leading to central DI, and thus, amphotericin B toxicity should be suspected.

Amphotericin B is a highly effective antifungal agent that binds with ergosterol, a key component of fungal cell membranes, and forms pores that result in leakage of monovalent ions and cell death (6). Because human and fungal cell membranes share common structures, amphotericin B can also lead to pore formation in human cell membranes with resulting toxicity (7). Because a large portion of the drug is excreted through the kidney, the renal tubules are particularly susceptible to injury (8). It is relatively common to see nephrotoxicity due to amphotericin B when cumulative doses exceed 4–5 g or the drug is administered with other potential nephrotoxins, such as calcineurin inhibitors or aminoglycosides (8,9). The consequences of the tubular membrane injury and changes in cellular permeability include prominent electrolyte disorders, such as hypokalemia, hypomagnesemia, and renal tubular acidosis (Figure 1). These abnormalities are generally reversible on discontinuation of amphotericin B and seem to be much less common with liposomal amphotericin B formulations (8,9).

Figure 1.

Effects of amphotericin B on distal tubule function. In the principal cell, amphotericin can have multiple effects, including increasing cell membrane permeability through the insertion of pores into the membrane that leak potassium into the tubular lumen and lead to hypokalemia. Amphotericin B also inhibits vasopressin-induced insertion of aquaporin 2 (AQP-2) channels into the luminal cell membrane. This leads to the development of concentrating defects and polyuria. In the intercalated cell, amphotericin B also creates pores in the cell membrane, which allow back diffusion of hydrogen ions into the cell with impairment of distal tubular acidification and the development of a nonanion gap acidosis. K+, potassium; Na+, sodium; V2 receptor, vasopressin type 2 receptor.

Other mechanisms of kidney injury include indirect effects secondary to activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators (thromboxane A2) (10). The latter effects are presumably responsible for the observed acute decreases in renal blood flow and GFR that are manifested as AKI (10). Prevention of the fall in GFR has been achieved through preadministration sodium loading (typically with intravenous fluids) and more recently, lipid-based formulations of amphotericin B (8–10).

Pertinent to this patient’s presentation is that amphotericin B can lead to reversible impairments in renal concentrating ability with resulting polyuria, aquaresis, and risk for hypernatremia (8–10). Amphotericin B–induced DI is vasopressin resistant and results from a distal tubular defect that is, in part, related to a reduction in the number of aquaporin-2 (AQP-2) channels in the distal tubule (11). This reduction in AQP-2 channels results from effects of amphotericin B on G-stimulatory proteins that are critical in the production of the second messenger cAMP, which subsequently leads to AQP-2 activation (11). In case reports, amphotericin B–induced nephrogenic DI typically resolves within 3 weeks after discontinuation of the drug (11).

Thus, for this patient with polyuria and hypernatremia associated with a low urine osmolality, the administration of vasopressin would not result in any change in urine osmolality or urine volume.

Question 3: Which of the Following Is Another Cause of Nephrogenic DI?

1. Metabolic alkalosis

2. Hypocalcemia

3. Hypokalemia

4. Hypomagnesemia

5. Trimethoprim

The correct answer is C (hypokalemia).

Hypokalemia (plasma potassium concentration usually ≤3 mEq/L) can lead to a modest reduction in urinary concentrating ability. The magnitude of the concentrating defect was evaluated in a study in which hypokalemia was induced by a low-potassium diet (0.1 mEq/kg per day) in nine men. The maximum urine osmolality fell from a mean of 1140 mosmol/kg at baseline to 328 mosmol/kg at 4 weeks, despite the administration of exogenous vasopressin. Most of the reduction in concentrating ability occurred in the first 2 weeks (12).

Mechanistically, hypokalemia leads to reversible nephrogenic DI through two major mechanisms: (1) downregulation of AQP-2, which occurs through autophagic degradation of the channel, and (2) decreased activity of the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle with resultant decrease in the medullary concentrating gradient (13,14). The defect in urinary concentrating ability can be seen as early as 12 hours after the onset of potassium depletion and is reversible with normalization of potassium levels (15). Other causes of acquired nephrogenic DI include hypercalcemia and lithium use.

Summary

This patient developed significant tubular abnormalities after receiving amphotericin B therapy. These abnormalities reflect effects of amphotericin B that affect cell membrane function (hypokalemia and renal tubular acidosis) as well as intracellular processes (insertion of AQP-2 channels). Fortunately, these abnormalities are reversible with cessation of the therapy, but patients must be monitored, and these abnormalities must be treated to avoid serious complications.

Disclosures

M.H.R. has consultancy agreements with Johnson and Johnson (New Brunswick, NJ), Abbvie (North Chicago, IL), and Otsuka (Tokyo, Japan) and has received research funding from Otsuka and Kadmon (New York, NY). M.H.R. has received honoraria from the American Society of Nephrology (Washington, DC) and Baxter Scientific (Deerfield, IL). M.H.R. is an advisor or member of the Editorial Board of the American Journal of Kidney Disease and the Clinical Journal of the American Society of Nephrology.