Patients With Fungic Infections Clinical Trial
Official title:
Use of Spironolactone for the Prevention of Electrolyte Abnormalities in Patients Treated With Amphotericin B
Purpose Invasive fungal infections cause significant morbidity and mortality in
immunocompromised patients.
Amphotericin B deoxycholate (AmB) is a polyene antifungal agent. The broad spectrum of
activity contributed to it being considered the gold standard of antifungal therapy despite
being associated with high incidences of infusion related adverse events.
AmB exerts their antifungal effect binding to ergosterol; a sterol similar to cholesterol
found in fungal cell membranes. However AmB also binds to cholesterol molecules in mammalian
cell membranes forming intramembranous pores and vacuoles in the distal convoluted tubule of
the kidney producing its nephrotoxic effects.
Nephrotoxicity is the major adverse effect of AmB, often limiting administrations of full
dosage; it's manifested as acute kidney injury, impaired renal concentrating ability,
augmented urinary potassium secretion through tubular Na+/K+ ATPase, type-1 renal tubular
acidosis, which increases the elimination of potassium, and magnesium wasting. Furthermore
potassium depletion potentiates the tubular toxicity of AmB.
The management of potassium wasting may be difficult, even high intravenous doses of
potassium chloride may not be fully effective in correcting the hypokalemia. It has been
probed the use of potassium-sparing diuretics to limit electrolyte wasting in patients
treated with AmB.
In 1988 Smith et al, demonstrated that amiloride was well tolerated and provided effective
control of plasma potassium in patients treated with AmB. This finding was confirmed in 2001
by Bearden et al. However in our country the only available commercial presentation of
amiloride also contains hydrochlorothiazide, limiting its use in such patients.
Spironolactone acts on the distal renal tubule by competitive inhibition of aldosterone,
thereby blocking the exchange between sodium and both potassium and hydrogen in the distal
tubules and collecting ducts. These agents produce a sodium diuresis which results in
potassium retention. There is only one clinical trial by Ural et al, using spironolactone to
prevent hypokalemia in twenty-six neutropenic patients on AmB treatment; they demonstrated
that those patients receiving concomitant AmB and spironolactone (100mg bid) had
significantly higher plasma potassium levels than those receiving AmB alone (P=0.0027) and
required significantly less potassium supplementation to maintain their plasma potassium
within the normal range (P=0.022).
Renal vasoconstriction appears to play a major role in AmB induced reduction in GFR;
recurrent ischemia may lead to structural and tubular damage and permanent nephrotoxic
effects.
Aldosterone modulates the tone of the renal vasculature. Bobadilla et al have shown in
animal models of cytotoxic damage using cyclosporine; that a mineralocorticoid receptor
blockade with spironolactone reduces the structural renal damage, and also prevents renal
dysfunction due to afferent and efferent vasoconstrictions. This group has also shown that
prophylactic treatment with spironolactone completely prevents renal dysfunction and
histological signs of tubular injury from ischemia-reperfusion injuries. And also has
demonstrated the ability of spironolactone in animal models to protect the kidney after
establishing an ischemic insult, when spironolactone was administrated immediately or 3h
after the renal ischemic insult had occurred, reducing levels of sensitive biomarkers such
as Kim-1 and Hsp70.
The investigators' hypothesis is that administration of spironolactone in patients treated
with AmB will help to maintain significantly higher plasma potassium levels and will help to
reduce potassium and magnesium supplementation. Moreover spironolactone will help to reduce
the urinary excretion of potassium.
The investigators propose a randomized, double blind, placebo controlled trial approved by
the local ethical committee, to compare the efficacy and security of spironolactone to
reduce electrolytic derangements in three groups: AmB and placebo, AmB and spironolactone
100mg once a day, AmB and spironolactone 100mg twice a day. The investigators will include
12 patients per group. Researchers will collect daily plasma creatinine, sodium, potassium,
BUN and urinary potassium, as well as the values of potassium and magnesium supplements
administered orally or parenterally. The researchers will also collect by 7 days urinary
levels of NGAL, KIM-1 and Hsp-70 as tubular injury markers.
| Status | Terminated |
| Enrollment | 36 |
| Est. completion date | March 2015 |
| Est. primary completion date | March 2015 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 80 Years |
| Eligibility |
Inclusion Criteria: - Patients with indications for AmB treatment Exclusion Criteria: - Patients with acute kidney injury - Hyperkalemia =5.2 - Hypersensibility to spironolactone - HIV infection - Pregnant women - Solid organ transplant - Hemodynamic instability - CKDEPI =30ml/min/1.73m3 |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
| Country | Name | City | State |
|---|---|---|---|
| Mexico | Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán | México |
| Lead Sponsor | Collaborator |
|---|---|
| Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran |
Mexico,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Incidence of hypokalemia =3.5mEq/L | Researchers will collect daily plasma potassium | Up to the 5th day | No |
| Primary | Average potassium supplementation | Researchers will collect the values of potassium supplements administered orally or parenterally. | Within the first to 15 days | No |
| Primary | Incidence of hyperkalemia | Researchers will collect daily plasma potassium levels. | Up to the 5 day | Yes |
| Secondary | Acute kidney injury | Researchers will collect daily plasma creatinine and urinary output. We will define acute kidney injury by creatinine elevation =0.3mg/dL above de baseline or reduction in urinary output according to AKIN criteria. | Within the first 15 days | No |
| Secondary | Incidence of renal tubular damage | Researchers will also collect by 7 days urinary levels of NGAL, KIM-1 and Hsp-70 as tubular injury markers. | Up to the 7th day | No |
| Secondary | Incidence of hypomagnesemia | Researchers will collect daily plasma magnesium | Up to the 15 day | No |