Mucormycosis Treatment and Nephrotoxicity
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The frequency of ROCM (rhino-oculo cerebral mucormycosis) is increasing in the COVID 19 pandemic. The main reasons for this rising incidence of mucormycosis are uncontrolled diabetes mellitus, steroid use beyond the recommended duration, and immunocompromised state. Low pH because of diabetic ketoacidosis is a high-yielding domain for mucor spores to germinate. Besides, steroid usage decreases the phagocytic activity of WBC, leads to bronchoalveolar macrophases migration damage, ingestion, and phagolysosome fusion, thereby making the patient having diabetes most susceptible to mucormycosis. COVID-19 generally leads to endothelialitis, endothelial dysfunction, thrombosis, lymphopenia, and reduction in CD4+ and CD8 T cell levels and therefore leads to chances of having secondary or opportunistic fungal infection. Free iron is a great option for mucormycosis. Hyperglycemia leads to glycosylation of transferrin and ferritin and decreases iron-binding, thereby leading to enhanced free iron. Besides, rise in cytokines in patients with COVID-19, especially interleukin-6, raises free iron by raising ferritin levels because of increased synthesis and reduced iron aid. Concomitant acidosis raises free iron by a similar procedure, besides by decreasing the ability of transferrin to chelating iron.

 High glucose boosts glucose-regulator protein 78 (GRP-78) level of endothelium cells as well as fungal ligand spore coating homolog (CotH) protein, leading to angioinvasion, hematogenous distribution, and tissue necrosis.

Amphotericin B

The preferred drug for the treatment of mucormycosis remains amphotericin B.

The conventional amphotericin B (c-AmB) is widely used in developing countries due to cost-effectiveness and ease of availability. The common side effect is renal toxicity.

The attachment of the drug to ergosterol on the fungus cell wall, creating pores on the wall and inflow of potassium, causes cell death. The closeness of the drug to mammalian phospholipids on the cell wall causes a tubular impact on the drug.

The clinical demonstrations comprise renal inadequacy, urinary potassium waste and hypokalemia, urinary magnesium waste and hypomagnesemia, metabolic acidosis because of type 1 (or distal) renal tubular acidosis, and polyuria because of nephrogenic diabetic insipidus.


Growth in blood urea nitrogen (BUN) and serum creatinine (SCr) levels has been shown to take place in over 80% of patients getting AmB while this agent came into existence. Dose-dependent renal malfunction is reputed.

Patients receiving a cumulative dose of > 4g were shown to have permanent kidney damage and CKD. Reversibility of renal functions was seen in majority of those patients receiving less than 4g of dose; however, CKD was seen in some if other co-morbidities were present.  Radionucleotide studies have shown a reduction in glomerular filtration rate (GFR) and renal blood flow (RBF) during treatment. Acute vasoconstriction of the renal afferent arteriole has been shown with amphotericin B mainly due to increased synthesis of thromboxane A2. There are no demonstrable increases in the levels of endothelin, angiotensin, renin or aldosterone. The effects are seen in the areas of the kidney vulnerable to hypoxia i.e juxta medullary nephrons and near the TAL of loop of henle.

Hypokalemia and hypomagnesemia

There has been no vagueness in showing that AmB triggers renal potassium wasting and can generate significant potassium scarcity. Levels below 3 mmol/L have been shown in one-third of the patients in latest publications. Potassium and magnesium should be taken care of frequently at times of AmB therapy as depletion of these electrolytes can lead to adverse effects on the patient, including generalized weakness, which can advance as increasing paralysis with serious depletion, metabolic disorders, neurologic damage, arrhythmias, etc. Electrolyte issues may continue for weeks following the stopping of AmB therapy. An issue similar to type 1 renal tubular acidosis is shown. Potassium loss in the urine is because of the impact on H+ k+ATPase, which generally secretes hydrogen ion and absorbs potassium and passive diffusion of potassium across leaky cell membranes.

Magnesium absorption is majorly carried out in DCT and early gathering duct by means of TRMP 6 channel, for which the electrochemical gradient should be taken care by the basolateral Na K ATPase. Grade change takes place when Na K ATPase is impacted by the cAmB. Hypomagnesemia takes place after the 1st week of treatment with AmB.

A more problematic and rarely stated side effect of a quick infusion of AmB is hyperkalemia. Hyperkalemia can take place due to a serum AmB concentration–dependent change of potassium from the intracellular compartment.

Type 1 renal tubular acidosis

Acidification deficiency generally takes place before a substantial fall in GFR and is usually reversible within a few months of the therapy completion. The occurrence of clinically obvious acidosis with a reasonable dose of (< 1 g) is quite low (< 2%).

Studies have demonstrated abnormal response to acid loading when receiving > 1g AmB. It is typically seen as a normal anion gap metabolic acidosis with increased. Acidification defect occurs due to failure of the H+K+ATPase and H+ATPase or can occur more commonly due to back leak of H+ ions due to “leaky” membranes.

Polyuria and nephrogenic diabetes insipidus:

This is mostly invariably available in every patient and takes place early (1-2 weeks) in the duration of therapy. It is temporarily not associated with azotemia. It does not respond to vasopressin and is commonly reversible a few months after stopping of therapy.

The overall mortality is increased when AmB nephrotoxicity occurs in these patients who are already immunocompromised and have other risk factors. Studies have shown a 38% increase in mortality when AmB nephrotoxicity is seen.

Nephrotoxicity is more common in advanced age, pre-existing chronic kidney disease, concomitant use of ACEi or ARB use, NSAID or aminoglycosides, and volume depletion. It is prudent to remove all the other factors before deciding to discontinue this life-saving drug in mucormycosis when clinically indicated.

Three lipid formulations of AmB are now marketed for clinical use. AmB lipid complex (ABLC, Abelcet), AmB colloidal dispersion (ABCD, Amphocil), and AmBisome, which the only true liposomal AmB. Nephrotoxicity has been reported with these newer formulations but is less severe and rare in incidence.


Mucormycosis off-label salvage treatment is done with the help of posoconazole in patients intolerant to amphotericin B. Oral suspension of posaconazole absorption concerns, specifically reduced absorption with the presence of proton pump inbibitor or antimotility agent use has been handled with the emergence of a delayed-release tablet.

No nephrotoxicity has been demonstrated with the use of posoconazole till date

Dr. Balaji Kirushnan
Consultant Nephrologist
Kauvery Hospital Chennai

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