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ORIGINAL ARTICLE Table of Contents  
Ahead of print publication
Liver and renal function profile of mucormycosis cases receiving amphotericin B - A retrospective study


1 Department of Medicine, GMERS Medical College, Gotri, Vadodara, Gujarat, India
2 Department of Community Medicine, GMERS Medical College, Gotri, Vadodara, Gujarat, India

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Date of Submission03-Jun-2022
Date of Decision09-Aug-2022
Date of Acceptance22-Aug-2022
Date of Web Publication21-Sep-2022
 

  Abstract 


Background: Mucormycosis is a serious infection that needs to be treated with prescription antifungal medicine, usually amphotericin B. In the study, we have analyzed the side effects of amphotericin B because studies have revealed that the drug has toxic effects both on the liver and the kidneys. Methodology: This is a retrospective study and was conducted using a record of mucormycotic patients who were admitted at GMERS Gotri Medical College and Hospital, Vadodara. We included the patients who were admitted to the hospital from June 1, 2021, to August 31, 2021. Three reports each of liver and renal function tests (LFT and RFT) were collected. These reports were entered into the excel sheet and a result was framed. Results: A total of 64 patients were reviewed with the infection of mucormycosis. Increase in bilirubin levels and serum glutamic pyruvic transaminase (significant rise) levels and decrease in albumin levels and albumin/globulin ratio were observed in LFT 2 and LFT 3 after initiating amphotericin B therapy. Similarly, a rise in serum urea and creatinine levels was observed in RFT 2 and RFT 3. The number of patients with altered serum sodium and potassium levels did not vary much in the three consecutive RFT reports. Conclusion: Amphotericin B drug does have adverse effects on the liver and kidneys. The three consecutive RFT and LFT reports revealed liver and kidney dysfunction due to damage induced by the drug. These led to altered levels of the factors included in the respective LFT and RFT reports.

Keywords: Amphotericin B, hepatotoxicity, liver function test, mucormycosis, nephrotoxicity, renal function test


How to cite this URL:
Bavadiya B, Bhatt JH, Deshpande SV, Mehta KG, Raj R. Liver and renal function profile of mucormycosis cases receiving amphotericin B - A retrospective study. Apollo Med [Epub ahead of print] [cited 2022 Sep 27]. Available from: https://apollomedicine.org/preprintarticle.asp?id=356575





  Background Top


Mucormycosis, also known as black fungus, is a relatively rare but serious fungal infection. It is formally known as zygomycosis and usually affects people who are immunocompromised because of diabetes mellitus, steroid therapy, increased serum levels of iron, neutropenia, cancer, and organ transplantation. Mucormycetes are a group of fungi that cause mucormycosis. These are present in our surrounding environment, particularly in soil and in association with decaying organic matter, such as leaves, compost piles, and animal dung.[1] There are different types of infection caused by the fungus; different symptoms appear in a patient. There are different types of infection such as Rhinocerebral mucormycosis, pulmonary mucormycosis, cutaneous mucormycosis, and gastrointestinal mucormycosis. Each type elicits different symptoms.[2],[3],[4],[5]

Clinical and experimental studies reveal that individuals who lack phagocytic leukocytes or have impaired function of phagocytes are at higher risk of mucormycosis.[6] Phagocytes are dysfunctional in the presence of low pH and hyperglycemia. Fungal growth is promoted by elevated serum iron levels; all these factors predispose patients with diabetic ketoacidosis to mucormycosis infection.[7],[8] Mucormycosis is a serious infection and needs to be treated with prescription antifungal medicine, usually amphotericin B, posaconazole, or isavuconazole. These medicines are given through a vein or by mouth.[1] Increasing data support the need for surgical excision of infected and/or necrosed tissue whenever feasible. Based on their superior safety and efficacy, lipid formulations of amphotericin B have become the standard treatment for mucormycosis.[9] According to a study, experimental data suggest that the amphotericin B drug may interfere with the hepatic cytochrome P450 and may thus influence the metabolic capacity of the liver. Confirmation of such a finding in patients treated with amphotericin B would be of value. The incidence of severe acute or subacute hepatotoxicity in response to amphotericin B is very low.[10] Despite being the gold standard therapy (amphotericin B), according to a review, side effects of the drug are quite common, with nephrotoxicity being the most common. It has also manifested hepatotoxicity; however, renal damage is more significant than the liver. Acute renal failure is the most serious complication of this drug. Nephrotoxicity seems related to direct amphotericin B action on the renal tubules as well as to drug-induced renal vasoconstriction.[11] Thus, it is important to monitor the liver function and renal functions of the patients undergoing amphotericin B treatment. Among all the patients with mucormycosis that has grown to a level of 28,252 cases, 86% of cases have a history of COVID-19 and 62.3% have a history of diabetes. According to a study at a tertiary center in South India, Antifungal treatment was initiated in 30 patients, 29 of them were managed with amphotericin B (either conventional or liposomal formulation).[12]

The use of amphotericin B is on large scale due to its great therapeutic effects on mucormycotic patients; however, apart from treating these patients, we are under underscoring the adverse effects of this drug on the liver and kidneys. In this study, we are going to analyze the liver function test (LFT) profile and renal function test (RFT) profiles of the mucormycotic patients going through the treatment of amphotericin B. LFT will include total bilirubin (direct and indirect), alanine transaminase (ALT), total protein, albumin, albumin/globulin (A/G) ratio. A liver dysfunction will lead to abnormal levels of the different factors of LFT. Serum bilirubin and ALT levels may rise and serum albumin and A/G ratio may decrease. These are all consequences due to abnormal liver function.

RFT will include serum urea levels, serum creatinine levels, and serum sodium and potassium levels. In case of kidney function has been compromised, the function of excretion will not be up to the mark; therefore, urea and creatinine levels in the blood will begin to elevate indicating kidney damage (nephrotoxicity). Sodium and potassium levels in the blood have a normal range of 135–145 mEq/dl and 3.5–5.5 mEq/dl, respectively. However, there can be various causes behind the abnormal levels of sodium and potassium in the serum. It can be due to liver damage, renal damage, and increased or decreased intake. According to the analyses, a justification will be made for the effects of amphotericin B on hepatic and renal function.


  Methodology Top


Study type

This was a retrospective cohort study.

Sample size

We included the patients who were admitted to the GMERS Gotri Medical College and Hospital, Vadodara City, from June 1, 2021, to August 31, 2021.

Study design

Data related to the patient's demographics (excluding contact number) such as age, sex, occupation, religion, and region were obtained from the case reports. We noted the date of starting amphotericin B drug and analyzed LFT and RFT reports that were done routinely once a week to monitor the effects. Therefore, three reports each of LFT and RFT were collected. LFT 1/RFT 1 is the report done before starting the amphotericin B therapy. LFT 2/RFT 2 reports are the tests done after 1 week of initiating the therapy, and finally, LFT 3/RFT 3 are done after 2 weeks of initiating the therapy.

Study procedure

Data included in the LFT profile of the patients were collected and arranged accordingly in the Case Report Form of each individual. LFT reports included bilirubin, ALT (serum glutamic pyruvic transaminase [SGPT]), albumin, and A/G ratio. Later, the reports were transferred to the excel sheet and compared before and after starting the drug therapy. Any abnormalities observed were noted and considered for analysis in the study. Similarly, RFT profiles of patients were collected which included serum urea, serum creatinine, sodium levels, and potassium levels. Later on, similar procedures were followed as of LFT profile to observe the effects of amphotericin b drug in kidney functions.

Statistical analysis

We studied the records of mucormycosis patients who were admitted to the GMERS Hospital Gotri from June 1, 2021, to August 31. After collecting all the data from records, we assembled them in tabular statistics. Later on, we prepared a mean statistic of all the factors presented by LFT and RFT profiles of mucormycotic patients on amphotericin B treatment.

Statement of ethics

This study is of no minimal risk research by utilizing retrospective data collection. We did not include any patient intervention study; it is only a record-based study. The study did not harm any patient.


  Results Top


The research has included a total of 64 patients with mucormycosis on the treatment of amphotericin B admitted at GMERS Gotri Hospital, Vadodara, from April 10 to July 2021. There were 42 (65.62%) males and 22 (34.38%) females. 62 patients were Hindu and 2 patients were Muslim. 26 patients (40.26%) are residing in the urban area and 38 patients (59.38%) are residing in the rural area. 30 patients (46.88%) are illiterate, and 34 patients (53.12%) are literate.

[Table 1] shows the number of patients with abnormal values in different factors of LFT reports and percentage. Out of 64 patients, we reported that none of the patients had abnormal bilirubin in LFT before the application of amphotericin B; four patients had above normal bilirubin levels in LFT 2 and LFT 3 after the application of amphotericin B. This indicates that 6.25% of the patients showed above-normal bilirubin levels after the application of amphotericin B. Five patients (7.8%) out of 64 patients presented with raised SGPT levels in LFT 1, 13 patients (20.3%) in LFT 2, and 20 patients (31.25%) in LFT 3. 35 patients (54.7%) were reported with albumin level below the normal range in LFT 1, 42 patients (65.62) showed below normal in LFT 2, and 43 patients (67.18) showed below normal in LFT 3. The A/G ratio of 22 patients out of 64 was below the normal range in LFT 1, and 32 patients (50%) in LFT 2 and 32 patients (50%) in LFT 3 had A/G ratio below the normal range.
Table 1: Number of patients with abnormal values in respective factors of each liver function test reports and their percentage (n=64)

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[Table 2] shows the number of patients with abnormal values in different factors of RFT report and percentage. Out of 64 patients reported, 21 patients (32.8%) presented with urea levels above normal in RFT 1. 47 patients (73.33%) in RFT 2 and 43 patients (67.81%) in RFT 3 had urea levels above normal. 6 patients (9.4%) presented with creative levels above normal in RFT 1. After beginning the treatment of amphotericin B, increase in creatine level is seen in 20 patients (31.25%) in RFT 2 and 22 patients (34.38%) in RFT 3. 21 patients (32.8%) presented with decreased sodium levels in RFT 1, 26 patients (40.26%) in RFT 2, and 22 patients(34.38) in RFT3. A high level of potassium was seen in 4 patients (6.25%) in RFT 1, 8 (12.5%) patients in RFT 2, and 5 patients (7.8%) in RFT 3.
Table 2: Number of patients with abnormal values in respective factors of each renal function test reports and their percentage (n=64)

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  Discussion Top


Mucormycosis is a fungal infection of the sinuses, brain, or lungs; however, it may affect the gastrointestinal tract and skin as well occasionally. It more commonly occurs in a population with a weak immune system. Amphotericin is a potent antifungal agent, used as standard prophylaxis and a therapeutic drug for systemic infection. As shown in [Table 3], mucormycosis is more common in males compared to females as the study found males to be infected almost 2 times more than females. The higher male-to-female ratio would most likely be due to the higher prevalence of diabetes in males and their reduced regularity with antidiabetic treatment which can lead to a worsening of case.[13] Severely increased hyperglycemia can enhance this fungus growth. 38 patients (60%) belonged to the rural area whereas 28 were from urban areas. Mucormycosis is more commonly seen in people residing in rural areas due to lack of medical facilities and due to the lack of regular health check-ups in those areas, and because mucormycosis is diabetes defining disease, there might be the possibility of several diabetic patients remaining unaware of their illness that could have worsened and predisposed to diabetes.[14] In our study, 52 patients had rhino-orbito-cerebral mucormycosis, 9 patients had rhino-orbital, and 3 patients had rhino-cerebral mucormycosis. Our study included only those patients who were admitted to the mucormycosis wards and had undergone surgical treatment.
Table 3: Sociodemographic profile of admitted mucormycosis patients (n=64)

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The objective of the study is to assess the effect of amphotericin B on the liver and kidneys through LFT and RFT, respectively, before and after the treatment of amphotericin B. In [Table 1], various factors of LFT of the patient before the treatment of amphotericin B (LFT 1) and after or during the treatment of amphotericin (LFT 2 and LFT 3) are mentioned. Among all the patients, 6.25% (LFT 2 and LFT 3) of them developed hyperbilirubinemia with no other lying liver disease. The number of patients with increased bilirubin levels is not significantly high and could be considered either due to altered liver functions in systemic disease or might be due to amphotericin B-induced hepatotoxicity. Hyperbilirubinemia of amphotericin therapy is likely due to the inhibition of bilirubin transport mechanisms and is likely to occur in patients with genetic variations in the major hepatic bilirubin transporter 2.[15] Upon observing SGPT levels, 5 patients had above normal levels in LFT 1 that might be due to liver involvement in systemic infections, resulting in various types of abnormal liver function test results.[15] 13 (20.3%) patients showed an increase in SGPT levels after the initiation of treatment in LFT 2. 20 (31.25%) patients showed an increase in SGPT levels in LFT 3. Our report for raised liver enzymes quite closely matches the other study. Our study satisfactorily proves on a larger sample of 64 patients. A study revealed elevations in liver enzymes to be up to 20% of patients receiving amphotericin B. The liver injury arises as early as 4–14 days after starting therapy; this could be a valid reason for more rise in the percentage of patients with elevated SGPT levels after 2 weeks of initiation of amphotericin B drug therapy.[15] One more reason behind this could be more doses and duration of the amphotericin treatment are responsible for more hepatotoxicity. Human serum albumin is an important parameter for the routine assessment of the nutritional status of patients with acute and chronic conditions, and it is also an important part of LFT. 54.7% of patients presented with albumin levels below normal in LFT 1. Hypoalbuminemia is a common problem in hospitalized individuals. Along with the evolution of the disease itself, this condition might be a result of the aging process, with levels of albumin decreasing with advancing age.[16] 42 (65.62%) patients had albumin levels below normal in LFT 2 and 43 (67.18%) patients had below normal levels in LFT 3. Serum albumin levels often fall in hospitalized patients with critical diseases. Adding to this, albumin levels will not increase again until the recovery phase of the illness initiates. Increased risk of morbidity and mortality is correlated with lower serum albumin levels.[17] The rise in the percentage of patients having below normal albumin levels might be due to increasing data suggesting adverse effects of this drug on hepatic metabolic functions which may have led to impaired synthesis of albumin by the liver.[10] 22 (34.38%) patients out of 64 presented with an A/G ratio below normal; 32 (50%) patients showed an A/G ratio below normal in LFT 2 and LFT 3. Low albumin levels and low A/G ratio usually go hand in hand because globulin levels less commonly fluctuate as compared to albumin levels mainly in liver disease/dysfunction.[18]

[Table 2] shows the number of patients with abnormal values in respective factors of each RFT report and their percentage (%) (n = 64). 21 (32.8%) patients out of 64 presented with a urea level above normal before initiation of the amphotericin B therapy. The raised levels of urea presented by mucormycosis in hospitalized patients would most likely be due to diabetic comorbidity Chronic kidney disease (CKD) and Diabetic kidney disease (DKD) of the patients.[19] 47 (73.44%) patients showed raised urea levels after the treatment of amphotericin B in RFT 2 and 43 (67.18%) presented with urea levels above normal in RFT 3. The probable reason for this could be amphotericin B-induced nephrotoxicity. A review article mentions that amphotericin B usually causes reversible tubular damage which may lead to acute renal failure (the most common complication).[11] One more abstract stated that nephrotoxicity may cause azotemia, renal tubular acidosis, impaired renal concentrating ability, and electrolyte imbalance.[20] 6 (9.4%) patients presented with creatinine levels above the normal range in RFT 1. A study in Ethiopia reveals that patients with diabetes for more than 10 years had two times more chance of having impaired serum creatinine levels than patients with diabetes for less than 10 years.[21] Therefore, long-term diabetes could be the reason for raised serum creatinine levels in hospitalized mucormycosis patients. 20 patients (31%) had above-normal creatinine levels in RFT 2 and 22 (34%) patients presented with raised creatinine levels in RFT 3. This shows a significant rise in serum creatinine levels after initiating the amphotericin B therapy, and the previous studies also stated antibiotics as the relevant source of acute renal failure in systemic infections such as mucormycosis.[22] 21 (32.8%) patients presented with decreased sodium levels in RFT 1. Hyponatremia is considered common in patients admitted to medical wards. They may present at the time of admission or may develop during the period of hospitalization.[23] In the following reports of RFT 2 and RFT 3, the number of patients with below normal range of serum sodium levels was 26 (40.62%) and 22 (34.38%), respectively. The numbers are not significantly altered as compared to the RFT 1. Therefore, we can assume that amphotericin B-induced nephrotoxicity does not have a major effect on sodium levels. A study indicated that amphotericin B reduces the glomerular filtration rate by two mechanisms that are vasoconstriction and tubular dysfunction through tubuloglomerular feedback. This may overall lead to reduced sodium levels.[22] Four patients presented with potassium levels above normal in RFT 1. Eight patients presented with potassium levels above normal in RFT 2 and five patients presented with potassium levels above normal in RFT 3 after initiating the treatment of amphotericin B. The number of patients with altered serum potassium levels is not significantly high. Thus, we consider it to be due to late-stage CKD in diabetic patients and not due to amphotericin B-induced nephrotoxicity.[24] The study concludes that amphotericin B drug does have nephrotoxic and hepatotoxic adverse effects. The data satisfactorily reveals the effects of the drug on kidneys and liver by analyzing and discussing LFT and RFT reports taken over different periods.


  Conclusion Top


Mucormycosis is more common among males as compared to females as the study found males to be infected almost 2 times more than females. Mucormycosis is more commonly seen in people residing in rural areas due to inappropriate hygiene and lack of medical facilities. The number of patients with elevated SGPT levels was significant in LFT 2 and further increased in LFT 3; this might be due to the chronic toxic effects of amphotericin B on the liver. The study found that more than half of the total mucormycosis patients admitted to the hospital already had hypoalbuminemia before starting the amphotericin B therapy. 42 (65.62%) patients had albumin levels below normal in LFT 2 and 43 (67.18%) patients had below normal levels in LFT 3. Because albumin levels were low in more than half of the patients, the A/G ratio was also predicted to be low and the results were also satisfying. Urea and creatinine levels were already above-normal range in a few of the patients which might be because of the diabetes-related CKD. In the following LFTs and RFTs, the number of patients with raised serum urea and creatinine increased which suggests amphotericin B-induced nephrotoxicity. Finally, plasma sodium and potassium levels were also found to be decreased and elevated in RFT 1, respectively. However, the number of patients with altered electrolyte levels did not change significantly in RFT 2 and RFT 3 compared to RFT 1.

Patient consent

This study was a retrospective record-based study. All information was extracted from the medical records of patients admitted to our hospital. Hence, patient's consent for the study was not obtained. However, we have obtained clearance from the ethics committee and have obtained consent for publication from the ethics committee.

Conflicts of interest

There are no conflicts of interest.

Institutional Ethical Committee approval

This study was approved by the Ethics Committee, Institutional Human Ethics Committee, GMERS Medical College and Hospital, Gotri. IHEC/22/OUT/SRUG002.

Funding

Nil.

Authors' contributions

All authors have read and approved the manuscript. BJ, BB, DS, and RR planned the study. BJ and BB collected the data and performed the statistical analysis. BJ, BB, and MK wrote the paper (BJ-Bhatt Jugal, RR-Rikin Raj, DS-Despande Shubhangi, BB-Bavadiya Bhoomi, MK-Mehta Kedar).



 
  References Top

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2.
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Correspondence Address:
Bhoomi Bavadiya,
GMERS Medical College, Gotri, Vadodara, Gujarat
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_86_22




 
 
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    -  Bavadiya B
    -  Bhatt JH
    -  Deshpande SV
    -  Mehta KG
    -  Raj R


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