Acute Renal Failure due to Molnupiravire

doi:10.21203/rs.3.rs-1466695/v1

Molnipiravir is a promising RNA-Dependent RNA-Polymerase enzyme inhibitor that has started to be used in the treatment of SARS-COV-2. I present the first case who was infected with the Omicron variant and developed acute renal failure due to the use of molnipiravir.67 Year-old male patient with the diagnosis of hypertension and chronic obstructive pulmonary disease developed severe nausea, vomiting and diarrhea with the use of drugs. In the patient's examinations, severe deterioration in kidney functions occurred. The patient who developed acute tubular necrosis was taken to hemodialysis twice. IV hydration and supportive treatments were started. In the follow-up, clinical and renal functions improved. In patients over 65 years of age and with comorbidities, the adverse effects of molnipiravir should be considered and followed closely.

In Corona virus disease 2019 (COVID-19), positive developments have been achieved with vaccination and anti-viral treatments. Since the RNA-Dependent RNA-Polymerase (RdRp) enzyme plays an important role in the replication of Severe acute Respiratory Syndrome Virus (SARS-COV-2), it is important for antiviral treatment targets[1, 2]. Favipravir and remdesivir are RdRp inhibitors and have been approved for the treatment of infection. Both drugs have been shown to reduce clinical symptoms and slow down progression[3, 4]. However, due to the fact that there are only intravenous (IV) forms of remdesevir and its weak pharmacokinetic efficacy in favipravir, an alternative treatment has been sought. Recently, orally available molnupiravir is promising due to its tolerability and positive efficacy profile. It suppressed the replication of SARS-COV-2 through inhibition of RdRp and attracted great attention by providing a rapid and effective reduction in viral load. It was developed by scientists at Emory University (USA)(5,6). In phase-1 and 2 studies, tests were completed in terms of efficacy, tolerability and safety profile[7, 8]. Phase-3 studies are ongoing, and although it is stated that the side-effect profile is mild and similar to the placebo group [9], I present a case of severe acute renal failure (ARF) that, as far as I know, developed due to the use of molnupiravir.

The case is a 67-year-old male patient who has been diagnosed with hypertension (HT) and chronic obstructive pulmonary disease (COPD) for 10 years. Regularly uses perindopril/indamapide(10/2,5mg) tablet(tb),metoprolol 100 mg tb,formoterol-budesonide inhaler(inh),tiotropium bromide(inh). On 17.02.2022, he applied to the Kırsehir Training and Research Hospital pandemic emergency with complaints of fever, weakness, fatigue, sweating and myalgia. Since his clinic was good, no laboratory examination and direct X-ray/thorax CT were not taken from the patient. PCR test was taken. SARS-COV-2-Omicron variant came back positive. On 18.02.2022, molnupiravir 200 mg tablet (tb) was started as 2x800 mg outpatient treatment by the healthcare teams. Used it regularly for 5 days. He continued on his own medicines as well. During this time, he received only paracetamol tb as an analgesic. He did not use non-steroidal anti-inflammatory. However, the patient had severe nausea, vomiting and diarrhea 15–20 times a day with the use of molnupiravir. Oral intake is impaired. He could not provide fluid hydration. Diarrhea disappeared after the medication was discontinued, but complaints of nausea, vomiting and loss of appetite persisted. He applied to the emergency department on 07.03.2022 with these complaints. Fever: 36.1 Pulse: 106 Blood Pressure: 90/60 Respiratory rate: 18 oxygen saturation (SpO2): 96. His general condition was poor, he had a sluggish and tired appearance. The tongue was dry, the eyeballs were sunken, the skin turgor pressure was low. Re-evaluated for SARS-COV-2 infection. PCR test came back negative. Pneumonia or any focus of infection was not detected. In the examinations of the patient whose kidney functions were normal before, at the time of admission to the emergency department, urea: 190mg/dL, Blood Urea Nitrogen (BUN): 89 mg/dL, creatinine (cre): 8.9 mg/dL, GFR: 5 ml/min (Table-1). GFR levels were calculated with Chrocic Kidney Disease Epidemiology Cooperation (CKD-EPI) formula[10]. There was severe metabolic acidosis in venous blood gas (Table-2). Urinary catheter inserted. Residual urine output of 10–20 cc was observed. Proteinuria, 1 (+) erythrocyte and leukocytes were detected in spot urine (Table-3).According to clinical and laboratory findings, emergency hemodialysis (HD) indication was made in the patient. He was placed on hemodialysis for 2 hours with a temporary HD catheter. Ultrafiltration (UF) was not performed because there were no signs of hypervolemia such as pretibial edema and pulmonary edema. Low molecular weight heparin was used as anti-coagulation. 80 cc/hour saline (0.9%) IV was started. Nephrotoxic agents avoided. After the first dialysis, he was taken to HD for a second time for another 4 hours, as uremia and acidosis continued at a serious rate in his control examinations (Tables-1 and 2). UF not done again. In terms of etiology, urinary system USG was performed. Parenchymal echogenicity of both kidneys was observed as grade-1 increased (Table-3). In the follow-ups, the patient's clinic tended to improve. Urine output was about 70–80 cc per hour. He was followed up without dialysis. Anti-hypertensive drugs were not used during the hospitalization. Blood pressures remained stable.Renal functions (Table-1) and proteinuria returned to normal(Table-3). His acidosis improved (Table-2). Hemodialysis and urinary catheters were removed. He was discharged with recommendations.

Nausea, vomiting and diarrhea developed as side effects of molnupiravir in the patient. As a result, dehydration occurred..In a randomized study by Bernal et al. on outpatients using molnupiravir, the most frequently reported side effects were diarrhea, nausea, and dizziness. Painter et al. reported the most common side effect of diarrhea in a placebo-controlled study [11, 7].Continuation of anti-hypertensive drugs together with these side effects caused hypotension and hypovolemia, leading to severe renal perfusion failure. The patient applied to the emergency department approximately 10 days later, although the use of the medication ended and his complaints continued. Because of this delay in admission to the hospital, the initial prerenal azotemia progressed further, causing severe reductions in renal perfusion. As a result of these, it is possible that acute renal failure due to ischemic acute tubular necrosis has developed. Because the causes leading to prerenal azotomy (nausea, vomiting, bleeding, burns, dehydration, fluid sequestration into the third spaces) can lead to ischemic acute tubular necrosis. Both have the same spectrum[12]. BUN/Cre: 89/8.9 = 10 at the time of first presentation of the case. This is a finding in favor of acute tubular necrosis. Because this rate is < 20, it shows that it is of renal origin[13]. A small amount of residual urine after urinary catheterization indicated that there was no post-renal ARF. Nausea and vomiting during emergency admission are due to uremia. He was taken to hemodialysis only 2 times, on 07-08.03.2021. With adequate hydration and hemodynamic stabilization, his clinic tended to improve. Normal urine output was achieved. When the records of the patient in the information management system of the Ministry of Health of the Republic of Turkey were examined, it was determined that he had Urea: 36 mg/dL, BUN: 17 mg/dL ,cre: 1.2 mg/dL ,GFR: 63 ml/min on 19.01.2021 (Table-1). Although GFR levels were consistent with stage-2 Chronic Kidney Disease (CKD), the absence of other data showing kidney damage and normal kidney sizes did not clearly suggest a diagnosis of CKD. The final GFR level of the remaining patient was 74 ml/min (Table-1). Complaints such as nausea, vomiting and diarrhea due to the use of molnipiravir in patients over 65 years of age and those with chronic diseases should be seriously considered. This situation may cause severe dehydration and ARF in patients.The patient should definitely be informed and communicated. When necessary, the nearest health institution should be consulted. Otherwise, it may lead to increased mortality and morbidity. It may bring additional financial burden. However, I recommend investigating the nephrotoxic effect of molnipiravir and re-evaluating the adverse effects in phase-3 studies.

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Written informed consent was obtained from the patient

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Table-1. Changes in the patient's kidney function tests and complete blood count

Variables	History
Variables	19.01. 2021	07.03. 2022	08.03. 2022	09.03. 2022	10.03. 2022	11.03. 2022	12.03. 2022	14.03. 2022
Urea(mg/dL)	36	190	153	123	103	75	59	32
BUN(mg/dL)	17	89	71	57	48	35	28	15
Cre(mg/dL)	1,2	8,9	7	3,13	1,78	1,42	1,31	1,04
GFR(mL/min)	63	5	7	20	39	51	56	74
Na(mmol/L)	136	136	137	137	139	142	141	140
K(mmol/L)	4,8	5	4,3	4,2	4,1	3,8	4,3	4
Ca(mmol/L)	10	9	8,4	8,4	8,3	8,1	7,8	7,9
P(mmol/L)	-	5,5	5,3	4	3,5	3	3	3,2
WBC(10³/µL)	9,61	10,01	8,89	9,58	10,81	13,05	10,57	8,55
Hgb(g/dL)	16,3	14,9	13	11,6	11,6	11,3	11,2	11,1
Hct %	51,3	47	39,9	34,7	35,1	34	34,4	32,9
MCV(fL)	94,3	92,9	90,7	89	88	89,9	89,4	88,4
MCH	30	29,4	29,5	29,7	29,1	29,9	29,1	29,8
PLT(10³ /µL)	275	281	236	185	190	193	204	222

BUN:Blood Urea Nitrogen;Cre:Creatinin;GFR:Glomerular Filtration Rate; Na:Sodium,K:potassium,

Ca:calsium ;P: phosphorus,;WBC:White Blood Cell; Hgb:Hemoglobin;Hct: hematocrit;Plt: Platelet;

MCV: Main Corpuscular Volume;MCH: Mean Corpuscular Hemoglobin

Table 2. Changes in the patient's venous blood gas

Venous Blood Gas Variables	History
Venous Blood Gas Variables	07.03.2022	08.03.2022	09.03.2022	14.03.2022
Ph	7,17	7,19	7,40	7,46
Po2	15,2	16,3	43,4	24,6
PCo2	39,7	40,9	29,2	37,2
HCO3-std	13,1	13,3	19,9	25,9
Lactate	0,7	0,5	0,5	0,8

Ph: potential hydrogen;Po2: partial oxygen;PCo2: partial carbon dioxide;HCO3-std: standard bicarbonate

Table 3. Urinary system USG and spot urine examinations

Urinary system USG	Both kidney sizes and localization are normal. Parenchymal echogenicity is compatible with grade-1 nephropathy. Bilateral PVE was not observed. The bladder is not full enough, there is a slight increase in trabeculation in the wall.
Spot urine variables	History
Spot urine variables	07.03.2022	14.03.2022
Spot urine protein	2(+)	Negative
Spot urine Density	1024	1012
Spot urine erythrocyte	1(+)	Negative
Spot urinary leukocytes	1(+)	1(+)
Hyaline eraser	Negative	Negative
Granular roller	Negative	Negative
Bacterium	Negative	Negative
Spot urine prote/cre	497(mg/dL)	148(mg/dL)

USG: ultrasonography; PCE: Pelvicalyceal Ectasia

Acute Renal Failure due to Molnupiravire

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Abstract

Introduction

Case Report

Discussion

Declarations

References

Tables

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