A Case Report of Tolvaptan Therapy for ADPKD Patients With COVID-19. The Need for Appropriate Counselling for Temporary Drug Discontinuation

Abstract

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) may require specific therapy with vasopressin receptor antagonists to slow the progression of renal disease. Because of its mechanism of action, the most common side effects are polyuria, nocturia, and polydipsia. Elevations of liver enzyme levels can also occur during treatment with Tolvaptan. Temporary drug withdrawal may be indicated if the patient is unable to hydrate adequately or if there are concomitant causes of dehydration, including major infectious events. During the Coronavirus Disease 2019 (COVID-19) pandemic, this should be considered in the management of patients on Tolvaptan therapy.

Case Report: We present the clinical case of a 51-year-old male with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and ADPKD receiving Tolvaptan therapy with particular reference to the medical management of the patient during the infectious event. The patient was instructed to discontinue promptly Tolvaptan as soon as symptoms appeared. He was treated with forced hydration and symptomatic therapy. Nevertheless, a transient elevation of liver enzyme levels was detected. The timely discontinuation of Tolvaptan therapy avoided the risk of potential hepatotoxicity in a condition of known susceptibility.

Conclusion: Tolvaptan therapy of patients with ADPKD is safe even during SARS-CoV-2 infection. There is need for appropriate and prompt patient counseling to avoid potentially adverse side effects.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder (1) responsible for up to 10% of European patients on renal replacement therapy (2) and the fourth most common cause for renal replacement therapy worldwide (3). ADPKD is genetically heterogeneous and is associated with a high degree of inter- and intra-family variability in disease course (3) until the end of stage renal disease (ESRD). Tolvaptan is indicated for adults with evidence of rapidly progressing disease with the aim of slowing cyst development and kidney function decline (2,4) according to the EMA and FDA recommendations. Tolvaptan, a selective antagonist of renal collecting duct Vasopressin receptor 2 (V2R), inhibits the activity of the antidiuretic hormone arginine vasopressin (AVP) inducing aquaresis and reducing urine osmolality. Because of its mechanism of action (increased excretion of electrolyte-free water), the most common side effects are polyuria, nocturia, and polydipsia (4).

Elevation of liver enzyme levels can also occur during treatment with Tolvaptan; however, these abnormalities respond to drug withdrawal or discontinuation (4). Therefore, all patients receiving this therapy should appropriately be instructed to increase water intake regardless of feeling thirsty (5), avoiding further additional potentially hepatotoxic factors such as drugs inhibiting the cytochrome P-450 enzyme CYP3A4 (4). Even infectious diseases can expose these patients to dehydration and drug coadministration. The management of Tolvaptan therapy during the COVID-19 pandemic may consider the possibility of SARS-CoV-2 infection and appropriate patient counseling should be implemented to avoid potentially adverse side effects.

Here, we report the case of a patient with ADPKD on Tolvaptan therapy who presented with COVID-19, with particular attention to the medical management of the case.

Written informed consent was obtained from the patient to publish this case report and any accompanying images.

Case Report

On January 8^th, 2021, a 51-year-old male affected by ADPKD on Tolvaptan therapy at the dosage of 120 mg per day (90 mg+30 mg) for more than 18 months, had a close contact with a person who was found to be COVID-19 affected two days later. This patient had a medical history of hypertension and allergic asthma in chronic therapy with Ace-Inhibitors, inhaled corticosteroid, and antiplatelet agent for primary prevention. He had a basal serum creatinine level of 1.39 mg/dl, an estimated glomerular filtration rate (eGFR) of 59 ml/min by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), and normal liver enzyme levels. Due to Tolvaptan therapy, the urine output of the patient was on average 8 l/day, with a urine osmolarity of 191 mOsm/kg and a body weight of 89 kg. The patient was instructed to discontinue promptly Tolvaptan in case of COVID-19 symptoms appearance and to monitor the body weight. Three days after exposure to the virus, the patient experienced fever and diarrhea. On January 13^th, diagnosis of COVID-19 was confirmed by RT-PCR assay on nasopharyngeal swab. Starting the day after Tolvaptan discontinuation, we immediately assisted to rapid normalization of urine output. The patient was receiving Renin–angiotensin–aldosterone system (RAAS) inhibitors for chronic hypertension, which were suspended due to excessive pressure control at the time of the symptom’s onset. Because of persistent hyperpyrexia and diarrhea, and the onset of dry cough in addition to a fall in oxygen saturation under <90% on a 6 min-walking test, he was admitted to the Hospital Department of Infectious Diseases on January 15^th.

On admission, the patient had a temperature of 37.5˚C, a blood pressure of 143/83 mmHg, heart rate of 99 beats/min, respiratory rate of 19 breaths/min, oxygen saturation in ambient air of 94%, and PaO2/FiO2 ratio of 290. Remaining physical examination was normal. Laboratory tests showed lymphopenia (0.57×10⁹/l, reference range=1.10-4.00); serum creatinine was 1.43 mg/dl, blood urea nitrogen (BUN) 33 mg/dl, eGFR 56 ml/min (CKD-EPI). Liver enzyme levels were normal. The electrolyte panel and coagulation tests were in range. High levels of creatine kinase (308 U/l, reference range <248 U/l), interleukine-6 (16.7 pg/ml, reference range ≤1.8 pg/ml), and c-reactive protein (1.85 mg/dl, reference range <0.50 mg/dl) were found. Procalcitonin and lactate levels were in range. Computed tomography (CT) scan of the chest showed bilateral ground glass opacities throughout the lungs with predominance in the left upper lobe and in the lower lung lobes (Figure 1A and B). Intravenous rehydration therapy was administered within the first week of hospitalization (0.9% saline solution 2 l/day). Paracetamol was given as needed with a maximum of three daily administrations; a single administration of non-steroidal anti-inflammatory drugs (NSAIDs) was needed for non-responsive hyperpyrexia. On admission, the patient was treated with Enoxaparin sodium at prophylaxis dosage and dexamethasone since January 19^th (up to twelve days after discharge). Intermittent fever (up to 38-38.5˚C two times per day) persisted during the hospitalization with a modest increase in inflammation index (c-reactive protein of 5.36 mg/dl and IL-6 207 pg/ml). Peripheral blood cultures, pneumococcal, and legionella urinary antigen test were negative. Urinalysis showed bacteria. Abdominal ultrasound showed no signs of complication. An empirical antimicrobial treatment was started on January 20^th with Ceftriaxone. In the following days, the patient became afebrile with hemodynamic stability and normal range of urine output. Five days after the admission, lab tests were repeated, and they demonstrated an improvement in renal function (serum creatinine levels of 1.18 mg/dl) with persistent lymphopenia. At the same time, we pointed out an elevation of transaminases levels and a repeated CT scan showed an increase in peripheral and subpleural ground-glass areas with a ring of peripheral consolidation (Figure 1C-D). The trends of the most important lab tests are reported in Table I.

Figure 1. Bilateral ground glass opacities with predominance in the left upper lobe (A) and in the lower lung lobes (B) Increased peripheral and subpleural ground-glass opacities with a ring of peripheral consolidation (C-D).

Table I. Laboratory test results on admission and on discharge.

*Reference range between brackets. WBC: White blood cells; eGFR: estimated glomerular filtration rate; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CPK: creatine phosphokinase; IL-6: interleukin 6.

Because of the persistent elevated state of liver enzymes after discharge, we recommended keeping the drug discontinuation. One month later, we assisted to normalization of liver enzymes and the patient re-started Tolvaptan therapy at the split-dose regimen of 60 mg per day (45 mg+15 mg). No elevations in liver enzymes were observed in the following monthly blood samples.

Discussion

COVID-19 can expose patients with ADPKD to dehydration risk due to major losses related to hyperpyrexia or the presence of symptoms, such as tachypnea, diarrhea, or due to the patient’s inability to hydrate adequately.

Patients with ADPKD can be treated with Tolvaptan to slow the progression of kidney disease. During therapy with Tolvaptan, the state of hydration must be constantly monitored because of the important diuretic effect of the therapy, which must be compensated by adequate water supply. The onset of systemic infections may therefore adversely affect the state of hydration and require temporary drug discontinuation to avoid complications related to dehydration (6).

Indeed, acute kidney injury (AKI) is a frequent condition in patients infected by severe SARS-CoV2, with a prevalence reported as high as 46% in large cohorts of hospitalized patients; mechanisms are most likely to be multifactorial and data thus far point to contributions from direct viral infection, inflammatory syndrome-mediated injury, hemodynamic instability, and perhaps hypercoagulable state (7).

Pre-renal AKI has been reported in up to 60% of patients with AKI infected with SARS-CoV2 due to the patient’s dehydration status: patients with underlying chronic kidney disease are more susceptible to AKI during COVID-19 (8).

In the reported case, COVID-19 infection increased the risk of sub-optimal state of hydration; the prompt discontinuation of Tolvaptan with a rapid normalization of the urine output together with a strict monitoring of body weight and fluid administration avoided a severe dehydration state and the onset of AKI.

A normal state of hydration even weeks prior to infection is supposed to play a role in the major outcomes of patients with SARS-CoV2 infection. Chronic hypertonicity, total body water deficit, and/or hypovolemia in the weeks before COVID-19 infection are assumed to result in one or more adaptations, preferably in retaining body water and favoring positive total body water balance when challenged by infection. These include greater abundance of angiotensin converting enzyme 2 (ACE2) receptors in the lungs, which increase the probability of COVID-19 infection, lung epithelial cells that are pre-set for exaggerated immune response, increased capacity for capillary leakage of fluid into the airway space, reduced capacity for active transport of fluid out of the airways, and reduced capacity for passive transport of fluid out of the airways (9). In light of these recent pathogenetic hypotheses, patients under Tolvaptan therapy must be particularly urged to constantly maintain a water supply that prevents sub-optimal hydration states.

A further important aspect to consider when evaluating Tolvaptan discontinuation during SARS-CoV2 virus infection is the possible elevation in liver enzymes, which occurs in a median of 15% up to 58% of patients with COVID-19. There are many potential etiologies contributing to elevated liver enzymes in patients with SARS-CoV-2 including direct liver injury, associated inflammatory responses, congestive hepatopathy, hepatic ischemia, drug-induced liver injury (DILI) (such as Remdesivir or Tocilizumab), possible HBV reactivation after immunosuppressive treatment and muscle breakdown (10). Since Tolvaptan is potentially hepatotoxic, drug discontinuation reduces the risk of potential hepatotoxic contribution in a condition of known susceptibility. In patients receiving Tolvaptan therapy who experienced COVID-19 infection, liver enzyme monitoring is important. In the presented case, we noticed a slight elevation in liver enzymes despite Tolvaptan drug discontinuation, attributable to COVID-19 infection; we decided to resume Tolvaptan once liver enzymes normalized. In the management of patients with ADPKD affected by SARS-CoV2 infection it is important to remember that these patients are often treated with renin-angiotensin-aldosterone system (RAAS) inhibitors.

The membrane-bound ACE2 is the receptor for SARS-CoV-2. Very early into the COVID-19 pandemic, studies have shown a high prevalence of cardiovascular comorbidities in patients with COVID-19, especially in those with severe forms of the disease. In addition, some animal data suggest that ACE2 expression might be increased in patients treated with Renin–angiotensin–aldosterone system blockers. This led several authors to hypothesize that angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may facilitate viral entry into host cells and therefore increase the risk for SARS-CoV-2 infection, and to raise the question of temporary treatment cessation during the pandemic or in patients with confirmed infection. Otherwise, observational studies on chronic exposure to RAAS blockers concluded to the absence of association between RAAS blockers and outcome of the disease (11). In our case, the RAAS inhibitor was suspended due to a tendency to hypotension at the onset of symptoms. If the drug is well tolerated during COVID-19 infection, discontinuation of RAAS inhibitor is not recommended.

In conclusion, Tolvaptan therapy in patients with ADPKD is safe even during the COVID epidemic. However, it is necessary to carry out patient counseling to clarify with the prescriber that in case of SARS-CoV2 virus infection, any temporary drug discontinuation will not lead to potential renal and extrarenal complications.

Conflicts of Interest

The Authors declare that they have no competing interests in relation to this study.

Authors’ Contributions

IC: Main investigator, review of clinical charts, management of a database to collect the essential clinical and demographic data of the patient, preparation of the manuscript, final revision, proofreading, submission; FI: support in the preparation of the manuscript; LG, MM: support in the collection of clinical and demographic data of the patient, and in the preparation of the manuscript, final revision; LM, PV: support in the preparation of the manuscript, in particular concerning the infectious aspects, final revision; AN, VA: draft and revision of the manuscript; GLM: conception of the work, main supervisor in all stages of the work, final substantial revision of the manuscript. All Authors read and approved the manuscript.