key: cord-1037501-s5v2olr9 authors: Dirim, Ahmet Burak; Demir, Erol; Safak, Seda; Garayeva, Nurana; Ucar, Ali Riza; Oto, Ozgur Akin; Yazici, Halil; Alibeyoglu, Alpay Medet; Kose, Murat; Esen, Figen; Yavuz, Serap Simsek; Turkmen, Aydin title: Hydroxychloroquine-associated Hypoglycemia in Hemodialysis Patients with COVID-19 date: 2020-07-12 journal: Kidney Int Rep DOI: 10.1016/j.ekir.2020.06.039 sha: 62f51b15f75779c972f06eff7e80e07a703f88da doc_id: 1037501 cord_uid: s5v2olr9 nan Coronavirus Disease 2019 (COVID-19) is a global health problem, but optimal treatment modality is unclear. The treatment protocol for patients with COVID-19 consists of azithromycin, hydroxychloroquine (HCQ), and low-molecular-weight heparin in our center. Also, we prescribe oseltamivir until the return of influenza test results. Initially, HCQ was administered to all our patients for five days to ten days (400 mg bid as a loading dose on the first day and then 200 mg bid as a maintenance dose for the next four to nine days), without renal dose adjustments, according to the drug manufacturer's recommendations for short-term drug treatment. HCQ is an immunomodulatory medication that has been used for decades to treat autoimmune disorders. Rheumatology guidelines recommend adjusting the daily dose according to body weight or serum drug levels for long-term therapies 1 . The efficiency of HCQ in COVID-19 is controversial, but many centers frequently used it as a treatment during the pandemic. Also, the optimal dosage and dose alterations of HCQ in kidney failure remain uncertain due to scant data for COVID-19 therapy. Here, we report three non-diabetic hemodialysis patients who developed hypoglycemia after HCQ treatment for COVID-19. A 64-year old female with end-stage kidney disease from hypertensive nephrosclerosis and a failed kidney transplantation recently on hemodialysis was admitted with fever. Her medications were amlodipine 10 mg/day, aspirin 100 mg/day, and prednisone 5 mg/day. The patient was not previously diagnosed with diabetes or had no history of a hypoglycemic event; the last HbA1c level was measured fifteen days ago and was 5.4%. Laboratory tests showed lymphopenia and elevated Creactive protein (CRP) levels ( Table 2) . Chest computed tomography (CT) was normal. Our COVID protocol was started after confirmed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the nasopharyngeal swab. On the fourth day of treatment, fasting hypoglycemia was noted with serum glucose level 50 mg/dl. The patient was diagnosed with stress-induced hypocortisolism, and the patient was treated with 500 ml/day of 10% dextrose infusion and 20 mg/day intravenous methylprednisolone. Despite these treatments, hypoglycemia persisted, and HCQ treatment was stopped on the fifth day of the treatment, but she required dextrose infusion forth to the sixth day of the hospitalization. Enteral or parenteral support was not added to the patient's nutritional program due to adequate oral calorie intake until the hypoglycemic period. Eventually, she was discharged on the tenth day of hospitalization without any other complications. A 61-year old hemodialysis patient was admitted with dyspnea and cough. Outpatient medications were aspirin 100 mg/day, sevelamer 2400 mg/day, and carvedilol 12.5 mg/day. The patient was not previously diagnosed with diabetes. Oxygen saturation was 88% in ambient air, and chest CT revealed bilateral ground-glass pneumonic opacities. Laboratory analyses revealed lymphopenia and elevated levels of ferritin and CRP ( Table 2 ). The nasopharyngeal swab test was positive for SARS-CoV-2. On the third day of the treatment, his clinical condition deteriorated with fluctuating levels of consciousness. The fasting blood glucose level was 52 mg/dl. Hence, dextrose infusion was administered. Any nutritional support was not provided to the patient due to adequate oral calorie intake until the hypoglycemic event. On the fourth day of the treatment, he was transferred to the intensive care unit (ICU) due to severe hypoxemia. Intermittent dextrose infusion was continued, and HCQ treatment was discontinued due to hypoglycemic episodes. Hypoglycemic events were resolved after the withdrawal of HCQ. Favipiravir was initiated after intubation for severe COVID-19 on the fifth day of hospitalization. Unfortunately, he died as a result of severe SARS-CoV-2 infection on the ninth day of hospitalization. A 74-year-old hemodialysis patient presented to the emergency department with a persistent cough for two days. Outpatient medications included carvedilol 6.25 mg/day and sevelamer 2400 mg/day. Similar to other patients, there was no history of diabetes or pre-diabetes. HbA1c was 5.2% at the time of hospital admission. Oxygen saturation was 95% while breathing ambient air. Laboratory results demonstrated lymphopenia and elevated levels of CRP, lactate dehydrogenase (LDH), and ferritin (Table 2) . We observed bilateral ground-glass opacities in chest CT. The nasopharyngeal swab test confirmed the SARS-CoV-2 infection. He was started on the COVID-19 protocol. We noted asymptomatic fasting hypoglycemia on both mornings and evenings after the second day of treatment. The patient developed hypoxemia on the fifth day of the medication. Favipiravir treatment was added to the treatment due to severe clinical status. HCQ was withdrawn due to hypoglycemia, after which we did not observe any hypoglycemic incidents until the discharge on the sixteenth day of hospitalization. Nutritional support and dextrose infusion were not needed due to adequate oral calorie intake. Also, postprandial glucose levels were normal during the hypoglycemic period. HCQ is an antimalarial drug with immunomodulatory effects and widely used for rheumatic diseases. Also, previous studies have shown that HCQ interferes with the glycosylation of ACE-2, the receptor of SARS-CoV-2, and inhibits viral fusion into cells 2,3 . Although controversy continues over the effectiveness of HCQ, it is one of the most commonly prescribed drugs in the treatment of COVID-19. HCQ is mostly metabolized by the liver. However, approximately 25 % of the drug is excreted as unchanged into the urine 4 . HCQ is not removed by dialysis due to its large molecular size, and it is recommended to give a lower dose after each dialysis session 5, 6 . However, there is no current recommendation about the dosage of HCQ for patients with chronic kidney failure. The common side effects of HCQ are diarrhea, nausea, retinal toxicity, hypoglycemia, myelosuppression, and cardiomyopathy. They are more common in patients with liver or renal impairment and generally associated with cumulative dosage 7 . Also, hypoglycemia is a rare side effect of HCQ for both diabetic and non-diabetic patients 8-S1 . The exact mechanism of HCQ-induced hypoglycemia is not well known. Proposed mechanisms include improving insulin sensitivity, enhancing insulin-dependent glucose transport, and decreasing the degradation of intracellular insulin S1 . A study demonstrated that HCQ could increase insulin secretion and improve blood glucose levels in pre-diabetic patients S2 . Another trial also showed that chloroquine could lower glucose levels in diabetic patients with a similar mechanism S3 . HCQ-induced hypoglycemia in the non-diabetic population is quite rare. Although the exact mechanism is not well-known, a recently published case report showed that HCQ-induced hypoglycemia was associated with increased insulin and C-peptide levels in a non-diabetic patient. Hypoglycemic episodes were observed in our patients, especially during fasting times, similar to previous case report S4 . None of our six hemodialysis patients with or without hypoglycemia had a diagnosis of diabetes; however, we do not know if our patients are pre-diabetic due to the lack of prior tests. In addition, we cannot determine the exact mechanism of hypoglycemia due to the lack of insulin and C-peptide measurement during hypoglycemic attacks. Although HCQ-induced hypoglycemia is an exception in dialysis patients with rheumatic disease, to the best of our knowledge, this side effect has not been reported in COVID-19 patients before. This side could be associated with a second hit mechanism, such as a critical illness, besides the drug toxicity. Increased catabolism, malnutrition, liver failure, and septic status could also contribute to hypoglycemia in COVID-19 S4 . The liver function tests of our patients who developed hypoglycemia were in the normal range (Table-2) . Also, these patients had adequate nutrient intake. On the other hand, they were frail older adults with multiple comorbidities. Hence, we thought that the critical status associated with COVID-19 might enhance the hypoglycemic side effect of HCQ in our patients. Unfortunately, we were unable to measure HCQ blood levels. For this reason, it is not possible to establish a direct relationship between HCQ blood levels and hypoglycemic events. Interestingly, none of these patients associated with HCQ treatment have other side effects, such as QT prolongation. During the COVID-19 pandemic, the optimal strategy for the administration of HCQ is unclear. Hence, these protocols showed variability among COVID-19 treatment centers. A previous study has shown that HCQ is more effective than chloroquine if 400 mg is administered on the first day and 200 mg for the next four days S6 . However, the optimal renal dose adjustment strategy of HCQ for COVID-19 treatment is unknown in patients with chronic kidney disease. Some centers recommend 200 mg QD in hemodialysis patients thrice a week after dialysis sessions S7 . All of our patients who developed hypoglycemia were olygoanuric, and we assumed that increased exposure to HCQ caused hypoglycemia due to impaired urinary excretion of the drug in these patients. We did not observe any hypoglycemic events in dialysis patients during pandemic after dose-reduced protocol. On the other hand, despite the efficacy of hydroxychloroquine in COVID-19 treatment is unclear S9,S10 , dose reduction could be associated with the decreased potency of HCQ for COVID-19 treatment. However, there is not sufficient data for this concern. In conclusion, we suggest reducing the HCQ dosage in hemodialysis patients since it reduces the hypoglycemic side effect. Also, dose adjustment could be considered according to weight in patients with chronic kidney disease. Screening for the side effects of HCQ is essential in these patients. The authors declare no conflicts of interest. Case-2 Case-3 Age (year) 64 61 74 Hydroxychloroquine Blood Levels in SLE: Clarifying dosing controversies and improving adherence Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro A dose-ranging study of the pharmacokinetics of hydroxychloroquine following intravenous administration to healthy volunteers COVID-19 therapeutic options for patients with kidney disease Bioavailability of hydroxychloroquine tablets in healthy volunteers A case of administration of hydroxychloroquine in a hemodialysis patient with COVID-19 Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis Hypoglycemia induced by hydroxychloroquine in a non-diabetic patient treated for RA The optimal treatment of COVID-19 in patients with chronic kidney disease remains unknown. 4. New well-designed and qualified trials for the treatment of COVID-19 are needed None of the authors had a personal or financial conflict of interest.