key: cord-0904846-bphiflba
authors: Khusid, Johnathan A.; Atallah, William M.; Kyprianou, Natasha; Gupta, Mantu
title: What Stone-formers Should Know About Vitamin C and D Supplementation in the COVID-19 Era
date: 2020-08-08
journal: European urology open science
DOI: 10.1016/j.euros.2020.07.006
sha: e9edbb4b8595fc3b92c8e4dacfa05b0517436d08
doc_id: 904846
cord_uid: bphiflba

nan

COVID-19; Kidney stones; Dietary supplementation; Urology #body Coronavirus disease 2019 (COVID-19) has rapidly evolved into a pandemic but remains without a well-defined treatment or prevention strategy. Research efforts have focused on the use of existing medications, such as azithromycin, hydroxychloroquine, remdesivir, and famotidine. The use of vitamin supplements, particularly vitamins C and D has also garnered great interest. Prior research on respiratory infections suggests that vitamin C and D supplementation may be beneficial [1] [2] [3] [4] . However, crucially needed data from double-blind controlled studies are lacking.

Vitamin C is metabolized to oxalate and vitamin D regulates calcium homeostasis. Thus, these supplements are potentially lithogenic. Nephrolithiasis is a common urologic pathology and it is critical for practitioners to counsel stone-forming patients on the safety of vitamin C and D supplementation in the COVID-19 era, particularly given that universal facemask precautions may limit routine oral hydration. Here we highlight relevant literature regarding vitamins C and D and their relationship to respiratory infections and nephrolithiasis to guide practitioners during the COVID-19 pandemic (Table 1) .

Vitamin C is an antioxidant critical for immune system function [5] . A large meta-analysis found that vitamin C supplementation at doses of 200 mg/d was associated with shorter duration of the common cold [4] . Furthermore, high-dose intravenous vitamin C improved outcomes in critically ill patients with sepsis and acute respiratory distress syndrome [1] . Studies on the role of vitamin C in COVID-19 management are ongoing.

Although generally well tolerated, vitamin C is associated with adverse effects at higher doses. Of urological interest, vitamin C is metabolized to oxalate and excess consumption may lead to hyperoxaluria [5] . Daily supplementation with 2000 mg/d of vitamin C was associated with increased urinary oxalate [6] . Furthermore, stone-formers treated with 1000 mg/d had an increase in 24-h urinary oxalate from 31 mg to 50 mg [6] . Literature on the impact of lower vitamin C doses on hyperoxaluria is limited but suggests a dose-dependent linear relationship [7] . Notably, oxalate excretion is significantly higher for vitamin C doses of 1000 mg/d compared to ≤200 mg/d [7] . Although the data available are limited, a linear relationship is intuitive given that oxalate is a metabolic byproduct of vitamin C [5] .

Large population-based studies on vitamin C intake and nephrolithiasis suggest an increase in risk for men but not women [8] . Among men, vitamin C supplementation at doses 1000 mg/d was associated with a higher risk of developing incident kidney stones, whereas there was no such association for women [8] . It is unclear whether gender differences are due to metabolic or behavioral differences. However, given the evidence linking vitamin C to hyperoxaluria, it is reasonable for female stone-formers to use caution with supplementation as well. Accordingly, we recommend advising stone-forming patients, particularly men, to avoid vitamin C supplementation at doses 1000 mg/d. Patients who initiate vitamin C supplementation should be monitored with 24-h urine oxalate levels.

Vitamin D helps in regulating calcium and phosphate stores in the body and is required for proper immune system function. A large meta-analysis found that vitamin D supplementation reduced the risk of acute respiratory infections [3] . The overall number needed to treat was 33, but was only four in the group with existing vitamin D deficiency. Interestingly, the protective effect was not dose-dependent. The underlying mechanism is unknown but may relate to calcium homeostasis, as viruses alter cellular calcium levels to facilitate survival and reproduction [9] . A recent analysis of European nations also found that lower vitamin D levels were associated with higher COVID-19 caseload and mortality [2] .

The relationship between vitamin D and nephrolithiasis has generated significant interest as the majority of kidney stones are calcium stones. A meta-analysis assessing the general risks of vitamin D supplementation identified an increase in nephrolithiasis risk [10] . However, in the majority of the studies included, co-administration of calcium was not standardized in the experimental and control groups. Thus, the study findings were not reflective of isolated vitamin D supplementation and may be secondary to calcium co-administration.

A subsequent meta-analysis focused on the impact of long-term vitamin D supplementation on calcium metabolism and nephrolithiasis risk; calcium supplementation did not differ between the control and experimental groups in the studies included [11] . The authors concluded that 24 wk of supplementation was associated with an increase in the risk of hypercalciuria but not in the risk of nephrolithiasis. Since many of the studies had follow-up of <1 yr, it is unclear if this hypercalciuria associated with vitamin D is transitory or whether longer follow-up would have identified differences in nephrolithiasis risk.

Another meta-analysis by the same team found that patients receiving 2800 IU/d of vitamin D for at least 1 yr had a borderline increase in the risk of hypercalciuria but no increase in the risk of nephrolithiasis events [12] . In the studies analyzed for nephrolithiasis risk, doses ranged from 20 000 IU/wk (~2850 IU/d) to 40 000 IU/wk (~5700 IU/d) and none identified a higher risk of nephrolithiasis events. This suggests that vitamin D supplementation up to the reported upper tolerable dose (4000 IU/d) does not confer an increase in the risk of nephrolithiasis, although it may increase the risk of hypercalciuria. Thus, stone-formers initiating vitamin D supplementation should be monitored with 24-h urine studies for the development and subsequent resolution of hypercalciuria.

Circumstantial evidence suggests that vitamin C and D supplementation may be beneficial in the management of COVID-19. However, supplementation with these vitamins is not without risk. Vitamin C supplementation at doses 1000 mg/d should be used with caution, particularly in men, and patients should be monitored with 24-h urine studies for hyperoxaluria. Vitamin D supplementation at doses ≤4000 IU/d appears to be safe for at least 1 yr, although patients should be monitored with 24-h urine studies for the development and subsequent resolution of hypercalciuria. Given the rapid spread and morbidity of COVID-19, all health care practitioners are responsible for understanding how potential treatments for the virus impact common pathologies within their scope of practice. Accordingly, double-blind controlled studies on the benefits of vitamins C and D for COVID-19 and potential sequelae of their use for this indication, such as nephrolithiasis, are critically needed. SRMA Adults enrolled in randomized controlled trials of 1 yr of high-dose (2800 IU/day) VDS in which CCS was consistent between the control and experimental arms VDS vs placebo Patients receiving high at higher risk of kidney borderline higher risk o BID = twice daily; CCS = calcium co-supplementation; ICU = intensive care unit; IVVC = intravenous vitamin C; NSFs = non-stone-formers; SRMA = systematic review and metaanalysis; VCS = vitamin C supplementation; VDS = vitamin D supplementation.

Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial

The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Vitamin C for preventing and treating the common cold

Vitamin C: the known and the unknown and Goldilocks

Effect of vitamin C supplements on urinary oxalate and pH in calcium stone-forming patients

Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance

Total, dietary, and supplemental vitamin C intake and risk of incident kidney stones

Viral calciomics: interplays between Ca 2+ and virus

Vitamin D supplementation for prevention of mortality in adults

Hypercalcemia, hypercalciuria, and kidney stones in long-term studies of vitamin D supplementation: a systematic review and meta-analysis

Urological, Boston Scientific, Olympus, Lumenis, and Retrophin outside the scope of the current study. The remaining authors have nothing to disclose.