Effect of Ascorbic Acid on the Kidneys

Abstract

Vitamin C is necessary for the human body since it aids in the synthesis of many structural proteins and functions as an enzyme cofactor. For many years, it has been consumed as part of a diet and as a food supplement due to its antioxidant properties and immunomodulatory effect. For many years, scientists have been researching the therapeutic effects of vitamin C. The only efficacy proven in these researches extending to the present day is on scurvy. The adverse effects of vitamin C, which is currently being tested in a variety of diseases as well as its therapeutic effects, are of interest. The effect on the increase in urinary oxalate of oxalic acid produced by metabolization is linked to the formation of calcium oxalate stones. There are many studies on this effect with different forms and doses of vitamin C administration. Furthermore, researchers approach the effect it has on nephropathy with skepticism. The effect of vitamin C on the kidney is evaluated in this study by incorporating various viewpoints.

1. Introduction

Vitamin C is known as the antiscorbutic vitamin. Vitamin C, whose discovery began with scurvy treatment research, is known as ascorbic acid due to its Latin origin, ‘scorbutus, hence ‘a-scorbutus’. This definition also includes L-dehydroascorbic acid, which is easily converted to ascorbic acid in the human body [1, 2].

The most important advocate of vitamin C in history is Linus Pauling, winner of the Nobel Prize in Chemistry and the Nobel Peace Prize [3]. All of Pauling’s ideas about the benefits of vitamin C in fighting colds and cancer were rejected at the time [4].

For many years, different doses and therapeutic forms of vitamin C have been used to treat colds [5]. Researchers believe that this activity is due to its immunomodulatory role on the immune system, which promotes T cell development [6]. There have also been studies that show parenterally administered vitamin C has chemotherapeutic efficacy in cancer treatment [7]. In many biochemical reactions in the body, vitamin C acts as an electron donor or reducing agent. Vitamin C is used in chronic hemodialysis patients to both prevent and repair oxidant damage to DNA, lipids, and proteins by reducing intracellular reactive oxygen species (ROS) [8, 9]. In addition, it acts as a cofactor for 8 basic enzymes. It is also essential for the biosynthesis of collagen, catecholamines, and carnitine in the body [10].

In recent years, studies have revealed that vitamin C, which has been studied in such a wide range of therapeutic areas, has negative effects, particularly at high doses. Vitamin C has antioxidant activity in low doses and pro-oxidant activity in high doses, according to studies. The chemotherapeutic efficacy, especially in the parenteral use of high doses, is also based on this basis. Furthermore, one study observed that oral administration of doses greater than 2 g causes osmotic diarrhea and painful abdominal distension [11]. Similarly, polyuria has been reported following parenterally high-dose vitamin C administration [2].

In the light of past and present research, the therapeutic efficacy of vitamin C is still unclear, as are its adverse effects. Because ascorbic acid participates in drugs and antioxidant diet contents in different combinations and different forms. In addition, the data obtained from the studies also differ. Considering the differences between oral and parenteral use of ascorbic acid, it is usual to have differences of opinion among physicians regarding the daily use of ascorbic acid in treatment [4]. Studies that clarify vitamin C’s therapeutic efficacy will provide the foundation for its widespread safe use.

The debate regarding the beneficial effects of vitamin C on living organisms is still ongoing. The only clinical trial of vitamin C that has been proven is its prophylactic and therapeutic effect on scurvy [4].

Following absorption, vitamin C levels rise in the blood and then in the tissues. There is no excretion in the urine during this time. Following this, levels begin to decrease in tissues, first in the blood and then in leukocytes and platelets. In individuals without any renal function problems, most of the surplus metabolized in the blood and tissues is excreted in the urine [12]. Vitamin C is metabolized into oxalate. Oxalate formation potentially leads to kidney stone formation [2].

Efficacy studies on the kidney are also common in vitamin C research. However, there are differences of opinion on the adverse effects of vitamin C on the kidney. The effect of vitamin C on the kidney was evaluated in this study by incorporating various viewpoints.

2. Oxalate formation from ascorbic acid

Ascorbic acid metabolism is closely linked to its antioxidant function. Circulating ascorbic acid loses two electrons respectively. The intermediate compound formed by the loss of the first electron is an ascorbate radical, which is a type of free radical. The ascorbate radical is stable and non-reactive compared to other radicals. The loss of the second electron results in the oxidized product dehydroxy ascorbic acid. Dehydroxy ascorbic acid can be non-enzymatically converted to unstable and open-chain diketogluconic acid. The breakdown of diketogluconic acid results in the formation of oxalate [13, 14] (Figure 1).

Figure 1.

Ascorbate metabolism [13].

2.1 The road to kidney stone formation

Kidney stones affect 10% of the world’s population. Although the structure of kidney stones varies, calcium oxalate stones are the most common. Oversaturation of the urine with calcium oxalate creates a driving force in the kidney, resulting in crystal precipitation. The accumulated crystals form calcium oxalate stones [15].

The main determinants of urinary oxalate excretion and the formation of calcium oxalate crystals appear to be dietary oxalate and its precursors. It is known that the ratio of dietary oxalate intake to oxalate in urine is 50% in healthy individuals. Endogenous biosynthesis, dietary intake, renal and fecal excretion are all balanced to maintain oxalate homeostasis. Endogenous oxalate biosynthesis and transport may be disrupted by genetic mutations such as hyperoxaluria, increased dietary oxalate precursors, and gastrointestinal pathologies caused by microbial factors [15, 16].

Oxalate is a potentially toxic substance eliminated from the kidneys through glomerular filtration and tubular secretion. Increased oxalate concentrations in the blood and urine have been linked to kidney stone formation. The increase in oxalate concentration is explained by an increase in ascorbic acid synthesis as a metabolic end product or by dietary intake of oxalate and its precursors [16, 17].

The first studies on endogenous oxalate synthesis stemmed from research on kidney stone formation in people with primary hyperoxaluria, a rare genetic disease. As a result of the research, it was discovered that endogenous oxalate biosynthesis was higher in these patients than in healthy people. The liver is the primary site of endogenous oxalate production [15, 18].

Glyoxalate has been identified as an oxalate precursor in the liver. Lactate dehydrogenase is the enzyme responsible for the conversion of glyoxalate to oxalate. Hydroxyproline, glycine, phenylalanine, glyoxal, and glycolate are all precursors to glyoxalate synthesis [15, 19]. The most important factor to increase oxalate formation is dietary ascorbic acid. Ascorbic acid is thought to be an important component of the structure of calcium oxalate crystals since it is converted to oxalate non-enzymatically as a result of its metabolization. Calcium oxalate crystals are formed when oxalate combines with cations such as calcium. Calcium oxalate crystals that form build up in the kidney and cause stone formation. Crystal deposition and stone formation may result in renal tubular damage [20, 21, 22].

2.2 Effect of ascorbic acid on kidney stone formation

In adults, the recommended daily dose of vitamin C is 75 mg/day based on average requirements. This value varies according to age, gender, and some genetic diseases. Furthermore, the upper limit of tolerability in humans has been reported to be 2000 mg/day [11]. Consumed vitamin C is partly converted into oxalate crystals and excreted in the urine. This increases the risk of the formation of calcium oxalate crystals [23].

Despite the fact that studies on the relationship between ascorbic acid and the formation of calcium oxalate stones have been ongoing for more than half a century, the nature of this relationship is still unknown. The foundations that are defended theoretically have not corresponded in practice exactly. The studies conducted in this context have led to differences of opinion. Studies on ascorbic acid causing stone formation can be summarized as follows.

Ascorbic acid’s potential to cause kidney stone formation has been discussed since the discovery of oxalate formation as a result of its metabolism. Hellman and Burns conducted the first studies demonstrating that ascorbic acid can be converted to oxalate as a result of metabolism in 1958. In their study, they suggested that ascorbic acid is metabolized to oxalate and excreted in the urine. As a result, it has been proposed that ascorbic acid is the most important oxalate precursor in the structure of calcium oxalate stones [13, 24]. In studies conducted to prove this hypothesis, evidence was presented by Atkins et al. in 1964 and Baker et al. in 1966 that endogenous oxalate synthesis from ascorbic acid contributes approximately 40% to urinary oxalate excretion [13, 25, 26]. However, due to the difficulty in applying the methods used for oxalate determination at the time, these results are now contradicted. Since ascorbic acid can be metabolized non-enzymatically to oxalate in vitro, these inconsistencies in urinary oxalate measurement persist to this day [15, 23].

Taylor et al. were the first to investigate the effect of ascorbic acid consumption on kidney stone formation in the most comprehensive way. They studied the relationship between stone formation and dietary diversity in men for 14 years, as well as how this relationship changes with age. A total of 1473 cases of kidney stones were reported in this study of nearly 50,000 people, with a higher proportion in men aged 45–59 years. In the face of this ratio, vitamin C was thought to affect kidney stone formation. The role of calcium, magnesium, and potassium in the diet, as well as their potential impact on stone formation, were also investigated. The study also presented opinions that calcium consumption reduces oxalate excretion in the urine by forming a complex with oxalate in the intestine and prevents stone formation [27]. Although high-dose vitamin C supplements are restricted to prevent stone formation in men, this and other studies with similar findings have concluded that dietary vitamin C intake should not be restricted [21].

Another large study looked at the renal effects of vitamin C consumption in the diet and as a dietary supplement. This study looked at how men and women formed stones differently. For nearly 12 years, the effect of vitamin C consumption in diet and tablet form on kidney stone formation has been studied by approximately 157,000 healthcare professionals of various ages. This study was evaluated alongside Taylor et al.’s 14-year study on men. The findings of this study, in which dietary variations were recorded on a regular basis, suggest that consuming vitamin C, either in diet or as a supplement, does not cause kidney stones in women. Supplemental vitamin C consumption, on the other hand, is thought to be a significant cause of stone formation in men. The reason for the difference between men and women has not yet been clearly elucidated [12, 21, 28].

For 11 years, the last large cohort study in men looked at the incidence of kidney stone formation with vitamin C under dietary control. Participants in this study reported taking ascorbic acid as a food supplement. In this study of approximately 50,000 people, 436 people were found to have kidney stones for the first time. Stone samples taken from 3176 people were found to be calcium oxalate stones among the reported stone cases. This corresponds to 90% of all cases [29].

A comparison was made between healthy subjects and patients with the stone formation in a study that investigated the effect of daily consumption of 2 g ascorbic acid on urine pH and urinary oxalate formation. Each group was randomly divided into two groups for ascorbic acid and placebo administration. Urine pH was measured in both the placebo and ascorbic acid groups of participants in the study. No significant difference was found in terms of urine pH. However, a significant increase in urinary oxalate was observed in both healthy subjects who consumed ascorbic acid and individuals who developed calcium oxalate stones. Similarly, the urinary calcium oxalate saturation ratio was found to be significantly higher in both ascorbic acid and placebo groups. This diet-controlled study with similar age, gender, race, and body mass index distribution suggests that ascorbic acid consumption promotes the formation of calcium oxalate stones. In this study, urine samples were placed in acid medium to prevent the conversion of ascorbic acid to oxalate in vitro. When compared to previous studies, it has higher reliability for urinary oxalate determination [23]. Baxmann et al. reported in a similar study that vitamin C consumption increased urinary oxalate at a higher rate in patients with a history of kidney stones than in healthy subjects [30].

The half-life of vitamin C after parenteral administration is approximately one hour. After this time, urinary elimination begins [31]. There have been studies that show the benefits of high doses of vitamin C given intravenously, particularly in certain types of cancer, major burns, and sepsis [32, 33, 34]. However, according to a case report, a 74-year-old patient with endometrial cancer who was given 100 g of intravenous vitamin C weekly without medical supervision presented to the hospital 1.5 months later with acute renal failure. Serum creatine levels were found to be extremely elevated, and a renal biopsy revealed the presence of calcium oxalate crystals. It has been reported that the patient developed nephrotoxicity to the point where permanent renal replacement was required. This case shows that the use of vitamin C above therapeutic doses may have nephrotoxic effects on the kidney as well as stone formation [35].

Despite the fact that some of the studies involve large cohorts, there is no agreement on the effect of ascorbic acid on calcium oxalate stone formation due to the short duration of the majority of the studies, the lack of dietary control, the small number of individuals studied, and, most importantly, the lack of reliability in the sample measurement methods. However, the number of studies that do not support stone formation is considerably less than the number of studies that support it. The following are the main findings of these studies:

The theory that oxalate forms as a result of ascorbic acid metabolism and causes calcium oxalate stone formation is rejected by a center that regularly administers parenteral vitamin C to its patients. If this theory is correct, researchers believe that epidemic kidney stone formation should occur as herbivores can produce their own vitamin C and frequently have alkaline urine, which is one of the most common causes of kidney stones. The lack of such a situation, as well as the low rate of kidney stones reported despite parenteral vitamin C administration to their patients for over 20 years, is the basis for their rejection of this theory [12].

In one study, men and women were given equal amounts of parenteral vitamin C for 12 months. A total of 8% of the subjects had a history of kidney stones. Despite the fact that patients were given parenteral vitamin C in doses ranging from 1 g to 119 g, no results were obtained that provided clear evidence for kidney stone formation. There was no statistically significant change in glomerular filtration rate and serum creatine levels in these individuals [36].

The effect of ascorbic acid on kidney stone formation is still being debated today. The effect of urinary oxalate content on calcium oxalate stone formation is generally accepted. However, long-term maintenance of urinary oxalate concentrations is required for stone formation [2]. As a result, considering the duration and dose amount used therapeutically, we believe that the effect of vitamin C on stone formation may be limited. In individuals with normal renal function, parenteral administration and oral consumption at doses not exceeding 1000 mg daily are not objectionable due to its beneficial effects. However, in individuals with a history of kidney stones, the dose of vitamin C taken as a supplement should be adjusted. There is no need to restrict dietary vitamin C consumption in these people [14].

3. The effect of ascorbic acid on nephropathy

The formation of calcium oxalate crystals in the renal tubules causes acute and/or chronic renal function impairment. This condition is defined as oxalate nephropathy. Biopsy and radiology both show the formation of nephrocalcinosis in the renal parenchyma [37] .

There is disagreement among scientists on the effect of ascorbic acid on nephropathy as well as on the risk of stone formation. Biopsy and radiology both show the formation of nephrocalcinosis in the renal parenchyma.

A study was conducted on the prevention of acute kidney injury in Covid-19 patients with vitamin C. Covid-19 initiates a cytokine storm in the body, causing organ damage through inflammatory reactions. Inflammatory cytokines damage the renal tubules and impair renal function. Vitamin C’s antioxidant effect prevents the formation of ROS caused by cell damage. Vitamin C improves renal function by lowering plasma urea and creatine levels as well as renal tissue malondialdehyde levels [38].

Ascorbic acid is a vitamin known to have antioxidant properties. P-glycoprotein (P-gp) is a transporter protein expressed in the kidney and P-gp expression is induced by ROS. Many drugs are excreted more effectively when P-gp is present. Ascorbic acid’s antioxidant activity suppresses P-gp expression and is thought to have a positive effect on drug pharmacokinetics [39].

Acute renal dysfunction caused by contrast agents used in imaging methods occurs at a rate of 2% in healthy people and 11–45% in people with diabetes or chronic kidney disease. One study evaluated the use of vitamin C to prevent nephropathy. The study revealed that vitamin C had no effect on contrast-induced nephropathy. However, due to its antioxidant effect, it helped to reduce the oxidant load [40].

Recent studies have examined the effect of vitamin C on hemodynamic parameters in septic shock. Vasopressor therapy is required in the treatment of septic shock. These patients received parenteral vitamin C in addition to their usual treatment. When compared to other patients, parenteral vitamin C administration did not change the length of stay in intensive care; however, a statistically significant reduction in mortality rate was observed. In addition, a statistically significant decrease in the amount and duration of vasopressor administration has been reported [38, 41, 42]. In addition to these studies, there have been reports that vitamin C use in septic shock causes nephropathy.

Parenteral vitamin C was administered to patients hospitalized for sepsis in a retrospective study that reported that parenteral vitamin C administration causes nephropathy. However, it was reported that high doses of parenteral vitamin C caused nephrotoxicity; there was no reduction in the mortality rate [43, 44].

Hyperoxaluria has a nephrotoxic effect in the renal tubules. In two cases admitted to hospital with severe burns, high doses of parenteral vitamin C were administered as part of treatment. Two patients developed severe oligoanuric acute kidney injury after receiving 101 g and 224 g of vitamin C twice daily, respectively. The death occurred in two patients. Oxalate nephropathy was reported to have developed in two cases at autopsy [45]. A female patient in intensive care for septic shock was given parenteral vitamin C for two months, according to a 2017 case report. A biopsy revealed that the patient had oxalate nephropathy [46, 47].

4. Conclusion

Since the day it was defined, vitamin C has been the subject of research for the treatment of a wide range of diseases. Due to differences in the data obtained from the studies, there is no consensus on its therapeutic and adverse effects. The benefits of vitamin C should not be underestimated, although its only proven therapeutic efficacy is reported to be on scurvy. It is important to know that the most reliable source of vitamin C is what we consume through food. If necessary, the consumption of supplements in doses not exceeding 1000 mg per day is also recommended.

The reason why the effects of vitamin C on the kidney vary across studies is still unclear. Theoretically, oxalate formed as a result of vitamin C metabolism should cause stone formation. However, variables such as the amount of vitamin C used in the studies, the variety of drugs given to patients, the differences in the patient population, and the duration of use have resulted in disparities in kidney stone outcomes. Similarly, it is expected to exert an antioxidant effect on nephropathy. However, there are studies that show the opposite result. Pharmacokinetic parameters that may not have been elucidated in humans should also be considered as the reason for these differences. In order to minimize adverse effects, new dose-controlled studies need to be conducted, and differences between studies need to be clarified. Studies that will clarify the therapeutic efficacy of vitamin C will provide the basis for its safe use to become widespread.