Introduction

Despite prohibition and drug screening by most international athletic organizations, anabolic steroids are still used to increase muscular mass and thus obtain the best results in sports competitions. The use of these substances has reached alarming proportions in the last 3 decades and is now considered a public health problem [1, 2]. The most frequently used anabolic substances are those related to testosterone. Their use began in the 1950s with muscular exercise athletes and bodybuilders [3, 4]. A number of adverse effects have been described, including virilization, feminization, adverse lipid profile, psychiatric disorders, liver disease and, possibly, an increased risk of malignant disease [5].

Acute kidney injury (AKI) associated with anabolic steroid use is rare, and only a few cases have been reported in the medical literature [5]. The pathophysiology as well as clinical presentation of anabolic steroid-induced AKI is not known. The objective of this study is to present two cases of AKI developed after using anabolic steroids and vitamin supplements.

Case report

Case 1

A 21-year-old male athlete reported that 1 month before admission he had experienced progressive abdominal pain associated with nausea, vomiting, dizziness and weakness. He also had headache, fever and profuse sweating. He was taking anabolic steroids and veterinary supplements containing vitamins A, D and E. The vitamin supplement had in each 100 ml the following composition: vitamin A 20,000,000 IU, vitamin D 35,000,000 IU and vitamin E 6,000 IU (commercial name AD-THOR™). The patient reported having taken 50 ml once a week for the past month. He had no previous medical history and was not taking any other substances. He presented to the Emergency Department with abdominal pain, nausea and vomiting. Physical examination revealed no important abnormalities, except a painful and tender abdomen and tattoos on his upper limbs. He had nausea and vomiting, associated with arterial hypertension (BP 160 × 120 mmHg) and oliguria. Laboratory tests on admission showed urea of 79 mg/dl, serum creatinine 3.9 mg/dl, Na 134 mEq/l, K 3.5 mEq/l, Ca 13.2 mEq/l, LDH 342 IU/l and albumin 4.3 g/l; urinalysis showed leukocyturia (+++), hematuria (+) and proteinuria (traces). Proteinuria was 259 mg/24 h and urinary calcium 552 mg/24 h. Serology for HIV, viral hepatitis, cytomegalovirus and toxoplasmosis was negative. Blood and urine cultures were also negative. Blood pressure control was achieved after administration of three anti-hypertensive drugs (captopril, nifedipine and methyldopa). An ultrasound showed normal-sized kidneys (right: 10.1 × 5.1 × 4.1 cm, left: 10.4 × 51 × 4.9 cm), with no abnormalities. An ultrasound of his renal arteries showed no abnormalities. Ophthalmological evaluation showed no hypertensive retinopathy. The patient became stable, but with only mild improvement of renal function 10 days after admission (Ur 56 mg/dl, Cr 2.6 mg/dl) and with increasing levels of total serum calcium (14 mEq/l). Vigorous hydration with saline 0.9% and furosemide was started on admission to treat the hypercalcemia. A renal biopsy was performed and showed a moderate interstitial inflammatory infiltrate with eosinophils, interstitial edema, calcium deposits and mild acute tubular necrosis (Figs. 1, 2). Treatment with hydration and furosemide was continued, and prednisone (1 mg/kg/day) was started on the 7th day of hospital stay because of persistent hypercalcemia (Ca 12.2 mEq/l). He became stable and was discharged 20 days after admission with recovering renal function (Ur 50 mg/dl, Cr 1.4 mg/dl) and a calcium level of 10 mEq/l. He was continued on maintenance therapy with oral prednisone for 6 weeks.

Fig. 1
figure 1

Renal biopsy showing moderate interstitial inflammatory infiltrate with eosinophils (arrow), interstitial edema and calcium deposits (arrowhead)

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Fig. 2
figure 2

Renal biopsy showing mild acute tubular necrosis (arrows)

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Case 2

A 30-year-old male bricklayer had taken anabolic steroids for the past 2 years in association with vitamins A, D and E and dexamethasone 12 mg every 2 weeks. The doses of vitamins were the same as described for the first patient. One month before admission he developed diarrhea, nausea, vomiting and fever. He presented to the Emergency Department with persistent vomiting. He denied any past medical history. At physical examination he was in good general condition except for a painful abdomen on palpation. Blood pressure was normal. Laboratory tests on admission showed serum urea of 52 mg/dl, serum creatinine of 1.9 mg/dl, Hb 13 g/dl, Ht 42%, white blood cells 14,000/mm3, platelets 258,000/mm3 and Ca 11 mEq/l; urinalysis showed protein (++) and blood (+). Urinary calcium was 390 mg/24 h. The ultrasound of the abdomen showed no abnormalities; kidney size was normal (right: 11 × 6 × 5.7 cm, left: 12 × 6 × 5.8 cm). Venous hydration and furosemide were administered. He was also given prednisone at a dose of 1 mg/kg/day. There was no improvement of renal function (Ur 68 mg/dl, Cr 3.2 mg/dl), and a renal biopsy was performed. A mild interstitial lymph mononuclear inflammatory infiltrate with eosinophils was found, with no remarkable tubular abnormalities. He became stable, with renal function recovery after 1 month of hospital stay (Ur 42 mg/dl, Cr 1.3 mg/dl at discharge).

Discussion

Acute kidney injury (AKI) is seldom described after the use of anabolic steroids and vitamin supplements. There were no other factors that could cause AKI in the cases described here. Renal abnormalities in athletes can range from benign hematuria to exercise-related AKI [6]. Athletes can develop AKI because of some known factors, such as dehydration, rhabdomyolysis and use of non-steroidal anti-inflammatory drugs (NSAIDs) when practicing strenuous exercises [7–9]. In our patients none had used NSAIDs, and rhabdomyolysis and dehydration were not present. Therefore, we believe that the substances taken by the patients led to the development of AKI.

It is estimated that 67% of athletes in the USA use some kind of anabolic substances [2]. An estimated 3 million people in the USA use anabolic steroids to enhance athletic performance or to improve their appearance [9]. The use of doping agents is not restricted only to athletes. It is nowadays observed among young people in schools and non-competing amateurs [1].

A recent Brazilian survey among young bodybuilders found more than 25 different substances used by this population. The most common substances were Durasteron (testosterone), Stradon P (testosterone + stradiol), Deca-durabolin (nandrolone), Uniciclo (algestone + stradiol), Premarim (estrogens), veterinay vitamin supplements with vitamins A, D and E, Potenai (vitamin B) and also the anti-parasitologic drug ivermectin [10]. The main purpose for the use of these substances reported by these young athletes was rapid increase in muscle mass [10]. The majority of people interviewed did not know the risks of using anabolic steroids [10]. In another Brazilian survey, 38% of the interviewed athletes had knowledge of the danger involved in using anabolic steroids [11].

The adverse effects of anabolic steroid abuse are well described and tend to disappear after drug withdrawal. Because use of anabolic steroids is illicit, much of our knowledge of their side effects is derived from case reports, retrospective studies or comparisons with studies in other similar patient groups [12]. The main side effects include acne (40–54%), testicular atrophy (40–51%), gynecomastia (10–34%), skin lesions (34%) and pain at the injection site (36%) [4, 13]. Other less common side effects include hepatic dysfunction, psychiatric disorders, reduction of thyroid hormones production, cardiovascular diseases, hypertension, hypertrophic cardiomyopathy, arrhythmias and thrombosis [2, 4, 13, 14].

Renal abnormalities related to the use of anabolic steroids in supra-physiologic dose are not well described. Renal side effects of these substances have been reported, leading to acute kidney injury and even Wilms’ tumors in isolated cases [12]. Yoshida et al. [5] reported the case of a 26-year-old man who developed severe cholestasis and AKI after using stanozolol, a frequently used veterinary drug. Renal biopsy showed acute tubular necrosis. The possible causes of renal failure in this case were cholestasis and hyperbilirubinemia induced by the use of stanozolol. Habscheid et al. [15] also reported a case of cholestasis and AKI in a young male after the use of an anabolic substance (methandienone), with clinical improvement after anabolic withdrawal and administration of ursodeoxycholic acid. Rhabdomyolysis has also been linked to the possible pathophysiology of anabolic steroid abuse-induced AKI [16].

Another important point to consider is the use of vitamin supplements, which was reported by our patients. In the last few years use of nutritional supplements in massive doses by athletes has been observed. Nutritional supplements are believed to be safe, with the only known health risks consequent to intolerance or overdosing [17]. Nutritional supplements are used worldwide without any consideration of their real effectiveness or usefulness, or of their mechanisms of action when effective [18–20]. Herbal products are also largely used by athletes, and AKI has been described in association with their use. It is believed that some herbs can induce rhabdomyolysis and consequently AKI [21]. Experimental studies suggest that the use of isotonic sport drinks can induce the formation of intra-vesical matrix, suggesting a potential lithogenic risk [22] and suggesting that nutritional supplements can be dangerous, too.

Our patients had taken vitamins A, D and E supplements intended for veterinary use. The dose administered for each patient was very high (around 2,500,000 IU per week), which led to the development of hypercalcemia. Renal biopsy showed interstitial nephritis, calcifications and acute tubular necrosis.

Interstitial nephritis has been described in a patient taking multiple food supplements, mainly creatine, with recovery after discontinuing these supplements [23]. Creatine supplementation appears safe when used by healthy adults at the recommended loading (20 g/day for 5 days) and maintenance doses (≤3 g/day). In patients with a history of renal disease or those taking nephrotoxic medications, creatine may be associated with an increased risk of renal dysfunction. Some studies investigated the long-term use of creatine supplementation in high doses and showed that its use can be dangerous, leading to interstitial nephritis and renal failure [23].

The use of high doses of vitamin D was probably responsible for the development of hypercalcemia, which in turn played an important role in the pathogenesis of AKI [24, 25]. Hypercalciuria was also observed among our patients, and this could contribute to renal dysfunction. Massive use of vitamin D with consequent development of AKI and association with hyperparathyroidism has been described. Tuon et al. [26] described the case of an HIV patient with severe hypercalcemia consequent to vitamin D intoxication and secondary renal failure associated with tenofovir. Serum creatinine and calcium returned to near normal levels after vitamin D discontinuation, saline infusion and furosemide administration. In our patients the administration of saline solution and furosemide was also effective in decreasing serum calcium levels and contributed to renal function recovery. Furosemide seems to play a protective role against drug nephrotoxicity [27]. Other cases of AKI associated with excess vitamin D intake have been reported [28, 29]. A hypothesis to explain the mechanisms involved in hypercalcemia-induced AKI include volume depletion and renal vasoconstriction that lead to AKI in the setting of hypercalcemia. Long-lasting hypercalcaemia leads to calcium deposits in the kidneys (nephrocalcinosis), which can cause AKI and chronic renal failure [28] (Table 1).

Table 1 Clinical and laboratory features of two patients with acute kidney injury due to anabolic steroid and vitamin supplement abuse
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Medical case reports about AKI induced by anabolic steroids and vitamin supplements are rare in the literature. A brief description of the main reported cases on this subject is shown in Table 2.

Table 2 Reported cases of kidney injury and other complications associated with the use of anabolic steroid and vitamin supplements
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In summary, AKI is an important complication of anabolic steroid and vitamin supplement abuse. The exact pathophysiology of this type of AKI remains unclear. The main cause of renal dysfunction in these cases seems to be drug-induced interstitial nephritis and vitamin D intoxication, which lead to hypercalcemia and elevated urinary calcium, a known inducer of AKI. It is mandatory to start early treatment for serious hypercalcemia, with vigorous venous hydration, diuretics and corticosteroids.