Discussion
Four bodybuilders developed acute renal insufficiency while using commercial nutritional supplements consisting of protein and creatine combined with anabolic steroid injections. Biopsies demonstrated acute tubular injury, and when the injections and supplement use were stopped, serum creatinine levels became normal within 4 weeks.
The findings raised the possibility of the hypervitaminosis D-induced nephrocalcinosis recently encountered in four Brazilian bodybuilders [18–20]. These subjects developed hypercalcemia and renal failure with nephrocalcinosis while injecting veterinary grade vitamin D with estimated doses of >10 million IU annually. Of note was that the injections were not for vitamin D but for the silicone-like effect of the oily carrying medium that was used to add bulk to specific muscle groups. Our findings differ from those of the Brazilians in that none of our patients were hypercalcemic or took large doses of vitamin D, and none of our biopsies could be considered to show nephrocalcinosis.
Closely related to hypervitaminosis D is the milk- or calcium-alkali syndrome [21–23]. This is caused by an excessive consumption of milk or anti-acid calcium carbonate compounds. Currently, the calcium-alkali syndrome is primarily seen in post-menopausal women taking supplemental calcium and vitamin D for osteoporosis. The occurrence in bodybuilders is not specifically reported apart from hypervitaminosis D, and among our patients, milk and other calcium consumption could not be considered greatly excessive.
Acute phosphate nephropathy with intratubular calcium phosphate deposition that somewhat resembles the pathology of our patients is caused by oral sodium phosphates used for bowel preparation before colonoscopy [24]. Protein powder contains little inorganic phosphate with three daily supplement servings providing <0.5 g [25]. Creatine is sold mainly in the form of a monohydrate also with little phosphorus. Daily 2–3 L milk consumption will add 1.6–2.4 g to a normal dietary phosphorus intake of 1.0–1.5 g [25]. This is well below the 11 g oral intake used in bowel preparations [24]. In addition, the negative von Kossa stains indicates that the mainly amorphous tubular concretions found in the kidneys of our patients were acutely precipitated and had not complexed into crystalline hydroxyapatite with prominently stained phosphates that are seen in hyperphosphatemic nephropathy as well as other forms of neprocalcinosis [26].
For most athletes, sports nutritionists recommend a daily protein intake of 1.4–1.7 g/kg/day, less than half of what was used by our patients [2, 27]. There is substantial experimental and clinical data supporting the safety of creatine supplementation when it is used in the recommended amounts, but there is concern that excess dietary protein and creatine that is not accompanied by increased fluid intake may lead to a relative hypovolemia [6–9]. The clinical presentation of our three of our patients was in the summer. Iraqi summers are very hot, and by Western standards, the regional gymnasiums are warm and trainee hydration less than optimal.
In previously reported cases of acute kidney injury in creatine users, one demonstrated acute tubular necrosis, but two were classified as acute interstitial nephritis suggesting idiosyncratic allergic reactions [10–12]. Our patients' biopsies showed acute tubular necrosis that could be nephrotoxic or ischemic [28, 29]. In either case, this type of kidney injury among otherwise healthy young men is a rare event and points to a causal relationship with supplement and steroid use. Two of our patients had significant chronicity in their renal biopsies. This raises the possibility of preexisting chronic kidney disease that may or not be related to supplement use, but more likely reflects the risk that acute kidney injury of any type carries for chronic kidney disease [28, 29].
We must emphasize that a specific offending agent cannot be identified in this case material, and it may be the combination of excess creatine and protein with steroid injections that compounds risk not incurred with the individual substances. Our working hypothesis is that under hydration rather than direct toxicity precipitated the kidney injury.