End-stage renal disease in a bodybuilder: a multifactorial process or simply doping?

Roger Hartung,1, Jens Gerth1, Reinhard Fünfstück1, Hermann-Josef Gröne2 and Günter Stein1

1 Department of Internal Medicine IV, Friedrich-Schiller-University of Jena and 2 Department of Pathology, German Cancer Research Center, Heidelberg, Germany

Keywords: anabolic androgen steroids; bodybuilder; clenbuterol; end-stage renal disease; high-protein diet; hypertensive nephrosclerosis



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
The one-time British Prime Minister Winston Churchill [1] once said ‘sports is murder’—and a growing list of articles dealing with the problems of bodybuilding and the use (or abuse) of anabolic androgen steroids (AAS) to enhance muscle growth, to increase strength, and to improve physical performance seems to underline his position.

In the United States, as many as 1 million individuals are estimated to use drugs for athletic achievements or for gaining a more muscular appearance. Reported untoward negative effects of AAS-supported bodybuilding include an increase in coronary risk factors, acute myocardial infarction, cholestatic jaundice, abnormal liver function, rhabdomyolytic complications, and severe mood and psychotic disorders.

We report on a possible renal side-effect in a patient using the ß2 adrenoreceptor agonist clenbuterol and AAS.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 27-year-old man was referred to our department by a general practitioner because of azotaemia, with s-creatinine 754 µmol/l, s-urea 26.3 mmol/l, s-uric acid 444 µmol/l, a semiquantitative urine protein excretion of >500 mg/l, and haematuria of >250 RBC/µl. He reported a sudden short syncopal status during his work as a coach-builder, with an elevated systolic BP of 200 mmHg. Moreover, he complained about frequent fits of dizziness, fatigue and vision loss during the previous 3 months.

There was no family history of chronic illness, hypertension, or renal or systemic diseases. His past medical history revealed recurrent episodes of pharyngitis in childhood more than three times a year. He was a non-smoker, not exposed to animals, and did not travel. The last documented clinical status was his military examination 9 years previously, with no indication of any physical disability.

In his spare time he had been an active bodybuilder for 5 years with an extensive physical exercise programme three to four times a week for 3–4 h. He had regularly taken a high-protein commercial diet (Designer protein®, BMS-Sporternährung Gronau, Germany) with more than 2 g/kg body weight/day containing L-glutamine 33.3 g, taurine 33.3 g, and creatine 210 g. Additionally he had taken AAS (testosterone/Depot-Rotex Medica®) 750–1000 mg/week at 6-week intervals as well as clenbuterol (Spiropent® tablets) t.d.s. according to official guidelines [2] for 18 months. The sources of supply were often unknown. Sometimes he got them from unchecked dealers, mostly from East-European countries. He reported on progressive peripheral oedema and an attack of gout during drug intake, which began 1 year before presentation. He denied the use of analgesic drugs, non-steroidal anti-inflammatory drugs (NSAID), laxatives, or diuretics.

Physical examination showed an athletic (81 kg, 1.86 m) man with appropriate muscular tone, trifling peripheral oedema, no signs of cardiac or pulmonary decompensation, with a regular heart beat of normal frequency without any murmurs or pericardial rubbing. The blood pressure was 190/110 mmHg without any side difference by single measurement. During ambulatory 24-h registration (Spacelabs® model 90207, Redmond Inc., Washington, USA), a hypertensive profile was obvious with 98.1% of systolic and 92.6% of diastolic and 100% of night-time values above the well-defined threshold respectively. MAPNIGHT/DAY-ratio was 0.9.

Pertinent laboratory findings included s-creatinine (1030 µmol/l) with a creatinine clearance of 10.2 ml/min/1.73 m2, and elevated s-urea (31.6 mmol/l), moderately increased s-uric acid (485 µmol/l), hyperphosphataemia (2.54 mmol/l), high intact parathyroid hormone (iPTH) level (281 ng/l) with low 1.25-(OH)2D3 (<2.0 pg/ml), hypoproteinaemia (55.0 g/l), increased s-IgG (4.4 g/l), total cholesterol (6.42 mmol/l), low-density lipoprotein (LDL) cholesterol (4.53 mmol/l), LDL/high-density lipoprotein (HDL) ratio (4.04), cholesterol/HDL cholesterol ratio (5.73), lipoprotein (a) (Lp(a)) (37.7 mg/dl), and haemoglobin (Hb)A1C (6.6%). Red blood cell count showed a decreased Hb (5.5 mmol/l), haematocrit (0.27), and reticulocyte count (6%), i.e. normochromic normocytic anaemia. Serum electrolytes (Na+, K+, Ca2+, PO4, C1-, Mg2+), acid–base-status, liver function parameters, and serological findings (hepatitis B and C viruses, HIV, leptospira, hantavirus) revealed no pathological findings.

Urinary erythrocyte and leukocyte counts were 200/µl (40% dysmorphic) and 15/µl respectively. Bacteriuria was not present. The urine volume was 2.5 l/day. The protein excretion rate was 4532 mg/l, showing an unselective glomerular/tubular pattern (microalbumin 2490 mg/l; {alpha}1-microglobulin, 175.0 mg/l; IgG, 183 mg/l).

The ECG showed signs of left ventricular hypertrophy with a Sokolow–Lyon index of 5.9 mV and distinct repolarization disturbances corroborated by the echocardiographic findings of an enlarged left atrium and ventricle, massive left ventricular muscle gain, left ventricular posterior wall diameter (LVPWd), 141 mm, LVDs, 436 mm with increased echogenicity, a diffusely diminished left ventricular contractility (ejection fraction of approximately 40%) and septal wall thickening interventricular septum diameter (IVSd) 14.4 mm. There were no signs of valve dysfunction or pericardial effusion.

Chest X-ray revealed a considerable left ventricular hypertrophy (lung/heart ratio, 2.1). Ultrasound of the kidneys showed normal size but shrunken cortex (7 mm) without a clear differentiation between cortex and medulla as well as an increased echogenicity.

Funduscopic examination yielded no significant hypertensive lesions.

Renal biopsy was performed and revealed nephrosclerosis with pronounced obstructive lesions of preglomerular vessels—hypertension-like vascular damage, global glomerulosclerosis in 10 of 12 glomeruli and diffuse chronic tubulo-interstitial damage (Figures 1Go, 2Go).



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Fig. 1. Interlobular artery with severe luminal narrowing and broadened intima and subintima with fat cells and increased matrix that also supplemented the medial vascular smooth-muscle cells. Inset. Immunohistology for complement factor C1q that is strongly positive in an arteriole with positive label in intima and media and also total obstruction of the arteriolar lumen: interpreted as hypertensive morphological sequelae.

 


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Fig. 2. As a consequence of the massive obstructive lesions in preglomerular vessels, global glomerulosclerosis and diffuse chronic tubulo-interstitial damage was observed with tubular atrophy, interstitial matrix increase, and reactive mononuclear interstitial infiltration.

 
No histological similarities to cyclosporin toxicity or simple arteriosclerotic lesions were observed. The patient commenced haemodialysis treatment three times a week and was prepared for renal transplantation.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
In the present case, several possible pathogenic factors for the development of end-stage renal disease (ESRD) may be considered. Due to the advanced chronic damage the histological findings were not definite enough to allow an exact differentiation or definition of the primary underlying aetiological factors.

An isolated effect of beta-adrenergic substances on the acceleration of a hypertensive renal damage process may be considered, although this has not yet been documented. Especially under intermittent treatment with unphysiological to toxic doses of clenbuterol in rats, an acute increase in muscle blood flow and hypertensive reaction hints at a transient intrinsic blood pressure activity of clenbuterol which could not be sustained by chronic treatment because of a remarkable beta-adrenergic receptor down-regulation [3]. However, the observation of increased plasma glucose and serum insulin levels in patients with essential hypertension after mabuterol suggests a role of beta-2-adrenoreceptor in the pathogenesis of insulin resistance and its negative renal sequelae [4]. Other data argue for a possible blood-pressure-independent role of the sympathetic nervous system in renal damage in experimental hypertension [5]. Our echocardiographic findings seems to underline this link, although there is no proof of a pathogenic association between AAS and cardiohypertrophic effects.

Although ‘hypertensive nephrosclerosis’ is quite often a misdiagnosis (because of the scarce available histological evidence) a considerable portion of hypertensives—with constitutional, socio-economic, ethnic, and environmental varieties—appears to suffer from ‘true’ hypertensive nephrosclerosis, even if only a small percentage of these patients develops ESRD [6]. Nevertheless, the accelerating effects of a high protein consumption in the process of chronic renal failure has been well known for more than a century.

Bodybuilders often prefer a high-protein and creatine-supplemented diet to achieve maximum skeletal muscle hypertrophy and training adaptations during intense exercise.

Furthermore, attention should also be paid to the possibility of interstitial nephritis as an adverse effect of clenbuterol, although there are no reports on a direct link or renal complications during application. The observation of prevention of cyclosporin-induced nephrotoxicity in rats by the ß2-adrenoreceptor agonist clenbuterol due to isolated renal cortical vasodilatation caused by reduced intracellular calcium argues against a pathogenic role of the adrenoreceptor agonist in inducing renal damage [7].

Lifestyles which lead to chronic hypovolaemia, especially in subjects with a bodily-stressed personality, may magnify renal damage processes, and are frequently found among bodybuilders (or ballet dancers) and are often exacerbated by an on-the-spot use of diuretics [8].

Zeier et al. [9] clearly demonstrated recently that AAS such as testosterone at different doses plays a permissive role for renal compensatory growth in rats. They mentioned that the magnitude of renal risks in adults depend on gender and may be presumably mediated via sex hormones. This is presumably mediated by renal testosterone receptors and may set the stage for accelerated progression of renal disease in the organism exposed to male sex hormones [10].

The growing number of papers investigating the atherogenic effects of AAS caused by marked HDL-level depression suggests an additional independent risk factor. Bodybuilding is increasingly popular and ‘doping’ more than a phrase since the ‘Tour de France 1998’. In view of the reported case, the following quotation out of an official guide book for the use of AAS in bodybuilding seems to be nearly sarcastic: ‘If the claims about the risks of physical damage were true, no professional bodybuilders would exist any more since all of them would have died long ago. In fact, the non-stop use of steroids is quite usual in ambitious athletes and results in constant increase rates ... E.g. if a 24-year-old athlete becomes the world champion, he has a good physical predisposition and looks back on an almost non-stop steroid consumption of several years.’ [2].

In conclusion, we suggest that the use of clenbuterol and AAS provides a scenario that may increase the risk of renal failure especially in pre-existing kidney diseases. Renal failure due to consumption of (intermittent) high to toxic doses of beta-adrenergic substances and/or AAS should be recognized in general. Bodybuilders, usually exposed to forced muscle gain and hypertensive situations, should be considered a high-risk group in particular.



   Notes
 
Correspondence and offprint requests to: Dr Roger Hartung, Erlanger Allee 101, D-07740 Jena, Germany. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Chomley AR. Churchill—Ende einer Legende. Propyläen Press, Berlin, 1995
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Received for publication: 26.10.99
Revision received 8. 6.00.