Rhabdomyolysis and exercise-associated hyponatremia in ultra-bikers and ultra-runners

The most important result was that two (15.4 %) ultra-runners from 13 hyponatremic
and four (4.0 %) ultra-runners from 100 normonatremic finishers (5.3 % from a total
number of finishers) developed post-race CK levels higher than 10,000 U/L without
the occurrence of renal failure and the necessity of a medical treatment.

Pre-race characteristics of cases with rhabdomyolysis (cases 1–6)

The present case 1 (51-year-old man) and case 2 (38-year-old woman) with EAH and rhabdomyolysis
were among the faster, but not younger finishers in their races. Female 24RUNner case
2 was even the first according to the absolute order among both genders. The 153-km
ultra-runners with EAH and rhabdomyolysis (three men and one woman) exhibited an average
age of 38?±?8 years in a study by Ellis et al. 14]. In a recent study published by Hoffman et al.8], a 161-km hyponatremic ultra-runner with rhabdomyolysis was 53 years old. In the
study of Boulter et al.17], three (from four with acute renal failure) hyponatremic male 89-km ultra-marathoners
noted their average age of 34.0?±?8.7 years. In the study of Bruso et al. 6], 161-km ultra-runners with EAH and rhabdomyolysis were men with an average age of
39?±?7 years and they tended to be younger and faster than those not developing EAH
with rhabdomyolysis. The present normonatremic male cases with rhabdomyolysis (cases
3–6) with mean age 35.0?±?9.4 were among the faster finishers and they were on average
younger compared to the rest of the normonatremic athletes. As described by Hoffman
et al. 7] in their study of 161-km finishers of “Western States Endurance Run” (WSER) with
rhabdomyolysis, blood CK concentrations were not related to finish time, age or the
number of prior similar completed races. The comparison of the present hyponatremic
cases (1,2) and normonatremic cases (3–6) with rhabdomyolysis was impossible due to
the low number of cases. Nevertheless, when we compared all hyponatremic and normonatremic
cases, the present older and more trained (i.e. more years spent by running/biking) hyponatremic ultra-athletes developed higher
post-race CK concentrations than the younger ones and the less trained hyponatremic
ultra-athletes. Moreover, the present faster normonatremic finishers developed higher
post-race CK concentrations than the slower normonatremic finishers. On the contrary,
race experience (i.e. the number of finished ultra-marathons) or the training frequency and length (i.e. number of training hours per week) related to an increased CK neither in hyponatremic,
nor in normonatremic ultra-athletes. Gender was not related to CK in the present ultra-athletes.
The rare incidence of women with EAH and rhabdomyolysis probably reflects the ratio
of female to male finishers in similar ultra-endurance races 6].

Creatine kinase concentrations

Normal CK post-race values are up to?~?2,000 U/L 9]. In accordance to Sinert et al. 31], inclusion criteria were an elevated CK of more than 500 U/L and they reported exertional
rhabdomyolysis with admission CK levels between 700 U/L and 167,000 U/L. CK levels
of roughly 500–1500 U/L 24] or approximately over 2,000 U/L are used as the criterion for statin myopathy 39], 40] and CK above 10,000 U/L as diagnosis of rhabdomyolysis 27], 31]. In the present study, CK???2,000 U/L and associated myopathy developed three (23.1 %)
hyponatremic (one male and one female 100RUNners and one male 24MTBer) and fifteen
(15 %) normonatremic (six male 24MTBers, two male and one female 24RUNners, three
male and one female 100RUNners and two male SMTBers) ultra-athletes. Overall, eighteen
(15.9 %) of all present ultra-athletes (n?=?113) developed exercise-associated myopathy.

Cases 1 and 2 developed biochemical EAH and exercise-induced rhabdomyolysis with CK
levels of 14,512 U/L and 15,172 U/L, respectively. The rest of the hyponatremic group
(n?=?11) had CK range from 691 U/L to 3,163 U/L. In the normonatremic cases 3, 5 and 6
with rhabdomyolysis post-race CK increased in the range from 12,768 U/L to 20,280
U/L. Aside from cases 1 and 2, normonatremic cases 3, 5 and 6 exhibited CK concentrations
higher than 14,512 U/L, the lower initial post-race value of two cases with EAH and
rhabdomyolysis. The study of the 153-km ultra-runners with EAH and rhabdomyolysis
described CK levels in the range from 15,636 U/L to more than 100,000 U/L 14]. Rhabdomyolysis in combination with EAH in one male athlete was presented by Putterman
35] with CK 1,545 U/L which peaked at 10,300 U/L. Boulter et al.17] described in three 89-km runners with EAH and rhabdomyolysis CK levels in a wide
range from 5,718 U/L to 48,934 U/L. Hoffman et al.16] observed higher blood CK concentrations among those with EAH than those not developing
EAH at the 2011 WSER. In 161-km ultra-run race mean CK concentrations were even 54,583
U/L in the hyponatremic group and 30,335 U/L in the normonatremic group 16]. Percentage change in CK was significantly higher in the present hyponatremic compare
to normonatremic ultra-athletes. Hyponatremic finishers with an average post-race
CK 3,658?±?5,029 U/L tended to develop exercise induced rhabdomyolysis more than present
normonatremic ultra-athletes with an average post-race CK 2,025?±?4,094 U/L.

We could not compare validly different kinds of races and ultra-disciplines due to
the small number of participants in some observed races. Nevertheless, post-race plasma
CK significantly increased in male and female finishers in all races (SMTB, 24MTB,
24RUN and 100RUN), except female SMTBers with a non-significant increase. Notwithstanding,
in comparison of all ultra-runners (n?=?31) and all mountain bikers (n?=?82) post-race CK levels were significantly higher in the present ultra-runners. Despite
a dissimilar number of participants in each race discipline we found the highest post-race
CK levels in the 24RUNners and the 100RUNners with a significantly higher increase
of post-race CK in 24RUNners compared to 24MTBers. Moreover, cases 1 and 6 were from
100RUN and cases 2, 3, 4 and 5 were 24RUNners. In accordance to Hoffman et al. 8] mild to moderate elevations of CK are common in long running distance and exertional
rhabdomyolysis is often associated with EAH. Skenderi et al. 1] assumed that prolonged exercise at even moderate intensity can induce asymptomatic
exertional rhabdomyolysis. In their study of 246-km ultra-runners an increase of post-race
CK was 43,763 U/L; nevertheless, the ultra-runners did not require hospitalisation.
The reasons for an increase in CK could be also the duration of races and the large
eccentric component of ultra-running races 7], 12]. On the contrary, a low increase of CK of 542 U/L during 24 h after the exercise
appeared after two hours of cycling 25]. The groups of ultra-runners and MTBers were not equal; nevertheless, the present
ultra-runners tended to develop more frequently exercise-induced rhabdomyolysis than
the present ultra-MTBers.

Normonatremic cases 3 and 6 (1.8 % from the total of 113 ultra-athletes) developed
post-race CK concentration of 20,280 U/L, a level associated with renal failure 31]. Acute kidney injury is a complication of severe rhabdomyolysis (CK 60,000 U/L
to 80,000 U/L) and the prognosis is worse with renal failure 38]. However, no present finisher developed acute kidney injury or renal failure or need
a medical treatment. In the present study the post-race CK levels were not as high
as in other studies. However, the average increase was from 2,665 % to 26,209 % in
all cases with rhabdomyolysis. Factors associated with acute renal failure include
rhabdomyolysis with CK concentrations higher than 20,000 U/L or higher than five times
the normal value 31], 38]. However, no defined level exists. Following Meijer et al.30], the risk of acute renal injury in rhabdomyolysis is low at CK levels lower than
15,000 U/L to 20,000 U/L. Acute renal injury with CK levels at 5,000 U/L usually occurs
with hypovolemia (low circulating volume) or aciduria (acidic urine) 26], 27], 29], 31]. However, exercise may induces factors protect against hypovolemia and aciduria.
Exercise-induced rhabdomyolysis with mean CK concentrations up to 40,000 U/L 1], 31] has not been reliable to diagnose renal failure 17]. Blood CK concentration was reported from the 161-km WSER in 1980 through 1983 3], 4], 1995 5], 2009 6] and 2010 7] and Bruso et al. 6] first defined the relationship between EAH and rhabdomyolysis in the 161-km ultra-run
in five runners with CK values of 40,000 U/L. CK concentrations in the 2010 WSER finishers
were higher than values previously reported 7]. Hoffman et al. 7] suggested that stress caused by trail running race with its challenging conditions
produced severe muscle damage. However, CK values higher than 20,000 U/L are common
for this type of event and seldom result in detrimental consequences. Hoffman et al.7] found no athlete with acute renal failure, despite high mean CK levels of 32,956
U/L. Thirty-nine ultra-runners finishing a 245-km race with CK values exceeding 40,000
U/L also had not been shown to have acute renal failure 1]. On the contrary, four cases of acute renal failure in the Comrades marathon had
various levels of CK values of 39,000 U/L, 29, 800 U/L, 24,120 U/L and 2,220 U/L 17]. In the cohort of twenty-six patients with severe rhabdomyolysis the average level
of CK with 38,351 U/L was predicted the development of acute renal failure 30]. Nevertheless, exercise-induced rhabdomyolysis rarely progresses to acute renal failure
27], 31] and less severe forms of rhabdomyolysis or in cases of hyperCKemia (i.e. chronic or intermittent muscle destruction) present with no renal failure 26]. Moreover, exertional muscle damage produced by eccentric exercise can lead to an
elevated CK without renal impairment 2], 39]. CK level is, therefore, not useful in distinguishing acute renal failure 2], 31], 41]. Given the wide range of CK levels the value of CK is limited to diagnose rhabdomyolysis
30]. Factors for renal failure in cases of exertional rhabdomyolysis in marathon running
could be a pre-existing viral/bacterial infection, heat stress, dehydration, latent
myopathy, NSAID (non-steroidal anti-inflammatory drugs), other drugs or analgesic
use 2], 27], 31]. In the present study we were not able to observe these factors in ultra-athletes.
However, the present results support hypothesis that the magnitude of elevated CK
do not have exactly and always predict acute renal failure 2], 31], 38], 39], 41].

Plasma [Na
⁺
] and [K
⁺
] concentrations

Plasma [Na
⁺
] decreased in cases 1 and 2 with rhabdomyolysis and EAH and cases 3 and 5 with rhabdomyolysis
within the hyponatremic and the normonatremic group with a significantly higher increase
in the hyponatremic group. In different kinds of the present races limited by various
numbers of participant’s plasma [Na
⁺
] decreased in all ultra-disciplines. Hyponatremia as the most common electrolyte
disorder associated with ultra-running and muscle-cell swelling with mechanical stress
caused by running (footrace) may result in skeletal muscle damage, rhabdomyolysis,
or acute renal injury 27]. However, we found no study about the occurrence of rhabdomyolysis and EAH in cycling
races. Also the present post-race CK levels were significantly higher in the ultra-runners
and no mountain biker presented EAH with rhabdomyolysis or just rhabdomyolysis. Blood
[Na
⁺
] and CK concentrations were negatively correlated in 161-km ultra-runners 16]. In all present finishers (n?=?113), in hyponatremic and in normonatremic finishers, CK concentrations were not
associated with plasma [Na
⁺
]. In a recent study of Hoffman and Stuempfle 15] from the WSER in 2011 and 2013, a significant relationship between plasma [Na
⁺
] and CK concentration was also evident, however, without the difference between the
hyponatremic and the normonatremic group due to wide variability in creatine kinase
concentrations. Similarly, in the study of Hoffman et al.7], the relationship between blood CK and [Na
⁺
] did not reach statistical significance.

The recognition of electrolyte abnormalities associated with rhabdomyolysis and induced
acute kidney injury like hyperkalemia (serum [K
⁺
]???5.5 mmol/L) is important to remove [K
⁺
] from the body 26]. Hyperkalemia can be classified according to serum [K
⁺
] into mild (5.5 – 6.5 mmol/L), moderate (6.5 – 7.5 mmol/L) and severe (7.5 mmol/L)
hyperkalemia 42]. A metabolic disorder known to cause EAH and rhabdomyolysis is also hypokalemia,
when [K
⁺
] depletion due to cell swelling eventually induces rhabdomyolysis 35]. None of present ultra-athletes showed post-race hypokalemia. Present case 1 developed
post-race plasma [K
⁺
] 5.2 mmol/L and case 2 plasma [K
⁺
] of 4.6 mmol/L. A study of four athletes with EAH and rhabdomyolysis showed plasma
[K
⁺
] in the range from 4.1 mmol/L to 4.9 mmol/L 14]. The present levels of post-race plasma [K
⁺
] were higher than in the study of Bruso et al. 6] with an average of 4.0 mmol/L (range 3.4 – 4.9 mmol/L) in his 5 cases with EAH and
rhabdomyolysis and higher than in the study of Boulter et al.17] with an average of 4.4 mmol/L.

The interesting finding was that the present cases 1 and 2 showed pre-race values
of plasma [K
⁺
] (6.8 mmol/L and 6.5 mmol/L, respectively) which tended to be higher than in other
hyponatremic ultra-athletes. In the present cases with just rhabdomyolysis (cases
3–5), post-race plasma [K
⁺
] ranged from 4.8 mmol/L to 5.0 mmol/L, only case 6 reached 6.7 mmol/L (moderate post-race
hyperkalemia). Another finding was the post-race decrease of plasma [K
⁺
] in all cases (1–5), except case 6. The reason could be probably pre-race mild to
severe hyperkalemia in cases 1–5 due to the range of pre-race plasma [K
⁺
] from 5.9 mmol/L to 8.1 mmol/L (case 4 with 8.1 mmol/L). On the contrary, case 6
presented with a pre-race level of 4.9 mmol/L and therefore probably exhibited post-race
increase of plasma [K
⁺
]. The average post-race plasma [K
⁺
] in the present normonatremic finishers was in the range from 3.8 mmol/L to 8.2 mmol/L
and twenty-seven (27 %) athletes developed levels higher than 5.5 mmol/L. Their average
pre-race plasma [K
⁺
] was 5.4?±?1.2 mmol/L (range 3.5 mmol/L to 9.2 mmol/L) with fifteen (15 %) ultra-athletes
with pre-race level???5.5 mmol/L. Hyponatremic finishers had an average post-race
plasma [K
⁺
] in the range from 4.4 mmol/L to 6.5 mmol/L with four (30.8 %) finishers with a level
higher than 5.5 mmol/L. Even in five (38.5 %) hyponatremic finishers pre-race plasma
[K
⁺
] reached levels of???5.5 mmol/L. Post-race plasma [K
⁺
] significantly decreased in both genders in 24MTBers and 24RUNners and non-significantly
in male 100RUNners despite the limitation of different number of finishers in each
ultra-endurance discipline.

Another finding was that pre-race plasma [K
⁺
] showed an average value of 6.7 mmol/L and 6.2 mmol/L in male and female 24RUNners,
respectively, 5.5 mmol/L and 6.2 mmol/L in male 24MTBers and male 100RUNners, respectively.
On the contrary, the lowest pre-race level was 4.4 mmol/L in male SMTBers, 4.7 mmol/L
in female SMTBers, 5.2 mmol/L in female 100RUNners, and we simultaneously found a
significant increase in post-race plasma [K
⁺
]. Overall, despite the genders and the various numbers of racers in each ultra-disciplines
57.9 % 24RUNners, 42.0 % of 24MTBers, 16.7 % 100RUNners and 6.3 % of SMTBers showed
pre-race hyperkalemia and 47.4 % 100RUNners, 28.1 % SMTBers, 20 % 24MTBers and 16.7 %
24RUNners developed post-race hyperkalemia.

A further interesting finding was that we found an association between pre-race levels
of plasma [K
⁺
] and post-race CK levels in the present finishers. The ultra-athletes with higher
pre-race plasma [K
⁺
] developed post-race higher CK levels. It also appears that races with a higher occurrence
of pre-race hyperkalemia tended to a lower occurrence of hyperkalemia post-race and
conversely. However, there was no significant relationship between pre-race plasma
[K
⁺
] and post-race plasma [K
⁺
] considering all present ultra-athletes. The presence of mild pre-race or post-race
hyperkalemia in some present hyponatremic and normonatremic cases supports either
excessive [K
⁺
] ingestion pre-race or during the race, ingestion of NSAID, reduced renal excretion
or tissue breakdown as in rhabdomyolysis 42]. Notwithstanding, we found no association between post-race plasma [K
⁺
] and CK concentration. We have to take into account that some results could be also
caused by pseudohyperkalemia from leakage of [K
⁺
] from the intracellular space during or after blood sampling in field conditions
42].

Plasma and urine creatinine concentrations

Muscle injury releases creatine and increases blood creatinine as one of parameters
of myocellular damage 31], 39]. Biochemical criteria for acute renal injury mean a blood creatinine concentration
more than 2.0 mg/dL and 1.5 times of the estimated baseline 27], 31], 39]. Post-race plasma and urine creatinine significantly increased and creatine clearance
decreased in all cases with rhabdomyolysis (cases 1–6), in the hyponatremic and the
normonatremic group and in both genders in all present different races. Current cases
1 and 2 with EAH and rhabdomyolysis developed an average post-race creatinine level
of 0.95 mg/dL (1.0 mg/dL and 0.8 mg/dL). In accordance to the study of Bruso et al. 6], their average level of post-race blood creatinine in cases with EAH and rhabdomyolysis
was higher than in the present study. Three cases in the study of Bruso et al. 6] developed acute renal failure with higher blood creatinine (2.8 mg/dL to 4.9 mg/dL)
than two cases without renal failure (1.1 mg/dL to 1.2 mg/dL), however, without a
difference in CK concentrations. Cases 3–6 with just rhabdomyolysis showed an average
post-race creatinine level in the range from 1.0 mg/dL to 1.2 mg/dL. In the study
of Hoffman et al. 38], the range for blood creatinine levels was similar as in the present cases with rhabdomyolysis
in the range from 1.1 mg/dL to 1.4 mg/dL. The present hyponatremic group developed
post-race creatinine concentration in the range from 0.8 mg/dL to 2.6 mg/dL and the
normonatremic group from 0.7 mg/dL to 3.4 mg/dL; however, without a significant difference
between both groups.

Present creatinine levels above the upper limit of normal were only found in one hyponatremic
male SMTBer (2.6 mg/dL, plus 271.4 %) and one male normonatremic SMTBer (3.4 mg/dL,
plus 240.0 %) from a total of 113 ultra-athletes. The 42-year old hyponatremic male
SMTBer (post-race plasma [Na
⁺
] 134 mmol/L) developed also high pre- and post-race levels of plasma [K
⁺
] (5.5 and 5.7 mmol/L), minus 3.8 percentage change in body mass; the highest percentage
decrease (minus 74.1 %) of creatine clearance within all finishers; however with post-race
CK just 1,197 U/L. The 26-year old normonatremic SMTBer showed plasma [Na
⁺
] 140 mmol/L, pre- and post-race levels of plasma [K
⁺
] 3.6 and 4.9 mmol/L, plus 0.6 % percentage change in body mass, the second highest
percentage decrease (minus 70. 4 %) of creatine clearance within all finishers; however
similarly with post-race CK only 1,168 U/L. Both current cases presented post-race
without the development of renal failure and the necessity of a medical treatment.
Neumayr et al. investigated the effect of marathon cycling on renal function in recreational and
professional road cyclists 22], 23] with no evidence for a significant skeletal muscle damage and a reduced renal perfusion
responsible for the slight impairment of renal function after marathon cycling 22]. In a study of the 38 recreational male marathon cyclists the increases in plasma
creatinine were 20 %, the decrease of creatinine clearance was similar 18 % 22]. In 16 professional road cyclists (525-km race), plasma creatinine rose by 33 %,
the decrease of creatine clearance was 25 % 23]. Two multi-stage mountain bikers in the present study developed the highest levels
of post-race plasma [K
⁺
] and the lowest concentrations of creatine clearance; however, both with low post-race
CK concentrations. Moreover, these hyponatremic multi-stage bikers showed a higher
percentage increase in post-race CK levels than normonatremic biker. In the study
of Hoffman et al.41], 4 % of their ultra-runners met the criteria for injury (i.e. blood creatinine 2.0 times of the estimated baseline) and 29 % for risk (i.e. blood creatinine 1.5 times of the estimated baseline) of acute renal injury and those
meeting the injury criteria had higher CK concentrations. Nevertheless, very few runners
seek or require medical treatment for acute renal injury 41]. In all present SMTBers plasma creatinine rose by 33.3 %?±?64.8 in men and by 21.9?±?15.7 %
in women with minus 17.4?±?19.3 % change in male creatine clearance and minus 19.8?±?10.8 %
change in female creatine clearance and their post-race creatine levels and post-race
percentage changes in CK were the lowest from all different ultra-disciplines in the
present study. These data confirm that the strains of ultramarathon cycling regardless
these two presented cases did not influence their renal function. Even though, Khalil
et al.43] suggested that acute renal failure is defined with serum creatinine 3-fold from
baseline, or??4 mg/dL with an acute rise of 0.5 mg/d L or greater. The present multi-stage
mountain bikers fulfilled these conditions; they did not seek or required medical
treatment for acute renal injury. In the present study, correlations between post-race
CK values and plasma creatinine, urine creatinine or creatine clearance values were
not found.

Limitations

We have to take into account that the number of present ultra-athletes in various
disciplines and gender representation was different. Further we did not observe a
urine dipstick for a urine colour, blood and myoglobin. However, direct measurement
of myoglobin is less reliable and not clinically useful 44]. Moreover, increased CK levels are associated with increased blood myoglobin 7], 38]. Hereafter, a development of rhabdomyolysis can delay several hours after the occurring
of EAH due to the changes in intracellular [K
⁺
] and the restoring of cellular volume 14]. Peak CK level is about 48 to 96 h after its presentation 44]. In the marathon cyclists renal parameters remained elevated during 24 h of recovery
22], 23]. We had no possibility to observe ultra-athletes one or more days after the race;
otherwise the danger of rhabdomyolysis could be higher.

Practical applications

The value of CK as a prognostic tool is limited, due to the wide inter-individual
range of CK levels. In situations where the diagnosis of EAH is uncertain, fluid restriction
during or after the race is contraindicated in case of dehydration and rhabdomyolysis
with impending acute kidney injury 8], 27], 29], 41].