26 March 2014

Acute kidney injury (AKI) following endurance running – Is ultramarathon running really healthy?

It is now a time in passing, in between the winter and spring, with cold clear weather and hard dry roads and trails. I am still tired since my trip to Canada last week and have difficulties finding the right geist so even running feels automatic and as a too long wait for something else.

Passing of a hill on my way to work

I tried to motivate myself by reading some interesting articles in the past days and they have led me to ask whether ultramarathon running is really healthy. The short answer is that we do not know. There are still no good prospective long-term studies of ultramarathon runners looking at morbidity and mortality. A large study called the Ultrarunners Longitudinal TRAcking (ULTRA) study has recently started with Dr Marty Hoffman at VA Northern California Health Care System and Univiversity California Davis and Dr Eswar Krishnan  at Stanford as the principal investigators.  The first baseline findings from this study has just been published, for instance in Hoffman &  Krishnan “Health and exercise-related medical issues among 1,212 ultramarathon runners: baseline findings from the ultrarunners longitudinal TRAcking (ULTRA) study”. PLoS ONE 2014; 9(1): e83867. In the long term this study has the potential to answer some of the more general health related questions.

The articles I have read have on the contrary argued that ultramarathon running is not healthy. These studies have looked at biochemical markers in the blood and urine of disease and organ pathologies and found highly abnormal values in ultramarathon runners following a race. That strenuous endurance physical activities like ultramarathon running lead to abnormal laboratory values has been known for quite some time, for instance reviewed by  Sanchis-Gomar and Lippi in the article “Physical activity - an important preanalytical variable” Biochemia Medica 2014; 24:68–79. What is new is the extent of the abnormality of the markers and that they involve markers normally used to diagnose for instance severe cardiac and kidney disorders. Lippi and co-workers looked at the emerging markers of severe cardiac disease and cardiovascular stress serum Copeptin and Midregion Proadrenomedullin (MR-proADM) after a 60 km ultramarathon in 16 healthy runners (Lippi et al “Serum copeptin and Midregion Proadrenomedullin (MR-proADM) after an ultramarathon” J Clin Lab Anal 2014 Epub ahead of print. They found that the serum concentrations of both copeptin and MR-proADM remarkably increased after the 60 km run, by 6.4 times (interquartile range (IQR), 2.710.4) and 2.3 times (IQR, 1.8-2.6), respectively. The percentage of subjects exhibiting values above the upper limit of the reference range in male was 0% for both copeptin and MR-proADM before the ultramarathon, but increased to respectively 81 and 63% postexercise. They authors ask based on these findings whether exhaustive exercise such as ultramarathon running might be considered globally beneficial or even safe, especially in unfit or/and untrained population. I agree fully with this question, but again, we do not know as an abnormal laboratory value by itself is not a disease. I will in a later blog post further look at what is known about the effects of running on the heart and here instead look at the real life-threatening disease acute renal failure which evidently is occurring in a small subset of runners following an ultramarathon.

I have in a recent blog post described the high risk of developing acute mountain sickness (AMS) and the less frequent, but much more severe, complications of high altitude during ultramarathon running in the mountains high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE). A more frequent severe medical complication of ultramarathons and other endurance races is acute kidney injury (AKI) and acute renal failure (ARF). I will in this blog post look at the frequency of kidney complications of ultramarathons and how it could be prevented and treated. The related complication exercise-associated hyponatremia (EAH), which is more frequent among runners having acute kidney injury, but were treatment is contradictory, will be discussed in a separate post.

How common is acute kidney injury (AKI) in ultramarathons?

That both ultrarunning and marathon running might lead to laboratory changes indicating kidney damage has been know long, see for instance the article by Irving and colleagues entitled “Plasma volume and renal function during and after ultramarathon running” published already in 1990 in Med Sci Sports Exerc. 1990; 22: 581-7. There have been a number of articles published since then, for instance the recently published article by Lipman and colleagues entitled “A prospective cohort study of acute kidney injury in multi-stage ultramarathon runners: The biochemistry in endurance runner study (BIERS)” published in Res Sports Med. 2014; 22: 185-192. This was a prospective observational study during the Gobi 2008; Sahara 2008; and Namibia 2009 RacingThePlanet 7-day, 6-stage, 150-mile foot ultramarathons in 30 participants (76% male with a mean age of 40 ± 11 years). Kidney functional laboratory parameters Creatinine (Cr) and glomerular filtration rate (GFR) were calculated and incidence of AKI were calculated and defined by the so called RIFLE criteria. Quite surprisingly, the majority of the participants (55-80%) developed AKI and significant renal impairment after each ultramarathon with significant declines in GFR after each stage compared with the pre-race baseline (p < 0.001). Nevertheless, there was no apparent cumulative effect observed and the renal function returned to near baseline levels between stages.

The similar results were found in the study “Variation of serum and urinary neutrophil gelatinase associated lipocalin (NGAL) after strenuous physical exercise” by Lippi and colleagus in Clin Chem Lab Med. 2012; 50:1585-9. In this study creatinine and neutrophil gelatinase associated lipocalin (NGAL) in serum (sNGAL) and urine (uNGAL) was assessed in 16 trained male runners before and after a 60 km ultramarathon. Serum and urinary creatinine increased significantly by 38% and 78%, respectively. The eGFR contextually decreased by 31%. sNGAL, uNGAL and uNGAL/creatinine ratio increased by 1.6-fold, 7.7-fold and 2.9-fold. In six of 16 athletes (38%), the acute post-exercise increase of serum creatinine met the criteria of AKI.

The prevalence figures of AKI of 55-80% and 38% following an ultramarathon could be compared with the similar prevalence of grade I AKI of 40% (McCullough et al “Changes in renal markers and acute kidney injury after marathon running” Nephrology. 2011; 16:194-199), 48% (Mohseni  et al “Prevalence of hyponatremia, renal dysfunction, and other electrolyte abnormalities among runners before and after completing a marathon or half marathon” Sports Health. 2011; 3: 145-51) and 30% (Kratz et al “Effect of marathon running on hematologic and biochemical laboratory parameters, including cardiac markers” Am J Clin Pathol 2002; 118: 856-863) found after a normal road marathon. No runner in these studies developed severe AKI. The study by McCullough and colleagues is interesting as they also performed cardiac MRI measurements in the 25 participants and the lack of changes in respect to inferior vena cava volume, ejection fraction, or atrial and ventricular volumes argue against volume depletion, fluid shift, or pre-renal azotemia as a lone cause of AKI. Instead they hypothesize that it is cardiac exhaustion might lead to AKI and suggested further research about long-term consequences of endurance running for renal function. For ultramarathon running I think a more likely cause of AKI is exertional induced muscle damage, so called rhabdomyolysis, as the waste products from the degraded muscle, in particular myoglobin, damages the kidneys leading to acute tubular necrosis (ATN). A good recent review of acute kidney injury following rhabdomyolysis is Bosch et al “Rhabdomyolysis and acute kidney injury” N Engl J Med 2009; 361: 62-72.
Rhabdomyolysis and Acute Kidney Injury. Figure from Bosch et al in NEJM 2009; 361: 62-72 
Rhabdomyolysis and acute kidney injury in ultramarathon running

A number of studies have found highly elevated levels of creatine kinase (CK), a biochemical marker of rhabdomyolysis, in runners of the 100 mile (161 km) Western States Endurance Run (WSER) (Lang et al 1983; Lang 1984; Lind et al 1996; Hoffman 2010; Hoffman 2012). There are no good concomitant measurements of CK and creatinine so it is not possible to assess the risk among the runners with rhabdomyolysis to develop acute kidney injury (AKI) or  acute renal failure (defined in most studies as increase in creatinine of >0.5 mg/dL above a presumed normal baseline. However, a small retrospective study from the laboratory of Hew-Butler and Hoffman of the 2009 WSER identified some clear cases of acute renal failure following rhabdomyolysis (Bruso et al “Rhabdomyolysis and hyponatremia: a cluster of five cases at the 161-km 2009 Western States Endurance Run” Wilderness Env Med 2010; 21: 303-308). Five (5) of the 400 starters of the 2009 WSER were hospitalized with hyponatremia and rhabdomyolysis and of these five three progressed to develop acute renal failure. These three patients were characterized by higher initial blood urea nitrogen (BUN; 43–69 vs 18–23 mg/dL) and creatinine (2.8–4.9 vs 1.1–1.2 mg/dL) levels but were not distinguished by CK concentrations. All of these three patients finished the race and appeared to have used NSAIDs to a greater extent, had a tendency to be younger and were

more likely to have lost body weight during the race. Two of the patients presented with classical symptoms of rhabdomyolysis and EAE, i.e. emesis, dizziness, lightheadedness, cough and dark urine in the first case and dizziness, lightheadedness, and anuria in the second case, at the medical tent at the finish. They were treated with intravenous normal saline, but then presented to the hospital within 24 hours with thigh pain and dark urine (case 1) and weight gain and anuria (case 2). The third case of acute renal failure was presented to the hospital 1 day after finishing the race with continued nausea and flank pain. It is clear that rhabdomyolysis and hyponatremia could co-exist in ultramarathon runners following a strenuous race like WSER and that this could progress to life-threatening renal failure. There appears not to be any clear correlation between EAH with low blood sodium concentrations and blood CK levels (Hoffman et al 2012), but in addition to the report by Bruso and colleagues there are some other case reports reporting this (Ellis et al  “Case report: exercise-associated hyponatremia with rhabdomyolysis during endurance exercise” Phys Sportsmed 2009; 37: 126 –132).

 A recent laboratory study has looked at the effect of muscle damaging exercise followed by running in heat on AKI and found that a hot environment might be considered an additional risk factor for development of AKI (Junglee et al 2013 “Exercising in a hot environment with muscle damage: effects on acute kidney injury biomarkers and kidney function”  Am J Physiol Renal Physiol. 2013 30: F813-20).  

Diagnosis, treatment and prevention of AKI following an ultramarathon

From the above it is obvious that a large number of runners will have laboratory evidence of at least mild acute kidney injury (AKI) following an ultramarathon race, but very few will progress to acute renal failure (ARF). A very interesting recent study by Hoffman and colleagues looked whether it would be possible to by taking a urine dipstick of finishers at the 2011 100 mile (161 km) WSER ultramarathon to diagnose AKI (Hoffman et al “Urine dipstick analysis for identification of runners susceptible to acute kidney injury following an ultramarathon” J Sports Sci. 2013; 31: 20-31. Post-race urine dipstick testing was completed on 152 (49%) and post-race blood also was obtained from 150 of those runners. Based on "injury" and "risk" criteria for acute kidney injury of blood creatinine 2.0 and 1.5 times estimated baseline, respectively, 4% met the criteria for severe AKI and an additional 29-30% met the criteria for having mild AKI/risk of severe AKI. Interestingly, urine dipstick tests that read positive for at least 1+ protein, 3+ blood, and specific gravity ≥ 1.025 predicted those meeting the severe AKI criteria with sensitivity of 1.00 (95% confidence interval [CI] 0.54-1.00), specificity of 0.76 (95% CI 0.69-0.83), positive predictive value of 0.15 (95% CI 0.06-0.30), negative predictive value of 1.00 (95% CI 0.97-1.00), and likelihood ratio for a positive test of 4.2. It would thus be possible to quickly screen runners for the risk of development of severe AKI both during the race and immediately post-race by taking a urine dip-stick. Most runners of risk of severe AKI will not feel anything until quite late in the disease process and then mostly note that there will be less urine production, something which is common anyway after an ultramarathon. It is easier to diagnose rhabdomyolysis, which usually present with the classical triad of muscle aches, weakness and dark colored urine.

Treatment of both AKI and rhabdomyolysis is generally early, aggressive repletion of fluids. However, it is not that easy and treatment should be supervised and managed by a specialist. For instance, a major caveat and risk is that the runner has exercise associated hyponatremia (EAH) as well, where normal fluid resuscitation could be deleterious. Checking for signs of fluid overload and EAH such as weight gain during the race and ideally also blood sodium levels is really important before starting treatment.

There are neither no good studies how to best prevent AKI in association with an ultrarunning racing. Most races now include a medical check-up before the race and I would recommend including testing for an underlying kidney disease, which would obviously be a major risk factor for post-race AKI, by at least measurement of baselevel creatinine. To prevent rhabdomyolysis there are some indications that Vitamin C and Vitamin E substitution might be beneficial, but there exists no controlled studies whatsoever and no recommendations regarding this can therefore be given. Perhaps most importantly, there appears to be consensus in recommending avoidance of non-steroid anti-inflammatory drugs (NSAIDs) like Ibuprofen and Diklofenac before and during the race as it is known that they will stress the kidneys. I agree with this and think it better to follow this recommendation; despite the lack of good clinical studies here as well.

In summary, I do not know whether ultrarunning is healthy. Probably not at least during races, but long term data is lacking. With the right precautions and awareness of the objective, physical and medical dangers I think the unhealthy consequences, like the risk of development of acute kidney injury, can be managed.

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