An epidemic of chronic kidney disease (CKD) of unknown cause is occurring along the Pacific Coast of Central America. First reported in 2002 in sugarcane workers in El Salvador, it also occurs in other persons — mainly men — who work long and hard in the heat, including in construction and mining. This disease has likely been present for decades, but it seems to be on the increase, and mortality from CKD in this part of the world is increasing fast. A major effort is ongoing to find the cause and cure. If the most popular hypothesis of causation pans out, this novel epidemic of CKD may have implications for endurance athletes who live, train, and compete in the “hotspots” of our planet. Let me explain.
Heat Stress Nephropathy
This epidemic of CKD, also known as Mesoamerican nephropathy, occurs mainly in agricultural workers, especially sugarcane cutters, working in the hotter, lower altitudes along the Pacific, all along Central America, from Guatemala to Panama. The victims initially are asymptomatic, with little or no proteinuria or hematuria, but elevated serum creatinine levels. Kidney biopsy shows tubular atrophy, interstitial fibrosis, and glomerulosclerosis, with signs of kidney ischemia. Even without common risk factors, such as diabetes or hypertension, this CKD usually leads to end-stage renal disease. Some say that 20,000 people have already died from this epidemic.
Although a hunt for environmental toxins is on, emerging evidence supports the current leading hypothesis of causation, “heat stress nephropathy,” from repeated, unrecovered episodes of “prerenal” acute kidney injury (AKI) due to dehydration, volume depletion, mild rhabdomyolysis, and uricosuria — all caused by laboring day after day in intense heat, with inadequate hydration and little chance to rest in the shade. This hypothesis also may be popular because of an emerging scientific consensus on global warming (2,4,10).
Recent research, if still limited in scope and detail, tends to support this hypothesis. In a study of 28 sugarcane workers before and after a workday, all had a fall in estimated glomerular filtration rate (eGFR) of about 20%, serum creatine kinase (CK) levels doubled, and nearly 20% had a rise in serum creatinine consistent with mild AKI (12). Among 189 sugarcane cutters (90% men) across a work shift, 23 men started with a low eGFR (<60 mL/min), and although weight changes were variable, significant rises (about 10%) were seen in serum creatinine, urea nitrogen, and uric acid, suggesting a heavy load on the kidneys to counteract dehydration during the work shift. The authors conclude that prevention may be as simple as providing more water, rest, and shade (1).
The hypothesis that repeated dehydration from heat stress nephropathy can cause CKD is novel, but the concept of acute heat stress nephropathy goes back at least 50 yr to studies of soldiers who suffered heat stroke and severe acute tubular necrosis (AKI) exercising in the heat. Most soldiers who survived were said to show “complete clinical recovery of renal function” (14,15). There is, however, one report nearly 50 yr ago of four Bantu gold miners who developed heat stroke with AKI that recovered only to present later with CKD due to chronic interstitial fibrosis (7). Also relevant is recent research in endurance athletes and in volunteers simulating the work of firefighters.
Firefighters and Athletes
In a new study, biomarkers of dehydration and AKI were gauged in 29 young, healthy adults (10 women) who simulated two work durations of firefighters. In firefighter gear, they walked uphill on a treadmill in a hot, humid environmental chamber. In one trial, they walked for 40 min; in another trial, 60 min. The longer trail evoked greater increases in serum creatinine and plasma neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker of renal tubular injury, along with a greater rise in body core temperature, a greater loss of body fluids, and a greater fall in plasma volume. The authors conclude that biomarkers of AKI are shaped by the degree of hyperthermia and hypovolemia evoked by exercise in the heat (13).
An earlier study fits this theme and — by evoking mild rhabdomyolysis — may come closer to what sugarcane cutters endure. Researchers hypothesized that muscle-damaging exercise, before exercise in the heat, would increase kidney stress. Studied were 10 healthy young men, recreational athletes. In randomized, cross-over trials of treadmill running, they first ran for 60 min either downhill (to evoke mild rhabdomyolysis), or intensity-matched, on the flat. Then they ran for 40 min in the heat. The downhill run did evoke mild muscle damage (compared to the flat run), as reflected by a greater rise in CK and in interleukin-6 (IL-6). Both trials evoked similar mild dehydration and hyperthermia (which was slightly greater in the “muscle-damage” trial). The muscle-damage trial evoked a greater rise in urine and plasma NGAL and in serum creatinine. In fact, by Acute Kidney Injury Network (AKIN) criteria, 5 of the 10 men in the muscle-damage trial developed stage 1 AKI (rise in creatinine > 0.3 mg/dL) versus none in the flat-run trial. The authors conclude that prior muscle-damaging exercise is a novel risk factor for AKI when exercising in the heat (5).
Besides heat stress, physiological shunting of blood during strenuous exercise can tax kidney function; renal blood flow can fall to 25% of basal level. To learn more about heat stress, exercise, and kidney function, Yale nephrologists studied 22 men and women (mean age, 44 yr) who completed the 2015 Hartford Marathon (average ambient temperature, only 62°F). Of the 22 runners, by AKIN criteria (rise in serum creatinine), 17 developed stage 1 AKI and one developed stage 2 AKI. Urine microscopy scores (of renal tubular epithelial cells and granular casts) — along with a rise in NGAL — suggested that the main cause of AKI was acute tubular injury. However, by the day after the race, creatinine had fallen back to (or near) baseline in all 22 runners, suggesting that any AKI was temporary. Also, despite many years of training and racing, none of the 22 runners had evidence of CKD (9).
Prior studies of marathoners or ultramarathons also suggest that any AKI is mild and temporary. Right after a Detroit marathon, 10 of 25 runners had stage 1 AKI (by AKIN criteria), but not the next day (11). In a multistage ultramarathon race, most runners developed mild AKI during the grueling stages, but renal function returned to near normal between stages and no cumulative effect was seen (8). In a 100-km ultramarathon in Taiwan, 22 of 26 runners developed AKI by AKIN (18 stage 1; 4 stage 2) during the race, but all were back to normal one day later (6). Finally, in a comprehensive field study of data from 3 yr of the Western States Endurance Run, the authors note that it is common for 161-km ultramarathoners to meet AKI criteria after a race, albeit usually only mild AKI. Those most likely to meet the AKI criteria finish faster, lose more weight, and have higher postrace serum CK and urea nitrogen levels. However, in the few who ran more than one such ultramarathon, there was no evidence that those who got AKI the first time got worse AKI the next time, suggesting to the authors that any AKI from an ultramarathon is not cumulative and is likely associated in most cases with complete recovery of renal function (3).
It is too early to know whether the Mesoamerican epidemic of CKD is — for endurance athletes who live, train, and compete in the heat — a red herring or a canary in the coalmine. So far, the evidence in athletes suggests any AKI is temporary and not cumulative. Maybe the AKIN criteria are too sensitive for healthy athletes in action. AKI seems to be a syndrome, embracing not only kidney disease, but also functional impairment relative to physiologic demands. The latter may be mainly what we are dealing with in endurance athletes in action. Also, AKIN criteria are meant to be applied only after achieving adequate hydration. By that time, say, the day after the marathon or ultramarathon, current research suggests that most athletes are no longer classified by AKIN as having AKI.
Time will tell whether the heat stress nephropathy hypothesis explains the troubling and deadly epidemic of CKD in laborers in Central America. Let us hope they soon find the cause and cure. Also, let us learn from it the lessons we need to learn.
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