Selection Committee Member: Chirag Parikh @KidneydrChirag
Chirag Parikh is a Professor of Medicine and the Division Director of Nephrology at Johns Hopkins University. His research is developing biomarkers of renal tubular injury, repair, and inflammation to dissect the heterogeneity in acute and chronic kidney disease to advance precision medicine in kidney diseases.
Selection Committee Member: Maryam Khosravi @_Dr_MK
Maryam Khosravi is a nephrologist in London, UK, currently a Senior Clinical Fellow on Intensive Care at the Royal Free Hospital NHS Trust. She is an honorary research scientist at University College London where she is using zebrafish with genetic tools, including CRISPR/Cas9 gene editing, to model disease.
Writer: Matthew Graham-Brown @DrMattGB
Matt Graham-Brown is an NIHR Academic Clinical Lecturer in Renal Medicine at the University of Leicester and the John Walls Renal Unit, Leicester, UK. His research investigates the cardiovascular effects of lifestyle interventions in patients with kidney disease.
Competitors for the Exercise Nephrology Region
This is a great bracket, especially for a tournament that rewards stamina and persistence. Exercise is one of those things everyone ‘knows’ is good for you. It’s good for everyone, right? We tell patients it’s good for them. We encourage patients to exercise and be physically active. We tell them it will help them lose weight and improve their cardiovascular health. We tell them it will help them sleep better and improve their quality of life. We might even tell them it will help them stay healthy to receive a kidney transplant, or make their kidney transplant last longer.
But we’re appropriately cautious, too, aren’t we? We tell people to be sensible when they train to make sure they don’t ‘overdo it’. We remind people to stay hydrated during activities, but to avoid extremes of over- and under-hydration. We advise people to stick to established training plans and not to get suckered by wonder-supplements that claim to be able to turn everyone into Olympians. We know this is all good advice, don’t we?
Well, maybe. Yes, we probably ‘know’ many of these things, but not because there is an undeniable fortress of trial evidence to support our claims. We know much of this through shared experience, from learning from our physical therapist colleagues (who really know what they’re talking about in these matters), and, most importantly, we know this because we listen to and learn from our patients.
For the most part, all of the above is good, sensible advice and we should keep encouraging patients to maintain an active lifestyle (whether they do or not is a different story). The first half of the draw pits exercise in patients with established kidney disease on dialysis versus exercise in those with a kidney transplant. Which is more important? Which is the more worthy? In the second half of the draw we see the ‘toxic effects’ of exercise on the kidney in patients with normal kidney function versus the kidney problems you might encounter in athletes who use performance-enhancing substances. Important considerations for all, so let’s have a look.
Athletes on Dialysis
All the data that we have show that patients on dialysis are among the most physically inactive and deconditioned patients with chronic illnesses and that physical activity levels associate directly with outcomes. When you think about the burdens of dialysis, the enforced sedentary time, the pervasive tiredness many experience following dialysis, the limited amount of ‘free-time,’ and the associated co-morbidities for many dialysis patients, this is not a big surprise.
There are, of course, notable exceptions. This year, Maddy Warren @queenofdialysis became the first patient on dialysis to complete the London Marathon – an incredible achievement. Maddy is a huge advocate of home dialysis due to the flexibility and control it gives her over her life, and certainly it’s difficult to see how a patient undertaking traditional daytime, in-center dialysis could have trained for and completed a marathon as Maddy did. For many unit-based dialysis patients, these achievements may seem like a fantasy, but there are multiple examples in the literature and data on the effects of exercise on multiple aspects of health for patients on hemodialysis.
For patients treated with hemodialysis, ‘exercise’ comes in many forms. Exercise during dialysis (intradialytic exercise), often on a modified bike, has the advantages of being convenient, making use of otherwise lost time, and having good adherence rates.
However, the potential cardiorespiratory adaptations may not be as impressive as when exercise is delivered between dialysis sessions (interdialytic exercise), which potentially result in greater cardiopulmonary adaptations, but (as you might expect), adherence to such programs is poorer.
So are there data that exercise improves things for patients on hemodialysis? Well yes, there are data and some of it are pretty good. Adequately powered randomized trial data have shown us that a structured resistance training program improves strength, physical functioning, body weight and body composition, and reduces systemic inflammation in patients on dialysis.
Additionally, structured aerobic training between dialysis sessions significantly improves functional capacity. Systematic reviews have also suggested that exercise improves the physical component of quality of life for many patients, though this may not be true for all forms of exercise. Hopefully, the results of the PEDAL study (a UK-based multi-center randomized clinical trial) will add significantly to this evidence base. These are all good things, and for me, they are enough on their own to encourage and support patients on dialysis to engage in regular exercise programs and to support the delivery of exercise programs in dialysis units.
Questions do remain, however. Does exercise improve cardiovascular health? Does it make you live longer? The truthful answer to both these questions is maybe. There are small studies that suggest exercise during dialysis improves left ventricular ejection fraction as well as reduces epicardial fat thickness, markers of oxidative stress, and atheromatous coronary artery disease, but these studies are small, and as the authors point out, are underpowered to detect the differences they describe. We also do not have compelling empirical data that exercise interventions improve mortality for dialysis patients. That said, there has been some encouraging data on this recently in a large retrospective study, which should inform the design of a future prospective study in the future. Importantly, none of the research around exercise in dialysis patients (of any form) has identified potential harm.
While policymakers may be happy in supporting clinicians to encourage patients on dialysis to undertake exercise, they are unlikely to insist on the implementation of exercise programs without evidence of mortality benefit and cost-effectiveness analyses. These areas are the ones that require further study.
What is clear to me, (full disclosure, I have worked on a large randomized trial of exercise in patients on dialysis for the last 4 years), is that for some patients, a structured program of exercise is life-changing, and for some patients it is not. We have had stories of people who couldn’t climb stairs and patients who needed walkers to get from the car to the dialysis unit who were randomized to the exercise intervention in our study, and on completing the program, they can now get out to do their own shopping, go for walks with their grandchildren, and walk their kids to school.
These are powerful tales when heard first-hand and, in the absence of evidence to the contrary, are, by themselves, enough for me to advocate for ‘exercise’ as ‘good for dialysis patients’. As in the general population (and even among nephrologists!), there are a number of patients who are simply not interested in taking part in exercise even though we tell them earnestly that it might do them some good. While there are definitely evidence gaps that need to be filled in this field generally, understanding and working how to overcome this, the human factor, is perhaps the most important of them all.
Athletes with Kidney Transplants
A kidney transplant is what we all wish for our patients with kidney failure. Not only does it give patients the best outcomes in terms of longevity, it gives them the most normal, least restrictive life. Next time you’re thinking about all the benefits of transplantation over remaining on dialysis, spare a thought for Maslow’s hierarchy of needs.
Life on dialysis can sustain the basic needs of physiology and safety and it is perfectly possible to have meaningful, loving relationships as a patient on dialysis. However, achieving ultimate self-fulfillment, accomplishing life goals, and reaching one’s full potential may be more difficult for patients on dialysis than for patients with a well-functioning kidney transplant. So how does ‘exercise’ fit into this?
Well, in a lot of ways. Perhaps most simply, even being able to undertake exercise in a ‘normal’ way may be hugely significant for someone who has been restricted on dialysis. Unfortunately, there are many patients who feel unable to return to ‘normal’ physical activity levels, and the reasons for this are manifold: fear of the negative effects of exercise, low self-confidence and expectations, as well as poor exercise self-efficacy. These may all impact directly on a patient’s ability to achieve fulfillment and self-actualization.
There is a subtler side to this though. Many patients who have received a kidney transplant feel they have been given a precious gift and that they have an obligation to their donor to look after the transplant and make the most of it. Undertaking exercise fulfils both of these ‘obligations’, and a focus group we conducted for kidney transplant patients picked up on these themes. The patients at our focus group wanted to stay healthy, live physically active lives, and make the most of the gift of a kidney, but they absolutely did not want to harm the kidney in any way and really didn’t know how exercise ‘safely’. It is what you might call a ‘catch-22’.
What do we know about the effect of exercise in patients with kidney transplants? Well, this population is probably less well-‘studied’ than the dialysis population, but a recent systematic review suggests exercise training in kidney transplant patients improves VO2 peak (surprise surprise!) and quality of life. Although it doesn’t improve graft function, it doesn’t seem to make it worse. There is nothing convincing to show that regular exercise improves long-term graft survival, but we do know that graft survival is worse if patients gain weight following transplant, so it’s not unreasonable to suppose exercising might be good for graft longevity.
Similarly, while there are no large studies that have assessed the safety of exercise in patients with kidney transplants, there are no safety signals in the literature that should raise concern. The putative cardiovascular benefits of exercise in this population are clear and small studies of supervised exercise programs in kidney transplant recipients have been shown to improve a variety of cardiometabolic risk factors, including metabolic profile vascular stiffening, central adiposity, and cytokine profiles. That said, data pertaining to the possible benefits on hard outcomes simply do not exist at this time.
We do need more trial data about the effects of exercise on a range of outcomes in patients with kidney transplants, but this will be no good if it can’t be put to use. Understanding the motivators and barriers to exercise for these patients will be essential in order to help them not only potentially improve their health, but also enjoy a full and active life. For me, the next steps for both these areas will be teasing out which patients derive the most benefit from exercise interventions, which (if any) patients might be at potential harm, and how we can overcome the patient, physician, and institutional barriers to exercise.
Ok, time for some balance. Extolling the virtues of exercise is all very well, but the laws of medicine mean exercise cannot be all good, all the time, for all people. Of course that is right; there are, after all, no ‘always’ or ‘nevers’.
I’m sure everyone has come across examples in their clinical practice of patients who have overdone it while training and developed rhabdomyolysis. That’s a nice, straightforward complication of overzealous training, right? There are probably some things worth considering when one encounters such a patient.
Exertional rhabdomyolysis is well-described among athletes and military personnel who are typically fit and healthy; they present with muscle pain, high creatine kinase, and often with myoglobinuria and an acute kidney injury (AKI). Patients who fit this phenotype will usually have undertaken particularly strenuous exercise and it is important to capturing this in the history.
Why? Well, because not all people who present with exercise-induced rhabdomyolysis are elite athletes or soldiers. Some are perfectly ‘normal’ individuals who have done what you might consider to be a ‘normal’ amount of exercise. In these patients, rhabdomyolysis occurs because of one of the following:
- The exercise has been undertaken in a particularly stressful environment
- It is the first manifestation of an underlying genetic muscle disorder (such as type 1 ryanodine receptor-related conditions)
- There is an underlying disorder of calcium homeostasis, structural myopathy, or underlying sickle cell trait
All of these are important not to miss, but hand-on-heart, who routinely considers these things when you see a case of ‘exercise-induced rhabdomyolysis’? Scalco et al cover this beautifully for those wanting to review this in more detail. Most young, fit people who develop exercise-induced rhabdomyolysis will recover completely, but many of those found to have an underlying or predisposing cause need referral for specialist care, so think twice the next time you see one of these patients.
There was also a time not so long ago when the medical literature was littered with reports of athletes developing acute hyponatremia (particularly during endurance events), with occasionally tragic and fatal consequences. The majority of these relate to excessive water ingestion and ‘overhydration’ in an attempt to avoid ‘dehydration’ and the mechanisms for that are pretty clear. There are, however, fewer cases where excessive sodium loss in sweat plays a role. In these cases, dermal sweat losses contribute to a relative dilutional exercise-associated hyponatremia as part of a pathophysiological continuum. Drinking to thirst seems to be the sensible advice, but a recent study showed many endurance runners plan to volitionally ingest water before being thirsty in an attempt to maintain hydration and performance.
Typical hydration guidelines for endurance events suggest avoiding more than a 2% decrease in body mass over the course of the event, but there is some evidence that those undertaking ultra-endurance may need to tolerate body mass losses of significantly greater than 2% to avoid overhydration and the risks of hyponatremia. While sensible advice can get you so far, if someone comes to you asking for specific advice on training for an ultra-marathon, specialist referral is probably advisable!
Lastly, it would be remiss not to mention the recent studies that suggest otherwise healthy individuals who run marathons develop serological and urinary markers of AKI. This was covered extensively in a previous #NephJC chat and was a really nice piece of clinical research. Mansour et al showed in sampled subjects who completed a marathon that the majority of participants developed markers of renal injury, severe enough to be classified as at least stage 1 AKI. As you might imagine, this was headline fodder for the press, but does it actually mean running marathons is bad for you or for you and your kidneys?
Well no, I don’t think so. The ‘AKI’ described resolves incredibly quickly and there appear to be no long-term sequelae; if marathon running caused CKD, wouldn’t we have seen some of them in clinic by now? This is really interesting work, but for me the biomarker changes do not reflect ‘AKI’; more likely, they highlight some of the current limitations of our most recent definition of what constitutes an AKI. That said, this does potentially provide an interesting model for future study. And also don’t forget that up to 75% of marathon runners use NSAIDs – head over to the Pain Region to hear more on this, but maybe this isn’t such a great idea if you are already at risk for AKI.
So there you go: 3 examples of exercise and exercise-related activity not being terribly good for you. Do they (themselves) represent an enormous public health issue, or tremendous amount of work for nephrologists? Probably not, but they showcase interesting (patho)physiology, clinical challenges, and pathological entities, and are therefore worthy of our consideration.
The final contender in the bracket is perhaps the one with the darkest reputation: kidney-related injury caused by taking performance-enhancing drugs. I expect most nephrologists have encountered at least one case in their clinical practice of a patient who developed a kidney problem related to drugs taken to improve performance or enhance the results of training, so an understanding of some of the different scenarios and ways these present is useful.
Anabolic steroids have frequently been implicated in the development of kidney injury and a number of possible mechanisms of injury are described in the literature. There are increasing reports of AKI caused by acute bile nephropathy secondary to (androgenic) anabolic steroid use. Such patients will invariably present with cholestatic jaundice and hepatotoxicity following anabolic steroid use and develop bile cast nephropathy, which may or may not be reversible. The renal injury in these cases most likely occurs due to direct bile acid injury to tubular cells, as well as obstructing bile acid casts.
There is a nicely described case series of 10 bodybuilders who used anabolic steroids and went on to develop proteinuria and patterns of focal segmental glomerulosclerosis (FSGS) on biopsy. All patients had glomerulomegaly, various patterns of FSGS (including the collapsing variant), and 7 out of 10 showed significant degrees of fibrosis and tubular atrophy. Interestingly, serum creatinine stabilized with reduction in proteinuria or discontinuation of anabolic steroids and concomitant weight loss. Clearly, the authors are describing a secondary FSGS, resulting from post-adaptive glomerular changes. These are undoubtedly driven by increased body mass, but it is conceivable there is an additional direct nephrotoxic effect from anabolic steroids.
There is a single reported case of nephrocalcinosis possibly secondary to anabolic steroid use in a bodybuilder who presented with AKI and hypercalcemia, although the mechanisms for this presentation are far from clear.
Finally, a case of clenbuterol-induced rhabdomyolysis has recently been described. Clenbuterol is a veterinary bronchodilator, but can increase protein deposition and lipolysis similar to anabolic steroids. The cardiotoxic effects of clenbuterol are well-established, but this was the first case to have implicated clenbuterol as a possible cause of rhabdomyolysis. A word of caution, however; the case above describes the development of rhabdomyolysis in a patient taking clenbuterol, but the patient was also training vigorously in the period when he presented with AKI. This reader is not convinced the AKI can be definitely attributed to clenbuterol and it’s perfectly possible the muscle breakdown was simply caused by overzealous training, but it is still worthy of inclusion and discussion.
Anabolic steroids in combination with high protein intake and creatine supplementation have also been implicated in the development of acute tubular necrosis and AKI. A case series described 4 patients who all presented with AKI and acute tubular necrosis on kidney biopsy. After discontinuation of anabolic steroids and supplements, the AKI resolved; however, the degree of interstitial fibrosis and tubular atrophy on two of the kidney biopsy samples implied that, left unchecked, this would have progressed to end-stage kidney disease (ESKD). I, for one, know I have seen patients present with ESKD in this way.
The relative contributions of steroid use vs protein and creatine supplementation cannot be discerned from these cases, however, as the AKI resolved on cessation of steroid injections and supplements at the same time. Although there are reports in the literature of patients developing acute interstitial nephritis while taking creatine (and additional other supplements), I cannot find any conclusive evidence that these supplements in and of themselves led to the acute interstitial nephritis. Similarly there is a report of the development of AKI and lactic acidosis in a patient taking creatine and metformin, but whether taking creatine contributed to the development of the AKI or the lactic acidosis is debatable.
Perhaps the best evidence that dietary supplements may have deleterious effects on the kidney is a case of AKI that occurred in a soldier taking a supplement called NO-XPLODE (which contains creatine among other things). In this case, the AKI was severe with acute tubular necrosis on biopsy and normal glomeruli. Kidney function returned to normal on discontinuation of the supplement and the authors were confident the patient had not taken additional performance-enhancing substances. The authors of this case astutely pointed out that it was not possible to define from the packaging the precise amounts and combinations of ingredients in this particular NO-XPLODE product and that tighter regulation of this was needed. Indeed, the case highlighted some of the deep-rooted problems with dietary supplementation use and how the lack of safety assurance data makes it difficult to estimate and advise how likely this is to happen to others.
Anabolic steroids cause renal injury in a variety of well-described ways, with supporting histology. Creatine and supplements may cause renal injury, but literature supporting a clear association is less strong, although this may partly be due to the relatively low levels of regulations around the composition and nature of training supplements and an almost complete lack of safety data. What is clear is there is work to be done at a public health and government level to improve awareness and standards around these issues.
In certain circumstances, exercise can lead to a variety of kidney injuries in a small number of otherwise healthy individuals. Similarly, performance-enhancing drugs (particularly anabolic steroids) cause kidney injury in a variety of ways in a small number of patients. And that is key for me: these problems affect a small number of people. Regular, sensible exercise on a population level is undoubtedly beneficial. Physicians and health care providers should be aware of the rare side effects of exercise to be able to appropriately advise patients and to always remember to take a thorough drug history (including supplements and steroid use) in relevant clinical situations.
Matt Graham-Brown COI: Completed PhD working on the CYCLE-HD study (ISRCTN11299707). Chief Investigator on the recently funded ECSERT study (Kidney Research UK grant reference KS_RP_003_20180913).
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