A Different Creatine Question
Ask most people what creatine has to do with the kidneys and you will get some version of the same worry: does taking creatine damage them? It is one of the most persistent myths in sports nutrition, and we will deal with it directly later in this article. But there is a second, far less familiar question hiding behind it, and it turns the usual concern completely upside down. What happens to creatine when the kidneys stop working?
The answer, according to a research group at the University of Groningen in the Netherlands, is striking. People whose kidneys have failed, and who depend on dialysis to stay alive, do not have too much creatine. They have far too little. Their bodies largely lose the ability to make it, their treatment actively washes it out of their blood, and their recommended diets increasingly contain none of it. The result, the researchers argue, is a chronic creatine deficiency that may quietly contribute to some of the most crushing problems these patients face: muscle wasting, exhaustion, low mood, and foggy thinking.
This article is based on a conference presentation by Prof. Stephan Bakker, a professor of internal medicine at the University of Groningen and one of the leading researchers on creatine metabolism in kidney disease. His group published the case for this idea in a peer reviewed article in the journal Nutrients in 2021, and the argument they lay out is one of the most interesting stories in creatine research today. We have checked the key claims against the published evidence and flagged where the science is solid, where it is promising, and where it is still a hypothesis waiting for trial results.
The Daily Creatine Leak
To understand why kidney patients end up short of creatine, it helps to understand a quirk of creatine chemistry that affects every human being.
Creatine is a small nitrogen containing compound that acts as a rapid energy buffer inside cells. Together with its charged form, phosphocreatine, it allows tissues with sudden energy demands, above all skeletal muscle, the heart, and the brain, to regenerate ATP almost instantly. More than 90 percent of the body’s creatine sits inside muscle and nerve tissue, with smaller amounts in other cells, including red blood cells.
Here is the quirk: creatine is not stable. Every day, about 1.6 to 1.7 percent of the body’s entire creatine pool spontaneously degrades into creatinine. This is a purely chemical process; no enzyme drives it and no enzyme can reverse it. Creatinine is a waste product, and in a healthy person the kidneys filter it out of the blood and excrete it in urine. That is exactly why doctors use blood creatinine as a kidney function test.
Because of this constant leak, the creatine pool must be refilled continuously. According to Bakker, and consistent with the wider literature, a typical omnivorous diet covers roughly half of the daily requirement, mainly through meat, fish, and dairy. The other half has to be manufactured inside the body. Eat less meat, and the body has to make more. This division of labor matters enormously for what comes next, because the main factory for that internal production turns out to be an organ most people would never guess.
The Kidney as a Creatine Factory
Everyone learns the classic jobs of the kidneys: removing excess fluid, clearing metabolic waste such as urea and creatinine, and producing the hormone erythropoietin, which drives red blood cell production. Lose kidney function and you retain fluid, accumulate waste, and develop anemia. Textbooks also mention that the kidney activates vitamin D.
Bakker highlights a function that rarely makes it into the textbooks at all: the kidney is a site of chemical synthesis, and one of the things it synthesizes is the direct precursor of creatine. The first and rate limiting step of creatine production is carried out by an enzyme called arginine:glycine amidinotransferase, or AGAT, which combines the amino acids arginine and glycine into a compound called guanidinoacetate. In humans, this step takes place primarily in the kidney, with smaller contributions from the pancreas and brain. The guanidinoacetate is released into the bloodstream, taken up by the liver, and converted there into creatine, which then travels to muscle and brain. Human studies measuring blood entering and leaving the kidney have confirmed that the organ genuinely produces and exports guanidinoacetate.
Conveniently for researchers, AGAT makes a second product: homoarginine, formed when the enzyme acts on lysine instead of glycine. Homoarginine is a metabolic end point, meaning the body does not convert it onward, which makes it a clean marker of how much AGAT activity a person has.
Bakker’s group put this marker to work using a remarkable natural experiment: living kidney donation. When a healthy person donates a kidney, waste products that depend on filtration, such as creatinine, rise in the blood, because the remaining kidney cannot fully compensate even with its considerable capacity for growth and hyperfiltration. In the talk, Bakker noted that donation effectively removes only about a third of total kidney function once that compensation is accounted for, yet creatinine still climbs by nearly half. If the kidney played no role in synthesis, other small water soluble compounds should rise in parallel. Instead, homoarginine and guanidinoacetate do the opposite: they fall. In the group’s published analysis, plasma homoarginine dropped about 12 percent after donation and urinary homoarginine excretion dropped about 25 percent, while guanidinoacetate fell even more steeply. Falling levels after the loss of kidney tissue are exactly what you would expect if the kidney is where these compounds are made.
The implication is sobering. If donating one healthy kidney measurably dents the body’s capacity to begin creatine synthesis, what happens to people whose kidney function is essentially gone?
Dialysis: Lifesaving but Costly
Chronic kidney disease is a leading cause of illness and death worldwide, and its most severe form, kidney failure, is treated with dialysis or transplantation. The scale is enormous. A systematic review in The Lancet estimated that about 2.6 million people worldwide received kidney replacement therapy in 2010 and projected that the number would more than double to around 5.4 million by 2030, with millions more needing treatment but unable to access it.
Hemodialysis, the most common form, is unambiguously lifesaving, but the burden is heavy. A typical patient travels to a dialysis center three times a week and spends about four hours per session connected to a machine that filters their blood. Quality of life is often poor, and the list of associated health problems is long: loss of muscle mass and strength, severe fatigue, depression, cognitive impairment, heart failure, and an increased susceptibility to infections along with worse outcomes when infections strike.
Bakker points to a structural reason why dialysis, for all its benefits, creates nutritional problems. A healthy kidney is not a simple sieve. After filtering the blood, it selectively reabsorbs valuable molecules, including glucose, amino acids, and creatine, and returns them to circulation, discarding only genuine waste. A dialysis membrane cannot do this. Whatever is small enough to pass through is lost into the dialysis fluid, valuable or not. Published measurements confirm, for example, that patients lose a substantial quantity of amino acids into the dialysate during every session. Repeated three times a week, year after year, this indiscriminate filtering adds up. Dialysis patients also generally produce little or no urine, so between sessions there is no renal fine tuning of anything at all.
Put the pieces together and dialysis patients face a triple problem with creatine specifically: they can barely make it, they cannot reabsorb it, and the machine that keeps them alive removes it.
Measuring the Deficiency
Hypotheses are cheap; measurements are not. To quantify what dialysis actually does to creatine balance, the Groningen team did something unusual: they collected the entire volume of used dialysis fluid from patients’ sessions, in large tanks, and analyzed it. As Bakker put it in the talk, the dialysate of a patient who no longer urinates is, functionally, their urine, and studying it reveals what the body is losing.
The published results paint a consistent picture. Across a single session, plasma creatine fell from about 26 to about 21 micromoles per liter, a relatively modest drop only because tissues release creatine to buffer the blood level. Each session removed roughly 719 micromoles of creatine along with its precursors, about 37 micromoles of guanidinoacetate and about 1,939 micromoles of arginine, plus around 15.5 millimoles of creatinine, the waste product that reflects how much creatine the body’s shrinking pool is burning through.
The truly telling number, though, is the baseline. Kidney failure normally causes small water soluble molecules to accumulate in the blood, because they are no longer filtered out; that is precisely why creatinine and urea run high in these patients. Creatine should behave the same way. Instead, Bakker reports that dialysis patients’ plasma creatine sits at roughly half the level his group measures in the general population, which he places at about 50 to 70 micromoles per liter. A molecule that ought to be elevated is instead markedly depressed, which is hard to explain by anything other than genuine depletion, likely extending into the tissues. Supporting that interpretation, older studies using phosphorus magnetic resonance spectroscopy found reduced phosphocreatine levels and a degraded energy state in both the skeletal muscle and hearts of dialysis patients.
The same study found that the lower a patient’s plasma creatine, the higher their odds of low muscle mass, low protein intake, low blood albumin, and severe fatigue, with each halving of plasma creatine roughly doubling to tripling those odds. Association is not causation, but the pattern fits the hypothesis uncomfortably well.
Muscle Mass and Survival
Why does any of this matter beyond biochemistry? Because in dialysis patients, muscle is survival equipment.
The dialysate collections gave the Groningen group a precise way to estimate muscle mass. Since creatinine is produced from creatine at that fixed rate of 1.6 to 1.7 percent per day, and nearly all creatine lives in muscle, the total creatinine appearing in a patient’s dialysate and any remaining urine works as a gauge of how much muscle they still carry.
The survival data attached to this measurement are stark. In the group’s published cohort, patients were divided into thirds by creatinine excretion rate. Over roughly two years of follow up, 62 percent of patients in the lowest third died. In the middle third, 7 percent died. In the highest third, none did. Bakker summarized it in the talk as only around 40 percent of the lowest group surviving two years, which matches the published figures. He argues the association holds after statistical adjustment for other factors, though it is worth saying plainly that this was a cohort of around 40 patients, so the finding, while dramatic, comes from a small study, and low muscle mass in these patients partly reflects other illness as well.
Still, the broader point is well supported across nephrology: in dialysis populations, markers of muscle mass, including serum creatinine itself, consistently predict survival. Muscle in these patients is not cosmetic. It is reserve capacity for surviving infections, hospitalizations, and the relentless catabolic stress of the treatment itself. Anything that silently erodes it deserves attention, and an ongoing creatine deficit is a plausible contributor.
Lessons From a Rare Genetic Disorder
If creatine deficiency really damages muscle and brain, nature has already run the experiment. A small number of children are born with genetic AGAT deficiency, meaning they carry the same enzymatic gap that Bakker believes dialysis patients acquire, but from birth and for genetic reasons.
The natural history of the condition is grim: untreated children develop intellectual disability, severe language impairment, and muscle weakness. Their brains, measured by spectroscopy, are nearly empty of creatine. In the womb they develop normally, because creatine crosses the placenta from the mother, which is a striking demonstration in itself that external creatine can substitute for internal production.
The treatment findings are even more instructive. Children diagnosed late and started on creatine in childhood show restored brain creatine, meaningful improvement in muscle strength, and only partial cognitive recovery. But in a published case where a boy was identified at birth, thanks to two affected older sisters, and started on creatine at four months of age, he showed normal psychomotor development, in sharp contrast to his sisters. Early, presymptomatic creatine supplementation appears to prevent the damage that late treatment can only partly undo. Bakker described this in the talk as the model for what he fears in dialysis: he joked darkly that dialysis seems to dialyze the muscles and the brains out of patients, and the genetics of AGAT deficiency show that a body cut off from creatine synthesis does suffer exactly in muscle and brain.
The analogy has limits. Dialysis patients are adults with developed brains and decades of normal creatine nutrition behind them, not infants; nobody expects effects of the same magnitude. But as proof that endogenous creatine synthesis matters, and that supplementation can fully compensate when started before damage accumulates, the genetic evidence is about as direct as biology gets.
Fatigue, Mood, and the Brain
Muscle is only half of the argument. The other half concerns how dialysis patients feel and think, and here the numbers deserve to be better known.
Fatigue is arguably the defining symptom of life on dialysis. Bakker’s published review cites a survey finding that captures its weight better than any scale: 94 percent of hemodialysis patients said they would accept more frequent dialysis if it increased their energy levels, while only 19 percent would do so for a survival gain of up to three years. In other words, most patients would trade treatment burden for feeling less exhausted far more readily than for living longer. Alongside fatigue sits protein energy wasting, the progressive depletion of the body’s protein and energy stores, which affects an estimated 50 to 75 percent of hemodialysis patients and is tied to worse survival and quality of life. Depression and cognitive impairment are also common, and impaired cognition creates its own downstream harm, since patients who struggle with memory and attention find it harder to follow the strict fluid limits, dietary rules, and medication schedules their condition demands.
Creatine is relevant to this cluster of problems because the brain is one of the most energy hungry organs in the body and runs on the same phosphocreatine buffer as muscle. This is not merely theoretical. A pooled analysis of randomized trials found that creatine supplementation improved memory in healthy people overall, with a notably stronger effect in adults aged 66 to 76 than in the young. A separate 2024 pooled analysis reached a similar verdict: meaningful gains in memory and processing speed, no clear effect on overall cognition, and only moderate certainty even for memory. On mood, the evidence is weaker still but intriguing. In a nationally representative American survey of more than 22,000 adults, depression was roughly 70 percent more prevalent among people in the lowest quarter of dietary creatine intake than in the highest, an association that survived adjustment for income, health access, activity, and medication use. Association is not causation, and small clinical trials of creatine for depression, mostly in women, remain preliminary.
Bakker’s review adds two further, more speculative possibilities, which we flag as exactly that. Creatine has been proposed to support immune cell function, which could matter in a population highly vulnerable to infection. And laboratory work suggests creatine helps protect red blood cell membranes from oxidative and mechanical stress, of the kind dialysis inflicts every session; if that held up clinically, it might reduce the doses of erythropoietin these patients need for anemia. Neither idea has been tested in dialysis patients. But they illustrate why the researchers consider creatine worth studying across so many outcomes at once: the compound sits at the crossroads of energy metabolism in precisely the tissues, muscle, brain, blood, and immune system, where dialysis patients struggle most.
The Plant Based Diet Factor
There is a further twist that makes this topic timely. The main dietary sources of creatine are meat and fish. Plants contain essentially none. Anyone moving toward plant based eating is therefore shifting the entire creatine burden onto their own internal synthesis, which is exactly the capacity that kidney disease destroys.
Two trends are converging here. The first is general: plant forward eating is growing across the population, and survey data suggest creatine intake is already modest for many people. An analysis of United States national nutrition data estimated that about 43 percent of adults consume less than one gram of dietary creatine per day. Research on vegetarians consistently finds lower creatine concentrations in muscle, plasma, and red blood cells compared with omnivores, though brain levels appear preserved, and shows that supplementation readily restores and even exceeds omnivore levels.
The second trend is specific to kidney medicine. Modern nephrology guidance increasingly encourages plant based diets for chronic kidney disease patients, for good reasons: plant foods deliver less phosphorus and less dietary acid, both of which are genuine problems in kidney failure. Bakker does not dispute those benefits. His point is narrower and worth hearing: a diet with no creatine, prescribed to patients with no capacity to synthesize creatine, who are simultaneously losing creatine into a dialysis machine three times a week, closes off every route by which the body maintains its creatine pool. The amino acid building blocks in plant foods do not help, because the enzymatic machinery to use them resides in the kidneys the patients no longer have. Healthy people on plant based diets keep making their own creatine. Dialysis patients on plant based diets, in Bakker’s framing, are left with almost nothing coming in at all.
Is Creatine Bad for Your Kidneys?
Now for the myth that hangs over this entire topic. The idea that creatine harms the kidneys comes almost entirely from a misunderstanding of blood tests. Creatine supplementation enlarges the body’s creatine pool, and since a fixed percentage of that pool degrades to creatinine daily, blood creatinine rises modestly. Because doctors use creatinine as a marker of kidney function, a supplement user’s routine lab work can look, at a glance, like early kidney trouble even when the kidneys are working perfectly.
The trial evidence is reassuring. A recent systematic review and pooled analysis of the randomized and observational literature concluded that creatine at standard doses modestly raises serum creatinine without evidence of actual kidney injury, and judged it likely safe for kidney function in healthy people and in the clinical populations studied. Reviews of creatine safety reach the same conclusion for healthy users while consistently adding a sensible caution: evidence is thinner in people who already have kidney disease, and those individuals should involve their medical team rather than self experiment. It is also worth knowing that creatinine based estimates of kidney function will read lower while supplementing, purely because of the extra creatinine load; measured filtration methods that do not rely on creatinine do not show this artifact.
So the honest summary runs opposite to the popular fear. For healthy kidneys, creatine at recommended doses has no demonstrated harmful effect, only a cosmetic effect on one lab number. And in the sickest kidneys of all, the emerging research question is not whether creatine is dangerous but whether its absence is.
Creatine in the Dialysis Fluid
Which brings us to the actual experiment. Bakker’s team is not proposing that dialysis patients simply take creatine powder. Oral supplementation in these patients has drawbacks: it typically means dissolving doses in significant volumes of water, and fluid intake is tightly restricted in dialysis; it demands lifelong daily compliance; and it does nothing to stop losses into the dialysate. Their alternative is elegant: dissolve creatine directly into the dialysis fluid itself. During a session, instead of creatine diffusing out of the blood into the fluid, it would diffuse from the fluid into the blood. The treatment that causes the loss becomes the delivery mechanism, with no extra fluid, no pills, and no compliance problem, since supplementation happens automatically whenever the patient shows up for the dialysis that keeps them alive.
The pilot study he presented is deliberately small and cautious: 16 hemodialysis patients in four ascending dose groups, receiving creatine concentrations of 0.5, 1.0, 1.5, or 2.0 millimoles per liter in the dialysate, with three patients on creatine and one on placebo in each group, in a randomized, double blind, placebo controlled design. Treatment runs six weeks, followed by a two week washout. The primary question is simply whether creatine gets in: the main endpoint is the creatine concentration inside red blood cells, used as a stand in for tissue uptake, alongside plasma levels. Secondary measures cover the outcomes that would ultimately matter: muscle mass and grip strength, physical performance, cognitive function, and questionnaires on fatigue, depression, frailty, and quality of life.
Two prior small trials of oral creatine in dialysis patients offer encouragement. In one double blind study of ten patients with frequent dialysis associated muscle cramps, creatine before sessions cut cramp frequency by 60 percent, with the benefit disappearing after washout. In another, with 30 patients, four weeks of creatine improved lean body mass and malnutrition inflammation scores versus placebo. Both were small pilots, and neither tested cognition, fatigue, or survival.
One disclosure belongs in any honest account: Bakker stated in the talk that the pilot is conducted and funded in partnership with a company holding a patent on intradialytic creatine supplementation, and the published review likewise discloses that a coauthor consults for that company, Crearene. That does not invalidate the science, the deficiency data stand on their own in peer reviewed journals, but readers should know that commercial interest and scientific enthusiasm are traveling together here, as they often do in translational research.
So where does the evidence honestly stand? That dialysis patients are creatine depleted is well documented by direct measurement. That creatine supports muscle when combined with resistance training, including in older adults, is backed by pooled trial data. That creatine may help memory, particularly in older people, is promising but not settled, and the links to depression are observational only. But the central claim, that supplementing creatine will actually improve how dialysis patients feel, function, think, and survive, is at this point a well argued hypothesis awaiting trial results, which is why this article carries an evidence rating of early. Bakker told his audience he expects a breakthrough. He may be right. Until the randomized data arrive, the accurate statement is that researchers have found a real, measurable deficiency, a biologically plausible mechanism, and a clever delivery method, and are now doing exactly what should be done: testing it properly.