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The renewed popularity of carbohydrate-restricted diets for obesity and related metabolic diseases resulted in a resurgence of ancestral-type diets that are higher in protein. This trend has brought back attention to an area of contention: the effects of a high-protein intake on kidneys.
Protein and Kidneys
Protein and its array of amino acids are the primary building blocks of muscles, bones, enzymes and many hormones, so maintaining sufficient protein intake is essential. But, a wave of research dating back to the 1980s suggested that consistently eating more than the body requires to run and repair itself may put a strain on kidneys.
The main topic of debate has to do with the metabolism and excretion of protein byproducts. One such byproduct is urea, a metabolite created from the conversion of ammonia by the liver following protein digestion. Urea gets sent to the kidneys, and it is usually readily filtered out.
However, according to a theory developed by a now-famous Harvard researcher named Barry Brenner, there is an upper limit of urea that can be safely excreted. Brenner argued that too much urea from excessive protein intake could overload the filtration unit of the kidney—known as glomerulus—and cause long-term renal injury .
The "Brenner Hypothesis" subsequently made its way into nutrition textbooks and guidelines despite the low certainty of the evidence surrounding these effects. Brenner's research used animal data and people with existing renal disease and might not apply to a healthy population.
As new scientists built upon Brenner's studies, they found that the kidneys adapt in response to varying protein consumption by increasing their filtration rate (eGFR) or physically expanding in size .
These adaptations were initially thought—by Brenner and others—to be signs of strain or damage. The majority of researchers invested in this field now seem to believe that they are normal and thus non-threatening .
Most of the data also does not support an increase in kidney problems amongst athletes, like bodybuilders, who consume much more significant amounts of protein than the average population. One study found no damage in the kidneys of athletes who habitually consumed protein over three times the RDA (0.8 g/kg/day) for a decade .
Prolonged intake of a large amount of protein may only be an issue in those with pre-existing kidney dysfunction . Some research suggests that protein intake often has to be reduced to prevent further disease development.
Kidney dysfunction encompasses people with renal failure, suffering from kidney stones or somewhat predisposed to kidney damage. In these individuals, reducing protein intake exerts a beneficial effect on kidney function because it alleviates the additional workload imposed on the kidney.
Another hypothesis for the interplay of high protein intake and kidney damage is the mTOR pathway, one of the body's most critical signaling pathways . When over-activated, mTOR can promote abnormal cellular events affecting excretory processes in the glomerulus .
There is significant heterogeneity between studies evaluating risk and questionable evidence for dismissing possible harmful effects. The context and specifics of intake are often not clearly stated or accounted for in all of these studies.
The studies also rely on suboptimal food questionnaires wherein the difference between the highest quartile of protein intake and the lowest intake is dismal (sometimes only a dozen grams per day).
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Comparing Normal- and High-Protein Diets in Healthy People
A small study of 14 trained individuals looked at how normal and high-protein diets compared to each other in terms of kidney risk markers .
The participants were men aged between 22 and 30 years old who had been doing resistance training for an average of 9 years before the start of the study.
In random order, each participant followed six months of a regular and high-protein diet. But, there was no washout period as is customary with crossover trials.
The standard diet saw the participants eating between 1.8 and 3.2 g of daily protein per kilogram of bodyweight. The high-protein diet saw them having up to 4.2g of protein/kg/day. During the high-protein phase, the extra protein was either supplemented from whey protein powder or obtained from dietary sources of their choice.
The researchers collected dietary self-reports for total energy and protein intakes via the MyFitnessPal app to facilitate recordkeeping.
Participants were tested at the start and on four subsequent occasions to assess each diet phase. The lab tests looked at eGFR; blood urea nitrogen (BUN), which indicates poor urea clearance by the kidney when high; creatinine, an indicator of filtering capacity; BUN to creatinine ratio, a sign that blood urea nitrogen is rising if elevated; serum albumin, a marker of kidney damage in lower concentrations; and electrolyte (Na, K, Cl) imbalance, which is a sign of advanced renal disease.
No significant differences were found in kidney risk markers between the high-protein and normal protein phases. While the mean eGFR increased slightly in both phases, this increase was more pronounced during the normal protein phase.
The increase in protein only raised eGFR by 3 mL/min. A normal eGFR is greater than 90 mL/min, and the high-protein data shows 98 mL/min. The urea/BUN ratio, BUN/creatinine ratio, creatinine and albumin levels stayed unchanged and in range throughout the experiment. Electrolytes were in the low normal range in both the standard and high-protein phases.
The caveats of this research are two-fold. First, the study is small and not randomized. Secondly, its first author, Jose Antonio, contributed a lot of studies to the literature on this topic with a very similar study design. He also happens to be the International Society of Sports Nutrition CEO. He is relatively opinionated about the superiority of higher protein diets in athletes and the general population.
Effect of Substituting Protein for Carbohydrates on Kidneys
Researchers at Johns Hopkins University conducted an ancillary study of OmniHeart, an NIH-sponsored trial investigating the overall health effects of three DASH-type diets with different macronutrient breakdowns .
The team ran some cutting-edge tests for kidney function based on separate samples from 164 healthy adults aged 30 and above participating in OmniHeart for six weeks.
The trial used a different definition of "high" protein intake than the unit of mass per bodyweight. In OmniHeart, the protein intake was either 15% (carbohydrate and unsaturated fat diets) or 25% (protein diet) of energy intake. For reference, protein intakes greater than 15% of total energy and as high as 35% of total calories qualify as high-protein diets .
The researchers looked at the effects of replacing carbohydrate and, to a lesser extent, unsaturated fat with protein on kidney function. The study is especially interesting because they opted for measures not typically seen in similarly-designed studies of high-protein diets and renal outcomes.
Instead of solely looking at eGFR or creatinine, they incorporated testing for "novel" markers like serum cystatin C and β2-microglobulin (B2M). These markers are considered more accurate and, thus, superior in detecting impaired kidney function.
There are two reasons why this is the case. First, cystatin C and B2M are unaffected by changes in blood creatinine naturally occurring from changing protein intakes. This means that they are more representative of decreased clearance by the kidneys. It also adds a layer of precision to calculations of eGFR, which is calculated from creatinine.
Second, cystatin C values have to differ by at least 37% of the reference mean value to show a change. In comparison, the equivalent value for serum creatinine is only about 14%.
This type of study also provides more meaningful data because it happens in metabolic ward-like conditions, where all meals were provided instead of complete free-living conditions.
The values for creatinine, B2M and cystatin C-based eGFR were compared as between-diet contrasts and against values for end-of-period measurements. Notably, the between-diet differences accounted for blood pressure and blood sugar control, both of which can sway results about kidney function.
The protein diet was associated with an increased eGFR (of about 4-5 mL/min between diets and 3.81 mL/min from baseline), independently of blood pressure. Cystatin C, B2M, and creatinine levels were lower at the end of the protein diet than the carbohydrate or unsaturated fat diet, which is good.
Impact of Short-Term "Protein Loading" on Healthy Kidneys
One research group tested whether drastically increasing protein intake in a short time leads to more changes in the kidneys than gradually changing protein intake . Research had proven this to be true in animals, when protein increased from 10-15% of calories, up to 35-45% of the diet [15,3].
This human study had 24 adults between the ages of 21 and 30 double their protein intake—from 1.2 g/kg to 2.4 g/kg—in the space of two weeks. Upon initial screening, the participants did not have kidney disease or were hypertensive.
In a crossover design, all participants followed the two diet protocols (1.2 and 2.4 g/kg of protein, respectively) for seven days each. A dietitian individually advised them to meet their protein intake requirements with real foods and under isocaloric conditions.
The researchers collected fasting blood and 24-hour urinary samples as part of their assessment on day 7 of both diets. The study estimated the GFR based on tests other than creatinine.
They used sinistrin, which is injected into participants to measure GFR. The kidneys will filter and excrete only half as much of the sinistrin if there is damage.
Other tests included BUN, albuminuria, renal blood flow, standalone creatinine and angiotensin. As measured in the study, Angiotensin II levels usually rise to maintain GFR when kidney workload increases.
The results showed that immediately going from an intake of 1.2 g/kg to 2.4 g/kg of daily protein is associated with higher than average blood values of protein metabolites. Specifically, BUN and uric acid concentrations were significantly higher in the high-protein diet phase.
Blood creatinine levels did not change when switching to a high-protein intake. Creatinine clearance, however, was elevated, which shows that the kidneys are working to their total capacity.
A trend was noted for adaptation in increasing sinistrin-based GFR, too. Still, it was not enough to clear uric acid and BUN over seven days. Importantly, urinary albumin was more than twice as high for participants in the high-protein phase. Renal blood flow and angiotensin II stayed unaffected for the most part.
The study challenges previously held assumptions about the harmful effects of protein intake on renal function taking longer to manifest and not being detectable in shorter-term studies.
This study is likely indicative of a "too much, too fast" situation. Controlled changes tend not to lead to adverse changes in kidney function . Until some evidence to the contrary comes to light, it may be prudent to change protein intake by small increments over time.
Nuanced, Individual Differences in Lifestyle
All three studies show evidence that there are functional changes in the kidneys related to varying protein intake but that these interactions have, for the most part, no apparent ill effects on kidney health. This suggests that we can put to rest the notion that high dietary protein is harmful to the kidneys.
In future studies, inter-individual differences in healthy populations need to be accounted for more accurately. The onus is on the author to convey an accurate impression of these differences and how they might impact outcomes before beginning the statistical shenanigans.
Acknowledging these differences also ensures that the effect has only one cause. Certain lifestyle choices often go hand-in-hand with the consumption of high-protein diets. They could conceivably be the real underlying causes or contributors to protective effects in the kidneys.
For example, it seems impossible to tease out the effects or absence of harm thereof of high-protein diets. People eating this way are the people by and large who care more about their health.
Similarly, as with most studies on renal function and high-protein diets, the research is performed on athletes (lifters). And we know that resistance training confers some protection against adverse renal outcomes .
Inter-individual variations in the expression of genes that govern amino acid metabolism, though rare, can potentially affect outcomes, too.
The most severe genetic susceptibilities, like urea cycle defects, are often asymptomatic through adulthood until dietary changes (protein supplementation) or metabolic demands (intense exercise) force a greater protein turnover rate. Whether gene variations affect the response to high protein levels remains largely unexplored but critically important.
Another limitation is that the definition of high-protein is unclear across-the-board. Researchers are looking for a dose relationship to ascertain the cause and effect of protein on renal functional changes.
Findings that show the risk of kidney damage from protein increases linearly with the amount of protein taken daily are more convincing.
There is a lack of agreement with what constitutes a "high" protein intake. Some studies define "high-protein" as 1.1+/-0.2 g/kg body weight, while others equate it to doses greater than 4 g/kg/day .
A different factor that is equally important but not addressed as often is the glycemic response to food. The Brenner studies were conducted in the context of a diet high in carbohydrates. The data tends to support that concomitant low to normal-carbohydrate intake with high protein does no harm.
The type of protein used matters, too, as it affects kidney function differently. Non-dairy animal proteins are thought to be more harmful. They can induce a greater hyper-filtration than the plant-based kind .
Putting It All Together
The belief that high protein diets damage the kidneys primarily stems from the fact that restricted protein diets are recommended for those with kidney damage, as it slows disease progression. However, at best, there is a weak case for any adverse effects in individuals with healthy kidneys.
Consuming up to approximately 4 g/kg/day appears to pose no increased health risk when kidney function is normal. More high-quality research is needed to establish interactions in terms of direction (increasing/decreasing protein) and magnitude.
Multiple studies using different designs showed similar findings regarding the adaptive effects of varying protein intake. Kidney work (GFR) routinely goes up, and kidney markers either do not change or change in a non-statistically significant way.
In light of the findings of uncontrolled changes in protein intake, the only caveat may be to avoid jumping in both feet at a time. However, the literature on this topic is still relatively scarce.
In future studies looking at high-protein diets and renal health, energy and macronutrient intake and lifestyle choices should be carefully considered.
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© 2022 Camille Bienvenu