Photo Credit: Jacob Wackerhausen

Greater protein intake in chronic kidney disease may lower mortality, and clinicians should routinely evaluate food intake with attention to energy and protein.

Older people with mild to moderate chronic kidney disease who eat more protein may have decreased mortality, according to findings published in JAMA Network Open.

Carla Maria Avesani, PhD, and colleagues analyzed data from 3 cohorts of community-dwelling adults 60 years or older with and without CKD. The researchers examined cumulative protein intake reported in validated dietary histories and questionnaires, and they recorded 10-year all-cause mortality from national death registers. They determined CKD by estimated glomerular filtration rates, urine albumin excretion, and diagnoses from medical records.

Dr. Avesani and Yelena Drexler, MD, MS, a nephrologist who was not involved in the study, shared their thoughts about the results with Physician’s Weekly (PW).

PW: Why was it necessary to conduct this study?  

Dr. Drexler: This study was important because of the knowledge gap regarding the overall health impact of limiting protein intake in older persons with mild or moderate CKD. According to current guidelines, adults with moderate CKD should restrict their protein intake to 0.6-0.8 g/kg per day based on evidence that a modest protein restriction may slow the progression of CKD and have favorable metabolic effects.

However, evidence regarding the benefit of protein restriction in older persons is limited. Moreover, among older adults with mild to moderate CKD, the benefits of protein restriction to delay CKD progression need to be balanced against the potential risks of protein restriction on sarcopenia and frailty.

A related area of research interest is the impact of the protein source, particularly whether a diet high in plant protein can provide the benefits of higher protein intake while mitigating the negative metabolic effects of high animal protein intake in older adults with CKD.

What are the study’s most important takeaways?

Dr. Avesani: If an older patient with stage 3 CKD spontaneously reduces their protein intake, they need to see a dietitian who can adjust their protein and energy intake to match their nutritional needs, and they need to be followed over time.

Some researchers and clinicians are misinterpreting our findings as saying that low-protein diets for older patients with CKD need to stop. However, the current paper has a cohort of patients different from those who receive dietary counseling to follow a low-protein diet. As we wrote, “The biological actions of protein sources could depend on total protein intake and the proportion of plant protein in the diet. Not only did 68% of total protein come from animal sources in our study, but the mean (SD) protein intake was well above the current recommendations for persons with moderate CKD. This may impair the generalizability of our findings to older adults following plant-based and/or low protein diets, and it is uncertain whether these results could be applied to persons with severe CKD.”

Did the results surprise you?  

Dr. Avesani: We were not sure what we would find. However, our initial hypothesis was that patients with lower spontaneous intake could be at risk for higher mortality because individuals with spontaneous low protein intake carry other nutrition conditions and dietary deficiencies that, as a whole, can increase mortality risk. I had expected plant-based and animal protein to have different effects on the association with mortality risk, but they did not. 

Dr. Drexler: Overall, the study results should not be too surprising since restriction of protein intake has not been consistently shown to reduce mortality among older adults with CKD.

While moderate protein restriction may slow the progression of CKD, this might be less relevant to an older population with mild to moderate CKD. For example, even a moderate slowing in the rate of GFR decline would not necessarily translate to a mortality benefit in someone older than 75 years of age with CKD stage 3 due to competing risk of death from reasons other than kidney failure.

On the other hand, a few of the results were somewhat surprising, including (1) that a “high” protein diet (I.e., 1.60 vs. 0.80 g/k/day), a level that even adults with mild CKD are advised to avoid, was associated with the lowest mortality risk, and (2) that the associations of plant protein intake and animal protein intake with mortality were equally strong (i.e., there was no signal that plant protein intake was any more beneficial than animal protein intake, except in the ancillary analyses where increasing plant protein intake over time (but not total or animal protein) was associated with lower mortality.

PW: How might the findings affect patient care? 

Dr. Avesani: Be aware and routinely evaluate the individual’s regular food intake with attention to energy and protein. For example, might the patient with spontaneous low protein intake also be malnourished? If yes, do not prescribe a low-protein diet. Instead, prioritize adjusting their energy and protein intake, treating malnutrition with adequate energy and protein intake, or both, until the patients are well nourished.   

Dr. Drexler: These findings may affect patient care because, despite guidelines recommending moderate dietary protein restriction in adults with moderate CKD, the benefits of protein restriction in older adults have not been definitively established in randomized controlled trials.

Clinicians may seek additional data on the risks and benefits of dietary protein restriction in older patients with mild to moderate CKD. While these findings cannot establish a definite causal relationship between higher protein intake and lower mortality, they might provide some reassurance to clinicians who feel that their patients may benefit from higher protein intake, especially if they are frail or need to increase their protein intake for other reasons (such as building muscle mass or recovering from illness). It was reassuring to see that higher protein intake was not associated with increased risk for mortality in this population.

PW: What limitations of the study are noteworthy?

Dr. Avesani: We did not have longitudinal dietary information from all participants, nor did we know whether providers had given protein intake targets to their patients with CKD. Being an observational study, we could not completely separate protein intake from other nutrients. Many variables were self-reported, and some were not accounted for. Additionally, measured GFR was not available from any cohort. Because most CKD cases were found through estimated GFR, we could not determine differences between CKD causes and transient and chronic declines in kidney function.

Dr. Drexler: This study’s major limitation is its observational design, which cannot definitively determine whether modifying protein intake will reduce mortality in older adults with CKD.

In particular, we cannot rule out ‘reverse causation.’ For example, a patient with frailty and other risk factors for mortality may have lower protein intake due to poor appetite and diet, resulting in an inverse relationship between protein intake and mortality due to their underlying condition rather than the effect of protein intake per se.

The ability to generalize results from predominantly White participants in Sweden and Spain to a diverse US population is also limited.

Finally, we should acknowledge the possibility that some older adults with normal age-related GFR decline may have been misclassified as having CKD based only on an estimated GFR below 60 without other signs of kidney damage. Conversely, some older adults with CKD and a lower serum creatinine due to lower muscle mass may have been misclassified as having “normal” estimated GFR when they did have CKD. 

PW: What questions remain unanswered for you?

Dr. Drexler: This study is important and certainly generates hypotheses. A major unanswered question is whether prescribing a diet with higher vs. lower protein intake would result in lower mortality in a prospective study of older adults with CKD. Such a trial would help settle the issue of whether older adults who spontaneously have higher protein intake have lower mortality due to better appetite and overall health or whether higher protein intake itself is protective.

Similarly, to determine whether higher plant protein intake relative to animal protein intake is associated with lower mortality risk, randomized studies that compare different protein sources while maintaining comparable levels of total protein intake and total caloric intake are needed.

Based on this study alone, I would caution against changing one’s practice or making definitive recommendations about high-protein diets in older adults with CKD. Prospective, randomized trials are needed to establish whether modifying the total, plant, and animal protein intake amounts can reduce mortality among older individuals with CKD.

Dr. Avesani: Do our findings apply where protein intake is lower or where plants are the main protein source? I would also be curious to investigate the association of spontaneous protein and energy intake with changes in muscle health markers such as muscle mass and function.

Studies in older adults with severe CKD and ethnically diverse populations are needed, as are randomized trials that examine whether modifying protein intake affects mortality in older persons with CKD.