To restrict or not to restrict – Understanding the conundrum of dietary protein restriction in chronic kidney disease

Introduction

Historically, protein restriction is one of the earliest interventions in the management of chronic kidney disease (CKD) and is still widely practiced by physicians, nutritionists, and patients dealing with this illness. However, protein restriction in patients with CKD is a contentious subject. Experimental studies[1] and multiple uncontrolled studies claimed the benefit of protein restriction,[2,3,4,5] but findings from randomized controlled trials have been largely negative or inconclusive.[6,7,8]

Unlike the era when trials of protein restriction were done, in today’s clinical practice, multiple interventions, supported by robust evidence, are available to retard the progression of CKD, such as blood pressure control, renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibition, and aldosterone receptor antagonists.[9] Also, in those with advanced kidney failure, rehabilitation with better dialysis or kidney transplant is widely available. Severe protein restriction carries the risk of malnutrition and associated complications. Severe protein restriction may alleviate symptoms of uremia in patients who chose not to avail renal replacement therapy for some reason and is no longer the primary pillar of treatment of CKD. However, the latest National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) 2020 guidelines made a strong recommendation for protein restriction (Grade 1A).[10] We argue that this statement is not supported by an adequate evidence base, is difficult to implement, and can be associated with potential harms. This review primarily concerns patients with non-diabetic CKD as data on protein restriction are very limited in diabetic CKD.[11]

Historical Background and Physiological Rationale of Protein Restriction

High protein diets in partially nephrectomized rats were harmful-manifesting as glomerulosclerosis, proteinuria, renal failure, and death. As early as the 1930s, Chanutin and colleagues[1] demonstrated that restricting dietary protein reduced histologic damage in kidneys and blood pressure in rats with CKD, while improving their survival. Similar results were shown by subsequent large-scale animal experiments. Unilaterally nephrectomized rats and one and one-third nephrectomized rats had a higher degree of proteinuria and higher incidence of glomerulosclerosis upon exposure to the high protein diet.[12] With a high calorie and minimum protein diet, urea excretion could be dramatically reduced and even an anuric patient with acute renal shutdown could be maintained without renal replacement therapy for over 3 weeks before ultimate recovery of the kidney function.[13]

A report in 1962,[14] describing the effect of protein restriction in eight patients with uremia, concluded that although a low-protein diet seemed to be beneficial in the subjects with regard to improvement of uremic symptoms and biochemical parameters, this had to be weighed against a significant risk of protein depletion, especially in long-term treatment of patients with CKD not on dialysis. These observations were supported by small-sized uncontrolled studies.[3,4]

Data from animal studies and observational studies in humans led to the famous Brennan hyperfiltration hypothesis[15] of CKD progression and interest in protein restriction as an intervention for CKD increased.

Nitrogenous wastes are the products of protein catabolism and start accumulating in blood with declining kidney function in CKD. So, prima facie, a low-protein diet may reduce ‘renal work’ and decrease the uremic solute concentrations. The mechanism of glomerular hyperfiltration after a high-protein diet is presumed to be mediated by afferent arteriolar vasodilation,[16] and protein restriction is expected to act on an axis similar to SGLT2 inhibitors, that is, afferent arteriolar vasoconstriction.

Phosphate, contained in high-protein food, such as meat and cheese, is retained in CKD and is associated with the vascular calcification, left ventricular mass, cardiac fibrosis, and CKD progression.[17]

Guidelines

The most recent guidelines are those given by the 2020 update to the KDOQI Clinical Practice Guideline for Nutrition in association with the Academy of Nutrition and Dietetics.[10] Most other guidelines recommend almost the ‘normal’ protein diets similar to the WHO-recommended protein intake for the general population, that is, 0.83 gm/kg/day[18] [Table 1].

Table 1.

Recommendation on protein intake in CKD by various guidelines

Guideline	Patient group	Recommended Dietary Protein Intake	Quality of evidence
KDOQI (2020)[10]	CKD stage 3–5, not on dialysis, non-diabetic	Low protein diet-0.55–0.6 gm/kg/day, or a supplemented very low protein diet- 0.28–0.43 gm/kg/day	1A
	CKD stage 3–5, not on dialysis, diabetic	0.6-0.8 gm/kg/day	Opinion
	CKD on dialysis, non-diabetic	1-1.2 gm/kg/day	Opinion
	CKD on dialysis, diabetic	1-1.2 gm/kg/day	Opinion
KDIGO guidelines (2012)[19]	Non diabetic CKD, with GFR <30 ml/min/1.73 m2	0.8 gm/kg/day	2B
KDIGO guidelines (2020)[20]	Diabetic CKD, not on dialysis	0.8 gm/kg/day	2C
2004 CARI (Caring for Australians and New Zealanders) guidelines[21]	Patients with progressive CKD	Not lower than 0.75 g/kg/day, with at least 50% high biological value protein and an energy intake of at least 35 kCal/kg/day	2
2009-2010 UK Renal	Stage 4-5 CKD, not on dialysis	0.75 gm/kg/day	2B
Association Guidelines[22]	Stage 5 CKD on dialysis	1.2 gm/kg/day	2B

Unlike all other guidelines,[19,20,21,22] where protein restriction is a suggestion (where different choices will be appropriate for different patients), KDOQI 2020 guidelines make a strong recommendation (where most patients should receive the recommended course of action).

Is this recommendation well supported by evidence? Can protein restriction be safely used in most patients with CKD? We critically analyze the available evidence on this topic in the following sections and highlight the limitations of the evidence supporting this recommendation and possible harms of wide application of protein restriction in CKD. Protein-restricted diets are typically classified as low-protein diet (LPD) and very-low-protein diet (VLPD) and refer to protein intake of about 0.6 gm/kg/day and 0.3 gm/kg/day, respectively.

Large and rigorously done trials showed no benefit of protein restriction

Most trials evaluating this intervention were limited by a small sample size: for example, only three of the six studies included in the latest Cochrane review,[23] which compared the impact of protein restriction on end-stage kidney disease or death enrolled more than 100 participants. This significantly limits the power of the studies, and conclusions derived therefrom cannot be considered definitive. The larger studies were either negative or inconclusive, for example:

In a multi-center trial,[6] conducted across 21 nephrology units in Italy, 491 patients (stratified into three groups as per severity of CKD) were randomized to controlled protein diet versus low-protein diet. While there was a borderline difference in renal survival in two of the three groups, no differences among the diet groups or sub-groups were observed with regard to mean plasma creatinine concentrations, creatinine clearance, and the slope of the plasma creatinine reciprocal. Notably, the low-protein diet group had poor adherence to the prescribed protein restriction. Proteinuria (and not the dietary protein intake) was independently associated with CKD progression. Authors concluded that their findings offer little, if any, support to the hypothesis that protein restriction retards CKD progression and careful medical care and a “normal” protein intake also allow very slow progression of CKD.

In Modification of Diet in Renal Disease (MDRD) trial,[7] which is by far the largest trial, 840 participants with CKD were randomized: 585 patients (with glomerular filtration rate (GFR) of 25 to 55 ml per minute) to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and 255 patients (with GFR of 13 to 24 ml per minute) to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement. The slope of GFR decline was the primary outcome of the study, and outcome assessment was complicated by the fact that there was faster decline in GFR in the initial months and slower decline in later months of the study with protein restriction. Overall, CKD progression was slow and the number of patients reaching the stage of kidney failure did not differ in any group.

Finally, a 2020 meta-analysis[23] involving the 17 studies with 2996 analyzed participants with non-diabetic CKD concluded that an LPD does not decrease the risk of dialysis or death and a VLPD probably reduces the number of people with CKD 4 or 5, who progress to end-stage renal disease (ESRD). However, in patients with CKD stage 3, restriction to low-protein diets makes very little or no difference. Authors highlighted the need for studies evaluating the adverse effects and the impact on quality of life of dietary protein restriction before these dietary approaches can be recommended for widespread use. The certainty of the evidence for end or change in GFR and body weight in this meta-analysis was assessed as very low.

Efficacy and effectiveness of protein restriction as a tool to retard CKD progression

Efficacy and effectiveness are the key metrics in determining the utility of health care interventions. Is protein restriction efficacious? In other words, does it work in clinical trials? Several issues limit the internal validity of the experimental and clinical trials of protein restriction. First, the animal data highlighting the benefits of restricted protein intake have used a very-high-protein diet (and not a normal protein diet) as a comparator. Second, even in the controlled scenario of the randomized trial, ensuring adequate separation between the groups regarding protein intake was difficult in most of the trials. As depicted in Table 2, only half or even less than 50% of the intended difference in the protein intake could actually be obtained in the dietary protein intake of the control and intervention arms of many trials. Locatelli et al.[6] found that in patients assigned to a low-protein diet, there was a median protein over-intake of 39.8% calculated by the 24-hour urea excretion method and 21.6% by the dietary interview method. They further found that the difference in protein catabolic rate between the study groups was much lesser that what was foreseen by the protocol. This significantly limits the generalizability of the results. Issues related to the measurements of the efficacy are discussed later.

Table 2.

Disparity in the intended and actual differences in protein intake in various randomized controlled trials

Study	Intended difference in protein intake	Actual difference in protein intake
Locatelli 1989[6]	0.4 g/kg/day	0.18 g/kg/day
MDRD 1989[7]	0.72 g/kg/day	0.4 g/kg/day
Bergstrom 1986[24]	0.45 g/kg/day	0.21 g/kg/day
Meloni 2004[25]	0.4 g/kg/day	0.87 g/kg/day
ESGCMCRF 1990[26]	0.4 g/kg/day	0.12 g/kg/day

Note that the actual difference in the protein intake of the two arms of many trial participants is less than prescribed

Close follow-up assessment by nutritionists is important to ensure compliance to the diet and prevent development of malnutrition. For example, in the MDRD trial,[7] baseline and monthly nutritional assessment was done for the first 3 months and subsequently bimonthly until the last follow-up. In addition, patients were seen by principal investigators every month. Such monitoring on protein-restricted diets is even more challenging in the real-world clinical settings. For these reasons, effectiveness (a measure of whether the intervention works in real-life clinical practice) of protein restriction is further limited. Practical difficulty of advising protein restriction was also highlighted by a study by Garneata et al.,[27] which randomized patients to a conventional LPD and a VLPD supplemented with keto analogues. They reported that keto analogue supplemented diet was nutritionally safe and may offer some benefit in deferring dialysis in CKD patients. All patients who were screened for this study were first advised a run-in period with a low-protein diet only. However, only 14% of the screened population could ultimately be randomized, indicating difficulty to comply or maintain a stable clinical course on a low-protein diet.

Protein restriction can negatively impact the quality of life. Rosman et al.[5] observed in their study that patients in the low-protein-diet group were often hungry at first and required frequent visits to the dietician to adjust their diet. They acknowledged that protein restriction does impair the quality of life, as was reflected by the proportion of dissatisfied patients in the initial part of the study. This issue was also highlighted by an analysis of the MDRD trial, assessing patient satisfaction with the protein-restricted diets.[28] Finally, in the opinion of the experts, only 15% of the patients in practice can comfortably follow a protein-restricted diet.[29]

Endpoint assessment

Decreasing protein intake is expected to reduce the generation of the uremic solutes in the short term and reduce the kidney disease progression by preventing hyperfiltration. Serum creatinine is the most commonly used marker of the kidney function in clinical practice due to its easy availability and low cost, but it is particularly unreliable to assess the kidney function in the setting of protein-restricted diets. With reduction in the muscle mass, creatinine generation decreases, and decreasing serum creatinine concentration (and consequent improvement in estimated glomerular filtration rate (eGFR)) may reflect loss of muscle mass. Therefore, directly measured GFR (mGFR) is needed to assess kidney function in such situations. Only three of the eight studies included in the latest meta-analysis[23] used mGFR as an outcome assessment measure, while all others used serum creatinine or some modification of the creatinine like eGFR, reciprocal of creatinine, and urinary creatinine.

Interestingly, two large studies[6,7] that used mGFR as an outcome measure failed to show the beneficial effect of protein restriction on kidney function. The only trial[27] that showed the benefits of VLPD on ESRD used serum creatinine-based eGFR as the outcome. Caution is needed even in the interpretation of the hard outcome like dialysis start in these settings as restricting protein can improve BUN concentration and alleviate some uremic symptoms, thereby delaying decision to start dialysis. This can be easily inferred from this trial where the difference in the ‘end of the study eGFR’ is insignificant (<2 ml/min); however, a large difference in the number of patients starting dialysis was noted. In these situations, waiting for starting RRT, even when kidney function has severely declined, can incur risk of malnutrition and subsequent adverse outcomes even after starting dialysis.

GFR decline is a surrogate outcome, may not necessarily translate into hard outcome benefit and a meta-analysis of randomized controlled trials (RCTs)[19] showed only a limited benefit of VLPD in delaying dialysis initiation with no effect on mortality.

Uncertain safety of protein restriction

Notably, there is a spontaneous decrease in the intake of protein in patients with progressive CKD.[30] Renal insufficiency is also an important independent risk factor for malnutrition in older adults independent of relevant demographic, social, and medical conditions.[31] Malnutrition is a common complication in patients with CKD and is associated with increased risk of death before and after initiation of dialysis.[32]

2020.Cochrane review evaluating the efficacy and safety of protein restriction in CKD concluded that most studies failed to report on impact of protein restriction on final nutritional status of the participants: 12 of the 15 studies did not report on this outcome. This report highlighted the need for better reporting of the safety and nutritional consequences of this intervention before its widespread use.

An analysis evaluating safety of protein restriction involving MDRD study participants[33] revealed that there was lesser energy consumption in the low-protein intake group, along with small but significant declines in various indices of nutritional status in patients with lower GFR, for example, serum transferrin, body weight, percent body fat, arm muscle area, and urine creatinine.

A long-term follow-up (until 2000) of the MDRD B trial was published in 2009.[34] Over this follow-up period, the hazard ratios were 0.83 (95% confidence interval, 0.62 to 1.12) for kidney failure, 1.92 (95% confidence interval, 1.15 to 3.20) for death, and 0.89 (95% confidence interval, 0.67 to 1.18) for the composite outcome in the VLPD group compared with the LPD group. VLPD not only did not decrease the risk of kidney failure but also increased the risk of death on long-term follow-up.

These data highlight the significant risk of malnutrition and possible increased risk of death in patients on VLPD.

Limited role in current practice

Large trials of protein restriction were performed in the 80s and 90s, when very few other strategies were available to retard CKD progression. Also, the dialysis was in its infancy, not widely available, and exorbitantly costly. The standard of care for the management of CKD has significantly changed over this time. Large trials demonstrating the importance of blood pressure (BP) control with inhibitors of the renin angiotensin aldosterone system in non-diabetic CKD like African American Study of Kidney Disease and Hypertension[35] were published after 2000. Many trials of protein restriction did not optimally utilize the important interventions like optimum BP control and RAAS inhibition as standard of care.

For example, a 1991 RCT[36] observed a difference in the mean blood pressure in the two study arms following randomization: 150/89 mmHg in the low-protein group and 146/87 mmHg in the control group. In present day clinical practice, blood pressure control is much more tightly regulated. Another large RCT[6] avoided the use of angiotensin-converting enzyme inhibitors in their study population, which is in contrast to their widespread use as adjunctive therapy in retarding CKD progression. Today, therapeutic armamentarium of CKD is further expanded with agents like SGLT2 inhibition and mineralocorticoid receptor antagonists and applicability of the older trial results to current day practice is severely limited.

Even the largest trial evaluating this issue, MDRD, faced the issue of a low event rate of dialysis and death due to slower decline in kidney function when patients were carefully treated for blood pressure and other risk factors. With wide use of other kidney protection strategies like optimum BP control, RAAS inhibition, and SGLT2 inhibition, it would be even more difficult to demonstrate any possible benefit of protein restriction in RCTs planned today.

Based upon the MDRD results, considering the slow rate of the progression in many patients with non-diabetic CKD, a trial to identify the meaningful difference in kidney function decline, dialysis, or death would need a sample size of over 500 patients in each arm. It is unlikely that such a trial will be designed in future, and a search at Clinical Trials Registry - India showed no current trial evaluating protein restriction in CKD.

Finally, the animal data associating protein intake with kidney damage need to be interpreted with caution as these experiments involved supra-physiological administration of the protein and did not evaluate normal versus protein-restricted diet.

Limited generalizability of the trials to India and other developing countries

While dietary protein intake is at or above the recommended intake of 0.8–1 gm/kg/day in most western countries, it is much lower in the developing world [Figure 1].[37] The average daily per-capita energy intake of an Indian adult residing in an urban or rural region was reported to be 2169 and 2214 kcal/daily, respectively, which is lower than the recommended 2500 kcal/day by the 2019 EAT-Lancet Commission[38]; also, only about 6–8% of the calories consumed are contributed by protein. Moreover, 60% of the total proteins are derived from cereals which are deficient in proteins of high biological value.[39]

Figure 1.

Protein intake in various regions of the world. Note that protein intake in Indians is significantly lower than the minimum recommended protein;, also, the intake of animal- based proteins of high biological value is limited in India

The probability of protein inadequacy based on requirement distribution ranges from 36% to 44% among rural and urban populations, respectively.[38] Even among those populations where the total protein intake appears to be adequate in terms of quantity and protein energy ratio (which refers to the proportion of total energy provided by protein in the diet), the protein quality remains poor across various regions in India.

Extrapolating results from studies done predominantly in Caucasians to the other populations that consume a predominantly vegetarian/mixed diet deficient in proteins of high biological value may cause more harm than any benefit. Also, dietary diversity in our country mandates a highly individualized nutritional management and ‘one size fits all’ approach may not be appropriate.

What about ketoanalogue-supplemented VLPD?

A Cochrane meta-analysis concluded that there is evidence of moderate certainty that VLPD (0.3–0.4 g/kg/day with supplements of essential amino acids and keto analogues) compared with low or normal protein intake, although has no benefit in the primary outcome of death, probably reduces the number of participants with CKD 4 or 5 who progress to CKD.[23] While one may gain some time before initiating dialysis, it potentially comes with significant harm. Although data on nutritional intake were not available during follow-up years, a long-term follow-up of the MDRD trial population,[34] 15 years after the original study, showed an increase in risk of death in the population assigned to a VLPD along with essential keto acids and amino acid supplementation.

Not only do they have limited proven efficacy, ketoanalogue significantly adds to the pill burden and cost of the therapy in CKD. The monthly cost of the therapy with some of the available preparations exceeds that of the dialysis or post-transplant immunosuppressant for 1 month. Most commonly used preparations cost 40–50 rupees per tablet, translating into the cost burden of about 6000–8000 rupees per month.

Conclusions

The current guideline recommendation of protein restriction by KDOQI in non-diabetic CKD is not based on the sufficient evidence base, is an outlier among the major guidelines, and needs to be interpreted with caution. It also does not take into account the significant regional and cultural differences in the dietary patterns. While it is reasonable to avoid excessive protein consumption in the CKD population, protein restriction has a limited role in the contemporary management of CKD. There is significant uncertainty about the safety and efficacy of protein-restricted diets, and as suggested by the Cochrane meta-analysis, a subset of patients with stage 4–5 CKD may be able to postpone dialysis with VLPD. This should be considered only after careful discussion with the patient about risk benefits, and these patients need close monitoring of nutritional parameters. Malnutrition is a serious risk and has a significantly negative impact on patient survival, and the role of frequent and careful nutritional monitoring in these situations cannot be over-emphasized.