Dietary Protein as Kidney Protection: Quality or Quantity?

• Alkali
• aging
• diet

CKD is a global health challenge, and diet is the largest CKD-related risk factor for death and disability.¹ Dietary protein restriction has been identified as a possible kidney-protective intervention, and some small-scale studies support its efficacy to slow nephropathy progression.² Nevertheless, the largest study to examine the effect of dietary protein restriction on nephropathy progression, the Modification of Diet in Renal Disease (MDRD) study, showed that GFR decline at 3 years was no different between patients given a low-protein diet (0.58 g/kg per day) and a usual-protein diet (1.3 g/kg per day).³ Because this landmark study failed to show benefit from reduction of the quantity of protein typical of diets ingested in developed societies, investigators began examining whether changing the quality of ingested protein might slow nephropathy progression.

The two changes in dietary protein quality currently receiving the most attention are substituting non-nitrogen ketoanalogue proteins and substituting plant-sourced for animal-sourced protein. Naturally occurring amino acids contain nitrogen, which when metabolized yield nitrogenous wastes that increase BUN and possibly other untoward effects on kidney function.⁴ Furthermore, diets in developed societies are largely acid producing because of the proportionately greater amount of animal-source proteins (which are acid producing) than plant-source proteins (which are largely base producing). Small-scale studies support that addition of plant-sourced protein, such as fruits and vegetables, improves metabolic acidosis, reduces kidney injury, and slows nephropathy progression.^5–7

The mechanisms by which changes in the quality of ingested protein might slow nephropathy progression are incompletely understood. Substituting non-nitrogen ketoanalogues might allow patients to realize the benefit of dietary protein while avoiding possible untoward effects of nitrogenous wastes.⁴ Furthermore, adding base-producing plant proteins might lower kidney levels of substances, which in the short term facilitate kidney acid excretion but in the long term induce interstitial fibrosis that mediates nephropathy progression.⁸ On the other hand, substituting plant-based for animal-based dietary protein promotes gut flora, which produce metabolites considered less nephrotoxic than flora promoted by animal-sourced protein,⁹ improves bone mineral parameters,^10,11 and reduces BP and body weight.^5–7,12

In this issue of the Journal of the American Society of Nephrology, Garneata et al.¹³ explored the potential contributions of ketoanalogues and plant-based diets to nephropathy progression by comparing effects of a very-low-vegetarian protein diet (0.3 g/kg per day) supplemented with ketoanalogues (VKD) with a usual mixed-source low-protein diet (0.6 g/kg per day) (LPD) on CKD progression to the end points of need for RRT or a 50% decline in baseline kidney function, measured as eGFR. This 18-month, prospective, randomized controlled trial of 207 patients involved a 3-month run-in to include only those who met compliance criteria. All participants were healthy, nondiabetic, white, and predominantly male, with an eGFR<30 ml/min per 1.73 m².

The authors report that a lower percentage of the VKD than LPD recipients (13% versus 42%) reached the primary end point of >50% reduction of initial eGFR. Moreover, RRT was initiated in a lower percentage (11% versus 30%) of VKD recipients. Efficacy of VKD to reduce renal end points was most noted in patients with initial eGFR<20 ml/min per 1.73 m². This greater benefit of the VKD diet on nephropathy progression was observed despite no differences in BP control or the percentage of patients receiving angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin-receptor blockers between groups. In addition, VKD recipients had lower serum urea, uric acid, and phosphate and higher serum calcium and bicarbonate than LPD recipients. Therapeutically, those in the VKD group had less need for calcium and bicarbonate supplementation despite improvement in these two parameters in VKD but not LPD.

This well done study contributes importantly to our understanding of the pathophysiology of nephropathy progression and will add to the growing body of data supporting the need to consider revising current recommendations intended to reduce the risk for further nephropathy progression in patients with CKD.

This study highlights the important benefits of the quality of the ingested protein, specifically plant-sourced compared with animal-sourced and ketoanalogue compared with nitrogen-based dietary protein, in patients with CKD who have reduced eGFR. Patients on the VKD diet had fewer kidney end points than LPD recipients, and so VKD was more kidney protective. In addition, VKD but not LPD recipients as a group achieved better metabolic control, including improved metabolic acidosis, higher serum calcium with lower serum phosphate, and lower serum urea. Although Garneata et al.¹³ emphasize the benefit of ketoanalogues as yielding these benefits, the data do not exclude a concomitant, or possibly even a proportionately greater contribution of the vegetarian protein component of VKD. Plant-based protein without ketoanalogues is kidney protective,^5–7 improves metabolic acidosis,^6,7 and increases serum calcium and reduces serum phosphate in patients with CKD.^10,11 The calcium component of ketoanalogues can act as a phosphate binder to increase serum calcium and reduce serum phosphate, and ketoanalogues themselves can reduce serum urea.⁴ Further studies will determine the proportionate contributions of the vegetarian compared with ketoanalogue components of the VKD diet or whether their combination was the critical contribution to the reported benefits.

The study by Garneata et al.¹³ does not help answer the question as to the potential kidney-protective benefit of reduction of conventional dietary protein. The LPD group ingested an amount of dietary protein (0.6 g/kg per day) lower than that eaten by most individuals in developed societies. The VKD group ate 0.3 g/kg per day vegetarian protein plus 1 capsule/5 kg per day ketoanalogues of non-nitrogen protein. Consequently, both groups ate a low-protein diet, although about half of the VKD diet was non-nitrogen protein. Studies comparing diets of similar character but with higher total protein content are needed to address the quantity question. Nevertheless, the strong statistical differences shown by the authors between VKD and LPD recipients with use of fewer patients than in the MDRD study supports that the two dietary protein qualities examined by Garneata et al.¹³ (plant-sourced and non-nitrogen protein) contribute proportionately more to kidney protection and improved metabolic profile than reduction in the quantity of conventional protein ingestion.

The authors make the interesting point that the kidney-protective effect of VKD was quantitatively better than that of ACEIs because reduction in the rate of eGFR decline in response to BP decline associated with VKD compared with ACEIs was greater with VKD.¹³ This assertion must be made with caution, however, because most (>70%) patients were already receiving ACEIs upon study entry and the authors did not report data for patients on said diets without ACEIs compared with those not on the diets but receiving ACEIs. Nevertheless, the effects of animal-sourced protein to exacerbate GFR decline in the partial nephrectomy model of CKD are mediated through angiotensin II (AngII) receptors and the benefit of plant-sourced protein to ameliorate GFR decline in this CKD model is associated with reduced kidney AngII levels.⁸ In addition, kidney protection provided by plant-sourced protein in patients with CKD is associated with reduced urine excretion of angiotensinogen,⁷ a marker of kidney AngII levels.¹⁴

These data suggest that the benefits of vegetarian diets on nephropathy progression are mediated at least in part through AngII receptors and support the contention of Garneata et al.¹³ and other investigators^5–7 that vegetarian and possibly ketoanalogue-supplemented diets are kidney-protective interventions adjunctive to ACEIs. These data help guide further study on how these diets provide kidney protection. These data also support the need for more and larger-scale studies that might help modify current recommendations regarding the quality of dietary protein in providing kidney protection in CKD.

Clinicians are justifiably concerned about prescribing plant-based diets to patients with CKD and low GFR because of the fear of inducing hyperkalemia in these patients with reduced potassium excretory capacity. Previous studies in patients with CKD who have reduced eGFR and were carefully selected to be at low risk for hyperkalemia showed that none of these patients developed hyperkalemia in response to addition of fruits and vegetable to their ad libitum diets,^5–7 even after having been on these diets for as long as 3 years and experiencing further eGFR decline. Importantly, Garneata et al.¹³ specifically did not document any substantial increment in serum potassium.¹³ These data add to the mounting evidence that plant-based diets can be safely given to patients with CKD and reduced GFR, but further efficacy and safety studies must be done before this can be offered as a general recommendation for patients with CKD.

Relatively low adherence to the prescribed diets reported by Garneata et al.¹³ is potentially discouraging for clinicians wanting to recommend dietary changes as kidney-protective interventions adjunctive to BP control with anti-AngII therapy. Only 42% of solicited patients agreed to take on the diet, and only 14% of those solicited ultimately were able to meet compliance criteria. As noted, the level of protein intake for both VKD and LPD recipients was much lower than protein intake typical of most individuals living in developed societies, and convincing a majority of patients with CKD to initiate and sustain such a diet could prove challenging. Continued study of the mechanism(s) by which changes in dietary protein quality and/or quantity mediate kidney protection is important to addressing this challenge. Specifically, is the kidney protection due to reduction in the quantity of conventionally ingested protein, to the addition of protein of the quality shown to be kidney protective, or to a combination thereof? In support of the “quality” possibility, simply adding plant-based protein to ad libitum diets of patients with CKD who have reduced eGFR was kidney protective and improved their metabolic profile.^5–7

Mounting evidence indicates that dietary intervention with plant-based, alkali-inducing diets is kidney protective. This study by Garneata et al.¹³ brings forth useful insights into strategies that can be aimed at slowing nephropathy progression and may lead to translational studies aimed at larger-scale patient populations in slowing nephropathy progression.

Although diet is the largest risk factor for CKD-related death and disability,¹ it is a relatively underused component of the clinician’s armamentarium in the fight to prevent ESRD with its detrimental consequences. The study of Garneata et al.¹³ adds to the data showing the importance of dietary interventions as kidney protection and specifically highlights the importance of the quality of ingested protein in providing this protection. The authors’ work will also help guide future research on how changes in dietary protein provide kidney protection, and these follow-up studies will help lead to revised recommendations for kidney protection.

• Copyright © 2016 by the American Society of Nephrology