Con: The role of diet for people with advanced Stage 5 CKD

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1 deferred to a later stage of CKD, and the safety of then starting low-intensity dialysis with further dietetic restriction in patients potentially at nutritional risk is uncertain and requires further evidence before being proposed as accepted practice. The evidence quoted raises concern about the applicability and safety of this approach. Locatelli et al. s study [6] is a modest-sized 12-month feasibility study published in 1994 that is nonrandomized and so cannot demonstrate benefit or safety compared with standard management. The article concludes with caution regarding tolerability of this regime by patients [6]. The Caria et al. non-randomized comparative trial [7] is small, including a total of only 68 patients split between the intervention of LPD with weekly hemodialysis and standard thriceweekly hemodialysis, with only 39.4% of the intervention group remaining on that treatment regime at 24 months [7]. Thus the potential benefits and safety of this approach are unproven. Finally the authors discuss the importance of quality of protein intake with differences between effects of protein red meat and plant sources. They hypothesize that less acid generation from reduced protein (or less animal protein) may slow progression of CKD. A counterargument is that even if this is the case, the benefits of correcting acidosis can be simply achieved by bicarbonate supplements. The importance of animal versus plant protein intake in CKD is an interesting area for future study but the evidence does not support routine adoption of this approach in CKD. Professors Kopple and Fouque raise some interesting areas in their article in favor of protein restriction. However, CKD patients already have to tolerate a wide range of burdens relating to treatment and disease, and I suggest that in the age of evidence-based medicine, and especially in these patients, Nephrol Dial Transplant (2018) 33: doi: /ndt/gfx294 Advance Access publication 19 February 2018 dietary management should focus on interventions of proven value. It should be individualized with clear goals, and should avoid additional imposition of aspects of diets without proven benefit or safety (especially in the aged population with CKD and multiple comorbidities, who have particular nutritional challenges [8] and are not really represented in many of the studies discussed in favor of protein restriction). REFERENCES 1. Kopple JD, Sorensen MK, Coburn JW et al. Controlled comparison of 20-g and 40-g protein diets in the treatment of chronic uremia. Am J Clin Nutr 1968; 21: Coresh J, Walser M, Hill S. Survival on dialysis among chronic renal failure patients treated with a supplemented low-protein diet before dialysis. JAm Soc Nephrol 1995; 6: Walser M. Effects of a supplemented very low protein diet in predialysis patients on the serum albumin level, proteinuria, and subsequent survival on dialysis. Mineral Electrolyte Metab 1998; 24: Menon V, Kopple JD, Wang X et al. Effect of a very low-protein diet on outcomes: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis 2009; 53: Cooper BA, Branley P, Bulfone L et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med 2010; 363: Locatelli F, Andrulli S, Pontoriero G et al. Supplemented low-protein diet and once-weekly hemodialysis. Am J Kidney Dis 1994; 24: Caria S, Cupisti A, Sau G et al. The incremental treatment of ESRD: a lowprotein diet combined with weekly hemodialysis may be beneficial for selected patients. BMC Nephrol 2014; 15: Johansson L, Fouque D, Bellizzi V et al. As we grow old: nutritional considerations for older patients on dialysis. Nephrol Dial Transplant 2017; 32: Con: The role of diet for people with advanced Stage 5 CKD Graham Woodrow 1,2,3 1 Renal Unit, St James s University Hospital, Leeds, UK, 2 Leeds School of Medicine, University of Leeds, Leeds, West Yorkshire, UK and 3 Renal Unit, St James s University Hospital, Leeds, West Yorkshire, UK Correspondence and offprint requests to: Graham Woodrow; ABSTRACT Restriction of dietary protein intake has been used in the management of chronic kidney disease (CKD) for many decades, yet remains controversial, with marked variations in its application in clinical practice. There is extensive literature on the subject, with some expert opinion advocating the use of protein restriction based on the balance of the available evidence. The largest randomized trial of low-protein diets is the Modification of Diet in Renal Disease study. Despite multiple secondary analyses, the essential intention-to-treat analysis failed to demonstrate a benefit in the primary outcome of rate of decline of glomerular filtration rate. There are criticisms of many published studies and meta-analyses, including the likelihood of VC The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 380

2 publication bias and unsuitable biochemical endpoints that may be affected by dietary restriction in the absence of effects on kidney function, leading to false positive findings. It is also uncertain whether any benefits observed in these often older studies would be derived in patients undergoing modern standards of CKD management, including blood pressure control and renin angiotensin blockade. Thus it is unclear whether, even in the strictly controlled environment of a clinical study, lowprotein diets significantly slow CKD progression. Important questions exist regarding the applicability of these diets in routine clinical practice. Even in carefully selected study populations with intensive dietetic input, adherence to low-protein diets is poor. It is likely that only a small minority of CKD patients in routine practice could adhere to these diets, and although risks of malnutrition arising from protein restriction are uncertain, they will be greater in less supervised care outside of studies. Keywords: chronic kidney disease, low-protein diet, malnutrition, protein energy wasting INTRODUCTION Nutrition and dietetic interventions are central in the management of chronic kidney disease (CKD) and dietary protein restriction has been utilized for several decades. However, despite extensive research to investigate the effects of protein restriction and debate in the medical literature, it continues to be a major source of controversy. There is significant variation in the application of protein restriction in clinical practice and in expert recommendations regarding its use, and if used, uncertainty about what the optimum nature and timing of such a diet should be. Prior to the availability of long-term renal replacement therapy, protein restriction offered a palliative approach to reducing the accumulation of uraemic toxins in patients with advanced renal failure to control symptoms [1]. With the advent of chronic dialysis, the focus for low-protein diets became the potential for slowing the progression of CKD by reducing glomerular hyperfiltration [2] and attempting to delay the requirement for renal replacement therapy. Given the huge impact of CKD and renal replacement therapy on patients, intervention to delay progression seems very laudable, so why is the use of low-protein diets controversial and inconsistent? Central questions in this debate are whether these diets are truly effective, whether they can be implemented in routine clinical practice, whether they provide benefit when used in addition to other aspects of modern CKD management and the balance of any benefit against potential risks and costs. The World Health Organization recommends that the median daily protein requirement for healthy adults is 0.66 g protein/kg body weight, with the 97.5th percentile of population requirements, i.e. the safe level of protein intake, being 0.83 g/ kg/day [3]. This represents an increase from their previous recommendations of a median requirement of 0.6 g protein/kg/ day, with a safe minimum protein intake target of 0.75 g/kg/day. Protein requirements in CKD to maintain a nutritional state are uncertain and the situation is complicated by the need to compensate for protein loss in proteinuria and catabolic stresses, which vary significantly between patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of CKD recommend a modest lowering of protein intake to 0.8 g/kg/day in adults with a glomerular filtration rate (GFR) <30 ml/min/1.73 m 2 and avoiding high protein intake (>1.3 g/kg/day) in CKD patients at risk of progression [4]. The UK Renal Association Clinical Practice Guideline on nutrition in CKD recommends a minimum prescribed daily protein intake in CKD Stage 4 or 5 not on dialysis of g/kg ideal body weight [5]. A range of restricted protein intakes have been investigated (in some studies with supplementation by essential amino acids or ketoacid analogues). The nature of ingested protein may also be important, with protein of high biological value with a high percentage of essential amino acids required to reduce the risk of malnutrition and ingestion of plant or animal protein possibly having differing effects on CKD progression [6, 7]. Typical restricted regimes include protein intake of 0.6 g/kg/day (sometimes referred to as low-protein diets) as well as more extreme restrictions including very low-protein diets, typically of 0.3 g/kg/day with additional supplementation by essential amino acids or ketoacid analogues. STUDIES OF LOW-PROTEIN DIETS WHAT ISTHEEVIDENCEFOREFFICACY? There have been a number of randomized controlled trials of protein restriction and several meta-analyses, with differing outcomes and interpretations of the results. The largest and most robust randomized trial is the Modification of Diet in Renal Disease (MDRD) study [8]. This study of >800 patients, investigated the effects of hypertension control and protein restriction on the progression of CKD, with GFR measured by 125 I-iothalamate clearances over a 2.2-year period in two substudies. Study A randomized patients with GFRs of ml/ min/1.73 m 2 in a two-by-two factorial design to normal protein intakes of 1.3 g/kg/day or reduced protein intake (0.58 g/kg/ day) and to mean blood pressures (BPs) of 107 or 92 mmhg. In Study B, patients with GFRs of ml/min/1.73 m 2 were randomized to a low-protein intake of 0.58 g/kg/day or a very low-protein intake of 0.28 g/kg/day plus keto acid/amino acid supplementation and again to two target BPs [8]. There was no difference in GFR decline between the normal and low-protein groups in Study A, and in Study B there was a non-significant (P ¼ 0.07) trend to a faster decline in GFR in the low-protein group than the very low-protein group [8]. Longer-term followup of the MDRD study participants also failed to find any benefit of protein restriction on CKD progression [9]. The MDRD study has been subject to a number of secondary analyses with varying conclusions [10], but the intention-to-treat primary outcome analysis showed no benefit of dietary protein restriction. A number of issues need to be considered in interpreting protein restriction studies that affect their validity and applicability to clinical practice. The majority of studies, even when randomized, are relatively small in size and results have been C o n T h e a r g u m e n t a g a i n s t d i e t a r y r e s t r i c t i o n i n C K D 381

3 variable. The potential for publication bias with nonpublication of negative trials is clear and is suggested by funnel plots in meta-analyses by Fouque [11] Fouque et al. [12] and Kasiske et al. [13]. A key methodological issue is the choice and validity of endpoints in these studies. Some studies, including MDRD, used gold standard measurements of kidney function as endpoints, but many others use blood test indicators. Serum creatinine and urea (or derived estimated GFR) have welldocumented limitations of accuracy and may be particularly affected by dietary or nutritional changes distinct from genuine changes in kidney function [14], potentially giving a false appearance of a beneficial effect of protein restriction on kidney function. These measures also reflect a biochemical measurement rather than a clinical outcome. Other study endpoints reflect clinical outcomes such as start of renal replacement therapy and patient survival. However, decisions about the timing of the start of renal replacement are at the clinician s discretion. This raises the possibility of clinician effects, with changes in serum urea and creatinine resulting from protein restriction leading to delay in the decision to start dialysis in proteinrestricted patients, even in the absence of a true effect on kidney function. There have been several meta-analyses of low-protein diets in CKD (accepting the potential limitations of meta-analysis). A Cochrane systematic review in 2007 by Robertson et al. [15] in patients with diabetic nephropathy showed non-significant slowing of progression with protein restriction. In 2008, Pan et al. [16] published a meta-analysis of eight randomized controlled trials in patients with diabetic nephropathy and found no impact on decreasing GFR (although they noted the modest duration of some of the studies). A meta-analysis by Fouque et al. [11] in 2000 in non-diabetic CKD patients, using renal death as the outcome measure (the study includes some but not all of the MDRD study data), suggested a reduced risk of renal death with protein restriction and an updated analysis [12] suggested a 32% decrease in renal death resulting from protein restriction over the study time periods. As with other metaanalyses, varying protein restrictions are included, making it unclear what an optimal diet would be. A meta-analysis by Kasiske et al. [13] in 1998 combining studies of non-diabetic and a smaller number of diabetic patients found a significant but small effect of protein restriction on the rate of progression. ARE STUDY RESULTS APPLICABLE TO 21st-CENTURY CKD PATIENT POPULATIONS AND CLINICAL PRACTICE? Many studies of protein-restricted diets are quite old and approaches to managing patients with CKD, which impact on progression, have changed significantly since these studies were performed. Most important is the management of hypertension with current tight BP control and widespread use of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers in hypertensive/proteinuric patients (which induce the same protective glomerular haemodynamic changes as may occur with protein restriction). As an example, in one meta-analysis only 9/108 diabetic patients received an ACE inhibitor [17]. It is unclear if any additional benefit would result from protein restriction in a patient with optimal management of hypertension on a maximum dose of ACE inhibitor. Are low-protein diets applicable to the elderly patients who dominate our CKD populations but are less likely to be recruited to clinical trials? There are concerns about applying protein restrictions to elderly patients, who already have lower dietary protein intakes and are developing physiological muscle loss, where a further reduction due to protein restriction could lead to critical functional changes in these vulnerable individuals. Cognitive deficit and financial limitations may also make it difficult for the elderly to effectively and safely follow a complex protein-restricted diet. Ethnic and cultural dietary variations between CKD populations raise the question of whether the results of protein restriction trials are applicable on an international basis as the KDIGO CKD guideline notes [4]. Providing intensive dietetic monitoring may be difficult in countries with lower health care resources. OTHER EFFECTS OF LOW-PROTEIN DIETS In addition to putative effects on glomerular hyperfiltration [2], there are other effects of protein restriction that could slow CKD progression and contribute to positive findings in some trials whose mechanisms could be replicated without protein restriction. Reduced hydrogen ion generation with improved acidosis has been observed with protein restriction [18], and correction of acidosis (most easily achieved by sodium bicarbonate supplements) may slow the decline of kidney function. Protein restriction also changes the intake of other nutrients, and beneficial effects occurring with protein restriction could result from reduced sodium and phosphate intake. APPLICABILITY IN ROUTINE PRACTICE A key question is whether the interventions and outcomes from protein restriction studies are transferrable into real-life clinical practice. Dietary restrictions are onerous and difficult even for general populations following healthy lifestyle diets, and are much more so for CKD patients with complicated dietary recommendations relating to CKD (and sometimes additional conditions including diabetes). Cianciaruso et al. [18] performed a randomized trial of the effects of protein intakes of 0.55 g/g/day versus 0.8 g/g/day on metabolic changes. Despite careful participant selection, there were problems with patient concordance, with 53% compliant in the 0.8 g/kg/day group but only 27% in the 0.55 g/kg/day group. The study showed no significant effects in the intention-to-treat analysis, but a per-protocol analysis of those compliant with the diets identified some biochemical effects. If such a small proportion of patients were able to follow the lower protein diet in a highly selected patient group with intensive dietetic monitoring, it raises doubts that this could be successfully employed on a long-term basis in real-life clinical practice with available resources for dietetic monitoring or that significant benefits would be gained by the 382 G. Woodrow

4 whole population. In the MDRD study, 35% and 46% of patients were adherent to the low-protein diet and only 25% to the very low-protein diet [19], despite extremely intensive dietician input [20] that could not be replicated on a long-term basis to whole CKD populations in practice. Satisfaction with the prescribed diets in the MDRD increased slightly over time in the usual protein group, but declined with protein restriction, and especially with the very low-protein diet, with satisfaction correlating to dietary adherence [21]. In an editorial in 2008, Kopple [22] estimated from personal experience that only 15% of patients with CKD can comfortably follow a protein-restricted diet. A recent study by Garneata et al. [6] suggested a benefit from a ketoanalogue-supplemented very low-protein vegetarian diet. However, after screening and a run-in period to determine dietary compliance, only 14% of patients were eligible for randomization, indicating compliance difficulties and that any benefits arising from complex protein-restricted diets would only be applicable to a small subgroup of patients. NEGATIVE EFFECTS OF PROTEIN RESTRICTION Malnutrition is a frequent complication of CKD with strong adverse prognostic significance [23]. Modern terminology refers to protein energy wasting, describing the complex situation where multiple factors, including inflammation and metabolic abnormalities, lead to a catabolic wasting state, with reduced dietary protein and energy intake being crucial contributory factors [23, 24]. It has been suggested that a protein intake of g/kg ideal body weight is sufficient to maintain stable protein stores in CKD [24, 25], but this requires maintaining adequate energy intake (30 35 kcal/kg/day ideal body weight) and may become inadequate during intercurrent illness [24, 25], which is common in our complex CKD patients. Protein intake falls spontaneously as GFR decreases, such that patients with advanced CKD may consume less protein than required to avoid malnutrition, with the need for caution in restricting protein as a result [26]. Cross-sectional analysis of MDRD data found correlations for declining protein and energy intake and a number of nutritional markers with lower GFR, with the conclusion that very careful monitoring is required of protein and energy intake for patients receiving a low-protein diet [27]. Thus there is the potential for metabolic or dietary changes or intercurrent illness to occur, causing protein depletion in patients on a low-protein diet, and clinical experience shows that nutritional loss is more difficult to reverse in CKD patients. There have been some reasons for concern regarding adverse effects of protein restriction, although evidence of risk is not conclusive. The MDRD study concluded that low and very low-protein diets are safe with no clear development of malnutrition [28]. However, several nutritional indices that were measured declined and dieticians found it difficult to maintain energy intake requirements in patients with protein restrictions, suggesting that intensive supervision is required to minimize the risk of malnutrition from protein restriction [28]. A followup of MDRD Study B demonstrated higher long-term mortality in the very low-protein group with ketoacid supplements than the comparator low-protein group [29]. This study has the strength of representing follow-up of a robust randomized study of protein restriction, though it lacks nutritional data in the period after completion of the study and the comparator is not an unrestricted protein intake group. Bellizzi et al. [30] observed no adverse effects (and possibly greater survival) of having previously received a very low-protein diet in the period after starting renal replacement therapy. However, the historical cohort design raises the possibilities of differences between groups that were uncorrected for in the analysis or greater mortality with the loss of patients prior to starting renal replacement therapy, and information about the control group s protein intake and dietetic management was lacking [30]. The absence of adverse effects of protein restriction in the highly controlled setting of some clinical trials with intensive dietetic review does not instill confidence that this would also be the case in standard clinical practice. CONCLUSIONS There are many demands made of patients with CKD, and major dietary changes have an important negative effect on quality of life, with dietary restrictions preventing eating enjoyable foods and impacting on normal behaviour in social situations. There is no convincing evidence that protein restriction slows CKD progression in humans; at best it may modestly delay the decision to start dialysis, although evidence for this is uncertain. It is also unclear whether any benefits would apply to patients receiving modern standards of CKD care, including hypertension control. Even if the most positive interpretations of these studies are accepted, the strongest argument against routine use of protein restriction in CKD is that even with intensive dietetic supervision, only a small proportion of patients will be able to comply with the prescribed diet, balanced against major impacts on quality of life and potential risk. Thus, while avoidance of excess protein intake seems a reasonable recommendation, protein restriction appears to be an unproven intervention with significant burdens and potential risks to patients and costs to CKD programmes. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1. Giovannetti S, Maggiore Q. A low nitrogen diet with proteins of high biological value for severe chronic uraemia. Lancet 1964; 283: Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically medicated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation and intrinsic renal disease. NEnglJMed1982; 307: World Health Organization, Food and Agriculture Organization of the United Nations, United Nations University. Protein and amino acid C o n T h e a r g u m e n t a g a i n s t d i e t a r y r e s t r i c t i o n i n C K D 383

5 requirements in human nutrition. Report of a joint FAO/WHO/UNU expert consultation. WHO Technical Report Series 935. Geneva: World Health Organization, Clinical practice guideline for the evaluation and management of chronic kidney disease. Chapter 3: Management of progression and complications of CKD. Kidney Int Supp 2013; 3: Wright M, Jones C. Renal Association clinical practice guidelines on nutrition in CKD. Nephron Clin Pract 2011; 118(Suppl 1): c153 c Garneata L, Stancu A, Dragomir D et al. Ketoanalogue supplemented vegetarian very low-protein diet and CKD progression. J Am Soc Nephrol 2016; 27: Goraya N, Wesson DE. Dietary protein as kidney protection: quality or quantity? J Am Soc Nephrol 2016; 27: Klahr S, Levey AS, Beck GJ et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994; 330: Levey AS, Greene T, Sarnak MJ et al. Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis 2006; 48: Levey AS, Greene T, Beck GJ et al. Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? J Am Soc Nephrol 1999; 10: Fouque D, Wang P, Laville M et al. Low protein diets delay end-stage renal disease in non-diabetic adults with chronic renal failure. Nephrol Dial Transplant 2000; 15: Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev 2009; 3: CD Kasiske BL, Lakatua JD, Ma JZ et al. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis 1998; 31: Tangri N, Stevens LA, Schmid CH et al. Changes in dietary protein intake has no effect on serum cystatin C levels independent of the glomerular filtration rate. Kidney Int 2011; 79: Robertson L, Waugh N, Robertson A. Protein restriction for diabetic renal disease. Cochrane Database Syst Rev 2007; 4: CD Pan Y, Guo LL, Jin HM. Low-protein diet for diabetic nephropathy: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008; 88: Pedrini MT, Levey AS, Lau J et al. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann Intern Med 1996; 124: Nephrol Dial Transplant (2018) 33: doi: /ndt/gfx294a Advance Access publication 19 February 2018 Opponent s comments Joel D. Kopple 1 and Denis Fouque Cianciaruso B, Pota A, Pisani A et al. Metabolic effects of two low protein diets in chronic kidney disease stage 4 5 a randomized controlled trial. NephrolDialTransplant2008; 23: Milas NC, Nowalk MP, Akpele L et al. Factors associated with adherence to the dietary protein intervention in the Modification of Diet in Renal Disease Study. J Am Diet Assoc 1995; 95: Dolecek TA, Olson MB, Caggiula AW et al. Registered dietitian time requirements in the Modification of Diet in Renal Disease Study. JAmDiet Assoc 1995; 95: Coyne T, Olson M, Bradham K et al. Dietary satisfaction correlated with adherence in the Modification of Diet in Renal Disease Study. J Am Diet Assoc 1995; 95: Kopple JD. Do low-protein diets retard the loss of kidney function in patients with diabetic nephropathy? Am J Clin Nutr 2008; 88: Fouque D, Kalantar-Zadeh K, Kopple J et al. A proposed nomenclature and diagnostic criteria for protein energy wasting in acute and chronic kidney disease. Kidney Int 2008; 73: Ikizler TA, Cano NJ, Franch H et al. Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism. Kidney Int 2013; 84: Lim VS, Kopple JD. Protein metabolism in patients with chronic renal failure: role of uremia and dialysis. Kidney Int 2000; 58: Ikizler TA, Greene JH, Wingard RL et al. Spontaneous dietary protein intake during progression of chronic renal failure. J Am Soc Nephrol 1995; 6: Kopple JD, Greene T, Chumlea WC et al. Relationship between nutritional status and the glomerular filtration rate: results from the MDRD Study. Kidney Int 2000; 57: Kopple JD, Levey AS, Greene T et al. Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease Study. Kidney Int 1997; 52: Menon V, Kopple JD, Wang X et al. Effect of a very low-protein diet on outcomes: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am J Kidney Dis 2009; 53: Bellizzi V, Chiodini P, Cupisti A et al. Very low-protein diet plus ketoacids in chronic kidney disease and risk of death during end-stage renal disease: a historical cohort controlled study. NephrolDialTransplant2015; 30: Received: ; Editorial decision: Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, the David Geffen School of Medicine at UCLA and the UCLA Fielding School of Public Health, Los Angeles, CA, USA and 2 Department of Nephrology, Centre Hospitalier Lyon Sud, Univ Lyon, UCBL, Carmen, Pierre-Bénite, France Correspondence and offprint requests to: Joel D. Kopple; We would like to thank Dr Woodrow for his scholarly and thoughtful comments in which he focused on the potential role of low-protein diets to slow the rate of loss of glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD). Regretfully, as indicated in the title of our article, The role of diet for people with advanced Stage 5 CKD, we addressed a somewhat different issue. As we discussed in our article, advanced CKD is defined as a GFR <10 20 ml/min/1.73 m 2 in VC The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 384