Opponent’s comments

Opponent’s comments I am grateful to Professors Kopple and Fouque for their manuscript arguing for the importance of diet in patients with advanced kidney disease. I believe that we agree on the great importance of many aspects of nutritional management in chronic kidney disease (CKD) and the crucial role dietitians play in caring for CKD patients, as I stated in my article. This involves aspects including individualized calorie and protein intake advice to prevent or treat protein-energy wasting (PEW) and obesity, sodium restriction, advice on fluid intake and management of hyperkalemia and hyperphosphatemia. In my argument against dietetic intervention however, following the suggested remit for my article, I focused on the role of protein restriction in patients with CKD. I was pleased to see a lot of concordance in my opponents’ article with my arguments against protein restriction in CKD. I think that we agree with the fact that the existing evidence [including the Modification of Diet in Renal Disease (MDRD) study] does not support the efficacy of protein-restricted diets in slowing down CKD progression. Also important is agreement that any possible benefits from protein restriction trials on CKD progression may not apply in the modern era of aggressive hypertension control and renin-angiotensin blockade in CKD. Perhaps most crucial from a pragmatic clinical point of view, is our agreement that in real-life nephrology outside of clinical trials there is great difficulty for most patients in complying with these diets over sustained periods of time, irrespective of any potential benefit. Professors Kopple and Fouque suggest that protein restriction in advanced renal failure may reduce uremic toxicity and lead to deferral of dialysis even if there is no impact on glomerular filtration rate (GFR) decline. They hypothesize that patient anxiety about starting dialysis may then act as an incentive for adherence to dietary restriction in advanced CKD in the hope of deferring dialysis. I believe this latter suggestion is unproven and there are multiple examples of situations where individuals have difficulty in making health and lifestyle choices despite strong evidence that a change would have a major benefit to the patient’s health. There are also concerns of risks about impact of protein restriction on patient outcomes in this setting, and a need for very close monitoring to prevent malnutrition, impacting on the patient and their quality of life. Studies of protein restriction to correct advanced uremic symptoms are quite old and non-randomized, as acknowledged by the authors, and one trial quoted described very significant patient intolerance of the low-protein diet (LPD) [1]. I would query whether a possible very modest duration in delay in commencing renal replacement therapy justifies this intervention. I do agree that a short period of tighter dietary control to facilitate establishing definitive dialysis access could be considered in individual patients. The authors suggest that LPDs produce favorable effects outwith of delaying CKD progression or dialysis initiation. These suggestions include the impacts of on sodium and water balance, potassium intake and bone mineral disorder. One feature of dietary interventions in CKD is that changes outside of the specific intended target nutrient often occur (either potentially beneficial or detrimental) and I agree that some of these changes may arise as part of a protein-restricted diet. However, I would argue that they are not always appropriate or beneficial to the individual patient and that this is not a valid alternative justification for broad imposition of protein restriction in these patients. Patterns of nutritional, hydration and metabolic abnormalities are complex and varied between patients and are optimally managed by individualized approaches combining dietary and medical interventions tailored appropriately to the individual patient. It is well established that PEW is a common complication of advanced CKD with major adverse prognostic significance. Whilst some (but not all) studies show an absence of evidence that protein restriction causes development of PEW, I would disagree with my opponents’ suggestion that this constitutes a benefit of these diets in preventing PEW. There is no evidence that they are superior to nonrestricted diets in this regard, and lack of an effect on PEW in carefully selected and monitored patients in trials of protein restriction over modest periods of time cannot be compared with historical observations of PEW prevalence in the general CKD population in separate studies. Professors Kopple and Fouque quote studies suggesting a potential survival benefit of protein restriction [2, 3] but as they acknowledge, there are major issues with the study quality, with comparisons with historical data making the strength of this conclusion quite weak. This contrasts with follow-up of the far stronger MDRD randomized controlled study observing increased mortality with very low-protein diet versus LPD [4]. One suggestion in the article is using protein restriction to facilitate incremental initiation of dialysis. The IDEAL study demonstrated no differences in outcome for patients randomized to start standard dialysis regimes at a lower target GFR or when symptomatic, compared with asymptomatic start at higher target GFR [5]. Thus, dialysis can already be completely 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 non-randomized 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 thrice-weekly 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, 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: 553– 564 Google Scholar CrossRef Search ADS PubMed  2 Coresh J, Walser M, Hill S. Survival on dialysis among chronic renal failure patients treated with a supplemented low-protein diet before dialysis. J Am Soc Nephrol  1995; 6: 1379– 1385 Google Scholar PubMed  3 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: 64– 71 Google Scholar CrossRef Search ADS   4 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: 208– 217 Google Scholar CrossRef Search ADS PubMed  5 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: 609– 619 Google Scholar CrossRef Search ADS PubMed  6 Locatelli F, Andrulli S, Pontoriero G et al.   Supplemented low-protein diet and once-weekly hemodialysis. Am J Kidney Dis  1994; 24: 192– 204 Google Scholar CrossRef Search ADS PubMed  7 Caria S, Cupisti A, Sau G et al.   The incremental treatment of ESRD: a low-protein diet combined with weekly hemodialysis may be beneficial for selected patients. BMC Nephrol  2014; 15: 172 Google Scholar CrossRef Search ADS PubMed  8 Johansson L, Fouque D, Bellizzi V et al.   As we grow old: nutritional considerations for older patients on dialysis. Nephrol Dial Transplant  2017; 32: 1127– 1136 Google Scholar PubMed  © The Author 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Opponent’s comments

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Publisher
Oxford University Press
Copyright
© The Author 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
ISSN
0931-0509
eISSN
1460-2385
D.O.I.
10.1093/ndt/gfx333a
Publisher site
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Abstract

I am grateful to Professors Kopple and Fouque for their manuscript arguing for the importance of diet in patients with advanced kidney disease. I believe that we agree on the great importance of many aspects of nutritional management in chronic kidney disease (CKD) and the crucial role dietitians play in caring for CKD patients, as I stated in my article. This involves aspects including individualized calorie and protein intake advice to prevent or treat protein-energy wasting (PEW) and obesity, sodium restriction, advice on fluid intake and management of hyperkalemia and hyperphosphatemia. In my argument against dietetic intervention however, following the suggested remit for my article, I focused on the role of protein restriction in patients with CKD. I was pleased to see a lot of concordance in my opponents’ article with my arguments against protein restriction in CKD. I think that we agree with the fact that the existing evidence [including the Modification of Diet in Renal Disease (MDRD) study] does not support the efficacy of protein-restricted diets in slowing down CKD progression. Also important is agreement that any possible benefits from protein restriction trials on CKD progression may not apply in the modern era of aggressive hypertension control and renin-angiotensin blockade in CKD. Perhaps most crucial from a pragmatic clinical point of view, is our agreement that in real-life nephrology outside of clinical trials there is great difficulty for most patients in complying with these diets over sustained periods of time, irrespective of any potential benefit. Professors Kopple and Fouque suggest that protein restriction in advanced renal failure may reduce uremic toxicity and lead to deferral of dialysis even if there is no impact on glomerular filtration rate (GFR) decline. They hypothesize that patient anxiety about starting dialysis may then act as an incentive for adherence to dietary restriction in advanced CKD in the hope of deferring dialysis. I believe this latter suggestion is unproven and there are multiple examples of situations where individuals have difficulty in making health and lifestyle choices despite strong evidence that a change would have a major benefit to the patient’s health. There are also concerns of risks about impact of protein restriction on patient outcomes in this setting, and a need for very close monitoring to prevent malnutrition, impacting on the patient and their quality of life. Studies of protein restriction to correct advanced uremic symptoms are quite old and non-randomized, as acknowledged by the authors, and one trial quoted described very significant patient intolerance of the low-protein diet (LPD) [1]. I would query whether a possible very modest duration in delay in commencing renal replacement therapy justifies this intervention. I do agree that a short period of tighter dietary control to facilitate establishing definitive dialysis access could be considered in individual patients. The authors suggest that LPDs produce favorable effects outwith of delaying CKD progression or dialysis initiation. These suggestions include the impacts of on sodium and water balance, potassium intake and bone mineral disorder. One feature of dietary interventions in CKD is that changes outside of the specific intended target nutrient often occur (either potentially beneficial or detrimental) and I agree that some of these changes may arise as part of a protein-restricted diet. However, I would argue that they are not always appropriate or beneficial to the individual patient and that this is not a valid alternative justification for broad imposition of protein restriction in these patients. Patterns of nutritional, hydration and metabolic abnormalities are complex and varied between patients and are optimally managed by individualized approaches combining dietary and medical interventions tailored appropriately to the individual patient. It is well established that PEW is a common complication of advanced CKD with major adverse prognostic significance. Whilst some (but not all) studies show an absence of evidence that protein restriction causes development of PEW, I would disagree with my opponents’ suggestion that this constitutes a benefit of these diets in preventing PEW. There is no evidence that they are superior to nonrestricted diets in this regard, and lack of an effect on PEW in carefully selected and monitored patients in trials of protein restriction over modest periods of time cannot be compared with historical observations of PEW prevalence in the general CKD population in separate studies. Professors Kopple and Fouque quote studies suggesting a potential survival benefit of protein restriction [2, 3] but as they acknowledge, there are major issues with the study quality, with comparisons with historical data making the strength of this conclusion quite weak. This contrasts with follow-up of the far stronger MDRD randomized controlled study observing increased mortality with very low-protein diet versus LPD [4]. One suggestion in the article is using protein restriction to facilitate incremental initiation of dialysis. The IDEAL study demonstrated no differences in outcome for patients randomized to start standard dialysis regimes at a lower target GFR or when symptomatic, compared with asymptomatic start at higher target GFR [5]. Thus, dialysis can already be completely 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 non-randomized 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 thrice-weekly 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, 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: 553– 564 Google Scholar CrossRef Search ADS PubMed  2 Coresh J, Walser M, Hill S. Survival on dialysis among chronic renal failure patients treated with a supplemented low-protein diet before dialysis. J Am Soc Nephrol  1995; 6: 1379– 1385 Google Scholar PubMed  3 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: 64– 71 Google Scholar CrossRef Search ADS   4 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: 208– 217 Google Scholar CrossRef Search ADS PubMed  5 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: 609– 619 Google Scholar CrossRef Search ADS PubMed  6 Locatelli F, Andrulli S, Pontoriero G et al.   Supplemented low-protein diet and once-weekly hemodialysis. Am J Kidney Dis  1994; 24: 192– 204 Google Scholar CrossRef Search ADS PubMed  7 Caria S, Cupisti A, Sau G et al.   The incremental treatment of ESRD: a low-protein diet combined with weekly hemodialysis may be beneficial for selected patients. BMC Nephrol  2014; 15: 172 Google Scholar CrossRef Search ADS PubMed  8 Johansson L, Fouque D, Bellizzi V et al.   As we grow old: nutritional considerations for older patients on dialysis. Nephrol Dial Transplant  2017; 32: 1127– 1136 Google Scholar PubMed  © The Author 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Mar 1, 2018

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