NDT Advance Access originally published online on April 10, 2008
Nephrology Dialysis Transplantation 2008 23(7):2118-2120; doi:10.1093/ndt/gfn175
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The long forgotten salt factor and the benefits of using a 5-g-salt-restricted diet in all ESRD patients
1 Monaco 98000 2 Bioscience Department, Fresenius Medical Care, Bad Homburg, FRG D-61346, Germany
Correspondence and offprint requests to: Stanley Shaldon, Monaco 98000. E-mail: stanley.shaldon{at}libello.com
Keywords: inflammation; lag phenomenon; non-osmotically active sodium; salt
Writing about older concepts of therapy in medicine often provoke an automatic negative response based on assumptions that they are dinosaurian and empirical and consequently unlikely to impact upon modern therapeutic paradigms unless supported by randomized controlled studies. However, occasionally, new ideas resuscitate these forgotten paradigms and allow one to make progress from observational studies without the benefit of evidence-based medicine [1].
Such is the case with the long abandoned use of a salt-restricted diet in the routine management of patients with end-stage renal disease (ESRD). The reason for this change of attitude is best exemplified by examining two recent learned proclamations. The first published in 2004 and entitled Dialysis Outcomes Quality Initiatives Guidelines on the problem of cardiovascular disease in ESRD patients (K/DOQI) devoted a miniscule paragraph in the lifestyle changes section to salt restriction, unconvincingly recommended in the very early stages of chronic kidney disease and positively contraindicated in later stages [1]. The second document, published 2 years later by the same learned body [2], devotes eight pages and over 60 references to the use of a salt-restricted diet in the treatment of ESRD patients on haemodialysis.
The reason for this significant change of policy may be traced to a potentially plausible and acceptable scientific explanation of a hitherto empirical observation that we published over 40 years ago [3]. When we described our initial dramatic results obtained with a 5-g-salt-restricted diet in severely hypertensive ESRD patients maintained on haemodialysis, we observed that it took several months to achieve ultimate drug-free blood pressure control. This late (lag) phenomenon was independent of the initial reduction in blood pressure associated with reducing extracellular volume and reaching an arbitrarily defined dry body weight. In addition, serial exchangeable sodium measurements showed no further reduction with the appearance of the ‘lag’ phenomenon (Figure 1). The lag phenomenon, now recognized by many authors, has been shown to be due to a reduction in peripheral resistance [4]. The possible explanation may be linked to the reduction of non-osmotically active sodium, first described 40 years ago [5] which is potentially bound in the interstitial matrix lining the intimal surface of blood vessels containing proteoglycans and glycosaminoglycans [6]; this sodium store takes months to normalize on a 5-g salt intake [7,8]. The concept depends upon observations in vitro that the gene responsible for inducing the inflammatory cytokine cycle, MAPK38 (mitogen-activated protein kinase), stimulated by a local high sodium concentration and resulting in an ADMA (asymmetric dimethyl arginine)-induced increase in peripheral resistance by reduction in nitric oxide synthesis will be reversed by a low-salt dietary intake, as will the production of inflammatory cytokines.
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Thus, the lesson to be learned from the almost unique experiences of Tassin [9] and Izmir [10] is that the most important determinant of improved survival in ESRD patients on haemodialysis is less related to the technical aspects of therapy, than to the insistence on a 5-g daily salt intake. Reinforcement of this concept has been provided by a 25% reduction in cardiovascular morbidity and mortality in a low-salt group (5 g per diem) compared to a normal unrestricted salt intake recently reported by Nancy Cook and colleagues in a randomized controlled study of ‘prehypertensive’ normals between ages of 35 and 55 years followed up for 10 years with compliance estimated by monthly 24-h urinary sodium determinations [11].
The tragedy of this conclusion is that the tendency to increase the salt intake of the world's population by the spread of processed food and instant cooking makes the problem of adherence to such a diet more difficult to achieve.
Conflict of interest declaration. None relevant to this article. Both authors own shares in Fresenius Medical Care. S.S. is a consultant for Fresenius Medical Care. J.V. is an employee of Fresenius Medical Care.
(See related article by D. A. McCarron. Dietary sodium and cardiovascular and renal disease risk factors: dark horse or phantom entry? Nephrol Dial Transplant 2008; 23: 2133–2137.)
(See related article by A. Mimran and G. du Cailar. Dietary sodium: the dark horse amongst cardiovascular and renal risk factors. Nephrol Dial Transplant 2008; 23: 2138–2141.)
(See related article by B. M. Moinier and T. B. Drüeke. Aphrodite, sex and salt—from butterfly to man. Nephrol Dial Transplant 2008; 23: 2154–2161.)
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- Kidney Disease Outcomes Quality Initiative (K/DOQI). Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Guideline 6: dietary and other therapeutic lifestyle changes in adults. Am J Kidney Dis (2004) 43(Suppl_1):s116.
- Kidney Disease Outcomes Quality Initiative (K/DOQI10. Clinical practice guidelines for hemodialysis adequacy update 2006. Guideline 5: on control of volume and blood pressure. Am J Kidney Dis (2006) 48(Suppl 1):s33.
- Comty C, Rottka H, Shaldon S. Blood pressure control in patients with end stage renal disease treated by intermittent haemdialysis. Proc Eur Dial Transplant Assoc (1964) 1:209–213.
- Shaldon S. Editorial: an explanation for the lag phenomenon in drug-free control of hypertension by dietary salt restriction in patients with chronic kidney disease on hemodialysis. Clin Nephrol (2006) 66:1–2.[ISI][Medline]
- Garnett ES, Ford PL, Golding R, et al. The mobilization of osmotically inactive sodium during total starvation in man. Clin Sci (1968) 35:93–103.[ISI][Medline]
- Titze J, Shakibaie M, Schaffihuber M, et al. Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol (2004) 287:H203–H208.
[Abstract/Free Full Text] - Ritz E. Where does some of the ingested sodium chloride hide without exerting osmotic pressure? J Am Soc Nephrol (2006) 17:3–11.
[Free Full Text] - Ritz E, Dikow R, Morath C, et al. 2006. Salt—a potential ‘uremic toxin’? Blood Purif (2006) 24:63–66.[CrossRef][ISI][Medline]
- Charra B, Calemard E, Cuch M, et al. Control of hypertension and prolonged survival on maintenance haemodialysis. Nephron (1983) 33:96–99.[ISI][Medline]
- Ozkahya M, Ok E, Toz H, et al. Long-term survival rates in haemodialysis patients treated with strict volume control. Nephrol Dial Transplant (2006) 21:3506–3513.
[Abstract/Free Full Text] - Cook N, Cutler JA, Obarzanek E, et al. Long term effects of sodium reduction on cardiovascular disease outcomes: observational follow up of the trials of hypertension prevention (TOPH). BMJ (2007) 334:885.
[Abstract/Free Full Text]
Accepted in revised form: 6. 3.08
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