Medical Hypotheses 82 (2014) 551–552
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Low dietary sodium in diabetes nephropathy Ian W. Seetho a,⇑, Sarah V. O’Brien b, Kevin J. Hardy b a b
Department of Diabetes & Endocrinology, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, United Kingdom Department of Diabetes & Endocrinology, St Helens & Knowsley Teaching Hospitals NHS Trust, Marshalls Cross Road, St Helens WA9 3DA, United Kingdom
a r t i c l e
i n f o
Article history: Received 29 October 2013 Accepted 5 February 2014
a b s t r a c t In a meta-analysis that investigated the effects of dietary sodium restriction in diabetes nephropathy, although blood pressure fell, there were significant increases in plasma renin and aldosterone levels. In this article, we hypothesise that in diabetic nephropathy, ACE-I or ARB treatment attenuates any rise in RAS hormones that might result from dietary salt restriction and that the beneficial effects of the salt restriction such as a lower blood pressure outweigh any potentially negative consequences of RAS activation such as a rise in intraglomerular pressure because of the synergistic effects of sodium restriction and RAS antagonist therapy. Ó 2014 Elsevier Ltd. All rights reserved.
Background The Brenner hypothesis states that increased intraglomerular pressure leads to increased glomerular filtration of protein, nephron loss and progression of renal disease [1,2]. Antihypertensive treatment reduces systemic arterial blood pressure and therefore reduces glomerular afferent arteriolar pressure, intraglomerular pressure and protein filtration, retarding the development and progression of renal disease. Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARB) not only lower blood pressure (and therefore reduce intraglomerular pressure through a fall in afferent arteriolar pressure), but also further reduce intraglomerular pressure by selective dilatation of the glomerular efferent arteriole. Thus, the reduction in proteinuria and beneficial renal effects of ACE-I and ARB treatment exceed that which can be explained on the basis of blood pressure reduction alone [3,4]. It is known that treatment that lowers blood pressure is likely to reduce proteinuria and retard development and progression of renal disease. Inhibition of the renin-angiotensin-aldosterone system (RAS) reduces intraglomerular pressure by selective dilatation of the glomerular efferent arteriole is likely to lower proteinuria and retard development and progression of renal disease. Conversely, treatment or changes that produce persistent elevation in blood pressure are likely to increase proteinuria and increase development and progression of renal disease. Therefore it is speculated that treatment or changes that persistently increase RAS hormones might constrict efferent arterioles, increase intraglomer⇑ Corresponding author. Address: Department of Diabetes & Endocrinology, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, United Kingdom. Tel.: +44 01515295885; fax: +44 01515285888. E-mail address: [email protected] (I.W. Seetho). http://dx.doi.org/10.1016/j.mehy.2014.02.009 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
ular pressure and therefore increase proteinuria and renal disease progression. Dietary sodium restriction enhances the anti-hypertensive and anti-proteinuric effects of ARB [5,6] and ACE-I treatment [7], and protects against diabetes nephropathy progression [8,9]. But, in a recent meta-analysis studying the effects of dietary sodium restriction in diabetes nephropathy, although blood pressure fell, there were significant increases in plasma renin and aldosterone levels [10]. This rise in renin and aldosterone in response to low dietary sodium has also been noted in Yanomamo Indians who consume low dietary sodium [10,11]. Thus, dietary sodium restriction has the beneficial effects of lowering systemic arterial blood pressure, glomerular afferent arteriolar pressure and intraglomerular pressure, but increases RAS hormones which might increase glomerular efferent arteriolar tone and intraglomerular pressure.
The hypothesis We hypothesise that in diabetes nephropathy, ACE-I or ARB treatment attenuates any rise in RAS hormones that might result from dietary salt restriction and that the beneficial effects of the salt restriction (lower blood pressure) outweigh any potentially negative consequences of RAS activation (a rise in intraglomerular pressure [13]) because of the synergistic effects of sodium restriction and RAS antagonist therapy [12]. Most people with diabetes nephropathy use ACE-I or ARB treatment and so salt restriction is a broadly useful intervention. Indeed, in a review by Jones-Burton et al. [14]looking at evidence in the literature linking sodium intake in the diet with chronic kidney disease progression, no adverse effects were found with reduced dietary salt consumption [14].
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I.W. Seetho et al. / Medical Hypotheses 82 (2014) 551–552
References
Fig. 1. Rise in RAS hormones with low sodium consumption.
Evaluation of hypothesis But what is the impact of salt restriction in diabetes nephropathy in the absence of ACE-I or ARB treatment? It is possible that even in this situation, the beneficial effects of salt restriction on blood pressure outweigh any potentially negative consequences of RAS activation, but it is also possible that without RAS inhibition by ACE-I or ARB treatment that the greater rise in RAS hormones leads to a larger rise in intraglomerular pressure, increased protein loss and subsequent disease progression (Fig. 1). Whether a low sodium diet reduces blood pressure but possibly leads to nephropathy progression without RAS antagonism with ACEIs and ARBs remains a hypothesis to be addressed in future research studies perhaps before the commencement of ACEI and ARB drug therapy given the already known beneficial effects of this treatment for diabetes nephropathy in the literature. Conflict of interest None. Sources of support We gratefully acknowledge the support of the University of Liverpool, University Hospital Aintree and St Helens & Knowsley Teaching Hospitals.
[1] Brenner BM, Meyer TW, Hostetter TH. Dietary Protein Intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 1982;307(11):652–9. [2] Martin WF, Armstrong LE, Rodriguez NR. Dietary protein intake and renal function. Nutr Metab 2005;2:25. http://dx.doi.org/10.1186/1743-7075-2-25. [3] Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Collaborative study group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345(12):851–60. [4] Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med 1993;329(20):1456–62. [5] Houlihan CA, Allen TJ, Baxter AL, Panangiotopoulos S, Casley DJ, Cooper ME, et al. A low-sodium diet potentiates the effects of losartan in type 2 diabetes. Diabetes Care 2002;25(4):663–71. [6] Vogt L, Waanders F, Boomsma F, de Zeeuw D, Navis G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol 2008;19(5):999–1007. [7] Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the anitproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989;36(2):272–9. [8] Giunti S, Barit D, Cooper ME. Mechanisms of diabetic nephropathy:role of hypertension. Hypertension 2006;48(4):519–26. [9] Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002;61(3):1086–97. [10] Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol and triglyceride. Cochrane Database Syst Rev 2011;11:CD004022. [11] Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a ‘‘no-salt’’ culture. Circulation 1975;52:146–51. [12] Slagman MCJ, Waanders F, Hemmelder MH, Woittiez AJ, Janssen WM, Lambers Heerspink HJ, et al. Holland nephrology study group. Moderate dietary sodium restriction added to angiotensin converting enzyme. Br Med J 2011;343:d4366. [13] Luik PT, Hoogenberg K, Van Der Kleij FG, Beusekamp BJ, Kerstens MN, De Jong PE, et al. Short-term moderate sodium restriction induces relative hyperfiltration in normotensive normoalbuminuric type 1 diabetes mellitus. Diabetologia 2002;45(4):535–41. [14] Jones-Burton C, Mishra SL, Fink JC, Brown J, Gossa W, Bakris GL, et al. An indepth review of the evidence linking dietary salt intake and progression of chronic kidney disease. Am J Nephrol 2006;26(3):268–75.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Low dietary sodium in diabetes nephropathy Ian W. Seetho a,⇑, Sarah V. O’Brien b, Kevin J. Hardy b a b
Department of Diabetes & Endocrinology, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, United Kingdom Department of Diabetes & Endocrinology, St Helens & Knowsley Teaching Hospitals NHS Trust, Marshalls Cross Road, St Helens WA9 3DA, United Kingdom
a r t i c l e
i n f o
Article history: Received 29 October 2013 Accepted 5 February 2014
a b s t r a c t In a meta-analysis that investigated the effects of dietary sodium restriction in diabetes nephropathy, although blood pressure fell, there were significant increases in plasma renin and aldosterone levels. In this article, we hypothesise that in diabetic nephropathy, ACE-I or ARB treatment attenuates any rise in RAS hormones that might result from dietary salt restriction and that the beneficial effects of the salt restriction such as a lower blood pressure outweigh any potentially negative consequences of RAS activation such as a rise in intraglomerular pressure because of the synergistic effects of sodium restriction and RAS antagonist therapy. Ó 2014 Elsevier Ltd. All rights reserved.
Background The Brenner hypothesis states that increased intraglomerular pressure leads to increased glomerular filtration of protein, nephron loss and progression of renal disease [1,2]. Antihypertensive treatment reduces systemic arterial blood pressure and therefore reduces glomerular afferent arteriolar pressure, intraglomerular pressure and protein filtration, retarding the development and progression of renal disease. Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARB) not only lower blood pressure (and therefore reduce intraglomerular pressure through a fall in afferent arteriolar pressure), but also further reduce intraglomerular pressure by selective dilatation of the glomerular efferent arteriole. Thus, the reduction in proteinuria and beneficial renal effects of ACE-I and ARB treatment exceed that which can be explained on the basis of blood pressure reduction alone [3,4]. It is known that treatment that lowers blood pressure is likely to reduce proteinuria and retard development and progression of renal disease. Inhibition of the renin-angiotensin-aldosterone system (RAS) reduces intraglomerular pressure by selective dilatation of the glomerular efferent arteriole is likely to lower proteinuria and retard development and progression of renal disease. Conversely, treatment or changes that produce persistent elevation in blood pressure are likely to increase proteinuria and increase development and progression of renal disease. Therefore it is speculated that treatment or changes that persistently increase RAS hormones might constrict efferent arterioles, increase intraglomer⇑ Corresponding author. Address: Department of Diabetes & Endocrinology, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, United Kingdom. Tel.: +44 01515295885; fax: +44 01515285888. E-mail address: [email protected] (I.W. Seetho). http://dx.doi.org/10.1016/j.mehy.2014.02.009 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
ular pressure and therefore increase proteinuria and renal disease progression. Dietary sodium restriction enhances the anti-hypertensive and anti-proteinuric effects of ARB [5,6] and ACE-I treatment [7], and protects against diabetes nephropathy progression [8,9]. But, in a recent meta-analysis studying the effects of dietary sodium restriction in diabetes nephropathy, although blood pressure fell, there were significant increases in plasma renin and aldosterone levels [10]. This rise in renin and aldosterone in response to low dietary sodium has also been noted in Yanomamo Indians who consume low dietary sodium [10,11]. Thus, dietary sodium restriction has the beneficial effects of lowering systemic arterial blood pressure, glomerular afferent arteriolar pressure and intraglomerular pressure, but increases RAS hormones which might increase glomerular efferent arteriolar tone and intraglomerular pressure.
The hypothesis We hypothesise that in diabetes nephropathy, ACE-I or ARB treatment attenuates any rise in RAS hormones that might result from dietary salt restriction and that the beneficial effects of the salt restriction (lower blood pressure) outweigh any potentially negative consequences of RAS activation (a rise in intraglomerular pressure [13]) because of the synergistic effects of sodium restriction and RAS antagonist therapy [12]. Most people with diabetes nephropathy use ACE-I or ARB treatment and so salt restriction is a broadly useful intervention. Indeed, in a review by Jones-Burton et al. [14]looking at evidence in the literature linking sodium intake in the diet with chronic kidney disease progression, no adverse effects were found with reduced dietary salt consumption [14].
552
I.W. Seetho et al. / Medical Hypotheses 82 (2014) 551–552
References
Fig. 1. Rise in RAS hormones with low sodium consumption.
Evaluation of hypothesis But what is the impact of salt restriction in diabetes nephropathy in the absence of ACE-I or ARB treatment? It is possible that even in this situation, the beneficial effects of salt restriction on blood pressure outweigh any potentially negative consequences of RAS activation, but it is also possible that without RAS inhibition by ACE-I or ARB treatment that the greater rise in RAS hormones leads to a larger rise in intraglomerular pressure, increased protein loss and subsequent disease progression (Fig. 1). Whether a low sodium diet reduces blood pressure but possibly leads to nephropathy progression without RAS antagonism with ACEIs and ARBs remains a hypothesis to be addressed in future research studies perhaps before the commencement of ACEI and ARB drug therapy given the already known beneficial effects of this treatment for diabetes nephropathy in the literature. Conflict of interest None. Sources of support We gratefully acknowledge the support of the University of Liverpool, University Hospital Aintree and St Helens & Knowsley Teaching Hospitals.
[1] Brenner BM, Meyer TW, Hostetter TH. Dietary Protein Intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 1982;307(11):652–9. [2] Martin WF, Armstrong LE, Rodriguez NR. Dietary protein intake and renal function. Nutr Metab 2005;2:25. http://dx.doi.org/10.1186/1743-7075-2-25. [3] Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Collaborative study group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345(12):851–60. [4] Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensinconverting enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med 1993;329(20):1456–62. [5] Houlihan CA, Allen TJ, Baxter AL, Panangiotopoulos S, Casley DJ, Cooper ME, et al. A low-sodium diet potentiates the effects of losartan in type 2 diabetes. Diabetes Care 2002;25(4):663–71. [6] Vogt L, Waanders F, Boomsma F, de Zeeuw D, Navis G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol 2008;19(5):999–1007. [7] Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the anitproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989;36(2):272–9. [8] Giunti S, Barit D, Cooper ME. Mechanisms of diabetic nephropathy:role of hypertension. Hypertension 2006;48(4):519–26. [9] Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 2002;61(3):1086–97. [10] Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol and triglyceride. Cochrane Database Syst Rev 2011;11:CD004022. [11] Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a ‘‘no-salt’’ culture. Circulation 1975;52:146–51. [12] Slagman MCJ, Waanders F, Hemmelder MH, Woittiez AJ, Janssen WM, Lambers Heerspink HJ, et al. Holland nephrology study group. Moderate dietary sodium restriction added to angiotensin converting enzyme. Br Med J 2011;343:d4366. [13] Luik PT, Hoogenberg K, Van Der Kleij FG, Beusekamp BJ, Kerstens MN, De Jong PE, et al. Short-term moderate sodium restriction induces relative hyperfiltration in normotensive normoalbuminuric type 1 diabetes mellitus. Diabetologia 2002;45(4):535–41. [14] Jones-Burton C, Mishra SL, Fink JC, Brown J, Gossa W, Bakris GL, et al. An indepth review of the evidence linking dietary salt intake and progression of chronic kidney disease. Am J Nephrol 2006;26(3):268–75.
