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Dietary salt and renal stone disease
THE LANCET
Urinary Na:K ratio* (mean for quartile)
Age, years (mean)
Urinary stone disease (%)
Men
1·88 3·11 4·41 7·27
46·8 48·7 49·2 51·3
2·4 4·3 5·1 6·5
Women
1·93 3·29 4·65 7·64
49·4 50·4 51·3 53·2
1·2 2·0 3·1 4·1
Logistic regression coefficient† Age-adjusted (p<0·05)
Multivariate adjusted‡ (p<0·05)
.. .. .. .. 0·0849 .. .. .. .. 0·1060
.. .. .. .. 0·0838 .. .. .. .. 0·1095
*Na mmol/L:K mmol/L; †Difference in prevalence of urinary stone disease per unit difference in urinary Na:K ratio (for men, mean Na:K was 4·16 [SD 2·35], for women 4·37 [2·46]; thus, for men 1 SD higher Na/K ratio was associated with 1·218 higher prevalence of renal stone disease and for women 1·309 higher, based on multivariate adjusted coefficients). ‡Adjusted for age, body mass index, treatment with allopurinol, treatment with thiazide diuretic (including chlorthalidone).
Relation of sodium:potassium ratio in morning first-void urine to prevalence of renal stone disease, men and women aged 25–74, Gubbio Population Study
As expected, on the basis of these facts, the Na:K ratio in morning firstvoided urine was significantly and independently related to prevalence of urinary stone disease in both men (n=1658) and women (n=1967) aged 25–74 at baseline in the Gubbio Population Study (table). 2 Results were similar with exclusion of five persons with urinary stone disease and plasma creatinine concentration greater than 0·106 µmol/L, and with inclusion in the multiple logistic model of plasma uric acid and reported alcohol intake. Correspondingly, the urinary sodium:creatinine ratio was positively related to renal stone disease (p=0·0002) and potassium:creatinine was inversely related (p=0·079) in a multiple logistic analysis with these variables, instead of the sodium:potassium ratio. During the 20th century in industrialised countries, occurrence of calcium-rich stone formation in the upper urinary tract has increased, 2 which must have an environmental, rather than genetic, basis: renal stone disease may be linked to affluence, with multiple dietary risk factors. 2–4 As noted by Unwin,1 a key aim of both prevention and treatment is to reduce urinary calcium excretion. Substantial reductions of dietary salt can contribute to achievement of this goal. In industrialised countries, salt is a major food additive; 75% and more of ingested salt—totalling an average of 9—10 or more grams per day (Ä155–172 mmol)—comes from processed and manufactured foods. 3,4 The food industry can help reduce salt intake (eg, to <6 g [100 mmol] per day), thereby contributing to the prevention and control of nephrolithiasis, and other diseases linked to excess salt intake. 3–5 Jeremiah Stamler, Massimo Cirillo Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois, USA; and Medical School of Second University of Naples, Italy
Vol 349 • February 15, 1997
1
2
3
4
5
Unwin R, Wrong O, Cohen E, Tanner M, Thakker R. Grand round: unravelling of the molecular mechanisms of kidney stones. Lancet 1996; 348: 1561–65. Cirillo M, Laurenzi M, Panarelli W, Stamler J. Urinary sodium-to-potassium ratio and urinary stone disease. Kidney International 1994; 46: 1133–39. National Research Council, Committee on Diet and Health, Food and Nutrition Board. Commission on Life Science. Diet and health: implications for reducing chronic disease risk. Washington DC: National Academy Press, 1989. Stamler J. The INTERSALT Study: backgrounds, methods, findings, and implications. Am J Clin Nutr (in press). Department of Health. Nutritional aspects of cardiovascular disease. Report of the Cardiovascular Review Group, Committee on Medical Aspects of Food Policy. London: HM Stationery Office, 1994 (Report on Health and Social Subjects #46).
SIR—In his Grand Round discussion on the molecular mechanisms of kidney stones (Dec 7, p 1561). 1 Thakker emphasises the discovery of gene mutations affecting the renal chloride channel CLCN5 in two rare types of hereditary nephrolithiasis (Dent’s disease and X-linked recessive nephrolithiasis [XRN]). He refers to a possible link between loss of renal chloride-channel function and the hypercalciuria responsible for nephrolithiasis. The channels encoded by the CLC genes are not the only type of chloride channels expressed in the kidney and we think that some support for the hypothesis formulated might come from consideration of cystic fibrosis, an autosomal recessive disease that is much more common than Dent’s disease or XRN. The cystic fibrosis gene encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions mainly as a cAMP-regulated chloride channel. Failure of CFTR activation accounts for most of the clinical features of cystic fibrosis in trachea,
pancreas, and intestine. 2 Because of its involvement in these secretory epithelia, CFTR was not thought to play a critical part in a reabsorptive organ such as the kidney. However, wild-type CFTR is expressed in kidney tubule epithelial cells, with a progressive increase during nephrogenesis and persistence after birth. 3 Although there is no characteristic renal phenotype in cystic fibrosis, microscopic nephrocalcinosis and hypercalciuria have been encountered in patients with the disease. Furthermore, the absence of renal dysfunction in these patients, and the detection of these abnormalities at birth, suggested that a primary abnormality of calcium metabolism in the kidney was present. 4 When considering a putative mechanism to link chloride-channel function and calcium reabsorption, Thakker evokes a loss of function of these channels in intracellular organelles at the proximal tubule level. It is puzzling that CFTR expressed within kidney tubule cells, especially those of the proximal tubule, can be found within endosomes and other vesicles. 3 Furthermore, defective acidification of intracellular organelles in cystic fibrosis5 suggests that, in intracellular membranes, CFTR may indeed function in parallel with proton (H+) pumps. Thus, the link between a defect in chloride-channel function and hypercalciuria is not restricted to diseases associated with mutations in the CLCN5 channel. Absence of clinical manifestations of hypercalciuria in cystic fibrosis might be due to the lethal course of the disease (mean survival <30 years 2) or, alternatively, to tissue-specific protective mechanisms. Olivier Devuyst Division of Nephrology, St Luc Academic Hospital, University of Louvain Medical School, B-1200 Brussels, Belgium
1
2
3
4
5
Wrong O, Unwin R, Cohen E, Tanner M, Thakker R, Fine LG. Grand round: unravelling of the molecular mechanisms of kidney stones. Lancet 1996; 348: 1561–65. Welsh MJ, Tsui LC, Boat TF, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 1995: 3799–876. Devuyst O, Burrow CR, Schwiebert EM, Guggino WB, Wilson PD. Developmental regulation of CFTR expression during human nephrogenesis. Am J Physiol 1996; 271: F723–35. Moriber-Katz S, Krueger LJ, Falkner B. Microscopic nephrocalcinosis in cystic fibrosis. N Engl J Med 1988; 319: 263–66. Barasch J, Kiss B, Prince A, Saiman L, Gruenert D, Al-Awqati Q. Defective acidification of intracellular organelles in cystic fibrosis. Nature 1991; 352: 70–73.
507
Urinary Na:K ratio* (mean for quartile)
Age, years (mean)
Urinary stone disease (%)
Men
1·88 3·11 4·41 7·27
46·8 48·7 49·2 51·3
2·4 4·3 5·1 6·5
Women
1·93 3·29 4·65 7·64
49·4 50·4 51·3 53·2
1·2 2·0 3·1 4·1
Logistic regression coefficient† Age-adjusted (p<0·05)
Multivariate adjusted‡ (p<0·05)
.. .. .. .. 0·0849 .. .. .. .. 0·1060
.. .. .. .. 0·0838 .. .. .. .. 0·1095
*Na mmol/L:K mmol/L; †Difference in prevalence of urinary stone disease per unit difference in urinary Na:K ratio (for men, mean Na:K was 4·16 [SD 2·35], for women 4·37 [2·46]; thus, for men 1 SD higher Na/K ratio was associated with 1·218 higher prevalence of renal stone disease and for women 1·309 higher, based on multivariate adjusted coefficients). ‡Adjusted for age, body mass index, treatment with allopurinol, treatment with thiazide diuretic (including chlorthalidone).
Relation of sodium:potassium ratio in morning first-void urine to prevalence of renal stone disease, men and women aged 25–74, Gubbio Population Study
As expected, on the basis of these facts, the Na:K ratio in morning firstvoided urine was significantly and independently related to prevalence of urinary stone disease in both men (n=1658) and women (n=1967) aged 25–74 at baseline in the Gubbio Population Study (table). 2 Results were similar with exclusion of five persons with urinary stone disease and plasma creatinine concentration greater than 0·106 µmol/L, and with inclusion in the multiple logistic model of plasma uric acid and reported alcohol intake. Correspondingly, the urinary sodium:creatinine ratio was positively related to renal stone disease (p=0·0002) and potassium:creatinine was inversely related (p=0·079) in a multiple logistic analysis with these variables, instead of the sodium:potassium ratio. During the 20th century in industrialised countries, occurrence of calcium-rich stone formation in the upper urinary tract has increased, 2 which must have an environmental, rather than genetic, basis: renal stone disease may be linked to affluence, with multiple dietary risk factors. 2–4 As noted by Unwin,1 a key aim of both prevention and treatment is to reduce urinary calcium excretion. Substantial reductions of dietary salt can contribute to achievement of this goal. In industrialised countries, salt is a major food additive; 75% and more of ingested salt—totalling an average of 9—10 or more grams per day (Ä155–172 mmol)—comes from processed and manufactured foods. 3,4 The food industry can help reduce salt intake (eg, to <6 g [100 mmol] per day), thereby contributing to the prevention and control of nephrolithiasis, and other diseases linked to excess salt intake. 3–5 Jeremiah Stamler, Massimo Cirillo Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois, USA; and Medical School of Second University of Naples, Italy
Vol 349 • February 15, 1997
1
2
3
4
5
Unwin R, Wrong O, Cohen E, Tanner M, Thakker R. Grand round: unravelling of the molecular mechanisms of kidney stones. Lancet 1996; 348: 1561–65. Cirillo M, Laurenzi M, Panarelli W, Stamler J. Urinary sodium-to-potassium ratio and urinary stone disease. Kidney International 1994; 46: 1133–39. National Research Council, Committee on Diet and Health, Food and Nutrition Board. Commission on Life Science. Diet and health: implications for reducing chronic disease risk. Washington DC: National Academy Press, 1989. Stamler J. The INTERSALT Study: backgrounds, methods, findings, and implications. Am J Clin Nutr (in press). Department of Health. Nutritional aspects of cardiovascular disease. Report of the Cardiovascular Review Group, Committee on Medical Aspects of Food Policy. London: HM Stationery Office, 1994 (Report on Health and Social Subjects #46).
SIR—In his Grand Round discussion on the molecular mechanisms of kidney stones (Dec 7, p 1561). 1 Thakker emphasises the discovery of gene mutations affecting the renal chloride channel CLCN5 in two rare types of hereditary nephrolithiasis (Dent’s disease and X-linked recessive nephrolithiasis [XRN]). He refers to a possible link between loss of renal chloride-channel function and the hypercalciuria responsible for nephrolithiasis. The channels encoded by the CLC genes are not the only type of chloride channels expressed in the kidney and we think that some support for the hypothesis formulated might come from consideration of cystic fibrosis, an autosomal recessive disease that is much more common than Dent’s disease or XRN. The cystic fibrosis gene encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions mainly as a cAMP-regulated chloride channel. Failure of CFTR activation accounts for most of the clinical features of cystic fibrosis in trachea,
pancreas, and intestine. 2 Because of its involvement in these secretory epithelia, CFTR was not thought to play a critical part in a reabsorptive organ such as the kidney. However, wild-type CFTR is expressed in kidney tubule epithelial cells, with a progressive increase during nephrogenesis and persistence after birth. 3 Although there is no characteristic renal phenotype in cystic fibrosis, microscopic nephrocalcinosis and hypercalciuria have been encountered in patients with the disease. Furthermore, the absence of renal dysfunction in these patients, and the detection of these abnormalities at birth, suggested that a primary abnormality of calcium metabolism in the kidney was present. 4 When considering a putative mechanism to link chloride-channel function and calcium reabsorption, Thakker evokes a loss of function of these channels in intracellular organelles at the proximal tubule level. It is puzzling that CFTR expressed within kidney tubule cells, especially those of the proximal tubule, can be found within endosomes and other vesicles. 3 Furthermore, defective acidification of intracellular organelles in cystic fibrosis5 suggests that, in intracellular membranes, CFTR may indeed function in parallel with proton (H+) pumps. Thus, the link between a defect in chloride-channel function and hypercalciuria is not restricted to diseases associated with mutations in the CLCN5 channel. Absence of clinical manifestations of hypercalciuria in cystic fibrosis might be due to the lethal course of the disease (mean survival <30 years 2) or, alternatively, to tissue-specific protective mechanisms. Olivier Devuyst Division of Nephrology, St Luc Academic Hospital, University of Louvain Medical School, B-1200 Brussels, Belgium
1
2
3
4
5
Wrong O, Unwin R, Cohen E, Tanner M, Thakker R, Fine LG. Grand round: unravelling of the molecular mechanisms of kidney stones. Lancet 1996; 348: 1561–65. Welsh MJ, Tsui LC, Boat TF, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 1995: 3799–876. Devuyst O, Burrow CR, Schwiebert EM, Guggino WB, Wilson PD. Developmental regulation of CFTR expression during human nephrogenesis. Am J Physiol 1996; 271: F723–35. Moriber-Katz S, Krueger LJ, Falkner B. Microscopic nephrocalcinosis in cystic fibrosis. N Engl J Med 1988; 319: 263–66. Barasch J, Kiss B, Prince A, Saiman L, Gruenert D, Al-Awqati Q. Defective acidification of intracellular organelles in cystic fibrosis. Nature 1991; 352: 70–73.
507