WORKSHOP LIFESTYLE AND DIET IN THE PREVENTION OF STONE DISEASE The key role of dietary calcium and sodium G. Gambaro, MD, PhD, A. Gemelli University Hospital Catholic University, Rome

Dietary factors and renal stones – rationale Changes in dietary patterns might explain changes in stone prevalence Geographic differences in stone prevalence Dietary intakes might modify urine composition Urine composition is the driving force of stone formation

NUTRITIONAL RISK FACTORS Fruits & vegetables Fructose Beverages Vitamins Overweight Calcium Oxalate Sodium Animal protein

NUTRITIONAL RISK FACTORS Fruits & vegetables Fructose Beverages Vitamins Overweight Calcium Oxalate Sodium Animal protein

Dietary calcium and renal stones 3,560 incident stones Ref. p = 0.40 p = 0.01 p = 0.005 p < 0.001 HPFS ≥60y HPFS <60y NHS I NHS II Q1 503 498 430 525 Q2 633 637 564 696 Q3 748 751 672 832 Q4 893 896 811 1008 Q5 1194 1218 1119 1357 Curhan, Ann Intern Med 1997; Curhan, Arch Intern Med 2004; Taylor, J Am Soc Nephrol 2004

Dietary calcium and urine composition Borghi, N Engl J Med 2002; Bushinsky, J Am Soc Nephrol 1998

The binding of calcium to oxalate in the gut lumen prevents the absorption of the latter

Oxalate plays a more important role than calcium in CaOx crystallization 2 mMol 0.1 mMol

Dietary calcium and renal stones Low calcium: 23/60 (38%) Normal calcium: 12/60 (20%) HR: 0.49 (0.24, 0.98; p = 0.04) 120 men w/ recurrent CaOx stones & hypercalciuria Group 1: 10 mmol/d Ca Group 2: 30 mmol/d calcium, 52 mmol/d animal protein, 50 mmol/d sodium Follow-up 5 years Borghi, N Engl J Med 2002

Calcium supplements and renal stones Curhan, N Engl J Med 1993; Ann Intern Med 1997; Arch Intern Med 2004; Jackson, N Engl J Med 2006

Calcium supplements and renal stones Timing of ingestion of calcium supplements? Usually taken without meals Other protective properties of dairy products?

Does the source of calcium matter? Dairy sources Other sources p=0.01 p=0.05 p=0.001 p=0.007 p=0.08 p=0.002 5,270 incident stones Ref. Ref. Taylor, J Urol 2013

Protein intake and renal stones Dairy p=0.59 p=0.89 p<0.01 p=0.91 p=0.69 p=0.64 Ref. Animal non-dairy Vegetable Ref. p=0.04 p=0.06 p=0.64 Ferraro, Clin J Am Soc Nephrol 2016

Schmidt JA et al. Serum Uric Acid Concentrations in Meat Eaters, Fish Eaters, Vegetarians and Vegans: A Cross-Sectional Analysis in the EPIC-Oxford Cohort. PLOS One 2013; 8(2): e56339 Hypouricemic effect of Dairy proteins Calcium

The risk of Metabolic Bone Disease in renal stone formers Investigator Measurement Method Measurement Site BMD Result Lawoyin 1979 SPA Radius ↓N Fuss 1983 ↓ Pacifici 1990 QCT Spine Bataille 1991 Borghi 1991 DPA Pietschmann 1992 DEXA, SPA Spine, radius Jaeger 1994 DEXA Spine, femur Weisinger 1996 Ghazali 1997 Giannini 1998 Misael da Silva 2002 Tasca 2002 Asplin 2003 Vezzoli 2003 Caudarella 2003 DEXA, QUS Radius, finger Melton 1998 Observed Expected Risk of fractures Coe FL et al. Effects of low-calcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects. Am J Med. 1982 Jan;72(1):25-32. Tasca 2009

NUTRITIONAL RISK FACTORS Fruits & vegetables Fructose Beverages Vitamins Overweight Calcium Oxalate Sodium Animal protein

Relationship between dietary and urinary oxalate Oxalate-free diet 12 healthy adults (6M, 6F) 29 ± 4 years Holmes, Kidney Int 2011

Dietary oxalate and renal stones 4,605 incident stones Ref. HPFS NHS I NHS II Q1 106 87 85 Q2 149 127 117 Q3 191 164 157 Q4 236 205 202 Q5 328 287 293 p = 0.01 p = 0.05 p = 0.57 Taylor, J Am Soc Nephrol 2007

Dietary oxalate and renal stones 4,605 incident stones Ref. HPFS NHS I NHS II Q1 106 87 85 Q2 149 127 117 Q3 191 164 157 Q4 236 205 202 Q5 328 287 293 Taylor, J Am Soc Nephrol 2007

Dietary oxalate and renal stones 4,605 incident stones Ref. HPFS NHS I NHS II Q1 106 87 85 Q2 149 127 117 Q3 191 164 157 Q4 236 205 202 Q5 328 287 293 p = 0.003 p = 0.54 Taylor, J Am Soc Nephrol 2007

NUTRITIONAL RISK FACTORS Fruits & vegetables Fructose Beverages Vitamins Overweight Calcium Oxalate Sodium Animal protein

Dietary sodium and renal stones ↑ urine excretion of sodium (≃dietary intake) increases urine calcium Association between dietary sodium and incident stones in WHI cohort Ref. p < 0.001 78,293 women 50-79y 1,952 incident stones Sorensen, J Urol 2012

Dietary sodium and renal stones ↑ urine excretion of sodium (≃dietary intake) increases urine calcium Association between dietary sodium and incident stones in WHI cohort No association in other longitudinal studies (HPFS, NHS I, NHS II) Curhan, Ann Intern Med 1997; Arch Intern Med 2004; Taylor, J Am Soc Nephrol 2004

Dietary sodium and renal stones ↑ urine excretion of sodium (≃dietary intake) increases urine calcium Association between dietary sodium and incident stones in WHI cohort No association in other longitudinal studies (HPFS, NHS I, NHS II) Caveat: assessment of dietary intake of sodium difficult with FFQ

Dietary sodium and calciuria and citraturia ↑ urine excretion of sodium (≃dietary intake) increases urine calcium 743 participants (407 F, 336 M) b = 0.01 (100 mmol uNa ≃ ↑ 1 mmol uCa) 90 mmol for 4 days Nouvenne A et al. Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial. Am J Clin Nutr 2010;91:565–70. Blackwood, J Hum Hypertens 2001; Lemann, Kidney Int 1991 High sodium intake is associated with low urinary citrate excretion 100 mmol uNa ≃ ↓urine citrate by 50 mg

Prezioso D et al. Dietary treatment of urinary risk factors for renal stone formation. A review of CLU Working Group. Archivio Italiano di Urologia e Andrologia 2015; 87(2), 105 Dietary calcium restriction is not recommended for stone formers with nephrolithiasis. Moderate dietary salt restriction is useful in limiting urinary calcium excretion and thus may be helpful for primary and secondary prevention of nephrolithiasis. A diet low in oxalate and/or a calcium intake normal to high (800-1200 mg/day for adults) reduce the urinary excretion of oxalate