Protein Intake and Diabetic Kidney Disease

1. Protein Intake and Diabetic Kidney Disease Robert C. Stanton Joslin Diabetes Center

2. 1/Serum Creatinine Plot

3. Low Protein Protects in Renal Ablation Model 24% Protein Diet Right Nephrectomy and Infarction of about 5/6th of the left kidney 6% Protein Diet Hostetter et al, AJP, 1981; 241:F85

4. High Protein Intake is Bad for Kidney Function • T. Hostetter T.W. Meyer B.M. Brenner • Hostetter, Meyer, and Brenner. • 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. • New England Journal of Medicine 1982:307:652-659

5. Caveman

6. Proposed Paleolithic Diet Sabre-toothed Tiger Chateaubriand for 2 Mastodon Protein Intake Vegetables Whole grains TIME -Months

7. http://paleodiet.com/ • The stone age diet: Based on in-depth studies of human ecology and the diet of man. Voegtlin, Walter L. (1975). Vantage Press. • An Evolutionary Perspective Enhances Understanding of Human Nutritional Requirements. Eaton, EatonIII, Konner,Shostak. J. Nutrition 1996:126:1732 • Paleolithicnutrition.Aconsiderationofitsnatureandcurrentimplications.Eaton,Konner1985: N.Engl.J.Med.312:283 Protein Intake Estimated at 2-3 grams/kg/day which was estimated to be about 30% of the diet.

8. Diets Today Contemporary Diet Recommendations: 15-20% of calories from protein often ranging from 0.8-1.4 g/kg/day Low Protein Diets that have been Recommended/Studied <0.8 g/kg/day <0.6 g/kg/day <0.3 g/kg/day

9. Protein Intake and Kidney Disease • By what mechanisms do changes in protein intake affect progression of kidney disease? • Do low protein diets slow progression of kidney disease? • Does the source or type of protein affect outcomes?

10. Kidney

11. Glomerulus

12. Micropuncture

13. Zatz et al, PNAS, 1985; 82:5963

14. Zatz et al, PNAS, 1985; 82:5963

15. Micropuncture studies were done between 2-10 weeks after inducing diabetes • Pathology was evaluated 11-13 months after inducing diabetes

16. Zatz et al, JCI, 1986; 77:1925

17. Zatz et al, JCI, 1986; 77:1925

18. Low Protein Diets and ACE Inhibitors/ARBs Slow Progression of Kidney Disease by Lowering Glomerular Pressures MAYBE

19. Protein Intake and Kidney Disease • Do low protein diets slow progression of kidney disease?

20. Protein Intake Affects Progression • High protein diets in animal models of kidney disease hasten decline in renal function. Low protein diets in animal models preserve kidney function. • High protein diets tend to raise urine protein levels and low protein diets tend to lower urine protein levels. • Urine Protein levels above 1 gm/day are directly correlated with progression of kidney disease. • Hence lowering protein in the diet will slow progression of kidney disease. • Maybe.

21. Nurses Health Study Knight et al, Ann Intern Med. 2003;138:460-467.

22. Protein Intake

23. High Protein Intake Apparently Increased Renal Decline in Women with Mild Renal Impairment but not Normal Renal Function MAYBE

24. Protein Intake and Urinary Albumin Excretion Rates in the EURODIAB IDDM Complications Study Diabetologia 40: 19971219-1226

25. Demographics

26. Protein Intake Appears to Adversely Affect Albumin Excretion Rate Only in Patients with Hypertension or Poorer Blood Glucose Control A1c>6.4% Hypertensive

27. Effect of Low Protein Diet Correlates with Blood Pressure and Glucose Control

28. Where’s the Beef? • Correlative Study - not a longitudinal study • The correlation between progression of kidney disease and levels of albumin in the microalbuminuric range is fuzzy. (Unlike the close correlation with cardiovascular disease) • The findings might be interpreted as providing another rationale for blood pressure control and glucose control rather than providing a reason for low protein intake

29. Microalbuminuria is positively associated with usual dietary saturated fat intake and negatively associated with usual dietary protein intake in people with insulin-dependent diabetes mellitus. Am J Clin Nutr. 1998; 67:50

30. Higher Dietary Fat Correlates with Microalbuminuria whereas Higher Protein Correlates with Lower Urine Albumin Levels

31. How About Very Low Protein Diets Giordano Kidney International 1982; 22:401

32. Kidney International 2007; 71:245

38. How About Type 2 Diabetes?Moderate Protein Diet Restriction Improves Things: I think? Pomerleau et al Diabetologia (1993) 36:829-834

39. Where’s the Beef? So maybe low protein diets are not beneficial. But a chronic high protein is clearly detrimental. Right?

40. High Protein Diets and Cardiovascular Disease It has been speculated that high protein diets worsen cardiovascular disease

41. High Protein Diets Improve CV Outcomes in Women Hu et al Am J Clin Nutr, 1999, 70:221

42. Protein Excretion and Kidney Disease Urine Protein Excretion (even in the microalbuminuric range) is strongly positively associated with cardiovascular disease

43. Microalbuminuria And Ischemic Heart Disease Risk General Population 6 5 Normoalbuminuria Microalbuminuria 4 Relative risk of IHD 3 2 1 0 Male Female 10-y follow-up, n = 2,085 Borch-Johnsen et al. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997.

44. 0 10 20 30 40 50 60 70 80 90 Effect of Proteinuria on All-Cause and CVD Mortality in Patients With Type 2 Diabetes • All-cause mortality • CVD mortality 1 1 0.9 0.9 A A 0.8 0.8 B 0.7 B 0.7 Survival 0.6 0.6 Overall <0.001 A vs B 0.013 A vs C <0.001 B vs C <0.001 Overall <0.001 A vs B <0.001A vs C <0.001 B vs C <0.001 C 0.5 0.5 C 0.4 0.4 0 0 0 10 20 30 40 50 60 70 80 90 • Months • Months B: C: A: • Urinary protein <150 mg/L • 150-300 mg/L • >300 mg/L Miettinen H et al. Stroke. 1996;27:2033-2039.

45. Many studies support a connection between urine protein and cardiovascular disease. Whether increased dietary protein adversely affects cardiac outcomes in patients with proteinuria is an open question.

46. Protein Intake and Kidney Disease Does the source or type of protein affect outcomes?

47. Vegetable Protein Appears to be be non-deleterious. Knight et al, Ann Intern Med. 2003;138:460-467.

48. Fish Protein Reduces Progression to Microalbuminuria in Type 1 Diabetic Patients Mollsten et al Diabetes Care, 2001, 24:805

49. Effects of soy protein on renal function and proteinuria in patients with type 2 diabetes. Anderson et al Am J Clin Nutr.1998, 68:1347S. NO CHANGE Soy diet worsened proteinuria

50. Following the Tradition