1. HYPERTENSION MORE THAN BLOOD PRESSURE ALONE!

2. Richard Bright( 1789-1858) the First Nephrologist* First observation of “hardened pulse”and renal damage at autopsy (1827) * Source: Richard Bright Web-page Internet First observation association of cardiac hypertrophy and shrunken kidneys (1836)

3. Hypertension: classical concepts Causal factorshypertension Target organ damage Brain Heart Kidney

4. Hypertension: classical concepts Causal factorshypertension Target organ damage Brain Heart Kidney HYPERTENSION FOLLOWS THE KIDNEY

5. Hypertension: classical concepts Causal factorshypertension Target organ damage Brain Heart Kidney HYPERTENSION FOLLOWS THE KIDNEY

6. Epidemiology Prevalence of hypertension very different between populations Hypertension is associated with end organ damage

7. Relationship between sodium intake and blood pressure around the world: population studies Northern Japan Southern Japan US Marshall islands Inuit Meneely & Dahl, 1961

8. Low salt and high salt populations

9. Relationship between sodium intake and end-organ damage portugal holland germany spain italy malta finland UK denmark iceland

10. Hypertension and CV mortality Domanski, JAMA 2002 Higher BP: worse outcome SBP and DBP are independent risk factors There is NO clearcut lower treshold!

11. Hypertension and end stage renal failure Hypertension and end stage renal failure Brancati, NEJM 1996 Higher BP: worse outcome SBP and DBP are independent risk factors There is NO clearcut lower treshold!

12. The remedy Lower blood pressure

13. The remedy Lifestyle intervention; Drug treatment Lower blood pressure Reduction target organ damage > Better outcome

14. The remedy Lifestyle intervention; Drug treatment Lower blood pressure Reduction target organ damage > Better outcome BENEFIT OF TREATMENT IS NOT EQUAL FOR ALL PATIENTS ! LIFESTYLE INTERVENTION & DRUG TREATMENT CAN POTENTIATE EACH OTHER ! INTERVENTION CAN IMPROVE OUTCOME ALSO INDEPENDENT OF EFFECT ON BLOOD PRESSURE !

15. The remedy Lifestyle intervention; Drug treatment Lower blood pressure Reduction target organ damage > Better outcome BENEFIT OF TREATMENT IS NOT EQUAL FOR ALL PATIENTS ! LIFESTYLE INTERVENTION & DRUG TREATMENT CAN POTENTIATE EACH OTHER ! INTERVENTION CAN IMPROVE OUTCOME ALSO INDEPENDENT OF EFFECT ON BLOOD PRESSURE !

16. Meta Analysis: Lower SBP Results in Less GFR Decline in Diabetics and Non-Diabetics 9598101104107110113116119 r = 0.69; P <0.05 MAP (mm Hg) GFR (mL/min/year) Untreated hypertension 0 -2 -4 -6 -8 -10 -12 -14 Parving HH et al. Br Med J. 1989 Viberti GC et al. JAMA. 1993 Klahr S et al. N Eng J Med. 1993* Hebert L et al. Kidney Int. 1994 Lebovitz H et al. Kidney Int. 1994 Maschio G et al. N Engl J Med. 1996* Bakris GL et al. Kidney Int. 1996 Bakris GL. Hypertension. 1997 GISEN Group. Lancet. 1997* *:Studies in nondiabetic nephropathy. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. 140/90130/85

17. PROTECTIVE EFFECT OF LOWER BLOOD PRESSURE ON LONG TERM RENAL OUTCOME DEPENDS ON PROTEINURIA ! Effect of poor BP control on GFR decline is larger in proteinuria Effect of poor BP control on GFR decline is larger in proteinuria Need for lower target blood pressure in proteinuric patients !!! Need for lower target blood pressure in proteinuric patients !!! MDRD study Peterson, Ann Int Med 1995; 123:745 Uprot :

18. Patients with vulnerable kidneys need a lower blood pressure ! ProteinuriaDiabetes

19. No specific vulnerability: More liberal regimen jusitified

20. The remedy Lifestyle intervention; Drug treatment Lower blood pressure Reduction target organ damage > Better outcome BENEFIT OF TREATMENT IS NOT EQUAL FOR ALL PATIENTS ! LIFESTYLE INTERVENTION & DRUG TREATMENT CAN POTENTIATE EACH OTHER ! INTERVENTION CAN IMPROVE OUTCOME ALSO INDEPENDENT OF EFFECT ON BLOOD PRESSURE !

21. Control of sodium status improves response to RAAS-blockade Uprot, g/d MAP, mmHG Heeg, Kidney Int 1989; 36,272Vogt en Waanders, JASN 2008 ACEi AIIA

22. The remedy Lifestyle intervention; Drug treatment Lower blood pressure Reduction target organ damage > Better outcome BENEFIT OF TREATMENT IS NOT EQUAL FOR ALL PATIENTS ! LIFESTYLE INTERVENTION & DRUG TREATMENT CAN POTENTIATE EACH OTHER ! INTERVENTION CAN IMPROVE OUTCOME ALSO INDEPENDENT OF EFFECT ON BLOOD PRESSURE !

23. Effect of high salt intake on long term outcome Is it all blood pressure??

24. Salt intake: effects on mortality in general population Increased mortality risk per 6 gr rise in salt intake Increased mortality risk per 6 gr rise in salt intake Interaction with BMI > 27 Interaction with BMI > 27 –HR normal weight: 0,98 ns –HR overweight : 1,56 –Effect ONLY present in overweight subjects Tuomilehto, Lancet 2001; 357:848-51

25. Sodium-sensitivity in obesity hypertension is reversible by weight loss 250 vs 30 mmol Na+; 2-weeks 250 vs 30 mmol Na+; 2-weeks Weight loss > 1 kg by 20-week program Weight loss > 1 kg by 20-week program Weight excess is a main determinant of sodium- sensitivity of blood pressure Weight excess is a main determinant of sodium- sensitivity of blood pressure Rocchini AP, NEJM 1989: 322: 476-7

26. Salt intake: effects on mortality in general population Increased mortality risk per 6 gr rise in salt intake Increased mortality risk per 6 gr rise in salt intake –Effect INDEPENDENT OF BLOOD PRESSURE! Tuomilehto, Lancet 2001; 357:848-51

27. High salt increases albuminuria in healthy subjects, independent of blood pressure A rise in salt intake leads to a 25 % rise in UAE in healthy volunteers without even a rise in BP ! A rise in salt intake leads to a 25 % rise in UAE in healthy volunteers without even a rise in BP ! JA Krikken, Kidney Int 2007: 71: 260-265

28. Salt status: associated with albuminuria independent of BP, but dependent on BMI (n=7913, Prevend population ) JC Verhave, Eur J Clin Invest 2004: 256: 324-30 27,3-67 24-27,3 16,3-24 BMI:

29. INTERACTION SODIUM STATUS-WEIGHT EXCESS Sodium sensitivity of blood pressure Sodium sensitivity of blood pressure Blood pressure Blood pressure CV outcomes – BP dependent AND BP independent CV outcomes – BP dependent AND BP independent Risk markers (NT-proBNP, UAE) Risk markers (NT-proBNP, UAE)

30. SODIUM EXCESS AND WEIGHT EXCESS Deadly twins! In normotensive AND in hypertensive subjects

31. SODIUM EXCESS AND WEIGHT EXCESS Deadly twins! MECHANISM ?

32. Effect of overweight on extracellular volume during low vs high sodium intake In slightly overweight young men, ECV is higher than in lean subjects, ONLY during high sodium In slightly overweight young men, ECV is higher than in lean subjects, ONLY during high sodium This is NOT accompanied by higher blood pressure. This is NOT accompanied by higher blood pressure. It IS accompanied by a rise in NT-proBNP: marker of CV risk It IS accompanied by a rise in NT-proBNP: marker of CV risk Visser en Krikken et al, Obesity, in press

33. Weight excess/obesity Weight excess/obesity Volume expanded during high sodium Volume expanded during high sodium In hypertensives: > rise in blood pressure In hypertensives: > rise in blood pressure In young normotensives: no signs at the outside In young normotensives: no signs at the outside

34. SODIUM SENSITIVITY = HIGHER ECV In young healthy volunteers ECV is higher in SS individuals, in particular, but not only, during high sodium In young healthy volunteers ECV is higher in SS individuals, in particular, but not only, during high sodium F.Visser, Am J Hyp 2008,21:323

35. Weight excess and high sodium Weight excess and high sodium A sodium-induced rise in BP may be the tip of the Iceberg, the ECV expansion underneath being the true pathogenetic factor hypothesis

36. Low Na+ diet reduces CV events and mortality on long term follow up (TOHP I and II) Prehypertensive subjects Prehypertensive subjects Dietary counseling n=327/1191, control 417/1191 Dietary counseling n=327/1191, control 417/1191 Baseline sodium excreton 150/182 mmol/d Baseline sodium excreton 150/182 mmol/d Reduction 50-40 mmol/d Reduction 50-40 mmol/d Blood pressure effect during trial hardly present Blood pressure effect during trial hardly present Most subjects overweight Most subjects overweight Cook, BMJ, april 20, 2007 TOHP I

37. The remedy Lifestyle intervention; Drug treatment Lower blood pressure Reduction target organ damage > Better outcome

39. Do you know the sodium intake of your patients?

40. 24-hour urine: unbiased and cheap assessment of sodium intake Allows unbiased feedback for patients

41. Do you know the PROTEIN intake of your patients? 24-hour urine: unbiased and cheap assessment of protein intake (urea excretion) Allows unbiased feedback for patients

43. Recommendations Gezondheidsraad limited effect of lowering sodium intake on prevention of hypertension on population level limited effect of lowering sodium intake on prevention of hypertension on population level use modest amounts of sodium (max 6 g) use modest amounts of sodium (max 6 g) combine these diet changes with low fat and high fruit intake combine these diet changes with low fat and high fruit intake hypertensives: replace other minerals for sodium hypertensives: replace other minerals for sodium