Plasma sodium as a predictor of death and non-osmotic sodium storage

Transcription

1 An update on sodium in CKD stage 5D Plasma sodium as a predictor of death and non-osmotic sodium storage Prof. Mustafa ARICI, MD Hacettepe University Faculty of Medicine Ankara-TURKEY

2 2 (new) questions... 1) Will plasma sodium be a new marker of mortality in stage 5D CKD patients? 2) Is plasma sodium reflecting the whole lot of sodium in the body in relation to body water, or is there sodium hidden in elsewhere?

3 We are eating too much salt...

4 in Turkey...

5 SALTURK Study 1970 participants (>18 years old and able to provide a medical history and 24-h urine sample) Random allocation from 14 cities February-April 2008 The mean daily urinary Na + : 308.3±143.1 mmol/day Mean daily salt intake of g/day Erdem Y, Arici M, et al. Blood Press Oct;19(5):313-8

6 CDC: Salt in US About 90% of Americans aged 2 years or older eat too much sodium.*. 44% of the sodium we eat comes from 10 types of foods. Top Sources of Sodium in the Diet Breads and rolls Cold cuts and cured meats Pizza Poultry Soups Sandwiches Cheese Pasta dishes Meat dishes Snacks Reducing the sodium Americans eat by 1,200 mg per day on average added up to $20 billion a year in medical costs

7 How much salt CKD patients are eating?

8 How much salt CKD patients are eating? 373 consecutive outpatients with CKD stages 1 5 (not on dialysis; men: 52.3%, mean age: 51.6±15.4 years) All patients had at least 3 or more nephrology visits and received information on reducing their sodium intake 2 consecutive 24-hour urinary sodium levels were obtained Kutlugün AA, Arıcı M, et al. Nephron Clin Pract. 2011;118(4):c361-6.

9 How much salt CKD patients are eating? 10.5 g/day 10.8 g/day 10.1 g/day 9.1 g/day 7.4 g/day Kutlugün AA, Arıcı M, et al. Nephron Clin Pract. 2011;118(4):c361-6.

10 How much salt CKD 5HD patients are eating? Mc Causland FR, et al. Kidney International (2012) 82, ;

11 How much salt CKD 5HD patients are eating? A post-hoc analysis of the Hemodialysis (HEMO) Study 1770 subjects; mean age 58 (±14) years; 44% were men, 63% were black, and 44% were diabetic Reported dietary intake was assessed from 2-day diet diary assisted recalls. Recall was performed on one dialysis and one non-dialysis day (most often on consecutive days) at annual intervals. Mc Causland FR, et al. Kidney International (2012) 82, ;

12 How much salt CKD 5HD patients are eating? Mean reported diet-na was 2240 (±1050) mg/day, Median was 2080 (IQR: )mg/day Mean NaCl intake 5.5 (±2.6) g/day Median NaCl intake 5.2 ( ) g/day Mc Causland FR, et al. Kidney International (2012) 82, ;

13 Dietary Sodium in CKD 5HD UF requirement- Sytolic BP - Serum Na Distribution of UF requirement, SBP, and serum Na, and associations with daily dietary sodium intake (g/day Mc Causland FR, et al. Kidney International (2012) 82, ;

14 Dietary Sodium in CKD 5HD Mortality Association between quartiles of dietary sodium intake and mortality. Hazard ratios (95% confidence intervals (CIs)) for all cause mortality according to quartiles (Q; referent Q1) of reported daily dietary sodium intake (mg/day) Mc Causland FR, et al. Kidney International (2012) 82, ;

15 Dietary Sodium in CKD 5HD Mortality However, the clinical implications of these findings may be limited considering the small magnitude of association (90 ml requisite ultrafiltrate per 1000 mg increment in diet-na intake; 130 ml ultrafiltrate per 1 mg/kcal increment in Na:Cal). Mc Causland FR, et al. Kidney International (2012) 82, ;

16 Dietary Sodium in CKD 5HD Mortality It is possible that in HD patients other sources of sodium (e.g., loading from relatively hypernatremic dialysate), non-osmotically mediated thirst (e.g., from transient intravascular hypovolemia following dialysis), or habitual drinking may have a greater role in determining IDWG and pre-dialysis SBP than previously recognized. Mc Causland FR, et al. Kidney International (2012) 82, ;

17 Dietary Sodium & Mortality in CKD-5D? Problems with estimating dietary sodium intake? 95 % confidence interval of the spline graphs crosses the hazard ratio of 1, which indicates that the null hypothesis cannot be rejected? J-shaped or U-shaped association? No relation with blood pressure? Mehdi Rambod, Ramin Tolouian. Kidney International (2012) 82,

18 All-cause mortality ESRD Incidence MERLIN C. THOMAS, et al FOR THE FINNDIANE STUDY GROUP. Diabetes Care 34: , 2011

19 305 incident patients, (129 men, 176 women), mean age of 59.4±14.2 years Low average sodium intake independently predicted the increased risk for overall and cardiovascular death after adjusting for recognized confounders. Further adjustment for dietary protein, energy, and other nutrient intakes individually had minimal impact on the association between average sodium intake and overall death, with hazard ratios varying between 0.35 and 0.44, and cardiovascular death, with hazard ratios varying between 0.06 and Clin J Am Soc Nephrol 5: , 2010

20 My 1 st question? Will plasma sodium be a new marker of mortality in stage 5D CKD patients?

21 ...or, what's so bad about plasma sodium??

22 Hyponatremia & Mortality Hyponatremia is strongly associated with an increased risk of death (47 %); even mild hyponatremia (serum sodium concentration meq/l) is associated with a 37% increased risk of in-hospital mortality Waikar SS, Mount DM, Curhan GC. Am J Med. 2009; 122(9):

23 Then, is plasma sodium also bad for CKD 5D? Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

24 Serum Na & Mortality in CKD-5HD 1549 oligoanuric participants in the HEMO study Mean (SD) age was 57.7 (14.2) years; 57% of participants were women; 64.2% were black Primary outcome: time to death from any cause Secondary analyses: time to death from cardiovascular disease The median number of serum sodium measurements per subject was 5 (IQR:3-8) Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

25 Baseline Serum Na Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

26 Serum Sodium in CKD-5HD The most statistically significant bivariable predictors of Higher serum sodium Black race Longer vintage Higher estimated Dry weight Serum albumin Serum creatinine Lower serum sodium Diabetes Higher UF volume Serum glucose Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

27 Serum Na & Mortality in CKD-5HD Lower serum sodium concentration was associated with greater all-cause mortality (P <.001). Considered as a continuous variable, each 4- meq/l (the observed SD in the sample) increment in serum sodium concentration was associated with a hazard ratio (HR) for allcause mortality of 0.84 (95% confidence interval [CI], ). Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

28 Serum Na & Mortality in CKD-5HD Upon multivariable adjustment, the association between serum sodium concentration and mortality was modestly attenuated, but remained statistically significant: HR 0.89; 95% CI, Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

29 Serum Na & Mortality in CKD-5HD Quartile 1 ( ) Quartile 2 ( ) Quartile 3 ( ) Quartile 4 ( ) Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84.

30 Serum Na & Mortality in CKD-5HD Quartile 1 ( ) Quartile 2 ( ) Quartile 3 ( ) Quartile 4 ( ) Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

31 Serum Na & CV Mortality in CKD-5HD Quartile 1 ( ) Quartile 2 ( ) Quartile 3 ( ) Quartile 4 ( ) Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

32 Serum Na & CV Mortality in CKD-5HD Quartile 1 ( ) Quartile 2 ( ) Quartile 3 ( ) Quartile 4 ( ) Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

33 Serum Na & Mortality in CKD-5HD That low serum sodium concentrations were associated with mortality in this population lends favor to the interpretation that hyponatremia might be directly toxic. The mechanism(s) by which low serum sodium concentration may affect survival are not entirely clear. Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

34 Serum Na & Mortality in CKD-5HD Alternative Explanations? Excessive free water intake or reduced solute intake? Angiotensin 2 as a potent dipsogenic effect? Interdialytic weight gain? Cyclical alterations in serum osmolality? Dialysate sodium Sodium modeling? Waikar SS, Curhan GC, Brunelli SM. Am J Med. 2011; 1224:77-84

35 Is plasma sodium also bad for CKD 5D? Am J Kidney Dis. 59(2): ,2012

36 Serum Na & Mortality in CKD-5HD 11,555 patients from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS), phases I ( ) and III ( ). Median follow-up was 12 months, with 1,727 deaths (15%) occurring during the study period (12,274 patient-years). The first 3 serum sodium measurements to compute each patient s mean serum sodium level Am J Kidney Dis. 59(2): , 2012

37 Serum Na Levels in CKD-5HD Serum sodium level was associated Positively with Male sex Black race Body mass index Serum albumin Serum creatinine Negatively with Neurologic disease Psychiatric disease WBC count Intradialytic weight loss (0.16 meq/l lower per 1% loss) Am J Kidney Dis. 59(2): , 2012

38 Serum Na & Mortality in CKD-5HD Higher mean serum sodium level was associated with lower all-cause mortality Models with various levels of adjustment showed that this association was significant and consistent. Am J Kidney Dis. 59(2): , 2012

39 Serum Na & Mortality in CKD-5HD After controlling for 10 patient characteristics, 14 comorbid conditions, 5 laboratory parameters, and facility clustering effects and stratifying by DOPPS phase and country, patients with serum sodium levels <137 meq/l had a 45% higher risk of death compared with patients with serum sodium levels >140 meq/l (hazard ratio [HR], 1.45; 95% confidence interval [CI], ; model 5). Am J Kidney Dis. 59(2):

40 Serum Na & Mortality in CKD-5HD

41 Serum Na & Mortality in CKD-5HD Am J Kidney Dis. 59(2):

42 Dialysate Na & Mortality in CKD-5HD A scatterplot confirmed the lack of correlation between dialysate sodium concentration and mean serum sodium level. Compared with HD patients with mean serum sodium levels 140 meq/l and a dialysate sodium prescription of 140 meq/l (reference), mortality risk was higher in HD patients with mean serum sodium levels <140 meq/l and dialysate sodium prescriptions of all 3 categories (P 0.05). Am J Kidney Dis. 59(2):

43 Dialysate Na & Mortality in CKD-5HD Am J Kidney Dis. 59(2):

44 Dialysate Na & Mortality in CKD-5HD Although our mortality analyses were adjusted for patient characteristics and comorbid conditions, serum sodium level was associated with certain indicators of general health, which might point to an apparently frail phenotype of patients with lower serum sodium levels. Despite adjusting extensively for case-mix, the possibility of residual confounding remains and causality cannot be established in the setting of an observational study. Am J Kidney Dis. 59(2):

45 My 2 nd question? Is plasma sodium reflecting the whole lot of sodium in the body in relation to body water, or is there sodium hidden in elsewhere?

46 What is all going with serum Na? J Clin Invest Sep;37(9):

47 Serum Sodium Concentration & Osmolarity J Clin Invest Sep;37(9):

48 Serum Sodium Concentration in Relation to Na e + K e / TBW Edelman equation Plasma water [Na + ] = 1.11 x (Na e + K e )/TBW 25.6 J Clin Invest Sep;37(9):

49 Clasical Sodium Model 2-compartment model Na + and its accompanying anions are the principal extracellular osmoles and act to hold water in the extracellular space; conversely K + salts account for almost all the intracellular osmoles and act to hold water within the cells. Titze J. Blood Purif 2008;26:95 99

50 Clasical Sodium Model Accumulation of 140 mmol Na + thus must inevitably lead to 1 liter extracellular volume retention to maintain isosmolality in this functional twocompartment model. Titze J. Blood Purif 2008;26:95 99

51 Water-free Na+ Retention

52 Water-free Na+ Retention Heer M, et al. Am J Physiol Renal Physiol 278:F585-F595, 2000.

53 Water-free Na+ Retention Heer M, et al. Am J Physiol Renal Physiol 278:F585-F595, 2000.

54 Water-free Na+ Retention 1) An osmotically inactive Na + storage mechanism (as characterized by a cation excess relative to water), 2) An osmotically neutral cation exchange mechanism (as characterized by a replacement of K + ions with Na + ions). Titze J. Blood Purif 2008;26:95 99

55 Osmotically Inactive Sodium Storage in the Skin Compared with 0.1% NaCl diet, the skin Na + content in rats fed 8% NaCl diet was increased by 35 45%. Am J Physiol Heart Circ Physiol 287:H203-H208, 2004 This finding draws attention to the potential role of the polyanionic character of the skin GAGs in the regulation of osmotically inactive skin Na + storage. Titze J. Blood Purif 2008;26:95 99

56 Osmotically Inactive Sodium Storage in the Skin Long-term salt deprivation was associated with decreased negative charge density of skin GAGs. This decrease in the polyanionic character was associated with the mobilization of osmotically inactive Na from reservoir tissue Markus Schafflhuber, et al. Am J Physiol Renal Physiol 292:F1490-F1500, 2007

57 Traditional view of Na and fluid retention British Journal of Nutrition (2009), 101,

58 Alternative view of Na and fluid retention British Journal of Nutrition (2009), 101,

59 Salt is not silent under the skin... NATURE MEDICINE VOLUME 15 [ NUMBER 5 [ MAY 2009

60 Salt is getting under our skin Ton J. Rabelink and Joris I. Rotmans. Nephrol Dial Transplant (2009) 24:

61 Sodium sensing in the interstitium Extrarenal regulatory mechanisms at the tissue level are operating to maintain interstitial electrolyte homeostasis in a concerted action of local interstitial control of the internal environmental composition and that subsequent renal adjustments are distal to this process. Titze J & Machnik A. Current Opinion in Nephrology and Hypertension 2010, 19:

62 Classical view of Sodium Homeostasis Titze J & Machnik A. Current Opinion in Nephrology and Hypertension 2010, 19:

63 Alternative view of Sodium Homeostasis tonicityresponsive enhancer binding protein Titze J & Machnik A. Current Opinion in Nephrology and Hypertension 2010, 19:

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65 VEGF-C levels are increased by a high-salt diet in proteinuric CKD patients and in healthy subjects, supporting a role for VEGF-C-mediated interstitial regulatory mechanisms in salt homeostasis in humans

66 In conclusion... Salt is still very dangerous

67 In conclusion... there is more in plasma sodium than we think... Look carefully to your patient s lab tests, especially the plasma sodium...

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69 PNAS 104 (41): , 2007

70 In conclusion... look carefully under the skin of your patients...there is more happening there than we think...

71 In conclusion... Medicine is a science of uncertainty and an art of probability William Osler

72 In conclusion... The more I read, the more I acquire, the more certain I am that I know nothing. François-Marie Arouet de Voltaire

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