plasma sodium as a predictor of death and non-osmotic ... · plasma sodium as a predictor of death...

Plasma sodium as a predictor

of death and non-osmotic sodium storage

Prof. Mustafa ARICI, MD Hacettepe University Faculty of Medicine

Ankara-TURKEY

An update on sodium in CKD stage 5D

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 ?

We are eating too much salt....

in Turkey....

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 18.01 g/day

Erdem Y, Arici M, et al. Blood Press. 2010 Oct;19(5):313-8

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.

.

Reducing the sodium Americans eat by 1,200 mg per day on average added up to $20 billion

a year in medical costs

http://www.cdc.gov/vitalsigns/Sodium/index.html

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

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.


Kutlugün AA, Arıcı M, et al. Nephron Clin Pract. 2011;118(4):c361-6.


10.5

g/day

10.8

g/day 10.1

g/day 9.1

g/day 7.4

g/day

Mc Causland FR, et al. Kidney International (2012) 82, 204–211;

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.


Mean reported diet-Na was

2240 (±1050) mg/day,

Median was 2080

(IQR: 1490–2850)mg/day

Mean NaCl intake 5.5 (±2.6) g/day

Median NaCl intake 5.2 (3.7-7.1) g/day



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


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)


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).



• 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.



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, 130 – 132

MERLIN C. THOMAS, et al FOR THE FINNDIANE STUDY GROUP. Diabetes Care 34:861–866, 2011

All-cause mortality ESRD Incidence

• 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 0.11.

Clin J Am Soc Nephrol 5: 240–247, 2010

My 1st question?

Will plasma sodium be a

new marker of mortality in

stage 5D CKD patients?

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

Hyponatremia & Mortality

Hyponatremia is strongly associated with an increased risk of death (47

%); even mild hyponatremia (serum sodium concentration 130-134

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):857-865.

Then, is plasma sodium also bad for CKD 5D ?

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

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)


Baseline Serum Na


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

• 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 all-cause mortality of 0.84 (95% confidence interval [CI], 0.78-0.90).



Upon multivariable adjustment, the association between serum sodium

concentration and mortality was modestly attenuated, but remained statistically significant: HR 0.89; 95%

CI, 0.82-0.96.




Quartile 1 (115-136) Quartile 2 (137-138) Quartile 3 (139-141) Quartile 4 (142-154)

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

Serum Na & CV 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.



• 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 ?

Serum Na & Mortality in CKD-5HD Alternative Explanations ?


Am J Kidney Dis. 59(2):238-248,2012

Is plasma sodium also bad for CKD 5D ?

• 11,555 patients from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS), phases I (1996-2001) and III (2005-2008).

• 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):238-248, 2012

• Serum sodium level was associated

Serum Na Levels in CKD-5HD

Am J Kidney Dis. 59(2):238-248, 2012

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)

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):238-248, 2012

• 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], 1.26-1.67; model 5).


Am J Kidney Dis. 59(2):238-248. © 2012

• 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 (P0.05).

Dialysate Na & Mortality in CKD-5HD

Am J Kidney Dis. 59(2):238-248. © 2012

• 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):238-248. © 2012

My 2nd 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 ?

J Clin Invest. 1958 Sep;37(9):1236-56.

What is all going with serum Na?

Serum Sodium Concentration & Osmolarity

J Clin Invest. 1958 Sep;37(9):1236-56.

Serum Sodium Concentration in Relation to Nae + Ke / TBW

Edelman equation Plasma water [Na + ] = 1.11 x (Na e + K e )/TBW – 25.6

J Clin Invest. 1958 Sep;37(9):1236-56.

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

Accumulation of 140 mmol Na + thus must inevitably lead to 1

liter extracellular volume retention to maintain isosmolality

in this functional two-compartment model.

Clasical Sodium Model


Water-free Na+ Retention


Heer M, et al. Am J Physiol Renal Physiol 278:F585-F595, 2000.

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).



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.


• 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

Osmotically Inactive Sodium Storage in the Skin

Traditional view of Na and fluid retention

British Journal of Nutrition (2009), 101, 1286–1294

Alternative view of Na and fluid retention

British Journal of Nutrition (2009), 101, 1286–1294

Salt is not “silent” under the skin....

NATURE MEDICINE VOLUME 15 [ NUMBER 5 [ MAY 2009

Salt is getting under our skin

Ton J. Rabelink and Joris I. Rotmans. Nephrol Dial Transplant (2009) 24: 3282–3283

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, 19:385–392

Classical view of Sodium Homeostasis


Alternative view of Sodium Homeostasis


tonicity-responsive enhancer binding protein

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

In conclusion.... Salt is still very dangerous

• Look carefully to your patient’s lab tests, especially the plasma sodium....

In conclusion.... there is more in plasma sodium than we think....

PNAS 104 (41): 16281-16286, 2007

In conclusion.... look carefully under the skin of your patients...there is more

happening there than we think...

In conclusion......

Medicine is

a science of

uncertainty and an

art of probability

William Osler

“The more I read,

the more I

acquire, the more

certain I am that

I know nothing.”

François-Marie Arouet de Voltaire

In conclusion......

plasma sodium as a predictor of death and non-osmotic ... · plasma sodium as a predictor of death...

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