Content

 Recap

 Study:
 Methods
 Results
 Discussion
 Strong points
 Weak points

 Take home message

Recap
 Cl - most abundant anion (extracellular fluid)
 Na - most abundant cation (extracellular fluid)
 Electroneutrality – Hidric/acidobazic balance
 Cl – fluid homeostasis-> high levels of Cl in the distal tube
-> supressed renin secretion.
 WNK (lysine deficient protein kinase)1 & 4 -> activity of NaCl
cotransporter (under Cl regulation)
 WNK 3 -> activity NaKCl2 ->sensing intracelular Cl

 Loop of Henle  Distal tube

CKD & Electrolyte abnormalities
 Electrolyte abnormalities - common complications

 Hyponatremia highly clinically relevant – well

established prognostic marker - poor outcomes -
death, CVE, progression of CKD and fracture.

 Hypochloremia? (Cl merely as counter of Na -

received little attention  ).
Methods
 Retrospective cohort study
 2661 pts CKD 3-5 non D
 11 years (Apr 2005 – May 2016)
 Exclusion- RTT/NaHCO3
 Cl at 3mths -> 4 grps (<104, 105-106, 107-108, >109)
 End-points:…….
 median follow-up of 4y-> 284
d, 416 h, RRT 335.

 loop and thiazide diuretics little

effect on serum Cl levels vs
spironolactone slightly increased
serum Cl levels.

 The change in serum Cl levels

over the study period was
trivial
Results
Patients in the first Cl quartile showed a 2.52-fold higher risk (95% CI 1.89–3.37; P<0.001) of the
composite endpoint compared with patients in the third Cl quartile.

The risk remained significant after adjustment for demographics and clinical factors: serum Na
levels, bicarbonate levels, anion gap and medication dose.
 Risk of death and cardiovascular hospitalizations
increases as serum chloride levels decrease

Model is adjusted for age, sex, body mass index, systolic blood pressure, diabetes mellitus, past hospitalizations
due to cardiovascular diseases, estimated glomerular filtration rate, hemoglobin, albumin, calcium, phosphate,
sodium, bicarbonate levels and medication dose (loop and thiazide diuretics, spironolactone and sodium
bicarbonate). The reference value of chloride is 107 mEq/L.
 Subgroup analysis -> no
significant effect
modification; the
interaction terms between
Cl and these covariates
were not significant.
 The risk in the first Cl
quartile was consistently
higher across all subgroups
 No significance in any
subgroups.
 Of note:
 the risk was elevated not only in
the lower Na subgroup (HR 2.04;
95% CI 1.48–2.80; P<0.001) but
also the higher Na subgroup (HR
1.65; 95% CI 1.23–2.23; P 0.001)
 LVEF not differ across Cl
quintiles (the median were
65%, 66%, 66%, 66%) The
first Cl quartile exhibited an
increased risk of all-cause
death and cardiovascular
hospitalizations.
 Serum Cl levels were not
associated with the risk of
progression to ESRD
Partea asta nu o inteleg!
 In reclassification analysis, both Cl and
Na improved the prediction of the
outcome. However, adding serum Na
levels to the multivariable model
including serum Cl levels improved
neither NRI nor IDI. In contrast, adding
serum Cl levels to the multivariable
model including serum Na levels
significantly improved the risk
prediction assessed by NRI and IDI. The
C-statistic of the multivariable model
without Cl and Na was 0.719. The
magnitude of improvement in the C-
statistic after the addition of Cl was
greater than after the addition of Na,
although it did not reach statistical
significance
 *the category-free net reclassification
index (NRI), the integrated
discrimination improvement (IDI) and
Harrell’s C-statistic were estimated
Discussion
 although serum Cl levels are routinely measured in daily
clinical practice of patients with CKD, the implication of
hypochloremia, unlike that of hyponatremia, has not been
fully studied.
 previous cohort study that found a significant association
between lower Cl and the elevated risk of death and CVE in
CKD did not address several important confounders
especially regarding acid–base disturbances
 previous study showed a J-shaped association of serum Cl
levels with mortality and CVE vs the risk was
monotonically decreased with increasing serum Cl levels.
Strong points
 validated this significant association in a larg sample
size, with adjustment for bicarbonate levels, anion gap,
and use of diuretics and sodium bicarbonate.

 time varying serum Cl levels thus accounting for its

variation over the course of CKD progression.

 the result was maintained even among patients

without hyponatremia
Weak points
 observational study design, which precludes causal
inference between Cl and prognosis of CKD patients
 no information about the volume status and severity of
underlying heart diseases
 information about hospitalizations outside the
hospital was not available -> it was not included in the
survival analyses
 this study was conducted in a single nephrology
center, the external validity should be further
confirmed
Take home messages
 we should now recognize the predictive role of Cl in
the mortality of CKD patients
 pay more attention to Cl in the clinical management of
patients with CKD
 clinically, lower serum Cl levels are related to poorer
loop diuretic responsiveness
 the prognostic impact of low Cl could be independent
of that of anion gap
 future interventional studies are required
Va multumesc!