Editor - The concept of “dialysis unphysiology” was first discussed by Carl Kjellstrand in 1975 (1) for the possible negative effects of the unphysiology of intermittent dialysis treatment. Kjellstrand argued that current intermittent hemodialysis practice is unphysiologic because it doesn't keep blood chemistries within normal limits, both before and after dialysis. The role that fluctuations in sodium concentration might make to this unphysiologic state, and in turn, to outcomes in dialysis patients has received scant attention. Dr Finnian McCausland and Dr. Susrut Waikar from the Brigham and Women’s Hospital / Harvard Medical School published a recent paper in NDT that examines this issue.
Dr McCausland received his medical training from University College Dublin, Ireland. He completed his internal medicine and nephrology training in Ireland before joining the combined Nephrology Program of Brigham and Women's/Massachusetts General Hospital in 2009. He is currently enrolled in the Scholars in Clinical Science Program of Harvard Medical School - active research interests include hemodialysis related electrolyte disturbances, hypotension and cardiovascular disease.
COMMENTARY- Dr. Finnian McCausland
Hyponatremia has been associated with adverse short and long-term outcomes in many subgroups of hospitalized patients (2). We previously investigated this association in chronic hemodialysis patients - a unique population to study, as they generally have little or no urine output, limiting the renal effects of vasopressin in the maintenance of osmolality. We found that the increased mortality associated with hyponatremia was present in dialysis patients also (3).
We then decided to further investigate the influence of differing dialysate sodium concentrations on serum sodium, systolic blood pressure and mortality in a sample of 2270 chronic hemodialysis patients (4). We originally hypothesized that those with lower pre-dialysis serum sodium who were dialyzed against a higher dialysate sodium (>140 mmol/L or modeled) would have worse outcomes compared to those who dialyzed against a lower dialysate sodium (≤140mmol/L).
The main results of our study confirmed our previous findings of increased mortality in those with lower pre-dialysis serum sodium - HR 0.72 (95% CI 0.63, 0.81) per 4mmol increase in pre-dialysis sodium. However, we found evidence for statistical interaction with the dialysate sodium concentration. In other words, the association of serum sodium and mortality is dependent on the dialysate sodium; similarly, the effect of dialysate sodium on mortality depends on the serum sodium. Most notably, we found that higher dialysate sodium was associated with higher mortality in those with higher, not lower, pre-dialysis serum sodium - contrary to our original hypothesis.
In addition, we noted that the pre-dialysis serum sodium concentration appears to be relatively preserved among hemodialysis patients, irrespective of the baseline dialysate sodium concentration used in their treatments, which supports the concept of an osmolar set-point. Furthermore, there was a wide variation both within and between clinical centers in terms of the dialysate sodium concentration utilized, likely reflecting differing physician and nursing practice patterns.
We found no association between higher dialysate sodium and systolic blood pressure and a modest clinical effect on inter-dialytic weight gain (0.11kg for higher vs lower dialysate sodium).
If the detrimental factor is truly net sodium gain, it may be the case that sodium loading occurs in patients with low serum sodium levels, irrespective of the dialysate sodium that is used (generally >136 mmol/L in most outpatient settings). For those with higher serum sodium, net sodium gain may only occur with the use of higher dialysate sodium concentrations (e.g. >140mmol/L or sodium modeling).
Since our findings were published, a similar study was published using DOPPS data. (5). This larger dataset (n=11,555) reported similar results to ours – HR 0.95 (95% CI 0.93, 0.97) per 1 mmol/L increment in serum sodium; and in mortality analyses restricted to those with serum sodium <137mmol/L, those dialyzed against higher dialysate sodium had a lower overall mortality.
Overall, our study findings should be interpreted as hypothesis-generating. Higher dialysate sodium may be associated with worse outcomes in many hemodialysis patients. However, there may be patients who in fact benefit from higher dialysate sodium. Individualizing the dialysate sodium prescription has been advocated by some, and is the focus of several ongoing investigations listed on clinicaltrials.gov.
The composition of the dialysate is one of the most central aspects of the hemodialysis prescription. We welcome the renewed focus in this area and eagerly await the results of carefully conducted randomized trials.
References
1. Kjellstrand CM, Evans RL, Petersen RJ, Shideman JR, von Hartitzsch B, Buselmeier TJ. The "unphysiology" of dialysis: a major cause of dialysis side effects? Kidney Int Suppl. 1975 Jan;(2):30-4. PubMed PMID: 1057690.
2. Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med 2009; 122: 857-865.
3. Waikar SS, Curhan GC, Brunelli SM. Mortality associated with low serum sodium concentration in maintenance hemodialysis. Am J Med 2011; 124: 77-84.
4. Mc Causland FR, Brunelli SM, Waikar SS. Dialysate sodium, serum sodium and mortality in maintenance hemodialysis. Nephrol Dial Transplant 2011: 2.
5. Hecking M, Karaboyas A, Saran R, et al. Predialysis Serum Sodium Level, Dialysate Sodium, and Mortality in Maintenance Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2011; 2011: 22.
