JOURNAL CLUB

Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis

Just released is a very interesting and well designed study by Foley and co-workers published in the New England Journal of Medicine (1). It is likely to garner much attention, both in nephrology and lay-public settings. In other words, it's a "must read".

Foley, Gilbertson, Murray and Collins are from the United States Renal Data System and the University of Minnesota, Minneapolis, USA.

In both the United States and worldwide, most dialysis patients receive dialysis using one of two schedules: Monday-Wednesday-Friday, or Tuesday-Thursday-Saturday. Either way, there is one 2-day interval between dialysis treatments- Friday to Monday or Saturday to Tuesday.

Kjellstrand and co-workers have maintained for many years (since 1978) that this treatment schedule is unphysiologic and might be associated with dialysis side-effects (2,3). They have suggested that removal of small solute is better by more frequent dialysis than three-times per week dialysis treatment (4). A study by Bleyer et al (5) reported a higher rate of sudden death that seemed to be related to the patient’s dialysis schedule. They reported that Monday–Wednesday–Friday HD patients were more likely to suffer cardiac arrest on Monday, and Tuesday–Thursday–Saturday HD patients were more likely to have cardiac deaths on Tuesday. Interestingly, Bleyer et al report that when individual death events were studied, cardiac arrest occurred more frequently during the 8 hours beginning at the start of dialysis and also during the extra weekend day (Sunday for Monday–Wednesday–Friday patients and Monday for Tuesday–Thursday–Saturday patients) (7). I would recommend reading Bleyer and colleagues excellent overview in Peritoneal Dialysis International (8) (it is open access). 

In the latest study (1), Foley et al examined the hypothesis that the long interdialytic interval is associated with excess mortality among U.S. patients receiving hemodialysis.

Foley evaluated the End-Stage Renal Disease Clinical Performance Measures Project  (CPM) cohort, comprising of 32,065 subjects. This was a nationally representative sample of U.S. patients receiving hemodialysis three times weekly, at the end of calendar years 2004 through 2007.  They compared rates of death and cardiovascular-related hospital admissions on the day after the long (2-day) interdialytic interval with rates on other days.

Specifically, they aimed to see if there were differences in overall mortality; cause-specific mortality, with causes grouped as cardiac, vascular, infectious, and other; cause-specific mortality for the five most commonly cited individual causes of death (cardiac arrest, withdrawal of treatment or uremia, myocardial infarction, septicemia, and stroke); cardiovascular-admission rates, a composite of first hospitalization for myocardial infarction, congestive heart failure, stroke, or dysrhythmia; and the individual components of the composite cardiovascular outcome.

The baseline data was as follows: the mean age was 62.2 years; 24.2% of the patients had been receiving dialysis treatment for 1 year or less, 45.1% were women, 36.3% were black, and 13.9% were Hispanic. Diabetes mellitus was the cause of end-stage renal disease in 43.7% of the patients, and for 27.7%, a catheter was used for vascular access for hemodialysis.

Over a mean follow-up period of 2.2 years, 41.1% of the study population died, causes of death were:

• 17.4% from cardiac causes
• 2.7% from vascular causes
• 4.8% from infectious causes
• 9.0% of the patients were admitted to the hospital with myocardial infarction, 33.1% with congestive heart failure, 7.1% with stroke, 25.9% with dysrhythmia, and 45.8% with any of these cardiovascular events.

The following event rates were higher on the day after the long interdialytic interval than on other days:

• all-cause mortality (22.1 deaths vs. 18.0 per 100 person-years)
• mortality from cardiac causes (10.2 vs. 7.5)
• infection-related mortality (2.5 vs. 2.1)
• mortality from cardiac arrest (1.3 vs. 1.0)
• mortality from myocardial infarction (6.3 vs. 4.4)
• admissions for myocardial infarction (6.3 vs. 3.9)
• congestive heart failure (29.9 vs. 16.9), stroke (4.7 vs. 3.1)
• dysrhythmia (20.9 vs. 11.0),
• Any cardiovascular event (44.2 vs. 19.7)

The greater adverse risk with the long (2-day) interdialytic interval held true when different subgroups were analyzed: i.e., regardless of prior duration of dialysis therapy, age, sex, race or ethnic group, cause of end-stage renal disease, type of vascular access, and status with respect to weight gain between dialysis sessions, wait-listing for a kidney transplant, diabetes, and recent cardiovascular admission.

Limitations of the study:

1. Possibility of confounding. However, as the authors discuss, because the same population was considered when comparing outcome rates on different days, it seems unlikely that unmeasured coexisting conditions could account for the findings.

2. USRDS is an administrative database and the limited accuracy of some of the data has been already recognized. The attribution of causes of death or or accuracy of the co-morbidities is also of limited accuracy.

3. The study assumes that patients maintain the 3 times/week schedule. It is likely that the schedule varies, and some patient’s flip from one schedule to the other and back as patients are hospitalized or travel.

Bottom-line:

A long (2 day) interdialytic interval is associated with a higher rate of death, cardiovascular complications, and hospitalizations.

The authors do not discuss in detail the potential explanations for their findings. 

However, earlier work suggests the possibility of either volume overload or an electrolyte flux (for example, potassium), as possible reasons. Karnik and co-workers (8) in reviewing 400 cases of cardiac arrest in dialysis patients noted that case patients were nearly twice as likely to have been dialyzed against a 0 or 1.0 mEq/L potassium dialysate on the day of cardiac arrest (17.1 vs. 8.8%), were on average older (66.3 +/- 12.9 vs. 60.2 +/- 15.4 years), more likely to have diabetes (61.8 vs. 46.8%), and more likely to use a catheter for vascular access (34.1 vs. 27.8%) than the general hemodialysis population. As well, 16 percent of patients experienced a drop in systolic pressure of 30 mm Hg or more prior to the arrest.

Bleyer writes in a commentary in Peritoneal Dialysis International (7) titled Clues at the Scene of the Crime: Sudden death in dialysis patients: “For the hemodialysis (HD) patient, incredible fluid fluxes occurring with dialysis result in repeated bouts of predialysis volume overload and intra- or postdialysis hypotension, each being a potent stressor. Similarly, potassium and other electrolytes undergo large fluxes with HD and hyperkalemia or hypokalemia precipitate cardiac arrest”.

More research is clearly needed, including randomized trials, before changing the dialysis prescription. 

What do we do in the mean-time? 

Sensible actions include: 1.) avoid abrupt electrolyte fluxes (for example, in potassium); at the very least, use a step strategy for treating hyperkalemia -- for example, for a potassium of 6 or 7 mEq/L, consider starting with a 3 mEq/L dialysate K (for an initial serum K of 6 mEq/L) or 4 mEq/L dialysate K (for an initial serum K of 7 mEq/L or greater) potassium bath and then reducing the potassium bath to 1 or 2 mEq/L in 2 or 3 down-ward steps. 2.) Install defibrillators in dialysis units -- after all airports and other public facilities have them -- why not dialysis units? 3.) Avoid a very low (zero or 1 mEq/L potassium) as a standard bath in patients who are unstable, have evidence of structural heart disease, or a history of cardiac arrhythmia. 4.) Manage large interdialytic fluid gains more actively by both aggressively counseling patient's on adherence, and prescribing additional dialysis or ultrafiltration therapy. 5) Continue to focus on screening patients for underlying cardiovascular disease.

References

1. Foley RN, Gilbertson DT, Murray T. Collins AJ  Long Interdialytic Interval and Mortality among Patients Receiving HemodialysisN Engl J Med 2011;365:1099-107.

2. Kjellstrand CM, Rosa AA, Shideman JR, Rodrigo F, Davin T, Lynch RE. Optimal dialysis frequency and duration: the “unphysiology hypothesis”. Kidney Int Suppl 1978;13:S120-S124.

3. Kjellstrand CM, Evans RL, Petersen RJ, Shideman JR, Von Hartitzsch B, Buselmeier TJ. The “unphysiology” of dialysis: a major cause of dialysis side ef- fects? Kidney Int Suppl 1975;7:30-4.

4. Ing TS, Meyers J, Schatell D, Kjellstrand CM. Better removal of small solutes by more frequent hemodialysis sessions than by conventional, thrice weekly hemodialysis sessions of similar weekly duration. Int J Artif Organs. 2006 Jun;29(6):639-40. PubMed PMID: 16841294.

5. Bleyer AJ, Russell GB, Satko SG. Sudden and cardiac death rates in hemodialy- sis patients. Kidney Int 1999;55:1553-9.

6. Bleyer AJ, Hartman J, Brannon PC, Reeves-Daniel A, Satko SG, Russell G, et al. Characteristics of sudden death in hemodialysis patients. Kidney Int 2006;69 : 2268-73.

7. Bleyer AJ. Clues at the scene of the crime: sudden death in dialysis patients. Perit Dial Int. 2009 Jan-Feb;29(1):23-5.  PubMed PMID: 19164249.

8. Karnik JA, Young BS, Lew NL, Herget M, Dubinsky C, Lazarus JM, Chertow GM. Cardiac arrest and sudden death in dialysis units. Kidney Int. 2001 Jul;60(1): 350-7. PubMed PMID: 11422771.