Progressive Loss of Kidney Function in HD Patients and Angiotensin Blockade

Among patients on hemodialysis (HD), treatment with irbesartan did not have significant affect on decline in glomerular filtration rate (GFR) or urine volume during 1 year of treatment. That was the primary finding of a study reported by Krista Dybtved Kjaergaard, MD, PhD, and colleagues in the American Journal of Kidney Diseases [2014;64(6):892-901].

All-cause mortality is 6.7 to 8.5 times higher among dialysis patients than in the general population, and full loss of GFR is associated with increased mortality. GFR values as small as one unit per week greater renal urea clearance have been shown to be associated with a significantly lower risk of death in patients receiving HD.

There are several advantages of preserved kidney function to HD patients, including a lower dialysis dose and more liberal fluid intake. Further less ultrafiltration requirement leads to smaller changes in fluid homeostasis and lower risk of hypotensive episode. Middle- and large-sized uremic toxins are cleared better, and the endogenous production of erythropoietin is maintained to some degree.

There have been studies demonstrating the preservation of GFR via treatment with both angiotensin-converting enzyme (ACEs)-inhibitors and angiotensin II receptor blockers (ARBs) in patients on peritoneal dialysis. Among patients on HD, there have been observational studies showing that GFR may be preserved with blockade of the renin-angiotensin-aldosterone system (RAAS), but there have been no randomized controlled trials.

The SAFIR (Saving Residual Renal Function in Hemodialysis Patients Receiving Irbesartan) study, was designed to determine whether RAAS blockade with the ARB irbesartan was associated with better preservation of GFR and urine volume, and a decrease in albuminuria, compared with placebo, among HD patients.

The primary outcomes of the multicenter, randomized, placebo-controlled, double-blinded trial were change in GFR measured as the mean of creatinine and urea renal clearance together with urinary volume; secondary outcomes included change in albuminuria, renin-angiotensin II-aldosterone hormone plasma levels, and time to anuria.

The study included adult HP patients from six HD centers. Eligible patients had urine output >300 mL/24 hours, HD vintage less than 1 year, and cardiac ejection faction >30%. Patients were randomly assigned to placebo or the ARB irbesartan, 300 mg daily. Target systolic blood pressure (BP) was 140 mm hg.

From the six centers, the researchers screened 752 patients. Of those 165 met eligibility requirements and 104 were included in the study. Prior to randomization, 22 patients were excluded. The remaining 82 patients were randomized in a 1:1 ratio to placebo (n=41) or irbesartan (n=41).

Baseline demographic and clinical characteristics were similar between the two groups, with the exception of four patients in the irbesartan group with failing kidney transplants, none of whom received calcineurin inhibitors. There was no significant difference in GFRs between the groups and median values were identical (5.1 mL/min/1.73 m2). Based on the mixed-effect model accounting for the follow-up of 12 months, change in GFR over time in the placebo group was not significantly different compared with the irbesartan group (P=.04). The GFR declined by 1.7 mL/min/1.73 m2 over 12 months in the placebo group compared with 1.8 mL/min/1.73 m2 in the irbesartan group (P<.001).

When dividing the patients into two equal-sized groups by baseline median GFR, there were no detected significant differences between groups over time with either high or low GFRs. There were no significant differences in urine volume at baseline or over time (P=.02), and albuminuria did not differ significantly between the groups at baseline or over time (P=.06).

The mean systolic BP of 140 mm Hg was achieved in both groups and BPs were comparable between groups throughout follow-up. Based on measurements at six visits, BPs did not differ significantly between groups over time (P=.05 for systolic BP and P=.5 for diastolic BP).

Rates of adverse events were similar between the two groups. Intradialytic hypotension occurred in <1% of dialysis sessions (50 and 63 episodes in the placebo and irbesartan-treated group, respectively, corresponding to annual incidence rates of 14% and 17%). Two patients in the irbesartan group developed severe diarrhea. None of the adverse events was characterized as suspected unexpected serious adverse events.

GFR decline rates and mortality rates in the study were much lower than expected, indicating a selection bias (only the healthiest patients were willing to participate). Further, 21% of included patients were excluded before baseline. The results may not be applicable to patients with a longer HD vintage. Longer follow-up may reveal benefits not seen after 1 year of irbesartan treatment, the researchers said.

“In conclusion, at equal BPs, we found no evidence of beneficial effects of irbesartan treatment compared to placebo on the decline in GFR, urine volume, and albuminuria after 1 year of follow-up in incident HD patients. Irbesartan was safe to use in the study population,” the researchers added.

Takeaway Points

  1. Among patients on HD, there have been observational studies showing that GFR may be preserved with blockade of the renin-angiotensin-aldosterone system (RAAS), but there have been no randomized controlled trials.
  2. The SAFIR (Saving Residual Renal Function in Hemodialysis Patients Receiving Irbesartan) study, was designed to determine whether RAAS blockade with the ARB irbesartan was associated with better preservation of GFR and urine volume, and a decrease in albuminuria, compared with placebo, among HD patients.
  3. There was no evidence of beneficial effects of irbesartan treatment compared to placebo on the decline in GFR, urine volume, and albuminuria after 1 year of follow-up in incident HD patients.