Antihypertensive Drug Effects on Surrogate End Points for ESRD: A Systematic Review

Chronic kidney disease (CKD) affects 10% to 15% of the population and is associated with progression to end-stage renal disease (ESRD) and premature death. Treatment aimed at lowering blood pressure is used to prevent kidney function failure and ESRD; however, ESRD is a less frequent outcome of CKD compared with cardiovascular disease and death and requires trials with large patient populations and long-term follow-up.

Surrogate markers of kidney function have been suggested to increase trial feasibility by shortening trial duration and reducing needed sample size to identify treatment benefit. Surrogate markers have included measures of urine albumin and rates of protein excretion to predict patient-centered outcomes of interest. Proteinuria and albuminuria are useful end points because excretion is association with progressive kidney disease in a dose-dependent manner.

Suetonia C. Palmer, Mb ChB, PhD, and colleagues recently conducted a systematic review using Bayesian bivariate meta-analysis methods to examine the correlation between the effects of drugs used to lower blood pressure  on doubling of serum creatinine level, halving of glomerular filtration rate (GFR), and measures of albuminuria and proteinuria with ESRD. Results of the review were reported in the American Journal of Kidney Diseases [2018;72(6):779-789].

Using an electronic search strategy, the researchers identified 4791 records; an additional 18 records were identified from reference lists in retrieved systematic reviews. Following application of inclusion criteria, 22 randomized trials representing 69,643 participants were included in the review.

The eligible trials were published between 1994 and 2017 and included between 24 and 8576 participants allocated to a treatment (median, 455). Follow-up time ranged from 4 to 72 months (median, 36 months). Baseline mean estimated GFR (eGFR) was reported in 72.7% (n=16) of the trials. Baseline mean eGFR was <30 mL/min/1.73 m2 in two studies, 30 to 45 mL/min/1.73 m2 in three studies, 45 to 60 mL/min/1.73 m2 in five studies, and 60 to 90 mL/min/1.73 m2 in six studies.

Baseline mean systolic blood pressure ranged between 108 and 167 mm Hg. Sixteen studies reported proportion of patients with diabetes. Of those, 11 included only participants with diabetes; three studies excluded patients with diabetes (n=240). Nineteen trials reported baseline levels of proteinuria or albuminuria; levels ranged from normal or mildly increased in two trials (albumin excretion rate equivalent of <30 mg/d), to moderately increased in 13 trials (30-300 mg/d), and severely increased in three trials (>300 mg/d).

Overall, 1627 participants progressed to ESRD, 2394 experienced doubling of serum creatinine level (15 trials), and 10 experienced halving of GFR (one trial). Progression of albuminuria was reported to occur in 1510 participants in five trials, regression of albuminuria was reported to occur in 2203 participants in two trials, and a continuous outcome measure for proteinuria or albuminuria was reported for 6220 participants in nine trials.

Due to incomplete methodological reporting, the risks of bias were frequently high or uncertain., Methodological reporting of the random sequence generation was consistent with low risk of bias in 41% of the studies (n=9), and treatment allocation was adequately concealed in 50% of studies (n=11). Both participants and investigators were blinded to treatment in 59% of studies (n=13); in 55% of studies, (n=12), outcome assessment was blinded. In 45% of studies (n=10), attrition from follow-up was low risk of bias. In 41% of studies (n=9), there were additional issues that indicated a possibly high risk of bias from other sources.

For patient-centered end points, the relative risk for ESRD was statistically significant in 3.4% of  treatment comparisons (n=1/29). For drug effects on surrogate renal outcomes, the risk estimate was statistically significant in 19% of treatment comparisons (n=4/21) for doubling of serum creatinine level, zero of one for halving GFR, two of seven for progression of albuminuria, two of two for regression of albuminuria, and eight of 17 for any continuous measure of albuminuria or proteinuria.

Low power due to infrequent outcomes of ESRD and incomplete data reporting in primary trials were cited as limitations to the study.

“In conclusion, there is no high-certainty evidence demonstrating the validity of serum creatinine level, eGFR, albuminuria, or proteinuria to estimate risks for ESRD in trials of blood-pressure lowering therapy. The correlation between antihypertensive drug effects on serum creatinine level, albuminuria, or proteinuria and ESRD is not sufficiently certain to enable confident use of these markers to guide clinical decision making or test the effectiveness of treatments to prevent ESRD,” the researchers said.

Takeaway Points

  1. Researchers conducted a systematic review to evaluate the correlation between antihypertensive drug effects on surrogate renal end points and end-stage renal disease (ESRD).
  2. The review identified 22 randomized controlled trials involving 69,642 eligible participants. The risk for ESRD was statistically significant in one of 29 (3.4%) treatment comparisons.
  3. There appeared to be little or no correlation between antihypertensive drug effects on serum creatinine level, albuminuria, proteinuria, and the corresponding effects on ESRD.