Individual Long-term Albuminuria Exposure During Angiotensin Receptor Blocker Therapy Is the Optimal Predictor for Renal Outcome

Tobias Felix Kröpelin; Dick de Zeeuw; Frank Arjan Holtkamp; David Kenneth Packham; Hiddo J. L. Heerspink


Nephrol Dial Transplant. 2016;31(9):1471-1477. 

In This Article

Abstract and Introduction


Background. Albuminuria reduction due to angiotensin receptor blockers (ARBs) predicts subsequent renoprotection. Relating the initial albuminuria reduction to subsequent renoprotection assumes that the initial ARB-induced albuminuria reduction remains stable during follow-up. The aim of this study was to assess individual albuminuria fluctuations after the initial ARB response and to determine whether taking individual albuminuria fluctuations into account improves renal outcome prediction.

Methods. Patients with diabetes and nephropathy treated with losartan or irbesartan in the RENAAL and IDNT trials were included. Patients with >30% reduction in albuminuria 3 months after ARB initiation were stratified by the subsequent change in albuminuria until Month 12 in enhanced responders (>50% albuminuria reduction), sustained responders (between 20 and 50% reduction), and response escapers (<20% reduction). Predictive performance of the individual albuminuria exposure until Month 3 was compared with the exposure over the first 12 months using receiver operating characteristics (ROC) curves.

Results. Following ARB initiation, 388 (36.3%) patients showed an >30% reduction in albuminuria. Among these patients, the albuminuria level further decreased in 174 (44.8%), remained stable in 123 (31.7%), and increased in 91 (23.5%) patients. Similar albuminuria fluctuations were observed in patients with <30% albuminuria reduction. Renal risk prediction improved when using the albuminuria exposure during the first 12 months versus the initial Month 3 change [ROC difference: 0.78 (95% CI 0.75–0.82) versus 0.68 (0.64–0.72); P < 0.0001].

Conclusions. Following the initial response to ARBs, a large within-patient albuminuria variability is observed. Hence, incorporating multiple albuminuria measurements over time in risk algorithms may be more appropriate to monitor treatment effects and quantify renal risk.


Albuminuria has been shown to be a good predictor and risk marker for renal morbidity and mortality.[1–5] The causality of this association is extensively debated, the cons stating that albuminuria increase is a consequence of renal/cardiovascular disease,[6] the pros stating that albuminuria leads to tissue damage.[7] This debate could be supported by data that show or deny that albuminuria lowering is associated with and predictive of renal disease protection, and in particular that the degree of renal protection is fully explained by the albuminuria reduction. This is not only important for the research into the mechanism, but also important in aiding the treatment of a patient, since one can estimate by the initial effects of the treatment (first couple of weeks/months) what will likely happen in the long run.

However, relating the lowering of a risk factor to subsequent renoprotection relies on the assumption that the initial reduction of the risk factor remains stable during prolonged follow-up. Blood pressure reduction in the first couple of weeks during antihypertensive treatment is indeed related to the degree of renoprotection. However, many patients can show a subsequent further decrease or increase in blood pressure, the latter being due to either drug effect escape or progression of the underlying disease. These blood pressure changes during treatment are important for accurately predicting the true effect of an antihypertensive on subsequent cardiovascular outcome.[8]

Given these considerations, the aim of this study was to assess whether taking into account the fluctuations in albuminuria within individuals (e.g. the exposure to albuminuria over time) after the initial response to angiotensin receptor blockers would be a more accurate and precise predictor of renal outcome.