During the last decades, renin-angiotensin system Inhibitors (RAS inhibitors ) have been the main therapeutic resource to slow down the progression of chronic kidney disease (CKD) of various etiologies.1–4 Both angiotensin conversion enzyme (ACEI) inhibitors and angiotensin II receptor antagonists (ARA), in addition to the effect on blood pressure control, they have also ascribed other benefits: hemodynamic, antiproteinuric, pleiotropic (antifibrogenic, etc.) that could justify the qualification of "reno-protectors".1–5

These favorable effects on the progression of CKD have been demonstrated based on rigorous studies in experimental animals and numerous clinical trials, well summarized in the review by Čertíková Chábová and Červenka.6 Such results strongly supported the strict control of the renin-angiotensin system (RAS) to the point that during the first decade of this century it was proposed to maximize the doses of these drugs and even combine them (dual RAS blockade with ACEI plus ARB), pursuing therapeutic objectives beyond the strict control of blood pressure, such as the reduction of proteinuria.5

High doses of RAS inhibitors and even dual blockade have been shown to be beneficial in the evolution and survival of some cardiovascular diseases,3,7–9 however the frequent association with accelerated decline of renal function and development of other adverse effects have questioned this treatment strategy in CKD, and especially in some kidney diseases such as diabetic nephropathy, or in patients with advanced CKD.6,10–14 Therefore there is a number of authors with opinions against the unrestricted use of these drugs in CKD.15–22 generating a clinical-therapeutic controversy that deserves to be investigated.

We have observed that in patients with advanced CKD the dual RAS blockade is associated with a faster decline of kidney function.23 Another important point of these previous observations is the great heterogeneity in the prescribed doses of RAS inhibitors adjusted to the patient weight or body surface. Thus, we were motivated to formulate the following questions: is there an association between the total adjusted dose of ISRA and the progression of advanced CKD?, and could the negative effect of the double RAS blockade on the progression of CKD be justified by a high total dose of RAS inhibitors or is it independent of the dose and other important confounding factors?

With the objective of answering these questions, the present observational study was performed in a cohort of patients with advanced CKD on treatment with RAS inhibitors.

Retrospective longitudinal observational study in a cohort of adult patients diagnosed with CKD stages 4–5 not on dialysis, followed in the advanced CKD (ACKD) outpatient clinic from January 2000 to December 2016. To be included in the study patients had to be followed in the ACKD clinic for more than 3 months; with at least 3 measurements of renal function; and being treated with RAS inhibitors for a minimum of 3 months before being included in the study.

All patients were referred to the ACKD clinic for progressive decline of renal function. Demographic and clinical data, and prescribed medication were obtained from medical records, physical examination and anamnesis were recorded. The comorbidity was evaluated at the time of inclusion, using the Davies index,24 and patients were categorized into 3 groups: no comorbidity, mild-moderate, or severe comorbidity.

Biochemical tests were performed in the same central laboratory (Clinical Analysis Service of Infanta Cristina Hospital) using conventional methods (Advia Chemistry Autoanalyzer, Siemens Healthcare Diagnostics, New York, USA ), in fresh samples ( not stored), and both the calibrations and the traceability of creatinine were performed according to the recommendations of international NKDEP standards.25 Glomerular filtration was estimated using the abbreviated formula MDRD.26

Patients were followed regularly with visits every 30–90 days. The rate of kidney function decline in each patient was determined by the linear regression of the estimated glomerular filtration rate over time elapsed between each control and the first appointment, with an accuracy of days. The resulting slope of this linear equation was expressed in ± ml / min / 1.73 m 2 / year. The negative or positive values of this slope meant progression of renal insufficiency or recovery of renal function, respectively.

The assessment of the comparative power of RAS inhibitors (equipotent dose) of each drug used was estimated following the prescription recommendations of the manufacturing laboratories on the daily doses required for blood pressure control in adults. This information is collected in bulletins of the Spanish Agency for Medicines and Health Products (AEMPS) as detailed in the Table 1.

Each of these daily doses was considered a therapeutic unit of similar potency (equipotent), which was added to combined treatments, and was normalized to a body weight of 70 kg or a body surface area of 1.73 m 2, thus a standardized equipotent dose parameter (SED) was established. For example, a patient with a body weight of 70 kg who took 20 mg of enalapril or 160 mg of valsartan or 16 mg of candesartan daily had a SED of 1. If these same doses were prescribed to a patient weighing 100 kg, the resulting SED would be 0.7; and if they were prescribed to a patient of 50 kg, the resulting SED is 1.4. If treatments were combined (double blockade) such as 20 mg of enalapril and 16 mg of candesartan in a 70 kg patient, the resulting SED is 2, and so on.

During the inclusion period, a total of 1580 incident patients were treated in the ACKD clinic and 1079 patients fulfilled the follow-up time criteria. Of these, 813 met the criteria of being treated with RAS inhibitors for more than 3 months before inclusion, and these were the patients included the study.

The demographic, clinical and biochemical characteristics of the total study group are shown in Table 2.

The mean age was 64 years, with a small predominance of men (53%) and a high prevalence of diabetes mellitus (40%). An outstanding clinical features of this group was the presence of nephropathies with proteinuria and high blood pressure.

90% of the patients received RAS-inhibitor in monotherapy, and the SED for a weight of 70 kg or a body surface area of 1.73 m2 were 0.99 and 1.03, respectively.

The rate of progression of CKD was significantly reduced in patients receiving RAS inhibitor in monotherapy as compared with those that had prescribed dual blockade of RAS inhibitor (−3.03 ± 5.37 vs. − 6.19 ± 5.57 ml / min / 1.73 m 2 / year, p < 0.0001).

Between these 2 subgroups there were also some differences in clinical characteristics, such as younger age, higher values of systolic blood pressure, and higher proteinuria in the subgroup treated with dual blockade of RAS inhibitor as compared with those treated with monotherapy (Table 2).

As expected, the SED-RAS inhibitor of the subgroup treated with dual blockade was significantly higher than that of those treated with monotherapy (1.52 ± 0.49 vs. 0.93 ± 0.44; p < 0.0001).

A significant linear correlation was observed between SED-RAS inhibitor and the slope GFR/ time (progression of CKD), whether normalization was performed for body weight (Fig. 1) or body surface (Fig. 2).

Fig. 1.

Linear regression between the slope of the glomerular filtration rate (GFR)/time and the standardized equipotent dose (SED) of renin-angiotensin system inhibitors (RAS-inhibitor) adjusted to a weight of 70 kg. The regression lines shown in the figure are those corresponding to the subgroups with double blockade and monotherapy, respectively.

The combined linear regression equation is: Slope GFR (ml/min/1.73 m2/year) = −1.672 – (1.71 × SED-RAS inhibitor); R = −0.149; p < 0.0001.

For monotherapy patients: Slope GFR/time = −1.88 – (1.24 × SED-RAS inhibitor); R = 0.101; p = 0.006.

For patients with double blockade: Slope GFR/time = −5.93 – (0.17 × SED-RAS inhibitor); R = 0.015; p = 0.89.

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Fig. 2.

Linear regression between the slope of the glomerular filtered ratio (GFR)/time and the standardized equipotent dose (SED) of renin-angiotensin system inhibitors (RAS-inhibitor) adjusted to 1.73 m2 body surface. The regression lines that appear in the figure are those corresponding to each subgroup with double blockade and monotherapy, respectively.

The combined linear regression equation is: Slope GFR (ml/min/1.73 m2/year) = −1.685 – (1.659 × SED-RAS inhibitor); R = −0.145; p < 0.0001.

For monotherapy patients: Slope GFR/time = −1.959 – (1.120 × SED-RAS inhibitor); R = 0.093; p = 0.012.

For patients with double blockade: Slope GFR/time = −6.279 – (0.053 × SED-RAS inhibitor); R = 0.004; p = 0.969.

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It was also observed that at the same SED-RAS inhibitor, patients treated with dual blockade had a more rapid deterioration of GFR (Fig. 1 and 2).

In the multivariate linear regression analysis of the variables associated with the progression of CKD, dual RAS blockade remained independently and significantly associated with the outcome variable (slope glomerular filtered rate / time), however the SED-RAS inhibitor lost statistical significance when this relationship was adjusted to the rest of the independent variables (Table 3).

Fig. 3 shows the association between proteinuria and progression of CKD. The regression lines corresponding to the subgroup treated with monotherapy or double blockade are presented. Most evident significant differences between the subgroups were observed in patients with proteinuria less than 5 g / day.

Fig. 3.

Linear regression between the slope of the glomerular filtration rate (GFR)/time and proteinuria. The regression lines shown in the figure correspond to each subgroup, with double blockade and monotherapy, respectively. The Y axis is represented with an exponential scale 0.5.

The combined linear regression equation is: Slope GFR/time (ml/min/1.73 m2/year) = −1.720 – (0.739 × proteinuria in g/g creatinine); R = 0.332; p < 0.0001.

For monotherapy patients: Slope FG/time = −1532 – (0.727 × proteinuria in g/g creatinine); R = 0.315; p < 0.0001.

For patients with double blockade: Slope FG/time = −4409 – (0.495 × proteinuria in g/g creatinine); R = 0.275; p < 0.011.

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The results of this study show that there is a significant association between the SED of RAS inhibitors and the slope of kidney failure progression in advanced stages of CKD. This progression of CKD is much faster when ACE inhibitors and ARBs (double lock) are combined, and it is independent of the SED and other relevant factors that might share the risk of progression and are a reason for prescription (for example: severity of hypertension, proteinuria, diabetes).

Although RAS inhibitors have been used to slow down the progression of CKD of various etiologies,1–4 more recently the view of some authors have questioned the use of dual blockade or even monotherapy in advanced CKD.15–22 Some observational studies and clinical trials have warned about the negative effect of dual blockade on the progression of CKD. In addition there is a clinical trial that attempts to analyze how the suspension of RAS inhibitors influences the progression of advanced CKD.27

In our patients the mean SED of RAS inhibitors approached the unit, but the wide range of prescribed doses is noteworthy. Although it was observed a significant linear regression between SED and the progression of CKD, the adjustment of the multivariate model by adding other important confounding variables ruled out a significant association between these 2 parameters. This finding uncovered the possibility of influence of the medical reason for the indication of RAS inhibitor. However, the dual blockade did maintain the independent association with CKD progression in adjusted models, including SED, as illustrated graphically in Fig. 1 and 2.

Dual blockade of RAS has demonstrated a renoprotective effect in some experimental models of renal failure in rats,6 however there are numerous clinical trials that have not been able to demonstrate this benefit in humans.10–14 This negative effect of double blockade on the progression of advanced CKD could be due to the efficacy of anti-RAS achieved with the combination of these drugs, which may be inappropriate for the pathophysiological conditions of advanced CKD such as an excessive control of systemic blood pressure and / or glomerular filtration pressure, with hemodynamic changes that may increase the risk of tubulointerstitial ischemia.

Although administration of double blockade to hypertensive rats has a very positive effect on subrogated objectives, such as blood pressure, proteinuria and left ventricular hypertrophy, paradoxically this association of drugs decreases renal function and increases glomerulosclerosis and interstitial fibrosis.28,29 It is suspected that this adverse effect is due to the inability to regulate renal blood flow as a result of "relative" hypotension and blockade of the actions of angiotensin II in the mechanism of glomerular-tubular feedback, and as a consequence of this deregulation it would cause ischemic damage and fibrosis.29

Sudden decrease in the glomerular filtration rate, up to a 30%, are frequently observed after initiation of treatment with RAS inhibitors, but it usually reverse in less than 2 months.4 In the present study, all the patients were being treated with RAS inhibitors for more than 3 months before their inclusion, therefore transitory changes in renal function can be ruled out.

The present study has limitations. Due to the retrospective design, definite causal relationships cannot be established, and since it was performed in a single center with certain treatment criteria, the results may not be generalized.

Another important limitation was the lack of control about compliance with treatment, and the effective amount of active ingredient of each prescription due to the large amount of generic medication dispensed, which as is well known and legally admitted can vary the content of active ingredient up to 20%. The pharmacokinetic peculiarities of each of the drugs used to calculate the therapeutic potency were not taken into account. Most RAS inhibitors are eliminated, in a high proportion, by the renal route, and in advanced stages of CKD a proportional dose adjustment is recommended, which is very similar for majority of RAS inhibitors.30,31

In conclusion, high SED of RAS inhibitors are associated with a more rapid deterioration of renal function in patients with advanced CKD, but this relationship loses significance when adjusted for other confounding variables. However, double blockade of RAS is independently associated with a more rapid deterioration of renal function that cannot be justified by higher SED.

According to these results, the most prudent recommendations in patients with advanced CKD would be to avoid double blockade of RAS and adjust the doses in monotherapy. Suspension of RAS inhibitors should be avoided until results of ongoing trials provide solid evidence; in these patients not only is the progression of CKD important, but also to maintain the potential cardioprotective effect of these drugs.9

The authors have no conflicts of interest to declare.