Abstract
The renin-angiotensin system (RAS) plays a fundamental role in preserving the circulation and yet, it may be injurious to heart and blood vessels and may also allow, and sometimes hasten, kidney disease progression. Thus, effective RAS inhibition may be a major pharmacologic necessity to control hypertension, to decrease cardiovascular complication, and to inhibit kidney disease progression. Unfortunately, the beneficial effects attained in the management of renal disease sometimes are incomplete. The reasons for these inadequate outcomes may include angiotensin escape or excessive local angiotensin production. Two pharmacologic strategies have been proposed to overcome this drawback including higher than recommended doses of RAS inhibitors and the combination of two different RAS inhibitors. However, three large studies have shown that these more intensive pharmacologic approaches should be treated with caution when applied to high-risk patients, as organ perfusion may fall to critical levels that may cause severe complications. Nevertheless, intensive RAS inhibition (including combination therapy) may be the sole alternative in patients with chronic kidney disease (CKD) in whom other therapeutics options have failed. In these cases, adequate precautions including close clinical and laboratory follow up should prevent major complications.
Introduction
The renin-angiotensin system (RAS) plays a critical role in preserving the circulatory volume and, therefore, adequate organ perfusion. Most likely, the mechanisms involved in this function were developed early in Paleolithic times when humanoids consumed a very low-salt diet based on herbs, grains, and seeds. In all probability, this limited salt intake promoted the early development of a highly effective RAS upon which rests modern man’s very efficient salt-conserving mechanisms. Indeed, the RAS can regulate organ perfusion pressure through changes in (a) vascular tone; (b) vascular structure, and (c) renal sodium handling.
Predictably, inhibition of RAS has shown multiple benefits. Indeed, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibition with aliskiren have shown efficacy not only in lowering blood pressure but also in heart failure, atherosclerosis, acute coronary syndrome, ventricular hypertrophy, atrial fibrillation, insulin resistance, and chronic kidney disease (CKD) of various etiologies including primary glomerulonephritis, vasculitis, diabetic nephropathy, nephrosclerosis, and others. This notion is sustained by a number of clinical trials that cannot discriminate whether the reported benefits result from an effect on local or systemic RAS inhibition. For these reasons, limiting the treatments to patients with elevated plasma-renin activity is incorrect.
Indeed, current data suggest that both circulating and local RAS contribute to disease progression and therefore, measurements of plasma-renin activity may fail to predict the response to RAS inhibition, even though plasma-renin activity correlates with cardiovascular complications [Alderman et al. 1991, 1997; Muhlestein et al. 2010].
Unquestionably, RAS deleterious outcomes arise through angiotensin II (Ang II) effects. Consequently, preventing the conversion of Ang I to Ang II, or blocking the angiotensin II receptor, type 1 (AT1) receptor, should void RAS negative effects. Regretfully, ACE inhibitors may block the synthesis of Ang II only partially as conversion of Ang I to Ang II can be achieved by mean of other enzymes [Hollenberg et al. 1998]. Moreover, parallel activation of non-ACE pathways may produce other angiotensin peptides that are capable of binding the AT1 receptors. These concepts have been proposed as explanations for the purported ACE ‘escape’ [Hollenberg et al. 1998]. On the other hand, blocking the AT1 receptor may stimulate the negative feedback mechanism, and by these means stimulate the synthesis of large amounts of Ang II that could then compete for AT1 receptor binding. Actually, inappropriate Ang II effects have been reported with both ACE inhibitors and ARBs [Wolf and Ritz, 2005].
Assuming that RAS inhibition in some patients may be less than complete, some investigators have suggested doses higher than the standard recommended [Kjeldsen et al. 2002; Mooser et al. 1990; Rakugi et al. 1994; Wagner et al. 1999; Wang et al. 1997].
The idea is to achieve a more complete RAS inhibition and thus, a more efficient therapeutic effect. As a result of the safe therapeutic profile of ACE inhibitors and ARBs the proposed intensified RAS inhibition should cause no significant intolerance [García et al. 2001].
In brief, intensive RAS blocking could provide greater antihypertensive and protective effects. For instance, reducing proteinuria in CKD is a vital objective that often cannot be achieved with standard recommended therapies. For this, intensive RAS inhibition has been recommended, not only for diabetic but also for nondiabetic nephropathies [Dell’Italia, 2011; Schrader et al. 2005].
Combination therapy in CKD
Intensive RAS blockade has been attempted through larger (supramaximal) doses of RAS inhibitors, or by the combined administration of two different kinds of RAS blocker (dual blockade). For instance, Weinberg and colleagues used increasing doses of candesartan in elderly normotensive patients with diabetic nephropathy, focal sclerosis, membranous nephropathy, and postinfectious glomerular disease. Increasing candesartan doses were associated with a significant decline in protein-excretion rate, which was unrelated to blood-pressure levels. The authors found no changes in serum creatinine or serum potassium [Weinberg et al. 2004].
Similar tolerance has been reported in several studies combining RAS inhibitors while showing beneficial effects on various therapeutic targets. For instance, candesartan was combined with lisinopril in the the Candesartan and Lisinopril Microalbuminuria (CALM) trial in hypertensive patients with microalbuminuria [Mogensen et al. 2000]. The authors reported a significant reduction in diastolic blood pressure and in protein-excretion rate with combined candesartan-lisinopril therapy compared with single treatment with either drug. There were no differences between groups in side effects. Parving and colleagues found a significant fall in protein-excretion rate in patients with diabetes type I, receiving combination therapy with losartan and enalapril, compared with single drug treatment [Parving et al. 2008]. Similarly, in the Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial, combined therapy was superior to monotherapy [Solomon et al. 2009].
Some studies though have been conflicting. Indeed, three trials concluded that combination therapy was unsafe. These were the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) [Mann et al. 2008], the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) [Parving et al. 2012], and more recently, the Veterans Affairs Combination Angiotensin Receptor Blocker and Angiotensin-converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy study (VA NEPHRON D) [Friend et al. 2013]. These apparent dissimilarities with previous reports could result from differences in inclusion and exclusion criteria. In fact, too liberal inclusion criteria, although increasing the number of randomized subjects, may trigger the inclusion of patients with excessive risk (Table 1).
Basal clinical characteristics in the combined treatment groups in the ONTARGET, ALTITUDE, and VA NEPHRON D trials.
ALTITUDE, Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; VA NEPHRON D, Veterans Affairs Combination Angiotensin Receptor Blocker and Angiotensin-converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy.
This may be the case for ONTARGET, a study that compared telmisartan plus ramipril against single therapy. The authors found no added benefit with combined blocking; moreover, they suggested that the combination therapy could be harmful [Mann et al. 2008]. However, the diabetics recruited in this study included individuals with high cardiovascular risk (coronary artery disease was present in almost 75% of the patients), and normal or near normal baseline blood pressure. Indeed, mean baseline blood-pressure levels in patients receiving both telmisartan and ramipril was 141.9 ± 17.6/82 ± 10.4 mmHg. Thus, basal blood pressure was normal in many patients and at lower levels of normality in some. Combined blocking could have triggered periods of critically low brain, coronary, or renal perfusion. In fact, adverse effects included syncope, falls, lipothymia, stroke, increased serum creatinine, hyperkalemia, etc. Each of these adverse effects may be the result of hypotensive episodes.
The ONTARGET results seem to indicate no benefit from combined therapy for CKD. These conclusions seem unwarranted for the following reasons: (a) significantly high protein-excretion rates were absent in many patients indicating limited kidney damage to halt or reverse, particularly in a rather short-term study with many normotensive individuals; (b) the average basal glomerular filtration rate (GFR) was normal (mean value: 73.6 ml/min); (c) only 36.7% of the patients were diabetics and many had normal blood pressure. Many of these patients were over 70 years of age, close to 75% had documented history of coronary artery disease, 1/3 were diabetic, and nearly 60% of them in each group were receiving a beta-blocker (making them more liable to complications from hemodynamic changes) (Table 1). In this study, acute hemodialysis was added to reach statistical power for renal outcomes and of course, acute renal injury may be unrelated to renal disease progression. Nevertheless, levels of serum creatinine were similar between groups.
Be that as it may, the use of antihypertensive agents, in particular RAS inhibitors, may be associated with decreased GFR due to a fall in renal perfusion pressure. These findings are of particular interest in light of an interesting recent report by Moniwa and colleagues, who reported the effects of combined large doses of valsartan and aliskiren in congenic mRen(2) Lewis hypertensive rats. Although they showed improvement in protein-excretion rate, blood-pressure levels, and left-ventricular weight/tibia length ratio with the combined therapy, there were remarkable tubular, interstitial, and glomerular changes in this dual-blocking group. The authors proposed that impaired autoregulation is the reason for the histologic changes. This is a very important notion that needs validation as aliskerin by itself induced humoral and histologic abnormalities. Thus, the findings need to be further explored in other models including normal animals. Moreover, they need to be evaluated in clinical settings [Moniwa et al. 2013].
Actually, this phenomenon implies a fall in glomerular perfusion pressure and not only is predictable but it may also be desirable because it reveals a reduction in glomerular pressure. Indeed, RAS inhibitors have been shown to decrease GFR through a hemodynamic mechanism that is not overtly harmful. In fact, in CKD, elevations of serum-creatinine levels after RAS inhibition point to better outcomes [Apperloo et al. 1997; Bakris and Weir, 2000]. A post-hoc analysis of the Reduction of Endpoints in Non Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study showed that patients with greater falls in GFR had better long-term preservation of kidney function [Holtkamp et al. 2011].
Other limitations in the ONTARGET included no close monitoring of the albumin-excretion rate and serum creatinine not measured with a standardized or centralized method. In addition, the doubling of serum creatinine was not confirmed. Moreover, the indication for hemodialysis was arbitrary and nonprotocol specified. The reasons for the indications for chronic hemodialysis were undefined in some patients.
The ALTITUDE had similar drawbacks. In the randomized population there were many patients over 70 years of age (the mean basal age in the dual-blocking group was 64.6 ± 9.6 years at randomization), indicating that an important number of patients were septuagenarian diabetics. The patients receiving combined aliskiren plus ACE inhibitors or ARB therapy had a mean baseline systolic blood pressure of 137 ± 16.2 mmHg and a mean baseline diastolic blood pressure of 74.1 ± 9.8 mmHg. Thus, many of the serious adverse effects could have been the result of poor perfusion pressure, a predictable complication in high-risk elderly patients. Again, falls, fainting, nonfatal cerebrovascular accidents, hyperkalemia, and increased serum creatinine are all well-known complications of inadequate perfusion and therefore avoidable. In the ALTITUDE study, patients with serum-potassium concentrations greater than 5 mmol/L were randomized to dual-drug treatment.This is important, because trial definitions may not reflect the clinical significance of a side effect. For instance, combination therapy compared with monotherapy was associated with an increased risk for moderate hyperkalemia (serum potassium > 5.5 mmol/L), but not of clinically significant hyperkalemia (serum potassium > 6 mmol/L) [Harel et al. 2012] (Figure 1).
Percentage of patients developing hyperkalemia ( > 5.5 to < 6 mmol/L and > 6.0 mmol/L in the aliskerin + angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) group (filled bars) and in the placebo + ACEi or ARBs group (white bars). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Increments of serum potassium from 5.0 mEq/L to 5.5 mEq/L have never been shown to be harmful to anyone. After all, the Nernst equation tell us that, if not accompanied by very low serum ionized calcium, this increment in 0.5 mEq/L in serum potassium, changes the membrane potential by about 3%, a phenomenon with no clinical consequences.
Friend and colleagues recently published a third large trial showing negative results from dual blocking [Friend et al. 2013]. This study evaluated losartan against losartan plus lisinopril in diabetic patients with a mean age of 64.7 ± 7.7 years in the combined therapy group and 64.5 ± 7.9 years in the control group. The design of this study eluded some of the reservations that had emerged with the ONTARGET and ALTITUDE studies. However, the baseline systolic blood pressure for the losartan + placebo group was 137 ± 16.0 mmHg and 136.9 ± 16.5 mmHg for the losartan + lisinopril group. The mean baseline diastolic blood pressure was 77.8 ± 9.9 mmHg in the losartan group and 72.5 ± 10.6 mmHg in the combined-therapy group. More than 1/3 of the patients in both groups had heart disease. Again, these statistics indicate that some patients were at the limit of perfusion in this largely elderly population. Moreover, close to 1/4 of the patients suffered coronary artery disease and the authors correctly acknowledged these features. The fall in perfusion pressure is supported by the two most important reasons for discontinuation in this trial: hyperkalemia and acute kidney injury. The latter, an abrupt loss of kidney function that can result from a transient hemodynamic change, is not necessarily a permanent injury to the kidney. In fact, in patients with CKD, if RAS inhibition neither increases serum creatinine nor decreases eGFR, an interfering effect should be suspected. Lastly, the authors in this study reported lack of benefit on renal function, but a mean 2.2 years follow up may be insufficient to see significant renal protection. In this respect, proteinuria, a risk factor closely associated with interstitial inflammation, is the most reliable predictor of long-term kidney damage [CKD Work Group, 2013].
Recently Chrysant and Chrysant (2015), based on the evidences available suggested that dual RAS blockade should not be a routine treatment for cardiovascular disorders, but included as reasonable indications for dual-blocking diabetic nephropathy with proteinuria and heart failure with reduced ejection fraction.
In brief, abundant evidence suggests that RAS inhibition is beneficial in CKD, while dual or intensive RAS inhibition may offer additional cardio-renal benefits, and it may be the only alternative when other therapies fail or are unsuitable. Its utilization has shown tolerability compared with placebo, particularly in patients at high risk for congestive heart failure (CHF), diabetes mellitus, or CKD [Yusuf et al. 2008; McMurray et al. 2008; Deinum et al. 1999; Kawazu et al. 2004; Freiberger et al. 2009]. It should be kept in mind that in CKD (diabetic and nondiabetic), the goal is not only blood-pressure control, but also reduction of proteinuria. Indeed, high protein-excretion rate is a risk factor for progression of kidney disease, and its reversion delays progression [Brenner et al. 2001; Jafar et al. 2001].
Nevertheless, the evidence indicates that intensive or dual blocking should be avoided in elderly patients with normal or borderline blood pressure and at high cardiovascular risk. When these treatments are indicated, blood pressure, serum electrolytes, and renal function should be carefully monitored. In these settings, potassium-sparing drugs, such as spironolactone, eplerenone, triamterene, and amiloride should be avoided. Also, dual blocking should be prescribed with great caution concurrently with drugs such as beta-blockers, no steroidal anti-inflammatory agents, calcineurin inhibitors, and heparin, and in patients suspected of suffering from hypoaldosteronism.
In summary, dual or intensive RAS blocking may be a worthy approach to prevent cardiac- or renal-disease progression. Judiciously applied while carefully monitoring clinical and laboratory parameters, this approach could offer a desirable alternative over hemodialysis or transplantation in many patients.
Footnotes
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.