Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations

Diabetic kidney disease (DKD) affects approximately one-third of patients with diabetes and taking into consideration the high cardiovascular risk burden associated to this condition a multifactorial therapeutic approach is traditionally recommended, in which glucose and blood pressure control play a central role. The inhibition of renin–angiotensin–aldosterone RAAS system represent traditionally the cornerstone of DKD. Clinical outcome trials have demonstrated clinical significant benefit in slowing nephropathy progression mainly in the presence of albuminuria. Thus, international guidelines mandate their use in such patients. Given the central role of RAAS activity in the pathogenesis and progression of renal and cardiovascular damage, a more profound inhibition of the system by the use of multiple agents has been proposed in the past, especially in the presence of proteinuria, however clinical trials have failed to confirm the usefulness of this therapeutic approach. Furthermore, whether strict blood pressure control and pharmacologic RAAS inhibition entails a favorable renal outcome in non-albuminuric patients is at present unclear. This aspect is becoming an important issue in the management of DKD since nonalbuminuric DKD is currently the prevailing presenting phenotype. For these reasons it would be advisable that blood pressure management should be tailored in each subject on the basis of the renal phenotype as well as related comorbidities. This article reviews the current literature and discusses potentials and limitation of targeting the RAAS in order to provide the greatest renal protection in DKD.


Introduction
Throughout their lifetime, approximately one-third of patients with diabetes will eventually develop diabetic kidney disease (DKD) [1]. Furthermore, DKD is currently the leading cause of chronic kidney disease as well as of endstage kidney disease (ESKD) worldwide [2]. In patients with type 2 diabetes, DKD entails an unfavorable impact on cardiovascular (CV) risk burden [3,4]. As a matter of fact, subjects with diabetes and renal impairment are more likely to die from CV disease than to survive long enough and face the need of renal replacement therapy [5].
In the context of this rather complex and clinically challenging scenario a multifactorial therapeutic approach has traditionally been recommended. As a matter of fact, more than a decade ago, in the Steno-2 study an intensified multifactorial intervention with tight glucose control, the use of renin-angiotensin-aldosterone system (RAAS) blockers, aspirin, and lipid-lowering agents on top of behavior modification had been proved to effectively reduce CV morbidity and mortality over a long-term follow-up in patients with persistent microalbuminuria [6]. Nowadays, a combination of optimal glycemic and blood pressure control by the use of RAAS system inhibitors is still the cornerstone for prevention and treatment of DKD [7].
Hypertension is a common condition in patients with diabetes and its prevalence in subjects with DKD is significantly higher than in general population and increases gradually according to glomerular filtration rate (GFR) decline, reaching the 90% in ESKD subjects [8]. Therefore, the management of hypertension plays a central role since an adequate blood pressure control is able to reduce the burden of albuminuria, the progression of DKD as well as CV risk burden. However, in this setting of intervention, blood pressure targets and pharmacological choices are still a matter of debate in clinical practice.

Antihypertensive treatment and renal protection in type 2 diabetes: the need for a patient centered approach
Albuminuria is a known marker of renal damage and has been shown to have a strong cardiovascular and renal predictive power. Furthermore, modifications of urinary albumin excretion under pharmacological treatment might impact CV and renal prognosis independent of blood pressure reduction [9][10][11]. In the classical, five-stage course of diabetic nephropathy, mostly derived from studies conducted in patients with type 1 diabetes, microalbuminuria has traditionally been taken to represent the first sign of renal involvement [12] (Fig. 1). According to this clinical paradigm, overtime, albuminuria eventually progresses to overt proteinuria, which in turn, precedes GFR decline. While the natural history of DKD in type 2 diabetes seems to be more heterogenous, the assessment of albuminuria has been traditionally considered the reference tool for diagnosis of diabetic nephropathy and the reduction of progression or regression of albuminuria has been the primary end-point in many clinical trials aiming at the evaluation of nephroprotection conferred by the pharmacological inhibition of RAAS [13].
More recent studies, however, have shown that DKD in both type 1 and type 2 diabetes has an heterogeneous histologic phenotype, with various involvement of glomeruli and the interstitium [14]. On the other hand, it has recently been reported that a considerable proportion of diabetic patients with reduced GFR have a normal or only slightly increased urinary albumin excretion indicating that GFR decline does not necessarily parallel changes in albuminuria [15,16]. Both features of DKD, reduction of GFR and albuminuria, have an independent prognostic role in terms of CV and renal events and, therefore, the awareness and a better knowledge of these different conditions might have an impact in the management of DKD. Several studies as well as real-life observations have pointed out that a strict blood pressure control is associated to a reduction of albuminuria, but is not always associated to a benefit in terms of GFR preservation [17,18]. Accordingly, it has been suggested that lower BP values might be beneficial in terms of renal protection in diabetic patients with an albuminuric phenotype, while in absence of albuminuria this benefit is uncertain [19]. Therefore, it seems that an individually tailored treatment strategy in terms of both optimal blood targets and choice of antihypertensive drugs combinations could be desirable on the basis of the presenting renal phenotype [20]. This issue needs to be verified by studies specifically conducted in patients with non-albuminuric renal impairment. DCRecent International Guidelines [21] suggest that in patients with diabetes and hypertension, blood pressure targets should be individualized through a shared decisionmaking process that addresses cardiovascular risk among other variables. For individuals at high or very high cardiovascular risk (with atherosclerotic cardiovascular disease or 10-year Atherosclerotic Cardiovascular Disease risk ≥ 15%) a blood pressure target of < 130/80 mmHg seems to be appropriate, if it can be safely attained, while for those at lower risk for cardiovascular disease (10-year Atherosclerotic Cardiovascular Disease risk < 15%) a target of < 140/90 mmHg is recommended.

The inhibition of RAAS along the renal continuum
DKD is a complex disease, wherein various pathological changes including glomerular hypertrophy with progressive mesangial expansion and tubulointerstitial fibrosis are associated with multiple pathophysiological abnormalities such as inappropriate activation of the RAAS at the systemic and tissue level [22,23]. Hypertension and hyperglycaemia play a central role in the development and progression of renal damage contributing to structural and functional alterations. In particular, at the renal level increase intraglomerular pressure, cellular growth, and fibroblast differentiation have been shown to favor the development of interstitial fibrosis and glomerular sclerosis. Reducing intraglomerular pressure with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) can minimize, or even prevent, glomerular disease and albumin excretion. Furthermore, several experimental, animal, and in vivo studies have shown that the pharmacologic inhibition of RAAS leads to attenuation of interstitial fibrosis and glomerular sclerosis by down-regulation of advanced glycation end-products, TGF-β, NADPH oxidase, reactive oxygen species, reduced expression of receptors for advanced glycation end-products, reduced type IV collagen excretion and reduced mesangial extracellular matrix accumulation [24]. For all these reasons RAAS inhibitors have traditionally represented the mainstay treatment of hypertension in diabetic patients [25]. In fact, the effect of pharmacological RAAS blockade at various levels, by using ACEIs, ARBs, direct renin inhibitors, and mineralocorticoid antagonists, has been evaluated along the renal continuum.

Potentials of RAAS Inhibition
Main clinical trials that have evaluated renal protective effect of RAAS blockade across the renal continuum in DKD are reported in Table 1.
Patients with normal albuminuria In diabetic patients without microalbuminuria RAAS blockade has been studied to evaluate the effect on the transition from normoalbuminuria to microalbuminuria. Trials conducted on type 1 diabetic patients, such as Renin-Angiotensin System Study (RASS) [26] and Diabetic Retinopathy Candesartan Trial (DIRECT)-Prevent 1, and DIRECT-Protect 1 [27] failed to show any benefit in the prevention of the development of microalbuminuria. In patients with type 2 diabetes results are inconclusive. In the HOPE (Heart Outcomes Prevention Evaluation) trial ramipril was not effective [28], while in the the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) [29] the 2 arms containing trandolapril showed similar benefit in preventing the development of albuminuria, and their effect seemed to be independent of blood pressure reduction. Furthermore, in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) [30] the use of olmesartan prevented or delayed the onset of microalbuminuria, but difference in blood pressure between the olmesartan and placebo arms were statistically different.
Patients with moderately increased albuminuria As for the transition from microalbuminuria to overt proteinuria in the IRMA-2 (Effect of Irbesartan in the Development of Diabetic Nephropathy in Patients With T2DM) trial [31] irbesartan reduced the risk for the development of overt proteinuria (defined as albumin excretion > 200 mg/day) and the effect was dose-dependent.
Patients with severely increased albuminuria More solid data support the use of RAAS inhibitors in DKD with overt albuminuria. The Collaborative study group evaluated the impact of captopril versus placebo on CKD progression in patients with type 1 diabetes and proteinuria [32]. Despite similar blood pressure control the captopril group had a significantly lower rates of chronic kidney disease progression or ESKD. Similarly, the data from the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) [33] and IDNT (Irbesartan Diabetic Nephropathy Trial) [34] trials confirmed the nephroprotective effect of ARBs, in patients with DKD with proteinuria.
Therefore, the use of RAAS blockers has been considered for many years the gold standard therapy to reduce cardiovascular risk and to slow the progression of diabetic nephropathy and previous guidelines recommended the use of RAAS blockers in all patients with diabetes without distinction [35]. However, while lower BP values and pharmacologic inhibition of the RAAS have consistently been shown to improve renal outcome in diabetic patients presenting with the traditional "albuminuric" renal phenotype, it is uncertain whether a similar therapeutic strategy should be applied in the absence of albuminuria. In fact, RCTs as well as real-life reports have demonstrated that the use of RAAS inhibiting drugs in patients with diabetic nephropathy has a clinical significant benefit in slowing renal progression only in people with increased albuminuria. Accordingly, more recently, guidelines do not recommend routine use of RAAS blockers in diabetic subjects unless in the presence of nephropathy with an urinary albumin-tocreatinine ratio greater than 30 mg/g creatinine in order to reduce the risk of progressive kidney disease [21,36,37]. Either an ACEI or an ARB are recommended, as these drug classes have shown similar nephroprotective effect. ARB have been studied more extensively than ACEi in patients with type 2 diabetes; on the other hand, no study has been completed with ARB in type 1 diabetes. As for dosage, in the absence of side effects the maximum tolerated dose approved for blood pressure treatment is usually recommended. While in the absence of albuminuria a less strict blood pressure control could be advisable and RAAS inhibitors may not necessarily represents the preferred antihypertensive drugs and treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes (ACE inhibitors, angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blockers) without cogent preference [21,25].

Limitations of RAAS inhibition
Several studies have explored the potential benefit of maximal inhibition of the RAAS by means of high doses monotherapy or combination drug. Dual RAAS blockade is based on the pathophysiological rationale of a more profound inhibition of the RAAS cascade which may counteract the well known "aldosterone escape" phenomenon observed in patients treated with a single agent. However, disappointing results from several mega trials with hard endpoints have subsided the initial enthusiasm on the promising effects of dual RAAS blockade on surrogate outcomes. In fact, the combination of two RAAS blocking drugs did not provide considerable benefit in terms of long term renal protection and was accompanied by higher incidence of acute kidney injury and hyperkaliemia as compared to single-drug therapy [38][39][40]. It is likely that dual/multilevel RAAS blockade completely abolishes the protective role of this system in maintaining renal haemodynamics under stressful conditions and, therefore, may favor AKI in hypovolemic patients. Accordingly, international guidelines currently discourage the use of dual RAAS blockade for the prevention and treatment of DKD [21,25].
Finally, mineralocorticoid receptor inhibitors (MRI) such as spironolactone or eplerenone might offer an additional opportunity for RAAS intervention by counteracting the "aldosterone breakthrough" that occurs in a subset of patients on RAAS-inhibiting therapy. Aldosterone is known to affect volume status by the regulating renal sodium reabsorption and exert profibrotic effects through increased production of TGF-beta, reactive oxygen, species, PAI-1 and increased collagen gene expression and synthesis [41,42] and, the use of MRI has been demonstrated to reduce inflammation and fibrosis at kidney level [43][44][45]. Several studies have shown that the addition of aldosterone receptor blockade to ACEI or ARB blockade can lead to further reduction in albuminuria including in DKD [46][47][48], however long-term data on the efficacy of mineralocorticoid receptor antagonists on hard endpoints, for example the development of ESKD or patient survival, are still lacking.

Conclusions
Multiple trials have demonstrated that the use of RAAS blocking drugs can slow progression to ESKD in patients with diabetic nephropathy and proteinuria > 300 mg/day, however single agent RAAS blockade is not sufficient in slowering progression in many patients. In fact, significant residual risk remains in patients with DN and many patients progress to ESKD despite standard recommended care, including optimal control of blood pressure, glycemia and lipids and the use of RAAS blockade [49,50]. Furthermore, a paradoxical J-curve relationship between BP reduction and renal morbidity may limit the benefit of aggressive treatment strategies, especially in elderly patients with a renal dysfunction without albuminuria [51]. Thus, different individually tailored therapeutic targets, that take into account specific cardiovascular and renal phenotype should guide therapeutic strategies. Given the steady increase in the prevalence of diabetes worldwide and the soaring costs related to its management, prevention and treatment of DKD remains an unmet clinical need. Within this context, recently developed therapeutic agents such as sodium-glucose co-transporter-2 inhibitors and glucagone like peptide-1 receptor agonist have shown promising therapeutic potential not only to reduce CV risk but also to slow the progression of kidney disease with beneficial effect on albuminuria as well as on GFR [52][53][54][55]. As a matter of fact, the nephroprotective effect of these drug classes, especially SGLT2-is, was shown to be additive to RAAS-is and consistent in various studies completed so far, irrespective of baseline GFR and the presence of albuminuria. Several mechanisms, both glycemic and extra glycemic, have been proposed to account for the observed benefit on renal and cardiovascular events [56][57][58][59].
Because of their remarkable antiproteinuric and renoprotective activity, confirmed in many large trials, SGLT2i may soon become, in association with RAASi, the standard of care to prevent DKD and retard its progression.

Take home messages
• Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease and represent a significant cause of morbidity and mortality worldwide due to the related cardiovascular risk burden. • The standard of care for management of DKD over the last three decades has been the control of cardiovascular risk factors and the pharmacologic inhibition of reninangiotensin-aldosterone system (RAAS). • Nowadays, non-albuminuric DKD is the prevailing phenotype. The nephroprotective role of intensive blood pressure control and the use of RAAS inhibitor in these patients is at present unclear. • Recent evidence supports a renal protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors independent of their hypoglycemic properties. • We suggest that co-treatment with RAAS and SGLT2 inhibitors may represent the new era of therapeutic options for DKD.