Abstract
The understanding of hypertensive chronic kidney disease (CKD) has recently been reshaped by the discovery of risk alleles associated with kidney disease. Recent studies have also changed our understanding of therapeutic targets for blood pressure control in the CKD population. Pharmacological and nonpharmacological hypertension interventions to control progression of CKD continue to evolve.
Keywords
ACE inhibitors, angiotensin, blood pressure, chronic kidney disease, CKD progression, hypertension, lifestyle modification, proteinuria, receptor blockers, therapeutics
Introduction
Hypertension affects around one-third of the US population and is one of the main preventable risk factors for death and chronic disease progression, including kidney disease. According to the US Renal Data System, hypertension was reported as the second leading cause of incident end-stage renal disease (ESRD) cases. Yet controversy remains over whether hypertension alone initiates chronic kidney disease (CKD) and leads to subsequent ESRD, or if hypertension as a cause of ESRD represents a subset of patients with diverse but uninvestigated or unrecognized etiological reasons for kidney disease. Indeed, hypertension and CKD can be viewed as a bidirectional relationship: CKD causing uncontrolled hypertension, and hypertension causing CKD. However, except for accelerated and malignant hypertension, the evidence supporting a causal relationship between mild to moderate hypertension and CKD is inconsistent and therefore this causality is still debated. On the other hand, it is well accepted that CKD causes and contributes to hypertensive disease. In that regard, we know that the prevalence of hypertension is higher in patients with CKD compared with the general population, and that this prevalence increases further as patients progress to ESRD. Furthermore, the severity of hypertension in CKD increases the risk for ESRD ; and lower blood pressure (BP) levels in patients with proteinuric kidney diseases are associated with lower CKD progression rates.
Management of hypertension in the context of CKD remains an evolving field. Recent data from the Systolic Blood Pressure Intervention Trial (SPRINT) have lent important insights regarding BP goals in the management of individuals with hypertensive CKD. Nonpharmacological management strategies, such as dietary changes, also remain a field of active investigation. Here we review clinical manifestations of hypertensive kidney disease; therapeutic strategies, including recent findings about BP goals; antihypertensive agents; and nonpharmacological management strategies.
Potential Mechanisms of Renal Injury in Hypertension
The mechanisms by which chronic mild to moderate hypertension may induce renal injury are less clear than those by which it perpetuates progression and acceleration of CKD. The pathophysiology of hypertension causing CKD in individuals with previous normal kidney function depends both on its chronicity and severity. Clear distinct pathological changes are described for long-term chronic mild to moderate hypertension and malignant/accelerated hypertension.
Pathophysiology of Renal Injury in Hypertensive Nephrosclerosis
The pathophysiology of mild to moderate hypertension causing renal injury is, as discussed before, inconsistent across animal and human clinical studies. The histological changes associated with this type of hypertension are arteriolar hyalinosis, medial hypertrophy, and intimal fibrosis. Arteriolar hyalinosis is not specific to hypertension and can be found in other conditions such as diabetes and aging. Nevertheless, these changes lead to ischemic glomerulosclerosis demonstrated by the collapse of capillary loops and wrinkling of the capillary basement membrane leading to wall thickening. This ultimately results in glomerular tuft retraction and filling of the Bowman space with collagen. In addition, the tubules may show areas of atrophy and tubular lumen dilatation as well as chronic interstitial inflammatory cells surrounding the areas of tubular atrophy.
Evidence suggests that impaired renal autoregulation results in the transmission of systemic pressure to the renal microvasculature. Most of the evidence for impaired renal autoregulation derives from animal models, but the ideal animal model to elucidate the real contribution of hypertension to renal injury has not been identified. When the threshold of autoregulation is exceeded, as is seen in malignant hypertension, an acute injury is expected despite a normal autoregulation mechanism. The presence of chronic hypertension tends to increase the limits of renal blood flow autoregulation as a means of adaptation. However, there are situations in which lower degrees of systemic BP can be transmitted to the capillary loop in the presence of additive preglomerular vasodilatory states (e.g., inhibition of prostaglandin production by nonsteroidal antiinflammatory drugs) and/or other causes of impaired renal autoregulation. In addition, local, genetic or acquired factors may also increase the susceptibility and degree of renal injury (e.g., impaired structural integrity of the podocyte in glomerular hypertrophy or blood-pressure independent activation of downstream pathways involving angiotensin II, aldosterone, and other deleterious molecules).
Once kidney disease is established, additional pathophysiological mechanisms interact to perpetuate a hypertensive state that consequently contributes to the progression of CKD. The prevalence of hypertension in CKD is high and increases with the severity of renal function ranging from 75% to 89% in advanced CKD stages. Ultimately, the main factors that account for the presence and exacerbation of hypertension in CKD include increased extracellular volume and increased vascular resistance. The main mechanisms that contribute to the presence and exacerbation of these factors are sympathetic nervous system overactivity and activation of the renin-angiotensin-aldosterone system (RAAS), which result in arterial stiffness and impaired renal and water excretion.
Increased volume and cardiac output are the first changes that begin even before any change in BP manifests. Once the vascular bed compliance can no longer compensate for the increase in the blood volume, hypertension develops. The increased extracellular volume expansion is related to the impaired salt and water excretion that occurs in CKD as a consequence of altered pressure natriuresis in the presence of a decreased glomerular filtration rate (GFR) and the presence of angiotensin II resultant from RAAS activation. This is also influenced by high dietary sodium intake. Most of the patients with moderate to advanced CKD face a state of volume expansion, which correlates with higher BP levels and worse clinical outcomes. These adverse outcomes are the result of not only hypertension but the direct and independent effects of volume expansion and sodium load.
The overactivity of the sympathetic nervous system in CKD contributes both to increased volume expansion and vascular resistance. There have been several stimuli identified for increased sympathetic activity in CKD (i.e., renal ischemia, hyperleptinemia, RAAS, uremic toxins, smoking, obesity, hypercapnia, and decreased nitric oxide availability). This overactivity has been documented in individuals with nondiabetic predialysis CKD. The consequences of this hyperactive sympathetic system are activation of the RAAS with increased release of renin and angiotensin II, vasoconstriction of renal vasculature with arterial smooth muscle and fibroblast proliferation, and salt and water retention. There is also evidence that sympathetic overactivity can result in increased local inflammatory cytokines, which could additionally potentiate the progression of CKD.
The components of the RAAS activation also result in both increased extracellular volume and vascular resistance. In the presence of decreased cardiac output, renin release is mediated by the sympathetic nervous system along with a fall in distal convoluted tubular sodium delivery due to increased proximal tubular sodium reabsorption with resultant afferent arteriole dilation by tubuloglomerular feedback. Renin has a bidirectional relationship with the sympathetic nervous system, which stimulates it further and results in the production of angiotensin II.
The effects of angiotensin II lead to several hemodynamic and nonhemodynamic changes that promote inflammation, extracellular matrix accumulation, and direct glomerular injury, which lead to hypertension exacerbation and CKD progression through increased glomerular and tubulointerstitial fibrosis. These effects are mainly mediated by the angiotensin type 1 (AT1) receptor. The main hemodynamic changes are to increase glomerular hypertension, upregulate the sympathetic nervous system, and impair the normal pressure natriuresis. There are many nonhemodynamic effects of angiotensin II that can also contribute to CKD progression, which are predominantly mediated through activation of the AT1 receptor. These include proteinuria and loss of glomerular size permselectivity, stimulation of mesangial proliferation, tumor growth factor-β (TGF-β) expression, extracellular matrix deposition, endothelial production of plasminogen activator inhibitor-1 (PAI-1), macrophage activation, phagocytosis, and adrenal aldosterone production. Furthermore, the contribution of increased renal tubular sodium reabsorption by aldosterone as a result of RAAS activation in CKD is also important for the increased extracellular volume component of hypertension in this state.
Finally, other factors that influence vascular resistance are endothelin and secondary hyperparathyroidism. The role of endothelin is important given its role in promoting vasoconstriction; increasing arterial stiffness; and promoting endothelial dysfunction, inflammation, and atherosclerosis, which exacerbate hypertension and progression of CKD. In addition, secondary hyperparathyroidism of CKD influences arterial stiffness through its association with arterial calcification among other cardiovascular (CV) effects.
Genetic Risk Markers
One important finding involves the recent identification of the genetic contribution of the apolipoprotein L1 ( APOL1 ) gene in the development of nondiabetic kidney disease in individuals of African ancestry (see Chapter 7 : Genetic Causes of Chronic Kidney Disease). APOL1 is a gene located on chromosome 22 that produces a protein that is a component of circulating high-density lipoprotein. Two alleles, APOL1 G1 and APOL1 G2, which are found with greater frequency in individuals with African ancestry, confer an increased risk of development of nondiabetic kidney disease in an autosomal recessive manner; that is, persons who possess two of these renal-risk alleles in APOL1 have a 10.5-fold greater risk for idiopathic focal segmental glomerulosclerosis (FSGS) and a 7.3-fold greater risk for hypertension-related ESRD compared with those with zero or one allele. It has been postulated that APOL1 G1 and G2 (the so-called “renal-risk alleles”) became more common in populations with African ancestry as the gene products of these alleles confer resistance against Trypanosoma brucei infection (the causative agent of African sleeping sickness) due to the trypanolytic actions of these proteins. Overall, APOL1 -associated nephropathy may account for a significant proportion of nondiabetic kidney disease in African Americans, including cases previously identified as hypertensive nephropathy, with estimates of up to 70% of all nondiabetic kidney disease in African Americans being due to APOL1 -associated nephropathy.
Diagnosis and Clinical Manifestations
Clinical Manifestations and Risk Factors
The clinical diagnosis of hypertensive CKD includes a long period of antecedent, poorly controlled hypertension, subnephrotic proteinuria (typically less than 1 g/day), and features suggestive of other end-organ complications of uncontrolled hypertension, such as hypertensive retinopathy or left ventricular hypertrophy, as well as a bland urine sediment. There are no well-defined criteria for clinical diagnosis of hypertensive CKD, and biopsy is typically unnecessary for diagnosis. Historically, the African American race has been recognized as a risk factor for hypertensive CKD, though more recent recognition of APOL1 risk alleles raises the possibility that the diagnosis of hypertensive CKD could represent a distinct clinical entity in people with African ancestry. One study that retrospectively compared biopsy specimens of African Americans diagnosed with hypertensive CKD with those of whites with the same diagnosis found that there were morphological differences in the global glomerulosclerosis lesions between the two groups, with African Americans having more of a “solidified” global glomerulosclerosis lesion, and that these differences were independent of BP and degree of proteinuria. A later study examined about 200 kidney biopsy specimens from African Americans diagnosed with hypertensive CKD and the relationship between these morphological differences and presence of APOL1 renal-risk alleles on genotyping. Individuals with two APOL1 renal-risk alleles were more likely to have a solidified global glomerulosclerosis lesion, compared with those with zero such alleles. Taken together, these studies suggest the possibility of different mechanisms of renal injury between individuals having two APOL1 renal-risk alleles and those who do not carry these genotypes.
Role of Kidney Biopsy
As the diagnosis of hypertensive CKD is primarily a clinical one, most patients receiving this diagnosis do not undergo biopsy, unless doubt on the part of the clinician exists as to the etiology of CKD. One study that affirms this approach drew data from the African American Study of Kidney Disease and Hypertension (AASK), in which 39 participants carrying a clinical diagnosis of hypertensive nephrosclerosis underwent renal biopsy, and histopathological examination showed changes consistent with this diagnosis in all but one biopsy specimen. Pathological findings of hypertensive nephrosclerosis include changes in the glomeruli, tubulointerstitium, and vasculature. Glomeruli may be normal or show wrinkling, or later global or segmental sclerosis ( Fig. 4.1A ). Tubular atrophy and hyaline casts may be present. Fibrous intimal thickening may be present in the arcuate and larger arteries ( Fig. 4.1B ). As discussed earlier, recent studies have demonstrated that renal biopsy specimens from individuals with two APOL1 renal-risk alleles may show different histopathological findings compared with those from individuals without such alleles. Malignant hypertension results in acute glomerular injury when the limits of autoregulation are exceeded and is characterized by focal fibrinoid necrosis (usually segmental), mesangiolysis, and occlusion of the capillary lumen by endothelial swelling and fibrin and platelet thrombi ( Fig. 4.1C ). This eventually leads to thickening of capillary walls and subendothelial widening resulting in double contour of the basement membrane. These acute changes may be indistinguishable from those of acute thrombotic microangiopathy ( Fig. 4.1D ). The chronic glomerular changes of malignant hypertension can involve either similar changes to those seen in benign hypertension; or a collapsed, almost acellular, glomerulus with subendothelial widening.
Therapeutics
In the next section, we will review evidence regarding the optimal BP goal for patients with hypertensive CKD and discuss the use of individual antihypertensive agents. These sections will also include a discussion of the recent major studies regarding BP control in CKD ( Table 4.1 ).
| Study | Population | Study Design | Intervention | Endpoints | Outcome |
|---|---|---|---|---|---|
| ACCOMPLISH | 11,506 people with hypertension at high risk for a cardiovascular event, including 1093 with CKD | Double-blind RCCT | Benazepril-amlodipine vs. benazepril-hydrochlorothiazide combination, follow-up over 2.9 years | CV death and CV event composite | Benazepril-amlodipine superior in preventing CV death/events (19.6% RR reduction). CKD patients also had lower rates of CKD progression |
| ALLHAT | >33,000 hypertensive adults age 55 and up who had at least one other CV disease risk factor; about 18% had CKD III or IV | Double-blind RCCT | Chlorthalidone vs. amlodipine vs. Lisinopril vs. doxazosin, follow-up 4.9 years | CV death and CV event composite | Chlorthalidone group had better BP control, lower CV events than lisinopril group; No difference in CKD progression rates |
| AASK | 1094 African Americans with hypertensive CKD | 3-by-2 factorial design | Ramipril, metoprolol, or amlodipine in intensive (MAP ≤92 mmHg) or standard (MAP 102−107 mmHg) BP control arms, follow-up over 3−6.4 years | Composite of eGFR loss of 50% from baseline, ESRD, or death | No difference between levels of BP control; lower risk of composite outcome with ramipril use |
| IDNT | 1715 hypertensive adults with diabetic nephropathy | Double-blind RCCT | Amlodipine, irbesartan, or placebo, followed over 2.6 years | Composite of doubling of serum creatinine from baseline, ESRD, or death | Irbesartan reduced the risk of the primary outcome by about one-third compared with amlodipine or placebo despite similar achieved blood pressure control |
| REIN | 186 patients with nonnephrotic proteinuria and CKD | Double-blind RCCT | Ramipril vs. placebo + conventional antihypertensive therapy, follow-up over a median of 2.7 years | Change in GFR and time to ESRD | Ramipril reduced the risk of progression to ESRD compared with placebo and also reduced proteinuria |
| SPRINT | 9361 hypertensive adults >50, without diabetes, including 2646 with nonproteinuric CKD (eGFR 20−60 mL/min/1.73 m 2 and urine protein <1 g/d) | RCCT | Two arms: standard BP goal of <140 mmHg SBP or intensive BP goal of <120 mmHg SBP. Different classes of medications could be used at the investigator’s discretion to achieve BP control. Follow-up over 3 years | CV events, decrease in GFR by 50% or ESRD, and death | Participants in intensive control arm (including those with CKD) had lower risk of CV events and death. Increased rate of AKI in intensive arm but not CKD progression |
Target Level of BP Control
The 2014 Eighth Joint National Committee guidelines recommend a goal BP for adults with hypertension and CKD of ≤140/90 mmHg. However, this consensus recommendation is not without some controversy given the conflicting findings of recent clinical trials including individuals with and without CKD. One further complication is that these trials have had heterogeneity in ascertained outcomes, depending on the population under study. For example, the Modification of Diet in Renal Disease (MDRD) and AASK failed to find benefit of intensive BP control in terms of CKD progression, whereas the SPRINT found benefit of intensive BP control in terms of CV but not renal outcomes (see the following discussion).
SPRINT enrolled more than 9000 hypertensive adults age 50 and older. Although diabetics were excluded, all participants had either an additional CV risk factor or CKD with an estimated GFR (eGFR) at study entry of 20 to 59 mL/min/1.73 m 2 (28% of the study cohort). Individuals with proteinuria of more than 1 g/day were excluded. Participants were randomized to two systolic BP control arms. The standard arm goal was a systolic blood pressure (SBP) goal of ≤140 mmHg and the intensive arm goal was a systolic BP goal of ≤120 mmHg. The study did not focus on a particular antihypertensive medication class, of which any or a combination could be prescribed at the investigators’ discretion to achieve the desired level of BP control. The primary endpoint was a composite outcome of myocardial infarction, stroke, acute coronary syndrome not classified as myocardial infarction, stroke, acute decompensated heart failure, or death related to CV cause. For participants with CKD, a renal endpoint was also assessed, defined as a loss of 50% of eGFR from baseline value or development of ESRD requiring long-term maintenance dialysis or transplantation. Participants in the intensive-treatment arm achieved a mean SBP of 121.4 mmHg vs. 136.2 mmHg in the standard-treatment arm within the first year, and the level of BP control was maintained over the course of the study for each group. The study was stopped early (at a median follow-up of 3 years) due to a statistically significant difference in the primary outcome between the BP control arms (1.65% per year in the intensive-treatment arm compared with 2.19% per year in the standard-treatment arm, P < .001). There was no difference in renal outcomes among participants with CKD (1.1% per year in both groups) ( Fig. 4.2 ). However, among participants without CKD, the risk of acute kidney injury was higher (4.1% in the intensive-treatment arm compared with 2.5% in the standard-treatment arm, P < .001). A more recent subgroup analysis of SPRINT participants with CKD found that intensive BP control resulted in a 19% lower risk of CV events and a 28% lower risk of all-cause mortality compared with standard BP control but did not have a significant effect on CKD progression rates. It should be noted that SPRINT participants with CKD had a mean eGFR of 47 mL/min/1.73 m 2 , and individuals were excluded with proteinuria >1 g/day at baseline. Therefore findings may not be generalizable to all patients with CKD.
In choosing optimal BP, the clinician and the patient need to balance pros and cons and take into consideration comorbid and demographic propensity for the development of CV events, as well as the risk for adverse events from increased BP control. The role of specific agents and lifestyle modification strategies are discussed in the following section.
Therapeutic Agents
RAAS Blockade
The RAAS, through the mediation of angiotensin-II, contributes to the progression of CKD in both its hemodynamic and nonhemodynamic effects. The pharmacological blockage of this system results in the lowering of BP in individuals with primary hypertension and CKD. In addition to this hemodynamic effect, there is considerable evidence from animal models of CKD that RAAS blockade using either angiotensin-converting enzyme inhibitors (ACEIs ) or angiotensin receptor blockers (ARBs) results in decreased glomerular pressure and consequently proteinuria, protects against arterial wall thickening, prevents activation of profibrotic and proinflammatory cytokines and macrophage recruitment. Human trials have confirmed the protective effects of these agents in both diabetic and nondiabetic individuals with CKD. We focus on those with nondiabetic hypertensive CKD in this section.
Angiotensin Converting Enzime Inhibitors
ACEIs inhibit the enzymatic conversion of angiotensin I to angiotensin II and have been shown to attenuate the decline of renal function in nondiabetic CKD populations. Although the first trial showing the benefit of ACEI was in a diabetic population, subsequent trials that have analyzed moderate nondiabetic, mostly hypertensive, CKD populations with eGFR ranging between 39 and 50 mL/min/1.73 m 2 have reported improved renal outcomes in this group. Maschio et al. randomized 583 European individuals with baseline creatinine clearance of 42 mL/min to benazepril or placebo. After 3 years of follow-up, these investigators found greater systolic and diastolic lowering effects in the benazepril group. The placebo group experienced a small increase in both SBP and diastolic blood pressure (DBP). There was a 53% overall risk reduction in the endpoint of doubling of serum creatinine or need for dialysis in the benazepril group compared with placebo. Also, the Ramipril Efficiency in Nephropathy (REIN) study randomized 352 individuals with two different strata of protein excretion (1 to 3 g per 24 h vs. >3 g per 24 h) to receive ramipril or placebo. Mean measured GFR was 40 mL/min/1.73 m 2 for the treatment group and 37 mL/min/1.73 m 2 for the placebo group. This trial saw a decrease in both SBP and DBP compared with baseline, but this was not statistically different between the ramipril and placebo groups in either stratum of proteinuria. However, the investigators observed a slower decline in GFR in the ramipril group from the strata with greater proteinuria that was independent of baseline and follow up BP levels. Although this finding was not seen for the ramipril group in the lower proteinuric strata, they did observe a 56% lower risk of progression to ESRD and 52% lower risk to progress to overt proteinuria in this stratum compared with placebo. The findings from AASK further support the role of ACEI to slow CKD progression. In this trial, 1094 African Americans were randomized to a normal or lower mean arterial blood pressure (MAP) and to one of three antihypertensive agents: ramipril, amlodipine, or metoprolol. Although this trial did not show a benefit of lower MAP in the primary outcome of CKD progression (doubling of serum creatinine, ESRD requiring maintenance dialysis or transplantation, or death), differences were seen with respect to this outcome between the groups treated with different antihypertensive agents: the ramipril group had 22% and 38% lower risk of the composite outcome of GFR decline, ESRD, or death compared with metoprolol and amlodipine, respectively. After the initial trial phase of AASK, participants were invited to enroll in an observational cohort phase and were followed for up to 12 years. An analysis of overall event rates during both the trial and cohort phase found no difference in the primary outcome over the entire period of follow-up between those initially randomized to intensive vs. standard control. However, the effects differed by level of baseline proteinuria ( P = .02 for interaction). Compared with individuals in the intensive BP control group with a protein–creatinine ratio of ≤0.22, individuals with a ratio >0.22 had a reduced risk for CKD progression (hazard ratio, 0.73; P = .01). Of note, follow-up BPs during this trial were similar between these three drug groups. The findings from this and other trials suggest a long-term effect of ACEI independent from its effect on BP. In the metaanalysis by Jafar et al., the slowing of CKD progression was more effective when antihypertensive regimens included ACEI. Whether this independent effect is driven by additional proteinuria decline from that attributed to BP lowering, or from other influence on the nonhemodynamic effects of RAAS, is still unclear. However, this concept of an independent RAAS blockade effect has been challenged by the results of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in nondiabetic CKD and some animal studies. The ALLHAT followed more than 33,000 adults older than 55 years with hypertension and one risk factor for heart disease randomized to receive chlorthalidone, amlodipine, or lisinopril for a combined primary outcome of fatal heart disease or nonfatal myocardial infarction. Approximately 18% of participants had CKD stage 3 or 4 at baseline. After almost 5 years of follow-up, ALLHAT investigators reported a superiority of chlorthalidone in preventing CV disease and no difference on the secondary outcome of reaching ESRD between the chlorthalidone and lisinopril groups. A post hoc analysis of CKD participants found no difference in the incidence of ESRD or a combined endpoint of ESRD and/or 50% decline in eGFR between the lisinopril and chlorthalidone groups. However, these results are difficult to interpret because proteinuria was not reported in this trial, and those in the lisinopril group were less adherent to the medication and had a statistically significant 2 mmHg higher BP level than the chlorthalidone group.
The main limitations to the use of ACEI in CKD patients are its associated increase in serum creatinine and hyperkalemia. The rise in creatinine noted in some of the trials has been attributed to the hemodynamic effect of the hypertensive therapy resulting in an initial fall in GFR within the first 2 months of therapy initiation but has also been associated with subsequent long-term renal protection. Therefore a rise in serum creatinine within 30% from baseline should not be of concern if stable within the first 2 months of therapy. Caution should be exercised if there is a larger increase in serum creatinine. In terms of hyperkalemia >5.0 mEq/L, the trials by Maschio et al. reported an increase of 0.5 mEq/L per liter in the serum potassium concentration in the ramipril group as opposed to no change in the placebo group. Five patients, three in the ramipril group and two in the placebo group, withdrew from the study due to hyperkalemia. In the REIN trial, only one patient withdrew from the study due to hyperkalemia, as opposed to two in the placebo group. The AASK trial had only three reports of hyperkalemia, but this was not statistically different from the other drug groups compared (amlodipine and metoprolol). Therefore the incidence of hyperkalemia observed in a nondiabetic CKD population treated with RAAS blockade remains low.
Angiotensin Receptor Blockers
The ARBs have a similar BP lowering effect as the ACEIs in the general population of hypertensive patients. These agents block the AT1 receptor resulting in blockage of angiotensin-II stimulation from any source, and produce elevations in both renin and angiotensin-II due to impaired feedback suppression. This potentially leads to stimulation of angiotensin receptor-2, which could counterbalance some of the effects mediated by AT1. However, the clinical significance of this is still unknown. Moreover, although there is plenty of evidence of similar BP control and proteinuria reduction to ACEI in animal models, the ARBs’ clinical effectiveness is based on large trials investigating diabetic kidney disease. There is currently no large randomized clinical trial available in a nondiabetic CKD population, and the clinical application of ARBs is based on results from smaller trials, which find similar BP control and reduction in proteinuria compared with ACEI in individuals with nondiabetic CKD. A stable, small rise in creatinine resultant from similar hemodynamic effects as ACEI has been observed for ARBs as well.
Combination Therapy ACEI and ARBs
There are several animal model and small trials that suggest that RAAS inhibition may be improved with combination therapy using both ACE and ARBs. However, a favorable clinical effect has not been shown when tested in large clinical trials. Specifically, the only trial that had reported a favorable effect of combination therapy in nondiabetic CKD has been discredited due to data inconsistencies. Therefore the evidence relies on other main trials showing an increased adverse effect of the combination therapy in different populations: those at high risk for vascular disease and those with diabetes. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) randomized more than 25,000 individuals at high risk for vascular disease to receive telmisartan, ramipril, or the combination of both. Despite a lower mean BP in the telmisartan and combination group compared with the ramipril group, there was no difference among the study groups in the composite CV primary outcome. However, the combination group had higher risk for hypotension, syncope, renal dysfunction, and hyperkalemia. A later post hoc analysis confirmed a higher risk for both a renal primary composite (dialysis, doubling serum creatinine, and death) and secondary outcomes (dialysis and doubling serum creatinine) for the combination group compared with the ramipril group. Most of these outcomes were driven by acute dialysis needs in the combination group; and the risk for chronic dialysis was not different among groups. Of note, this population had mild CKD with a baseline mean eGFR of 73 mL/min/1.73 m 2 and mean albuminuria of 82 mg/mmol of creatinine. Similar findings were noted in studies focusing on individuals with type 2 diabetes.
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