Optimizing Blood Pressure Control in Patients With Nondiabetic Glomerular Disease Kausik Umanath, Julia B. Lewis, and Jamie P. Dwyer Hypertension is a common problem among patients with glomerular disease and CKD. Optimal blood pressure targets for these patients have been the source of much debate. Careful review of the available data supports a blood pressure target of less than 140/90 mmHg. Consideration for a lower goal of less than 130/80 mmHg should be given for patients with heavy proteinuria. Renin-angiotensin system inhibitors should be used as the cornerstone of therapy for all patients with glomerular disease and CKD. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Hypertension, CKD, Glomerular disease

Introduction Hypertension complicates the management of most patients with CKD. Many seminal clinical studies over the past 4 decades have demonstrated that lowering blood pressure (BP) in individuals with hypertension reduces the risk of stroke and other cardiovascular (CV) events.1-9 Analysis of data across these studies resulted in a guideline goal BP of less than 140/90 mmHg.10 Unfortunately, patients with CKD were systematically excluded from many of these early BP trials. Thus, these early trials provided little information on the benefits of BP control on CV adverse outcomes in CKD patients or on preventing adverse kidney outcomes. However, CV disease is common in patients with CKD, and multiple observational studies have demonstrated a strong association among proteinuria, decreased glomerular filtration rate (GFR), and adverse CV events.11 In addition, observational studies have demonstrated a strong association between higher achieved BP and faster declines in kidney function. Thus, several guidelines have recommended a BP target of less than 130/80 mmHg for patients with CKD on the basis of subgroup or post hoc analysis of trials examining different BP goals in CKD patients.10,12-15 There has recently been some controversy surrounding these targets.16 For example, several small studies have suggested a J-shaped relationship between achieved BP and outcomes in the elderly, in individuals with vascular disease, and in CKD patients.17-21 This debate has led to more recent guidelines for CKD patients that have From Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, MI; Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN; and Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN. K.U., J.B.L., and J.P.D. are supported in part by the National Institutes of Health Heart, Lung, and Blood Institute Systolic Blood Pressure INTervention Trial (SPRINT) HHSN268200900046 C. Address correspondence to Jamie P. Dwyer, MD, MCN S-3223, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.01.006

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recommended a BP target of less than 140/90 mmHg.22 In this review, we will discuss the key clinical trials and evidence informing the clinician regarding optimal BP control in the patient with nondiabetic glomerular disease.

What Should the BP Goals Be in Nondiabetic CKD Patients? Observational studies,23-25 multiple small studies with surrogate outcomes,26-29 and 3 randomized controlled trials (ie, the Modification of Diet in Renal Disease [MDRD] study, the African American Study of Kidney Disease and Hypertension [AASK], and the Ramipril Efficacy in Nephropathy 2 [REIN-2] study) form a body of evidence to determine appropriate BP goals in CKD patients. These 3 randomized trials merit careful review.

MDRD The MDRD study randomly assigned 840 individuals with nondiabetic CKD to a mean arterial pressure (MAP) of 92 mmHg or less (roughly equivalent to 125/ 75 mmHg) vs 107 mmHg (roughly equivalent to 140/ 90 mmHg) and followed the rate of decline of GFR over 2.2 years. Over this time period, serial I125-iothalamate GFR measurements were taken and analyzed to test the hypothesis that the lower MAP goal would reduce the rate of decline of GFR. When analyzed by the intentionto-treat design on the study population as a whole, there was no significant benefit seen in the lower MAP group in slowing the rate of decline of GFR. The study was not designed nor did it have a sufficient number of subjects to examine the effect of different BP goals on CV outcomes. In addition, analysis of other kidney outcomes, including doubling of serum creatinine (SCr), ESRD, and death, showed no difference between the 2 BP groups.30 However, a subgroup analysis stratified by entry proteinuria demonstrated a slower rate of decline in kidney function for those subjects with greater than 3 g/24 hours (there were only 54 subjects in the subgroup with 3g/24 hours of proteinuria) who were randomized to the lower BP goal. In addition, when combined with

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BP Targets in CKD

the 103 subjects who entered the study with between 1 and 3 g of proteinuria in 24 hours, a benefit was seen for the lower MAP goal in this collection of 157 subjects. The 1- to 3-g/24-hour group did not show statistical significance on its own. Of note, there was more frequent use of renin-angiotensin system (RAS) inhibitors in the lower MAP group, which raises the potential of confounding because these agents are known modifiers of kidney disease progression.31 Despite these caveats, these results were used to support a BP goal of less than 130/80 mmHg in CKD patients with more than 1 g of proteinuria per day. In a post hoc observational study, MDRD subjects were followed for outcomes of ESRD (dialysis requirement or transplantation) or mortality 7 years after the primary study concluded. Of note, subjects over this 7-year period no longer had BP controlled to goals as in the original study. Subjects randomized to the lower BP group had a lower rate of ESRD and death despite no further BP intervention.32 The observational study did not stratify analyses by entry proteinuria. This follow-up data generate the hypothesis that a lower BP goal in CKD patients may reduce the rate of progression of kidney disease.

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intention-to-treat design while subjects actually had separate BP goals brings this conclusion into some question.

REIN-2 The REIN-2 study sought to evaluate if intensive BP control (,130/80 mmHg) as compared to conventional therapy (diastolic BP , 90 mmHg) in subjects with nondiabetic proteinuric nephropathies would reduce the rate of ESRD. This study was unique in that the investigators mandated fixed-dose background therapy with ramipril in both arms of the study. Three-hundred and thirty-eight patients were randomized 1:1 into the study and were followed for a median time of 19 months. There was no additional benefit of the more intensive BP target in terms of progression to ESRD.35 Thus, the results of REIN-2 do not support a lower BP goal for patients with CKD.

Optimal BP Targets

Outside of the 3 major studies discussed, observational studies, and multiple small studies with surrogate outCLINICAL SUMMARY comes, there are few other studies to guide BP targets  Hypertension complicates the management of many AASK in CKD patients. First, patients with CKD. many of the seminal hyperIn the AASK study, 1094  Recent controversy has sparked debate about appropriate tension studies systematiAfrican-American subjects blood pressure targets. cally excluded CKD with hypertensive nephro Proteinuric patients might need tighter BP control. patients. Thus, we are left sclerosis and a GFR between with MDRD, AASK, and 20 and 65 mL/minute per  Agents which block the renin-angiotensin system are the cornerstone of therapy. REIN-2 as the major ran1.73 m2 were randomized to domized controlled trials a MAP of 92 mmHg or less specifically designed for vs 102 to 107 mmHg (usual CKD patients assessing the potential benefits of the lower care) and followed for 3 to 6.4 years. There was no signifBP goals. There are a couple of critical points when icant benefit of the lower MAP goal in slowing the rate of judging the weight of the evidence in selecting a BP target decline in GFR. There was also no benefit to the lower for CKD patients. The AASK and MDRD studies targeted MAP group for the other clinical endpoints of doubling MAP. This means that one could have a range of systolic of SCr, ESRD, and mortality. It is interesting to note blood pressures (SBPs) that would still generate a MAP that, unlike the MDRD study, when subgroup analysis that is at goal for the study. Thus, targeting a MAP of was done stratifying by the degree of proteinuria upon 92 mmHg with resultant SBPs in a range of 98 to 154 is entry to the study, no benefit was seen in any subgroup.33 a distinctly different intervention when compared with AASK study participants entered a cohort phase at the targeting all patients to a specific SBP goal (Fig 1). conclusion of the main study and were followed for an Several observational studies23-25 and multiple small additional 5 years. Subjects were treated based on the results of the main study to a goal MAP of 107 mmHg until studies26-29 showed the benefit of lower BP targets with national guidelines dictated a goal BP of less than 130/80 respect to kidney and CV outcomes. However, given mmHg. Analysis of the cohort phase of the study showed their observational design, small size, and surrogate a benefit for those originally randomized to intensive BP endpoints, they did not have the ability to conclusively control in those subjects with an entry protein-toprovide evidence for a lower BP goal. The 3 major creatinine ratio of more than 0.22.34 The long-term prospective randomized controlled trials discussed above unfortunately did not show a benefit for kidney follow-up data in the AASK study generate a hypothesis outcomes upon primary analysis (Table 1). The current that a lower BP goal may have late manifesting benefit in debate surrounding the lower BP goals for proteinuric CKD patients in preventing kidney disease progression. CKD patients stems from the secondary analysis of the However, the absence of any benefit in the trial by the

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Figure 1. The solid line is the hypothetical distribution of the average mean systolic blood pressure found in the MDRD study low-MAP group. MAP, mean arterial pressure; MDRD, Modification of Diet in Renal Disease study. Republished with permission from Lewis, J Am Soc Nephrol. 2010; 21:1086-1092. Permission conveyed through Copyright Clearance Center, Inc.16

MDRD study31 and the long-term follow-up of the AASK cohort.34 A small subset of participants (54 subjects) with significant proteinuria (.3 g/day) benefited from the lower BP target in the MDRD study.31 The long-term follow-up of the AASK cohort suggests a benefit of a lower BP target for those individuals with proteinuria greater than 0.22 g at entry to the study. This benefit was only seen after several years of follow-up and after subjects were out of the active randomized controlled portion of the study.34 Thus, although these studies suggest that a lower BP target may be beneficial for a subset of CKD patients, care must be taken to ensure we do no harm to patients by lowering BP too much.

Is There Evidence that Lower BP Goals Could Cause Harm? A recent observational study has suggested that lowering BP in CKD patients below 120 mmHg increases the risk of stroke.21 In addition, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study randomly assigned 4733 diabetic patients with minimal CKD (SCr , 1.5 mg/ dL were excluded) to a target SBP of less than 120 mmHg vs a conventional target of less than 140 mmHg. There were no significant differences in the rates of CV outcomes between the 2 groups. The study also noted an increase in elevations in SCr in the intensive group and no difference between groups in the rate of ESRD or need for dialysis for any cause.36 Although ACCORD was a trial in diabetic subjects and thus outside of the scope of this

review, the fact that no benefit was seen for the intensive control group raises the concern that this may be true across other groups of subjects. The use of lower BP goals is of particular concern in those patients who are at risk of hypotension for other reasons, such as a tenuous state of fluid balance and frequent volume-depleting illnesses. In these patients, if their baseline BP is ‘‘too low,’’ then such an event can cause their BP to dip below a level at which they can adequately function and perfuse vital organs, thereby causing harm. This will be investigated thoroughly in the ongoing National Institutes of Health-sponsored Systolic Blood Pressure INTervention (SPRINT) trial, in which nearly 10,000 subjects with high CV risk have been randomized to 1 of 2 BP goals: less than 120/80 mmHg or less than 140/90 mmHg. The study has intentionally attempted to enrich the study population with CKD subjects to better inform us about optimal BP targets. It is interesting to note that SPRINT is excluding CKD subjects with proteinuria greater than 1 g/day on the basis of the totality of data including the subgroup analysis of the MDRD study discussed earlier. Given the present evidence, a goal SBP of less than 140 mmHg should be pursued in all patients with nondiabetic glomerular disease with a consideration for a goal of less than 130 mmHg in select patients with heavy proteinuria. These recommendations echo those of the recently released 8th Joint National Committee guidelines, which address all patients with CKD.37 It is reassuring that the guidelines are similar for diabetic and nondiabetic CKD patients.

Therapy of Hypertension Most of the data from the seminal BP studies referred to earlier illustrate that most patients will require an average of 3 antihypertensive agents to achieve the appropriate target BP.10 First and foremost, patients should be counseled on lifestyle modifications including a low-salt diet, an exercise regimen that is appropriate to maintain good CV health, and the cessation of tobacco abuse because each of these has been shown to assist with BP control in the general population.38 Subsequent to these interventions, pharmacologic therapy should be undertaken to a target BP of less than 140/90 mmHg.

Table 1. Summary of Prospective Randomized Controlled Blood Pressure Trials in Nondiabetic CKD Patients Study

Population

Mean Age (SD), y

Intervention

Primary Results

MDRD AASK

Subjects with nondiabetic CKD African Americans with GFR between 20 and 65 Subjects with nondiabetic proteinuric nephropathies

52 (12) 54.6 (10.6)

MAP of #92 vs 107 mmHg (usual care) MAP of #92 vs 102-107 mmHg (usual care)

No benefit No benefit

53.8 (15.3)

BP , 130/80 vs conventional therapy (DBP , 90 mmHg)

No benefit

REIN-2

AASK, African American Study of Kidney Disease and Hypertension; BP, blood pressure; DBP, diastolic blood pressure; GFR, glomerular filtration rate; MAP, mean arterial pressure; MDRD, Modification of Diet in Renal Disease study; REIN-2, Ramipril Efficacy in Nephropathy 2 study; SD, standard deviation.

BP Targets in CKD

Evidence to dictate the agents used to achieve a BP goal is somewhat lacking and difficult to interpret. The design of many studies targets a BP goal and allows for some discretion in the number and class of agents used to get to the goal. Thus, the control of other confounding factors outside of agent choice alone is often suboptimal to draw definitive conclusions about a specific agent or agent class. The notable exceptions are RAS-blocking medications, particularly angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Multiple large clinical studies have shown the benefit of captopril, irbesartan, and losartan independent of BP control in slowing the progression of proteinuric diabetic kidney disease.39-41 In addition, other randomized controlled trials, including AASK, have shown the benefit of RAS blockade in a nondiabetic population with and without substantial proteinuria.33,42,43 Meta-analyses of trials have also shown the benefit of RAS inhibition in CKD patients with proteinuria with respect to kidney and CV outcomes.44,45 Thus, although much of the direct trial evidence for RAS inhibition comes from diabetic patients, there are enough additional data to compel the clinician to treat all CKD patients with a RAS inhibitor. Particular attention should also be paid to a CKD patient’s volume status. Given the propensity for many glomerular disorders to present with substantial proteinuria, the nephrotic syndrome, and salt retention exacerbated by reduced GFR, patients can become volume overloaded, which will in many cases affect BP control. Patients with CKD will often respond to diuretics with lower BP even in the absence of overt edema. In a small study, thiazide diuretics and/or salt restriction seemed to potentiate BP and proteinuria reduction when added to background therapy with an angiotensin receptor blocker.46 Diuretics can also be helpful for the hyperkalemia associated with CKD and the use of RAS inhibitors. Diuretic regimens using a thiazide and/or a loop diuretic should be used if required. Hypertensive CKD patients can be challenging to treat because of the salt and water retention that often accompanies CKD. The results of the large clinical trials discussed in this review illustrate that CKD patients often require 3 drugs at full dose to achieve evidence-based BP targets.10,30,33,35,37 Therapy should include the use of a RAS-blocking medication and diuretics for the reasons outlined above.

Conclusion Hypertension complicates the management of most patients with CKD and many glomerular disorders. An optimal BP target for these patients has been the source of some recent controversy. Careful review of the available evidence supports a goal BP of less than 140/90 mmHg with consideration being given to a goal less than 130/80 mmHg for select patients with heavy pro-

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teinuria. Therapy should be anchored around the use of RAS-blocking medications.

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