An update on proteinuric chronic kidney disease: The dual-goal approach

BLOCKING RENIN-ANGIOTENSIN- ALDOSTERONE MORE COMPLETELY

These issues may be addressed by more complete inhibition of the renin-angiotensin-aldosterone system, now achievable with the addition of aldosterone receptor antagonists and direct renin inhibitors to the ACE inhibitors and ARBs. Although we lack long-term studies of the relative efficacy of these medicines alone or in various combinations, the multistep sequence of the renin-angiotensin-aldosterone system allows for the possibility that more complete suppression via coordinated pharmacologic attention to multiple sites will yield beneficial results.

Combining an ACE inhibitor and an ARB

Even in the absence of ACE, angiotensin II is also produced by other kinases and therefore is not completely suppressed by an ACE inhibitor. For this and other reasons, there are theoretical advantages to adding an ARB to an ACE inhibitor.

In the Combination Treatment of Angiotensin 2 Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-Diabetic Renal Disease (COOPERATE) study,²⁰ the combination of an ACE inhibitor and an ARB protected the kidneys better than either medicine alone, not only in terms of less protein in the urine but also in terms of significantly fewer patients progressing to the primary end points of doubling of serum creatinine or end-stage renal disease after 3 years of follow-up (11% of patients on combination therapy vs 23% on single therapy).

Aldosterone receptor antagonists or renin inhibitors plus ACE inhibitors and ARBs

Aldosterone escape is common during long-term therapy with ACE inhibitors and ARBs, and an aldosterone-receptor antagonist reduces proteinuria^11–13 and stabilizes kidney function¹³ in a manner additive to that of ACE inhibitors and ARBs.

Direct renin inhibitors overcome the reactive rises in renin activity and in angiotensin II that complicate therapy with ACE inhibitors and ARBs, and they also reduce urinary aldosterone excretion.¹⁴

When to consider combination therapy

Inhibition of the renin-angiotensin-aldosterone system at multiple sites may be considered in cases of persistent hypertension or proteinuria, or of progression of chronic kidney disease despite single-drug therapy, or more broadly, with increasing evidence that combination therapy may preserve the glomerular filtration rate.^13,20 This article suggests one way to apply the several available renin-angiotensin-aldosterone inhibitors, keeping in mind extensive interindividual variations, uncertain responses, and the absence of a linear evidence-based strategy known to be broadly successful.

INITIAL CONSIDERATION: WHAT IS THE BLOOD PRESSURE GOAL?

Determining the blood pressure goal for a patient may not be as straightforward as usually assumed. Typically, advisories suggest a discrete goal; for example, the Seventh Joint National Committee²² recommended a systolic blood pressure of 130 mm Hg or lower for patients with chronic kidney disease or diabetes. However, if we weigh the risks and benefits, we find that the situation is more nuanced. The blood pressure goal should vary among patients, depending on age, amount of proteinuria, whether the patient can tolerate the lowered blood pressure, and whether lowering the blood pressure to this goal stabilizes kidney function.

Long-term follow-up of the Modification of Diet in Renal Disease (MDRD) study demonstrated a benefit of setting the goal mean arterial pressure to less than 92 mm Hg (about 125 mm Hg systolic) regardless of proteinuria.²³ In addition, a meta-analysis suggested that nondiabetic proteinuric patients benefit from even lower systolic blood pressures (110–119 mm Hg).¹⁹

In older patients

However, in the MDRD study, the goal of approximately 125 mm Hg systolic pertained only to patients no older than 60 years.²³ The goal was increased to about 130 mm Hg for patients 61 to 70 years old. In addition, major clinical studies of chronic kidney disease have excluded patients older than 70 years.^2–7,23

Therapy for chronic kidney disease in this older age group is essentially unstudied, and we should be cautious about extrapolating results of aggressive blood pressure-lowering (and renin-angiotensin-aldosterone inhibition) from younger patients to older patients, who may have extensive vascular disease.^24,25

For patients older than 70 years, guidance is perhaps best provided by the Systolic Hypertension in the Elderly Program (SHEP), which found that lowering systolic blood pressure to an average of 143 mm Hg reduced the incidence of stroke and cardiovascular disease.²⁶ The SHEP study does not establish the optimal blood pressure goal for preventing progressive chronic kidney disease (or even cardiovascular disease) in the older age group. However, this is the lowest systolic pressure yet shown to be generally safe and associated with any improved outcome for these patients.

Additional studies are needed to evaluate whether this blood pressure level provides the best outcomes in patients with chronic kidney disease, or whether even lower blood pressures in the elderly are safe and will further improve either renal or cardiovascular outcomes.

In younger patients

In contrast, younger patients without diabetes or vascular disease may, in theory, be candidates for even lower blood pressure. No major study of chronic kidney disease isolated patients from about 20 to 40 years old for analysis, precluding direct evidence-based guidelines for this cohort at this time.

However, some of these patients may have had premorbid systolic blood pressures of 90 to 110 mm Hg, so systolic pressures of 110 to 120 mm Hg would be “hypertensive” by 10 to 30 mm Hg for them. It is possible that some patients in this cohort will tolerate a systolic pressure lower than 110 mm Hg, and that the lower blood pressure may provide additional long-term renal protection for them. This notion is theoretical, however, and has not been verified by clinical studies.

No one pressure fits all

In summary, an initial target systolic pressure for proteinuric patients, based on available evidence, might be less than 130 mm Hg for patients 61 to 70 years old,²³ less than 125 mm Hg for patients younger than 61 years,²³ and perhaps as low as 110 to 119 mm Hg for non-diabetic patients.¹⁹ Caution is advised against targeting systolic blood pressure less than 140 mm Hg for patients older than 70 years.

These are only initial goals and should be reevaluated as treatment progresses. The achieved blood pressure must be clinically tolerated—symptoms of tissue hypoperfusion indicate that the blood pressure is too low for the patient. In addition, the blood pressure goal (like the proteinuria goal) is only a surrogate end point, and if kidney function declines even though the surrogate end points are attained, then those end points should be reevaluated.

Tailoring blood pressure goals to the individual patient dovetails with the recent suggestion that blood pressure should not be perceived as a rigid dichotomy of “hypertension” vs “normal.”²⁷ There is, in general, a continuous correlation between blood pressure, beginning at low levels, and the risk of cardiorenal disease, and choosing an optimal blood pressure goal for an individual patient requires an ongoing assessment of benefits, risks, and side effects.