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

Cleveland Clinic Journal of Medicine. 2008 October;75(10):705-713

October 1, 2008|Cleveland Clinic Journal of Medicine

ABSTRACTLowering both blood pressure and urinary albumin excretion to specific goals may slow the progression of proteinuric chronic kidney disease. However, this dual-goal approach needs to be validated prospectively.

KEY POINTS

Evidence is emerging that urinary albumin is toxic to the kidney.
Lowering both blood pressure and urinary albumin excretion, as a means to prevent progressive renal disease, appears to require aggressive inhibition of the renin-angiotensin-aldosterone system, often with several complementary drugs, ie, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, aldosterone receptor antagonists, and possibly, direct renin inhibitors.
Volume status and potassium levels may help suggest which of several available drugs could be added at different times.
Serum potassium levels must be managed aggressively when using renin-angiotensin-aldosterone inhibitors in combination.

STARTING ANTIHYPERTENSIVE THERAPY

The question of which antihypertensive drug to try first is moot in chronic kidney disease because almost all patients need multiple medicines to reach their blood pressure goals.

The Seventh Joint National Committee recommended an ACE inhibitor for initial therapy in hypertensive patients with chronic kidney disease,²² although an ARB is a reasonable first choice for those with type 2 diabetes.^5,6

Diuretics potentiate the effects of ACE inhibitors and ARBs and are generally prescribed concomitantly or as the second choice.

A beta-blocker may be recommended as a third medicine (when needed), to provide a complementary class of antihypertensive, to address the high incidence of concomitant coronary artery disease and systolic dysfunction, and because of evidence that sympathetic excess contributes to the hypertension and progression of chronic kidney disease.^28,29 The National Kidney Foundation³⁰ suggests that the dose of beta-blocker be increased if the heart rate is greater than 84.

INTENSIFYING RENIN-ANGIOTENSIN-ALDOSTERONE INHIBITION: WHICH DRUGS, AND WHEN?

When hypertension and proteinuria persist despite the use of an ACE inhibitor or an ARB, additional inhibition of the renin-angiotensin-aldosterone system is generally recommended to lower both the blood pressure and the protein excretion. Increasing the dose of ACE inhibitor or ARB,^31–34 combining an ACE inhibitor and an ARB,²⁰ or adding an aldosterone receptor antagonist to either an ACE inhibitor or an ARB^11–13 have all been shown to reduce proteinuria (as a surrogate end point), and several studies have, importantly, found that these combinations preserve kidney function over time.^13,20

However, lacking long-term studies that compare these options, we cannot insist upon specific treatment choices or sequences in these situations.

An approach based on serum potassium and volume status

Nevertheless, physicians need to make decisions when hypertension or proteinuria persists despite initial therapy. In the absence of definitive clinical studies, one possible approach is to choose among the various drugs on the basis of the serum potassium level and volume status (Table 2).

For example, if a patient has obvious signs of volume excess (eg, edema, jugular venous distention, rales) and the serum potassium concentration is less than about 5.0 or 5.5 mEq/L, then an aldosterone receptor antagonist may logically be added or increased in dose.

Aldosterone is more than a kidney hormone

Of note, we now know that aldosterone does not act only on the renal tubule: recent studies have shown it to have adverse effects on cardiac remodeling, systemic vessels, and glomeruli.³⁵ The broadened indications for aldosterone receptor antagonists are listed in Table 3, with emphasis on prescribing them for patients with concomitant systolic dysfunction and proteinuria, as long as the serum potassium level is controlled.

Increasing the diuretic or renin-angiotensin-aldosterone inhibition

For patients who have obvious signs of volume excess and a serum potassium level greater than 5.0 mEq/L, the dosage of kaliuretic (potassium-excreting) diuretic (usually a loop diuretic in chronic kidney disease) can be increased. Although kaliuretic diuretics do not specifically lower proteinuria, they will help control volume and blood pressure and, by lowering the serum potassium level, facilitate the subsequent augmention of renin-angiotensin-aldosterone inhibition.

When a hypertensive patient does not seem to have excess volume or tachycardia and the serum potassium level is less than about 5.5 mEq/L, then additional renin-angiotensin-aldosterone inhibition is indicated.¹⁶ This may be accomplished either by increasing the ACE inhibitor or the ARB to its maximal antihypertensive dose or by starting combination therapy.

Starting a calcium channel blocker

When the serum potassium level is higher than about 5.5 mEq/L, further inhibition of the renin-angiotensin-aldosterone system is contraindicated, and a nondihydropyridine calcium channel blocker can be added for its anti-hypertensive and antiproteinuric effects.^16,36

When nondihydropyridine calcium channel blockers are contraindicated due to their antiinotropic effect, an attractive alternative may be to cautiously increase the dose of kaliuretic diuretics. Given the high prevalence of (often covert) volume excess in chronic kidney disease, empiric diuresis may lower blood pressure, particularly in patients already receiving several vasodilators.³⁷ Moreover, as mentioned, by reducing serum potassium, kaliuretic diuretics help allow for a subsequent increase in renin-angiotensin-aldosterone inhibition.

IF BLOOD PRESSURE IS NORMAL, BUT PROTEINURIA PERSISTS

Because lowering blood pressure does not necessarily reduce protein excretion, some patients achieve their blood pressure goal but still have excessive proteinuria. Proponents of the dual-goal approach suggest that these patients require further treatment modifications to reach the proteinuria goal and their optimal renal prognosis.

A number of options are available (Table 4), although none of them has been shown to be clearly superior to the others in clinical studies.

A cautious increase in renin-angiotensin-aldosterone inhibition is possible but is likely to be limited by low blood pressure. When applicable, any nonessential antihypertensive drug that does not specifically reduce proteinuria (ie, dihydropyridine calcium channel blockers and central and direct vasodilators) should first be discontinued. This allows additional renin-angiotensin-aldosterone inhibition to reduce proteinuria without causing hypotension.

In addition, “ultra-high” doses of these drugs—two or more times the maximal antihypertensive dose—appear to reduce proteinuria without further reducing blood pressure.^31–34

Various combinations of an ACE inhibitor, an ARB, and an aldosterone receptor antagonist (and possibly a renin inhibitor) may also be prescribed, striving for more complete suppression of the renin-angiotensin-aldosterone system, with dose adjustments to prevent hypotension.

References

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