An update on proteinuric chronic kidney disease: The dual-goal approach
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.
KEEPING SERUM POTASSIUM AT SAFE LEVELS
Intensive inhibition of the renin-angiotensin-aldosterone system, via higher doses or combination therapy, increases the risk of hyperkalemia. This risk must be addressed energetically to prevent a potentially life-threatening complication.
When prescribed by nephrologists in clinical studies, renin-angiotensin-aldosterone inhibition has proven safe, with minimal adverse events (including hyperkalemia), even with high doses,32–34 in stage 4 chronic kidney disease (ie, with a glomerular filtration rate of 15 to 29 mL/min/1.73m2, inclusively)7 and with combination therapy.11–13,20
However, the increased incidence of hyperkalemia reported with spironolactone in patients with congestive heart failure following publication of the Randomized Aldactone Evaluation Study38 suggests that safety in clinical studies should not be extrapolated to mean safety in routine, community use. Patients with chronic kidney disease should not be given high doses or combinations of these drugs unless the treating physician is experienced in the prevention and treatment of hyperkalemia; typically such therapy should be guided by a nephrologist.
When serum potassium levels exceed 5.6 mEq/L, renin-angiotensin-aldosterone inhibitors should be decreased in dose or discontinued.39 Ideally, the drug or drugs should be restarted (to provide the potential benefits of these classes of drugs) when hyperkalemia has resolved, but this requires not only resolution of hyperkalemia but also steps to prevent this serious problem from recurring. The serum potassium level should be checked frequently, particularly after any increase in renin-angiotensin-aldosterone inhibition.
Treating hyperkalemia
Potential treatments for hyperkalemia include dietary restriction, sodium bicarbonate,39 fludrocortisone (Florinef),40 kaliuretic diuretics, and sodium polystyrene sulfonate (Kayexalate). Nonsteroidal anti-inflammatory drugs should be avoided.
Dietary restriction should be particularly emphasized: if potassium intake is decreased to the same extent as renin-angiotensin-aldosterone inhibitors reduce its excretion, then the serum potassium level will remain acceptable. All dietary supplements whose contents are not precisely known should be proscribed. A list of high-potassium foods to avoid should be given with the initial prescription for the drug. If briefly reviewed at each visit, with feedback given based on measured serum potassium levels, dietary treatment is typically effective (personal observation).
Fludrocortisone is an option when dietary potassium restriction fails.
An increase in the dose of diuretic is typically required with fludrocortisone to prevent sodium retention. The combination of dietary potassium restriction, fludrocortisone (0.1 mg/day, 3–5 days a week), and furosemide (Lasix) allowed high doses of an ACE inhibitor or a combination of an ACE inhibitor and an ARB to be given in 132 patients with chronic kidney disease.40 Over several years, their mean peak potassium level was 4.87 mEq/L, and no instance of acute hyperkalemia requiried stopping the ACE inhibitor or ARB.
However, fludrocortisone is an aldosterone analogue with potentially long-term aldosterone-mediated injurious effects on heart and renal function, even though only low doses were required in the three-pronged approach to hyperkalemia.40 The long-term effect of a regimen of an ACE inhibitor plus an ARB plus fludrocortisone on cardiac and renal outcomes is unknown and of concern.
Therefore, fludrocortisone should probably be avoided in patients with systolic heart dysfunction and should be used cautiously in general. Its use might be limited to patients with proteinuric chronic kidney disease that progresses despite therapy, particularly when that progression is in the context of inability to give significant renin-angiotensin-aldosterone inhibition because of hyperkalemia.
MORE STUDY NEEDED
Chronic kidney disease treatment is becoming increasingly complex, with a lengthening list of potentially effective drugs, difficult-to-reach goals, and a less structured approach. This complexity is magnified by issues of potassium homeostasis and interindividual variations in response to renin-angiotensin-aldosterone inhibition.
More prospective studies are needed to confirm the benefits of targeting proteinuria along with blood pressure and the metrics of the goals in tandem, but, based on available information, the dual-goal approach has been recommended for proteinuric patients,10,15–18 and evidence is accumulating for greater renal protection from larger doses of renin-angiotensin-aldosterone inhibitors and from using these drugs in combination.
