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Treatment of Hypertension in Chronic Kidney Disease

Figure 46-2. Hypertension management algorithm for patients with CKD. Dosage adjustments should be made every 2 to 4 weeks as needed. The dose of one agent should be maximized before another is added. (ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CAD, coronary artery disease; CCB, calcium channel blocker; CHF, congestive heart failure; MI, myocardial infarction; UP:Cr, urinary protein-to-creatinine ratio.) (Adapted from reference 136 with permission.)

Antihypertensive Drug Choice

Several studies have confirmed the beneficial effects of ACEIs on renal function in patients with and without diabetes. Table 46–4 shows the results of the key studies that evaluated more than 100 diabetic subjects followed over 2 to 6 years. These studies show that the benefit of ACEI use in CKD is seen in both type 1 and 2 diabetic subjects, across different degrees of kidney damage (normoalbuminuria, microalbuminuria, frank proteinuria, and reduction in GFR), and are drug-class specific. These findings consistently support the role of ACEI therapy in the management of CKD. It is customary to begin at low doses and increase the dose at 4-week intervals to control the level of proteinuria. The dose is usually increased until proteinuria is reduced by 30% to 50% or the development of side effects such as elevations in serum creatinine or potassium occurs.

A meta-analysis that pooled several of the small and large randomized, controlled studies showed beneficial effects of ACEI therapy on diabetic nephropathy. Progression to proteinuria was reduced by 65% in patients with diabetes mellitus and microalbuminuria, and progression of nephropathy (doubling of serum creatinine) was reduced by 40% in patients with overt proteinuria (comprised of 30% diabetics and 70% nondiabetics; Fig. 46–3). However, a recent meta-analysis of 127 studies with more than 30,000 subjects suggests that the benefit of ACEIs and ARBs over other pharmacologic agents is related to blood pressure attained during the study rather than to special properties of the ACEI or ARB (e.g., antiproteinuric effects).

Some of the discrepancy in these results may be due to aldosterone escape in renin–angiotensin–aldosterone system blockade. Type 2 diabetic subjects with nephropathy who had increased aldosterone plasma levels during a mean 35-month treatment with losartan had a faster decline in the rate of GFR compared to those without aldosterone escape. Combination therapy of ACEI and ARBs or addition of an aldosterone inhibitor to ACEI or ARB was recently suggested to improve suppression of the renin–angiotensin–aldosterone system. Another study exploring the addition of an aldosterone receptor blocker to ACEI or ARB for renoprotection in type 1 diabetes was recently published. This study, conducted in 20 patients with proteinuria, showed a reduction in albuminuria by 30% with a significant daytime reduction of blood pressure in patients treated with spironolactone 25 mg once daily. The results are intriguing and need to be confirmed with larger numbers of patients with close monitoring for complications such as hyperkalemia.

The ARBs have also been shown to slow the progression of diabetic kidney disease. Table 46–5 summarizes data from several studies (with at least 100 patients) evaluating ARB efficacy in type 2 diabetes. All patients in these trials had at least a level of proteinuria consistent with microalbuminuria and all were hypertensive. With the exception of one, the studies were of a sufficiently long duration to determine the beneficial effects of ARBs on nephropathy. Of note, the beneficial effect of delaying the onset of diabetic nephropathy was significant in type 2 diabetic patients who received irbesartan 300 mg daily for up to 2 years. A similar trend (although not statistically significant) was observed in those subjects who received a lower dose of irbesartan (150 mg daily). The Evaluation of Losartan in the Elderly (ELITE) study, which assessed losartan versus captopril in diabetics and nondiabetics, showed comparable renal benefits of both ARBs and ACEIs in a population of heart failure patients. Currently, the data show efficacy of both ACEIs and ARBs in type 2 diabetes, whereas only ACEIs have been adequately evaluated in patients with type 1 diabetes. Thus, until head-to-head trials with these agents are assessed, they should not be considered interchangeable in all forms of diabetes.

Because ACEIs and ARBs have demonstrated efficacy in patients with diabetes, the possibility of using both agents in type 2 diabetics has been investigated. A short-term (12 to 24 week) study evaluated lisinopril (20 mg once daily) and candesartan (16 mg once daily) versus the combination in 199 patients. The reduction of urinary albumin-to-creatinine ratios was greater with combination therapy (50%) than with either lisinopril (39%) or candesartan (24%) alone. However, blood pressure reduction was also significantly greater in the combination therapy patients, making it unclear if the combination produced an enhanced antiproteinuric effect or if the reduction in the albumin-to-creatinine ratio could be attributable to the greater reduction in blood pressure.

Studies suggest that no individual ACEI drug is superior to any other ACEI. In patients with hypertension, the primary goal is to optimally treat the blood pressure to target, and the secondary goal is to control proteinuria. For normotensive patients with microalbuminuria, one should titrate the ACEI to reduce the degree of microalbuminuria. The antihypertensive ceiling effect noted for ACEI dosage titration has not been confirmed for lowering urinary protein excretion. However, patients with hypertension and proteinuria can still exhibit side effects associated with blood pressure lowering, and hence dosages should be titrated to the maximal level of proteinuria reduction without reducing the blood pressure to a level associated with adverse events including renal function compromise. Patients should be initiated on the lowest possible dose of ACEI and titrated to blood pressure control and proteinuria reduction. A specific recommendation regarding the dose to initiate therapy with a specific ACEI has not been established; consequently, the lowest recommended dose for the management of hypertension may be appropriate until such information is available. The clinician needs to evaluate the insurance coverage of specific agents in specific patients. In addition, one needs to consider the presence of other concomitant diseases and past history of treatment, as well as any side effects demonstrated with particular agents. Generally, ACEIs are more cost-effective than ARBs because of the availability of generic formulations. If and when patients exhibit adverse effects such as cough and/or hyperkalemia, a switch to an ARB is appropriate.

Because the clearance of all ACEIs (with the exception of fosinopril) is reduced in CKD, it is prudent to commence therapy at lower initial doses and subsequently titrate to achieve the optimal therapeutic effects and minimize potential toxicity. The antiproteinuric effects of ACEIs are not necessarily attained at the same doses as the antihypertensive effects. Thus patients who have reached their blood pressure goals may require further dosage adjustments to achieve maximal reductions in urinary protein excretion. Serum potassium needs to be monitored when initiating therapy with ACEIs, especially when patients are concurrently receiving drugs that may increase the risk of hyperkalemia, such as nonsteroidal antiinflammatory agents. Chapter 15 has a thorough discussion of dose, dose titration, monitoring, and adverse effects of ACEIs and ARBs.

Some calcium channel blockers (CCBs) decrease glomerular injury without negatively changing renal hemodynamics. The postulated mechanisms for this decrease in renal injury include suppression of glomerular hypertrophy, inhibition of platelet aggregation, and decreased salt accumulation. Although the data regarding dihydropyridine calcium channel blockers do not suggest any beneficial effects beyond those attributable to reducing blood pressure, there is some suggestion that the nondihydropyridine agents (diltiazem and verapamil) may have beneficial effects on proteinuria that are similar to those of ACEIs. A few studies suggest that the efficacy of combination therapy with ACEIs and nondihydropyridine CCBs may be superior in terms of proteinuria reduction than the use of either agent alone. Most clinicians, however, tend to use the combination of ACEI plus ARBs instead of either of the former agents plus a nondihydropyridine CCB. In general, nondihydropyridine CCBs are used as second-line antiproteinuric drugs when ACEIs or ARBs are not tolerated.