Treatment of Hypertensive Patients with Chronic Renal Insufficiency
The prevalence of hypertension in patients with chronic renal insufficiency from all causes increases linearly as renal function deteriorates, reaching approx 95% as patients approach end-stage renal disease. There is now substantial evidence that controlling blood pressure will slow the inexorable decline in renal function in patients with chronic renal insufficiency. Nevertheless, at a time when morbidity and mortality from cardiovascular disease is declining, the incidence of end-stage renal disease is increasing dramatically, particularly in African Americans, the elderly, and diabetics. There is no single explanation for this fact, but pertinent issues are as follows :
1. Should the general therapeutic approach to hypertension (nonpharmacologic and/or pharmacologic) differ in patients with chronic renal insufficiency vs essential hypertensive patients without renal insufficiency?
2. Will lowering blood pressure to levels below current standards (140/90 rnmHg; mean arterial pressure [mean arterial pressure] = 107) better preserve renal function without increasing adverse consequences?
3. Are there specific classes of antihypertensive drugs that are renoprotec-tive over and above their effect on blood pressure?
Nonpharmacologic therapy
The same nonpharmacologic measures useful in the treatment of essential hypertension can be applied to patients with hypertension and chronic renal insufficiency. However, in patients with chronic renal insufficiency, sodium restriction becomes the single most important nondrug approach. As glomerular filtration rate declines, sodium balance is maintained after some volume expansion but at the expense of hypertension. In addition to directly lowering blood pressure by diminishing extracellular volume and vascular reactivity, dietary sodium restriction also potentiates the effects of other antihypertensive medications, particularly angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Because the failing kidney is unable to accommodate rapidly to a low-sodium intake, sodium restriction must be accomplished gradually. Rapid and marked reduction of sodium intake may result in severe volume contraction and worsening renal function.
Pharmacologic therapy: diuretics
If the patient is unwilling or unable to adhere to a sodium-restricted diet, a diuretic should be used. Either a loop-active or thiazide diuretic may be used, with the choice generally determined by the level of renal function. As glomerular filtration rate falls below 35 mL/min (serum creatinine approx 2.5 mg/dL or greater), thiazides become ineffective and a loop-active diuretic is necessary. Combinations of the two types of diuretics have been particularly successful in renal failure patients who have been resistant to either used alone. Of the three available loop-active diuretics (furosemide, bumetanide, and torsemide), torsemide is the best orally absorbed drug. The response to diuretics is highly individual and the dose must be altered as the clinical response dictates.
As with dietary sodium restriction, severe volume contraction must be avoided. Therefore, patients should be monitored carefully by daily weights, blood pressure (particularly orthostatic measurements), and timely evaluation of renal function and electrolytes.
In general, the same drugs used in patients with essential hypertension with normal kidney function can be used in patients with hypertension and chronic renal insufficiency, including the choice of drug if there are comorbid conditions. Guidelines are provided elsewhere for appropriate reductions in the dose of renal metabolized drugs such as atenolol, nadolol, hydralazine, clonidine, and captopril. Caution must be exercised with aradren-ergic blockers, which have been reported to produce significant ortho-static hypotension particularly in patients with autonomic neuropathy associated with chronic renal insufficiency. Centrally acting a2-adrenergic agonists may cause marked lethargy in patients with a glomerular filtration rate <20 mL/min and should be administered at reduced doses. angiotensin-converting enzyme inhibitors (and probably angiotensin receptor blockers) should be used cautiously in patients with proven or suspected renal artery disease because they may precipitate an acute loss of kidney function. In fact, if this occurs in a patient previously not suspected of having renal artery stenosis, the diagnosis should then be seriously considered.
In the most recent Joint National Committee report (VI), two specific recommendations were made regarding the treatment of patients with hypertension and chronic renal insufficiency. First, blood pressure should be lowered to at least 130/85 mmHg in patients with proteinuria in excess of 1 g/24 h. Second, patients with hypertension who have chronic renal insufficiency should receive, unless contra-indicated, an angiotensin-converting enzyme inhibitor to control hypertension and to slow the progression of renal failure. Next, these recommendations are evaluated in light of the available literature.
Hypertensive nephrosclerosis and chronic renal insufficiency
Will lowering blood pressure to the levels suggested (unrelated to the drugs used) slow the progression of renal disease without undesirable side effects? With regard to hypertensive nephrosclerosis, there still are no data from large-scale, prospective, randomized studies designed to specifically examine whether lowering the blood pressure prevents or slows progression of renal failure. Furthermore, the appropriate goal blood pressure in these patients is not established. However, there are data from a variety of studies suggesting that aggressive treatment of essential hypertension even with traditional therapy such as diuretics and β-blockers can stabilize renal function as assessed by the serum creatinine. In the Hypertension Detection and Follow-up Program, the stepped-care group, which achieved a mean blood pressure of 129/86 mmHg, significantly lower than the usual-care group (139/90 mmHg), showed stabilization of renal function after 1 yr of treatment. Similarly, in the Multiple Risk Factor Intervention Trial, with a 7-yr follow-up period of 5061 Caucasian males with mild to moderate hypertension, those subjects with a diastolic blood pressure (diastolic blood pressure) above 95 mmHg had a more rapid decline in renal function compared with those patients with a diastolic blood pressure of <95 mmHg. In African-American men, slowing in the progression of chronic renal insufficiency was observed down to a diastolic blood pressure of 75 mmHg. Although the risk for renal dysfunction was highest in men with severe hypertension, there was also an increased risk in subjects with a diastolic blood pressure of 85-90 mmHg compared with those with a systolic blood pressure (systolic blood pressure) of <120 mmHg and a diastolic blood pressure of <80 mmHg. This suggests that the lower blood pressure the greater the renal protection, and that the traditional target blood pressure of 140/90 mmHg may be too high. Those subjects whose follow-up systolic blood pressure exceeded 140 mmHg had the most rapid decline in renal function. Other studies have confirmed these findings.
The African-American Study of Kidney Disease trial is ongoing and is designed to determine the optimum blood pressure to prevent worsening renal function in African Americans with hypertensive nephrosclerosis and chronic renal insufficiency and to determine the effects of an angiotensin-converting enzyme inhibitor, calcium antagonist, or β-blocker on the progression of chronic renal insufficiency in these subjects. Until the results of this trial are known, it appears reasonable to lower systolic blood pressure to < 135 mmHg and diastolic blood pressure to <85 mmHg in patients with hypertensive nephrosclerosis and chronic renal insufficiency.
Progression of chronic renal insufficiency of diverse etiologies: what should the goal blood pressure be?
The Modification of Diet in Renal Disease (MDRD) was a large, prospective, randomized trial that compared the effects of “usual” blood pressure control (mean arterial pressure of 107 mmHg in patients younger than age 60 yr and 113 mmHg for those older than 60) with “strict” control (mean arterial pressure of 92 and 97 mmHg for the two age groups, respectively) in 840 patients with chronic renal insufficiency (glomerular filtration rate range of 13-55 mL/min). Patients were generally treated with angiotensin-converting enzyme inhibitors or calcium channel blockers (calcium channel blockers), with diuretics, and with other drugs as necessary. Those patients with a glomerular filtration rate of 25-55 mL/min in the strict control group had a less rapid decline in glomerular filtration rate, which correlated significantly with the level of urinary protein excretion at baseline; that is, those patients with protein excretion >1 g/d demonstrated a slower rate of decline of renal function than the higher blood pressure group. A longer follow-up period would have been necessary to determine whether the low blood pressure goal is beneficial in patients with proteinuria of only 0.25-1.0 g/d. There was no beneficial effect of the lower blood pressure in patients with a glomerular filtration rate between 13 and 24 mL/min, nor in patients with adult polycystic kidney disease or chronic interstitial nephritis.
Support for the MDRD findings relative to blood pressure control and proteinuria is provided by the Northern Italian Cooperative Study Group, which evaluated more than 400 patients with nondiabetic chronic renal insufficiency over a 30-mo follow-up period. In this study, an mean arterial pressure >107 mmHg, associated with increasing levels of proteinuria, predicted a worse outcome. Aggressive blood pressure control to an mean arterial pressure of < 107 mmHg correlated with a diminution in proteinuria and prolonged renal survival compared with those patients with a higher blood pressure. Several other smaller studies confirm these findings.
The results of the studies in patients with diabetic nephropathy also suggest that renal function deteriorates more slowly with more aggressive lowering of blood pressure and concomitant reduction in protein excretion. The beneficial effect of lower blood pressure is continuous down to an systolic blood pressure of approx 130 mmHg and a diastolic blood pressure of 70 mmHg.
The Collaborative Study Group examined 409 patients with type I diabetic nephropathy. Lower systolic blood pressure correlated with remission from nephrotic range proteinuria. When the mean arterial pressure was reduced to 92-95 mmHg, the benefit of the lower blood pressure was observed regardless of whether or not an angiotensin-converting enzyme inhibitor was used. The apparent renoprotective effect of captopril was observed only at the usual levels of blood pressure control (unpublished observations).
Kasiske et al., in a large meta-analysis of patients with diabetic nephropathy (type I and II), noted that a reduction in blood pressure, regardless of type of antihypertensive agent used, was associated with a relative higher glomerular filtration rate in diabetics with proteinuria. The glomerular filtration rate was 3.7 mL/ min higher in patients for each 10 mmHg decrease in mean arterial pressure, emphasizing again the importance of aggressive control of blood pressure. In none of the studies reported were there more cardiovascular or other adverse events in strict blood pressure control groups.
Are there reno protective antihypertensive drugs?
Angiotensin-converting enzyme inhibitors
Although patients with chronic renal insufficiency and hypertension generally respond to the same classes of antihypertensive agents as do patients without renal disease, angiotensin-converting enzyme inhibitors are particularly suited for these patients in whom the renin-angiotensin system is activated. It has also been suggested that this class of drugs has a specific renoprotective effect distinct from the level of blood pressure by lowering intraglomerular hydrostatic pressure (PGc), which is elevated in a variety of experimental models of chronic renal insufficiency and appears to be one of several factors that contribute to the progression of renal failure. Zucchelli et al., Hannedouche et al., and Maschio et al. demonstrated an advantage to angiotensin-converting enzyme therapy in preserving renal function above and beyond simply lowering blood pressure in patients with nondiabetic chronic renal insufficiency.
In the most recent studies reported by the Gruppo Italiano di Studi Epidemiologici in Nefrologia the effects of ramipril (an angiotensin-converting enzyme inhibitor) vs placebo were examined in nondiabetic chronic renal disease. The degree of blood pressure control was the same in both groups (144.6/88.2 mmHg in the ramipril group compared with 144.6/88.9 mmHg in the placebo group). Only angiotensin receptor blockers were excluded as additional antihypertensive drugs. The patients were divided into two stratums according to baseline proteinuria: stratum 1,1-3 g/24 h; stratum 2, >3 g/24 h. The trial was terminated early in stratum 2 patients because the angiotensin-converting enzyme inhibitor dramatically reduced the rate of decline of renal function compared with the placebo group. Ramipril induced an early reduction in 24-h urinary protein excretion, which correlated with the long-term effect on glomerular filtration rate decline and was the only covariate that predicted the drug’s renoprotective effect. The reduction in decline of renal function was greatest in patients with the highest baseline proteinuria and was not dependent on the initial degree of renal impairment or baseline or follow-up blood pressure, which was similar in both groups. These studies suggest that proteinuria, per se, may be “nephrotoxic.”
The core study patients who were originally on ramipril were continued on the drug and those initially on placebo were switched to ramipril at the end of the study. At the end of the follow-up study (4 h yr), the patients initially randomized to ramipril had a renal survival rate three times greater than those who were originally randomized to placebo and then switched to ramipril, suggesting that the earlier treatment with an angiotensin-converting enzyme inhibitor is begun, the more renoprotective it may be. However, the patients switched to ramipril also had a significant reduction in the rate of decline in glomerular filtration rate (from 0.81 in the original study to 0.14 mL/[minmo] in the follow-up study). These studies strongly suggest that angiotensin-converting enzyme inhibitors are renoprotective separate from their effect on blood pressure.
In a meta-analysis of 10 studies including 1594 patients, Giatras et al. demonstrated angiotensin-converting enzyme inhibitors to be more effective than other antihypertensive agents in reducing the development of end-stage renal disease in nondi-abetic renal disease, but not in decreasing mortality.
In the meta-analysis of 100 studies in both type I and type II diabetic patients noted earlier, only angiotensin-converting enzyme inhibitors had an additional favorable effect on glomerular filtration rate that was independent of the blood pressure.
The Collaborative Study Group, referred to earlier, definitively demonstrated that angiotensin-converting enzyme inhibition significantly reduces the rate of doubling of serum creatinine in type I diabetics at usual levels of blood pressure control. Other studies suggest that the early use of angiotensin-converting enzyme inhibitors in patients with type I and II diabetes and incipient diabetic nephropathy (microalbuminuria) without hypertension reduces the rate of appearance of overt nephropathy (macroalbuminuria).
Based on the available data, in both incipient and overt diabetic nephropathy and in other forms of chronic renal insufficiency, angiotensin-converting enzyme inhibitors should be the initial drug of choice unless a contraindication to its use exists.
Angiotensin Receptor Вlockers
Angiotensin receptor blockers are a new class of drugs that block the rennin-angiotensin system at a site different than do angiotensin-converting enzyme inhibitors and offer substantial promise as renoprotective drugs. This class of drugs selectively blocks the binding of angiotensin II to the type 1 angiotensin receptor on the cell membrane. Although there are no large-scale, prospective, double-blind studies published, there are promising observations regarding the possible role for angiotensin receptor blockers as renoprotective drugs. Gansevoort et al. found that an ARB was as effective in reducing urinary protein excretion in patients with chronic renal disease as an angiotensin-converting enzyme inhibitor (approx a 50% reduction for each drug).
Calcium Channel Blockers
There are data from both short- and long-term studies available to evaluate the renoprotective effect of calcium channel blockers. Verapamil and diltiazem most consistently lower urinary protein excretion in diabetic nephropa-thy. Bakris et al. studied 34 African Americans with type II diabetic nephropathy with renal insufficiency and proteinuria. After a mean follow-up of 54 ± 6 mo, patients taking verapamil had a slower rate of decline in creatinine clearance and a greater reduction in proteinuria compared with the group taking atenolol, despite similar blood pressure. In addition, a greater proportion of the atenolol group had a 50% or more increase in serum creatinine compared with the verapamil group.
Vellusie et al. compared the effects of an angiotensin-converting enzyme inhibitor (cilazapril) with a dihydropyridine calcium channel blocker (amlodipine) on glomerular filtration rate and albumin excretion in 44 type II diabetics with hypertension, 26 of whom were normoalbuminuric and 18 microalbuminuric. At 3 yr of follow-up, the decline in glomerular filtration rate and albumin excretion in both groups were similar. Other studies also suggest that calcium channel blocker s (both dihydro- and nondihydropyridine) may be beneficial in stabilizing renal function in patients with chronic renal insufficiency.
Conclusion
Treatment of hypertension in patients with renal insufficiency is indicated at any stage of the disease. It would appear that the goal blood pressure should be an mean arterial pressure of 100 mmHg or less and that an angiotensin-converting enzyme inhibitor is the drug of choice. Diuretics are probably the second-line drugs of choice. A calcium channel blocker (diltiazem or verapamil) should be added to achieve goal blood pressure, followed by other antihypertensive agents, as necessary. The role of angiotensin receptor blockers has not been well defined, but they may be as useful as angiotensin-converting enzyme inhibitors or possibly even additive. Thus, the recommendations of sixth report of the Joint National Committee are well founded, with the possibility that a blood pressure even lower than 130/85 mmHg (mean arterial pressure of 100 mmHg) may be necessary in all patients with chronic renal insufficiency.
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