Effect of antihypertensive treatment on kidney function in primary (essential) hypertension

INTRODUCTION — Kidney function may deteriorate because of uncontrolled hypertension. Even minimal elevations in blood pressure (BP) are associated with increased renal arteriosclerosis in autopsies [1]. Since adequate control of hypertension may slow the rate of kidney dysfunction [2], the effects of antihypertensive therapy on kidney function need to be carefully considered.

Antihypertensive therapy has both acute and chronic effects on kidney function in patients with primary hypertension (formerly called "essential" hypertension). In early disease, for example, kidney function is usually normal; in this setting, lowering the BP induces little change in glomerular filtration rate (GFR) [3] (see "Renal effects of ACE inhibitors in hypertension"). Black patients may have an initial decrease in GFR compared with an increase in White patients [4].

This topic reviews the chronic and acute effects of antihypertensive therapy on kidney function in patients with primary hypertension. Goal BP and the choice of antihypertensive agent are discussed in separate topics:

●(See "Goal blood pressure in adults with hypertension".)

●(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

●(See "Treatment of hypertension in patients with diabetes mellitus".)

CHRONIC EFFECTS — Patients with prolonged uncontrolled hypertension are at increased risk of developing chronic kidney disease [5]. The risk of this complication is much greater in Black patients and in patients with more severe hypertension (figure 1). (See "Burden of hypertension in Black individuals".)

It must be emphasized, however, that the percentage of patients with mild hypertension who develop end-stage kidney disease (ESKD) is relatively small, being less than 1 percent after 16 years in the Multiple Risk Factor Intervention Trial (MRFIT) trial [5]. (See "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis", section on 'Incidence of kidney failure'.)

Prolonged blood pressure (BP) control will usually minimize the degree of renal damage, leading to a stable plasma creatinine concentration [2]. There are, however, patients in whom proteinuria develops or the plasma creatinine concentration continues to rise slowly over a period of years despite seemingly adequate antihypertensive therapy. This is most likely to occur in Black patients, in patients who have underlying chronic kidney disease (CKD) or a family history of ESKD, and in patients with vascular disease, which is suggested by the presence of older age, higher baseline BP, or hyperuricemia.

Hyperuricemia (independent of diuretic therapy) has been attributed to a reduction in renal blood flow induced by the arterial and arteriolar disease [6]. However, some have proposed that it may have a key causal role in the onset of primary hypertension, with increased uric acid levels resulting in endothelial dysfunction, vasculopathy, and elevated BP [7]. Nevertheless, there is so far little evidence that treatment of hyperuricemia has a role in the treatment of hypertension.

Why renal damage may progress despite seemingly adequate control of the hypertension is uncertain. It is possible that some of these patients have a different kidney disease that is worsened by hypertension (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults"). Among Black patients, the increased risk for progression of kidney disease is likely related to a genetic defect with less contribution from hypertension. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'FSGS in Black patients'.)

Alternatively, aiming for a BP of 140/85 to 90 mmHg may be inadequate to prevent renal damage in some patients. It is possible that maintaining a lower BP would be more beneficial in this setting [8] (see "Goal blood pressure in adults with hypertension"). The observation from a large epidemiologic study that higher BP within the normal range may be associated with kidney injury over a period of many years is compatible with the hypothesis that more intensive BP control may be beneficial in some patients [9]. That hypothesis, however, was not supported by the kidney outcomes of the Systolic Blood Pressure Intervention Trial (SPRINT), nor was it supported by outcomes in the Secondary Prevention of Small Subcortical Strokes (SPS3) study (see "Goal blood pressure in adults with hypertension"). Moreover, based upon the findings of the Third National Health and Nutrition Examination Survey of a representative sample of the United States population, an estimated 5.6 million people have an elevated serum creatinine that is strongly related to inadequate treatment of hypertension [10].

The potential superiority of angiotensin-converting enzyme (ACE) inhibitors may be due to the fact that, at least in animal models, these drugs lower the intraglomerular pressure by preferentially decreasing the resistance at the efferent (postcapillary) glomerular arteriole [11]. In human studies, ACE inhibitors or angiotensin receptor blockers (ARBs) slow the progression of diabetic and nondiabetic nephropathy, particularly in the presence of proteinuria [12].

In some studies, other drugs that presumably lack this preferential effect on efferent arteriolar resistance have also been found to slow the rate of renal damage, similar to ACE inhibitors [13]. However, most studies support the notion that ACE inhibitors are more effective in this regard in many forms of proteinuric kidney disease [2]. It is difficult to assess the relative importance of the specific type of drug versus the effective reduction of BP or the relief of other major risk factors [2,14]. However, these considerations are based upon studies performed in patients with known kidney disease, and their importance for patients with primary hypertension is unknown. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

ACUTE EFFECTS — Despite the long-term renal benefit of antihypertensive therapy in most patients, the initial reduction in blood pressure (BP) may be associated with a transient elevation in the plasma creatinine concentration, which reflects a fall in the glomerular filtration rate (GFR). This effect is most likely to occur with moderate to severe hypertension. An increase in serum creatinine with initial antihypertensive treatment is usually associated with one or more of the following:

●A relatively marked and rapid reduction in BP, often exceeding 25 mmHg [15].

●Use of an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or direct renin inhibitor, particularly in those with atherosclerotic vascular disease or an acute lowering of blood pressure. In the presence of a drug-induced fall in renal perfusion pressure, angiotensin II participates in the autoregulatory response that attempts to maintain the GFR; this contribution is blocked by an ACE inhibitor or ARB. The development of acute kidney injury (AKI) is most common in bilateral renal artery stenosis. (See "Renal effects of ACE inhibitors in hypertension" and "Treatment of unilateral atherosclerotic renal artery stenosis", section on 'Medical therapy'.)

●Concurrent volume depletion, most often due to diuretic therapy, which makes maintenance of the GFR more angiotensin II dependent.

●Concurrent heart failure.

●The use of nonsteroidal antiinflammatory drugs.

The impairment in GFR following the institution of antihypertensive therapy is usually moderate and at least partially reversible within several weeks. The proper approach varies with the clinical setting:

●Temporarily discontinuing treatment is indicated in patients who have had an excessive reduction in BP. In this setting, therapy can usually be safely restarted at a lower dose. Particular caution is needed with ACE inhibitors and ARBs.

●Continuing antihypertensive therapy is reasonable as long as the rise in the plasma creatinine concentration is less than 30 percent of the pretreatment level. This is based upon the evidence that persistent BP control will lead to regression of arteriolar hyperplasia, and the plasma creatinine concentration will generally return to or occasionally fall below the pretreatment level over a period of weeks to months. In many studies, ACE inhibitors produced a transient initial rise in serum creatinine but a beneficial effect on kidney function and other outcomes in the long term [16-18].

In a population-based cohort study from the United Kingdom, impairment of GFR following institution of renin-angiotensin system blockade was associated with more renal and cardiovascular events in the long term [19]. This observation, however, may represent the underlying risk factors in the population rather than a direct effect of the GFR impairment; by contrast, analyses of randomized trials of renin-angiotensin system inhibitors failed to confirm such an association [20].

●Reversing volume depletion by discontinuing excessive diuretic therapy may be beneficial when an unacceptable decline in GFR follows the institution of an ACE inhibitor [21]. If this is ineffective or the patient has not been taking a diuretic, then switching to a drug that does not reduce intraglomerular pressure (such as a calcium channel blocker) is indicated.

●Evaluation for unrecognized bilateral renal artery stenosis should be considered, particularly in older patients with extensive atherosclerosis elsewhere, or if kidney function rapidly deteriorates soon after starting a drug that inhibits the renin-angiotensin system. The selection of patients who should be screened for renal artery stenosis is discussed elsewhere. (See "Evaluation of secondary hypertension", section on 'Clinical clues for renovascular hypertension'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Antihypertensive therapy has both acute and chronic effects on kidney function in patients with primary hypertension (formerly called "essential" hypertension). (See 'Introduction' above.)

●Goal blood pressure (BP) and the choice of antihypertensive agent are discussed in separate topics:

•(See "Goal blood pressure in adults with hypertension".)

•(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

•(See "Treatment of hypertension in patients with diabetes mellitus".)

●Prolonged BP control will usually minimize the degree of renal damage, leading to a stable plasma creatinine concentration. However, proteinuria may develop or the plasma creatinine concentration may continue to slowly rise in some patients. (See 'Chronic effects' above.)

●Despite the long-term renal benefit of antihypertensive therapy, the initial reduction in BP may be associated with a transient elevation in the plasma creatinine concentration. The development of acute kidney injury (AKI) is usually associated with a relatively marked reduction in BP; the use of an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or direct renin inhibitor; concurrent volume depletion; and nonsteroidal antiinflammatory drugs. (See 'Acute effects' above.)

●The impairment in glomerular filtration rate (GFR) following the institution of antihypertensive therapy is usually reversible. The proper approach to treatment varies with the clinical setting. A mild impairment (a rise in serum creatinine of less than 30 percent of the pretreatment level) does not require altering the antihypertensive therapy in most cases. (See 'Acute effects' above.)