Hypertension, Renal Disease, and Drug Considerations

Abstract

The incidence of chronic kidney disease is steadily increasing in the United States. The magnitude of this problem is such that virtually all health care providers are being called upon to manage these patients. The interplay between chronic kidney disease and drug therapy is complex in that the kidney is both a target for drug effect as well as a moderator of drug elimination. Renal drug elimination occurs by filtration, secretion, and/or metabolism. For renally‐cleared compounds, drug clearance typically falls in tandem with the loss of renal function. This process is noteworthy for drug accumulation when the glomerular filtration rate approaches the 30‐cc/min range. The kidney is a target for drug effect in relationship to blood pressure and protein excretion. Angiotensin‐converting enzyme inhibitor and angiotensin receptor blocker therapy (usually given along with a diuretic) are the drug classes that have been shown to be effective for reduction in both blood pressure and protein excretion in the chronic kidney disease patient. A number of questions still remain unanswered in the pharmacotherapy of chronic kidney disease, including the optimal dose for these drugs as well as what represents the most favorable achieved blood pressure.

Chronic kidney disease (CKD) is increasing annually. For example, if the trends of the past two decades persist, approximately 175,000 new cases of end‐stage renal disease will be diagnosed in the year 2010; the total number of end‐stage renal disease patients will be close to 650,000. It is important, therefore, for health care providers to be sensitive to how kidney disorders influence both the handling (pharmacokinetics) and actions (pharmacodynamics) of medications. This statement is particularly true for drugs such as antihypertensive compounds and diuretics. Moreover, renal and cardiac diseases, such as congestive heart failure, often coexist. These two diseases further complicate the interpretation of drug handling/action in the CKD patient.

CHRONIC KIDNEY DISEASE

The term CKD has been loosely applied to any circumstance where kidney function is abnormal on other than an acute basis; accordingly, this term lacked clarity. Defining CKD and classifying it according to stages of severity was essential for providers, patients and their families, and investigators.

The National Kidney Foundation Kidney Disease Outcome Quality Initiative has now developed clinical practice guidelines to define and classify stages in the progression of CKD. ¹ CKD has been defined as the presence of kidney damage or a decreased level of kidney function (glomerular filtration rate [GFR] <60 mL/min/1.73‐m²) for 3 months or more, irrespective of the diagnosis (Figure 1). The staging of CKD served as a prompt for more careful patient monitoring since adverse outcomes of CKD increase over time in tandem with disease severity.

Figure 1.

Stages of chronic kidney disease: National Kidney Foundation Kidney Diseae Outcomes Quality Initiative Classification. GFR=glomerular filtration rate; CKD=chronic kidney disease; ESRD=end stage renal disease; RCN=radiocontrast nephropathy. Adapted from the National Kidney Foundation. Am J Kidney Dis. 2002;39 (suppl 2):S1‐S246.

RELEVANCE OF DRUG ACCUMULATION

The total body clearance of a compound is influenced by the function of multiple organs, including the liver and kidney, as well as skin, intestine, and muscle. Renal clearance is an important contributor to the total body clearance of a number of compounds, which in cardiovascular (CVR) therapeutics include angiotensin‐converting enzyme (ACE) inhibitors, certain β blockers, and most diuretics. ² – ⁴ The contribution of renal clearance to total body clearance increases in importance when a drug's renal elimination is >50% of total body clearance. Renally‐cleared compounds accumulate at GFR values <60 mL/min, a process that becomes particularly significant when the GFR falls to <30 mL/min. ²

Drug accumulation is relevant in a number of ways for antihypertensive and/or CVR compounds. First, if the compound administered has a narrow therapeutic window, its accumulation can quickly exceed the boundaries of the desired pharmacologic effect with undesirable consequences. For instance, the accumulation of an antihypertensive compound can result in an exaggerated fall in blood pressure (BP). If the GFR further decreases as the result of a fall in BP, the renal clearance of a compound can be further reduced, more drug accumulates, and BP decreases even further. ⁵ Second, if an administered compound has well‐established concentration‐related side‐effects, they will occur more often and with possibly greater severity with drug accumulation, which is the case with renally‐cleared β blockers and the side effects of lethargy and/or sedation. Finally, drug accumulation increases the risk of drug‐drug interactions and increases the risk from concurrent therapies.

RENAL DRUG HANDLING

Various combinations of filtration, tubular secretion/passive reabsorption, and/or intrinsic renal metabolism are involved in the clearance of a renally eliminated compound. It is a generally held belief that renal failure is a process characterized by concurrent loss of all nephron components/functions, however, this impression is not always the case. Certain renal diseases may be predominantly tubulointerstitial and have a lesser impact on the renal clearance of drugs cleared predominantly by glomerular filtration. The opposite occurs when in the presence of tubulointerstitial disease a tubularly‐cleared drug accumulates without a significantly reduced GFR. ⁶

DOSE ADJUSTMENT IN RENAL DISEASE

Medication dose adjustment in CKD is often necessary. Reduced elimination of a drug prolongs both the time required to reach steady state and half‐life. Therefore, whenever it is necessary to rapidly achieve a therapeutic steady state level for a medication, a loading dose should be considered, such as with digoxin when given for rate control with supraventricular tachycardia. To maintain a therapeutic level and, at the same time, avoid drug accumulation and toxicity in a patient with reduced renal function, the clinician must consider either reducing the size of the maintenance dose or extending the interval between doses. In many instances, a combination of both approaches is used. In practice, these changes should match the degree of renal impairment. In addition, for a drug whose serum level is easily measured, dosage adjustments can be guided by serum drug levels and further refined by a patient's therapeutic response and/or side‐effect profile.

BASIS FOR USE OF ANTIHYPERTENSIVE MEDICATIONS IN CKD

Antihypertensive medications are commonly used in the CKD patient. First, BP reduction will slow the rate of progression of renal disease, which is the case irrespective of the type of medication(s). ¹ , ⁸ , ⁹ Second, certain antihypertensive compounds, such as ACE inhibitors and angiotensin receptor blockers (ARBs), will significantly reduce protein excretion and will further slow the progression rate of renal disease beyond what is seen with BP reduction. ¹⁰ , ¹¹ Third, these antihypertensive compounds also exhibit CVR renal protective effects, which is an important feature of drug therapy in CKD; these patients typically exhibit a high CVR event rate. ¹ , ⁸ , ¹² Despite the strength of the evidence supporting BP and proteinuria reduction in the CKD patient, however, there remain many unanswered questions (Table I).

Table I.

Uncertainties With Antihypertensive Medications and Chronic Kidney Disease

Appropriate BP targets (<140 mm Hg) for optimal vascular (coronary artery disease and stroke) outcomes

Appropriate BP targets (<140 mm Hg) in patients with proteinuric and non‐proteinuric kidney disease

Appropriate doses of ACE inhibitors or ARBs in proteinuric kidney disease and CHF and how to target the optimal doses

Benefits of combining ACE inhibitors and ARBs in proteinuric kidney disease and CHF

BP=blood pressure; ACE=angiotensin‐converting enzyme; CHF=congestive heart failure; ARBs=angiotensin receptor blockers

There is an important interface between the treatment of CKD‐related hypertension and the level of extracellular fluid volume (ECV) expansion. It is well known that ECV is expanded in the CKD patient. In these patients, the process of ECV expansion parallels the degree of GFR impairment and corresponds to approximately 5%–10% of body weight, even in the absence of peripheral edema. ¹³ Of note, sodium retention not only has a major role in the pathogenesis of secondary hypertension in patients with CKD but it also precludes optimal control of BP during pharmacological treatment with nondiuretic antihypertensive agents, especially vasodilators. In the presence of persistently poor adherence to salt restriction (urinary sodium excretion >100 mmol/d) and/or marked ECV expansion, natriuretic agents become the cornerstone in the treatment of CKD‐related hypertension. ¹⁴ Moreover, efficient control of ECV expansion significantly improves the antiproteinuric effects of agents that interrupt the renin‐angiotensin system. ¹⁵

DIURETICS IN RENAL DISEASE

Whereas thiazide diuretics can be considered for use in stage I‐III CKD, a loop diuretic is typically the choice in stage IV‐V CKD. ¹⁶ A thiazide‐type diuretic still considered for use in stage IV‐V CKD is metolazone. Metolazone is often given together with a loop diuretic, particularly in diuretic‐resistant states. Multiple nephron segments responsible for sodium resorption can be blocked, and an effective diuresis develops. Metolazone is poorly absorbed, which should be taken into account when determining a dose and frequency of dosing. ¹⁷

Although a large dose of a thiazide diuretic will initiate a diuresis in patients with mild renal insufficiency, the response in patients with a CL_creat of <≈50 mL/min is more limited. In the setting of CKD, patients are not “resistant” to a thiazide diuretic per se; rather, the basis for failure of a thiazide diuretic is an insufficient potency to meet the needs of such patients. In patients receiving fixed‐dose combination antihypertensive therapy containing a thiazide diuretic, a loop diuretic should be considered (together with the other component of the fixed‐dose combination) when CL_creat values drop to below 50 mL/min if BP control is inadequate and/or edema is present. ¹⁸ Fixed‐dose combination antihypertensive therapies with a thiazide diuretic component do not require change in the non‐edematous CKD patient with good BP control.

Potassium‐sparing diuretics are generally used cautiously in patients with CKD because of the risk of hyperkalemia. The potassium‐sparing diuretics spironolactone and eplerenone differ mechanistically from amiloride and triamterene in that they are aldosterone‐receptor antagonists. This blockade of aldosterone effect is the basis for their use in hypertension, renal disease, and congestive heart failure. ¹⁹ Dosage adjustment for aldosterone receptor antagonists is not based solely on the level of renal function; rather, it is governed, in part, by the possibility of clinically‐relevant hyperkalemia. ²⁰ Spironolactone and/or its metabolites have a prolonged potassium‐sparing effect, which should be accounted for when it is prescribed. Although not formally studied in CKD, the shorter duration of action of eplerenone may result in less significant changes in serum potassium.

ALPHA ADRENERGIC ANTAGONISTS IN RENAL DISEASE

The pharmacokinetics of the peripheral α blockers prazosin, terazosin, and doxazosin are not altered in the setting of CKD, therefore, dose adjustment on a pharmacokinetic basis is not required. These compounds are used in the hypertensive CKD patient as useful add‐on compounds in the setting of resistant hypertension, ²¹ however, α‐adrenergic antagonists do not enjoy unique CVR or renoprotective effects in the CKD population. The efficacy of α‐adrenergic antagonists in the treatment of hypertension has been limited by a tendency to increase plasma volume, a phenomenon that may be more evident at higher doses and in the CKD patient, therefore, these drugs are most effective when used with diuretic therapy. ²²

CENTRAL α‐AGONISTS IN RENAL DISEASE

Central α‐agonists, such as clonidine and guanfacine, are still used in the hypertensive CKD patient. Guanfacine is predominantly hepatically cleared and does not accumulate in CKD. Clonidine, unlike guanfacine, undergoes modest renal clearance; its plasma half‐life is somewhat prolonged in the CKD patient, although there are no specific recommendations for dosage adjustment in this population. ²³ Patients who suddenly stop oral clonidine occasionally experience rebound hypertension, which occurs less frequently in the CKD patient because of its delayed clearance. Although clonidine accumulates with repetitive dosing in the CKD patient, “paradoxical hypertension,” a phenomenon that occurs at high plasma clonidine levels, seems not to occur. In addition, clonidine‐treated patients with CKD and sinus node dysfunction are at risk of significant bradycardia. ²⁴ In these patients, clonidine is best avoided. Central α‐agonists do not have unique CVR or renoprotective effects in the CKD population beyond what is to be expected with BP reduction.

BETA BLOCKERS IN RENAL DISEASE

Beta blockers are commonly utilized drugs in the CKD patient either for the treatment of hypertension and/or for their cardioprotective effects. ²⁵ , ²⁶ , ²⁷ The renoprotective effects of β blockers in the CKD population have been established in a number of trials where they have been employed as adjunctive therapy. ²⁷ The BP‐lowering effect of β blockers is somewhat unpredictable in the CKD patient unless combined with a diuretic. The selection of a β blocker in a CKD patient should be made with some knowledge of the elimination characteristics of the drug as well as whether the compound has active metabolites (Table II). ²⁵ With renally‐cleared β blockers, systemic accumulation in a CKD patient does not generally improve BP control; β blocker accumulation can be accompanied by frequent concentration‐dependent side effects. If side effects occur, two options exist: to continue the offending β blocker with empiric dose reduction or convert to a hepatically‐cleared β blocker. The latter is generally a preferred clinical approach.

Table II.

Elimination Characteristics of β Blockers

Drug	Active Metabolites	Accumulation in Renal Disease
Acebutolol	Yes	Yes
Atenolol	No	Yes
Betaxolol	No	Yes
Bisoprolol	No	Yes
Carteolol	Yes	Yes
Carvedilol	Yes	No
Celiprolol	Yes	No
Esmolol	No	No
Labetalol	No	No
Metoprolol	No	No
Metoprolol LA	No	No
Nadolol	No	Yes
Nebivolol	No	No
Oxprenolol	No	No
Penbutolol	No	No
Pindolol	No	No
Propranolol	Yes	No
Propranolol‐LA	Yes	No
Sotalol	No	Yes
Timolol	No	No

CALCIUM‐CHANNEL BLOCKERS IN RENAL DISEASE

Calcium‐channel blockers (CCBs) are commonly used drugs in patients with CKD because of the consistency of their BP lowering response. In general, the volume of distribution, protein binding, and plasma half‐life of CCBs are comparable in CKD patients and normal renal function subjects; thus CCBs do not require dose adjustment in CKD patients based on pharmacokinetic considerations. ²⁸ In addition, coronary artery disease is common in CKD patients. Drugs in this class are effective coronary vasodilators. Dihydropyridine and non‐dihydropyridine CCBs, such as verapamil and diltiazem, reduce BP similarly in CKD patients. The addition of a CCB to other drug classes, including diuretics, produces an additive response. ²⁹

The renal effects of CCBs are a matter of some debate. Much of the discussion concerning this drug class has centered on the divergent antiproteinuric effects of dihydropyridine and non‐dihydropyridine CCBs. Consistently greater reductions in proteinuria have been seen with non‐dihydropyridine CCBs such as verapamil and diltiazem, despite BP reduction comparable to those seen with dihydropyridine CCBs. ³⁰ This greater antiproteinuric effect with non‐dihydropyridine CCBs consigns dihydropyridine CCBs such as amlodipine or isradipine to a secondary treatment position in proteinuric CKD patients when these two CCB classes are being considered as monotherapy options. ³⁰ , ³¹ , ³² When given in combination with either an ACE inhibitor or an ARB, the treatment advantage of a non‐dihydropyridine over a dihydropyridine CCB probably becomes less important. ³³

CCB‐related side effects may be of more significance when these drugs are used in the CKD patient. CKD patients tend to be constipated, a process aggravated by verapamil. In addition, CCBs can produce a vasodilatory peripheral edema, which is a type of edema without weight gain. When a true volume‐expanded form of peripheral edema exists, as is often the case in CKD, and a CCB is administered, any intensification of edema cannot be considered an accurate reflection of the patient's ECV state unless it is accompanied by additional weight gain. ³⁴

ACE INHIBITORS IN RENAL DISEASE

ACE inhibitors are frequently used in patients with CKD for the treatment of hypertension and/or for their cardiorenal protective effects. The BP‐lowering effect of ACE inhibitors is generally less in volume‐expanded forms of hypertension, as in the case of CKD. In the CKD patient, the addition of a diuretic to an ACE inhibitor is frequently necessary to lower BP. In the CKD patient, a goal BP of 130/80 mm Hg is currently recommended. This goal BP presumably defines the optimal BP for both renal and CVR protection. In the CKD patient, it is unclear as to whether achieved BP values <130/80 mm Hg confer additional renal benefits and, if so, whether any such favorable response is drug‐class specific. There is insufficient experimental evidence to determine if a J‐ or U‐shaped relationship exists for renal outcomes and BPs <130/80 mm Hg.

Most ACE inhibitors are exclusively renally cleared with varying degrees of filtration and tubular secretion (organic anion secretory pathway) (Table III). ² , ³⁵ Dual‐routes‐of‐elimination ACE inhibitors are those whose active diacid is both hepatically and renally cleared. There are only two such compounds, fosinopril and trandolapril. This property of combined renal and hepatic elimination minimizes accumulation in CKD as dosing to steady state occurs. ³⁶ To date, a specific adverse effect has not been identified from ACE inhibitor accumulation, although cough has been suggested, but not proven, to be an ACE inhibitor side effect relating to drug concentrations.

Table III.

Elimination and Dosing Characteristics of Angiotensin‐Converting Enzyme Inhibitors

		Usual Total Dose and/or Range (mg) —Renal Failure		Recommended Dose Titration (mg) in Renal Failure
Drug	Trade Name	(Frequency Day) (Clcreat 10–30 mL/min)	(Frequency Day) (Clcreat 0–10 mL/min)	(Frequency Day)
Benazepril	Lotensin	5 (1)	Same	Titrate to maximum of 40 mg
Captopril	Capoten	75% of normal dose (CLcreat10–50 mL/min)	50% of normal dose
Enalapril	Vasotec	2.5 (1)	2.5 (1)	Titrate to a maximum of 40 mg
Fosinopril	Monopril	No adjustment	No adjustment	Usual dose titration to effect
Lisinopril	Prinivil, Zestril	5 (1)	2.5 (1)
Moexipril	Univasc	3.75 (1) (CLcreat <40 mL/min)	Same	Titrate to maximum of 15 mg
Perindopril	Aceon	2.0 (every other day) (CLcreat 15–29 mL/min)	2.0 (on dialysis day) (CLcreat <15 mL/min)
Quinapril	Accupril	2.5 (1)	Same
Ramipril	Altace	25% of normal dose (CLcreat <40 mL/min)	Same
Trandolapril	Mavik	0.5 (1)	Same	Titrate to optimal response
CLcreat=creatinine clearance

It is probable that the longer drug concentrations remain elevated, once a response to an ACE inhibitor has occurred, the more likely it is that BP, renal function, protein excretion, and potassium handling will be impacted in some manner. To this end, there is emerging support for treatment stratagems employing high ACE inhibitor doses, however, the findings with such an approach have been variable. ³⁷ , ³⁸ , ³⁹ At this time, guidelines do not suggest titration of an ACE inhibitor or an ARB dose to a level beyond what might be necessary for BP control in the CKD patient. If an ACE inhibitor dose is titrated upwards in a CKD patient with already well‐controlled BP, it is a process undertaken on an empiric basis.

Some patients are sensitive to the effects of an ACE inhibitor, particularly those who have an activated renin‐angiotensin‐aldosterone system; thus even minimal degrees of ACE inhibitor accumulation can pose a problem. ⁵ The major adverse consequences of ACE inhibitor accumulation are prolonged BP reduction, an extended decrease in GFR, and/or an unacceptable increase in serum potassium concentration. The fact that these physiologic and biochemical sequelae occur does not mandate permanent discontinuation of an ACE inhibitor. In many cases the offending ACE inhibitor can be cautiously reintroduced. ⁴⁰

The current product label recommendations, which suggest that ACE inhibitor doses should be reduced in moderate‐to‐severe CKD, vary somewhat from compound to compound (Table III). These differing dosage recommendations are not particularly germane to the use of ACE inhibitors in patients with CKD. ACE inhibitors are typically titrated to effect when given to the CKD patient. It is therefore not necessary to reduce the dose of an ACE inhibitor simply because it is accumulating. As previously mentioned, if the ACE inhibitor effect, BP reduction, or the side effect, drop in GFR and/or hyperkalemia, occur, then the dose should be reduced if not temporarily discontinued. When the dose of a renally‐cleared ACE inhibitor is reduced in the setting of an excessive BP drop or a significant fall in GFR, the process of recovery can be a protracted one, which is consistent with the very slow elimination of such an ACE inhibitor when renal failure is present. Recovery of BP or renal function can oftentimes be hastened by careful volume repletion if intravascular volume contraction exists. Whereas parameters such as BP and renal function are sensitive to the concentration of an ACE inhibitor, hyperkalemia may be less so. If hyperkalemia occurs with an ACE inhibitor, a reduced dose or use of a non‐accumulating ACE inhibitor can be considered. If hyperkalemia persists and ACE inhibition remains vital (e.g., ACE inhibitor treatment in congestive heart failure), a potassium‐binding resin (Kayexalate) can be used.

ARBs IN RENAL DISEASE

The ARBs have recently been studied as to their renal and/or hepatic handling (Table IV). Like ACE inhibitors, ARB monotherapy is generally less efficacious in the treatment of CKD‐related hypertension and typically requires the addition of a diuretic to maximize its BP‐lowering effect. These drugs undergo significant hepatic elimination with the exception of candesartan, olmesartean, and the E‐3174 metabolite of losartan, which are 40%, 60%, and 50% hepatically cleared, respectively. ⁴¹

Table IV.

Mode of Elimination for Angiotensin Receptor Antagonists

Drug	Trade Name	Renal (%)	Hepatic (%)
Candesartan	Atacand	60	40
Eprosartan	Teveten	30	70 (unchanged)
Irbesartan	Avapro	1	99 (2C9)
Losartan	Cozaar	10	90 (2C9/3A4)
Olmesartan	Benicar	35–50	50–65 (unchanged)
E‐3174	Metabolite of losartan	50	50
Telmisartan	Micardis	1	99 (unchanged)
Valsartan	Diovan	30	70 (unchanged)

The mode of elimination for an ARB may prove an important variable in the renally‐compromised patient. In patients who develop a sudden change in renal function with an ARB that is hepatically cleared, the process will be self‐limited by the ongoing hepatic disposition of the compound, a protective feature of drug elimination not present with renally‐cleared compounds, which is a phenomenon not dissimilar to what is observed with ACE inhibitors with a dual route of elimination. ² , ⁵ Like ACE inhibitors, the dose of an ARB given to a CKD patient should be adjusted to achieve a specific goal BP and thereafter empirically for any additional antiproteinuric effect.

CONCLUSIONS

BP control remains the cornerstone of therapy in the CKD patient. IN most instances, the hypertensive CKD patient requires multiple drugs to reach goal blood pressure. Multiple antihypertensive drug combinations are possible in the CKD patient. One combination of note is that of an agent that blocks the effects of the renin‐angiotensin system given together with a loop diuretic and any of several other drug classes, as necessary. In attempting to achieve goal BP in the CKD patient, the differing pharmacokinetics of various antihypertensive compounds should be considered. In so doing, the likelihood of attaining goal BP increases and side effects can be kept to a minimum.