Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical School, Dallas, TX, USA
Correspondence and offprint requests to: Biff F. Palmer, MD, Professor of Internal Medicine, Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical School, 5323 Harry Haines Boulevard, Dallas, TX 75390-8856, USA. Email: biff.palmer{at}utsouthwestern.edu
Keywords: angiotensin-converting enzyme inhibitors; angiotensin receptor blockers; hyperkalaemia; hypertension; serum creatinine
Introduction
Guidelines governing the optimal treatment of blood pressure in patients with chronic renal failure emphasize the need for more stringent blood pressure control and the use of drugs that interfere with the reninangiotensin system [1,2]. As this approach is adopted, physicians will commonly encounter patients where blood pressure control is accompanied by an increase in the serum creatinine concentration and patients who develop hyperkalaemia. How physicians respond to these events is of considerable importance.
In the patient with an increase in serum creatinine concentration, decreasing the dose of antihypertensive medications and allowing blood pressure to increase will cause the serum creatinine concentration to return to the original baseline. Unfortunately, such an approach is not optimal for the long-term preservation of renal function and should be discouraged. Small and non-progressive increases in the serum creatinine concentration accompanying better blood pressure control do not reflect structural injury to the kidney but rather reflect a favourable effect on renal haemodynamics and in particular a lowering of intraglomerular pressure.
For those patients with hyperkalaemia, discontinuation of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy without first taking steps to minimize this complication is also not in the patients best interest given the potential cardiovascular benefits afforded by these agents. By taking several precautions, the majority of patients at risk for hyperkalaemia can be treated successfully rather than unnecessarily being labelled as intolerant to these drugs.
Blood pressure control and increases in the serum creatinine concentration
An increase in the serum creatinine concentration in the setting of better blood pressure control is seen primarily in patients with chronic renal failure. Loss of renal mass leads to disturbances in the autoregulatory ability of the remaining renal vasculature such that intraglomerular pressure begins to vary directly with changes in systemic arterial pressure [3,4]. In some patients, this impairment is severe enough that a completely pressure-passive vasculature is present where any change in mean arterial pressure is matched by a proportional change in intraglomerular pressure. Such changes explain why even modest degrees of systemic hypertension can be an important factor contributing to further renal function loss [5].
These same changes also explain why hypertensive chronic renal failure patients are more likely to develop an increase in the serum creatinine concentration when blood pressure is lowered. A blunted ability of the pre-glomerular circulation to vasodilate in response to better blood pressure control will cause an exaggerated fall in intraglomerular pressure. This change in renal function is haemodynamic in origin and does not represent structural injury to the kidney. In many patients, renal function will either improve or resolve with long-term blood pressure control, reflecting restoration of renal autoregulation back towards normal. In those patients whose renal function remains reduced, the long-term renal outcome is still improved as a result of better blood pressure control [6,7].
Renal dysfunction that accompanies antihypertensive therapy is a result of blood pressure lowering and is independent of the agent utilized. ACE inhibitors and ARBs are more commonly associated with this complication since any decline in intraglomerular pressure due to blood pressure lowering will be exaggerated by concomitant vasodilation of the efferent side of the glomerular circulation.
Consider a 52-year-old man with diabetic nephropathy and a baseline creatinine concentration of 1.8 mg/dl who on physical examination is noted to have a blood pressure of 148/92 mmHg. He is started on an ACE inhibitor, and 2 weeks later his blood pressure has fallen to 138/82 mmHg. A repeat serum creatinine concentration is now 2.2 mg/dl. Rather than discontinuing the ACE inhibitor potentially depriving this patient of an agent that can both slow the progression of his chronic renal disease and provide long-term cardiovascular protection, the appropriate response is to continue the drug and recheck laboratory values in 1 week to ensure the creatinine has stabilized at the higher value. One should not view a 2030% increase in the serum creatinine concentration that then stabilizes as a contraindication to intensive blood pressure control or, as in this case, use of an ACE inhibitor [8].
In those situations in which the initial rise in creatinine is >30% or the repeat value shows a progressive increase, then the appropriate response is to discontinue the drug and initiate a search for other causes of renal dysfunction. There are several conditions in which use of ACE inhibitors or ARBs may cause exaggerated or progressive declines in renal function. The first setting involves significant (usually >70%) bilateral renal artery obstruction or unilateral renal artery obstruction to a solitary functioning kidney. Under these conditions, increased tone of the efferent arteriole acts to attenuate the decline in intraglomerular pressure that results from the arterial obstruction. The trade-off is that renal function and the glomerular filtration rate become dependent upon sustained constriction of the efferent vessel by angiotensin II. A similar dependence can develop in patients with polycystic kidney disease where the renal arteries become extrinsically compressed by large cysts [9]. Unless the underlying obstruction can be treated, then other classes of antihypertensive agents will have to be utilized.
ACE inhibitors and ARBs can also cause an azotaemic response under conditions of an absolute (gastroenteritis, aggressive diuresis, poor oral intake) or effective reduction in circulatory volume (moderate to severe congestive heart failure). In these settings, angiotensin II-mediated constriction of the efferent arteriole serves to minimize the decline in glomerular filtration rate that otherwise would occur as a result of the fall in renal perfusion pressure. In the volume-contracted patient, the appropriate response is to discontinue the drug and only restart it once the extracellular fluid volume has been replenished. In a patient with congestive heart failure, these drugs will increase the creatinine when the decrease in intraglomerular pressure resulting from efferent vasodilation is not offset by an increase in renal perfusion. This can occur in patients with severely depressed cardiac function in which afterload reduction can no longer increase cardiac output, or in the setting of aggressive diuresis.
A similar mechanism is responsible for renal dysfunction that occurs in patients given ACE inhibitors or ARBs in the setting of non-steroidal anti-inflammatory drugs (NSAIDs), cyclosporin A or early sepsis [1012]. These settings are all associated with increased vasoconstriction of the renal vasculature. ACE inhibitor- or ARB-induced efferent vasodilation in the face of decreased perfusion pressure accounts for the fall in glomerular filtration rate.
Hyperkalaemia complicating the use of ACE inhibitors and ARBs
Use of ACE inhibitors or ARBs in patients with chronic renal disease can be associated with hyperkalaemia. As with a rise in the serum creatinine concentration, many physicians respond to even mild increases in the serum potassium by immediately discontinuing these drugs without first considering steps that might be taken to minimize this complication. In many instances, physicians are reluctant even to initiate such therapy simply because the patient has an elevated creatinine concentration. Such an approach is strictly to the patients disadvantage since patients with more advanced renal insufficiency derive a greater amount of protection from renal disease progression with these drugs [13]. While close monitoring is required, several steps can be taken to minimize the likelihood of developing hyperkalaemia.
One should review the patients medication profile and, wherever possible, discontinue drugs that can impair renal potassium excretion. NSAIDs, either prescribed or those taken over-the-counter, are common offenders in this regard [12]. The patients should be placed on a low potassium diet, with specific counselling against the use of potassium-containing salt substitutes. Diuretics are particularly effective in minimizing hyperkalaemia. In patients with a serum creatinine <1.8 mg/dl, thiazide diuretics can be used but, with more severe renal insufficiency, loop diuretics are required. In chronic renal failure patients with metabolic acidosis (bicarbonate concentration <20 mEq/l), sodium bicarbonate should be administered. Decreasing the dose of the ACE inhibitor or switching to one that is not totally dependent on renal excretion may be of help. In one study of patients with mild chronic renal failure, use of an ARB was found to have less of an effect on increasing serum potassium when compared with an ACE inhibitor [14]. However, this difference was small and, at present, these agents should be viewed as having similar risks for developing hyperkalaemia. Intermittent use of a potassium-binding resin can be tried; however, this drug is poorly tolerated when used on a chronic basis and has been associated with gastrointestinal ulceration [15].
With implementation of these steps, the risk of hyperkalaemia severe enough to warrant discontinuation of ACE inhibitors or ARBs is quite low even in patients with moderate to severe renal insufficiency. In patients with chronic renal disease, the serum potassium should be checked within 12 weeks of starting an ACE inhibitor or an ARB. If the potassium concentration increases to a value >5.6 mEq/l despite the precautions noted above, then another class of antihypertensive therapy will need to be utilized.
Conflict of interest statement. None declared.
References
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