Hypertension and the kidney: Determinants of the response to antihypertensive therapy and their implications

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  • Hypertension and the kidney: Determinants of the response to antihypertensive therapy and their implications

    Medicine has long recognized an association between hypertension and the kidney. The kidney may be a culprit or a victim in the process. As a culprit, the kidney may be responsible for the pathogenesis of hypertension in many patients, and in virtually all patients the renal response to antihypertensive therapy is a major determinant of its success or failure. In some patients, hypertension can lead to renal injury and even end-stage renal disease. Indeed, 25% of patients entering dialysis or transplant programs in the United States today have hypertension as the primary or sole mechanism, and another 25% have the complex combination of diabetes and hypertension as the cause. Antihypertensive therapy appears to be successful in preventing or arresting the renal response in accelerated hypertension, regardless of the treatment used to reduce blood pressure. However, treatment appears to be less successful in preventing the progression of moderate hypertension to end-stage renal disease. Substantial evidence suggests that angiotensin-converting enzyme inhibition and calcium channel blockade may prevent this progression when other antihypertensive therapy does not. The renal response to an angiotensin-converting enzyme inhibitor or a calcium channel-blocking agent appears to be determined by the pathogenetic features of the hypertension, and this may be an important determinant of the efficacy of the agents selected. Although still indistinct, the guidelines favoring selection of a specific antihypertensive agent are gradually emerging. (AM HEART J 1993;125:604-6.)

    Norman K. Hollenberg, MD, PhD Boston, Mass.

    Investigators who have approached the problem of the pathogenesis of essential hypertension from a wide variety of views have found it difficult to describe a possible pathogenetic sequence without implicating the kidney. l-6 In animal models7eg and in humans,lO* l1 studies based on transplantation have suggested that genetic information predisposing to hypertension is coded in the kidney. The pathogen- esis is likely complex in each patient, and probably differs from patient to patient. In some patients the hypertension is especially sensitive to sodium intake, whereas in others it is not. l2 In some patients plasma renin activity is elevated, and in others it is not5 Some patients have an increase in circulating cate- cholamines and presumably an increase in sympa- thetic nervous system activity; in others this evidence

    From the Departments of Medicine and Radiology, Harvard Medical School and Brigham and Womens Hospital.

    Reprint requests: Norman K. Hollenberg, MD, PhD, Brigham and Womens Hospital, 75 Francis St., Boston, MA 02115,.

    Copyright 1993 by Mosby-Year Book, Inc. 0oor.L8703/93/$1.00 + .lO 4/o/42394

    is absent. Unfortunately, no simple means of iden- tifying pathogenesis in the individual patient cur- rently exists, and few physicians attempt to do so when selecting therapy.

    Whether the kidney is involved when hypertension is initiated, ample evidence suggests that the renal response to antihypertensive therapy is a crucial de- terminant of whether the antihypertensive therapy will be successful. The first recognition of this prin- ciple came from Guyton et al.* Their analog computer model of the cardiovascular system provided com- pelling evidence, which was strongly supported by observations from the clinic and the laboratory, that the kidney must be engaged to sustain hypertension however it is initiated. A second important principle was first clearly enunciated by Koch-Weser13 in his description of standard triple therapy, a combination of a vasodilator, a diuretic, and a @-adrenergic- blocking agent. A vasodilator is a rational first agent to select for the treatment of hypertension because resistance to blood flow is increased and a vasodila- tor reverses that fundamental hemodynamic abnor- mality. Koch-Weser also suggested that a vasodilator was ineffective when used alone, because it activated


  • Volume 125

    Number 2. Part 2 Antihypertensive therapy and the kidney 605

    several systems that limit the antihypertensive re- sponse. The addition of a /3-adrenergic-blocking agent and a diuretic could be seen as enhancing the therapeutic response primarily by blocking these re- active systems.

    In this context, much of the recent advance in an- tihypertensive therapy makes a great deal of sense. Special attention has been given to angiotensin-con- verting enzyme (ACE) inhibition and calcium chan- nel blockade. Both approaches involve vasodilation, and both classes of agents have intrinsic to their ac- tion a special influence on the kidney, including pro- duction of a natriuresis and a reduction either in an- giotensin II formation or the vascular response to angiotensin II. The remarkable efficacy of these classes of agents probably reflects their substantial direct and indirect influences on the kidney.l


    We have known since the 1960s that the overall morbid event rate is reduced by antihypertensive therapy in severe hypertension and that the explo- sive, rapidly progressive renal failure associated with accelerated hypertension can be prevented or ar- rested. During the past decade, however, a disturbing fact has emerged: The prevalence of end-stage renal disease in the United States has increased progres- sively, primarily as a result of an increase in the number of patients with renal failure resulting from hypertension or diabetic nephropathy., l6 Indeed, this has occurred despite a concurrent decrease in cardiovascular mortality from cerebrovascular events and even coronary events in this population and does not reflect malignant hypertension as a cause.

    In one small study at a single center, Rostand et a1.17 found a substantial frequency with which other- wise unremarkable mild-to-moderate essential hy- pertension progressed to renal insufficiency. Al- though the criteria used to rule out primary renal disease were lax, this also applies to the data base from end-stage renal disease programs.15, l6 What emerged was that a category of patients, elderly, black, and male, was especially at risk,li which was supported by findings in the Hypertension Detection and Follow-up Program. s In this study there was a substantial frequency with which a significant de- cline in renal function occurred, again especially in black patients. Both studies used long-standing tra- ditional therapy, including a diuretic and methyl- dopa or a @-blocker as treatment. The possibility that the use of a diuretic contributed to the progressive loss of kidney function in selected patients is intrigu- ing, although clear evidence to support this is lacking. In an extended analysis of the European Working

    Party Trial of High Blood Pressure in the Elderly, a study that was conducted primarily in whites and that used diuretics as treatment, a decline in renal function occurred in the treated group but not in the placebo group. It is difficult to argue with the authors conclusion that renal impairment is more likely to be a consequence of the diuretic treatment they used than of the hypertension per se. However, their experience in whites may not be reflected in other races. In the Baltimore Longitudinal Study on Aging, again conducted in a predominately white population, hypertension indeed accelerated the loss of kidney function associated with aging, and diuretic treatment may have also done ~0.~~


    By the late 1970s a consensus of informed opinion held that antihypertensive therapy prevented not only the renal injury of accelerated hypertension, but also could at least partially reverse the process once established. Moreover, the nephropathy of type I di- abetes mellitus could be delayed and slowed. Because these conclusions were straightforward and the indi- cation to treat hypertension was clear whether or not renal disease was present, essentially no controversy ensued. During the past decade a new debate has be- gun, which is based on several lines of investigation. The issue is currently not whether to treat hyperten- sion, all agree tha.t hypertension when pressed should be treated, but rather, do specific agents exert a dif- ferential influence on the renal response?

    One major line of investigation that has influenced these thoughts has come from studies in animal models. A wide variety of insults can lead to chronic, progressive renal destruction. When a septic, immu- nologic, metabolic, or toxic injury is involved, the re- sponsible insult may or may not make a continuing contribution. The most unambiguous information has come from a model based on the remnant kid- ney. ;l If one kidney and a substantial portion of the other kidney are removed, a small residue of perfectly normal kidney tissue remains. In a manner identical to all forms of chronic progressive renal disease, that small remnant undergoes unremitting progressive glomerular sclerosis, which leads to a uremic death. The resultant end-stage kidney disease is essentially identical to that associated with other forms of injury.

    The initial response of the remnant kidney can be seen as adaptive: With hypertrophy, blood flow to each glomerulus increases, as does its glomerular fil- tration rate. The result is short-term improvement in kidney function. However, as noted by Brenner,l

  • 606 Hollenberg February 1993

    Amermn Heart Journal

    short-term adaptation might prove to be maladap- tive in the long run. The short-term increase in the glomerular filtration rate reflects an increase in renal plasma Now and a sharp increase in glomerular cap- illary hydrostatic pr


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