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Clinical Relationships between Arterial Hypertension and the Kidneys
CLINICAL RELATIONSHIPS BETWEEN ARTERIAL HYPERTENSION AND THE KIDNEYS
DAVID A. RYTAND, M.D.'*' ARTERIAL hypertension is only a sign of disease, not necessarily a disease in itself. Even though careful search of most hypertensive patients usually fails to disclose a reason for the abnormal pressure, it is stilI useful in protecting other patients from improper treatment, in the management of the hypertensive patient, and in arriving at a prognosis. During this search, it is not uncommon to discover proteinuria or other evidence of renal disease; the purposes of this paper are to discuss the diagnostic and therapeutic problems raised by the occurrence of a renal lesion in the hypertensive patient, and to review the pertinent basic concepts which have been so well summarized recently. I, 2, 3 ETlOLOGIC RELATIONSHIPS BETWEEN HYPERTENSION AND THE KIDNEYS
At least logically, there are three ways by which hypertension and the kidneys could be related: renal lesions might cause arterial hypertension, hypertension might result in renal disease, and still other disorders might simultaneously damage the kidneys and elevate the blood pressure. Unfortunately, the following separation of certain situations into these three categories is more certain in black and white than it is in actual patients. Renal Disease Causing Hyper+ension.-Many varieties of bilateral primary disorders of the kidneys result in hypertension, especially when renal failure (uremia) is present; among others, these include glomerular nephritis in early and late stages, polycystic disease, pyelonephritis, and obstruction of the urinary tract. Patients with periarteritis nodosa, disseminated lupus or related syndromes are usually hypertensive only with associated renal failure; their arterial pressures are normal either when the kidneys are not involved or when renal tubular degeneration predominates. 4 These syndromes therefore seem to behave as glomerular nephritis in relation to hypertensive effect. The mechanism by which renal disease elevates arterial pressure is not established, nor has it been thoroughly studied. Diffuse renal lesions have been compared, without adequate basis, to experiments in which the pressure is raised by partial occlusion of the renal artery; it has been claimed that renal ischemia is responsible for hypertension in both. Although the perfusibiIity of the kidneys removed at necropsy From the Department of Medicine, Stanford University School of Medicine, San Francisco, California. • Assistant Professor of Medicine, Stanford University School of Medicine. 535
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DAVID A. RYTAND
is very low when renal damage has caused death in uremia, 5 indirect estimations of renal blood flow during life in patients with glomerular nephritis seem to indicate hyperemia. 3 In rats made hypertensive with a diffuse renal lesion after subtotal nephrectomy, blood flows through the abnormal remnant of kidney at a normal rate. 6 On the other hand, the rate of renal blood flow is surprisingly low in subjects with coarctation of the aorta,7 in whom the kidneys are apparently normal otherwise; it has been suggested that the arterial hypertension with this anomaly represents the clinical counterpart of the Goldblatt type of experiment. Experimental studies on this variety of hypertension, caused by partial occlusion of a renal artery, show that it persists after denervation by transplanting the kidney, 8 thereby involving a humoral substance. Whether this constricts arterioles by peripheral action or via the central nervous system9 is not certain, and its relation to the renin-angiotonin series is not established. Recent attempts have not yet succeeded in naming the juxtaglomerular apparatus as the precise source, within the kidney, of renal hypertension. 3 In the last few years attention has been directed to unilateral renal lesions, usually atrophic pyelonephritis, as a cause of hypertension; since such lesions are removable they might be of more practical importance than bilateral ones. Unfortunately, arterial hypertension is rarely associated with lesions of this type and is even less often relieved by nephrectomy;l. 10 we have seen only two successful results in this clinic. Complete removal of both kidneys causes little or no increase in arterial pressure experimentally. Clinically, hypertension is rare in acute anuria and is uncommon in some varieties of chronic renal disease; these include the "surgical" types of renal lesions, the nephrotic stage of glomerular nephritis, amyloidosis, and the lesiqns with multiple myeloma and subacute bacterial endocarditis (even with uremia). There is no satisfactory explanation for the usual failure of these lesions to elevate arterial pressure. Essential Hypertension.-High blood pressure follows gross renal disease in only a small proportion of all hypertensive patients, and is even more rarely associated with other etiologic factors such as a tumor of the adrenal medulla. In the great majority of cases, careful search fails to reveal a reason for the elevated diastolic pressure level; in these patients it may then be said that essential hypertension is present. Now it is obvious that there must be some underlying reason for the generalized arteriolar construction which is manifest clinically as hypertension; the renal factor was partially discussed above. It may now be added that essential hypertension is regarded by some to be of renal origin, although this view is becoming less popular as the evidence for it grows more complex. 1 • 2 Although an obscure metabolic fault in the kidneys 2 may eventually
ARTERIAL HYPERTENSION AND THE KIDNEYS
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become established as the cause of essential hypertension, simple renal ischemia increasingly seems less likely to be involved. The arteriolar lesions found in the kidneys at necropsy are usually absent earlier in the disease,!1 and even after death renal perfusibility is not often decreased in the absence of uremia. 5 Clinicians have long been impressed by the "nervous" element in patients with essential hypertension; studies have newly emphasized the fact that organic disease of the central nervous system in man and experimental interference with the nervous system in animals may be followed by an elevation of arterial pressure. A neurogenic element has been implicated even with renal hypertension. 9 Hypertension Causing Renal Disease.-The concept that essential hypertension had its origin in renal ischemia arose, at least in part, from the fact that vascular changes are associated with hypertension of any cause, and are often prominent in the renal vessels. These changes are of two kinds, corresponding roughly to the size of the involved vessels. First, renal arterioles presumably participate in the generalized systemic arteriolar constriction which causes hypertension, as well as in the medial hypertrophy which is an early sequel. Secondly, increased arterial pressure initiates or accelerates atherosclerosis; it is chiefly this alteration in the larger arteries which complicates the course of the hypertensive patient, as by occluding cerebral or coronary arteries. Renal arterial pressure remains normal distal to the partially constricted artery responsible for hypertension in the rest of the experimental animal; under these conditions, vessels in the kidney are protected from the changes occurring elsewhere. 12 In essential hypertension there is no such protection, and therefore renal arteriosclerosis accompanies cerebral, retinal and cardiac arteriosclerosis. This event may add a renal factor to hypertension which arose elsewhere, and produces abnormal results when renal' blood flow and other functions are measured by modern methods.!' 2 It is of more practical importance to recognize that renal arteriosclerosis, while not often causing death in uremia, is the lesion responsible for the abnormal urine of most hypertensive patients. Anatomic changes in the shrinking kidneys are evident in the urine in the form of moderate amounts of protein, with a few casts, erythrocytes, leukocytes and renal tubular cells in the sediment. If heart failure supervenes, the urinary abnormalities increase in degree with renal congelition. Gross hematuria may accompany the malignant stage of essential hypertension with arteriolar medial necrosis, or may appear as part of uremia's purpura. As function decreases, urine becomes dilute and its specific gravity less variable. Rough tests of the blood show retention of metabolites. Hypertension and Renal Lesions Associated with a Third Factor.-More than a few uncertainties were noted above; we know even less about
538
DAVID A. RYTAND
states in which the blood pressure and kidneys are involved more or less at the same time in the presence of a third process. One could, of course, include the periarteritis nodosa group and even acute glomerular nephritis in this section, but two other illustrations may be better. The first of these is that of intercapillary glomerulosclerosis, a renal lesion usually found only in middle-aged patients with diabetes mellitus, and then especially together with a syndrome of arterial hypertension, marked proteinuria and abnormal urinary sediment, edema due chiefly to hypoproteinemia, and renal failure. l3 The diabetes almost always comes first, and is mild. Microscopic lesions may be of severe degree without the complete syndrome, and the causal relationships are not yet clear. The syndrome is of particular interest because it is uncommon for hypertension to exist with edema caused by low concentration of the serum protein and with intense renal tubular degeneration and proteinuria (the nephrotic syndrome). This unusual combination is even more striking in eclamptogenic toxemia (pre-eclampsia), no longer thought to be the result of disturbed renal function.14 Here again one finds a third factor, an abnormal state during pregnancy, associated in unknown ways with hypertension and a degenerative renal lesion, and with edema often a consequence of hypoproteinemia. Unlike the syndrome in the previous paragraph, renal failure is rare in pre-eclampsia. Prolonged toxemia is often followed by persistent hypertension. Pre-eclampsia occurring late in pregnancy is to be distinguished from those situations in which the course of previously existing hypertension or renal disease is complicated by the occurrence of pregnancy. Under these conditions the original disorder may remain relatively unchanged, but usually becomes worse comparatively early. After termination of pregnancy, the underlying condition may be little or no more severe than before. Pre-existing hypertension is much more apt to cause trouble than a previous renal lesion with normal pressure and function. GUIDES TO DIFFERENTIAL DIAGNOSIS
With the above material as background, the significance of family and personal histories, physical examination and laboratory studies may now be discussed. Family History.-The patient with essential hypertension may tell of a high incidence of hypertensive disease or its sequels in his family history. So may the one who has polycystic kidneys, although he is apt to speak of kidney trouble. "High blood pressure" as a cause of death in aged relatives may usually be ignored, as an elevation of systolic pressure with normal diastolic pressure is common with arteriosclerosis; the latter, not hypertension, may also have been responsible for cardiac and cerebral manifestations. Personal History.-The recent "present illness" part of the story is apt to consist of shortness of breath, fatigue or other complications
ARTERIAL HYPERTENSION AND THE KIDNEYS
539
of hypertension; it must be carefully heard for its clues to proper management of the patient. More rarely the complicated illness suggests a syndrome in the periarteritis nodosa group as the patient tells of asthma, joint troubles and a rash; the aging gentleman's difficulty in emptying his obstructed bladder may be important; abdominal pain in another leads to the discovery of polycystic kidneys; the presence of advanced pregnancy scarcely needs telling. The past personal history is more useful in evaluating the significance of renal disorders accompanying hypertension. In earlier examinations (for life insurance, pre-employment, military service, and so forth), was high blood pressure found before or after albumin in the urine? Had the patient had trouble, or the physician betrayed alarm toward the end of pregnancy? Was a bad sore throat followed shortly by the puffy eyelids or smoky urine of acute glomerular nephritis? Had there been a period of painful burning or frequent urination, or chills with fever and backache, as the early events of urinary tract infection which has become chronic pyelonephritis? Was there ever an operation on or about or below a kidney, as a possible cause of unilateral renal disease? Was the urine ever bloody, possibly at a time when there was severe colicky pain of a stone? Such specific questions help in deciding whether a renal lesion found with hypertension plays an etiologic role or is merely a complication. Physical Examination.-The physical examination also serves two purposes, first in evaluating the damage done by hypertensive disease and secondly in seeking a reason for hypertension. As to the latter, simple inspection reveals the typical facial erythema with disseminated lupus; polycystic kidneys are found on palpation; dilated intercostal arteries and delayed, small or absent femoral pulses indicate coarctation (with which hypertensive retinopathy is strangely uncommon). Since these are so rarely found, examination is most helpful in finding what harm has been done by elevated pressure in the way of vascular changes; particularly, one notes any signs of cerebral arteriosclerosis, looks for retinal damage, and searches for the cardiac enlargement, gallop, basal rales or systemic congestion of heart failure. These, more than the mere level of arterial pressure, determine the prognosis and guide management of the patient. Laboratory Studies.-There are only three really important laboratory a'ids for an understanding of most patients with renal disease and hypertension; these are careful examination of the urine, a simple test of r~nal function, and pyelograms by intravenous injection of a contrast medium if renal function seems normal. To be sure, other methods of study are indicated in a very few patients. It may be helpful to find an elevated concentration of serum globulin when one of the periarteritis group is suspected, or to confirm that suspicion by muscle biopsy; a roentgenogram may reveal the notched ribs and absent aortic knob typical of coarctation. StilI
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DAVID A. RYTAND
other laboratory studies may be useful in assessing what damage hypertensive disease has done. The radiologist's finding of cardiac enlargement and pulmonary congestion will often confirm the results of physical examination or the patient's story of breathlessness. The electrocardiogram is apt to be misleading, except for characteristic changes of myocardial infarction, because of the high incidence of abnormal T waves with left ventricular preponderance. The urine may be apparently normal not only when renal disease is absent, but also in two situations in which renal lesions play a part in elevating arterial pressure. First, with complete obstruction of a ureter the abnormal side contributes nothing at all to the urine; secondly, healed or atrophic pyelonephritis may similarly alter blood pressure with little or no urinary evidence of its presence. One must also remember that hyaline casts and erythrocytes are dissolved in alkaline urine, particularly if dilute, and that it is more difficult to detect small amounts of protein in dilute urine. Concentration tests are best used not as tests of renal function but as a means of obtaining concentrated urine suitable for examination; this should include the method of Addis. 15 Erythrocytes and especially leukocytes in the sediment, with small degrees of proteinuria, suggest pyelonephritis. This is sometimes erroneously diagnosed when glomerular nephritis is present, an error caused by misinterpretation of the latter's renal tubule epithelial cells as "pus cells." Casts (hyaline, granular or epithelial) do not mean glomerular nephritis, but occur with any diffuse renal lesion. It is obvious that urinary tract infections are commonly found as complications of hypertension; they cause it much less often. Early in glomerular nephritis the predominance of blood casts and erythrocytes over leukocytes and tubule cells simplifies the diagnosis. Later, blood casts may be found only after long search. In the nephrotic stage such evidence of glomerulitis is usually lacking; the urine is full of protein, hyaline casts with fat droplets, and renal tubule cells packed with fat (oval fat bodies); similar findings occur in other nephrotic syndromes. Later in glomerular nephritis, the renal lesion as judged by urinalyses seems less intense; there are moderate and roughly proportional excesses of protein, erythrocytes, leukocytes and renal epithelial cells, and granular or epithelial casts. With the dilute urine of advanced renal disease hyaline casts are rare, but broad casts a"ppear; the latter are found with renal failure of many causes. Both the urine and clinical features of late glomerular nephritis are indistinguishable from those of renal arteriosclerosis following essential hypertension. The presence of blood casts, fatty cells or casts, and broad casts all at once is highly suggestive of one of the periarteritis nodosa syndromes. 4 Tests of renal function need not be complicated. The main question is whether renal disease is confined to one kidney or has involved both; the latter is established by finding an elevation of thf:" blood
ARTERIAL HYPERTENSION AND THE KIDNEYS
541
urea 16 or creatinine concentration above normal upper limits (generously 50 mg. and 2 mg. per 100 cc. respectively). Some clinicallaboratories seem able to measure blood urea-nitrogen (25 mg. per 100 cc.) or total nonprotein nitrogen (50 mg. per 100 cc.) more accurately than urea. Creatinine is less subject than other substances with nonprotein nitrogen to extrarenal.sources of elevated concentration; urea, for example, may be increased in the blood in the absence of any renal disease. Otherwise, nothing is gained by measuring more than one of these substances, and very little useful information is added by determinations of dye excretion or clearances. Intravenous pyelography will rarely be either successful or helpful when simple tests show reduction of renal function; then measurement of residual urine volume in men and stereoscopic roentgenograms of the kidney region (for renal size or stones) are in order. Intravenous pyelograms of the hypertensive patient are made either in the seeming absence of a renal lesion (normal urine) or in the presence of urinary abnormalities without reduced renal function, in an effort to uncover the rare instances of hypertension caused by renal disease amenable to specific treatment; this really means a unilateral abnormality. RENAL DISEASE AND THE TREATMENT OF HYPERTENSION
Enthusiasm aroused by apparent discovery of such a cause must be tempered before advising nephrectomy. Minor deviations from perfectly normal pyelograms are common, and apart from the operative risk it is sometimes harmful to remove a kidney which appears to be functionless;10 even in apparently well selected patients unilateral nephrectomy seems to be successful in curing hypertension in only one case out of ten. 1, 10 Atrophic pyelonephritis, with a small and functionless kidney on intravenous pyelography, is the lesion most frequently found when good results follow nephrectomy. Precise indications for the latter are not yet established. Of two successful cases in this clinic,17 repeated pyelography in one showed unilateral loss of function but the removed kidney appeared almost normal; in the other, a previous renal operation had led to diffuse lesions in a kidney which nevertheless was able to concentrate the contrast medium. Having found a suspicious appearance, intravenous pyelography should be repeated. If the lesion is still present, cystoscopy is necessary not. only for further exploration of the abnormal side but to obtain urine from, and assure the normal function of, the other side. Complete normality of the opposite kidney will not guarantee success on nephrectomy, but abnormalities there cast grave doubt on the advisability of operation. The pre-eclamptic toxemia of pregnancy, when mild, may be controlled by management which stresses rest and sedatives, with a diet
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DAVID A. RYTAND
providing an adequate amount of protein while restnctmg sodium; diuretics are sometimes necessary. Unfortunately, prolonged toxemia is frequently followed by a form of hypertension which apparently is not distinguishable from essential hypertension; this does not so often come after severe toxemia, which is not allowed to be present very l('mg. Since fetal mortality in toxemia is lower when labor is induced a month before term, such interference seems best for both mother and child when toxemia persists in spite of modern management. But for the removal of a fetus from the pregnant uterus or the rare attack on a unilateral renal lesion, the conditions reviewed above are not often subject to specific therapy. Yet the presence of kidney disease alters treatment of the hypertensive patient in various ways. Sulfonamides will frequently be given to patients with urinary tract infections; with impaired renal function more than the usual precautions should be taken. We are not convinced of their reported beneficial action in glomerular nephritis, but the latter does not contraindicate their use when necessary. Those who use thiocyanate in hypertension should avoid it when renal lesions are present. The management of congestive heart failure in hypertension is made more difficult by the presence of true uremia (not including the relatively slight reduction of function in the congested kidney). Mercurial and even other diuretics may then not be used safely, digitalis and related glucosides more likely produce vomiting, and the associated anemia necessitates more thought before phlebotomy. One often desires to replenish the sodium and water stores of the uremic patient who is dehydrated; this must be done cautiously in the presence of hypertension, even when heart failure is not obvious, in order to avoid pulmonary edema. . While dietary reduction of urinary nitrogen excretion is not useful in hypertension without renal involvement, there is every reason to believe it reduces renal work and is therefore indicated when bilateral kidney damage is present18 in an effort to minimize progression of the lesion. Urinary nitrogen is best reduced by a diet which first supplies an adequate number of calories and which daily gives about 0.5 gm. of protein per kilogram of body weight; to the latter must be added an amount of protein equal to its daily loss in the urine. Dietetic details, including the need of vitamin and mineral supplements, must be decided in each individual case. Finally, when section of the splanchnic nerves is contemplated, the presence of a renal lesion requires further consideration. The chances of a successful result are worst in those hypertensive patients who most need help, those with renal damage in the malignant phase of essential hypertension. On the other hand, nerve-cutting operations have succeeded in lowering arterial pressure at least temporarily in patients whose primary trouble was glomerular nephritis; that disease does not
ARTERIAL HYPERTENSION AND THE KIDNEYS
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contraindicate operation, no matter how bad the urine appears, if uremia is absent and hypertension dominates the clinical picture. BIBLIOGRAPHY
1. Goldring, W. and Chasis, M.: The Commonwealth Fund, New York, 1944. 2. Smith, H. W.: J. Mt. Sinai Hosp., 10:59 (May-June) 1943. 3. Bradley, S. E.: New England J. Med., 231:421-426, 452-458 (Sept. 21 and 28) 1944. 4. Krupp, M.: Arch. Int. Med., 71:54-61 ,Jan.) 1943. 5. Cox, A. J., Jr. and Dock, W.: J. Exper. J\led., 74:167-175 (Sept.) 1941. 6. Dock, W. and Rytand, D. A.: Proc. Soc. Exper. Biol. & Med., 36:196-198 (March) 1937. 7. Friedman, M., Selzer, A. and Rosenblum, H.: J. Clin. Investigation, 20:107-111 (March) 1941. 8. Blalock, A. and Levy, S. E.: Ann. Surg., 106:826-847 (Nov.) 1937. 9. Dock, W., Shidler, F. and Moy, B.: Am. Heart J., 23:513-521 (April) 1942. 10. Sensenbach, W.: Arch. Int. Med., 73:123-130 (Feb.) 1944. 11. Castleman, B. and Smithwick, R. H.: J.A.M.A., 121:1256-1261 (April 17) 1943. 12. Wilson, C. and Pickering, G. W.: Clin. Sc., 3:343-355 (Aug.) 1938. 13. Siegal, S. and Allen, A. c.: Am. J. Med. Sc., 201:516-528 (April) 1941. 14. Rytand, D. A.: Stanford M. Bull., 1:203-208 (Nov.) 1943. 15. Addis, T.: J.A.M.A., 85:163-167 (July Hl) 1925. 16. MacKay, E. M. and Rytand, D. A.: Arch. Int. Med., 55:131-140 (Jan.) 1935. 17. Wallace, C. J.: To be published. Stanford M. Bull., 1945. 18. Addis, T.: J. Urol., 41:126-136 (Feb.) 1939.
DAVID A. RYTAND, M.D.'*' ARTERIAL hypertension is only a sign of disease, not necessarily a disease in itself. Even though careful search of most hypertensive patients usually fails to disclose a reason for the abnormal pressure, it is stilI useful in protecting other patients from improper treatment, in the management of the hypertensive patient, and in arriving at a prognosis. During this search, it is not uncommon to discover proteinuria or other evidence of renal disease; the purposes of this paper are to discuss the diagnostic and therapeutic problems raised by the occurrence of a renal lesion in the hypertensive patient, and to review the pertinent basic concepts which have been so well summarized recently. I, 2, 3 ETlOLOGIC RELATIONSHIPS BETWEEN HYPERTENSION AND THE KIDNEYS
At least logically, there are three ways by which hypertension and the kidneys could be related: renal lesions might cause arterial hypertension, hypertension might result in renal disease, and still other disorders might simultaneously damage the kidneys and elevate the blood pressure. Unfortunately, the following separation of certain situations into these three categories is more certain in black and white than it is in actual patients. Renal Disease Causing Hyper+ension.-Many varieties of bilateral primary disorders of the kidneys result in hypertension, especially when renal failure (uremia) is present; among others, these include glomerular nephritis in early and late stages, polycystic disease, pyelonephritis, and obstruction of the urinary tract. Patients with periarteritis nodosa, disseminated lupus or related syndromes are usually hypertensive only with associated renal failure; their arterial pressures are normal either when the kidneys are not involved or when renal tubular degeneration predominates. 4 These syndromes therefore seem to behave as glomerular nephritis in relation to hypertensive effect. The mechanism by which renal disease elevates arterial pressure is not established, nor has it been thoroughly studied. Diffuse renal lesions have been compared, without adequate basis, to experiments in which the pressure is raised by partial occlusion of the renal artery; it has been claimed that renal ischemia is responsible for hypertension in both. Although the perfusibiIity of the kidneys removed at necropsy From the Department of Medicine, Stanford University School of Medicine, San Francisco, California. • Assistant Professor of Medicine, Stanford University School of Medicine. 535
536
DAVID A. RYTAND
is very low when renal damage has caused death in uremia, 5 indirect estimations of renal blood flow during life in patients with glomerular nephritis seem to indicate hyperemia. 3 In rats made hypertensive with a diffuse renal lesion after subtotal nephrectomy, blood flows through the abnormal remnant of kidney at a normal rate. 6 On the other hand, the rate of renal blood flow is surprisingly low in subjects with coarctation of the aorta,7 in whom the kidneys are apparently normal otherwise; it has been suggested that the arterial hypertension with this anomaly represents the clinical counterpart of the Goldblatt type of experiment. Experimental studies on this variety of hypertension, caused by partial occlusion of a renal artery, show that it persists after denervation by transplanting the kidney, 8 thereby involving a humoral substance. Whether this constricts arterioles by peripheral action or via the central nervous system9 is not certain, and its relation to the renin-angiotonin series is not established. Recent attempts have not yet succeeded in naming the juxtaglomerular apparatus as the precise source, within the kidney, of renal hypertension. 3 In the last few years attention has been directed to unilateral renal lesions, usually atrophic pyelonephritis, as a cause of hypertension; since such lesions are removable they might be of more practical importance than bilateral ones. Unfortunately, arterial hypertension is rarely associated with lesions of this type and is even less often relieved by nephrectomy;l. 10 we have seen only two successful results in this clinic. Complete removal of both kidneys causes little or no increase in arterial pressure experimentally. Clinically, hypertension is rare in acute anuria and is uncommon in some varieties of chronic renal disease; these include the "surgical" types of renal lesions, the nephrotic stage of glomerular nephritis, amyloidosis, and the lesiqns with multiple myeloma and subacute bacterial endocarditis (even with uremia). There is no satisfactory explanation for the usual failure of these lesions to elevate arterial pressure. Essential Hypertension.-High blood pressure follows gross renal disease in only a small proportion of all hypertensive patients, and is even more rarely associated with other etiologic factors such as a tumor of the adrenal medulla. In the great majority of cases, careful search fails to reveal a reason for the elevated diastolic pressure level; in these patients it may then be said that essential hypertension is present. Now it is obvious that there must be some underlying reason for the generalized arteriolar construction which is manifest clinically as hypertension; the renal factor was partially discussed above. It may now be added that essential hypertension is regarded by some to be of renal origin, although this view is becoming less popular as the evidence for it grows more complex. 1 • 2 Although an obscure metabolic fault in the kidneys 2 may eventually
ARTERIAL HYPERTENSION AND THE KIDNEYS
537
become established as the cause of essential hypertension, simple renal ischemia increasingly seems less likely to be involved. The arteriolar lesions found in the kidneys at necropsy are usually absent earlier in the disease,!1 and even after death renal perfusibility is not often decreased in the absence of uremia. 5 Clinicians have long been impressed by the "nervous" element in patients with essential hypertension; studies have newly emphasized the fact that organic disease of the central nervous system in man and experimental interference with the nervous system in animals may be followed by an elevation of arterial pressure. A neurogenic element has been implicated even with renal hypertension. 9 Hypertension Causing Renal Disease.-The concept that essential hypertension had its origin in renal ischemia arose, at least in part, from the fact that vascular changes are associated with hypertension of any cause, and are often prominent in the renal vessels. These changes are of two kinds, corresponding roughly to the size of the involved vessels. First, renal arterioles presumably participate in the generalized systemic arteriolar constriction which causes hypertension, as well as in the medial hypertrophy which is an early sequel. Secondly, increased arterial pressure initiates or accelerates atherosclerosis; it is chiefly this alteration in the larger arteries which complicates the course of the hypertensive patient, as by occluding cerebral or coronary arteries. Renal arterial pressure remains normal distal to the partially constricted artery responsible for hypertension in the rest of the experimental animal; under these conditions, vessels in the kidney are protected from the changes occurring elsewhere. 12 In essential hypertension there is no such protection, and therefore renal arteriosclerosis accompanies cerebral, retinal and cardiac arteriosclerosis. This event may add a renal factor to hypertension which arose elsewhere, and produces abnormal results when renal' blood flow and other functions are measured by modern methods.!' 2 It is of more practical importance to recognize that renal arteriosclerosis, while not often causing death in uremia, is the lesion responsible for the abnormal urine of most hypertensive patients. Anatomic changes in the shrinking kidneys are evident in the urine in the form of moderate amounts of protein, with a few casts, erythrocytes, leukocytes and renal tubular cells in the sediment. If heart failure supervenes, the urinary abnormalities increase in degree with renal congelition. Gross hematuria may accompany the malignant stage of essential hypertension with arteriolar medial necrosis, or may appear as part of uremia's purpura. As function decreases, urine becomes dilute and its specific gravity less variable. Rough tests of the blood show retention of metabolites. Hypertension and Renal Lesions Associated with a Third Factor.-More than a few uncertainties were noted above; we know even less about
538
DAVID A. RYTAND
states in which the blood pressure and kidneys are involved more or less at the same time in the presence of a third process. One could, of course, include the periarteritis nodosa group and even acute glomerular nephritis in this section, but two other illustrations may be better. The first of these is that of intercapillary glomerulosclerosis, a renal lesion usually found only in middle-aged patients with diabetes mellitus, and then especially together with a syndrome of arterial hypertension, marked proteinuria and abnormal urinary sediment, edema due chiefly to hypoproteinemia, and renal failure. l3 The diabetes almost always comes first, and is mild. Microscopic lesions may be of severe degree without the complete syndrome, and the causal relationships are not yet clear. The syndrome is of particular interest because it is uncommon for hypertension to exist with edema caused by low concentration of the serum protein and with intense renal tubular degeneration and proteinuria (the nephrotic syndrome). This unusual combination is even more striking in eclamptogenic toxemia (pre-eclampsia), no longer thought to be the result of disturbed renal function.14 Here again one finds a third factor, an abnormal state during pregnancy, associated in unknown ways with hypertension and a degenerative renal lesion, and with edema often a consequence of hypoproteinemia. Unlike the syndrome in the previous paragraph, renal failure is rare in pre-eclampsia. Prolonged toxemia is often followed by persistent hypertension. Pre-eclampsia occurring late in pregnancy is to be distinguished from those situations in which the course of previously existing hypertension or renal disease is complicated by the occurrence of pregnancy. Under these conditions the original disorder may remain relatively unchanged, but usually becomes worse comparatively early. After termination of pregnancy, the underlying condition may be little or no more severe than before. Pre-existing hypertension is much more apt to cause trouble than a previous renal lesion with normal pressure and function. GUIDES TO DIFFERENTIAL DIAGNOSIS
With the above material as background, the significance of family and personal histories, physical examination and laboratory studies may now be discussed. Family History.-The patient with essential hypertension may tell of a high incidence of hypertensive disease or its sequels in his family history. So may the one who has polycystic kidneys, although he is apt to speak of kidney trouble. "High blood pressure" as a cause of death in aged relatives may usually be ignored, as an elevation of systolic pressure with normal diastolic pressure is common with arteriosclerosis; the latter, not hypertension, may also have been responsible for cardiac and cerebral manifestations. Personal History.-The recent "present illness" part of the story is apt to consist of shortness of breath, fatigue or other complications
ARTERIAL HYPERTENSION AND THE KIDNEYS
539
of hypertension; it must be carefully heard for its clues to proper management of the patient. More rarely the complicated illness suggests a syndrome in the periarteritis nodosa group as the patient tells of asthma, joint troubles and a rash; the aging gentleman's difficulty in emptying his obstructed bladder may be important; abdominal pain in another leads to the discovery of polycystic kidneys; the presence of advanced pregnancy scarcely needs telling. The past personal history is more useful in evaluating the significance of renal disorders accompanying hypertension. In earlier examinations (for life insurance, pre-employment, military service, and so forth), was high blood pressure found before or after albumin in the urine? Had the patient had trouble, or the physician betrayed alarm toward the end of pregnancy? Was a bad sore throat followed shortly by the puffy eyelids or smoky urine of acute glomerular nephritis? Had there been a period of painful burning or frequent urination, or chills with fever and backache, as the early events of urinary tract infection which has become chronic pyelonephritis? Was there ever an operation on or about or below a kidney, as a possible cause of unilateral renal disease? Was the urine ever bloody, possibly at a time when there was severe colicky pain of a stone? Such specific questions help in deciding whether a renal lesion found with hypertension plays an etiologic role or is merely a complication. Physical Examination.-The physical examination also serves two purposes, first in evaluating the damage done by hypertensive disease and secondly in seeking a reason for hypertension. As to the latter, simple inspection reveals the typical facial erythema with disseminated lupus; polycystic kidneys are found on palpation; dilated intercostal arteries and delayed, small or absent femoral pulses indicate coarctation (with which hypertensive retinopathy is strangely uncommon). Since these are so rarely found, examination is most helpful in finding what harm has been done by elevated pressure in the way of vascular changes; particularly, one notes any signs of cerebral arteriosclerosis, looks for retinal damage, and searches for the cardiac enlargement, gallop, basal rales or systemic congestion of heart failure. These, more than the mere level of arterial pressure, determine the prognosis and guide management of the patient. Laboratory Studies.-There are only three really important laboratory a'ids for an understanding of most patients with renal disease and hypertension; these are careful examination of the urine, a simple test of r~nal function, and pyelograms by intravenous injection of a contrast medium if renal function seems normal. To be sure, other methods of study are indicated in a very few patients. It may be helpful to find an elevated concentration of serum globulin when one of the periarteritis group is suspected, or to confirm that suspicion by muscle biopsy; a roentgenogram may reveal the notched ribs and absent aortic knob typical of coarctation. StilI
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other laboratory studies may be useful in assessing what damage hypertensive disease has done. The radiologist's finding of cardiac enlargement and pulmonary congestion will often confirm the results of physical examination or the patient's story of breathlessness. The electrocardiogram is apt to be misleading, except for characteristic changes of myocardial infarction, because of the high incidence of abnormal T waves with left ventricular preponderance. The urine may be apparently normal not only when renal disease is absent, but also in two situations in which renal lesions play a part in elevating arterial pressure. First, with complete obstruction of a ureter the abnormal side contributes nothing at all to the urine; secondly, healed or atrophic pyelonephritis may similarly alter blood pressure with little or no urinary evidence of its presence. One must also remember that hyaline casts and erythrocytes are dissolved in alkaline urine, particularly if dilute, and that it is more difficult to detect small amounts of protein in dilute urine. Concentration tests are best used not as tests of renal function but as a means of obtaining concentrated urine suitable for examination; this should include the method of Addis. 15 Erythrocytes and especially leukocytes in the sediment, with small degrees of proteinuria, suggest pyelonephritis. This is sometimes erroneously diagnosed when glomerular nephritis is present, an error caused by misinterpretation of the latter's renal tubule epithelial cells as "pus cells." Casts (hyaline, granular or epithelial) do not mean glomerular nephritis, but occur with any diffuse renal lesion. It is obvious that urinary tract infections are commonly found as complications of hypertension; they cause it much less often. Early in glomerular nephritis the predominance of blood casts and erythrocytes over leukocytes and tubule cells simplifies the diagnosis. Later, blood casts may be found only after long search. In the nephrotic stage such evidence of glomerulitis is usually lacking; the urine is full of protein, hyaline casts with fat droplets, and renal tubule cells packed with fat (oval fat bodies); similar findings occur in other nephrotic syndromes. Later in glomerular nephritis, the renal lesion as judged by urinalyses seems less intense; there are moderate and roughly proportional excesses of protein, erythrocytes, leukocytes and renal epithelial cells, and granular or epithelial casts. With the dilute urine of advanced renal disease hyaline casts are rare, but broad casts a"ppear; the latter are found with renal failure of many causes. Both the urine and clinical features of late glomerular nephritis are indistinguishable from those of renal arteriosclerosis following essential hypertension. The presence of blood casts, fatty cells or casts, and broad casts all at once is highly suggestive of one of the periarteritis nodosa syndromes. 4 Tests of renal function need not be complicated. The main question is whether renal disease is confined to one kidney or has involved both; the latter is established by finding an elevation of thf:" blood
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urea 16 or creatinine concentration above normal upper limits (generously 50 mg. and 2 mg. per 100 cc. respectively). Some clinicallaboratories seem able to measure blood urea-nitrogen (25 mg. per 100 cc.) or total nonprotein nitrogen (50 mg. per 100 cc.) more accurately than urea. Creatinine is less subject than other substances with nonprotein nitrogen to extrarenal.sources of elevated concentration; urea, for example, may be increased in the blood in the absence of any renal disease. Otherwise, nothing is gained by measuring more than one of these substances, and very little useful information is added by determinations of dye excretion or clearances. Intravenous pyelography will rarely be either successful or helpful when simple tests show reduction of renal function; then measurement of residual urine volume in men and stereoscopic roentgenograms of the kidney region (for renal size or stones) are in order. Intravenous pyelograms of the hypertensive patient are made either in the seeming absence of a renal lesion (normal urine) or in the presence of urinary abnormalities without reduced renal function, in an effort to uncover the rare instances of hypertension caused by renal disease amenable to specific treatment; this really means a unilateral abnormality. RENAL DISEASE AND THE TREATMENT OF HYPERTENSION
Enthusiasm aroused by apparent discovery of such a cause must be tempered before advising nephrectomy. Minor deviations from perfectly normal pyelograms are common, and apart from the operative risk it is sometimes harmful to remove a kidney which appears to be functionless;10 even in apparently well selected patients unilateral nephrectomy seems to be successful in curing hypertension in only one case out of ten. 1, 10 Atrophic pyelonephritis, with a small and functionless kidney on intravenous pyelography, is the lesion most frequently found when good results follow nephrectomy. Precise indications for the latter are not yet established. Of two successful cases in this clinic,17 repeated pyelography in one showed unilateral loss of function but the removed kidney appeared almost normal; in the other, a previous renal operation had led to diffuse lesions in a kidney which nevertheless was able to concentrate the contrast medium. Having found a suspicious appearance, intravenous pyelography should be repeated. If the lesion is still present, cystoscopy is necessary not. only for further exploration of the abnormal side but to obtain urine from, and assure the normal function of, the other side. Complete normality of the opposite kidney will not guarantee success on nephrectomy, but abnormalities there cast grave doubt on the advisability of operation. The pre-eclamptic toxemia of pregnancy, when mild, may be controlled by management which stresses rest and sedatives, with a diet
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providing an adequate amount of protein while restnctmg sodium; diuretics are sometimes necessary. Unfortunately, prolonged toxemia is frequently followed by a form of hypertension which apparently is not distinguishable from essential hypertension; this does not so often come after severe toxemia, which is not allowed to be present very l('mg. Since fetal mortality in toxemia is lower when labor is induced a month before term, such interference seems best for both mother and child when toxemia persists in spite of modern management. But for the removal of a fetus from the pregnant uterus or the rare attack on a unilateral renal lesion, the conditions reviewed above are not often subject to specific therapy. Yet the presence of kidney disease alters treatment of the hypertensive patient in various ways. Sulfonamides will frequently be given to patients with urinary tract infections; with impaired renal function more than the usual precautions should be taken. We are not convinced of their reported beneficial action in glomerular nephritis, but the latter does not contraindicate their use when necessary. Those who use thiocyanate in hypertension should avoid it when renal lesions are present. The management of congestive heart failure in hypertension is made more difficult by the presence of true uremia (not including the relatively slight reduction of function in the congested kidney). Mercurial and even other diuretics may then not be used safely, digitalis and related glucosides more likely produce vomiting, and the associated anemia necessitates more thought before phlebotomy. One often desires to replenish the sodium and water stores of the uremic patient who is dehydrated; this must be done cautiously in the presence of hypertension, even when heart failure is not obvious, in order to avoid pulmonary edema. . While dietary reduction of urinary nitrogen excretion is not useful in hypertension without renal involvement, there is every reason to believe it reduces renal work and is therefore indicated when bilateral kidney damage is present18 in an effort to minimize progression of the lesion. Urinary nitrogen is best reduced by a diet which first supplies an adequate number of calories and which daily gives about 0.5 gm. of protein per kilogram of body weight; to the latter must be added an amount of protein equal to its daily loss in the urine. Dietetic details, including the need of vitamin and mineral supplements, must be decided in each individual case. Finally, when section of the splanchnic nerves is contemplated, the presence of a renal lesion requires further consideration. The chances of a successful result are worst in those hypertensive patients who most need help, those with renal damage in the malignant phase of essential hypertension. On the other hand, nerve-cutting operations have succeeded in lowering arterial pressure at least temporarily in patients whose primary trouble was glomerular nephritis; that disease does not
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contraindicate operation, no matter how bad the urine appears, if uremia is absent and hypertension dominates the clinical picture. BIBLIOGRAPHY
1. Goldring, W. and Chasis, M.: The Commonwealth Fund, New York, 1944. 2. Smith, H. W.: J. Mt. Sinai Hosp., 10:59 (May-June) 1943. 3. Bradley, S. E.: New England J. Med., 231:421-426, 452-458 (Sept. 21 and 28) 1944. 4. Krupp, M.: Arch. Int. Med., 71:54-61 ,Jan.) 1943. 5. Cox, A. J., Jr. and Dock, W.: J. Exper. J\led., 74:167-175 (Sept.) 1941. 6. Dock, W. and Rytand, D. A.: Proc. Soc. Exper. Biol. & Med., 36:196-198 (March) 1937. 7. Friedman, M., Selzer, A. and Rosenblum, H.: J. Clin. Investigation, 20:107-111 (March) 1941. 8. Blalock, A. and Levy, S. E.: Ann. Surg., 106:826-847 (Nov.) 1937. 9. Dock, W., Shidler, F. and Moy, B.: Am. Heart J., 23:513-521 (April) 1942. 10. Sensenbach, W.: Arch. Int. Med., 73:123-130 (Feb.) 1944. 11. Castleman, B. and Smithwick, R. H.: J.A.M.A., 121:1256-1261 (April 17) 1943. 12. Wilson, C. and Pickering, G. W.: Clin. Sc., 3:343-355 (Aug.) 1938. 13. Siegal, S. and Allen, A. c.: Am. J. Med. Sc., 201:516-528 (April) 1941. 14. Rytand, D. A.: Stanford M. Bull., 1:203-208 (Nov.) 1943. 15. Addis, T.: J.A.M.A., 85:163-167 (July Hl) 1925. 16. MacKay, E. M. and Rytand, D. A.: Arch. Int. Med., 55:131-140 (Jan.) 1935. 17. Wallace, C. J.: To be published. Stanford M. Bull., 1945. 18. Addis, T.: J. Urol., 41:126-136 (Feb.) 1939.