The Ophthalmologic Aspects of Chronic Renal Disease

THE OPHTHALMOLOGIC ASPECTS OF CHRONIC RENAL DISEASE ROBERT W. HOLLENHORST CHRONIC renal disease may be either a primary affection or it may be secondary to various systemic disorders. The term "primary chronic renal disease" covers chronic glomerulonephritis, pyelonephritis, unilateral atrophic kidney, polycystic kidneys and in some cases perinephritis. In the main only those patients who have elevation of the blood pressure during the natural history of the disease have significant alterations in the retina. Chronic glomerulonephritis most frequently of all the primary renal diseases produces lesions in the retina and in the retinal vessels. Renal involvement may be secondary to diffuse arteriolar disease with hypertension, resulting either in the arteriolosclerotic type of kidney or in malignant nephrosclerosis. Periarteritis nodosa and lupus erythematosus usually involve the kidney at some time in their course. Intercapillary glomerulosclerosis is a frequent complication of far-advanced diabetes. The relationship of chronic renal disease to alterations in the retinal vessels, retina and optic nerves has long been an intriguing problem. The observation of the ocular manifestations furnishes a valuable index for prognosis in most of these diseases. The similarity in structure and caliber of the retinal and renal prearterioles and arterioles, their apparently similar reactions to hypertensive and arteriolosclerotic processes, and the ready visualization of the retinal vessels make the ophthalmoscopic examination of patients who have renal diseases a useful adjunct in evaluation of these affections. The processes which involve the arterioles of the kidney seem to be reflected in the arterioles of the retina more faithfully than in those of any other organs. These relationships have become fairly well recognized, but the explanation of these phenomena is still obscure. Since the first mention of diminution of vision in the final stages of kidney diseases by Richard Bright in 1836, the first report of a microscopic examination of the retina in this disease by Tiirck in 1850, and the first description of the ocular fundi in Bright's disease by Heymann in 1856, a voluminous literature has arisen which describes and attempts to explain the retinal changes accompanying the various phases of hypertensive cardiovasculorenal disease. The extent of this material is far too large for review here. There are several excellent accounts of the historical development of present-day concepts of the signifi1023

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cance of retinal vascular lesions, particularly those by Greear and Wagener.;14 Certain criteria are known by whieh it often is possible to differentiate the retinal changes accompanying chronic primary renal disease from those that occur when involvement of the kidney is secondary to other diseases. However, in many cases differentiation is not possible. These relationships will be discHssed in further detail. ETIOLOGIC FACTORS OF THE RETINAL LESIONS

The local mechanisms responsible for the lesions observed in the retina in the course of chronic renal disease have not yet been definitely determined. Some of the factors in chronic renal disease which bring about these lesions and other systemic disturbances are reasonably well established; others still are obscure. Secondary Hypertension. The onset of secondary hypertension in chronic renal disease, especially in chronic glomerulonephritis, is contantly associated with narrowing of the retinal arterioles and, if the hypertension is severe, with the more severe degrees of retinopathy. There appear to be two types of secondary hypertension: Cl) chronic hypertension of low grade which may exist during periods of remission in the renal disease, or in the less severe exacerbations, and (2) acute angiospastic hypertension. The first type is not accompanied by re'inal and diffuse arterioloselerosis and probably is a reflex hypertension brought about through renal anoxia and designed to maintain a higher head of pressure in the afferent renal arterioles. With this form of hypertension retinallesiom; usually are not visible but mild narrowing of the al'terioles may be present. Acute angiospastic hypertension probably results from severe renal ischemia. This form of hypertension usually produces marked retinal arteriolar constriction of both the generalized and the focal types, and there is often retinopathy or neuJ'oretinopathy as a manifestation of decompensation of the retinal circulation. Arteriolosclerosis is absent. Increased Pressure of Cerebrospinal Fluid. This occurs in some patients who have chronic renal disease, and it probably occasionally accounts for the development of papilledema. However, a considerable number of patients who have neuroretinopathy do not have increased intracranial pressure, and consequently their papilledema must be ascribed to one of the other factors. Increased Capillary Fragility or Permeability. This may be concerned in the production of the retinal lesions. Although hypertension is most commonly present whenever retinopathy develops, hemorrh ages and white patches may be present in the retina in certain eases of renal disease when hypertension is absent. Presumably, such lesions

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can be due to an increase in the capillary fragility or permeability brought about by involvement of either the arteriolar side of the vascular circulation or of the venom; 8ide, or both. Such damage to the arteriolar walls may result from anoxia produced either by anemia or by certain a8 yet undetermined toxic faetors. The capillary fragility or permeability may be increased by venous sta8is that may be followed by venous varicosities, formation of aneurysms and va8cular proliferation. As a consequence, serum proteins, cellular constituents and other components of the blood may leak through the damaged capillary walls. This would produce ophthalmoscopically visible hemorrhages and heavy white deposits in the retinal tissues. The cottonwool patches seen in relatively avascular areas of the retina are probably ischemic infarcts. Presumably, papilledema as well may be produced by local vascular changes of this nature. Edema. Edema of the retinal tissues has been thought by some authors to be a part of the generalized edema of the bodily tissues which occurs in nephrosis and in the nephrotic phase of nephritis. This is probably the source of the peripapillary retinal edema which is seen occasionally in these conditions. However, that generalized edema is not a major factor in the production of the retinopathy of chronic renal disease is shown by the relatively rare occurrence of even mild retinopathy in eases of severe nephrosi8, whereas the highest incidence of severe retinopathy is found in cases of chronic renal disease without generalized edema. Primary Hypertension. Finally, primary hyperten8ion i8 a factor of not inconsiderable importance in the production of the retinal changes found in chronic renal disease. Renal arterioloselerosis is considered by some authors to be the cause of essential hypertension. More probably both it and retinal arterioloselerosis are secondary and more or less parallel manifestations of primary hypertension. Because of the high incidence of diffuse arteriolar disease with hypertension in the general population, it is inevitable that a considerable proportion of patients who have chronic renal disease also have concomitant primary hypertension. This is a factor which mU8t be considered in the interpretation of the retinal findings in chronic renal disease, since patients who have retinal arterioloselerosis probably have primary hypertension accompanying their renal disease. Certain patients may have slight elevation of the blood pressure with~ut systemic symptoms for many years but it usually is accompanied by the gradual development of retinal, renal and generalized arterioloselerosis. Thus the arterioloselerotic kidney with impairment of renal function is produced. In the retina may be seen moderate generalized narrowing of the arterioles and moderate to marked

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arteriolosclerosis. Some of the retinal arterioles may be completely occluded and there are occasionally acute arteriolar closure, and often thrombosis of the venous branches with resultant severe retinal hemorrhage. Punctate white deposits may occasionally be found in the deeper retinal layers residual to the edema accompanying such venous occlusions. This is the so-called chronic non progressive or benign hypertension. In contrast to this form of primary hypertension may be noted the changes of the chronic progressive type of hypertension. The levels of blood pressure usually are higher and often systemic symptoms appear fairly early in the course of the disease. In the retina may he seen generalized and focal narrowing of the arterioles as well as a mild, or moderate degree of arteriolosclerosis. In periods of exacerbation of the hypertensive disease, retinopathy may develop; the arterioles hecome more narrow and the focal constrictions more intense, while soft fluffy superficial patches (cotton-wool patches), hemorrhages in all layers of the retina and varying degrees of edema of the retina make their appearance. Later, tiny shiny punctate groups of "edema residues" may be seen in the areas of edema, sometimes forming a partial or complete macular star. This is the retinopathy of hypertension group 3 (Keith-Wagener classification)19 and is usually accompanied by minor functional changes in the heart and kidneys, the latter manifested by albuminuria and cylindruria. Hypertension, group 4 (malignant hypertension, malignant nephrosclerosis) produces more marked retinal changes including edema of the optic disks; also there may be obvious dysfunction of the heart, kidneys or central nervous system. Nearly always there is some subretinal edema which occasionally may be sufficient to cause detachment of the retina. As will be shown later, these changes are different from those seen when hypertension is unquestionably secondary to chronic renal disease, since the arteriolar changes of primary hypertension are basically chronic in nature with considerable arteriolosclerosis as a rule being present on which acute spastic lesions may be superimposed. On the other hand, the arteriolar lesions associated with hypertension that is secondary to chronic renal disease are more acute in nature, and are basically angiospastic. Retinal arteriolosclerosis is absent, or if present it is of only minimal degree. Comment. It is noteworthy that the one feature which is common to all chronic diseases of the kidneys, that is, renal insufficiency 'with retention of urea, according to present concepts is not responsible for any of the retinal manifestations of these diseases. Volhard emphasized this point in 1929, when he introduced the term "angiospastic retinitis" and stated that the retinal lesions were not due to

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azotemia, but rather were ischemic consequences of spastic arteriolar phenomena. PATHOLOGIC FEATURES OF RETINAL LESIONS

The lesions which occur in the retina as the result of primary hypertension, chronic renal disease and other systemic conditions producing either hypertensive or toxic retinal manifestations are superficially similar in ophthalmoscopic and histologic appearance, although there are important differences. In general, the retinal lesions which have been termed "hypertensive retinopathy," consist of cotton-wool patches, hemorrhages, edema of the retina and edema residues. As a rule, hemorrhages alone are not considered to be retinopathy.35 If papilledema is associated with retinopathy, the resultant ophthalmoscopically visible picture is termed "hypertensive neuroretinopathy." The cotton-wool patches are the fluffy white patches of focal necrosis situated in the nerve fiber layer of the retina, seen on histologic examination to be composed of edematous degenerated cells, probably glial cells, the socalled cytoid bodies. 9 These are thought to be ischemic, anoxic or toxic in origin. The hemorrhages may be situated in any of the retinal layers. They are usually flame shaped but may be round and of petechial type. Edema of the retina has been discussed. Partial absorption of the aqueous portion leaves the tiny punctate bright shining deposits of albumin, lipoid and hyaline substances in the deeper layers of the retina. These are particularly well seen ophthalmoscopically when they are arranged radially in Henle's fiber layer in the macula to form the so-called macular star. Microscopically, the hyaline-lipoid deposits are seen to be invaded by phagocytic cells. Edema of the optic disks is usually of low degree, ordinarily of less than 2 to 3 diopters, and it gradually shades off into the edematous retina. Histologically, sclerosis of the choroidal arteries and subretinal edema are always found in the more severe degrees of hypertensive retinopathy and not infrequently these changes are visible ophthalmoscopically. Small transparent globules of edema, i disk diameter or less in size, may be seen, and occasionally these globules may be observed to coalesce and cause exudative detachment of the retina. These lesions probably are due to anoxic damage to the capillary walls either by spastic or toxic phenomena. They often leave residual yellowish-white depigmented patches with an adjacent dot of pigment (Elschnig's spots). Epichoroidal deposits of pigment (Siegrist's spots) along the course of sclerosed choroidal arteries probably result from previous angiospasm and edema.

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OPHTHALMOSCOPICALLY VISIBLE RETINAL MANIFESTATIONS OF RENAL DISEASE

The retinal arterioles are not involved in renal disease unless the diastolic blood pressure becomes elevated, and, as has been noted, retinal lesions only rarely appear in the absence of hypertension. Consequently, in primary renal disease, ophthalmoscopy may reveal no abnormalities in the arterioles until late in the course and often only in the terminal phases. On the other hand, in essential hypertension, the retinal arterioles show mild involvement throughout the course of the disease, and generalized arteriolar narrowing and arteriolosclerosis are already present in some degree by the time the elevation of blood pressure is first discovered. Nevertheless, in some cases of advanced renal disease with chronic hypertension it is not possible by means of ophthalmoscopic examination to establish the primary cause of the disease, whether it is e,;sential hyperten,;ion with secondary renal involvement or primary renal disease with secondary hypertension. The hypertension of relatively few patients can be definitely proved to be on a renal basis according to most authorities. With the exception of patients who have acute or chronic glomerulonephritis, this is even true of patients who have demon,;trable renal lesions. Furthermore, as Wagener33 pointed out, there is no certainty that the angiospastic episodes are directly attributable to the renal lesion. The incidence of hypertension in renal disease for the most part appear,; to be no higher than the incidence of hypertension in the general population. 16 Smith stated, "there is no good evidence for a higher incidence of hypertension in patients with any conditions except glomerulonephritis, and possibly pyelonephritis and pyonephritic atrophy." Glomerulonephritis. Involvement of the retina is rather commonly seen in this renal affection. Thi,; is particularly true of chronic glomerulonephritis, occasionally of the subacute variety, but only rarely of acute glomerulonephritis. Acute Glomerulonephritis. Occasionally in the first few days of the affection a few flame-shaped hemorrhages and mild retinal edema may be seen on ophthalmoscopic examination, but these manifestations usually do not persist. Such lesions may be the result of increased capillary permeability, toxic or angiospastic ischemia, or the "expansion of the extracellular water" in the body as described by Seegal. Several reports in the literature describe the retinal involvement in cases of acute glomerulonephritis. Fishberg and Oppenheimer found the blood pressure elevated in 21 of 27 cases. There were severe retinallesions in only 2 of these cases, in both of which papilledema was present. Sixteen of the 27 patients had normal retinas. The descrip-

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tions of the remaining 9 cases were difficult to interpret. Gresser reported 31 cases of acute glomerulonephritis, in 4 of which the chronic phase later developed. One patient had a few retinal hemorrhages and small plaques of exudate, and another had several retinal hemorrhages; these were probably of toxic origin. Gresser stated that 22.5 per cent of his patients had retinal or papillary edema, which is rather difficult to reconcile with the rest of his report, since no other ocular changes were mentioned in the eyes of these patients. Brod recently reported 62 cases of acute glomerulonephritis. He found retinal changes in 7 (11.3 per cent), hemorrhages in only 2 of the 7 and edema of the optic disks in 3. The retinas of these 5 patients returned to normal while under observation. Two patients who had hypertensive neuroretinopathy still had retinopathy several months later. The blood pressure of all 7 was elevated considerably but returned to normal while the patient was still under observation. These studies are difficult to interpret, but they seem to indicate that the incidence of retinal involvement is somewhat less than 15 per cent and that hypertension is usually present when retinopathy occurs. If the retinopathy does not subside rapidly, the glomerulonephritis is probably passing into the chronic phase. Chronic Glomerulonephritis. In order to understand the appearance of the retina and the retinal vessels in chronic glomerulonephritis, the general nature of this disease must be taken into consideration. Its cause is not known. but there is seemingly a toxic disturbance of the arterioles and capillaries in which the permeability of their walls is increased. 81l It may develop after previous acute nephritis, or the onset may be insidious without early signs other than albumin and cells in the urine. The three important clinical manifestations of the syndrome are renal insufficiency, dropsy and hypertension. Any of these, as stated by Pruitt, may be present alone or in any combination, but the most common is the hypertension. Anemia frequently d.:velops fairly early in the disease, sometimes becoming severe. The retinal changes, therefore, may stem from three main sources: (1) toxicity, (2) anemia and (3) hypertension. The leaf->t common retinal lesion which is found in association with chronic glomerulonephritis is that characterized by slight edema of the retina and occasionally by edema of the margins of the optic disks; thi~ lesion usually is accompanied by a few flame-shaped hemorrhages and one or several superficial fluffy white cotton-wool patches. Rarely in this type of retinopathy may be seen small globular areas of choroidal edema. This is the so-called toxic retinopathy which is seen in many septic conditions and especially in the group of diseases collectively termed the "diffuse collagen diseases."17 Similarly, in anemic

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retinopathy there may be mild edema of the retina and of the margins of the optic disks; but in this type of retinopathy the number of larger fluffy white superficial patches in the retina may be greater and there are relatively few hemorrhages. The few that are present often have white centers. In this type of retinopathy the optic disks and the retina are very pale because of the systemic anemia. According to Wagener34 the concentration of hemoglobin is usually less than 40 per cent of normal if anemic retinopathy is present. In uncomplicated cases of these forms of retinopathy the arterioles are normal or slightly dilated. The third type of retinopathy encountered in chronic glomerulonephritis is that which has been termed the "retinopathy of nephritis," or when the optic disks are involved "neuroretinopathy." This type of retinopathy is considerably more common and characteristically is probably a combination of toxic and anemic retinopathy with acute hypertensive retinopathy. The retina and the optic disks are nearly always anemic, sometimes to such a degree as to render difficult the ophthalmoscopic identification of the retinal vessels. The optic disks are pale even in the presence of papilledema in contrast to the hyperemic optic disks associated with malignant hypertension or the choked disks accompanying increased intracranial pressure. Usually no signs of venous congestion are noted. The caliber of the arterioles is extremely attenuated, at times so markedly that they narrow to invisibility a millimeter or two from the optic disks. When the arteriolar narrowing is not so extreme, intense focal constrictions are visible. In the typical case no retinal arteriolosclerosis is present in the early stages. However, if the arteriolospasm has persisted for some weeks, there may be a degree of focal postspastic arteriolosclerosis. The typical retinopathy of glomerulonephritis differs from that of malignant hypertension in that in the former (1) there is usually relatively little retinal hemorrhage; (2) only a small number of superficial fluffy white cotton-wool patches are present, and these usually are larger in size than those associated with primary hypertension; (3) there is anemic pallor of the disks and retina, and (4) there is often massive edema of the posterior pole of the eye involving the optic papilla, macula and the surrounding retinal tissues. If the edema has been present for several weeks, it is possible to find the tiny punctate bright spots which have been called "edema residues." These may become very prominent in the retina as further edema absorbs, so that the former edematous area may show extensive deposits of these albuminous materials, with the formation of a star-shaped figure in the macular area and a snowbank appearance around the optic disks. Such extensive edema is rare in malignant hypertension. Occasionally, patches of choroidal edema may be

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visible, and rarely, when such patches of subretinal edema coalesce, detachment of the retina may occur. The toxic and anemic factors in the retinopathy are probably represented by the cotton-wool patches and by the small flame-shaped or round hemorrhages with white centers, which often are present. The association of acute angiospastic retinopathy with anemic retinopathy gives the characteristic retinal picture of chronic glomerulonephritis. The retinal picture of advanced malignant hypertension cannot be distinguished from that which appears in some cases of advanced chronic glomerulonephritis in which the blood pressure has been elevated for a long time. This possibly is due to the development of complicating diffuse arteriolar disease and consequent moderately severe retinal arteriolosclerosis, associated with only mild anemia in the case of advanced chronic glomerulonephritis. Both conditions may produce the same retinal picture if the patients survive sufficiently long. In severe degrees of macular edema, visual acuity is always impaired owing to the presence of a relative central scotoma. This impairment of visual acuity occasionally is the presenting complaint, just as it is at times that of patients who have malignant hypertension. The vision is only rarely impaired to the level of ability to count fingers only, as the patients usually are able to read large print. The degree of visual loss such as described by Bright, "his vision indistinct; his hearing depraved; he is suddenly seized with a convulsive fit, and becomes blind," probably rarely occurs because of involvement of the retina. Such a severe degree of visual loss probably results from cerebral edema, specifically of the occipital lobes, which may be responsible for transient homonymous hemianopsia or more often for complete amaurosis. The incidence of retinal lesions in chronic glomerulonephritis has been the subject of several excellent reports in the literature. Probably the most easily studied are the reports of 56 cases analyzed by Graham and reviewed by Wagener. 32 All these patients died of chronic glomerulonephritis and the diagnosis was verified at necropsy. All but 4 patients had elevated blood pressure. Including these 4 patients, a total of 10 (17.8 per cent) had normal ocular fundi until death. Seven had a few hemorrhages in the retina; and one of these also had several cotton-wool patches, which were considered to be on an anemic basis. Thirty-nine had acute angiospastic retinopathy, in 3 of whom the retinopathy disappeared before death. Thirty-one of the 39 (79.5 per cent) had no chronic retinal arteriolosclerosis, whereas 8 had sclerosis of the retinal arterioles. The condition of the retina of 1 of these 8 simulated the retinopathy of hypertension, group 3,

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and that of 7 simulated the neuroretinopathy of hypertension, group 4.1 9 Two of the 31 patients who had acute angiospastic retinopathy without arteriolosclerosis also had ophthalmoscopically visible lesions of the choroidal arteries. Those patients who had retinal arteriolosclerosis also had marked arteriolosclerosis in the kidneys and other organs demonstrated at necropsy. Graham and Wagener observed a second series of patients for whom the clinical diagnosis of chronic glomerulonephritis was made and who did not die during the period of observation. Of these patients 34 per cent had normal fundi, 8 per cent had hemorrhages of the anemic type and only 18 per cent had acute angiospastic retinopathy without chronic retinal arteriolosclerosis. In 8 percent of the cases, retinopathy simulating diffufOe arteriolar disease with hypertension was present, while in 32 per cent of the series definite arteriolosclerosis with,mt retinopathy was observed. The discrepancies in percentages between these two series led the authors to two conclusions: 1. Some of the second series may have actually had diffuse arteriolar disease instead of chronic glomerulonephritis; this condition would account for the higher incidence of arteriolosclerosis in this series. 2. The lower incidence of retinopathy in the second series probably indicates that acute angiospastic retinopathy in chronic glomerulonephritis is a terminal event. In the main, this is true, but in a few cases, recession of the retinopathy does occur along with improvement in the general condition of the patient. In toxemia of pregnancy due to chronic glomerulonephritis, retinopathy is likely to develop much earlier in the course of the pregnancy than it does in the usual hypertensive toxemia of pregnancy. The retinopathy is of the acute hypertensive type and is not in itself pathognomonic of nephritis. Since the usual hypertensive toxemia of pregnancy does not fall within the scope of this paper, the retinal changes in this condition will not be described in detail. These lesions are usually of the acute hypertensive type, the first to appear being generalized and focal constrictions of the arterioles. The development of retinopathy is rare under modern methods of treatment. These patients, however, may develop chronic vasculorenal disease in later years. According to Herrick and Tillman 30 per cent of patients who had hypertensive toxemias of pregnancy had elevation of blood pressure at the end of the first year after delivery and 50 per cent at the end of the third year. In Peckham and Stout's series 50 per cent showed chronic vascular or renal disease five years after toxemia of pregnancy, whereas 35 per rcnt of Stander's group had such involvement. The chronic hypertension developing in the majority of these

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patients after the hypertensive toxemia of pregnancy appears to be of the type associated with diffuse arteriolar disease, and chronic retinal arteriolosclerosis is the usual ophthalmoscopic finding. Nephrosis. Since genuine nephrosis, the nephrotic type of glomerulonephritis, and amyloid nephrosis ordinarily are not associated with hypertensive levels of blood pressure, involvement of the retina or of the retinal vascular tree is uncommon. In some cases there may be slight edema of the retina, espec;ally in the peripapillary region. Sometimes macular edema causes diminution of visual acuity. This may improve if the patient is placed in an upright position. Wagener32 mentioned mild transient lipemia retinal is in which the retinal vessels have a creamy hue. Rarely, sub retinal edema may cause detachment of the retina, which to some extent is positional. Nephrotic edema often involves the skin of the eyelids, and is so severe at times that the examiner cannot expose the eyes for examination. Usually there is associated a marked pale chemosis of the conjunctiva, which sometimes is sufficiently severe to cover the corneas. Pyelonephritis. According to Braun-Menendez, patients who have pyelonephritis have a higher incid~nce of hypertension than the general population as determined by control statistics. This is apparently especially true of the patients in the healing phase, since it is during the stage of renal scarring that the blood pressure may rise. Pyelonephritis accompanied by hypertension ordinarily is not distinguishable ophthalmoscopically from essential hypertension, since chronic retinal arteriolosclerosis may be present in both. In some cases of pyelonephritis the retinopathy present may simulate that of either chronic glomerulonephritis or malignant hypertension. According to Braasch and Jacobson, the blood pressure is usually less than 180 mm. of mercury systolic. Wagener 32 stated that if the pyelonephritis is severe, occasional small hemorrhages or a cotton-wool patch may be observed in the retina as a toxic manifestation in the absence of hypertension. In an occasional case of pyelonephritis, a unilateral atrophic kidney may develop. Unilateral Atrophic Kidney. Barker reported 51 cases, mostly collected from the literature, in which unilateral atrophic kidneys were removed in an attempt to treat the hypertension; in 41 per cent the blood pressure became normal or nearly normal, and in another 15 per cent the blood pressure was reduced significantly. The ophthalmoscopic. findings in these cases were said to differ in no respect from those in cases of essential hypertension, and both good and poor results were obtained from nephrectomy in the groups of cases in which hypertensive retinopathy was present and those in which it was absent. However, as exemplified by the case of Kennedy and co-

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workers, those patients who have a pure acute hypertensive retinopathy and are operated on before complications develop may have excellent results. When chronic retinal arteriolosclerosis is present, the operative results are usually poor. Polycystic Kidneys. In this condition hypertension occurs slightly more frequently than in the general population. RaIl and Odel have recently reported data on 207 patients who had congenital polycystic disease of the kidneys; 146 (73 per cent) of these had hypertension. Ocular examination was carried out on 105 of the total group. The retinal findings were not remarkably different from those of patients suffering from essential hypertension. Of the 13 who had normal blood pressure, 9 had normal ocular fundi, whereas 4 had retinal arteriolosclerosis and arteriolar narrowing. Of the 92 who had hypertension and were examined ophthalmoscopically, 21 (22.8 per cent) had normal fundi, 67 (72.8 per cent) had arteriolar changes only, 1 patient had hypertensive retinopathy and normal blood urea, another had hypertensive retinopathy with elevation of the blood urea, and 2 patients had hypertensive neuroretinopathy associated with elevated blood urea. Perinephritis. In spite of the successful experimental production of hypertension in animals by wrapping the kidneys with cellophane, clinically there is no good evidence that perinephritis can produce hypertension. 3 Consequently, no change in the retinas would be anticipated unless essential hypertension occurs concomitantly. Intercapillary Glomerulosclerosis. This syndrome, attended by varying degrees of albuminuria, nephrotic edema, hypertension and renal insufficiency, occurs occasionally in a case of diabetes as described by Kimmelstiel and Wilson in 1936, and produces characteristic hyaline-like masses between the capillaries of the glomerular tuft. It is often accompanied by changes in the retina. In an excellent paper by Henderson, Sprague and Wagener, the relationship of this condition to the retina is reviewed. These authors pointed out that the typical lesions in the kidney are not specific for diabetes, since they occur also in association with glomerulonephritis and amyloidosis. The most severe lesions, however, were found in diabetic patients. It was found that in 32 of 111 cases of diabetes which came to necropsy, intercapillary glomerulosclerosis was present and in 79 it was not. Retinopathy was present in only 22.8 per cent of cases without intercapillary glomerulosclerosis. Retinopathy was present in 68.8 per cent of patients with this complication (22 cases). Among the patients who had advanced renal lesions, 86 per cent had retinopathy, whereas only 53 per cent of those who had early renal changes had retinopathy. Typical diabetic retinopathy was present

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in most cases in which retinopathy was present. Purely hypertensive retinopathy was present in only 1 case, while diabetic retinopathy was present in 21 cases. Henderson, Sprague and Wagener stated: "In many of the latter cases there were changes in the fundi attributable to both diabetes and hypertension; namely, the punctate hem orrhage and waxy exudates characteristic of diabetic retinopathy, and the superficial hemorrhages, cotton-wool patches, arteriolosclerosis and spastic narrowing of the retinal arterioles characteristic of hypertensive retinopathy." Also "the predominant cause of the retinal changes observed in intercapillary glomerulosclerosis is diabetes rather than renal disease or hypertension." At necropsy, all diabetics who had had diabetic retinopathy with venous disease and proliferative changes were found to have intercapillary glomerulosclerosis. Also, 8 of 9 patients in whose retinas hemorrhages, punctate white dots and cotton-wool patches were noted had intercapillary glomerulosclerosis. The incidence of this renal complication among patients who had less severe retinopathy was much lower. Thus, patients who had the higher and severer degrees of retinopathy more regularly had intercapillary glomerulosclerosis. The presence of intercapillary glomerulosclerosis can be postulated clinically with a fairly high degree of certainty in cases in which severer types of diabetic retinopathy are observed with extensive punctate hemorrhages, large amounts of waxy deposits, and venous dilatation and aneurysmal irregularity with vascular and connective tissue proliferation. It is even more certain to be present in those patients who, in addition, have the superimposed changes of severe hypertensive disease: arteriolar spasm, arteriolosclerosis, cotton-wool patches, and, occasionally, papilledema. Periarteritis Nodosa and Disseminated Lupus Erythematosus. Involvement of the kidneys as well as involvement of the ocular structures is not uncommon, probably because these diseases involve primarily the collagen tissues and predominantly the vascular structures. In each of these diseases there may be direct involvement of the vascular structures of the eye and orbital tissues, although ocular lesions are considerably more varied in periarteritis nodosa. Often seen in the retina of these patients is a toxic retinopathy indistinguishable from that found in some cases of acute or chronic glomerul.onephritis, and pyelonephritis. However, if the kidneys are involved by periarteritis nodosa26 or disseminated lupus erythematosus and marked elevation of the blood pressure ensues, the retinal changes characteristic of acute hypertensive retinopathy and neuroretinopathy may develop; these are accompanied rather often in periarteritis nodosa by detachment of the retina. In some instances,

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periarteritis nodosa may be superimposed on glomerulonephritis or on primary hypertensive disease, in which event the retinal picture may be either that of chronic glomerulonephritis or malignant hypertension. PROGNOSTIC SIGNIFICANCE OF OPHTHALMOSCOPIC FINDINGS

The onset of retinopathy has long been recognized as bearing a significant rdationship to the prognosis of most of these diseases. The data on the mean survival time of large groups of patients in several of these conditions following the development of retinopathy have been well worked out. However, the range of survival time in individual patients is rather wide. Several authors have computed the survival curves for their patients who had chronic glomerulonephritis. Graham found that after the onset of retinopathy the mean life expectancy was 4.3 months as compared to thirteen months after its onset in malignant hypertension or nephrosclerosis. Cannady and O'Hare found that no patient in their series survived more than twenty-three months after retinopathy developed, while the average was 6.3 months. In a series of 49 cases of chronic glomerulonephritis followed by Horn, Klemperer and Steinberg, neuroretinopathy was regularly found associated with the severer degrees of vasculorenal lesions. In their group of cases of "slowly progressive" lesions, neuroretinopathy was not found although retinopathy and papilledema were encountered in 62 per cent of the group of "transitional accderated" lesions and in 96 per cent of the group of "advanced accelerated" lesions. Nevertheless, an occasional patient will be found who has experienced an acute angiospastic attack in chronic glomerulonephritis, but whose retinopathy has improved or gradually disappeared as the blood pressure had diminished. Some of these patients may remain fairly well for a considerable time, while others, as shown by Graham, may die even during the time the retinopathy is improving. Patients in whom the retinopathy is associated with severe retinal arteriolosclerosis seem to have a longer life expectancy than do those who have minimal or no arteriolosclerosis. In a series of cases of hypertension secondary to unilateral renal disease Barker found that good results followed removal of the affected kidney in some instances in spite of the presence of retinopathy or neuroretinopathy. The superimposition of hypertensive retinopathy on the retinopathy of diabetes indicates in a high percentage of cases that renal involvement has occurred and usually that renal insufficiency is also present. There are no survival curves in the literature on intercapillary glomerulosclerosis. Mixed hypertensive and diabetic retinopathy

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or proliferative retinopathy are of relatively serious significance when compared with uncomplicated central punctate retinopathy. However, the development of such a retinopathy is not nearly so terminal an event as is the development of neuroretinopathy in either malignant nephrosclerosis or chronic glomerulonephritis; consequently the prognosis is better. In the series reported by Henderson and associates, the patients who had intercapillary glomerulosclerosis on the basis of chronic glomerulonephritis lived only from one to four months. Those who had intercapillary glomerulosclerosis associated with diabetes lived for months to years after onset of the syndrome. The onset of angiospastic retinopathy in disseminated lupus erythematosus and periarteritis nodosa is a serious sign. It is usually a terminal event, indicative of severe hypertension associated with involvement of the arterioles of the kidney. SUMMARY AND CONCLUSIONS

The most characteristic retinal picture of chronic renal disease is angiospasm and acute hypertensive retinopathy or neuroretinopathy with anemia. These appear only when the peripheral diastolic blood pressure is elevated to a pathologic degree, and then the retinal changes are approximately proportionate in degree to the height of the blood pressure. The retinal changes are independent of the existence of azotemia. The retinopathy of chronic renal disease in many cases may be distinguished from that of malignant hypertension by the presence of anemia, and the absence of or minimal degree of retinal arteriolosclerosis. In the retinopathy of chronic renal disease, marked edema of the retina is strikingly seen, while this is less evident in malignant hypertension. In chronic renal disease, toxic or anemic retinopathy may be present alone or combined with acute angiospastic retinopathy. Toxic retinopathy may be seen in acute, subacute and chronic glomerulonephritis, periarteritis nodosa, and disseminated lupus erythematosus, even in the absence of hypertension. Periodic examination of the retinal arterioles is of importance in the observation of these patients, since the presence of considerable angiospasm gives an indication of the imminent onset of retinopathy and cqnsequent entry into a severe phase of the disease. The mean life expectancy in chronic glomerulonephritis in which retin.opathy is present is about four to six months as compared to about thirteen months in malignant hypertension, although individual patients who have the former have survived as long as twenty-three months, and those who had the latter up to twelve years.

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Acute hypertensive retinopathy occurring in chronic glomerulonephritis, periarteritis nodosa and disseminated lupus erythematosus is evidence of entry into the terminal phases of these diseases and indicates involvement of the renal arterioles. REFERENCES 1. Barker, N. W.: Hypertension and Unilateral Renal Disease. Nebraska M. J. 34:9-11 (Jan.) 1949. 2. Braasch, W. F. and Jacobson, C. E.: Chronic Bilateral Pyelonephritis and Hypertension. J. Uro!. 44:571-579 (Nov.) 1940. 3. Braasch, W. F. and Wood, W. W., Jr.: Clinical Perinephritis and Its Effect on Blood Pressure. J. Uro!. 48:343-349 (Oct.) 1942. 4. Braun-Menendez, Eduardo and others: Renal Hypertension. (Translated by Lewis Dexter.) Springfield, Illinois, Charles C Thomas, 1946, 451 pp. 5. Bright: Cases and Observations, Illustrative of Renal Disease Accompanied With the Secretion of Albuminous Urine. Guy's Hosp. Rep. 1:338400,1836. 6. Brod, Jan: Acute Diffuse Glomerulonephritis. Am. J. Med. 7:317-335 (Sept.) 1949. 7. Cannady, E. W. and o 'Hare , J. P.: A Critical Survey of the Retinal Lesions in Chronic Glomerular Nephritis. J.A.M.A. 103:6-10 (July 7) 1934. 8. Fishberg, A. M. and Oppenheimer, B. S.: The Differentiation and Significance of Certain Ophthalmoscopic Pictures in Hypertensive Diseases. Arch. Int. Med. 46:901-920 (Dec.) 1930. 9. Friedenwald, J. S.: Disease Processes Versus Disease Pictures in Interpretation of Retinal Vascular Lesions. Arch. Ophth. 37:403-427 (Apr.) 1947. 10. Graham, R. W.: Ophthalmoscopically Visible Retinal Lesions in Chronic Glomerulonephritis. Occurrence and Characteristics. Arch. Ophth. n. s. 26:435-465 (Sept.) 1941. 11. Greear, J. N., Jr.: The Eye in Hypertensive Cardiovascular Disease: a Comparative Ophthalmoscopic and Pathologic Study. Tr. Am. Ophth. Soc. 38:397-469, 1940. 12. Gresser, E. B.: Studies of Retinopathies. Il. Essential Hypertension. Ill. Diffuse Glomerular Nephritis. Correlation of Retinal States With Blood-pressure, Renal Functional Status, Etc. Am. J. Ophth. 18:426431 (May) 1935. 13. Henderson, L. L., Sprague, n. G. and Wagener, H. P.: Intercapillary Glomerulosclerosis. Am. J. Med. 3:131-144 (Aug.) 1947. 14. Herrick, W. W. and Tillman, A. J. B. with the Collaboration of Lucile Grebenc: The Mild Toxemias of Late Pregnancy; Their Relation to Cardiovascular and Renal Disease. Am. J. Obst. & Gynec. 31:832844 (May) 1936. 15. Heymann: Ueber Amaurose bei Brightischer Krankheit, und Fettdegeneration der Netzhaut. Arch. f. Ophth. 2:137-150, 1856. 16. Hines, E. A., Jr. and Lander, H. H.: Factors Contributing to the Development of Hypertension in Patients Suffering From Renal Disease. J.A.M.A. 116:1050-1052 (Mar. 15) 1941.

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17. Hollenhorst, R. W. and Henderson, J. W.: The Ocular Manifestations of the Diffuse Collagen Diseases. Am. J. M. Sc. 221:211-222 (Feb.) 1951. 18. Horn, Henry, Klemperer, Paul, and Steinberg, M. F.: Vascular Phase of Chronic Diffuse Glomerulonephritis. Arch. Int. Med. 70:260-283 (Aug.) 1942. 19. Keith, N. M., Wagener, H. P. and Barker, N. W.: Some Different Types of Essential Hypertension: Their Course and Prognosis. Am. J. M. Sc. 197:332-343 (Mar.) 1939. 20. Kenlledy, R. L. J., Barker, N. W. and WaIters, Waltman: Malignant Hypertension in a Child; Cure Following Nephrectomy. Am. J. Dis. Child. 61 :128-134 (Jan.) 1941. 21. Kimmelstiel, P. and Wilson, C.: Intercapillary Lesions in Glomeruli of Kidney. Am. J. Path. 12:83-98 (Jan.) 1936. 22. Peckham, C. H. and Stout, M. L.: Low Reserve Kidney. Am. J. Surg. 31 :92-97 (Jan.) 1936. 23. Pruitt, R. D.: Bright's Disease: Clinical Manifestations in Relation to Etiology and Prognosis. New England J. Med. 235:674-677 (Nov. 7) 1946. 24. RaIl, J. E. and Odel, H. M.: Congenital Polycystic Disease of the Kidney: Review of the Literature, and Data on 207 Cases. Am. J. M. Sc. 218:399407 (Oct.) 1949. 25. Ralston, D. E. and Kvale, W. F.: The Renal Lesions of Periarteritis Nodosa. Proc. Staff Meet., Mayo Clin. 24:18-27 (Jan. 19) 1949. 26. Scegal, Beatrice: Acute Diffuse Glomerulonephritis. Am. J. Med. 7:386389 (Sept.) 1949. 27. Smith, H. W.: Hypertension and Urologic Disease. Am. J. Med. 4:724-743 (May) 1948. 28. Stander, H. J.: Quoted by Norton, J. F. and ConneIl, J. N.: Management of Toxemias of Pregnancy. New Jersey M. J. 33:500 (Sept.) 1936. 29. Tiirck: Quoted by Graefe, A. and Saemisch, Th.: Handbuch del' gesamten Augenheilkunde. Berlin, Julius Springer, 1918, vol. 15, pt. 2, p. 208. 30. Vancura, A.: Neuroretinitis albuminurica u chronickych nefritid. Albuminuric neuroretinitis in chronic nephritis. (Abstr.) Excerpta Medica (Section 12, Ophthalmology) 2:441, 1948. 31. Volhard: Die Pathogenese del' Retinitis Albuminurica. Zentralbl. f. d. ges. Ophth. 21 :129-136, 1929. 32. Wagener, H. P.: Retinal Lesions in Nephritis and Hypertension. In Berglund, Hilding, Medis, Grace, Huber, G. C., Longcope, W. T. and Richards, A. N.: The Kidney in Health and Disease. Philadelphia, Lea & Febiger, 1935, pp. 622-637. 33. Wagener, H. P.: The Clinical Interpretation of Retinal Vascular Lesions in Hypertension and Nephritis. Pennsylvania M. J. 40:705--711 (June) 1937. 34. Wagener, H. P.: Retinopathy in Glomerulonephritis. Am. J. M. Sc. 209:257-267 (Feb.) 1945. 35. Wagener, H. P., Clay, G. E. and Gipner, J. F.: Classification of Retinal Lesions in the Presence of Vascular Hypertension. Report Submitted to the American Ophthalmological Society by the Committee on Classification of Hypertensive Disease of the Retina. Tr. Am. Ophth. Soc. 45:57-73, 1947.