Diastolic hypertension and chronic proteinuria

Diastolic

Hypertension

and Chronic

Proteinuria* S. EDWARD KING, New York,

M.D.

New York

minant of patient response for re-examination. Even with advanced renal disease awareness of the serious portent was limited to a small minority. At the initial hospital survey and on re-examination detailed histories and complete physical examinations were performed with several sitting blood pres-

OLLOW-UP STUDIES’ on patients with orthostatic and asymptomatic proteinuria indicate that these conditions are no exceptions to the rule, that continued proteinuria signifies chronic renal disease. Despite the deceptively benign initial clinical picture, proteinuria was found to persist or increase in the great majority of these patients, and a considerable number eventually presented other clinical evidence of organic renal disease. These observations have been confirmed by recent biopsy studies. Glomerular lesions reminiscent of subsiding acute and chronic membranous glomerulonephritis, and others of a more subtle and focal nature, have been reported in patients with relatively early fixed orthostatic proteinuria.2 More advanced renal disease may be anticipated in patients with protracted chronic orthostatic proteinuria and particularly in those patients in whom an increasing and continuous proteinuria develops. Causal relationships between chronic pyelonephritis and hypertension in older age groups become obscured by customary elevations in blood pressure. The aging factor is excluded in this study which is limited to young persons under thirty years of age. Observations summarized here suggest that chronic pyelonephritis with or without congenital renal malformations and occlusive renal vascular disease is a major disorder leading to renal hypertension.

F

sure readings taken by accepted methods. Patterns of proteinuria were defined by methods previously described.3 Urine specimens were centrifuged and examined for protein with freshly prepared 20 per cent aqueous sulfosalicylic acid reagent, turbidity being estimated in strong indirect light against a black background. With solutions of known albumin concentration, 5 mg. per cent or less was detected regularly by blind tests with this method. Positive protein reactions with sulfosalicylic acid reagent were checked by heat and acetic acid. Several careful microscopic examinations of the urinary sediment from freshly voided specimens were made in each instance and usually an Addis count. Pyuria (indicating urinary tract infection) was defined as a minimum of 4 white blood cells per high power field or two million cells per twelve hour Addis count. Microhematuria was defined as a minimum of 3 red blood cells per high power field or one million per twelve hour Addis count. The usual clinical tests of renal function were performed and excretory urography freely offered. Absence of symptoms and frequent disinclination to lose time from work limited excretory urography to about half the patients with orthostatic proteinuria. Urographic findings in this group usually were unpredictable and frequently surprising. By concentrated efforts excretory urography was obtained in the majority of patients with asymptomatic continuous proteinuria; some rejected detailed study. The method of Brod4 was followed for excretory urography using multiple films with a sensitive radiopaque dye, sodium diatrizoate (Hypaquem) to demonstrate disparities of dye concentration and excretion. Retrograde urography, ureteral catheterization, cystoscopy and other procedures, including occasional exploratory and definitive surgical intervention, were employed as specifically indicated. The

CLINICAL MATERIAL AND METHODS Six hundred twenty-three young proteinuric males (last mean age twenty-six years) were re-examined at intervals of five to ten years (average six years). Of this total 531 cases initially presented chronic orthostatic proteinuria and ninety-two cases presented chronic, continuous, asymptomatic proteinuria. The interval history indicated that awareness of renal disease or hypertension was not an important deter-

* Based on Cooperative Proteinuria Albuminuria Projects, New York, supported in part by the Bureau of State Services; the U. S. Public Health Service; and Research and Development Section, Office of the Surgeon General, Department of the Army (R & D Project 6-61-01-002). MAY 1962

669

King

670

GROUP I (435 PATIENTS1

GROUP II (96 PATIENTS1

GROUP IlI I92 CASES)

FIXED MITHOSTATIC PROTEHURIA

ORWIlSTATy: PRCGQESYffi TO CONTHvoLtS PROTElNURlA

PERSkSTAhT ASYMPTOMATIC CWllNWUS PftOlEINWA

60

m

MASTax URMK:

* XI

HwERTENslOll PYELaERRrns

MEaN HTERWL

BETVmN

MAN

AGE

PRESENT

s 1 l 90

w

. t RIlYLRI

.16

HP I bm

oByRwT13Ns’

SEcaaun

1

* 6.2 YEms

YEARS

FIG.1.

Development (mean interval between observations equals 6.2 years) of diastolic hypertension and chronic pyelonephritis in young persons (mean present age equals 26 years) with chronic asymptomatic orthostatic and continuous proteinuria. diagnosis of chronic primary pyelonephritis was made on the combined basis of composite clinical features5 and results of excretory urography read independently by radiologist and urologist. The diagnosis of obstructive and major anomalous lesions of the urinary tract and atrophic kidney was rarely in doubt following excretory and retrograde urography and urologic study. In view of the major importance of excretory urography in the diagnosis of chronic pyelonephritis and other renal lesions, positive results in patients with fixed orthostatic proteinuria are tabulated as percentages of those radiologically examined. However, for conservative estimate, the percentage incidence of abnormal findings in the

ninety-two patients with advanced renal disease has been calculated from the total number in the group. Clas$ca~ion of Cases: For purposes of tabulation

patients were divided into three groups, based upon the proteinuria pattern evolution and thus indicating degree of renal injury. These ranged from the mildest: Group 1 (435 cases with fixed orthostatic proteinuria) ; to moderately severe: Groufi II ninetysix cases progressing from orthostatic to continuous proteinuria); to advanced renal disease: Group III (ninety-two cases with chronic continuous proteinuria of considerable duration) (Fig. 1). Other parameters of renal damage and impaired function, i.e. abnormal urinary sediment and impairment of renal function closely paralleled and confirmed this grouping.

RESULTS Diastolic In

Hybertension

accordance

hypertension twenty-six

over.

In

with in

years) view

this

in Chronic Proteinuria:

usual

standards,6

young

is defined of observations

age as

diastolic

group

90 mm. suggesting

(mean

Hg or that

consistent diastolic levels above 80 mm. Hg often predict subsequent hypertension,? this level is set as borderline hypertension. Diastolic hypertension was recorded on reexamination in sixty-three of 435 cases (15 per cent) of Group I (mild renal disease), in thirtyfour of ninety-six cases (35 per cent) of Group II (moderate disease) and in fifty-two of ninety-two cases (57 per cent) of Group III Combined border(advanced renal disease). line and established diastolic hypertension were recorded in sixty-three of ninety-six cases in Group II and seventy-five of ninety-two in Group III (Table I). Roth hypertension and proteinuria were found initially in only forty of 623 patients. Twenty-seven of these forty patients revealed renal disease of such nature, that in conjunction with the proteinuria pattern evolution, it was &dent that renal disease was the primary disorder. In only thirteen cases did history and detailed study favor essential hypertension, presumably with nephrosclerosis, as the cause of proteinuria. Chronic Pyelonefihritis in Patients with Chronic Proteinuria: Particular attention is focused in this report upon the frequency of development of overt chronic pyelonephritis in patients with chronic proteinuria. Other renal diseases, manifested by orthostatic and chronic asympwill be reported subtomatic proteinuria, sequently. The difficulties in diagnosis of some forms of chronic pyelonephritis are well known.5*8 Reliance here was placed upon THE

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Diastolic

Hypertension

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Proteinuria

671

TABLE I Diastolic Hypertension in Patients with Chronic Proteinuria *

-

Diastolic

Groups by Severity Renal Disease

of

Proteinuria Pattern Evolution

Blood Pressure

(mm.

Hg) Cases of Proteinuria a”d Diastolic Blood

No. of CZWX

Cases of Diastolic

Re-examinationt

Simultaneously

Cases

Per Cent

Per Cent

435

...

.,.

63

14.5

13

50

96

63

65.6

34

35.4

9

25

92

75

81.5

52

56.5

18

34

149

22.1

40

CZ.ZS

-__ Group

I:

Mild

disease

Group II: Moderately severe disease Group “I: disease Totals

Advanced

Persisting orthostatic Orthostatic now continuous Persisting, continuous

623

138

*All male subjects. t Six years later.

initial

mea”

age rwenty years.

Groups

I and II =

80 per cent

TABLE

+

veterans;

Group

III =

109

I

15 per cent

+

veterans.

II

Chronic Pyelonephritis in Patients with Chronic Proteinuria

-

I Xastolic

Groups by Severity of Renal Disease

Proteinuria Pattern Evolution

Blood

Pressure

>

90 mm.

Hg

Diastolic

Blood

Pressure

<

90 mm.

Hg

__- _ Chronic

Pyelonephritis

Chronic

I

Pyelonephritis All cases

Pyelonephritis

Cases

C.3S.S

Primary

Secondary

Total

Primary

Secondary

ChSS%

Total

__~__ Group I: Mild disease Group II: Modderately severe disease Group IX: Advanced disease TCltals Per cent

Persisting orthostatic Orthostatic now continuous Persisting, continuour

63

6

7

13

182

17

18

35

245*

48

34

10

11

21

62

10

19

29

96

50

52

22

16

38

40

7

4

11

92

49t

38 22.5

34 22.9

72 48.4

34 12.0

41 14.4

149

* Limited in this group to patients having excretory urography. t Actual incidence probably higher, since renal insufficiency impaired

combined clinical criteria and radiologic and urologic examination and occasionally upon tissue examination. Calyceal deformities and early disparities of opaque dye excretion have been accepted as reliable confirmatory radiologic evidence of primary pyelonephritis. Radiologic and urologic methods of detection of obstructive lesions of the urinary tract and of major urologic malformaticns also are reliable, provided renal function has not been excessively compromised. The diagnosis of chronic pyelonephritis was made in forty-eight (19 per cent) of 245 patients in Group I who were studied radiologically (Table II). Fifty (52 per cent) of the ninety-six cases in Group II and forty-nine (53 per cent) of the ninety-two cases in Group III revealed chronic pyelonephritis. Pyelonephritis was present in fifty-nine (70 per cent) of MAY

1962

284

diagnostic

value

75 62.4

433

147 29.5

of urography.

eighty-six patients in Groups II and III with diastolic hypertension, and in forty (40 per cent) of 102 patients in the same groups with apparently normal diastolic pressures. Primary pyelonephritis was observed in thirty-two (38 per cent) of eighty-six patients in Groups II and III with diastolic hypertension and in seventeen (18 per cent) of 102 normotensive subjects in these groups. Conversely in patients with pyelonephritis, the incidence of diastolic hypertension appeared to increase with severity of renal disease, being 36 per cent in Group I, 41 per cent in Group II and 71 per cent in Group III. Potentially Curable Hypertension in Chronic Proteinuria: In a routine unselected survey by excretory urograms of nearly 400 patients with chronic proteinuria, fifty-two instances of obstructive and major congenital and acquired

abnormalities of the urinary tract with and without infection were discovered. The great majority of the abnormalities were unilateral and included hydronephrosis due to aberrant renal arteries in fifteen, unilateral atrophic kidney in nine, marked nephroptosis in six and bifid renal pelvis or double ureter in six. Tuberculosis of kidney and ureter was found in four as well as other miscellaneous lesions in inDiastolic hypertension (3 90 dividual cases. mm. Hg) was present in twenty-nine of these fifty-two patients and diastolic pressures between 80 to 89 mm. Hg in eleven. Most patients with unilateral renal disease of this kind represent instances of potentially curable hypertension.

COMMENT Average and arbitrary limits defining normal ranges of blood pressure may be deceptive. Hines and Lander7 found that 65 per cent of apparently normal persons and those with urologic disease, who initially presented diastolic blood pressures between 85 to 89 mm. Hg, later developed significant hypertension. One likely explanation is that these persons in fact had already developed hypertension, which later reached definitely abnormal levels with progression of the disease. Inherent factors have been invoked to account for the development of hypertension in some patients and its absence in others with apparently identical urologic disease. In any instance diastolic blood pressure levels at 90 mm. Hg in persons under thirty years of age can be accepted as abnormal. Hamilton6 estimated the incidence of essential hypertension in persons in this age group as under 5 per cent. The dejinition of clinically signz$icant proteinuria is vague and difficulties may be compounded by careless laboratory technic and unduly liberal interpretation. Demonstration of small quantities of protein in urine specimens of apparently normal persons by complex method has encouraged unjustified disregard of traces or even larger amounts of urine protein when overt renal disease is not evident clinically. Proteinuria in patients with latent renal disease, particularly pyelonephritis, thus frequently escapes detection. Data on partitions of the multiple solid components, that have been demonstrable in trace amounts by ultrafiltration and dialysis of urine specimens of presumably normal persons,gJO cannot be applied unreservediy to

clinical problems. In one report9 three of the originally selected apparently normal subjects were later considered cases of orthostatic proteinuria. In brief, most of the filtrable solid components reported in normal urinelo is a mixture of peptides and low molecular weight solids without protein characteristics, usually soluble in acid media and not precipitated by commonly employed qualitative urine protein reagents. The same holds true for the mucoid, alkaline buffer insoluble fraction and other components which also are dissolved by heat. A small fraction (13 per cent of total urinary solids) represents the true serum proteins of normal urine which at a high range of excretion may approach 45 mg. per twenty-four hours. With 1,500 cc. average twenty-four hour urine volume, protein concentration of normal urine would approximate 3 mg. per cent. Such concentrations are not detectable by standard qualitative tests for urine protein. It is conceivable, under conditions of greatly diminished urine flow, that proteins in normal urine could be concentrated sufficiently to give transient positive qualitative reactions.3 It is improbable, however, under daily varying conditions of urine flow and reaction, that positive tests for urine protein would be frequently duplicated in normal persons. Relationship of Proteinuria and Hypertension: Proteinuria has been reported” in 30 per cent of older persons with sustained diastolic blood pressures above 100 to 120 mm. Hg. Observations on young persons with less severe hypertension, examined at the same time and under conditions similar to those in this study, indicate a much lower incidence of proteinuria. The presumptive bases for proteinuria in essential hypertension are nephrosclerosis and hypertensive cardiac disease. Renal disease is frequently absent, even in patients undergoing surgery for hypertension.i2 The characteristic renal hemodynamic alterations in essential hypertension involving increased intraglomerular pressure under augmented stress conditions may increase protein passage through the glomerulus, provided glomerular lesions are present. Only slight proteinuria was induced in normal young persons, even with large intravenous doses of norepinephrinc, epinephrine and angiotension although very marked alterations in renal hemodynamics were induced.i3 In patients in this study prior evidence of proteinuria and individual clinical considerations indicate that renal disease was THE

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Diastolic

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primary in nearly all instances. Proteinuria in pyelonephritis, although usually present,4,14 is mild and orthostatic and often undetected because of the hyposthenuria and polyuria of the disease. Longcope and others14-i6 called attention to the diagnostic import of unexplained chronic proteinuria in inapparent renal infection. The temporal relationships between proteinuria and diastolic hypertension in patients in this study and the direct relationship between increasing renal injury and incidence of diastolic hypertension indicate the nephrogenic basis of the hypertension. The relatively high incidence of hypertension developing in these young persons with continuing proteinuria can be related only to underlying renal disease. Proteinuria, Renal Disease and Infection: Chronic pyelonephritis was the most frequent disease detected in patients in Groups II and III with advancing renal disease. In patients with comparable degrees of renal injury, pyelonephritis was considerably more frequent in those with hypertension (70 per cent) than in those with normal blood pressures (40 per cent). Primary pyelonephritis was twice as frequently associated with hypertension than the secondary type. It is possible that renal infection was present initially in some of these patients with chronic proteinuria, as the chronic inapparent form. From clinical history and radiologic findings it is apparent that in many other instances renal infection was superimposed upon urinary tract anomalies and miscellaneous renal diseases. Diffuse renal diseases observed here, manifested initially by orthostatic and mild proteinuria and hypertension, included diabetic glomerulosclerosis, polyarteritis, lupus erythematosis and chronic glomerulonephritis. Orthostatic proteinuria is known to follow acute glomerulonephritis as an apparently “healed with defect” lesion, or as a cryptogenic progressive variant.i7 In rare instances, hypertension may be the sole residue of a previously documented and otherwise apparently healed glomerulonephritis. Renal anomalies, including atrophic kidney, aberrant and accessory renal arteries, polycystic kidney and renal although frequently associated nephroptosis, with infection, may in themselves initiate renal hypertension. Protein&a and Occlusive Renal Artery Disease: Few patients in this study initially met accepted criteria for arteriography or even less formidable procedures utilized in detection of MAY

1962

and

Chronic

Proteinuria

673

occlusive renal artery disease. Recent revision in concept concerning the incidence, age of onset, duration and levels of blood pressure in occlusive renal artery disease18 presents the possibility that hypertension developing in some of these proteinuric patients may have been renovascular in origin. Conservative estimates suggest that renovascular disease is causative in about 5 per cent of patients with essential hypertension. Twenty-five of the hundred patients undergoing renal artery reconstructive surgery reported by Morrisi were in the twenty-one to thirty-five age group. Morris18 and Derrick and Tysoni have emphasized that stenosis of accessory and aberrant renal arteries with resulting segmental renal ischemia are not uncommon causes of renal hypertension, subject to cure by renal artery reconstruction. Functional improvement has been reported in revascularized kidneys of renal artery disease and apparent reversal of renal damage with abatement of hypertension.18 Proteinuria is often present in demonstrated renal artery stenosis.20 Morris’* also reported relief of hypertension after reconstructive surgery of minute renovascular lesions not detected by arteriography. Congenital Renal Anomalies: Major congenital anomalies were detected by routine urography in forty-eight of approximately 400 patients with chronic proteinuria who had had radiographs taken. In unilateral atrophic kidney marked nephroptosis, and in aberrant renal arteries hypertension could be ascribed to these anatomic distortions or to the frequently associated renal infection. Diagnosis of aberrant renal arteries was made radiologically by renal pelvic constriction or at surgical exploration. Other instances might have been demonstrable by renal arteriography. Postural diminution in renal blood flow and hypertension were reported in nephroptosis by McCann and Romansky. It is surmised that precise study of patients with chronic orthostatic and asymptomatic proteinuria and diastolic hypertension might well demonstrate frequent instances of surgically curable hypertension and medically preventable or controllable renal infection with resulting hypertension. The frequent association of chronic pyelonephritis and hypertension in these young proteinuric patients is strongly presumptive but not irrefutable evidence of causal relationship. It is possible, however, that hypertension

674 in some instances may be initiated by other renal diseases or malformations manifest by proteinuria and that renal infection is a superWith renal insufficiency imposed process. following superimposed infection late or accelerated hypertension is probably renoprival. SUMMARY 1. A high incidence of diastolic hypertension, several times above that anticipated in the age group, developed in a series of 623 young male subjects with prior chronic orthostatic and asymptomatic proteinuria. 2. The incidence of diastolic hypertension paralleled the degree of renal damage indicated by proteinuria and other parameters of renal Individual clinical disease and functions. study indicated that hypertension in the great majority of these patients was nephrogenic. 3. Chronic pyelonephritis was detectable with increasing frequency with progressing renal injury and hypertension. A direct causal relationship between renal infection and hypertension in these instances is probable. Renal infection may be initially present as inapparent chronic pyelonephritis or later superimposed upon various latent renal diseases and malformations, initially manifested by variable proteinuria. 4. Unsuspected unilateral renal anomalies and obstructive lesions were discovered incidentally by routine excretory urography in approximately 15 per cent of these patients. Hypertension directly or indirectly induced by these lesions is considered potentially curable.

3. 4. 5. 6.

7.

8. 9.

10.

11.

12.

13.

14. 15. 16. 17. 18.

ACKNOWLEDGMENT The assistance of the Veterans Administration Hospitals, Bronx, Manhattan and Castle Point, New York, and the Diagnostic Service of New York City Health Department is gratefully acknowledged. REFERENCES 1. KING, S. E. Preliminary observations on patients with orthostatic proteinuria. New York StateJ. Med., 59: 825, 1959; ibid., 61: 2766, 1961. 2. ROBINSON,R. R., GLOVER, S. N., PHILLIPPI, P. J., LECOCQ, F. R. and LANGELIER,P. R. Fixed and

19.

20.

21.

reproducible orthostatic proteinuria. Am. J. Path., 39: 231, 1961. KING, S. E. Patterns of protein excretion by the kidneys. Ann. Int. Med., 42: 296, 1955. BROD, J. Chronic pyelonephritis. Lancrt, 1 : 973, 1956. KLEEMAN, C. R., HEWITT, W. L. and GUZE, L. B. Pyelonephritis. Medicine, 39: 3, 1960. HAMILTON,M.. PICKERING.G. W.. ROBERTS, J. A. F. and SO&Y, G. S. C. ‘Aetiology of essential hypertension. Ciin. SC., 13: 273, 1954. HINES, E. A., JR. and LANDER, H. H. Factors contributing to development of hypertension in patients suffering from renal disease. J.A.M.A., 116: 1050, 1941. BIRCHALL, R. Pyelonephritis. Am. J. ‘2iled., 28: 501, 1960. RIGAS, D. A. and HELLER, C. G. The amount and nature of urinary proteins in normal human subjects. J. Clin. Invest., 30: 853, 1951. BOYCE, W. H. and KING, J. S. Total nondialyzable solids in human urine. J. Clin. Znuest., 38: 1525, 1959. MOYER, J. H. Renal hemodynamic changes in patients with hypertension. In: The First Hahnemann Symposium on Hypertensive Disease, p. 135. Philadelphia, 1959. W. B. Saunders. CASTLEMAN,B. and SMITHWICK,R. H. Relation of vascular disease to hypertensive state based on study of renal biopsies from 100 hypertensive patients. J.A&I.8., 121: 1256, 1943. KING, S. E. and BALDWIN,D. S. Production of renal ischemia and proteinuria by adrenal medullary hormones. Am. J. Med., 20: 217, 1956. KING, S. E. and GRONBECK,C. Benign and pathologic albuminuria. Ann. Int. Med.. 36: 765. 1952. LONGCOPE,W. T. Chronic bilateral pyelonephritis. Ann. ht. Med., 11: 149, 1937. RAASCHAU, J. Studies of Chronic Pyelonephritis. Copenhagen, 1948. Ejnar Munksgaard. KING, S. E. Latent (cryptogenic) chronic glomerulonephritis. Circulation, 24: 972, 1961. MORRIS, G. C. Surgical considerations in renal Hypertension, vascular hypertension. In: Recent Advances, p. 221. Edited by Brest, A. N. and Moyer, J. H. Philadelphia, 1961. Lea & Febiger. DERRICK, J. R. and TYSON, K. R. T. Aberrant renal arteries in systemic hypertension. Cimdation, 24: 1192, 1961. YENDT, E. R., KERR, W. K., WILSON, D. R. and JAWORSKI,2. F. The diagnosis and treatment of renal hypertension. Am. J. Med., 28: 169, 1960. MCCANN, W. S. and ROMANSKY, M. J. The effect of ptosis of the kidneys on blood pressure, renal blood flow and glomerular filtration. T. A. Am. Physicians, 55 : 240, 1940.

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