- Email: [email protected]
Natural History of Hypertension in Renal Parenchymal Disease
Natural History of Hypertension in Renal Parenchymal Disease William B. Blythe, MD • This paper discusses the author's version of the known and unknown in the natural history of hypertension in renal parenchymal disease. Discussed in particular are the prevalence of hypertension in various forms of renal parenchymal disease at various levels of renal function, pathogenesis of hypertension in renal parenchymal disease, and the course of hypertension in these diseases. © 1985 by The National Kidney Foundation, Inc. INDEX WORDS: Hypertension; natural history; renal parenchymal disease.
I
N my judgment, there is no one homogeneous natural history of hypertension in renal parenchymal disease if one takes natural history to be an exposition of the prevalence, course, and pathogenesis of hypertension and renal parenchymal disease to mean all diseases that afflict the substance of the kidney (exclusive of disease of the renal artery and essential hypertension itself). Thus, I should like to try to see if we can determine what is known, and what is not known, about how prevalence, course, and pathogenesis of hypertension might vary as a function of the type of renal disease and the severity of the disease as reflected by renal function. Being interested not only in natural history of disease but also in history per se, I should like to begin with Dr Richard Bright who was the first to recognize a connection between the kidney and hypertension. In 1836, Dr Bright published two papers in the first volume of the Guy's Hospital Reports. The second of these is entitled "Tabular View of the Morbid Appearances Occurring in One Hundred Cases in Connection with Albuminous Urine with Observations."l Among other things, Dr Bright wrote: From the analysis of the following tabular view, many curious facts respecting the derangement of different organs connected with granular kidneys are brought to light. The first circumstance which strikes the mind, is the extent and frequency to which the derangement of one organ is connected with the derangement of several others; yet we are not at liberty to asFrom the Division of Nephrology, Department of Medicine, University of North Carolina, Chapel Hill. Address reprint requests to Dr William B. Blythe, Division of Nephrology, Department of Medicine, University of North Carolina, School of Medicine, Chapel Hill, NC 21514. © 1985 by The National Kidney Foundation, Inc. 02 72-63861851020A50-07$03. 0010 A50
sume, that the disease of the kidney has been the primary cause on which the disease of the rest depended. It may be, that some other organ has first suffered, and that the kidneys, t.ogether with the rest, have become involved. I confess I am inclined to believe that the kidney is the chief promoter of the other derangements. . .. The deviations from health in the heart are well worthy of observations: they have been so frequent, as to shew a most important and intimate connection with the disease of which we are treating. The obvious structural changes in the heart have consisted chiefly of hypertrophy with or without valvular disease; and what is most striking, out of fifty-two cases of hypertrophy, no valvular disease whatsoever could be detected in thirty-four: but in eleven of these thirty-four, more or less disease existed in the coats of the aorta; still, however, leaving twenty-two without any probably organic cause for the marked hypertrophy generally affecting the left ventricle. This naturally leads us to look for some less local cause, for the unusual efforts to which the heart has been impelled: and the two most ready solutions appear to be, either that the altered quality of the blood affords irregular and unwonted stimulus to the organ immediately; or that it so affects the minute and capillary circulation, as to render greater action necessary to force the blood through the distant sub-division of the vascular system. . .. It is observable, that the hypertrophy of the heart seems, in some degree, to have kept pace with the advance of disease in the kidneys; for in by far the majority of cases, where the muscular power of the heart was increased, the hardness and contraction of the kidney bespoke the probability of a long continuance of the disease.
Dr Bright's prescience is indeed remarkable. A century and a quarter later, the evidence tells us that of all hypertension, 5% to 10% is probably caused by renal disease, which in some circumstances increased cardiac output rather than increased total peripheral resistance is the cause for hypertension. Whereas in others the obverse is true, and finally, the longer the course, and the greater the severity of the renal disease, the greater the severity of the hypertension. HYPERTENSION IN RENAL DISEASE
Figure I is a caricature of two extreme courses that could lead to what we know is a firm anchor Hypertension and the Kidney: Proceedings of a Symposium
A51
HYPERTENSION IN RENAL PARENCHYMAL DISEASE
It is most often moderate and is usually most mani-
61001-------------------GLOMERULAR and SMALL ARTERY DISEASES
"Vi c ~
(l)
a.
I
>.
~
~
50
c'" (l)
:g
INTERSTITIAL DISEASES
(L
~
100
75
50
25
0
GFR (% of Normal)
Fig 1. A theoretical portrayal of the relationships between prevalence of hypertension and type of renal disease and degree of renal function.
point in the course of hypertension in renal parenchymal disease and that is true end-stage disease in which there is no renal function. There are earlier reports that show the prevalence of hypertension in patients on chronic dialysis to be around 85 %.2-5 In my experience, the figure is closer to 100%. Let's look closer at the caricature in order to determine how the available data fit, and might not fit, in relationship to the prevalence of hypertension before end-stage renal disease is reached. The curve at the top of the figure suggests that in renal parenchymal disease, in which there is involvement of the small arteries and/or glomeruli, the prevalence of hypertension is 100% at the onset of the disease and remains so until end-stage disease is reached. The curve at the bottom of the graph suggests that the prevalence of hypertension in interstitial disease is quite low until severe renal failure develops. Glomerular and Small Artery Disease
Those glomerular and small artery diseases which are generally thought to be associated with a high prevalence of hypertension are shown in Table 1. Hypertension is present in over 75 % of cases of postinfectious acute glomerulonephritis. 6 Table 1. Glomerular and Small Artery Diseases Associated With High Prevalence of Hypertension Acute post-infectious glomerulonephritis Glomerulonephritis secondary to systemic vasculitides Polyarteritis involving the kidney Scleroderma involving the kidney Crescentic glomerulonephritis Focal glomerulosclerosis Diabetic glomerulosclerosis Renal infarction
fest at the onset of clinical evidence of the presence of renal disease. Hypertension in systemic lupus erythematosus is not common in the absence of renal involvement or even when there is minimal renal involvpment; however frequency ranges from about 15% to 50% in those patients with overt renal disease.7-9 In hypersensitivity angiitis, hypertension is frequently absent and when present is usually mild. to It is common in polyarteritis nodosa, is associated with high levels of renin, and in fact not uncommonly reaches the malignant phase. II It is interesting and of note, that in the experience of Walker and colleagues, hypertension is not present in acute oliguric renal failure secondary to polyarteritis nodosa.1 2 Oliver and Cannon have found that 52 % of their patients with scleroderma have hypertensionY It is present in 35 % to 50 % of patients with idiopathic crescentic glomerulonephritis at the onset of clinical disease. 14.15 Hypertension develops in about one-third of patients with focal glomerulosclerosis, usually in association with progressive renal insufficiency. 16.17 Of patients with diabetic glomerulosclerosis, 50% to 75 % develop hypertension, and its presence has been reported to correlate more closely with the degree of arteriolosclerosis rather than glomerulosclerosis. 18 Renal infarction is one of those conditions which various authors cite as a cause for hypertension. 19-21 It is difficult to be certain of the prevalence of renal infarction and even of the prevalence of hypertension in recognized renal infarction. However, the evidence suggests that the prevalence is quite high in the recognized cases. Table 2 shows the glomerular disease in which there is general agreement that the prevalence of hypertension is lower than in the other diseases that have been mentioned. Hypertension is not common in patients with membranous nephropathy until late in the course when renal failure develops. 22.23 It occurs in about 30% of patients at most, with mesangioproliferative glomerulonephritis, and is almost always mild. 24 Table 2. Glomerular Diseases Associated With Lower Prevalence of Hypertension Membranous glomerulopathy Mesangioproliferative glomerulonephritis IgA nephropathy
A52
WILLIAM B. BLYTHE
Table 3.
Interstitial Diseases Associated With Hypertension
Associated With Low Prevalence
Associated With High Prevalence
Phenacetin nephropathy Polycystic kidney disease Chronic pyelonephritis Medullary cystic disease
We now realize that the clinical manifestations of IgA nephropathy are more varied than was formerly thought. Therefore, hypertension is probably more common. Nevertheless, the blood pressure is usually normal; although mild, and rarely even severe, hypertension may be present in patients with more advanced disease. 25-27 Chronic Interstitial Diseases
Table 3 illustrates the prevalence of hypertension in the more common of the chronic interstitial diseases. I have listed phenacetin nephropathy first, because in my part of the world (the southeastern United States) phenacetin nephropathy has been the most common form of chronic interstitial disease. In fact, it has ranked just below hypertension and diabetes mellitus as a common cause of end-stage renal disease for the patients in our chronic dialysis program. Phenacetin has now been removed from all over-the-counter analgesic preparations and we therefore expect to see the incidence decline. Phenacetin nephropathy is a curious disease in that it appears to have different clinical characteristics in different parts of the world. One of the characteristics that varies depending upon geographical location is hypertension. In Australia, there is a very high prevalence of hypertension as reported by Kincaid-Smith and colleagues. 28.29 The prevalence in Scandinavia,3o.31 the United Kingdom,32 and the United States 33 .34 appears to be much lower. However, even in the United States, Murray and Goldberg have reported hypertension to occur in as many as 50% oftheir patient population. 34 Two comments about this should be made. Firstly, in our experience in North Carolina, hypertension is distinctly uncommon until salt and water retention occur as a consequence of end-stage renal disease. In fact, it is our experience that most of our patients not only do not have hypertension but from time to time develop dehydration, hypotension, and acute deterioration in renal function as a consequence of an inability of the kidney to properly
conserve sodium. Secondly, it is not possible in general (I base my judgment from reviewing the published articles) to relate the prevalence of hypertension to the degree of renal function. Thus, I suspect, without clear evidence, that the presence of hypertension is most often associated with severe impairment of renal function. My comments about the prevalence of hypertension in chronic pyelonephritis have much in common with my comments about phenacetin nephropathy. As Freedman has written, "The frequency of hypertension in patients with chronic pyelonephritis has been reported to range from 12 % to 85 % depending on methods of selection of patients, the criteria used for the diagnosis of hypertension and pyelonephritis, the ages of the patients, the presence of a family history of hypertension, and the stage and type of renal disease. One can find figures to support virtually any argument."35 Our experience in Chapel Hill and my perusal of the literature lead me to make two observations: The first is that I believe that chronic infectious pyelonephritis is a rare disease which was overdiagnosed in the forties, fifties, and sixties; and the second is that hypertension is rare, and mild when it does occur, in patients with chronic pyelonephritis until significant renal failure develops. There is also a difference of opinion concerning the frequency of hypertension in patients with medullary cystic disease. Gardner holds the view that hypertension may be common in the early stages of the disease but becomes much less frequent as the salt-wasting stage of the disease develops. 36.37 Other investigators find hypertension to be rare until significant renal failure develops with retention of salt and water. 38 .39 Hypertension is quite common in polycystic kidney disease. Estimates of the frequency range from 39 % to 75 %.4042 Again, it should be emphasized that these series vary considerably in the incidence of hypertension at the time of presentation while serum creatinine remains normal. Nevertheless, the results of most studies suggest that there is a high incidence of hypertension before signifiant renal failure develops. To summarize then about the prevalence of hypertension in the various types of kidney disease, I believe that our caricature is just that, a caricature. However, I do believe that it does not approach being a travesty.
HYPERTENSION IN RENAL PARENCHYMAL DISEASE cIOO,-----------------------~ ,/ Q
'"c !':'
,/
GLOMERULAR and SMALL ARTER Y DISEASE S
a. I
'"
,/ ,/ ,/ ,/
,/ ,/
:;:: 50
,/
~
,/ ,/
,/ ,/ ,/
--100
/'
---
--- INTERSTITIAL
D ISEAS ES
--75
50
25
GF R. ( % of N ormal )
o
Fig 2. A more realistic portrayal of the relationship between prevalence of hypertension and type of renal disease and degree of renal function.
In my judgment, the situation is closer to what I have portrayed in Figure 2. Here again is the prevalence of hypertension plotted against renal function . The dashed line separates the slide into two halves and moves from a 0 %prevalence at normal renal function to 100% prevalence at 0 renal function. I am convinced that, in general, the glomerular and small-artery diseases can be placed in the upper section of the graph and the interstitial diseases in the lower section. Thus, the prevalence of hypertension is higher in the glomerular and small-artery diseases when renal function is normal or close to normal than it is in the interstitial diseases and that as renal function deteriorates the prevalence of hypertension approaches 100% regardless of the type of associated renal disease. Prevalence of Hypertension and Status of Renal Function
There have been few studies, and no prospective studies to my knowledge, that have systematically examined the relationship between hypertension and status of renal function in patients with different types of renal parenchymal diseases. There are no studies in which the hyertension has not been treated. One retrospective study aimed at this question was undertaken by Vendemia and colleagues. 43 They studied 290 adult patients with renal parenchymal diseases divided into two major groups: 184 with glomerulonephritis and 106 with tubulointerstitial diseases. The patients in the first group were classified on clinical, histological , and immunohistologic grounds as follows : 87 cases of IgA nephropathy, 40 cases of membranous glomerulopathy, 30 cases of membranoproliferative disease, and 29 cases of focal glomerulosclerosis. In the second group,
A53
there were 56 cases of polycystic kidney disease, 26 cases of chronic pyelonephritis, and 24 cases of analgesic nephropathy. The patients were followed for a period ranging from I month to 127 months. Twenty-eight percent of patients with glomerulonephritis and 60 % of those with tubulo-interstitial disease interrupted medical control for more than one year and were considered dropouts. The clinical course of the diseases were divided into four phases according to the level of renal function: Phase 1: "Normal renal function" was defined by a normal GFR and a serum creatinine < 1 mgm/lOO mL; Phase 2: "Mild renal failure" defined by a GFR that was about 50% of normal and a serum creatinine between 1. 1 and 3 mgml 100 mL; Phase 3: "Severe renal failure;' was defined by a GFR that was about 25 % of normal and a serum creatinine between 3.1 and 7 mgm/l00 mL; Phase 4: "End-stage renal failure" was characterized by a GFR less than 10 % of normal and a serum creatinine > 7.0 mgml 100 mL. The results are shown in Figures 3 and 4. The prevalence of hypertension in the different subgroups of glomerulonephritis is shown in Figure 3. In the late stages of renal failure, all the subgroups had a similar prevalence of hypertension of about 100%, whereas in the early phases, the patients with focal glomerulonephritis had a strikingly higher prevalence than those with membranoproliferative, membranous, and IgA disease. The prevalence of hypertension in the tubulointerstitial diseases is shown in Figure 4. The
50
--FGS ------- IoIPGM - - - MGM
10
- ' - ' - BO
7
mgY. SERUM CREATIMItiE
Fig 3. The relationship between prevalence of hypertension and type of glomerular disease and plasma creatinine concentration. 43 (Reprinted with permission. 43 ) FGS = focal glomerulosclerosis; MPGN = membranoproliferative glomerulonephritis; MGN = membranous glomerulonephropathy; BO = Berger's disease.
A54
WILLIAM B. BLYTHE 1l1li
~~~ .... 0
10
20
~ 0:::
t3
1.5
lL..
o
w
--PtD lO
----- PI - - - AI
7 ...", SE. . ClUT1IIII
Fig 4. The relationship between prevalence of hypertension and type of renal interstitial disease and plasma creatinine concentration. 43 (Reprinted with perrnission. 43) PCD = polycystic kidney disease; PN = pyelonephritis; AN = analgesic nephropathy.
patients with pyelonephritis and those with analgesic nephropathy had a similar prevalence of hypertension in all four phases. The patients with polycystic kidney disease showed the same prevalences throughout the course. There was a significant difference between polycystic kidney disease only in the intermediate phases. Although there are flaws in the study in that many patients were not followed throughout the course of the study, hypertension was treated, and there were intercurrent treatments such as the exhibition of steroids, which tends to support our notions, at least in regards to the glomerular diseases . The prevalence of hypertension in the interstitial diseases is higher than I would have predicted at the more normal levels of renal function and lower at the levels of renal function approaching endstage disease. What is the effect of hypertension on the development, and course, of chronic renal failure in renal parenchymal diseases? To my knowledge, there are no studies that answer the question for the various parenchymal diseases. There are the studies of Mogensen that show an effect of treating hypertension on the rate of deterioration of renal function in patients with diabetic nephropathy. Fig 5 is taken from one of Mogensen's earlier studies. 44 Plotted along the vertical axis is the rate of decline in glomerular filtration rate and on the horizontal axis two points: before and during treatment of hypertension. It can be seen in this small group of patients that treatment decreases the rate
5
10
U W
o
lL..
o
w
0.5
~
0:::
o '---'-___
---L_
Before Treatment
During Treatment
Fig 5. The effect of treating hypertension on the rate of decline of renal function in patients with diabetic nephropathy. (Modified and reprinted with permlssion.44)
of decline in glomerular ftItration rate. These findings have been amply confirmed. Furthermore, some early studies of Dr James Woods and mine45 showed that treatment of malignant hypertension tends to minimize decline in renal function . Recent studies from Dr Pettinger's group in Dallas show that treating benign and malignant essential hypertension reduces the rate of decline in renal function. 46 PATHOGENESIS OF HYPERTENSION IN RENAL PARENCHYMAL DISEASES
Natural History
Other papers in this supplement address the various systems and mechanisms that are involved with the pathogenesis of hypertension in renal parenchymal diseases, so my comments will be brief. Let's begin with patients requiring chronic maintenance dialysis. The classic study which started the dissection of our understanding of the hemodynamic patterns in patients on maintenance dialysis was one performed by Vertes and colleagues in 1969 Y These investigators described two distinct patterns of response of blood pressure to achievement of "dry weight" by hemodialysis. The first pattern, seen in 35 of 40 patients studied, was one in which there was an excellent blood pressure response to the attainment of "dry weight." The second pattern, seen in five patients, was one in
A55
HYPERTENSION IN RENAL PARENCHYMAL DISEASE
Table 4. Study
Frohlich et ai, Brod et ai,
196949
197550
Hemodynamic Alterations In Early Renal Failure
Renal Function
Hematocrit
Cardiac Index
Not markedly impaired
Not anemic
Normal
Increased
GFR-20-80 mUmin (mild to moderate)
Not anemic
Elevated
Same as controls
which blood pressure was not controlled despite the attainment of "dry weight" and the use of large doses of antihypertensive drugs. In this group of five, plasma renin activity was approximately ten-fold higher than in the first group. There emerged from this study the view that hypertension in patients on maintenance dialysis is either volume (or sodium) dependent or renin dependent. We know that the situation is not that simple. Rather than there being two distinct types of hypertension in this setting, it appears more likely that different blood pressure responses to dialysis and different blood pressure patterns in patients on maintenance dialysis can be attributed to a spectrum of relationships among renin, extracellular volume, and cardiac output. For example, Onesti and colleagues have extensively studied the relationship between cardiac output, anemia, total peripheral resistance, and hypertension in patients on maintenance dialysis. 48 They found them to have increased cardiac output that was due to anemia. When the anemia was corrected, cardiac index decreased. Concomitantly peripheral resistance rose and there was a marked increase in blood pressure. From the perspective of our subject, it should be emphasized that there has been no examination of the relationship of the various factors involved in hypertension in dialysis patients and the type of renal disease with which they are afflicted. Let's move now to patients with minimal renal failure. The early data are conflicting in regards to the hemodynamic characteristics and, to my knowledge, no one has attempted to correlate the hemodynamic characteristics with the type of renal parenchymal disease or to systematically study the hemodynamic parameters at various levels of renal function. The conflict is summarized in Table 4. Dr Frohlich and colleagues found cardiac index to be normal and peripheral resistance to be increased 49 and Dr Brod and coworkers have found cardiac index to be increased and peripheral resistance to be normal . 50 I believe that most of the data in regard to patho-
Total Peripheral Resistance
genesis of hypertension support the view that, early in the course of renal disease, those patients with glomerular and/or small artery disease are apt to exhibit subtle, and sometimes clearly overt, salt and water retention with hypertension as a consequence and later on in the course of the disease increased peripheral resistance due to generalized vascular disease which may be a consequence of hypertension per se or some function thereof.
SUMMARY What we need to bring our knowledge of the natural history of hypertension in renal parenchymal disease up to a 1984 standard is a prospective study in which (1) contemporaneous methods of diagnosis are employed to determine the type of disease; and (2) the prevalence, hemodynamic, and pathogenetic patterns are determined at different levels of renal
REFERENCES I. Bright R: Tabular view of the morbid appearances in 100 cases connected with albuminous urine, with observations, in Osman AA (ed) Original Papers of Richard Bright on Renal Disease, London, Humphrey Milford, Oxford University Press, 1937, pp 132-148 2. Curtis JR, Eastwood JB , Smith EKM, et al: Maintenance hemodialysis. Q J Med 38:49-89, 1969 3. Hegstrom RM, Murray JS, Pendras Jp, et al : Hemodialysis in the treatment of chronic uremia. Trans Am Soc Artif Intern Organs 7: 136-144, 1961 4 . Schupak E, Sullivan JE , Lee DV: Chronic hemodialysis in "unselected" patients. Ann Intern Med 67:708-717,1961 5. Thompson GE, Waterhouse K, McDonald HP Jr, et al: Hemodialysis for chronic renal failure . Arch Intern Med 120:153- 167,1967 6. Levy JE, Salinas-Madrigal L, Herdson PB , et al: Clinicopathologic correlations in acute poststreptococcal glomerulonephritis . Med 50:453-501, 1971 7. Harvey AM, Shulman LE, Tumulty PA, et al: Systemic lupus erythematosus: a review of the literature and clinical analysis for 138 cases. Med 33:291-437, 1954 8. Budman DR, Steinberg AD : Hypertension and renal disease in systemic lupus erythematosus. Arch Intern Med 136:1003-1007,1967 9. Soffer LJ, Southren A, Weiner HE, et al: Renal manifestations of systemic lupus erythematosus: a clinical and pathologic study of 90 cases. Ann Intern Med 54:215-225, 1961
A56 10. G1assock RJ, Cohen AH: Secondary glomerular diseases in Brenner BM, Rector FC Jr (eds) The Kidney. Philadelphia, WB. Saunders, 1981, p. 1520 11. Zeek PM: Periarteritis nodosa: a critical review. Am J Clin Path 22:777-790, 1952 12. Walker WG, Solez K: Renal involvement in disorders of connective tissue, in Earley LE, Gottschalk CW (eds), Strauss and Welt's Diseases ofthe Kidney (ed 3), Boston, Little Brown, 1979, p 1271 13. Oliver JA, Cannon PJ: The kidney in scleroderma. Nephron 18:141-150, 1977 14. Leonard CD, Nagle RB, Striker GE, et al: Acute glomerulonephritis with prolonged oliguria. Ann Intern Med 73:703-711, 1970 15. Mathew TH, Kincaid-Smith P: Severe fibrin and crescent glomerulonephritis: clinical and morphological aspects of 33 patients, in Kincaid-Smith P, Mathew TH, Becker EL (eds), Glomerulonephritis: morphology, natural history, and treatment. New York, Wiley, 1973, pp 727-734 16. Newman WF, Tisher CC, McCoy RC, et al: Focal glomerular sclerosis: contrasting clinical patterns in children and adults. Med 55:67-87, 1976 17. Velosa JA, Donadio JV Jr, Holley KE: Focal sclerosing glomerulopathy: a clinicopathologic study. Mayo Clin Proc 50:121-133,1975 18. Churg J, Dolger H: Diabetic renal disease, in Earley LE, Gottschalk CW (eds) Strauss and Welt's Diseases of the Kidney (ed 3), Boston, Little Brown, 1979, p 1210 19. Ben-Asher S: Hypertension caused by renal infarction. Ann Intern Med 23:431-436, 1945 20. Schambelan M, Glickman M, Stockigt MD, et al: Selective renal-vein renin sampling in hypertensive patients with segmental renal lesions. N Engl J Med 290:1153-1157, 1974 21. Bookstein 11: Segmental renal artery stenosis in renovascular hypertension. Radiology 90:1073-1983, 1968 22. Franklin WA, Jennings RB, Earle DP: Membranous glomerulonephritis: long-term serial observations on clinical course and morphology. Kidney Int 4:36-56, 1973 23. Churg J, Ehrenreich T: Membranous nephropathy in Kincaid-Smith P, Mathew TH, Becker EL (eds), Glomerulonephritis, New York, J Wiley and Sons, 1972, pp 443-448 24. Glassock RJ, Cohen AH, Bennett CM, et al: Primary glomerular diseases, in Brenner BM, Rector FC Jr (eds), The Kidney. (ed 2). Philadelphia, WB Saunders, 1981, p 1428 25. Jennette JC, Wall SD: The clinical and pathologic heterogeneity of IgA nephropathy. The Kidney 16:17-23, 1983 26. McCoy RC, Abramosky CR, Tisher CC: IgA nephropathy. Am J Path 76:123-144, 1974 27. Clarkson AR, Seymour AE, Chan YL, et al: Clinical, pathological and therapeutic aspects of IgA nephropathy, in Kincaid-Smith P, d'Apice AJF, Atkins RC (eds), Progress in glomerulonephritis. New York, John Wiley and Sons, 1979, pp 247-259 28. Dawborn JK, Fairley KF, Kincaid-Smith P, et al: The association of peptic ulceration, chronic renal disease and analgesic abuse. Q J Med 35:69-83, 1966 29. Nanra RS, Stuart-Taylor J, DeLeon AH, et al: Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. Kidney Int 13:79-92, 1978 30. Nordenfelt 0, Ringentz N: Phenacetin takers deud with renal failure. Acta Med Scand 170:385-402, 1961 31. Olafsson 0, Gudsnundsson K, Brekkan A: Migraine,
WILLIAM B. BLYTHE
gastritis and renal papillary necrosis: a syndrome in chronic non-obstructive pyelonephritis. Acta Med Scand 179: 121-128, 1966 32. Murray R, Lawson D, Linton A: Analgesic nephropathy: clinical syndrome and prognosis. Brit Med J 1:479-482, 1971 33. Fellner S, Tuttle E: The clinical syndrome of analgesic abuse. Arch Intern Med 124:379-382, 1969 34. Murray T, Goldberg M: Chronic interstitial nephritis: etiologic factors. Ann Intern Med 82:453-459, 1975 35. Freedman LR: Interstitial renal inflammation, including pyelonephritis and urinary tract infection, in Earley LE, Gottschalk CW (eds), Strauss and Welt's Diseases of the Kidney (ed 3). Boston, Little Brown, 1979, p 838 36. Gardner KD Jr: Evolution of clinical signs in adultonset cystic disease of the renal medulla. Ann Intern Med 74:47-54, 1971 37. Gardner KD Jr: The medullary cystic diseases: the nephronophthisis-cystic renal medulla complex and medullary sponge kidney, in Earley LE, GottschalK CW (eds), Strauss and Welt's Diseases of the Kidney (ed 3), Boston, Little Brown, 1979, p 1151 38. Rayfield EF, McDonald FD: Red and blonde hair in renal medullary cystic disease. Arch Intern Med 130:72-75, 1972 39. Strauss MB: Microcystic disease of the renal medulla, in Strauss MB, Welt LG (eds), Diseases of the Kidney (ed 2), Boston, Little Brown, 1971, p 1260 40. Dalgaard OZ: Bilateral polycystic disease of the kidneys. A follow-up of two hundred and eighty four patients and their families. Acta Med Scand, Suppl 328, 1957 41. Schacht FW: Hypertension in cases of congenital polycystic kidney. Arch Intern Med 47:500-509, 1931 42. Rail JE, Odel HM: Congenital polycystic disease of the kidney: review of the literature and data on 207 cases. Am J Med Sci 218:399-407, 1949 43. Vendemia F, Fornasieri A, Velis 0, et al: Different prevalence rates of hypertension in various reno-parenchymal diseases, In Blaufox MD, Bianchi C (eds), Secondary forms of hypertension: current diagnosis and management. New York, Grune & Stratton, 1981, pp 89-94 44. Mogensen CE: Long-term antihypertensive treatment inhibiting progression of diabetic' nephropathy. Brit Med J 285:685-688, 1982 45. Woods Jw, Blythe WB: Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 277:57-61, 1967 46. Mitchell HC, Graham RM, Pettinger WA: Renal function during long-term treatment of hypertension with minoxidil. Comparison of benign and malignant hypertension. Ann Intern Med 93:676-681, 1980 47. Vertes V, Cangiano JL, Berman LB, et al: Hypertension in end-stage renal disease. N Engl J Med 280:978-981, 1969 48. Onesti G: Management and treatment of hypertension secondary to acute and chronic renal disease, in Genest J, Kouo E, Kuched 0 (eds): Hypertension: physiopathology and treatment. New York, McGraw-Hill, 1977, p 1119 49. Frohlich ED, Tarazi RC, Durtan HP: Reexamination of the hemodynamics of hypertension. Am J Med Sci 257:9-23, 1969 50. Brod J: Chronic renal parenchymal disease and hypertension. Kidney Int 8:S235-S242, 1975
I
N my judgment, there is no one homogeneous natural history of hypertension in renal parenchymal disease if one takes natural history to be an exposition of the prevalence, course, and pathogenesis of hypertension and renal parenchymal disease to mean all diseases that afflict the substance of the kidney (exclusive of disease of the renal artery and essential hypertension itself). Thus, I should like to try to see if we can determine what is known, and what is not known, about how prevalence, course, and pathogenesis of hypertension might vary as a function of the type of renal disease and the severity of the disease as reflected by renal function. Being interested not only in natural history of disease but also in history per se, I should like to begin with Dr Richard Bright who was the first to recognize a connection between the kidney and hypertension. In 1836, Dr Bright published two papers in the first volume of the Guy's Hospital Reports. The second of these is entitled "Tabular View of the Morbid Appearances Occurring in One Hundred Cases in Connection with Albuminous Urine with Observations."l Among other things, Dr Bright wrote: From the analysis of the following tabular view, many curious facts respecting the derangement of different organs connected with granular kidneys are brought to light. The first circumstance which strikes the mind, is the extent and frequency to which the derangement of one organ is connected with the derangement of several others; yet we are not at liberty to asFrom the Division of Nephrology, Department of Medicine, University of North Carolina, Chapel Hill. Address reprint requests to Dr William B. Blythe, Division of Nephrology, Department of Medicine, University of North Carolina, School of Medicine, Chapel Hill, NC 21514. © 1985 by The National Kidney Foundation, Inc. 02 72-63861851020A50-07$03. 0010 A50
sume, that the disease of the kidney has been the primary cause on which the disease of the rest depended. It may be, that some other organ has first suffered, and that the kidneys, t.ogether with the rest, have become involved. I confess I am inclined to believe that the kidney is the chief promoter of the other derangements. . .. The deviations from health in the heart are well worthy of observations: they have been so frequent, as to shew a most important and intimate connection with the disease of which we are treating. The obvious structural changes in the heart have consisted chiefly of hypertrophy with or without valvular disease; and what is most striking, out of fifty-two cases of hypertrophy, no valvular disease whatsoever could be detected in thirty-four: but in eleven of these thirty-four, more or less disease existed in the coats of the aorta; still, however, leaving twenty-two without any probably organic cause for the marked hypertrophy generally affecting the left ventricle. This naturally leads us to look for some less local cause, for the unusual efforts to which the heart has been impelled: and the two most ready solutions appear to be, either that the altered quality of the blood affords irregular and unwonted stimulus to the organ immediately; or that it so affects the minute and capillary circulation, as to render greater action necessary to force the blood through the distant sub-division of the vascular system. . .. It is observable, that the hypertrophy of the heart seems, in some degree, to have kept pace with the advance of disease in the kidneys; for in by far the majority of cases, where the muscular power of the heart was increased, the hardness and contraction of the kidney bespoke the probability of a long continuance of the disease.
Dr Bright's prescience is indeed remarkable. A century and a quarter later, the evidence tells us that of all hypertension, 5% to 10% is probably caused by renal disease, which in some circumstances increased cardiac output rather than increased total peripheral resistance is the cause for hypertension. Whereas in others the obverse is true, and finally, the longer the course, and the greater the severity of the renal disease, the greater the severity of the hypertension. HYPERTENSION IN RENAL DISEASE
Figure I is a caricature of two extreme courses that could lead to what we know is a firm anchor Hypertension and the Kidney: Proceedings of a Symposium
A51
HYPERTENSION IN RENAL PARENCHYMAL DISEASE
It is most often moderate and is usually most mani-
61001-------------------GLOMERULAR and SMALL ARTERY DISEASES
"Vi c ~
(l)
a.
I
>.
~
~
50
c'" (l)
:g
INTERSTITIAL DISEASES
(L
~
100
75
50
25
0
GFR (% of Normal)
Fig 1. A theoretical portrayal of the relationships between prevalence of hypertension and type of renal disease and degree of renal function.
point in the course of hypertension in renal parenchymal disease and that is true end-stage disease in which there is no renal function. There are earlier reports that show the prevalence of hypertension in patients on chronic dialysis to be around 85 %.2-5 In my experience, the figure is closer to 100%. Let's look closer at the caricature in order to determine how the available data fit, and might not fit, in relationship to the prevalence of hypertension before end-stage renal disease is reached. The curve at the top of the figure suggests that in renal parenchymal disease, in which there is involvement of the small arteries and/or glomeruli, the prevalence of hypertension is 100% at the onset of the disease and remains so until end-stage disease is reached. The curve at the bottom of the graph suggests that the prevalence of hypertension in interstitial disease is quite low until severe renal failure develops. Glomerular and Small Artery Disease
Those glomerular and small artery diseases which are generally thought to be associated with a high prevalence of hypertension are shown in Table 1. Hypertension is present in over 75 % of cases of postinfectious acute glomerulonephritis. 6 Table 1. Glomerular and Small Artery Diseases Associated With High Prevalence of Hypertension Acute post-infectious glomerulonephritis Glomerulonephritis secondary to systemic vasculitides Polyarteritis involving the kidney Scleroderma involving the kidney Crescentic glomerulonephritis Focal glomerulosclerosis Diabetic glomerulosclerosis Renal infarction
fest at the onset of clinical evidence of the presence of renal disease. Hypertension in systemic lupus erythematosus is not common in the absence of renal involvement or even when there is minimal renal involvpment; however frequency ranges from about 15% to 50% in those patients with overt renal disease.7-9 In hypersensitivity angiitis, hypertension is frequently absent and when present is usually mild. to It is common in polyarteritis nodosa, is associated with high levels of renin, and in fact not uncommonly reaches the malignant phase. II It is interesting and of note, that in the experience of Walker and colleagues, hypertension is not present in acute oliguric renal failure secondary to polyarteritis nodosa.1 2 Oliver and Cannon have found that 52 % of their patients with scleroderma have hypertensionY It is present in 35 % to 50 % of patients with idiopathic crescentic glomerulonephritis at the onset of clinical disease. 14.15 Hypertension develops in about one-third of patients with focal glomerulosclerosis, usually in association with progressive renal insufficiency. 16.17 Of patients with diabetic glomerulosclerosis, 50% to 75 % develop hypertension, and its presence has been reported to correlate more closely with the degree of arteriolosclerosis rather than glomerulosclerosis. 18 Renal infarction is one of those conditions which various authors cite as a cause for hypertension. 19-21 It is difficult to be certain of the prevalence of renal infarction and even of the prevalence of hypertension in recognized renal infarction. However, the evidence suggests that the prevalence is quite high in the recognized cases. Table 2 shows the glomerular disease in which there is general agreement that the prevalence of hypertension is lower than in the other diseases that have been mentioned. Hypertension is not common in patients with membranous nephropathy until late in the course when renal failure develops. 22.23 It occurs in about 30% of patients at most, with mesangioproliferative glomerulonephritis, and is almost always mild. 24 Table 2. Glomerular Diseases Associated With Lower Prevalence of Hypertension Membranous glomerulopathy Mesangioproliferative glomerulonephritis IgA nephropathy
A52
WILLIAM B. BLYTHE
Table 3.
Interstitial Diseases Associated With Hypertension
Associated With Low Prevalence
Associated With High Prevalence
Phenacetin nephropathy Polycystic kidney disease Chronic pyelonephritis Medullary cystic disease
We now realize that the clinical manifestations of IgA nephropathy are more varied than was formerly thought. Therefore, hypertension is probably more common. Nevertheless, the blood pressure is usually normal; although mild, and rarely even severe, hypertension may be present in patients with more advanced disease. 25-27 Chronic Interstitial Diseases
Table 3 illustrates the prevalence of hypertension in the more common of the chronic interstitial diseases. I have listed phenacetin nephropathy first, because in my part of the world (the southeastern United States) phenacetin nephropathy has been the most common form of chronic interstitial disease. In fact, it has ranked just below hypertension and diabetes mellitus as a common cause of end-stage renal disease for the patients in our chronic dialysis program. Phenacetin has now been removed from all over-the-counter analgesic preparations and we therefore expect to see the incidence decline. Phenacetin nephropathy is a curious disease in that it appears to have different clinical characteristics in different parts of the world. One of the characteristics that varies depending upon geographical location is hypertension. In Australia, there is a very high prevalence of hypertension as reported by Kincaid-Smith and colleagues. 28.29 The prevalence in Scandinavia,3o.31 the United Kingdom,32 and the United States 33 .34 appears to be much lower. However, even in the United States, Murray and Goldberg have reported hypertension to occur in as many as 50% oftheir patient population. 34 Two comments about this should be made. Firstly, in our experience in North Carolina, hypertension is distinctly uncommon until salt and water retention occur as a consequence of end-stage renal disease. In fact, it is our experience that most of our patients not only do not have hypertension but from time to time develop dehydration, hypotension, and acute deterioration in renal function as a consequence of an inability of the kidney to properly
conserve sodium. Secondly, it is not possible in general (I base my judgment from reviewing the published articles) to relate the prevalence of hypertension to the degree of renal function. Thus, I suspect, without clear evidence, that the presence of hypertension is most often associated with severe impairment of renal function. My comments about the prevalence of hypertension in chronic pyelonephritis have much in common with my comments about phenacetin nephropathy. As Freedman has written, "The frequency of hypertension in patients with chronic pyelonephritis has been reported to range from 12 % to 85 % depending on methods of selection of patients, the criteria used for the diagnosis of hypertension and pyelonephritis, the ages of the patients, the presence of a family history of hypertension, and the stage and type of renal disease. One can find figures to support virtually any argument."35 Our experience in Chapel Hill and my perusal of the literature lead me to make two observations: The first is that I believe that chronic infectious pyelonephritis is a rare disease which was overdiagnosed in the forties, fifties, and sixties; and the second is that hypertension is rare, and mild when it does occur, in patients with chronic pyelonephritis until significant renal failure develops. There is also a difference of opinion concerning the frequency of hypertension in patients with medullary cystic disease. Gardner holds the view that hypertension may be common in the early stages of the disease but becomes much less frequent as the salt-wasting stage of the disease develops. 36.37 Other investigators find hypertension to be rare until significant renal failure develops with retention of salt and water. 38 .39 Hypertension is quite common in polycystic kidney disease. Estimates of the frequency range from 39 % to 75 %.4042 Again, it should be emphasized that these series vary considerably in the incidence of hypertension at the time of presentation while serum creatinine remains normal. Nevertheless, the results of most studies suggest that there is a high incidence of hypertension before signifiant renal failure develops. To summarize then about the prevalence of hypertension in the various types of kidney disease, I believe that our caricature is just that, a caricature. However, I do believe that it does not approach being a travesty.
HYPERTENSION IN RENAL PARENCHYMAL DISEASE cIOO,-----------------------~ ,/ Q
'"c !':'
,/
GLOMERULAR and SMALL ARTER Y DISEASE S
a. I
'"
,/ ,/ ,/ ,/
,/ ,/
:;:: 50
,/
~
,/ ,/
,/ ,/ ,/
--100
/'
---
--- INTERSTITIAL
D ISEAS ES
--75
50
25
GF R. ( % of N ormal )
o
Fig 2. A more realistic portrayal of the relationship between prevalence of hypertension and type of renal disease and degree of renal function.
In my judgment, the situation is closer to what I have portrayed in Figure 2. Here again is the prevalence of hypertension plotted against renal function . The dashed line separates the slide into two halves and moves from a 0 %prevalence at normal renal function to 100% prevalence at 0 renal function. I am convinced that, in general, the glomerular and small-artery diseases can be placed in the upper section of the graph and the interstitial diseases in the lower section. Thus, the prevalence of hypertension is higher in the glomerular and small-artery diseases when renal function is normal or close to normal than it is in the interstitial diseases and that as renal function deteriorates the prevalence of hypertension approaches 100% regardless of the type of associated renal disease. Prevalence of Hypertension and Status of Renal Function
There have been few studies, and no prospective studies to my knowledge, that have systematically examined the relationship between hypertension and status of renal function in patients with different types of renal parenchymal diseases. There are no studies in which the hyertension has not been treated. One retrospective study aimed at this question was undertaken by Vendemia and colleagues. 43 They studied 290 adult patients with renal parenchymal diseases divided into two major groups: 184 with glomerulonephritis and 106 with tubulointerstitial diseases. The patients in the first group were classified on clinical, histological , and immunohistologic grounds as follows : 87 cases of IgA nephropathy, 40 cases of membranous glomerulopathy, 30 cases of membranoproliferative disease, and 29 cases of focal glomerulosclerosis. In the second group,
A53
there were 56 cases of polycystic kidney disease, 26 cases of chronic pyelonephritis, and 24 cases of analgesic nephropathy. The patients were followed for a period ranging from I month to 127 months. Twenty-eight percent of patients with glomerulonephritis and 60 % of those with tubulo-interstitial disease interrupted medical control for more than one year and were considered dropouts. The clinical course of the diseases were divided into four phases according to the level of renal function: Phase 1: "Normal renal function" was defined by a normal GFR and a serum creatinine < 1 mgm/lOO mL; Phase 2: "Mild renal failure" defined by a GFR that was about 50% of normal and a serum creatinine between 1. 1 and 3 mgml 100 mL; Phase 3: "Severe renal failure;' was defined by a GFR that was about 25 % of normal and a serum creatinine between 3.1 and 7 mgm/l00 mL; Phase 4: "End-stage renal failure" was characterized by a GFR less than 10 % of normal and a serum creatinine > 7.0 mgml 100 mL. The results are shown in Figures 3 and 4. The prevalence of hypertension in the different subgroups of glomerulonephritis is shown in Figure 3. In the late stages of renal failure, all the subgroups had a similar prevalence of hypertension of about 100%, whereas in the early phases, the patients with focal glomerulonephritis had a strikingly higher prevalence than those with membranoproliferative, membranous, and IgA disease. The prevalence of hypertension in the tubulointerstitial diseases is shown in Figure 4. The
50
--FGS ------- IoIPGM - - - MGM
10
- ' - ' - BO
7
mgY. SERUM CREATIMItiE
Fig 3. The relationship between prevalence of hypertension and type of glomerular disease and plasma creatinine concentration. 43 (Reprinted with permission. 43 ) FGS = focal glomerulosclerosis; MPGN = membranoproliferative glomerulonephritis; MGN = membranous glomerulonephropathy; BO = Berger's disease.
A54
WILLIAM B. BLYTHE 1l1li
~~~ .... 0
10
20
~ 0:::
t3
1.5
lL..
o
w
--PtD lO
----- PI - - - AI
7 ...", SE. . ClUT1IIII
Fig 4. The relationship between prevalence of hypertension and type of renal interstitial disease and plasma creatinine concentration. 43 (Reprinted with perrnission. 43) PCD = polycystic kidney disease; PN = pyelonephritis; AN = analgesic nephropathy.
patients with pyelonephritis and those with analgesic nephropathy had a similar prevalence of hypertension in all four phases. The patients with polycystic kidney disease showed the same prevalences throughout the course. There was a significant difference between polycystic kidney disease only in the intermediate phases. Although there are flaws in the study in that many patients were not followed throughout the course of the study, hypertension was treated, and there were intercurrent treatments such as the exhibition of steroids, which tends to support our notions, at least in regards to the glomerular diseases . The prevalence of hypertension in the interstitial diseases is higher than I would have predicted at the more normal levels of renal function and lower at the levels of renal function approaching endstage disease. What is the effect of hypertension on the development, and course, of chronic renal failure in renal parenchymal diseases? To my knowledge, there are no studies that answer the question for the various parenchymal diseases. There are the studies of Mogensen that show an effect of treating hypertension on the rate of deterioration of renal function in patients with diabetic nephropathy. Fig 5 is taken from one of Mogensen's earlier studies. 44 Plotted along the vertical axis is the rate of decline in glomerular filtration rate and on the horizontal axis two points: before and during treatment of hypertension. It can be seen in this small group of patients that treatment decreases the rate
5
10
U W
o
lL..
o
w
0.5
~
0:::
o '---'-___
---L_
Before Treatment
During Treatment
Fig 5. The effect of treating hypertension on the rate of decline of renal function in patients with diabetic nephropathy. (Modified and reprinted with permlssion.44)
of decline in glomerular ftItration rate. These findings have been amply confirmed. Furthermore, some early studies of Dr James Woods and mine45 showed that treatment of malignant hypertension tends to minimize decline in renal function . Recent studies from Dr Pettinger's group in Dallas show that treating benign and malignant essential hypertension reduces the rate of decline in renal function. 46 PATHOGENESIS OF HYPERTENSION IN RENAL PARENCHYMAL DISEASES
Natural History
Other papers in this supplement address the various systems and mechanisms that are involved with the pathogenesis of hypertension in renal parenchymal diseases, so my comments will be brief. Let's begin with patients requiring chronic maintenance dialysis. The classic study which started the dissection of our understanding of the hemodynamic patterns in patients on maintenance dialysis was one performed by Vertes and colleagues in 1969 Y These investigators described two distinct patterns of response of blood pressure to achievement of "dry weight" by hemodialysis. The first pattern, seen in 35 of 40 patients studied, was one in which there was an excellent blood pressure response to the attainment of "dry weight." The second pattern, seen in five patients, was one in
A55
HYPERTENSION IN RENAL PARENCHYMAL DISEASE
Table 4. Study
Frohlich et ai, Brod et ai,
196949
197550
Hemodynamic Alterations In Early Renal Failure
Renal Function
Hematocrit
Cardiac Index
Not markedly impaired
Not anemic
Normal
Increased
GFR-20-80 mUmin (mild to moderate)
Not anemic
Elevated
Same as controls
which blood pressure was not controlled despite the attainment of "dry weight" and the use of large doses of antihypertensive drugs. In this group of five, plasma renin activity was approximately ten-fold higher than in the first group. There emerged from this study the view that hypertension in patients on maintenance dialysis is either volume (or sodium) dependent or renin dependent. We know that the situation is not that simple. Rather than there being two distinct types of hypertension in this setting, it appears more likely that different blood pressure responses to dialysis and different blood pressure patterns in patients on maintenance dialysis can be attributed to a spectrum of relationships among renin, extracellular volume, and cardiac output. For example, Onesti and colleagues have extensively studied the relationship between cardiac output, anemia, total peripheral resistance, and hypertension in patients on maintenance dialysis. 48 They found them to have increased cardiac output that was due to anemia. When the anemia was corrected, cardiac index decreased. Concomitantly peripheral resistance rose and there was a marked increase in blood pressure. From the perspective of our subject, it should be emphasized that there has been no examination of the relationship of the various factors involved in hypertension in dialysis patients and the type of renal disease with which they are afflicted. Let's move now to patients with minimal renal failure. The early data are conflicting in regards to the hemodynamic characteristics and, to my knowledge, no one has attempted to correlate the hemodynamic characteristics with the type of renal parenchymal disease or to systematically study the hemodynamic parameters at various levels of renal function. The conflict is summarized in Table 4. Dr Frohlich and colleagues found cardiac index to be normal and peripheral resistance to be increased 49 and Dr Brod and coworkers have found cardiac index to be increased and peripheral resistance to be normal . 50 I believe that most of the data in regard to patho-
Total Peripheral Resistance
genesis of hypertension support the view that, early in the course of renal disease, those patients with glomerular and/or small artery disease are apt to exhibit subtle, and sometimes clearly overt, salt and water retention with hypertension as a consequence and later on in the course of the disease increased peripheral resistance due to generalized vascular disease which may be a consequence of hypertension per se or some function thereof.
SUMMARY What we need to bring our knowledge of the natural history of hypertension in renal parenchymal disease up to a 1984 standard is a prospective study in which (1) contemporaneous methods of diagnosis are employed to determine the type of disease; and (2) the prevalence, hemodynamic, and pathogenetic patterns are determined at different levels of renal
REFERENCES I. Bright R: Tabular view of the morbid appearances in 100 cases connected with albuminous urine, with observations, in Osman AA (ed) Original Papers of Richard Bright on Renal Disease, London, Humphrey Milford, Oxford University Press, 1937, pp 132-148 2. Curtis JR, Eastwood JB , Smith EKM, et al: Maintenance hemodialysis. Q J Med 38:49-89, 1969 3. Hegstrom RM, Murray JS, Pendras Jp, et al : Hemodialysis in the treatment of chronic uremia. Trans Am Soc Artif Intern Organs 7: 136-144, 1961 4 . Schupak E, Sullivan JE , Lee DV: Chronic hemodialysis in "unselected" patients. Ann Intern Med 67:708-717,1961 5. Thompson GE, Waterhouse K, McDonald HP Jr, et al: Hemodialysis for chronic renal failure . Arch Intern Med 120:153- 167,1967 6. Levy JE, Salinas-Madrigal L, Herdson PB , et al: Clinicopathologic correlations in acute poststreptococcal glomerulonephritis . Med 50:453-501, 1971 7. Harvey AM, Shulman LE, Tumulty PA, et al: Systemic lupus erythematosus: a review of the literature and clinical analysis for 138 cases. Med 33:291-437, 1954 8. Budman DR, Steinberg AD : Hypertension and renal disease in systemic lupus erythematosus. Arch Intern Med 136:1003-1007,1967 9. Soffer LJ, Southren A, Weiner HE, et al: Renal manifestations of systemic lupus erythematosus: a clinical and pathologic study of 90 cases. Ann Intern Med 54:215-225, 1961
A56 10. G1assock RJ, Cohen AH: Secondary glomerular diseases in Brenner BM, Rector FC Jr (eds) The Kidney. Philadelphia, WB. Saunders, 1981, p. 1520 11. Zeek PM: Periarteritis nodosa: a critical review. Am J Clin Path 22:777-790, 1952 12. Walker WG, Solez K: Renal involvement in disorders of connective tissue, in Earley LE, Gottschalk CW (eds), Strauss and Welt's Diseases ofthe Kidney (ed 3), Boston, Little Brown, 1979, p 1271 13. Oliver JA, Cannon PJ: The kidney in scleroderma. Nephron 18:141-150, 1977 14. Leonard CD, Nagle RB, Striker GE, et al: Acute glomerulonephritis with prolonged oliguria. Ann Intern Med 73:703-711, 1970 15. Mathew TH, Kincaid-Smith P: Severe fibrin and crescent glomerulonephritis: clinical and morphological aspects of 33 patients, in Kincaid-Smith P, Mathew TH, Becker EL (eds), Glomerulonephritis: morphology, natural history, and treatment. New York, Wiley, 1973, pp 727-734 16. Newman WF, Tisher CC, McCoy RC, et al: Focal glomerular sclerosis: contrasting clinical patterns in children and adults. Med 55:67-87, 1976 17. Velosa JA, Donadio JV Jr, Holley KE: Focal sclerosing glomerulopathy: a clinicopathologic study. Mayo Clin Proc 50:121-133,1975 18. Churg J, Dolger H: Diabetic renal disease, in Earley LE, Gottschalk CW (eds) Strauss and Welt's Diseases of the Kidney (ed 3), Boston, Little Brown, 1979, p 1210 19. Ben-Asher S: Hypertension caused by renal infarction. Ann Intern Med 23:431-436, 1945 20. Schambelan M, Glickman M, Stockigt MD, et al: Selective renal-vein renin sampling in hypertensive patients with segmental renal lesions. N Engl J Med 290:1153-1157, 1974 21. Bookstein 11: Segmental renal artery stenosis in renovascular hypertension. Radiology 90:1073-1983, 1968 22. Franklin WA, Jennings RB, Earle DP: Membranous glomerulonephritis: long-term serial observations on clinical course and morphology. Kidney Int 4:36-56, 1973 23. Churg J, Ehrenreich T: Membranous nephropathy in Kincaid-Smith P, Mathew TH, Becker EL (eds), Glomerulonephritis, New York, J Wiley and Sons, 1972, pp 443-448 24. Glassock RJ, Cohen AH, Bennett CM, et al: Primary glomerular diseases, in Brenner BM, Rector FC Jr (eds), The Kidney. (ed 2). Philadelphia, WB Saunders, 1981, p 1428 25. Jennette JC, Wall SD: The clinical and pathologic heterogeneity of IgA nephropathy. The Kidney 16:17-23, 1983 26. McCoy RC, Abramosky CR, Tisher CC: IgA nephropathy. Am J Path 76:123-144, 1974 27. Clarkson AR, Seymour AE, Chan YL, et al: Clinical, pathological and therapeutic aspects of IgA nephropathy, in Kincaid-Smith P, d'Apice AJF, Atkins RC (eds), Progress in glomerulonephritis. New York, John Wiley and Sons, 1979, pp 247-259 28. Dawborn JK, Fairley KF, Kincaid-Smith P, et al: The association of peptic ulceration, chronic renal disease and analgesic abuse. Q J Med 35:69-83, 1966 29. Nanra RS, Stuart-Taylor J, DeLeon AH, et al: Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia. Kidney Int 13:79-92, 1978 30. Nordenfelt 0, Ringentz N: Phenacetin takers deud with renal failure. Acta Med Scand 170:385-402, 1961 31. Olafsson 0, Gudsnundsson K, Brekkan A: Migraine,
WILLIAM B. BLYTHE
gastritis and renal papillary necrosis: a syndrome in chronic non-obstructive pyelonephritis. Acta Med Scand 179: 121-128, 1966 32. Murray R, Lawson D, Linton A: Analgesic nephropathy: clinical syndrome and prognosis. Brit Med J 1:479-482, 1971 33. Fellner S, Tuttle E: The clinical syndrome of analgesic abuse. Arch Intern Med 124:379-382, 1969 34. Murray T, Goldberg M: Chronic interstitial nephritis: etiologic factors. Ann Intern Med 82:453-459, 1975 35. Freedman LR: Interstitial renal inflammation, including pyelonephritis and urinary tract infection, in Earley LE, Gottschalk CW (eds), Strauss and Welt's Diseases of the Kidney (ed 3). Boston, Little Brown, 1979, p 838 36. Gardner KD Jr: Evolution of clinical signs in adultonset cystic disease of the renal medulla. Ann Intern Med 74:47-54, 1971 37. Gardner KD Jr: The medullary cystic diseases: the nephronophthisis-cystic renal medulla complex and medullary sponge kidney, in Earley LE, GottschalK CW (eds), Strauss and Welt's Diseases of the Kidney (ed 3), Boston, Little Brown, 1979, p 1151 38. Rayfield EF, McDonald FD: Red and blonde hair in renal medullary cystic disease. Arch Intern Med 130:72-75, 1972 39. Strauss MB: Microcystic disease of the renal medulla, in Strauss MB, Welt LG (eds), Diseases of the Kidney (ed 2), Boston, Little Brown, 1971, p 1260 40. Dalgaard OZ: Bilateral polycystic disease of the kidneys. A follow-up of two hundred and eighty four patients and their families. Acta Med Scand, Suppl 328, 1957 41. Schacht FW: Hypertension in cases of congenital polycystic kidney. Arch Intern Med 47:500-509, 1931 42. Rail JE, Odel HM: Congenital polycystic disease of the kidney: review of the literature and data on 207 cases. Am J Med Sci 218:399-407, 1949 43. Vendemia F, Fornasieri A, Velis 0, et al: Different prevalence rates of hypertension in various reno-parenchymal diseases, In Blaufox MD, Bianchi C (eds), Secondary forms of hypertension: current diagnosis and management. New York, Grune & Stratton, 1981, pp 89-94 44. Mogensen CE: Long-term antihypertensive treatment inhibiting progression of diabetic' nephropathy. Brit Med J 285:685-688, 1982 45. Woods Jw, Blythe WB: Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 277:57-61, 1967 46. Mitchell HC, Graham RM, Pettinger WA: Renal function during long-term treatment of hypertension with minoxidil. Comparison of benign and malignant hypertension. Ann Intern Med 93:676-681, 1980 47. Vertes V, Cangiano JL, Berman LB, et al: Hypertension in end-stage renal disease. N Engl J Med 280:978-981, 1969 48. Onesti G: Management and treatment of hypertension secondary to acute and chronic renal disease, in Genest J, Kouo E, Kuched 0 (eds): Hypertension: physiopathology and treatment. New York, McGraw-Hill, 1977, p 1119 49. Frohlich ED, Tarazi RC, Durtan HP: Reexamination of the hemodynamics of hypertension. Am J Med Sci 257:9-23, 1969 50. Brod J: Chronic renal parenchymal disease and hypertension. Kidney Int 8:S235-S242, 1975