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Home , Glomerulosclerosis, Nephrotic syndrome, Pyelonephritis

Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

POSTGRAD. MED. J. (I963), 39, 12I

FUNCTIONAL ASPECTS OF THE OF RENAL DISEASE JAN BROD, MI.D., D.Sc. Director, Institute for Cardiovascular Researc3t, Prague 4, Czechoslovakia

IF we read through both the basic papers which process, which might be present only in other William Bright wrote some 136 and 127 years ago, portions of the organ. In chronic , and which laid the foundations of clinical nephro- for example, we can find quite normal areas of logy, we can recognize in the detailed clinical in close approximation to areas severely description the , the effects altered by the chronic process. of severe and the signs of chronic However, morphological criteria are but one renal or cardiac insufficiency. These are the end- consequence of the disease-process-the other stages which follow almost all types of chronic consequence consisting of the renal functional renal disease, and these late phenomena cannot be changes, which are no less specific than the used to differentiate between the various morpho- details of micro-morphology. Our own work, logical entities which the pathologists later con- and that of others, has led us to the conclusion structed from the original tissue of ' Bright's that a study of renal function can give us a great disease '. Such a differentiation was, of course, to deal of information not only concerning the degree no purpose at the period when therapeutic of the disease process-hitherto its main applica-by copyright. medicine knew little else than venesection, tion-but also as to the nature of the disease calomel, diaphoretics, suction-cups and a few process, with a high degree of reliability. I hope other which Bright prescribed with both that the material I shall present you, summarising enthusiasm and conviction for his patients. Even some 25 years of observations on 3,685 patients, in the century following Bright we had little else in will transmit this conviction to you as well. our therapeutic armamentarium than a low- protein, low-salt and fluid restriction, so that, Methods again, the differential diagnosis of renal disease The methods used by us in these studies are by no

was to little avail. means highly specialized ones--they are within the http://pmj.bmj.com/ The situation in therapy today is quite different, reach of any local hospital, and in Czechoslovakia they and attempts at differential diagnosis have thereby have been introduced into the routine investigational procedure of most medical wards. In addition to history taken on considerable practical importance. Since and physical findings, they include: (i) qualitative and morphology of the kidney itself has been the clas- quantitative analysis of in terms of the content of sical criterion of diagnosis, kidney biopsy can be of protein and formed elements in the Addis sediment; great assistance, particularly when combined with (2) an approximation to glomerular filtration rate by means of the endogenous clearance in one histochemistry and electron microscopy of the 24-hour urine sample or in several 3- to 4-hour speci- on September 29, 2021 by guest. Protected biopsy material. These latter techniques have mens over the course of a single day; (3) measurement taught us a great deal of the early stages of kidney of the concentrating ability, which is a very sensitive disease, since such cases do not come to the post- indicator of tubular function; (4) in selected cases investigation of diluting ability; (5) in cases where mortem table. It must be stressed, however, that asymmetry of the disease-process is suspected, investiga- biopsy is not without risk, that it requires the tion of creatinine concentration or clearance measure- services of a pathologist experienced in inter- ments with urine obtained from each separately preting such material, that even in the best of by catheterization; (6) where indicated, urography, pyelography, aortography or tomography with retro- hands about one-quarter of all biopsies ends up peritoneal air insufflation; (7) if bacterial is with no kidney tissue in the needle, that the biopsy suspected, the urine is cultured, and if the culture is piece may contain so few glomeruli that any positive then quantitative estimation of bacterial' interpretation at all is risky, and that one has no contamination of the urine is carried out. If there are more than io,ooo organisms per ml. of urine, bacterial guarantee at all that the region of kidney punc- infection is highly suspect, and if this count is greater tured by the needle actually contains the disease than ioo,ooo infection is certain. of Diseases Lecture given at the London Hospital on June 20, Functional Classification Renal I962, and at Bristol University on July 3, I962. The simplest method of functional classification Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

I122 POSTGRADUATE MEDICAL JOURNAL March I963 of renal disease is according to the degree to which kidneys, and skin. Renal vasoconstriction may glomerular and tubular function is altered viz: result in a decrease in glomerular filtration. Such (i) There are disease-states which primarily in- a decrease of glomerular filtration in an otherwise volve glomerular filtration, leaving tubular intact , regardless of how it comes about, function intact. has, among others, two consequences of interest: (2) There are others in which glomerular and (i) The decreased filtered load of osmotic material tubular function are altered in a more or less to the individual nephron has the opposite effect parallel fashion. on final osmolarity of the urine to that of the (3) There are further states in which tubular raised osmotic load in osmotic diuresis. Here, malfunction is the only demonstrable defect as we know, urine osmolarity decreases asympto- for long in the course of the disease, glomerular tically in the direction of plasma osmolarity. With alteration being a late development (Table I). a decrease in filtered osmotic load urine osmolarity is increased to high values, even in the absence of TABLE I ADH (Shannon, 1942; de Wardener and del FUNCTIONAL CLASSIFICATION OF CHRONIC Greco, I956). (2) When glomerular filtrate is low RENAL DISEASE and the plasma coursing through the is I. GLOMERULAR FUNCTION RESTRICTED MORE THAN TUBULAR FUNCTION in contact with this structure for a longer-than- A. On Heemodynamic Basis: normal period, there is a greater-than-normal i. Orthostatic diffusion of protein into the glomerular filtrate 2. Emotional proteinuria (Goverts and Lambert, 1953). At least in some 3. Exertional proteinuria this diffusion may lead to amounts 4. 5. Essential hypertension (early) of protein in the lumen which cannot be re- B. On Organic Basis: absorbed in entirety by the tubular cells. The (a) Without grave changes of basal unreabsorbed remnant appears then in the urine membrane: along with occasional hyaline casts which are the Vascular nephrosclerosis of this but also with occasionalby copyright. (b) With grave changes of basal membrane: gel-form protein, I. Diabetic tubular cells and granular casts due to saturation 2. of these cells with protein transport and subse- 3. Nephropathia gravidarum quent disintegration (Addis, 1942). II. PARALLEL REDUCTION OF GLOMERULAR AND TUBULAR FUNCTION: This is the mechanism of proteinuria which occurs with severe muscular exercise, and during III. TUBULAR FUNCTION RESTRICTED MORE THAN orthostasis in some individuals with circulatory GLOMERULAR FUNCTION: dysregulation in the erect posture (orthostatic i. Chronic pyelonephritis proteinuria), with so-called ' negative emotional 2. Polycystic states' such as fear, anxiety, anticipation-thesehttp://pmj.bmj.com/ latter situations being haemodynamically com- In individual sub-groups it is of assistance to parable to preparation for muscular activity determine the quality of the glomerular ab- (Brod, Fencl, Hejl and Jirka, 1959), and in normality, the presence of the nephrotic syndrome, congestive failure. In the first three states hypertension, infection, etc. mentioned above, there is no protein in the morn- Disease-states with Primary Involvement of ing urine, which immediately suggests that there is the Glomerular Apparatus no organic disease in the kidneys themselves. on September 29, 2021 by guest. Protected Glomerular filtration can be decr¢ased by lesions Greater can be caused by the proteinuria which restrict the filtration area with infiltration or of congestive failure, which lasts as long as failure formation, despite a lack of tubular involve- is present: if there is nocturia, the diurnal curve of ment, but also by any state causing vasoconstric- glomerular filtration shows a rise to normal at tion in the kidney. In the first group we find night, which is of diagnostic significance (Fig. i) diabetic glomerulosclerosis, renal amyloidosis, (Brod and Fejfar, 1950). In severe cases, where toxaemia of and primary nephro- glomerular filtration is depressed over the entire sclerosis arising on the basis of hypertension of 24 hours and the protein and cellular content of 'long duration. In the second group we find states the urine is somewhat higher, high urine specific in which there is a generalized hlmodynamic gravity, which shows a normal nephron popula- reaction to an imbalance between the tissue re- tion even with a glomerular filtration rate as low as quirement of oxygen and the ability of the 50 to 30 ml./min., can exclude organic renal circulatory apparatus to deliver it to the tissues, disease. In these cases, blockage of the adre- resulting in in muscles and adrenergic nergic mechanism by means of dibenamine will be vasoconstriction in the splanchnic bed, the followed by a rise in renal plasma flow and Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

March I963 BROD: Functional Aspects of the Differential Diagnosis of Renal Disease 123

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FIG. 2.-Frequency of the various types of Addis tato 09(GR)pgPala tubla srebopto009 fwaeRa Al * count in chronic pyelonephritis, chronic glomerulo- or TIff and vascular nephrosclerosis. FIG. i.-Diurnal rhythm in the rate of glomerular filtration (GFR), tubular reabsorption of (R) and urine flow (V) in a normal subject and in a patient with heart failure. R is given as ' of GFR {GFR-V X IOO and varies normally between 4. 0o04. U *0 4. CL) iGFR narrow limits (98.3 to 99.7%). Note that the noc- turia in the cardiac patient is due in the first place 0

to an increase of GFR from subnormal values in by copyright. day-time to low-normal values at night.

*. o 4. PVELOtEpte * 4. l o *o GLOMERJLONEPHR. o glomerular filtration (Brod, Fejfar and Fejfarova', 1010 VAS. NEPIRO0SIL. U I954). A similar situation might be encountered in the 1005 c O RO f50 initial stages of essential hypertension, where the GLOMERULAR FILTRATION ,l/i' are kidneys morphologically intact and where a FIG. 3.-Correlation of glomerular filtration and maxi- decreased glomerular filtration rate is due to mum concentrating ability in patients with vascular http://pmj.bmj.com/ vasoconstriction. Glomerular filtration rises nephrosclerosis (NSCL), chronic glomerulo - when is normalised with rauwolfia nephritis (GLOM) and chronic pyelonephritis (Brod and (PN). The diagnosis in all patients has been Fencl, I955), during sleep (Brod and proved morphologically (biopsy or autopsy). At Fencl, 1958), with sedatives (Ratn6r, 1959) and all stages of the restriction of GFR patients with pyrogens (Bradley, Chasis, Goldring and Smith, chronic pyelonephritis concentrate less and patients 1945). Suspicion of primary renal disease can with vascular nephrosclerosis concentrate better remain in this case only if we find proteinuria. than patients with chronic glomerulonephritis. In our experience, however, the latter is not on September 29, 2021 by guest. Protected frequent or significant and the urinary sediment with proteinuria does not differ from that found in rise in formed elements and casts, with values cases of orthostatic proteinuria. seldom exceeding 200,000 to 300,000 (Fig. 2). Proteinuria in essential hypertension becomes a With destruction of glomeruli, entire nephrons are more fixed part of the disease-picture when the then put out of action, thus increasing the osmotic high blood pressure has lasted some time and has load on the remaining nephrons. An osmotic led to arteriolosclerotic changes in the renal diuresis results which limits the concentrating vessels with the start of slow, progressive vascular ability of the kidney, but the latter impairment is nephrosclerosis involving part of the glomerular mild in comparison with the degree of limitation of vascular bed. In this latter situation the diurnal glomerular filtration, as can be seen in Fig 3. variation in glomerular filtration rate is decreased , which is present in a or disappears entirely. Even in such cases the portion of hypertensive patients, regardless of degree of proteinuria usually does not exceed i g./ whether it is the causative agent of the hyper- 24 hr. with uncomplicated vascular nephro- tension or merely a complicating factor, does not sclerosis. The Addis count shows only a small produce a different functional picture from that Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

I24 POSTGRADUATE MEDICAL JOURNAL March I963

O/ juvenile hypertensives in this stage of the disease 0/ 44 28 54 actually in 46%. This would suggest that renal 100- artery stenosis is a secondary phenomenon due to acceleration of the atherosclerotic process in hyper- tension. However, the age distribution of patients 80 with renal artery stenosis (Fig. 5), with a clear double-peaked curve, allows the possibility that stenosis in young patients can be a separate disease 60 entity and be associated with the later develop- ment of hypertension. Our present research 40. programme with aortographic investigation of all hypertensives found in a large, unselected popula- tion, should give the answer to this question. The 20- preliminary data do show that suspicion of stenosis is aroused in cases of severe hypertension with signs of organic cardiovascular involvement, particularly if there is apparent asymmetry of the SrAGE I STAGE2 kidneys in the plain abdominal X-ray. Small changes in the basement membrane of the NORMAL "ESSENT HYPERT glomerular capillaries, the slight degree of escape of protein into the glomerular filtrate and final urine, the insignificant changes in the urinary sediment and the lack of signs of protein depletion differentiate the renal correlate of hypertension * RELN ART STENOSIS (primary vascular nephrosclerosis)-from the other FIG. 4.-Incidence of renal artery stenosis in normo- three disease processes which involve the filtrationby copyright. tensive subjects and in patients with essential area of the glomerulus: diabetic glomerulosclero- hypertension divided according to the absence or sis, renal amyloidosis and nephropathy of preg- presence of clinical signs of organic cardiovascular nancy. In these diseases, there is a deposition changes into stages I and II (Hejl, Prat and Dejdar, I 962). of mucoproteins and mucopolysaccharides, mani- festations of a generalized metabolic disturbance, in the basement membrane of the glomerular capillaries. In amyloidosis this infiltration can also be in the basement membrane of the tubules. NItIBER This in 15 deposition the glomerular-capillary wallshttp://pmj.bmj.com/ 0 leads to an enormous rise in glomerular per- 0 meability to protein, with intense proteinuria, a saturation of the tubular cells with reabsorbed too10 a a 0a protein and the appearance of such packed cells as well as of their product-granular casts- o 0 0 a in the urinary deposit, and finally the appearance 50 0 0 0 of the nephrotic syndrome. There is a progressive * 0 0 0 0R~ decrease in the glomerular filtration area, with on September 29, 2021 by guest. Protected * 0 * final disappearance of filtration. o * *ST(NOSIS Diabetic glomerulosclerosis, or Kimmelstiel- 0 * * 0 Wilson disease, is found in some 22.9% (Horn and Smetana, 1942) to 63.7% (Laipply, Eitzen 10 20 30 40 50 60 YEARS and Dutra, I944) of diabetics, depending on whether one uses as the histological criterion of the FIG. 5.-Prevalence of renal artery stenosis according to age (Hejl, Pralt and Dejdar, 1962). diagnosis the presence of characteristic hyaline balls or diffuse thickening of the basement membrane, the latter being an earlier stage of the lesion (Fig. 6a, b). just described. As can be seen in Fig. 4 (Hejl, Prait Diabetic glomerulosclerosis is one of the most and Dejdar, 1962) this finding is rare (3%) in difficult of clinical diagnoses, since we only the early phases of hypertension, whereas in recognize it pre-mortem in 6.3% of diabetics. paients with organic complications renal artery The causes of the different percentages noted by stenosis was found in 38.5% of cases, and in the pathologist and the clinician are two in Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

March 1963 BROD: Functional Asp3cts of the Differential Diagnosis of Renal Disease 125

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FIG. 6.-Microscopical picture of diabetic glom,rulosclerosis. (a) Early-with predominant thickening of the capillary walls; (b) late-with typical formation of nodules (courtesy of Dr. Rossmann). number: in some of our diabetics we make the which are difficult to see under ordinary micro- wrong diagnosis of glomerulosclerosis from pro- scopy. By the time the disease presents itself teinuria and cedema which are actually due to clinically-which is rare in a diabetic of less than congestive failure. On the other hand, in the ten years duration-there is usually a rapid pro- initial stages the presence of morphological gression to uramic death or cardiac failure or both changes need not be accompanied by pathological which, according to our own experience, supervene by copyright. changes in the urine (Brun, Gormsen, Hilden, within four to five years of the first clinical Iversen and Raaschou, I953). We are therefore recognition of this disease. faced with the prospect that diagnosis at an early The functional diagnosis (Table 2) is based stage, which by correction of the metabolic dis- upon: (i) Proteinuria in ioo% of cases, with turbance might perhaps still be amenable to the- more than IO g./24 hr. in 56.4%, and numerous rapy, will be only possible by repeated biopsy tubular cells, counted along with the leucocytes in during the course of , and will probably the Addis count, and casts. Due to the defect in require electron microscopy to detect changes fat metabolism also present, the casts and epithelial http://pmj.bmj.com/

TABLE 2 THE LEADING DIAGNOSTIC FEATURES OF DIABETIC GLOMERULOSCLEROSIS AND RENAL AMYLOIDOSIS. CHRONIC PYELONEPHRITIS HAS BEEN PRESENTED FOR COMPARISON Diabetic Chronic glomerulosclerosis Amyloidosis pyelonephritis

Past history ...... Diabetes Chron. infection 79.3% Pain 64.7% on September 29, 2021 by guest. Protected (over io years 88.9%) Rheum. arthritis 20.7% Frequency 44.4% Proteinuria > 5g./24 hr. .. .. 69.5' 89.5% II.0% Addis count: Erythrocytes + + + }7*3O/ 3.6% I6.o% Leucocytes ± 73/ 36 6o Erythrocytes + 0// 0 Leucocytes +±+± ± ± 304 25.0% Leucocytes+± 30.4% 35.7% 76.o% Erythrocytes + Leucocytes + Sf 21.7% 3570/ 8.o% Casts o.i -I mu. .. 43-5 /0 40.7% 31.0% > I mil. .. 47.8%, 37.0% I I.0% ...... 26.3%/ 77.200 0 Hypoalbuminamia ...... 88.8%/ 77.2% 0 Nephrotic ...... 65.2% 86.5% 0 ESR > 50 mm...... 87.0% 92.6% Rare Hypertension ...... 69.5% 24.2% 59-7% Diabetic retinopathy 0...... 95.0% 0 0 Congo red test positive .. .. 0 80.o% 0 Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

I26 POSTGRADUATE MEDICAL JOURNAL March I963

DIADEGrcLOMECbLOSCLEUROSS V-r 0,1206. . tOfX P045

RENAL AMYLOlDOSIS Y * 1014,6 - 0.08P.

BP mmHg

tOO- MrlIAL OCSERV. ° FINAL OBSERV.

CLOMERULAR FiLrRATN RATE .1/ -.. FIG. 7.-Correlation of glomerular filtration and maxi- mum concentrating ability in patients with diabetic 0 SO 100 150 glomerulosclerosis, renal amyloidosis and chronic GL OMERULAR FIL rRATION RArE nt/l min. pyelonephritis. The diagnosis in all patients has FIG. 8.-Correlation between systolic blood pressure been proved histologically. There is no great and the rate of glomerular filtration in patients difference in the relationship in the first two with diabetic glomerulosclerosis. Although there diseases. The regression line for chronic pyelo- is a slight tendency to higher pressures in patients nephritis is far below those for the other two with severely restricted GFR, the correlation is diseases. very low. The same is true for diastolic pressure. by copyright. cells are filled with refractile droplets of fat. alteration in the rate of glomerular filtration ' Leucocytes 'in the Addis count usually exceed 50 (Fig. 8). million/24 hr. only when there is urinary tract It is clear, then, that the diagnostic signs of infection also present. Erythrocytes are not diabetic glomerulosclerosis are diabetes of long prominently represented in the sediment. The duration and retinopathy, without which the renal severe proteinuria results in the nephrotic syn- lesion does not appear, the finding of marked drome, present in 65.2% of clinically diagnosed proteinuria with only insignificant hxematuria, but cases, and present in all patients with a daily loss of with many fat-containing epithelial cells and

protein greater than 5 g. Progressive decrease in granular casts, marked decrease in glomerularhttp://pmj.bmj.com/ glomerular filtration rate, also contributed to by filtration with relatively little change in con- congestive failure and atherosclerotic closure of centrating ability, and the presence of the nephro- the smaller renal vessels, is in contradistinction to tic syndrome. As we shall see, these criteria are the normal concentrating ability. The latter may quite the reverse of what is found in chronic decrease late in the course of the disease due to pyelonephritis, which is another frequent compli- osmotic diuresis from reduction of the nephron cation in diabetes and may, of course, also population, just as in primary vascular nephro- complicate diabetic glomerulosclerosis. Signs of sclerosis (Fig. 7). In three patients in whom the pathology in the basement membrane of the on September 29, 2021 by guest. Protected exceptional finding of hyposthenuria was present, glomerular capillaries (proteinuria, nephrotic syn- there was also . drome) differentiate diabetic glomerulosclerosis Aside from the kidneys, there are specific from hypertensive disease per se and from vascular diabetic lesions in the retinal vessels, which were nephrosclerosis, both of which may complicate present in 950/O of our cases. The reverse is not the course of diabetes mellitus (Table 3). true, however. Iversen and Ohlsen (195I) re- On the other hand, it is very difficult to dif- ported that only seven of i6 diabetics with retino- ferentiate on functional grounds renal amyloidosis pathy showed simultaneous signs of a renal lesion. from diabetic glomerulosclerosis, if the former is a We found hypertension less frequently than of a purulent or wasting disease which would be expected from the earlier reports. Normal has also occurred in the course of diabetes: the pressures were found in two of 23 patients and five absence of retinopathy and the presence of a showed the ' windkessel ' type of hypertension. normal blood pressure are of assistance. Definite diastolic hypertension was present in The causes of amyloidosis in our series of 29 69.S% of cases, but there was no correlation cases are shown in Table 4. The first clinical between the degree of the latter and the degree of signs of amyloidosis appeared from three months Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

March I963 BROD: Functional Aspects of the Differential Diagnosis of Renal Disease 127

TABLE 3 in some cases with markedly decreased con- DIFFERENTIAL DIAGNOSIS OF DIABETIC GLOMERULO- centrating ability, with only moderate decrease in SCLEROSIS, RENAL AMYLOIDOSIS AND VASCULAR NEPHRO- glomerular filtration, is probably due to the SCLEROSIS presence of amyloid in the basement membrane Diabetic Vascular of the tubules and collecting ducts. glomerulo- Amyloi- nephro- Hypertension proved to be rare despite the sclerosis dosis sclerosis marked degree of renal pathology (Fig. 9). Diabetes mellitus .. > IO yrs. Only five patients had a raised pressure, and three Diabetic retinopathy + ++ - - of these had very low rates of glomerular filtration. Proteinuria .. .. + ++ + ++ o- It is difficult to say whether the absence of Addis count: to Erythrocytes .. + + o- i hypertension is due the presence of the provo- Leucocytes . . ++ + - ± cative disease or focus or to some other cause. Casts +..+++ + ++ o - The lack of hypertension can to some degree Conc. power/GFR.. t t t be used in the differential diagnosis of renal Asymmetry .. o 0 0 X-ray of kidneys . 0 0 0 diseases with massive proteinuria and the neph- Nephrotic syndrome + + + + rotic syndrome, and in the case of glomeruloneph- Blood pressure .. I - ritis further assistance is given by the history, the predominance of erythrocytes in the Addis count and the presence of erythrocyte-and blood- casts (Table 3). In the case of disseminated TABLE 4 erythematosus there are in addition signs CAUSES OF AMYLOIDOSIS AND SIGNS OF SIMULTANEOUS INVOLVEMENT OF OTHER ORGANS AMONG THE PATIENTS of systemic involvement. When the nephrotic OF THE INSTITUTE FOR CARDIOVASCULAR RESEARCH syndrome is present along with thrombophlebitis of the lower extremities or constrictive pericarditis, CAUSES OF AMYLOIDOSIS: Tuberculosis of bones .. .. 8 (27.6%0) or the appropriate histories thereof, one must also Tuberculosis of lungs .. .. 6 (20.7%) consider the rare possibility of of theby copyright. Bronchiectasis .. .. *- 4 (I3.8%) renal vein. Rheumatoid arthritis .. .. 6 (20.7%) The importance of early diagnosis of renal Chronic osteomyelitis .. .. 3 (1O.3 %) Ulcerative colitis ...... I (345%) amyloidosis can be seen from evidence that Lymphogranulomatosis . .. I 5°) radical treatment of the evocative pathological process leading to amyloidosis in the early stages Total .. .. 29 (IOO.O%) of the latter can occasionally prevent the further SIMULTANEOUS CLINICAL INVOLVEMENT OF OTHER progress of renal degeneration. ORGANS: The last of the diseases in this group-

Liver ...... *- 9 (3I-.°%) toxacmia of pregnancy-also involves a de- http://pmj.bmj.com/ G.I. tract ...... *- 4 (I3.8-%) position of mucopolysaccharides in the basement Spleen ...... 4 (I3.8%) membrane of the glomerular capillaries. This again leads to proteinuria and an increase in tubular cells present in the ' leucocyte ' fraction to 32 years after the start of the initial pathology, of the Addis count, along with hyaline and with an average of II.3 years, and there was no granular casts and a moderate decrease in glo- clustering of cases in this wide range of time. merular filtration rate. For the same reasons as There were signs of extra-renal amyloidosis in in renal amyloidosis, tubular concentrating ability on September 29, 2021 by guest. Protected 34.4% and the Bennhold (Congo Red) test was remains fairly well preserved in the face of positive in 8o%, and at the lower margin of restriction of the rate of glomerular filtration. significance in 12%. Diagnostic difficulties arise in differentiating Proteinuria (Table 2) is usually massive from the between nephropathia gravidarum and glomerulo- very start: 86.3% excreted more than 5 g. in 24 nephritis or the renal affection in hypertension hr. and showed the presence of the nephrotic (Table 5). As opposed to the hypertensive kidney, syndrome. As in diabetic glomerulosclerosis, nephropathia gravidarum is associated with a there are many epithelial cells in the ' leucocyte ' greater degree of proteinuria, more elements in the fraction of the Addis count and many casts, with urinary sediment, a lower filtration fraction, only mild red-cell excretion. cedema and hypoproteinaemia. Glomerulonephri- Fig. 7 shows the regression curve of the rate of tis, on the other hand, is differentiated by many glomerular filtration and concentrating ability in more red cells and erythrocytic casts in the our cases, and this was not markedly different from urinary sediment, by a far greater restriction of that found in nephrosclerosis and glomerulo- the concentrating ability, and by the history, if it sclerosis. The somewhat greater scatter of values is known that the renal disease started before B1 Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

I28 POSTGRADUATE MEDICAL JOURNAL March 1963

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5C 20il 0 50 1O0 t50 200 GLOMERULAR FILTRATION RATE 50 mt/l min. FIG. 9.-Correlation between diastolic pressure and the rate of glomerular filtration in patients with renal amyloidosis. It may be noted that with one exception the only registered elevations of blood pressure were found in patients with a severely restricted GFR.

FIG. iondieetopmndct ofrh inofactglomerulaobtuio-) TABLE 5 Oriateidiaethe percenagsicienceprtiui,gauaatheof DIFFERENTIAL DIAGNOSIS OF TOxAMIA OF PREGNANCY Toxaemia Essential of hyper- Glomerulo- and reduced concentrating ability (Brod, I99) pregnancy tension nephritis by copyright. Proteinuria .. ++ o- ++ Addis count: structures, in particular the tubules, can also serve Erythrocytes . . + O -+ + + + as the -container for this immunological Leucocytes . . + o -z + + reaction. The decrease in concentrating ability Ery/Leuco .. 4. = t Casts + + + + early in the course of glomerulonephritis Conc. power/GFR t 1i = could be attributed to the osmotic effect of a Filtrastion fraction 4 t 4 decreased nephron population. Against this Asymmetry .. - argument is the fact that reduced concentrating X-rays of kidneys ability remains for months after signs Blood pressure . o- t of the acute Nephrotic stage of the disease, such as a low glomerular http://pmj.bmj.com/ syndrome + + filtration, have been completely normalized (Fig. IO). D)espite a large amount of experimental data, the pathological basis of glomerulonephritis pregnancy. Pyelonephritis is a common renal remains unclear. The working hypothesis most complication of pregnancy, but the functional in agreement with known clinical facts is that diagnosis is quite clear in terms of differentiation the disease arises as a result of an allergic reaction from nephropathia gravidarum. involving the walls of capillaries and the smooth on September 29, 2021 by guest. Protected musculature of the arterioles, both in and outside Renal Disease, Involving Glomerular and the kidneys. In the latter organ these alterations Tubular Function in Parallel tend to block glomerular circulation and produce Our second group of renal diseases is repre- an inflammatory exudation into Bowman's capsule, sented in the first instance by glomerulonephritis. with a resulting fall in glomerular filtration, The name itself tells us that the disease process (rarely anuria), proteinuria and excretion involves the glomeruli, and experimental work of erythrocytes, leucocytes and erythrocytic and over the past I 5 years has shown that immunotoxic granular casts into the urine. The initial decrease reactions, thought to lie at the basis of this disease, in concentrating ability has already been men- can produce a similar picture in animals and tioned. Extrarenally, spasm of the smooth that the antigen- reaction occurs in the muscle of the arteriolar wall leads to a rise in basement membrane of the glomerular capil- blood pressure, increased capillary permeability laries. However, the work of Schwentker and and a shift of fluid into the interstitial space, Comploier (I939) and the more recent observation and the resulting mobilisation of the ' dehydration of Antoine (I96I) have shown that other renal reactions' leading to salt retention and cedema Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

March I963 BROD: Functional Aspects of the Differential Diagnosis of Renal Disease 129

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FIG. I I.-Grouping of leading signs and their development in a group of 66 patients with acute glomerulonephritis in the course of the first six months. The whole group has been split into subgroups according to the presence (+) or absence ( - ) of the individual signs, indicated on the left side of the graph. The figures in circles indicate the number of patients in each subgroup. Note that at the start over 8o% of the patients exhibited all the four leading signs (hypertension, cedema, reduced GFR and changes in the urine). After one month these were still http://pmj.bmj.com/ present in only one-third of the patients and after two months they subsided in all but two patients. However, only a small fraction of the patients moved into the subgroup 'healed '; in the majority signs of renal involvement persisted. After the acute phase there follows obviously a phase in which residual changes are present in the kidneys. The patient may be quite symptom-free at this stage of the disease.

formation. This assumed independent course of months in the great majority of patients. The vascular changes in the kidneys and outside ofthem signs of obstruction of the glomerular circulation on September 29, 2021 by guest. Protected is supported by data from a series of 66 patients decreased, glomerular filtration rose again to treated during the war in British Military Hospitals normal values and hypertension and cedema in North Africa and Italy (Fig. ii) (Brod, I949). receded, though not all necessarily at the same As can be seen, some patients with acute glomeru- rate, which again lends support to the idea that the lonephritis had combined renal and extrarenal changes are independent expressions of the manifestations, while others showed only renal disease-process. However, signs of a lesion of damage with or without glomerular blockade. the glomerular membrane, such as proteinuria, There was a continuous gradation between these microscopic hlimaturia, and erythrocytic casts and two groups, suggesting that they all had the same leucocytes in the urinary sediment remained in disease. At the other end of the scale the signs of some cases, along with signs of a decreased area for the renal lesion were pushed into the background, glomerular filtration-a decrease in the diurnal leaving at the end only hypertension and cedema. variation in glomerular filtration. Like the previous figure also, the present one The further course of the disease can show three demonstrates that the full-blown picture of the types of development. The signs of the disease acute disease tends to subside within one to two can decrease over the following weeks or months, Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

130 POSTGRADUATE MEDICAL JOURNAL March I963

B.-

OEDEMA URINE /OL. 24h GLOMERULAR FILTRATION - d/lnw, (dai4 aver) - PROTEINURIA (24h) X I4AEMATURIA 20 ,iii eryfhr09fes/24h LEUCOCYTES 23 III aN CT | FIG. 12.-Diagrammatic representa- TUBULA RO -tion of the development of T 9glomerulonephritis. CONC ABILITY

DILUTION ABIUTY

ERYTHROCYTES SED/IENTATION RATE

HAEM'0LOBIN % 0 - by copyright. 1 0 - 12 DURATION WrSWEEIIIg | MNON 1 1-15 YEARS 0-5 EAS 1-2 YEARS SFArREE ACUTr rCRM/NAL INTER- VASC RESIDALREIUA LArENrLATENCONICEROTNEpyC ERINAL SAEVAL STAGE STAGE STrAGE STrAGE STUAGEMI ) ACUTE' ______GLONERULONEPM9IT CHRONIC GLONERULONEPNRITIS

or the patient remains unchanged for years, or the decreased concentrating ability is in contrasthttp://pmj.bmj.com/ glomerular filtration can progressively decrease at with the highly concentrated urine of the cardiac a greater or lesser rate, either continuously, or in patient, while with the exception of cases with jumps, this being possibly related to intercurrent renal infarction, hlimaturia in congestive failure is infection (Fig. I2). insignificant. Acute tubular insufficiency is usu- The nephrotic syndrome or hypertension can ally preceded by shock or intoxication, and neither complicate the further course of the disease, be it hypertension nor cedema belong to the initial signs. otherwise stationary or progressive. Hypertension If a small sample of urine can be collected in acute occurs mainly in patients with disease of longer tubular insufficiency, the presence of red cells is on September 29, 2021 by guest. Protected duration, and where glomerular filtration has without diagnostic-significance, but their absence decreased to below 50 to 6o ml./min. (Fig. I3). rules out glomerulonephritis, just as in the case of This hypertension may take on a malignant a below I.012. With simple character and be the predominant clinical sign, febrile proteinuria the rate of glomerular filtration while the functional state of the kidney remains as is normal (provided that the basic disease has not before, that is with red cells predominating in the resulted in dehydration or myocardial damage), Addis count, with marked proteinuria, casts in the the concentrating ability is normal and the urinary urine, and a more or less parallel decrease in the sediment may contain only an increased amount rate of glomerular filtration and concentrating of hyaline casts. ability. Malignant hypertension which occurs in chronic Recognition of the fully developed picture of cases of severe essential hypertension might also be acute glomerulonephritis is not difficult (Table 6). accompanied by a marked increase in proteinuria As opposed to aedema from right-sided congestive and the number of elements in the urine, and one failure the venous pressure is normal and the rate finds left ventricular hypertrophy, which is not of glomerular filtration does not increase at night; present early in acute glomerulonephritis. There Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

laircl i 963 -ROD FunctiliAspects o' thie Diffrrential Diagnosis of Renal Disease I3

CLOMERULAR FILTRATION mt/l min. Differential diagnosis may be difficult in the >50 <50 >50 (50 >50 <50 latent stage of chronic glomerulonephritis with only residual changes in the urine, particularly if 77 19 71 28 148 4? there is no history of an acute initial disease 90. (Table 7). As opposed to benign forms of pro- CHRONIC teinuria, protein is present in the morning urine, GLOMERULO- 60 the Addis count is high and there are functional NEPHRITIS 40i signs of renal impairment. A history of oadema and oliguria is evidence against chronic pyelone- phritis, whereas a history of back pain, nephro- 200- lithiasis or some other urological disease such as 17 8 53 14 70 22 repeated cystitis speak in favour of the latter

80- diagnosis. Proteinuria greater than S g., 24 hr., a CHRONIC large number of casts in the sediment (over I to 2 PYELONEPHRITIS 60- million in 24 hr.) as well as a marked increase in both red and white cells in the sediment are all evidence for glomerulonephritis, ral her than 40-ji 20- pyelonephritis, in addition to a concentrating ability which is decreased in proportion to the 94 27 124 42 218 69 degree of decrease in the rate of glomerular filtration. Symmetrical renal involvement, as CLOMERULO- 801 determined by separate collection of urine from NEPHRITIS * oO-94-0I4 2 each ureter, is not characteristic of pyelonephritis. PYELONEPHRITIS 40- X-ray investigation of the urinary passages can also be used to test for symmetrv, and a normal 20J picture here is not the rule in pyelonephritis. by copyright. We can exclude primary vascular nephrosclerosis LESS TIAN 3 YPS MORE THAN 3YRS TOTAL accompanying hypertensive disease by the fact DURATION OF DISEASE that in a disease of a short duration and without lIG. 13. Incidence of hypcrtcrnsion (B.P. over 145 9)5 grave kidney involvement there is often no rise mm. Hg) in patients with chronic glomerulo- in blood pressure (Fig. 13). Nephrosclerosis is nephritis and chronic pyelonephritis in relation to the grade of rs-duction of GFR and to the duration not accompanied by marked proteinuria or a high of the disease. Addis count, the concentrating ability is only moderately affected and usually far less than one

might expect from the degree of depression of http://pmj.bmj.com/ is also a highi filtration fraction* (if known), glomerular filtration. Tlahe filtration fraction is while the frequent albsence of erythrocytes raised in nephrosclerosis, but decreased in or casts in the urine also tends to exclude glomerulonephritis. Of the other disease-states glomerulonephritis. associated with the nephrotic syndrome, amyloid *lRtio of the rate of gloncerUllar filtration 'renal can be excluded on the basis of the history, the plasma flow (PAH clcaranrce). lack of red cells in the urinary sediment, a satis- on September 29, 2021 by guest. Protected

I) 1FRE'NTII DIA1G)1(;NOSIS OF Ai 're ( L()NllRt ',N I'1 AUlTll Acuite Heart Acute tubular lebrile M\allignant gr10IICu-loIlepri-Itis failre |insuflicicncy proteinuria hypertension I Iistorv Iifcction l( Dysprea Shock; lever Hypertension intoxication Anuria 'Venous pressure Noctuirnal rise in GFR . + Conc. po\w..er Addlis coutnt: Elrthrocvtes + o - - + 0 -+ LeuICOCVteS 0 0 - Casts + + + + + Filtration fr-action B2 Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from IiOSTGiRADOUATiiIE MEl,'DI(CAL, JOURNAL March I963

TABLE 7 DIFFERENTIAL DIAGNOSIS OF C1IRONIC GLOMERULONE-PIIRITIS Chronic Diabetic Vascular glomerulonephritis Amyloidosis glomerulosclerosis Pyclonephritis nephrosclerosis Proteinuria + + + + + + + + + Addis count: Erythrocytes + + - + 1 0 - Leucocytes + A+ ++ + + + o - Erv./Leuco.- Casts + +++ +++ o- - Conc. powcr/GFR Filtration fraction Asymmetry + X-rays of kidneys - - +-+ Blood pressure - I I' Nephrotic syndrome o- + + + -

factory concentrating ability and absence of hyper- tension provided that the patient is not in renal failure. The first three of these criteria also exclude diabetic glomerulosclerosis, quite apart from the fact that for the latter diagnosis we must also observe diabetes and retinopathy. Differentiation between glomerulonephritis and nephropathia gravidarum has already been dis- 4, cussed. The very difficult differentiation from renal may be assisted by a by copyright. history of thrombosis of the lower extremities, the -.41#,.**.. presence of visible collateral vascular channels on the abdominal wall, and the combination of a satisfactory concentrating ability with only slight FIG. 14. Progress of GFR in patients with chronic pyelonephritis (PN) and chronic glomerulo - haematuria. nephritis (GN) who were first seen with a GFR These differential diagnostic criteria remain reduced below 35 ml./min. Note that the rate of valid even in the presence of renal failure. Fig. 14 descent of GFR is faster in patients with glomerulo- nephritis than pyelonephritis and that in the course shows that even at this stage these criteria are not of seven years all the patients with glomerulo- merely of academic interest, since using them we nephritis were dead, while 8o0" , of the pyelo-http://pmj.bmj.com/ can determine the prognosis, which is very dif- nephritics survived. The ages of both groups ferent in glomerulonephritis as compared with were comparable (Prit, Fencl and Jirka, I96I). pyelonephritis (Prait, Fencl and Jirka, I96I).

Renal Diseases, Affecting Primarily Tubular Function

Group 3 contains those renal diseases which on September 29, 2021 by guest. Protected affect primarily tubular function, and which is represented by chronic pyelonephritis and poly- cystic disease. The correctness of this classifica- tion in the case of pyelonephritis can be seen already by observing a histological section (Fig. I5), where it can be observed that the normal contour of the tubule is lost in an interstitial in- flammatory infiltrate, spreading irregularly through the kidney, whereas glomeruli are involved, in the form of a glomerulitis, only very late in the course FIG. I5 Microscopical picture of chronic pyelo- of the disease. Lambert (I943) has established nephritis. Note the heavy round-cellular infiltra- the primary involvement of the tubules in poly- tion of the left half of the kidney and the normal cystic disease by means of a plastic reconstruction appearance of the right half. In the inflamed zone the outlines of the tubules have practicallv which revealed that the cysts originated from the disappeared, while the structure of glomeruli is tubular lumen. In addition, these inadequate well preserved. Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

March 1963 13RGD: Functional Aspects of the Differential Diagnosis of Renal Disease I33

*1. PROTEINURIA > 59 < 5g PN GLOM. PN CLOM. foo- (14) (79) (118) 80- (72) 100 60- 80, 40 l 60 % 20- 40 20 STERILE ZERO <103/1MIL. >103/ IML.

CULTURE + COUNT: 25,764 -2, 55,541 p < 0,004 p < 0,001 U GLOMERUL ONEPHRITIS U PYCLONPARRITIS FIG. I 7.-Severity of proteinuria in chronic pyelo- FIG. i6.-Quantitative bacteriology of the urine in nephritis (PN) and chronic gJomerulonephritis chronic glomerulonephritis and chronic pyelo- (GLOM). nephritis. Note the high incidence of severely infected in chronic pyelonephritis (Prat and Horik, in press). filtrate. This tubular involvement from the early stages of the disease is one of the causes of the continuing tendency to extracellular dehydration organs are also very susceptible to infection and in these patients, which acts in the opposite by copyright. chronic pyelonephritis. direction from the tendency to cdema formation Chronic pyelonephritis arises on the basis of an in congestive failure. Since protein-loss is small interstitial infection and in 6o% of cases the causa- and since there is a tendency to lose salt rather than tive agent can be isolated from the urine in retain it, the nephrotic syndrome is never seen in quantities which exclude the possibility of chance chronic pyelonephritis. contamination of the samples, i.e. usually more The irregularity of the spread of the disease than io,ooo and as a rule up to ioo,ooo organisms/ process in the kidney explains the asymmetry of ml. (Fig. i6). With late involvement of the the two kidneys found in go% of cases by analysis glomeruli proteinuria need not be, but usually is, of creatinine concentration separately in the urine present, but seldom reaches values greater than collected by catheter from each ureter (Prat and http://pmj.bmj.com/ I to 2 g./24 hr. (Fig. 17). It is perhaps a conse- Kocvara, 1957) (Fig. i8), as well as by X-ray quence of an abnormal circulation in the glomeruli studies of the size and shape of the kidneys and due to pressure from the inflammatory . the rate at which injected contrast material In favour of this is the fact that treatment of the appears in the (Dejdar, I959). The infection at this stage may result in a rise in latter technique has also demonstrated abnormal glomerular filtration. In addition to protein and shapes of the calyces, papilla and pelvis, and micro-organisms in the urine we can also find there abnormal motility of the ureter in serial films on September 29, 2021 by guest. Protected a direct reflection of the interstitial (Figs. I9 and 20). in the form of leucocytes, which are more There are, therefore, a large number of signs numerous in the Addis count than red cells in which assist in the diagnosis of this most frequent 75% of cases (Fig. 2). Casts, so typical in histo- of renal diseases, provided that we consider this logical section, arising in nephrons which have diagnosis not only in clear urological cases, but been blocked by the inflammatory process, are few also in all cases of asymptomatic proteinuria, or absent. hypertension with proteinuria and even in There is a characteristic decrease in concen- patients with vague, general complaints, e.g. trating ability present from the early stages of the minimal temperatures. Urinary examination disease, in sharp contrast to the lack of involve- will then give rise to the initial suspicion of ment of glomerular filtration, as can be seen in pyelonephritis, and the above detailed tests can Fig. 3. As opposed to glomerulonephritis and establish the presence of the disease (Table 8). vascular nephrosclerosis, there is a decrease in the The presence of the nephrotic syndrome ex- specific gravity of the urine in the final stages of cludes the diagnosis of chronic pyelonephritis. the disease to values below those of the glomerular Even without cedema, the presence of heavy Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

134 POSTGRADUATE MEDICAL JOURNAL March I963

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20 2,38 3,82 2,08 FIG. i8.-Ratio of the concentration indices of endo- genous creatinine of the left and right kidney in 1,8 subjects with normal kidneys (left upper group), in patients with chronic glomerulonephritis and vascular nephrosclerosis (right upper group) and in patients with chronic pyelonephritis. The thin lines indicate the +io% limit, within which are o,2 situated almost all the data of subjects with normal kidneys and with the symmetrical bilateral diseases. In the right subgroup of pyelonephritis a unilateral disease was suspected on other grounds, whereas 0,8 no such suspicion existed in cases in the left sub- 0,6 group (Prat and Kocvara, 1957). IIj 0,4 I//a. b 0,2 by copyright.

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FIG. I9.-X-ray picture of chronic pyelonephritis. Note the unequal size of the two kidnevs, the blunting of the calyces, the flattening of the papilla and the uneven thickn2ss of the parenchyma overlying the renal pelvis (Dejdar, 1959). Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

March I963 BROD: Functional Aspects of the Differential Diagnosis of Renal Disease 135

WI ASYMETRY corresponds to the decrease in the rate of RENAL SHADOW: WlDrH OF Of INDIVIDUAL glomerular filtration. Primary vascular nephro- PARENCHYMA: SIGNS sclerosis is an after-effect of hypertension, and can DECREASED VAGUE CHANGES |WIDENING RIC-T - LEFT thus be excluded in of cases of pyelonephritis To INVISIBLE To IN SIZE OR 40% DENSITY UNETEC TABLE NARROWING who run the course of their disease with normal OUTLINES IPARENCHYMAlIOf pressures. In the presence of hypertension, the %LAYEPS pyelonephritic case will show a predominance of 100 leucocytes in the urinary sediment, , a 80 greater restriction of concentrating ability in rela- 60 tion to the level of glomerular filtration, asym- metry and pathological X-ray findings. Polycystic disease shows a similar accentuation of loss of concentrating ability in relation to glomeru- lar filtration as in pyelonephritis, but the urine is not infected and does not contain leucocytes if the polycystic organ has not become secondarily IORPHOLOCICAL CHANGES FUNCTIONAL CHANCES infected (Table 8). The most important dif- OF PYELOURETERAL SYSTEM: OF URINARY TRACT: ferential diagnostic criteria are the findings on TYPICAL ISEGMENTAL |URETERAL HYPERTONIC HYPOTONIC DEFORMATION IOR GENERAL DILATATlON AND palpation and X-ray. OF FORNIX DILATATION HYPODYNAMIC Table 9 summarizes the differential diagnostic AND PAPILLA OF PASSAGES criteria of the individual disease states, as presented 100 above. The validity of these criteria is docu- mented in Fig. 2I, which shows the high degree of correlation between the functional diagnosis and 60 the histological findings. Moreover, the func-

tional diagnosis is at the same time a quantitative by copyright. one, and gives more information than can be 4010*0 obtained from a small biopsy sample. -' UCLOMERULONEPHRITIS IPYELONEPHRITIS Conclusion FIG. 20.-Summary of the X-ray findings in chronic pyelonephritis. Patients with chronic glomerulo- Modern renal physiology-from its very begin- nephritis were used for comparison (Dejdar, I959). nings in London with Bowman and Cushny-has put clinical on a scientific basis which was lacking when Bright first set his observations

down on paper. It is to be hoped that it will http://pmj.bmj.com/ proteinuria and casts in the urinary sediment continue to provide more effective measures to rather indicate glomerulonephritis, diabetic glome- control and eradicate kidney disease, with which rulosclerosis, amyloidosis or nephropathia gravi- until recently the physician was forced to play darum. The last-named three syndromes in more the role of the observer than of the addition show a higher concentrating ability than therapeutist.

TABLE 8 on September 29, 2021 by guest. Protected DIFFERENTIAL DIAGNOSIS OF CHRONIC PYELONEPHRIT IS AND POLYCYSTIC KIDNEY DISEASE Chronic Vascular pyelo- Polycystic nephro- nephritis kidneys sclerosis /JCC 1ASE CASS e SCASES *CAS Proteinuria .. A- + o- ± o- ± Addis count: Erythrocytes .. ± o- i o - *ACCNT+ Leucocytes .. o- o--t Ery./Leuco. .. - Casts Conc. power/GFR 1 Asymmetry . . ± + COMPARISON Or CINICAL DIACNOSS AND PAHTMOCCAL FINOINGS X-rays ... .. + + FIG. 21.-Degree of agreement between the clinical Blood pressure .. o- + and morphological diagnosis of the most important Nephrotic syndrome renal diseases. Postgrad Med J: first published as 10.1136/pgmj.39.449.121 on 1 March 1963. Downloaded from

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March I963 BROD: Functional Aspects of the Differential Diagnosis of Renal Disease 137 REFERENCES ADDIS, T. (1942): Proteinuria, Trans. Ass. Amer. Phys., 57, io6. ANTOINE, B. (I96I): Personal communication. BRADLEY, S. E., CHASIS, H., GOLDRING, W., and SMITH, H. W. (1945): Hemodynamic Alterations in Normotensive and Hypertensive Subjects During the Pyrogenic Reaction, J. clin. Invest., 24, 749. BRIGHT, W. (I827): ' Reports of Medical Cases Selected with a View of Illustrating the Symptoms and Cure of Diseases by a Reference to Morbid Anatomy '. London: Longman, Rees, Orme, Brown and Green. (I836): Cases and Observations Illustative of Renal Disease Accompanied with the Secretion of Albuminous Urine, Guy's Hosp. Rep., I, 338. BROD, J. (1949): Acute Diffuse Glomerulonephritis, Amer. J. Med., 7, 3I7. and FEJFAR, Z. (I950): The Origin of (Edema in Heart Failure, Quart. Y. Med. (N.S.), I9, I87. , and FEJFARovA, M. H. (1954): The Role of Neurohumoural Factors in the Genesis of Renal Hmmo- dynamics Changes in Heart Failure, Acta med. scand., I48, 273. and FENCL, V. (I955): Ledvinova hemodynamika a funkce v priubehu lecby hypertensni choroby vytazkem z Rauwolfia serpentina Rivad?escinem (Renal Hxmodynamic and Function in the Course of Therapy of Essential Hypertension with an Extract of Rauwolfia Serpentina Rivadescin), Vnitfni Lik., I, 539. (1958): Mechanismus celkovych a ledvinovych hemodynamicky'ch zmen v pruibehu dne i noci. II. Chovani hypertonikiu (Mechanism of General and Renal H2emodynamic Changes During Day and Night. II. Behaviour of Hypertensives), (as. Lek. ees., 97, 1025. ) ~, HEJL, Z., and JIRKA, J. (I959): Circulatory Changes Underlying Blood Pressure Elevation During Acute Emotional Stress (Mental Arithmetic in Normotensive and Hypertensive Subjects), Clin. Sci., I8, 269. BRUN, C., GORMSEN, H., HILDEN, T., IVERSEN, P., and RAASCHOU, F. (1953): , Amer. Y. Med., I5, I 87. DEJDAR, R. (1959): Die chronische Pyelonephritis in roentgenographischer Darstellung. Eine zusammenfassende Studie zur Diagnostik morphologischer und funktioneller Veriinderungen pyelonephritiskranker Nieren, Fortschr. Rontgenstr., go, I98. GOVIERTS, P., and LAMBERT, P. P. (1953): Physiopathologie de la proteinurie, J. Urol. mid. chir., 59, 693. HEJL, Z., PRAT, V., and DEJDAR, R. (1962): Vyznam aortografie pro klinickou diagnostiku hypertense (Significance of Aortography for the Clinical Diagnosis of Hypertension), Czechosl. Cardiol. Soc., Prague, April 4. HoRN, R. C., and SMETANA, H. (I942): Intercapillary Glomerulosclerosis, Amer. J. Path., I8, 93. IVERSEN, P., and OHLSEN, A. S. (1951): Intercapillary Glomerulosclerosis, Acta med. scand., 139, 319. LAIPPLY, T. C., EITZEN, O., and DUTRA, F. R. (I944): Intercapillary Glomerulosclerosis, Arch. intern. Med., 74, 354 by copyright. LAMBERT, P. P. (I943): 'Le rein polykystique.' Paris: Masson. PRAT, V., and KoCVARA, S. (I957): Oddelene funkcni vysetreni ledvin: Metodika a klinicke6 pouziti' (' Separate Exami- nation of Renal Function: Method and Clinical Use '). Praha: St. zdrav. nakl. , FENCL, V., and JIRKA, J. (ig6i): Priibeh clronicke renalni insuficience u nemocnych chronickou pyelo- nefritidou a u nemocnych chronickou glomerulonefritidou (The Course of Chronic Renal Failure in Patients with Chronic Pyelonephritis and Chronic Glomerulonephritis), Czechosl. Urol. Soc., Smolenice, October 25. -, and HORAK, 0. (1962): Porovnani bakteriologickych naleziu u chronicke pyelonefridity au chronicke glomerulo- nefritidy (Comparison of Bacteriological Findings in Chronic Pyelonephritis and in Chronic Glomerulonephritis), Vnitfni. Lik. in press. RATNER, N. N. (1959): Znachenie issledovanii funktsii pochek dlia differentsiainoi diagnostiki khronicheskogo pielo- nefrita, khronicheskogo glomerulonefrita i gipertonicheskoi bolezni, X nauchnaia sessiya Instituta terapii AMN SSSR 14, March i6. http://pmj.bmj.com/ SCHWENTKER, F. F., and COMPLOIER, F. C. (1939): The Production of Kidney by Injection of Homo- logous Kidney Plus Bacterial Toxins, J. exp. Med., 70, 223. SHANNON, J. A. (1942): The Control of the Renal Excretion of Water. I. The Effect of Variations in the State of Hydration on Water Excretion in Dogs with , Y. exp. Med., i6, 371. DE WARDENER, H. E., and DEL GREco, F. (I955): The influence of Solute Excretion Rate on the Production ofa Hypotonic Urine in Man. Clin. Sci., 14, 715. , (1956): The Effect on Urine Osmolarity of a Transient Reduction in Glomerular Filtration Rate and Solute Output during a 'Water Diuresis '. J. Physiol., 131, 307. on September 29, 2021 by guest. Protected